WO2022033563A1 - Jak抑制剂化合物及其用途 - Google Patents

Jak抑制剂化合物及其用途 Download PDF

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WO2022033563A1
WO2022033563A1 PCT/CN2021/112352 CN2021112352W WO2022033563A1 WO 2022033563 A1 WO2022033563 A1 WO 2022033563A1 CN 2021112352 W CN2021112352 W CN 2021112352W WO 2022033563 A1 WO2022033563 A1 WO 2022033563A1
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compound
formula
characteristic peaks
xrpd
group
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路良
赵赛赛
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河南迈英诺医药科技有限公司
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Priority to JP2023507517A priority Critical patent/JP2023536892A/ja
Priority to EP21855613.2A priority patent/EP4186908A4/en
Publication of WO2022033563A1 publication Critical patent/WO2022033563A1/zh
Priority to US18/168,874 priority patent/US20230192710A1/en

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Definitions

  • the present application provides a novel pharmaceutically active compound that can be used to inhibit Janus kinase (JAK).
  • the present application also relates to compositions comprising said compounds, and to the use of said compounds and said compositions in the field of medicine.
  • Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine and serine/threonine kinases. Inappropriate kinase activity due to mutation, overexpression or inappropriate regulation, dysregulation or dysregulation, and overproduction or underproduction of growth factors or cytokines is implicated in many diseases, including but not limited to cancer, cardiovascular disease, Allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders and neurological and neurodegenerative disorders (eg Alzheimer's disease).
  • diseases including but not limited to cancer, cardiovascular disease, Allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders and neurological and neurodegenerative disorders (eg Alzheimer's disease).
  • Inappropriate kinase activity triggers a variety of biological cellular responses related to cell growth, cell differentiation, cell function, survival, apoptosis and cell motility involved in the above and related diseases.
  • protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention.
  • the JAK family of cellular protein tyrosine kinases plays an important role in cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al., Genome Biology 2004, 5, 253).
  • JAKs are a family of intracellular non-receptor tyrosine kinases that play a role in cytokine receptor signaling through interactions with signal transducers and activators of transcription (STAT). important role.
  • the JAK/STAT signaling pathway is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Compared with other signaling pathways, the transmission process of this signaling pathway is relatively simple, and it is mainly composed of three components, namely tyrosine kinase associated receptor (tyrosine kinase associated receptor), tyrosine kinase JAK and signal transducer. and the transcriptional activator STAT.
  • cytokines and growth factors transmit signals through the JAK-STAT signaling pathway, including interleukins (such as IL-2-7, IL-9, IL-10, IL-15, IL-21, etc.), GM-CSF ( Granulocyte/macrophage colony stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PRL (prolactin), EPO (erythropoietin), TPO (thrombopoietin), PDGF (platelet derived factor) and interferons (including IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , etc.) and so on.
  • interleukins such as IL-2-7, IL-9, IL-10, IL-15, IL-21, etc.
  • GM-CSF Granulocyte/macrophage colony stimulating factor
  • GH growth hormone
  • EGF epidermal growth factor
  • PRL prolactin
  • EPO erythropoietin
  • TPO thro
  • the common feature of these receptors is that the receptor itself does not have kinase activity, but the intracellular segment has a binding site for the tyrosine kinase JAK. After the receptor binds to the ligand, the tyrosine residues of various target proteins are phosphorylated by the activation of the JAK bound to it to realize the signal transduction from extracellular to intracellular.
  • JAKs are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors.
  • JAK is the abbreviation of Janus kinase in English, Janus in Roman mythology is the two-faced god in charge of the beginning and the end.
  • the so-called two-faced kinase is because JAK can both phosphorylate the cytokine receptors to which it binds and phosphorylate multiple signaling molecules that contain specific SH2 domains.
  • the JAK protein family includes 4 members: JAK1, JAK2, JAK3 and TYK2.
  • JH JAK homology domains
  • JH1 domain is the kinase domain, and its function is to encode a kinase protein.
  • JH2 domain is a "pseudo" kinase domain, which regulates the activity of JH1
  • JH3-JH7 constitutes a four-in-one domain that regulates the binding of JAK to receptors.
  • STAT is a class of cytoplasmic proteins that can bind to DNA in the regulatory region of target genes and is the downstream substrate of JAK. Seven members of the STAT family have been found, namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT proteins can be divided into the following functional segments in structure: N-terminal conserved sequence, DNA binding region, SH3 domain, SH2 domain and C-terminal transcriptional activation region. Among them, the most conserved and functionally important segment in sequence is the SH2 domain, which has the exact same core sequence "GTFLLRFSS" as the SH2 domain of the tyrosine kinase Src.
  • the JAK-STAT signaling pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation.
  • inflammatory diseases mainly include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis and Crohn's disease; while tumor diseases mainly involve myelofibrosis, polycythemia vera and essential platelets hyperplasia.
  • JAK-STAT signaling pathway has been reported to be closely related to the cytokine storm in the new coronary pneumonia (Covid-19).
  • JAK is a very important drug target. JAK inhibitors developed for this target are mainly used to screen therapeutic drugs for hematological diseases, tumors, rheumatoid arthritis and psoriasis. JAK-1, JAK-2 and TYK-2 are expressed in various tissues and 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. Studies have shown that JAK2 inhibitors are suitable for use in myeloproliferative diseases (Santos et al., Blood, 2010, 115:1131; Barosi G. and Rosti V., Curr. Opin.
  • inhibitors of JAK3 are suitable as immunosuppressants (eg, US Pat. No. 6,313,129; Borie et al., Curr. Opin. Investigational Drugs, 2003, 4:1297).
  • JAK inhibitors are expected to be used in the treatment of severe pneumonia such as new coronary pneumonia to suppress inflammatory responses, reduce the risk of cytokine storms, and thus reduce mortality (Wei Luo et al., Trends in Pharmacological Science, 41(8) June 2020 , “Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19”).
  • JAK inhibitors have a certain effect on the treatment of pruritus (Landon K. Oetjen et al., Cell, 171, P217-228, September 21, 2017, "Sensory Neurons Co- opt Classical Immune Signaling Pathways to Mediate Chronic Itch”).
  • JAK inhibitors approved by FDA and EMA include Tofacitinib (Tofacitinib), Ruxolitinib (Ruxolitinib), Oclacitinib (Oclacitinib) and so on.
  • JAK inhibitors in the middle and late clinical stage include, for example, Filgotinib, Peficitinib, and the like.
  • Tofacitinib a JAK3 inhibitor
  • Pfizer was developed by Pfizer and was approved by the FDA in November 2012 for the treatment of moderate-to-severe rheumatoid rheumatoid arthritis in adult patients with inadequate response or intolerance to methotrexate arthritis. It is the first oral JAK inhibitor approved for the treatment of RA. After that, it was approved by Japan's PMDA in March 2013 under the trade name Xeljanz. On March 16, 2017, Pfizer China announced that the CFDA has officially approved the marketing application of Pfizer's oral JAK inhibitor.
  • tofacitinib is close to being approved for psoriasis, ulcerative colitis, juvenile idiopathic arthritis and other indications; clinical trials for the treatment of Crohn's disease, alopecia areata and other indications have also entered the mid-to-late clinical stage .
  • the main side effects of tofacitinib are the rate of serious infections and increased low-density lipoprotein levels. The most common adverse reactions are upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat, and nasopharyngitis.
  • tofacitinib can cause side effects such as anemia and neutropenia.
  • Filgotinib a JAK1 inhibitor
  • Filgotinib is a selective JAK1 inhibitor with reported IC50s of approximately 10 nM, 28 nM, 810 nM and 116 nM for JAK1, JAK2, JAK3 and TYK2, respectively.
  • JAK inhibitors Although some JAK inhibitors have been approved and some are in the clinical research stage, these JAK inhibitors are not satisfactory in terms of efficacy or safety. Therefore, there is always a need for JAK inhibitors with better efficacy and/or fewer side effects.
  • One purpose of this application is to provide a new class of JAK inhibitors that can replace existing JAK inhibitors, thereby providing more options for the treatment of JAK-related diseases.
  • a further object of the present application is to provide a new class of JAK inhibitors with better efficacy and/or better safety than existing JAK inhibitors.
  • a still further object of the present application is to provide different solid forms of novel JAK inhibitors that are more suitable for pharmaceutical formulation.
  • the application provides a compound in solid form, the compound is a compound of formula (I)
  • Isotopically labeled compounds of compounds of formula (I), optical isomers of compounds of formula (I), geometric isomers of compounds of formula (I), tautomers of compounds of formula (I), compounds of formula (I) A mixture of isomers, a pharmaceutically acceptable salt of a compound of formula (I), or a solvate of any of these compounds.
  • the solid form of the compound is crystalline.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound in solid form as described in the first aspect of the application and one or more pharmaceutically acceptable carriers, adjuvants or excipients.
  • the pharmaceutical composition may be in the form of a dispersion or a solution.
  • the application provides a compound in solid form according to the first aspect of the application or a pharmaceutical composition according to the second aspect of the application, prepared for the treatment and/or prevention of a disease or disorder associated with JAK use in medicines.
  • the application provides a method of treating a disease or disorder associated with JAK, the method comprising administering a therapeutically effective amount of a compound in solid form according to the first aspect of the application or the second aspect of the application
  • the pharmaceutical composition is administered to a patient in need.
  • the patient is preferably a mammal, more preferably a human patient.
  • the route of administration can be oral, topical, parenteral, bronchial or nasal. Of these, oral administration is preferred.
  • the present application provides a novel compound that inhibits JAK, thereby providing more options for the prevention or treatment of JAK-related diseases.
  • the present application provides multiple solid forms of the compound, including multiple crystal forms and amorphous forms, these different solid forms have different chemical and physical properties, and different metabolic properties in vivo, so they are medicines.
  • the production, storage and selection of different pharmaceutical dosage forms provides more freedom, so that new pharmaceutical dosage forms with higher bioavailability and/or better efficacy can be provided.
  • a first aspect of the present application relates to solid forms of compounds of formula (I)
  • the compound of formula (I) can be named as (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-di Hydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone.
  • compounds of the present application encompasses compounds of formula (I), isotopically labeled compounds of compounds of formula (I), optical isomers of compounds of formula (I), compounds of formula (I) Geometric isomers, tautomers of compounds of formula (I), mixtures of isomers of compounds of formula (I), or solvates of any of these compounds.
  • optical isomer means that when a compound has one or more chiral centers, each chiral center may exist in R configuration or S configuration, and various isomers thus constituted are optical isomers Construct.
  • Optical isomers include all diastereomers, enantiomers, mesomers, racemates or mixtures thereof.
  • Optical isomers can be separated, for example, by chiral chromatography columns or by chiral synthesis.
  • Geometric isomer means that when a double bond exists in a compound, the compound may exist as cis isomer, trans isomer, E isomer and Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or mixtures thereof.
  • tautomer refers to an isomer resulting from the rapid movement of an atom in a molecule between two positions. Those skilled in the art can understand that tautomers can be transformed into each other, and may reach an equilibrium state and coexist in a certain state.
  • compound of formula (I) described herein also encompasses any tautomer of the compound of formula (I).
  • isotopically labeled compound refers to a compound in which one or more atoms have been replaced by an atom having the same atomic number as the atom normally found in nature, but a different atomic mass or mass number.
  • isotopes suitable for inclusion in the compounds of the present application include isotopes of hydrogen such as 2 H(D) and 3 H(T), isotopes of carbon such as 11 C, 13 C and 14 C, and isotopes of chlorine such as 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O, 17 O and 18 O, and sulfur isotopes, such as35S .
  • isotopes of hydrogen such as 2 H(D) and 3 H(T)
  • isotopes of carbon such as 11 C, 13 C and 14 C
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such
  • isotopically-labeled compounds of the compounds of formula (I), such as those containing radioactive isotopes, are useful in drug and/or substrate tissue distribution studies.
  • the radioisotopes deuterium (ie 2 H) and carbon-14 (ie 14 C) are particularly useful for this purpose in view of ease of introduction and convenience of detection means.
  • substitution with heavier isotopes such as deuterium may provide certain therapeutic benefits resulting from greater metabolic stability ( For example, increased in vivo half-life or reduced dosage requirements).
  • positron emission isotopes such as 11 C, 18 F, 15 O and 13 N can be used in Positron Emission Topography (PET) studies for detection of substrate acceptor occupancy states.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the compounds of formula (I) can generally be prepared analogously to those described in the Examples and Preparations appended hereto by conventional techniques known to those skilled in the art or by the use of a suitable isotopically-labeled reagent in place of a previously used non-labeled reagent method to prepare.
  • the compounds of the present application may be pharmaceutically acceptable salts of compounds of formula (I), in particular acid addition salts of compounds of formula (I).
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to: mucus, hippurate, ascorbate, succinate, naphthalene-2-sulfonate, acetate, adipate, aspartate, benzoate , Benzenesulfonate, Bicarbonate/Carbonate, Bisulfate/Sulfate, Borate, Camphorsulfonate, Citrate, Cyclohexylamine Sulfonate, Ethanedisulfonate, Formate , fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride/chloride, hydrogen Bromide/bromide, hydroiodide/iodide, 2-
  • Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are their hydrochloride, phosphate, maleate, L-tartrate, fumarate, mucate, citrate, p-toluenesulfonate acid salt, methanesulfonate, benzenesulfonate.
  • the most preferred pharmaceutically acceptable salts of the compounds of formula (I) are their phosphates, maleates, mesylates.
  • pharmaceutically acceptable means that the corresponding compound, carrier or molecule is suitable for administration to a mammal, preferably a human.
  • the term refers to use in mammals (preferably humans) certified by any national regulatory agency such as CFDA (China), EMEA (Europe), FDA (United States), or the like.
  • pharmaceutically acceptable salts of compounds of formula (I) is used to denote pharmaceutically acceptable salts of compounds of formula (I) in any form, ie encompassing compounds of formula (I), compounds of formula (I) ) isotopically labeled compounds of compounds, optical isomers of compounds of formula (I), geometric isomers of compounds of formula (I), tautomers of compounds of formula (I), isomers of compounds of formula (I) A pharmaceutically acceptable salt of any of the mixtures.
  • solid form of the compound and “solid form of the compound” are understood to have the same meaning and are therefore used interchangeably, meaning that the compound is predominantly present in solid form. It will be understood by those skilled in the art that a compound in solid form may exist as a crystal (crystalline form), an amorphous form (amorphous), or a mixture of the two.
  • crystalline form refers to a solid form that is a crystal, as can be determined, for example, by X-ray diffraction.
  • a crystalline form of a substance may be substantially free of amorphous and/or other crystalline forms.
  • a crystalline form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10% by weight of one or more amorphous and/or other crystalline forms.
  • the crystalline form of the substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92% %, about 91% or about 90% pure.
  • amorphous or “amorphous form” or “amorphous” (some prior art documents refer to it as “amorphous”) means a solid form that is not substantially crystalline, as can be determined, for example, by X-ray diffraction .
  • amorphous or “amorphous form” or “amorphous” describe a disordered solid form, ie, the solid form lacks long-range order.
  • an amorphous form of a substance may be substantially free of other amorphous and/or crystalline forms.
  • an amorphous form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7% by weight %, less than about 8%, less than about 9%, less than about 10% by weight of one or more other amorphous and/or crystalline forms.
  • the amorphous form of the substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or About 90% pure.
  • polymorph refers to different crystals having the same molecular structure, but formed due to different arrangements or conformations in the molecular lattice. It is well known in the art that compound crystals with the same molecular structure but different crystal forms may have different chemical and physical properties such as bioavailability, solubility, dissolution rate, chemical physical stability, melting point, color, filterability, hygroscopicity, and density.
  • the solid form is a crystal of a compound of formula (I) or a crystal of a salt of a compound of formula (I) prepared in the Examples section of the present application.
  • the solid form of the compound of formula (I) is the phosphate crystal form A of the compound of formula (I), the maleate salt crystal form A of the compound of formula (I), the methanesulfonic acid salt of the compound of formula (I) Acid salt crystal form B, formula (I) compound hydrate crystal form A, formula (I) compound crystal form B, etc.
  • the solid form is the crystal of the compound of formula (I) or the crystal of the salt of the compound of formula (I) prepared in the Examples section of the present application, the powder of the crystal (or crystal form)
  • the X-ray diffraction pattern preferably has one or more characteristic peaks at the same position of the diffraction angle (2 ⁇ ) in the corresponding XRPD spectrum determined in the Examples section of the present application.
  • the "one or more characteristic peaks" refers to at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 characteristic peaks.
  • characteristic peak is understood to be the peak or peaks with the greatest relative intensity in the XRPD spectrum.
  • the diffraction angle (2 ⁇ ) positions of the can have differences of ⁇ 0.50°, ⁇ 0.40°, ⁇ 0.30°, ⁇ 0.20°, preferably ⁇ 0.10°.
  • the powder X-ray diffraction pattern of the crystal (or crystal form) is substantially the same as the corresponding XRPD pattern determined in the Examples section of this application.
  • the "XRPD spectra are substantially the same" means: the two XRPD spectra are completely identical, or although there are differences, those skilled in the art can confirm that the differences are insubstantial and are caused by different sample purities, assay conditions, and instruments. Errors or operating habits, and thus confirm that the two XRPD patterns were obtained from the same crystal.
  • the solid form is a crystal of a compound of formula (I) or a crystal of a salt of a compound of formula (I) prepared in the Examples section of the present application
  • the crystal (or crystal form) of TGA Or the DSC curve preferably has at least 1, at least 2, at least 3, or at least 4 characteristic peaks at the same position as the corresponding TGA or DSC curve determined in the Examples section of the present application.
  • "Characteristic peaks” are here understood as endothermic or exothermic peaks in the TGA/DSC curve.
  • the temperature at the peak position may have differences of ⁇ 5°C, ⁇ 4°C, ⁇ 3°C, ⁇ 2°C, and ⁇ 1°C.
  • the TGA/DSC curve of the crystal (or crystal form) is substantially the same as the corresponding TGA/DSC curve determined in the Examples section of the present application.
  • the "substantially the same TGA/DSC curves” means: the two TGA curves and/or DSC curves are identical, or although there are differences, those skilled in the art can confirm that the differences are insubstantial and are caused by different Sample purity, assay conditions, instrumental errors or operating habits, and thus confirm that the two TGA curves and/or DSC curves are obtained from the same crystal.
  • a preferred embodiment of the present application relates to the crystalline form A of the compound hydrate of formula (I), the powder X-ray diffraction pattern (XRPD) of which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 8.67 ⁇ 0.10°, 13.39 ⁇ 0.10°, 15.05 ⁇ 0.10°, 17.38 ⁇
  • XRPD powder X-ray diffraction pattern
  • One or more characteristic peaks at diffraction angles (2 ⁇ ) of 0.10°, 21.24 ⁇ 0.10°, 22.86 ⁇ 0.10°, 24.89 ⁇ 0.10° preferably having selected from 8.67 ⁇ 0.10°, 11.53 ⁇ 0.10°, 13.39 ⁇ 0.10° , 15.05 ⁇ 0.10°, 17.38 ⁇ 0.10°, 21.24 ⁇ 0.10°, 21.63 ⁇ 0.10°, 22.19 ⁇ 0.10°, 22.86 ⁇ 0.10°, 23.43 ⁇ 0.10°, 24.89 ⁇ 0.10° at one or more diffraction angles (2 ⁇ ) characteristic
  • the TGA/DSC curve of the crystalline form A of the compound hydrate of formula (I) has multiple thermal signals in the range of about 50-290°C.
  • a preferred embodiment of the present application relates to the crystalline form B of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 7.70 ⁇ 0.10°, 11.20 ⁇ 0.10°, 12.46 ⁇ 0.10°, 15.44 ⁇ 0.10° , 18.17 ⁇ 0.10°, 18.48 ⁇ 0.10°, 19.27 ⁇ 0.10°, 21.84 ⁇ 0.10°, 22.94 ⁇ 0.10°, 24.29 ⁇ 0.10°, 25.40 ⁇ 0.10°, 27.92 ⁇ 0.10° at one or more diffraction angles (2 ⁇ ) characteristic peaks, preferably having selected from 7.70 ⁇ 0.10°, 11.20 ⁇ 0.10°, 12.46 ⁇ 0.10°, 15.44 ⁇ 0.10°, 18.17 ⁇ 0.10°, 18.48 ⁇ 0.10°, 18.93 ⁇ 0.10°, 19.27 ⁇ 0.10°, 19.50° ⁇ 0.10°, 20.83 ⁇ 0.10°, 21.84 ⁇ 0.10°, 22.94 ⁇ 0.10°, 23.22 ⁇ 0.10
  • the TGA/DSC curve of Form B of the compound of formula (I) has an endothermic peak at about 319.1°C (onset temperature).
  • a preferred embodiment of the present application relates to the crystalline form C of the hydrate of the compound of formula (I), the powder X-ray diffraction pattern (XRPD) having a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 4.96 ⁇ 0.10°, 7.66 ⁇ 0.10°, 10.18 ⁇ 0.10°, 11.07 ⁇
  • XRPD powder X-ray diffraction pattern
  • One or more characteristic peaks at diffraction angles (2 ⁇ ) of 0.10°, 14.73 ⁇ 0.10°, 22.87 ⁇ 0.10° preferably having selected from 4.96 ⁇ 0.10°, 7.66 ⁇ 0.10°, 10.18 ⁇ 0.10°, 11.07 ⁇ 0.10
  • the TGA/DSC curve of Form C of the compound hydrate of formula (I) has a thermal signal at about 78.1°C (onset temperature), at about 279.4°C (onset temperature) and 303.8°C (onset temperature). temperature) there is a thermal signal.
  • a preferred embodiment of the present application relates to the crystalline form G of the compound hydrate of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 6.42 ⁇ 0.10°, 7.04 ⁇ 0.10°, 7.69 ⁇ 0.10°, 12.52 ⁇ 0.10°, 15.81 ⁇ 0.10°, 18.83 ⁇ 0.10°, 22.85 ⁇ 0.10°, 23.40 ⁇ 0.10°, one or more characteristic peaks at the diffraction angle (2 ⁇ ), preferably having selected from 6.42 ⁇ 0.10°, 7.04 ⁇ 0.10 degrees One or more characteristic peaks at the ° diffraction angle (2 ⁇ ).
  • XRPD powder X-ray diffraction pattern
  • the TGA/DSC curve of the crystalline form G of the compound hydrate of formula (I) has a thermal signal at about 81.2°C (onset temperature), and at about 209.6°C (onset temperature), about 314.0°C ( There are two thermal signals at the onset temperature).
  • a preferred embodiment of the present application relates to the phosphate crystal form A of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 5.29 ⁇ 0.10°, 7.47 ⁇ 0.10°, 10.61 ⁇ 0.10°, 19.16 ⁇
  • XRPD powder X-ray diffraction pattern
  • One or more characteristic peaks at diffraction angles (2 ⁇ ) of 0.10° and 21.32 ⁇ 0.10° preferably having a characteristic selected from the group consisting of 5.29 ⁇ 0.10°, 7.47 ⁇ 0.10°, 10.61 ⁇ 0.10°, 15.94 ⁇ 0.10°, 16.77 ⁇ 0.10° , 18.68 ⁇ 0.10°, 19.16 ⁇ 0.10°, 21.32 ⁇ 0.10° and 25.36 ⁇ 0.10° one or more characteristic peaks at diffraction angles (2 ⁇ ).
  • the TGA/DSC curve of the phosphate crystal form A of the compound of formula (I) has a number of sharp endothermic peaks at about 279.3<0>C (onset temperature).
  • a preferred embodiment of the present application relates to the maleate salt form A of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 4.55 ⁇ 0.10°, 8.78 ⁇ 0.10°, 12.69 ⁇ 0.10°, 13.96 ⁇ 0.10°, 16.62 ⁇ 0.10°, 17.61 ⁇ 0.10°, 18.32 ⁇ 0.10°, 25.39 ⁇ 0.10°, 26.53 ⁇ 0.10° at diffraction angles (2 ⁇ ), preferably with one or more characteristic peaks selected from 4.55 ⁇ 0.10° 0.10°, 8.78 ⁇ 0.10°, 12.69 ⁇ 0.10°, 13.74 ⁇ 0.10°, 13.96 ⁇ 0.10°, 16.62 ⁇ 0.10°, 17.61 ⁇ 0.10°, 18.32 ⁇ 0.10°, 21.72 ⁇ 0.10°, 25.39 ⁇ 0.10°, 26.53 ⁇ One or more characteristic peaks at a diffraction angle (2 ⁇ ) of 0.10°.
  • XRPD powder X-ray diffraction pattern
  • the TGA/DSC curve of the maleate salt form A of the compound of formula (I) has two thermal signals at about 211.2°C and about 278.1°C (onset temperature).
  • a preferred embodiment of the present application relates to the mesylate salt form B of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 5.91 ⁇ 0.10°, 9.22 ⁇ 0.10°, 15.83 ⁇ 0.10°, 17.73 ⁇ 0.10°, 19.02 ⁇ 0.10°, 25.01 ⁇ 0.10°, one or more characteristic peaks at diffraction angle (2 ⁇ ), preferably having a characteristic selected from the group consisting of 5.91 ⁇ 0.10°, 9.22 ⁇ 0.10°, 15.83 ⁇ 0.10°, 17.73
  • the TGA/DSC curve of the mesylate salt form B of the compound of formula (I) has two endothermic signals at about 234.4°C (peak temperature) and about 264.1°C (onset temperature).
  • a preferred embodiment of the present application relates to the hydrochloride salt form A of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 8.05 ⁇ 0.10°, 17.11 ⁇ 0.10°, 18.02 ⁇ 0.10°, 20.84 ⁇ 0.10°, 21.09 ⁇ 0.10°, 22.77 ⁇ 0.10°, 23.14 ⁇ 0.10° diffraction angle (2 ⁇ ), preferably with one or more characteristic peaks selected from the group consisting of 8.05 ⁇ 0.10°, 15.04 ⁇ 0.10°, 17.11 ⁇ 0.10 °, 18.02 ⁇ 0.10°, 20.44 ⁇ 0.10°, 20.84 ⁇ 0.10°, 21.09 ⁇ 0.10°, 22.07 ⁇ 0.10°, 22.77 ⁇ 0.10°, 23.14 ⁇ 0.10°
  • XRPD powder X-ray diffraction pattern
  • the TGA/DSC curve of the hydrochloride salt form A of the compound of formula (I) has three endothermic peaks at about 80.1°C, about 118.0°C (peak temperature) and about 224.5°C (onset temperature), and at about There was an exothermic signal at 231.5°C (onset temperature).
  • a preferred embodiment of the present application relates to the tartrate salt form A of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 7.90 ⁇ 0.10°, 8.69 ⁇ 0.10°, 13.12 ⁇ 0.10°, 13.43 ⁇
  • XRPD powder X-ray diffraction pattern
  • One or more characteristic peaks at diffraction angles (2 ⁇ ) of 0.10°, 18.11 ⁇ 0.10°, 21.28 ⁇ 0.10°, 22.90 ⁇ 0.10° preferably having selected from 7.90 ⁇ 0.10°, 8.69 ⁇ 0.10°, 13.12 ⁇ 0.10° , 13.43 ⁇ 0.10°, 15.08 ⁇ 0.10°, 17.17 ⁇ 0.10°, 17.44 ⁇ 0.10°, 18.11 ⁇ 0.10°, 19.40 ⁇ 0.10°, 20.74 ⁇ 0.10°, 21.28 ⁇ 0.10°, 22.90 ⁇ 0.10°, 24.15 ⁇ 0.10° , one or more characteristic peaks at the diffraction angle (2 ⁇ ) of 24
  • the TGA/DSC curve of the tartaric acid form A of the compound of formula (I) has two thermal signals at about 125.2°C and about 168.8°C (onset temperature).
  • a preferred embodiment of the present application relates to the fumarate salt form A of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) having a value selected from the group consisting of 4.96 ⁇ 0.10°, 7.66 ⁇ 0.10°, 10.21 ⁇ 0.10°, 11.06 ⁇ 0.10°, 14.74 ⁇ 0.10°, 16.11 ⁇ 0.10°, 22.87 ⁇ 0.10°, 25.10 ⁇ 0.10° diffraction angle (2 ⁇ ) one or more characteristic peaks, preferably having selected from 4.96 ⁇ 0.10°, 7.66 ⁇ 0.10°, 10.21 ⁇ 0.10°, 11.06 ⁇ 0.10°, 12.44 ⁇ 0.10°, 14.74 ⁇ 0.10°, 16.11 ⁇ 0.10°, 19.25 ⁇ 0.10°, 22.87 ⁇ 0.10°, 23.54 ⁇ 0.10°, 24.27 ⁇ 0.10°, 25.10 ⁇ One or more characteristic peaks at 0.10°, 25.37 ⁇ 0.10° diffraction angle (2 ⁇ ).
  • XRPD powder X-ray
  • the TGA/DSC curve of the fumaric acid form A of the compound of formula (I) has multiple thermal signals at about 71.1°C, about 205.3°C, about 273.7°C and about 299.4°C (onset temperature).
  • a preferred embodiment of the present application relates to the crystalline form A of the mucic acid salt of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 4.98 ⁇ 0.10°, 10.22 ⁇ 0.10°, 11.07 ⁇ 0.10°, 14.75 ⁇ 0.10°, 14.94 ⁇ 0.10°, 16.13 ⁇ 0.10°, 19.65 ⁇ 0.10°, 30.79 ⁇ 0.10° diffraction angle (2 ⁇ ), preferably with one or more characteristic peaks selected from the group consisting of 4.98 ⁇ 0.10°, 7.69 ⁇ 0.10 degrees ) at one or more characteristic peaks.
  • XRPD powder X-ray diffraction pattern
  • two thermal signals are observed at about 69.8°C and about 210.4°C (onset temperature) in the TGA/DSC curve of the mucic acid salt form A of the compound of formula (I).
  • a preferred embodiment of the present application relates to the citrate salt form A of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 4.85 ⁇ 0.10°, 6.42 ⁇ 0.10°, 14.63 ⁇ 0.10°, 17.12 ⁇ 0.10°, 20.75 ⁇ 0.10°, 25.34 ⁇ 0.10°, one or more characteristic peaks at diffraction angles (2 ⁇ ), preferably having a characteristic selected from the group consisting of 4.85 ⁇ 0.10°, 6.42 ⁇ 0.10°, 7.64 ⁇ 0.10°, 14.63 ⁇ One or more features at 0.10°, 15.40 ⁇ 0.10°, 17.12 ⁇ 0.10°, 18.12 ⁇ 0.10°, 18.84 ⁇ 0.10°, 19.37 ⁇ 0.10°, 20.75 ⁇ 0.10°, 25.34 ⁇ 0.10°, diffraction angle (2 ⁇ ) peak.
  • XRPD powder X-ray diffraction pattern
  • the TGA/DSC curve of the citrate salt form A of the compound of formula (I) has three endothermic peaks at about 68.2°C (peak temperature), about 154.4°C and 164.0°C (onset temperature).
  • a preferred embodiment of the present application relates to the citrate salt form B of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 4.96 ⁇ 0.10°, 7.67 ⁇ 0.10°, 10.20 ⁇ 0.10°, 11.04
  • XRPD powder X-ray diffraction pattern
  • One or more characteristic peaks at ⁇ 0.10°, 14.73 ⁇ 0.10°, 19.23 ⁇ 0.10°, 22.86 ⁇ 0.10°, 23.54 ⁇ 0.10°, 24.28 ⁇ 0.10°, 25.08 ⁇ 0.10° diffraction angle (2 ⁇ ) preferably with Selected from 4.96 ⁇ 0.10°, 7.67 ⁇ 0.10°, 10.20 ⁇ 0.10°, 11.04 ⁇ 0.10°, 12.42 ⁇ 0.10°, 14.73 ⁇ 0.10°, 16.09 ⁇ 0.10°, 17.55 ⁇ 0.10°, 19.23 ⁇ 0.10°, 22.86 ⁇ 0.10
  • the TGA/DSC curve of the citrate salt form B of the compound of formula (I) has four adsorptions at about 73.1°C, about 280.2°C, about 301.6°C (onset temperature) and about 179.7°C (peak temperature). heat peak.
  • a preferred embodiment of the present application relates to the p-toluenesulfonate salt form A of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 5.90 ⁇ 0.10°, 9.34 ⁇ 0.10°, 14.87 ⁇ 0.10° , 15.33 ⁇ 0.10°, 17.88 ⁇ 0.10°, 18.76 ⁇ 0.10°, 19.71 ⁇ 0.10°, 24.26 ⁇ 0.10° diffraction angle (2 ⁇ )
  • XRPD powder X-ray diffraction pattern
  • one or more characteristic peaks preferably have selected from 5.90 ⁇ 0.10°, 9.34 ⁇ 0.10°, 12.99 ⁇ 0.10°, 14.87 ⁇ 0.10°, 15.33 ⁇ 0.10°, 16.10 ⁇ 0.10°, 17.88 ⁇ 0.10°, 18.76 ⁇ 0.10°, 19.34 ⁇ 0.10°, 1971 ⁇ 0.10°, 20.39 ⁇ 0.10°, 24.26
  • the TGA/DSC curve of p-toluenesulfonic acid Form A of the compound of formula (I) consists of two thermal signals at about 121.2°C and about 222.3°C (onset temperature).
  • a preferred embodiment of the present application relates to the benzenesulfonate salt form A of the compound of formula (I), which has a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 5.82 ⁇ 0.10°, 6.74 ⁇ 0.10°, 11.85 ⁇ 0.10°, One or more characteristic peaks at diffraction angles (2 ⁇ ) of 16.38 ⁇ 0.10°, preferably having a characteristic selected from the group consisting of 5.82 ⁇ 0.10°, 6.74 ⁇ 0.10°, 11.85 ⁇ 0.10°, 16.38 ⁇ 0.10°, 19.46 ⁇ 0.10°, 20.20 ⁇ One or more characteristic peaks at a diffraction angle (2 ⁇ ) of 0.10°.
  • XRPD powder X-ray diffraction pattern
  • the TGA/DSC curve of the benzenesulfonic acid crystal form A of the compound of formula (I) has multiple thermal signals at about 60-200°C.
  • a preferred embodiment of the present application relates to the benzenesulfonate salt form B of the compound of formula (I), the powder X-ray diffraction pattern (XRPD) having a powder X-ray diffraction pattern (XRPD) selected from the group consisting of 4.93 ⁇ 0.10°, 5.63 ⁇ 0.10°, 9.02 ⁇ 0.10°, One or more characteristic peaks at 10.89 ⁇ 0.10°, 14.84 ⁇ 0.10°, 17.55 ⁇ 0.10°, 18.84 ⁇ 0.10°, 23.12 ⁇ 0.10°, 25.55 ⁇ 0.10°, 26.14 ⁇ 0.10° diffraction angle (2 ⁇ ), preferably has a selected from 4.93 ⁇ 0.10°, 5.63 ⁇ 0.10°, 9.02 ⁇ 0.10°, 10.30 ⁇ 0.10°, 10.89 ⁇ 0.10°, 11.43 ⁇ 0.10°, 14.23 ⁇ 0.10°, 14.84 ⁇ 0.10°, 17.04 ⁇ 0.10°, 17.55 ⁇ One of 0.10°, 18.84 ⁇ 0.10°, 19.66 ⁇ 0.10°, 20.
  • the TGA/DSC curve of the benzenesulfonic acid form B of the compound of formula (I) has two thermal signals at about 90.1°C (peak temperature) and about 236.7°C (onset temperature).
  • the solid form is the phosphate crystalline form A of the compound of formula (I), the maleate crystalline form A of the compound of formula (I), the methanesulfonic acid of the compound of formula (I)
  • the solid form is the phosphate salt form A of the compound of formula (I), the maleate salt form A of the compound of formula (I), the mesylate salt of the compound of formula (I) Crystal Form B, Crystal Form A of Compound Hydrate of Formula (I), Crystal Form B of Compound of Formula (I), each of which has substantially the same TGA and/or DSC curve as the corresponding crystal form described in the Examples section of the present application .
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound in solid form as described in the first aspect of the application and one or more pharmaceutically acceptable carriers, adjuvants or excipients.
  • compositions of the present application may be solid compositions or liquid compositions (eg, dispersions or solutions).
  • the pharmaceutical composition of the present application can be formulated for oral, topical (including but not limited to topical, spray, etc.), parenteral (including subcutaneous, intramuscular, cortical and intravenous) administration, bronchial administration or nasal administration as required dosage form.
  • parenteral including subcutaneous, intramuscular, cortical and intravenous
  • bronchial administration or nasal administration as required dosage form.
  • the pharmaceutical composition of the present application is formulated into a dosage form (formulation) suitable for external use or bronchial administration or nasal administration. More preferably, the pharmaceutical composition of the present application is formulated into a dosage form (formulation) suitable for external use.
  • the preparation may be tableted, placed in hard gelatin capsules in powder or granule form, or in the form of troches or lozenges.
  • Solid carriers can include conventional excipients such as binders, fillers, tableting lubricants, disintegrating agents, wetting agents, and the like.
  • the tablets can be film coated by conventional techniques if desired.
  • a liquid carrier the preparation may be in the form of a syrup, emulsion, ointment, soft gel capsule, sterile vehicle for injection, aqueous or non-aqueous liquid suspension, or it may be taken before use with water or other appropriate Carrier-reconstituted dry product.
  • Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavoring and/or coloring agents.
  • the carrier will usually comprise sterile water, at least in large part, although saline solutions, dextrose solutions, and the like may also be used.
  • injectable suspensions may also be employed, in which case conventional suspending agents may be employed.
  • Conventional preservatives, buffering agents, etc. can also be added to parenteral dosage forms.
  • Pharmaceutical compositions are prepared by conventional techniques suitable for the desired formulation containing appropriate amounts of the active ingredient (ie the compound of formula (I) of the present application).
  • compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions (eg, suspensions or emulsions) and sterile powders for sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents, dispersants include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (eg, olive oil) and injectable organic esters (eg, ethyl oleate).
  • compositions may also contain various excipients such as preservatives, wetting agents, emulsifying agents and dispersing agents. Inhibition of the action of microorganisms can be ensured by various antibacterial and antifungal agents (eg, parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents such as sugars, sodium chloride, and the like may also be included. Prolonged absorption of the injectable pharmaceutical dosage form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • agents delaying absorption for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert excipient (or carrier) (eg, sodium citrate or dicalcium phosphate), which may also include: (a) fillers or admixtures (eg, starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) binders (eg, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia); (c) Humectants (eg, glycerol); (d) disintegrants (eg, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solutions Blockers (eg, paraffin); (f) absorption enhancers (eg, quaternary ammonium compounds); (g) wetting agents (e
  • Solid compositions of a similar type can also be used as fillers in soft-filled and hard-filled gel capsules using excipients such as lactose and high molecular weight polyethylene glycols and the like.
  • Solid dosage forms eg, tablets, dragees, capsules, pills, and granules
  • coatings and shells eg, enteric coatings and others known in the art. They may contain opacifying agents, and they may also release the active compound or a combination of various active compounds in a certain part of the intestinal tract in a delayed manner.
  • useful embedding compositions are polymeric substances and waxes.
  • the active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups and elixirs.
  • liquid dosage forms may contain inert diluents (eg, water or other solvents), solubilizers, and emulsifiers (eg, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene, etc.) commonly used in the art methanol, benzyl benzoate, propylene glycol, 1,3 butanediol, dimethylformamide), oils (specifically, cottonseed oil, groundnut oil, corn oil, olive oil, castor oil, sesame oil), propylene Fatty acid esters of triols, tetrahydrofuran alcohols, polyethylene glycols and sorbitan or mixtures of these substances, etc.
  • inert diluents eg, water or other solvents
  • solubilizers eg, is
  • compositions can also include, for example, wetting agents, emulsifying and suspending agents, perfuming, flavoring, and perfuming agents.
  • suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and Gum tragacanth or a mixture of these substances, etc.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and Gum tragacanth or a mixture of these substances, etc.
  • Dosage forms for topical administration of the compounds of the present application include ointments, powders, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any required preservatives, buffers or propellants.
  • Ophthalmic formulations, ophthalmic ointments, powders and solutions are also included within the scope of this application.
  • Topical dosage forms of the compounds of the present application may be in the form of water-in-oil (W/O) or oil-in-water (O/W) emulsions, multiple emulsions, such as water-in-oil-in-water (W/O/W) or oil-in-oil In the form of oil-in-water (O/W/O) emulsions, or prepared as aqueous or lipid dispersions, gels or aerosols.
  • External dosage forms of the compounds of the present application may contain additives and formulation adjuvants such as emulsifiers, thickeners, gelling agents, water fixatives, spreading agents, stabilizers, dyes, fragrances and preservatives.
  • emulsifiers include stearic acid, triethanolamine and PEG-40-stearate.
  • Suitable thickeners include glyceryl monostearate, carbomer and PEG600.
  • Suitable preservatives include propylparaben and chlorocresol.
  • Suitable spreading agents include dimethicone and polydimethylcyclosiloxane.
  • Suitable water fixatives include polyethylene glycols, preferably polyethylene glycol 600.
  • Topical dosage forms of the compounds of the present application may include ointments, lotions, gels, emulsions, microemulsions, sprays, skin patches, and the like, which may be applied topically to treat atopic dermatitis, eczema, psoriasis, scleroderma Disease, itching, vitiligo, hair loss and other skin diseases.
  • the topical dosage form of the compound of the present application is an ointment, which can be applied topically to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo, alopecia, and the like.
  • the amount of the compound of formula (I) in the pharmaceutical composition and dosage form can be appropriately determined by those skilled in the art as needed, eg the compound of formula (I) can be present in the pharmaceutical composition or dosage form in a therapeutically effective amount.
  • the present application provides a compound in solid form according to the first aspect of the present application, or a pharmaceutical composition according to the second aspect of the present application, prepared for the treatment and/or prevention of a disease or disorder associated with JAK Use in medicine.
  • Diseases or conditions associated with JAK include, but are not limited to:
  • Autoimmune diseases or disorders including single organ or single cell type autoimmune disorders, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune Orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic invasive hepatitis, ulcerative colitis and Membranous glomerulopathy, those involving systemic autoimmune disorders (eg systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, Polyarteritis nodosa, multiple sclerosis, and bullous pemphigoid) and other O-cell (humoral) or T-cell autoimmune diseases
  • Cancers or tumors including digestive/gastrointestinal, colorectal, liver, skin (including mast cell and squamous cell carcinoma), breast and breast, ovarian, prostate, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, myeloma (including multiple myeloma), myeloproliferative disorders, proliferative diabetic retinopathy, or disorders associated with angiogenesis (including solid tumors);
  • leukemia including acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
  • kidney cancer including acute myeloid leukemia
  • diabetes including type 1 diabetes or complications of diabetes
  • Eye diseases, disorders, or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis (including Behcet's disease-related uveitis and phakic uveitis), keratitis, herpes Keratitis, keratoconus, corneal epithelial dystrophy, leukoplakia, pemphigus, Mollen ulcer, scleritis, Grave's eye disease, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye) , vesicles, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis, or ocular neovascularization;
  • Bowel inflammation, allergy, or condition including Crohn's disease and/or ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis;
  • Neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury, stroke, glutamate neurotoxicity or Hypoxia; ischemia/reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia or platelet aggregation;
  • Allergies including allergic dermatitis in mammals (including allergic diseases such as allergy to bites), summer eczema, sweet itch, emphysema, inflammatory airway disease, recurrent gas Airway obstruction, airway hyperresponsiveness, or chronic obstructive pulmonary disease;
  • Asthma and other obstructive airway diseases including chronic or refractory asthma, advanced asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, or dusty asthma;
  • Transplant rejection including islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection (e.g. bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, extremity, liver, lung, muscle, myoblast , nerve, pancreas, skin, small intestine or trachea) or xenograft;
  • organ and cell transplant rejection e.g. bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, extremity, liver, lung, muscle, myoblast , nerve, pancreas, skin, small intestine or trachea
  • Severe pneumonia caused by influenza virus or coronavirus infection including Sars, Mers and Covid-19 (new coronary pneumonia), especially in new coronary pneumonia, suppressing inflammatory response, suppressing or preventing cytokine storm.
  • the application provides a method of treating a disease or disorder associated with JAK, the method comprising administering a therapeutically effective amount of a compound in solid form according to the first aspect of the application, or the second aspect of the application
  • the pharmaceutical composition is administered to a patient in need.
  • the patient is preferably a mammal, more preferably a human patient.
  • the route of administration can be oral, topical (including but not limited to topical application, spraying, etc.), parenteral (including subcutaneous, intramuscular, cortical and intravenous) administration, bronchial administration or nasal administration and the like.
  • nasal administration or external administration is preferable. More preferably it is administered externally.
  • a therapeutically effective amount is an art-recognized term.
  • the term refers to an amount necessary or sufficient to eliminate, reduce, or maintain the goals of a particular treatment regimen.
  • the effective amount may vary depending on factors such as the disease or disorder being treated, the particular targeting construct being administered, the size of the subject, or the severity of the disease or disorder.
  • the effective amount of a particular compound can be determined empirically by one of ordinary skill in the art or by a physician without undue experimentation.
  • a therapeutically effective amount of a therapeutic agent used in vivo may depend on a number of factors, including: the mode and method of administration; any other materials included in the drug in addition to the agent. In vitro or in vivo assays may optionally be used to help determine optimal dosage ranges.
  • the compounds of the present application demonstrated excellent efficacy as JAK kinase inhibitors in experiments (better than existing JAK kinase inhibitors such as Filgotinib or Tofacitinib), and potentially had a favorable safety profile.
  • Figure 1 shows the XRPD pattern of Form A of the compound of formula (I);
  • FIG. 1 shows the TGA/DSC curve of Form A of the compound of formula (I);
  • Fig. 3 shows the XRPD comparison chart before and after heating of the crystal form A of the compound of formula (I);
  • Figure 4 shows the variable temperature XRPD pattern of Form A of the compound of formula (I);
  • Figure 5 shows the XRPD pattern of Form B of the compound of formula (I);
  • Figure 6 shows the TGA/DSC curve of Form B of the compound of formula (I);
  • Figure 7 shows the variable temperature XRPD pattern of Form B of the compound of formula (I);
  • Figure 8 shows the XRPD pattern of Form C of the compound of formula (I);
  • Figure 9 shows the TGA/DSC curve of Form C of the compound of formula (I).
  • Figure 10 shows the XRPD comparison diagram before and after heating of the crystal form C of the compound of formula (I);
  • Figure 11 shows the XRPD pattern of Form D of the compound of formula (I);
  • Figure 12 shows a comparative XRPD graph of Form D of the compound of formula (I);
  • Figure 13 shows the XRPD pattern of Form E of the compound of formula (I);
  • Figure 14 shows the TGA/DSC curve of Form E of the compound of formula (I);
  • Figure 15 shows the XRPD comparison chart before and after heating of the crystal form E of the compound of formula (I);
  • Figure 16 shows the variable temperature XRPD pattern of Form E of the compound of formula (I);
  • Figure 17 shows the XRPD pattern of Form F of the compound of formula (I);
  • Figure 18 shows the TGA/DSC curve of Form F of the compound of formula (I);
  • Figure 19 shows the comparison of XRPD before and after heating of Form F of the compound of formula (I);
  • Figure 20 shows the XRPD pattern of Form G of the compound of formula (I);
  • Figure 21 shows the TGA/DSC curve of Form G of the compound of formula (I);
  • Figure 22 shows the variable temperature XRPD pattern of Form G of the compound of formula (I);
  • Figure 23 shows the XRPD pattern of Form J of the compound of formula (I).
  • Figure 24 shows a comparative XRPD graph of Form J of the compound of formula (I);
  • Figure 25 shows the XRPD pattern of Form H of the compound of formula (I);
  • Figure 26 shows the XRPD pattern of Form I of the compound of formula (I);
  • Figure 27 shows the XRPD pattern of the phosphate crystal form A of the compound of formula (I);
  • Figure 28 shows the TGA/DSC curve of the phosphate crystal form A of the compound of formula (I);
  • Figure 29 shows the XRPD pattern of the maleate salt Form A of the compound of formula (I);
  • Figure 30 shows the TGA/DSC curve of the maleate salt Form A of the compound of formula (I);
  • Figure 31 shows the XRPD pattern of the mesylate salt Form B of the compound of formula (I);
  • Figure 32 shows the TGA/DSC curve of the mesylate salt Form B of the compound of formula (I);
  • Figure 33 shows the XRPD pattern of the hydrochloride salt Form A of the compound of formula (I);
  • Figure 34 shows the TGA/DSC curve of the hydrochloride salt Form A of the compound of formula (I);
  • Figure 35 shows the XRPD pattern of the tartrate salt Form A of the compound of formula (I);
  • Figure 36 shows the TGA/DSC curve of the tartrate salt form A of the compound of formula (I);
  • Figure 37 shows the XRPD pattern of the fumarate salt Form A of the compound of formula (I);
  • Figure 38 shows the TGA/DSC curve of the fumarate salt Form A of the compound of formula (I);
  • Figure 39 shows the XRPD pattern of the mucic acid salt Form A of the compound of formula (I);
  • Figure 40 shows the TGA/DSC curve of the mucic acid salt Form A of the compound of formula (I);
  • Figure 41 shows the XRPD pattern of the citrate salt Form A of the compound of formula (I);
  • Figure 42 shows the TGA/DSC curve of the citrate salt form A of the compound of formula (I);
  • Figure 43 shows the XRPD pattern of the citrate salt Form B of the compound of formula (I);
  • Figure 44 shows the TGA/DSC curve of the citrate salt form B of the compound of formula (I);
  • Figure 45 shows the XRPD pattern of the p-toluenesulfonate salt Form A of the compound of formula (I);
  • Figure 46 shows the TGA/DSC curve of the p-toluenesulfonate salt Form A of the compound of formula (I);
  • Figure 47 shows the XRPD pattern of the benzenesulfonate salt Form A of the compound of formula (I);
  • Figure 48 shows the TGA/DSC curve of the benzenesulfonate salt Form A of the compound of formula (I);
  • Figure 49 shows the XRPD pattern of the benzenesulfonate salt Form B of the compound of formula (I);
  • Figure 50 shows the TGA/DSC curve of the benzenesulfonate salt Form B of the compound of formula (I);
  • Figure 51 shows a DVS diagram of the phosphate crystal form A of the compound of formula (I);
  • Figure 52 shows a DVS diagram of the maleate salt Form A of the compound of formula (I);
  • Figure 53 shows the DVS plot of the mesylate salt Form B of the compound of formula (I).
  • the compounds of the present application can be synthesized by a variety of methods familiar to those skilled in the art of organic synthesis. Exemplary synthetic methods for compounds of formula (I) are given in the following specific examples. Obviously, with reference to the exemplary schemes in this application, those skilled in the art can easily design other synthetic routes of compounds of formula (I) or synthetic routes of other compounds by appropriately adjusting reactants, reaction conditions and protecting groups.
  • crystalline or amorphous forms of the compounds of the present application can be obtained using purification, crystallization and/or drying methods familiar to those skilled in the art. Exemplary methods for the preparation of certain crystalline forms and amorphous forms are given in the following specific examples. Obviously, with reference to the exemplary schemes in this patent, those skilled in the art can easily design preparation methods for other crystal forms or amorphous materials by appropriately adjusting solvents, equipment and process conditions.
  • compound intermediate 1-1 to intermediate 1-15 are first synthesized, and then the compound of formula (I) is synthesized by using intermediate 1-15 as a starting material.
  • the chemical reagents, solvents and reaction equipment used in each chemical reaction in Example 1 are conventional raw materials and equipment in chemical synthesis, which can be easily obtained through commercial channels.
  • 5-Bromo-2-fluorophenol (200.0 mg, 1.05 mmol) and bis(tri-tert-butylphosphorus)palladium (10.7 mg, 0.02 mmol) were dissolved in 10 ml of THF. Nitrogen was replaced 3 times, the temperature was lowered to 10-20°C, 1 mol/L diethylzinc solution (2.3ml, 2.30mmol) was slowly added dropwise, the dropwise addition was completed, and the temperature was raised to 50°C. The reaction was overnight, cooled to 0°C, quenched by adding water, filtered with celite, washed with ethyl acetate, and extracted with ethyl acetate.
  • Oxalyl chloride (0.53g, 4.20mmol) was dissolved in dry 15ml dichloromethane, cooled to -78 degrees under nitrogen protection, DMSO (0.61g, 7.84mmol) was slowly added dropwise, and the reaction was completed for 30 minutes.
  • the purified product was dissolved in 25 ml of dichloromethane, and 5 ml of trifluoromethane was added dropwise. Acetic acid, stirred at room temperature for 30 minutes, concentrated, used dichloromethane three times with trifluoroacetic acid, concentrated, and purified by silica gel column to obtain a total of 210 mg of intermediate 1-16 with a yield of 39.2%.
  • the intermediate 1-17 (22.00g, 26.60mmol, 1.00eq) was added to a 1L three-necked flask, then DCM (330mL, 15V) was added to dissolve it, and then the temperature was lowered to -70°C to -6()°C, magnetic stirring, Replaced with N 2 three times, slowly added BCl 3 (133 mL, 132.99 mmol, 5.00 eq, 1N in DCM) dropwise, the dropwise addition was completed in about 15 min, and the internal temperature during the dropwise addition was kept not exceeding -55 ° C, after the dropwise addition, continued at - The reaction was stirred at 70°C to -60°C for 1 h.
  • the crude product was sent to Prep-HPLC for purification (normal phase, 0.1% aqueous ammonia alkaline system, ethanol system), and the obtained fraction was concentrated to 200 mL at 40° C. when a large amount of solid was precipitated, filtered to obtain 5.90 g of pale yellow solid powder, namely formula (I) compound.
  • step b) Transfer 2 ⁇ L of the kinase (prepared in step 2.2.1.2) to the 384 reaction plate, add 1 ⁇ L of the test compound (prepared in step a) to the 384 reaction plate (Greiner, 784075), 1000rpm/min, centrifuge for 1min, Incubate at 25°C for 10min.
  • RLU Relative luminescence unit
  • step b) Transfer 2 ⁇ L of the kinase (prepared in step 2.2.1.2) to the 384 reaction plate, add 1 ⁇ L of the test compound (prepared in step a) to the 384 reaction plate (Greiner, 784075), 1000rpm/min, centrifuge for 1min, Incubate at 25°C for 10min.
  • RLU Relative luminescence unit
  • Compound inhibition rate (%inh) (negative control-compound)/(negative control-positive control) ⁇ 100%
  • the IC50 (50% inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:
  • Min is the positive control 10uM/100uM/30uM Filgotinib RLU value
  • Max is the negative control DMSO RLU value
  • SD is the standard error
  • AVE is the RLU mean.
  • Example 1 The test results show that the inhibitory activity of the compound of formula (I) obtained in Example 1 is much higher than that of Filgotinib (more than two orders of magnitude higher), and can effectively inhibit JAK1, JAK2, JAK3, and TYK2 at very low concentrations.
  • the purpose of this example is to detect the activity of the compounds in the JAK cell activity assay-human T cell proliferation assay.
  • T cells were sorted from human PBMC according to the human total T cell sorting kit.
  • T cells were stimulated with anti-CD3 antibody and anti-CD28 antibody, and incubated for 72h in a 37°C, 5% CO 2 incubator.
  • T cells were collected and cells were washed with PBS.
  • T cells (prepared in step c) were seeded into a 384-well reaction plate (prepared in step d), 35 ⁇ L/well, centrifuged at 1000 rpm for 1 min, incubated at 37° C., 5% CO 2 .
  • Compound inhibition rate (%inh) (negative control-compound)/(negative control-positive control) ⁇ 100%
  • the IC50 (50% inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:
  • Example 1 The polymorphism of the compound of formula (I) in Example 1 (also sometimes referred to hereinafter as the "free base” because it is a basic compound) was investigated by different crystallization methods, by X-ray powder diffraction (XRPD). ), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), nuclear magnetic resonance spectroscopy (1H NMR) and other methods to characterize and identify the various crystal forms obtained, in order to provide a basis for the production and formulation of pharmaceutical preparations and in accordance with.
  • XRPD X-ray powder diffraction
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • 1H NMR nuclear magnetic resonance spectroscopy
  • XRPD patterns were acquired on a PANalytical X-ray powder diffraction analyzer with scan parameters shown in the table below.
  • TGA and DSC graphs were collected on a TA Discovery TGA 5500 Thermogravimetric Analyzer and a TA Q2000/Discovery DSC 2500 Differential Scanning Calorimeter, respectively, and the test parameters are listed in the table below.
  • Liquid NMR spectra were acquired on a Bruker 400M NMR instrument with DMSO-d6 as the solvent.
  • Example 1 5.00 g of the compound of formula (I) obtained in Example 1 was added to a three-necked flask, 100 mL of methanol was added, the temperature was raised to 50-55 °C and stirred, the system became viscous, 50 mL of methanol was added, and the stirring was continued for 5 h. After filtration, the filter cake was rinsed with 20 mL of methanol, and dried under vacuum at 45° C. for 8 h to finally obtain 3.7 g of a crystal of the compound of formula (I), which was named as crystal form A.
  • Form A In order to study the properties of Form A, heating experiments were carried out on Form A. After the crystal form A was heated to 190 °C and lowered to room temperature under nitrogen protection, the sample was taken out and exposed to the air for XRPD test. The test results are shown in Figure 3, which shows that the crystal form of the sample has not changed, and the relative intensities of some diffraction peaks can be observed. reduce. Combined with the results of TGA/NMR, the change of crystallinity after heating is presumed to be caused by the removal of water, and the crystal form A may be a hydrate.
  • Form A In order to further determine the properties of Form A, a variable temperature XRPD test was carried out on Form A, and the results are shown in Figure 4. It shows that under the condition of 30 °C, the crystal form of the sample does not change after purging with nitrogen for 20 minutes; after heating to 190 °C and dropping to 30 °C under nitrogen purging, an anhydrous crystal form D (which exists only under the protection of nitrogen) is obtained ( The shift of the diffraction peak positions at different temperatures may be related to the lattice expansion caused by high temperature). Based on the TGA/DSC/NMR results of the above crystal form A, it can be determined that the crystal form change of the crystal form A after heating to 190 °C is caused by the removal of water in the sample, and the crystal form A is a hydrate.
  • the crystal form A was suspended and stirred in EtOH at room temperature for three days, centrifuged, and the solid was vacuum-dried at room temperature for about two hours to obtain crystals, which were named as crystal form B.
  • Form B lost 6.0% weight when heated to 150°C, presumably from the removal of solvent or water in the sample; an endothermic signal was observed at 319.1°C (onset temperature), presumably from sample melting.
  • the variable temperature XRPD test was carried out on the crystal form B, and the results are shown in Fig. 7.
  • the crystal form of the sample of crystal form B did not change after purging under nitrogen for 20 minutes; when it was heated to 150 °C under nitrogen purging, the diffraction peak position of the sample was slightly shifted compared with that of crystal form B, which was presumed to be related to the lattice expansion at high temperature. After cooling to 30 °C, the diffraction peak position of the sample is consistent with that of crystal form B, and the shift of the diffraction peak disappears.
  • the TGA weight loss comes from the water or solvent residue on the surface of the sample, and the crystal form B is judged to be Crystal-free type.
  • the hydrate crystal form A was suspended and stirred at room temperature in an acetone/H 2 O (v/v, 19:1) system containing L-ascorbic acid for three days, centrifuged, and the solid was vacuum-dried at room temperature for about two hours. Crystal, named Form C.
  • the crystal form A was heated to 190°C and lowered to 30°C under nitrogen protection, and the XRPD result is shown in Fig. 11 .
  • the hydrate crystal form A was suspended and stirred in EtOH at 50°C for one day, centrifuged, and the solid was placed at room temperature.
  • Form E In order to study the properties of Form E, heating experiments were carried out on Form E. After the crystal form E was heated to 120° C. and lowered to room temperature under nitrogen protection, the sample was taken out and exposed to the air for XRPD test. The NMR results showed that the molar ratio of EtOH to compound (I) in the sample after heating was 0.65:1.00 (5.7 wt%).
  • variable temperature XRPD test was carried out on the crystal form E.
  • the results are shown in Figure 16: after the sample was purged under nitrogen for 20 minutes, the crystal form did not change; when heated to 120 °C under nitrogen purging, the sample had transformed into an anhydrous crystal form D that only existed under the protection of nitrogen (a few diffraction patterns). The peak position is shifted compared with the crystal form D, which may be related to the different degrees of lattice expansion at different temperatures.
  • the XRPD pattern of the reference crystal form D was measured at 30 °C); continue to heat to 210 °C, the sample has turned to no Set; after cooling to 30°C, the sample is still amorphous, and it is observed that the sample gels, and it is presumed that the sample has melted.
  • the difference between the two heating results is related to whether the sample is exposed to air after heating, that is, no crystal form D is exposed. After heating in the air, it can quickly absorb the water in the environment and convert it into crystal form E. It is speculated that water molecules participate in the lattice composition of crystal form E.
  • Crystal form F Seed crystals of hydrate crystal form A and anhydrous crystal form B were suspended and stirred in acetone at 50°C for one day, centrifuged, and the solids were left open to dry at room temperature overnight to obtain crystals, which were named as crystal form F.
  • Form F In order to investigate the properties of Form F and to investigate the possible sources of thermal signals in DSC, heating experiments were carried out on Form F. After the crystal form F was heated to 170 °C and lowered to room temperature under nitrogen protection, the sample was taken out and exposed to the air for XRPD testing. No significant acetone residue was observed in the samples. Based on the data before and after heating, the change of crystal form can be observed in XRPD. TGA/NMR shows that the component removed after heating is mainly acetone. The conversion of crystal form F to crystal form G after heating may be caused by the removal of acetone. , it is judged that Form F may be an acetone solvate.
  • crystal form G After the acetone solvate crystal form F was heated to 170°C under nitrogen protection and lowered to room temperature, the sample was taken out and exposed to air to obtain crystals, which were named as crystal form G.
  • the TGA/DSC results of crystal form G show that: crystal form G loses 4.7% weight when heated to 100°C, correspondingly a thermal signal can be observed at 81.2°C (initial temperature), presumably from the solvent or water in the sample The removal of ; two thermal signals were observed at 209.6, 314.0 °C (onset temperature).
  • the NMR results of the crystal form G show that no obvious acetone residue is observed in the sample, and the crystal form G may be a hydrate or an anhydrous crystal form.
  • Form G was further investigated by variable temperature XRPD (form F was used as the starting material).
  • the results show that: after purging crystal form F under nitrogen for 20 minutes, the crystal form does not change; when heated to 170 °C under nitrogen purging, it has transformed into an anhydrous crystal form J that exists only under nitrogen protection; After cooling to 30°C, the sample was opened and exposed to the air to test XRPD. The results showed that it had transformed into crystal form G. It is speculated that after exposure to air, crystal form J absorbed the moisture in the environment and transformed into crystal form G. Crystal form G is Hydrate.
  • Crystal form J By heating the acetone solvate crystal form F to 170°C and lowering to 30°C under nitrogen protection, crystals were obtained and named as crystal form J.
  • the XRPD results of Form J are shown in FIG. 23 .
  • crystal form H After the crystal form E was heated to 150°C under nitrogen protection and lowered to room temperature, the sample was taken out and exposed to the air to obtain crystals, which were named as crystal form H, and the XRPD results were shown in FIG. 25 .
  • the hydrate crystal form C was heated to 150° C. under nitrogen protection and cooled to room temperature by variable temperature XRPD to obtain crystals, which were named as crystal form I, and the XRPD results are shown in FIG. 26 .
  • Example 1 Take the compound of formula (I) obtained in Example 1 as starting material, select different acids to carry out salt formation research, and carry out crystallization under different conditions, study the polymorphism of each salt, and by X-ray powder diffraction ( Various crystal forms were characterized by XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), hydrogen nuclear magnetic resonance (1H NMR), high performance liquid chromatography/ion chromatography (HPLC/IC) and other methods and identification in order to provide the basis and basis for the production and formulation of pharmaceutical preparations.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • HPLC/IC high performance liquid chromatography/ion chromatography
  • the XRPD patterns were collected on a PANalytical X-ray powder diffraction analyzer, and the scan parameters are shown in Table 10.
  • TGA and DSC graphs were collected on a TA Q5000/Discovery TGA 5500 Thermogravimetric Analyzer and a TA Discovery DSC 2500 Differential Scanning Calorimeter, respectively, and the test parameters are listed in Table 11.
  • Dynamic moisture sorption (DVS) curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg( NO3 )2 and KCl. DVS test parameters are listed in Table 12.
  • Liquid NMR spectra were collected on a Bruker 400M NMR instrument with DMSO-d6 as the NMR solvent.
  • the purity and solubility of the samples were collected by high performance liquid chromatography, and the molar ratio of the salt sample of the inorganic acid system was collected by high performance liquid chromatography and ion chromatography.
  • the high performance liquid chromatography was tested on an Agilent 1290 HPL, and the ion chromatography was collected on a Thermo ICS1100.
  • the specific instruments and test parameters are shown in Table 13 and Table 14.
  • the TGA/DSC data of phosphate crystal form A is shown in Figure 28: the weight loss of the sample when heated to 190 °C is 1.8%, which is presumed to be from the removal of water or solvent in the sample, which can be observed at 279.3 °C (onset temperature). A sharp endothermic peak, presumably from sample melting. Based on a small amount of weight loss before melting of the sample in TGA and only a single melting endothermic peak in DSC, it is judged that the phosphate crystal form A may be an anhydrous form.
  • the HPLC/IC results showed that the molar ratio of the compound of formula (I) to phosphate in the sample was 1:1.
  • the TGA/DSC of maleate Form A is shown in Figure 30.
  • the results show that the sample loses 3.3% weight when heated to 150°C, and two thermal signals can be observed at 211.2 and 278.1°C (onset temperature).
  • the NMR results of the mesylate crystal form B show that the molar ratio of the compound of formula (I) to methanesulfonic acid in the sample is 1:1.
  • the TGA/DSC data of the mesylate crystal form B is shown in Figure 32.
  • the weight loss of the sample when heated to 190 °C is 2.2%, presumably from the removal of water or solvent in the sample, at 234.4 °C (peak temperature) and 264.1 °C Two endothermic signals were observed at (onset temperature). Based on the small and slow weight loss before sample decomposition in TGA and the smoother curve before 190°C in DSC, it is speculated that the mesylate crystal form B is an anhydrous form.
  • the hydrochloride is prepared by using the compound hydrate crystal form A of the formula (I) as a raw material, and the specific preparation steps are as follows: Suspend and stir the compound hydrate crystal form A of the formula (I) and hydrochloric acid in EtOAc at room temperature according to a molar ratio of 1:1 for about 3 minutes. A day later, centrifugation was performed, and the solid was transferred to room temperature and vacuum-dried for 2 hours to obtain the hydrochloride salt form A.
  • the TGA/DSC of the hydrochloride form A is shown in Figure 34.
  • the results show that the sample loses 13.7% weight when heated to 240°C, and three endotherms are observed at 80.1, 118.0°C (peak temperature) and 224.5°C (onset temperature). peak, an exothermic signal was observed at 231.5°C (onset temperature).
  • the HPLC/IC results showed that the molar ratio of the compound of formula (I) to chloride ion in the hydrochloride crystal form A was 1:0.7 (it is speculated that the salt formation of the sample may be insufficient).
  • formula (I) compound hydrate crystal form A as raw material to prepare tartrate, the specific preparation steps are as follows: the formula (I) compound hydrate crystal form A and tartaric acid are suspended and stirred at room temperature in EtOAc according to a molar ratio of 1:1 for about 3 days. , centrifuged, and the solid was transferred to room temperature and vacuum-dried for 2 hours to obtain tartrate crystal form A.
  • the TGA/DSC of tartaric acid form A is shown in Figure 36, the results show that the sample loses 9.1% weight when heated to 200°C, and two thermal signals can be observed at 125.2 and 168.8°C (onset temperature).
  • the results of 1 H NMR showed that the molar ratio of the compound of formula (I) to tartaric acid in the tartrate salt form A was 1:1 (the 5 Hs overlapping with the compound of formula (I) had been deducted).
  • the fumarate is prepared by using the compound hydrate crystal form A of the formula (I) as a raw material, and the specific preparation steps are as follows: mix the compound hydrate crystal form A of the formula (I) and fumaric acid in Acetone/H 2 in a molar ratio of 1:1 After suspension and stirring at room temperature in O (19:1, v/v) for about 3 days, centrifugation, the solid was transferred to room temperature and vacuum-dried for 2 hours to obtain fumarate crystal form A.
  • the TGA/DSC of fumaric acid form A is shown in Figure 38.
  • the results show that the sample loses 7.5% weight when heated to 110°C, and loses 8.0% when heated to 250°C. Multiple heat signatures can be observed.
  • the results of 1 H NMR showed that the molar ratio of the compound of formula (I) to fumaric acid in the fumarate crystal form A was 1:0.6.
  • the specific preparation steps are as follows: the compound hydrate crystal form A of the formula (I) and the mucic acid are mixed in Acetone/H 2 O( 19:1, v/v), suspended and stirred at room temperature for about 3 days, centrifuged, and the solid was transferred to room temperature and vacuum-dried for 2 hours to obtain mucic acid salt crystal form A.
  • Figure 39 shows the XRPD results of mucic acid salt form A, and the specific data are as follows:
  • the TGA/DSC of mucic acid salt form A is shown in Figure 40.
  • the results show that the sample loses 4.4% in weight when heated to 100 °C, and loses 26.4% in weight when heated to 260 °C. At 69.8 and 210.4 °C (starting temperature) two can be observed. heat signal.
  • the results of 1 H NMR showed that the molar ratio of the compound of formula (I) to the mucic acid in the mucic acid salt crystal form A was 1:1.4.
  • the citrate salt is prepared by using the compound hydrate crystal form A of formula (I) as a raw material, and the specific preparation steps are as follows: the compound hydrate crystal form A of formula (I) and citric acid are respectively mixed in EtOAc, Acetone/H according to a molar ratio of 1:1. After suspension and stirring at room temperature in 2 O (19:1, v/v) for about 3 days, centrifugation, the solid was transferred to room temperature and vacuum-dried for 2 hours to obtain citrate crystal form A/B.
  • the TGA/DSC of citrate form A is shown in Figure 42.
  • the results show that the sample loses 9.1% weight when heated to 150°C.
  • Three endotherms are observed at 68.2°C (peak temperature), 154.4 and 164.0°C (onset temperature). peak.
  • the results of 1 H NMR showed that the molar ratio of the compound of formula (I) to citric acid in the citrate crystal form A was 1:0.5.
  • the TGA/DSC of citrate crystal form B is shown in Figure 44.
  • the results show that the sample loses 7.1% weight when heated to 100°C, and loses 6.8% when heated to 250°C; Four endothermic peaks were observed at the peak temperature).
  • 1 H NMR results showed that the molar ratio of the compound of formula (I) to citric acid in the citrate crystal form B was 1:0.5.
  • the specific preparation steps are: the compound hydrate crystal form A of the formula (I) and p-toluenesulfonic acid in a molar ratio of 1:1 in Acetone/ After suspension and stirring at room temperature in H 2 O (19:1, v/v) for about 3 days, centrifugation, the solid was transferred to room temperature and vacuum-dried for 2 hours to obtain p-toluenesulfonate crystal form A.
  • the TGA/DSC of p-toluenesulfonic acid form A is shown in Figure 46, the results show that the sample loses 5.1% weight when heated to 150°C, and two thermal signals can be observed at 121.2 and 222.3°C (onset temperature).
  • the results of 1 H NMR showed that the molar ratio of the compound of formula (I) to p-toluenesulfonic acid in the crystal form A of p-toluenesulfonic acid salt was 1:1.
  • the specific preparation steps are as follows: the compound hydrate crystal form A of the formula (I) and benzenesulfonic acid are respectively prepared in EtOH and Acetone according to a molar ratio of 1:1. /H 2 O (v/v, 19:1) was suspended and stirred at room temperature for about 3 days, centrifuged, and the solid was transferred to room temperature and vacuum-dried for 2 hours to obtain benzenesulfonate crystal form A/B.
  • the TGA/DSC of the benzenesulfonic acid crystal form A is shown in Figure 48.
  • the results show that the sample loses 9.0% in weight when heated to 150°C, and multiple thermal signals can be observed at 60-200°C.
  • the results of 1 H NMR showed that the molar ratio of the compound of formula (I) to benzenesulfonic acid in the benzenesulfonic acid crystal form A was 1:1.
  • the TGA/DSC of benzenesulfonic acid crystal form B is shown in Figure 50.
  • the results show that the sample loses 4.6% weight when heated to 100°C, and two thermal signals can be observed at 90.1°C (peak temperature) and 236.7°C (onset temperature).
  • 1 H NMR results showed that the molar ratio of the compound of formula (I) to benzenesulfonic acid in the benzenesulfonic acid crystal form B was 1:0.5.
  • the phosphate crystal form A horse phosphate crystal form A with higher XRPD diffraction peak intensity (sharp peak shape), smaller TGA weight loss, higher DSC melting temperature and higher ligand acid safety grade were selected.
  • Form A of acetic acid salt and crystalline form B of mesylate salt were further studied and evaluated.
  • Table 30 Summary of the solubility of the three salt forms at 25°C in different media 2
  • Relative purity is the ratio of the purity of the stability sample to the purity of the starting sample.
  • the DVS results of the three samples showed that the weight gain was 0.6-1.3%, the samples were slightly hygroscopic, and the crystal forms did not change after the DVS test. To sum up, the three batches of salt forms have good properties in terms of hygroscopicity and solid stability.
  • a drug screening system based on JAK1, JAK2, JAK3, and TYK2 kinases was used to detect the inhibitory ability of small molecule compounds on the kinase activity, respectively.
  • the kinase and its substrates IRS1, IGF1Rtide, Poly (4:1Glu, Tyr) undergo enzymatic reaction, consume ATP to produce ADP, and use ADP-Glo reagent and luminescence to detect the amount of the product to reflect the activity of the kinase.
  • step b) Transfer 2 ⁇ L of the kinase (prepared in step 2.2.1.2) to the 384 reaction plate, add 1 ⁇ L of the test compound (prepared in step a) to the 384 reaction plate (Greiner, 784075), 1000rpm/min, centrifuge for 1min, Incubate at 25°C for 10min.
  • c) Transfer 1 ⁇ L of the substrate mixture (prepared in step 2.2.1.3) to a 384 reaction plate, centrifuge at 1000 rpm/min for 1 min, and incubate at 25°C for 60 min.
  • the final concentrations of Tofacitinib and the test compound were 1000, 250, 62.5, 15.625, 3.906, 0.977, 0.244, 0.061, 0.015, 0.0038, nM.
  • the final concentration of DMSO was 0.5%.
  • the luminescence signal was read using a Biotek multi-plate reader. Signal intensity is used to characterize the degree of kinase activity.
  • Compound inhibition rate (%inh) (negative control-compound)/(negative control-positive control) ⁇ 100%
  • the IC50 (50% inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:
  • Min is the positive control 10uM/100uM/30uM Filgotinib RLU value
  • Max is the negative control DMSO RLU value
  • SD is the standard error
  • AVE is the RLU mean.
  • the mesylate salt of the compound of formula (I) also has JAK inhibitory activity, and its inhibitory activity is much higher than that of Tofacitinib (the inhibition of JAK1 and TYK2 is more than one to one order of magnitude higher. ), can effectively inhibit JAK1, JAK2, JAK3, TYK2 at very low concentrations.

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Abstract

本申请涉及一种JAK抑制剂化合物及其用途。具体地，本申请公开了固体形式的式(I)化合物、或其同位素标记化合物、光学异构体、几何异构体、互变异构体或异构体混合物、其药学上可接受的盐、或其溶剂化物。本申请还涉及固体形式的所述化合物在医学方面的应用。

Description

JAK抑制剂化合物及其用途
本申请要求2020年8月14日递交的中国发明专利申请202010818212.6的优先权，该在先申请的全部公开内容通过引用并入本申请。
技术领域
本申请提供了一种具有药学活性的新颖化合物，所述化合物可用于抑制Janus激酶(JAK)。本申请还涉及包含所述化合物的组合物，以及所述化合物和所述组合物在医药领域的用途。
背景技术
蛋白质激酶是催化蛋白质中特定残基磷酸化的酶家族，并广义地分类为酪氨酸和丝氨酸/苏氨酸激酶。由于突变、过度表达或不适当调节、调节异常或失调，以及生长因子或细胞因子的过度产生或产生不足所导致的不适当的激酶活性涉及许多疾病，其包括但不限于癌症、心血管疾病、变态反应、哮喘和其它呼吸疾病、自身免疫病、炎症疾病、骨病、代谢紊乱及神经病症和神经变性病症(例如阿尔茨海默病)。不适当的激酶活性触发多种生物细胞反应，所述生物细胞反应与涉及上述和相关疾病的细胞生长、细胞分化、细胞功能、存活、凋亡和细胞运动性有关。因此，蛋白质激酶已成为一类重要的作为治疗性介入的靶点的酶。特别地，细胞蛋白质酪氨酸激酶的JAK家族在细胞因子信号转导中扮演重要的角色(Kisseleva等人，Gene，2002，285，1；Yamaoka等人，Genome Biology 2004，5，253)。
从20世纪90年代初首个JAK被发现以来，JAK抑制剂的开发走过了近30年的历程。JAK是一类胞内非受体酪氨酸激酶家族，其通过与信号转导子和转录激活子(signal transducer and activator of transcription； STAT)之间的相互作用在细胞因子受体信号通路中发挥着重要作用。JAK/STAT信号通路参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程。与其它信号通路相比，这条信号通路的传递过程相对简单，它主要由三个成分组成，即酪氨酸激酶相关受体(tyrosine kinase associated receptor)、酪氨酸激酶JAK和信号转导子和转录激活子STAT。
许多细胞因子和生长因子通过JAK-STAT信号通路来传导信号，这包括白介素类(如IL-2～7，IL-9，IL-10，IL-15，IL-21等)、GM-CSF(粒细胞/巨噬细胞集落刺激因子)、GH(生长激素)、EGF(表皮生长因子)、PRL(催乳素)、EPO(促红细胞生成素)、TPO(促血小板生成素)、PDGF(血小板衍生因子)以及干扰素类(包括IFN-α，IFN-β，IFN-γ等)等等。这些细胞因子和生长因子在细胞膜上有相应的受体。这些受体的共同特点是受体本身不具有激酶活性，但胞内段具有酪氨酸激酶JAK的结合位点。受体与配体结合后，通过与之相结合的JAK的活化，来磷酸化各种靶蛋白的酪氨酸残基以实现信号从胞外到胞内的转递。
JAK是转导细胞因子信号从膜受体到STAT转录因子的细胞质酪氨酸激酶。如上所述，JAK是英文Janus kinase的缩写，Janus在罗马神话中是掌管开始和终结的两面神。之所以称为两面神激酶，是因为JAK既能磷酸化与其相结合的细胞因子受体，又能磷酸化多个含特定SH2结构域的信号分子。JAK蛋白家族共包括4个成员：JAK1、JAK2、JAK3以及TYK2，它们在结构上有7个JAK同源结构域(JAK homology domain，JH)，其中JH1结构域为激酶区，功能是编码激酶蛋白；JH2结构域是“假”激酶区，对JH1的活性起调节作用；JH3-JH7组成一个四合一结构域，调节JAK与受体的结合。
STAT是一类能与靶基因调控区DNA结合的胞质蛋白，是JAK的下游底物。目前已发现STAT家族的7个成员，即STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B及STAT6。STAT蛋白在结构上可分为以下几个功能区段：N-端保守序列、DNA结合区、SH3结构域、SH2结构域 及C-端的转录激活区。其中，序列上最保守和功能上最重要的区段是SH2结构域，它具有与酪氨酸激酶Src的SH2结构域完全相同的核心序列“GTFLLRFSS”。
JAK-STAT信号通路功能广泛，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程，目前与疾病及药物创新相关的研究大都集中于炎症性疾病及肿瘤性疾病。其中，炎症性疾病主要包括类风湿性关节炎、犬皮炎、银屑病、溃疡性结肠炎及克罗恩病；而肿瘤性疾病则主要涉及骨髓纤维化、真性红细胞增多症及原发性血小板增多症。另外，JAK分子自身的突变也会导致急性骨髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、乳腺导管癌及非小细胞肺癌(NSCLC)、真性红细胞增多症(PV)、特发性血小板增多症(ET)、特发性骨髓纤维化(IMF)、慢性粒细胞白血病(CML)等。此外，据报道JAK-STAT信号通路与新冠肺炎(Covid-19)中的细胞因子风暴密切相关。
JAK是一类非常重要的药物靶点，针对这一靶点而研发的JAK抑制剂主要用于筛选血液系统疾病、肿瘤、类风湿性关节炎及银屑病等治疗药物。JAK-1、JAK-2和TYK-2在人体各组织细胞中均有表达，JAK-3主要表达于各造血组织细胞中，主要存在于骨髓细胞、胸腺细胞、NK细胞及活化的B淋巴细胞、T淋巴细胞中。研究表明：JAK2抑制剂适用于骨髓增殖性疾病(Santos等人，Blood，2010，115：1131；Barosi G.和Rosti V.，Curr.Opin.Hematol.，2009，16：129；Atallah E.和Versotvsek S.，2009 Exp.Rev.Anticancer Ther.9：663)，JAK3的抑制剂适用作免疫抑制剂(例如美国专利6,313,129；Borie等人，Curr.Opin.Investigational Drugs，2003，4：1297)。另外，JAK抑制剂被认为有望在新冠肺炎等重症肺炎的治疗中用于抑制炎症反应、降低细胞因子风暴风险从而降低死亡率(Wei Luo等人，Trends in Pharmacological Science，41(8)·June 2020，“Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19”)。还有文献报道了JAK抑制剂对于瘙痒症的治疗有一定疗效(Landon K.Oetjen等人，Cell，171，P217-228，September 21，2017，“Sensory Neurons Co- opt Classical Immune Signaling Pathways to Mediate Chronic Itch”)。
目前，获得FDA、EMA批准的JAK抑制剂有Tofacitinib(托法替尼)、Ruxolitinib(鲁索利替尼)、Oclacitinib(奥拉替尼)等。处于临床中后期的JAK抑制剂有例如Filgotinib、Peficitinib等。
托法替尼，JAK3抑制剂，由辉瑞公司研发，于2012年11月获FDA批准上市，用于治疗成人患者的对甲氨喋呤应答不充分或不耐受的中度至重度类风湿性关节炎。系首个获批用于RA治疗的口服JAK抑制剂。之后于2013年3月获得日本PMDA批准上市，商品名为Xeljanz。2017年3月16日，辉瑞中国宣布，CFDA已正式批准辉瑞公司的口服JAK抑制剂的上市申请。据悉，该药物被批准用于对甲氨蝶呤疗效不足或对其无法耐受的中度至重度类风湿关节炎成年患者的治疗。目前，托法替尼用于银屑病、溃疡性结肠炎、青少年特发性关节炎等适应症已接近获批；治疗克罗恩病、斑秃等适应症的临床试验也已经进入临床中后期。托法替尼的主要副作用有严重感染率和低密度脂蛋白水平提高，最常见的不良反应为上呼吸道感染、头痛、腹泻、鼻充血、咽喉痛和鼻咽炎。此外，有临床研究报道，托法替尼可引起贫血和中性粒细胞减少症等副作用。
Figure PCTCN2021112352-appb-000001
Filgotinib，JAK1抑制剂，已于2018年9月完成三期临床试验，用于治疗风湿性关节炎。同时，Filgotinib用于治疗溃疡性结肠炎和克罗恩病的研究目前正处于临床二/三期试验中。Filgotinib是一种选择性JAK1抑制剂，其对JAK1、JAK2、JAK3和TYK2的IC50据报道分别约为10nM、28nM、810nM和116nM。
Figure PCTCN2021112352-appb-000002
虽然目前已有一些JAK抑制剂获批准上市，还有一些JAK抑制剂处于临床研究阶段，但这些JAK抑制剂在疗效或安全性方面并不尽如人意。因此，始终存在对疗效更好和/或副作用更少的JAK抑制剂的需求。
发明内容
本申请的一个目的是提供一类替代现有JAK抑制剂的新型JAK抑制剂，从而为JAK相关疾病的治疗提供更多的选择。
本申请的进一步目的是提供一类比现有JAK抑制剂功效更好和/或安全性更佳的新型JAK抑制剂。
本申请的更进一步目的是提供更适宜药剂配制的新型JAK抑制剂的不同固体形式。
在第一个方面，本申请提供了一种固体形式的化合物，所述化合物是式(I)化合物
Figure PCTCN2021112352-appb-000003
、式(I)化合物的同位素标记化合物、式(I)化合物的光学异构体、式(I)化合物的几何异构体、式(I)化合物的互变异构体、式(I)化合物的异构体混合物、式(I)化合物的药学上可接受的盐、或这些化合物中任意一种的溶剂化物。优选地，所述化合物的固体形式是晶体。
在第二个方面，本申请提供了一种药物组合物，其含有本申请第一方面所述的固体形式的化合物和一种或多种药学上可接受的载体、佐剂或赋形剂。例如，所述药物组合物可以是分散液形式或溶液形式。
在第三个方面，本申请提供了本申请第一方面所述的固体形式的化合物或本申请第二方面所述的药物组合物在制备用于治疗和/或预防与JAK相关的疾病或病症的药物中的用途。
在第四个方面，本申请提供了一种治疗与JAK相关的疾病或病症的方法，所述方法包括将治疗有效量的本申请第一方面所述的固体形式的化合物或本申请第二方面所述的药物组合物给予有需要的患者。其中，所述患者优选是哺乳动物，更优选是人类患者。其中给药途径可以是口服、外用、胃肠外施予、支气管施予或鼻施予等。其中，优选地通过口服施予。
本申请提供了一种新型抑制JAK的化合物，从而为JAK相关疾病的预防或治疗提供了更多的选择。另外，本申请提供了该化合物的多种固体形式，包括多种晶型和无定形物，这些不同的固体形式具有不同的化学性质和物理性质、在体内的代谢性能也不相同，因此为药物的生产、存贮和不同药物剂型的选择提供了更多的自由度，从而可以提供生物利用率更高和/或药效更好的新型药物剂型。
具体实施方式
下面具体描述本申请技术方案的实施方式。在这些具体描述之中，使用了一些技术术语。在本申请中，除非特别指明，所有的术语具有本领域技术人员所通常理解的含义。
本申请的第一方面涉及化合物的固体形式，所述化合物是式(I)化合物
Figure PCTCN2021112352-appb-000004
、式(I)化合物的同位素标记化合物、式(I)化合物的光学异构体、式(I)化合物的几何异构体、式(I)化合物的互变异构体、式(I)化合物的异构体混合物、式(I)化合物的药学上可接受的盐、或这些化合物中任意一种的溶剂化物。
式(I)化合物可以命名为(S)-(2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-4，6-二氢吡咯并[3，4-d]咪唑-5-(1H)-基)(3-羟基吡咯烷-1-基)甲酮。
为了简明起见，本文所使用的术语“本申请的化合物”涵盖了式(I)化合物、式(I)化合物的同位素标记化合物、式(I)化合物的光学异构体、式(I)化合物的几何异构体、式(I)化合物的互变异构体、式(I)化合物的异构体混合物、或这些化合物中任意一种的溶剂化物。
术语“光学异构体”意指，当化合物具有一个或更多个手性中心时，每个手性中心可以存在R构型或S构型，由此构成的各种异构体为光学异构体。光学异构体包括所有的非对映异构体、对映异构体、内消旋体、外消旋体或其混合物形式。例如，通过手性色谱柱或通过手性合成可以分离光学异构体。
术语“几何异构体”意指，当化合物中存在双键时，该化合物可以存在顺式异构体、反式异构体、E型异构体和Z型异构体。几何异构体包括顺式异构体、反式异构体、E型异构体、Z型异构体或其混合物形式。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的异构体。本领域技术人员可以理解：互变异构体之间可以互相转变， 在在某一状态下可能会达到一种平衡状态而共存。本文所述“式(I)所示的化合物”也涵盖式(I)化合物的任意互变异构体。
除非另有指明，本文提到“式(I)所示的化合物”或“式(I)化合物”或“本申请的化合物”时也涵盖该化合物中任一个原子被其同位素原子代替而得到的同位素标记化合物。
术语“同位素标记化合物”是指化合物中一个或者多个原子被具有与通常在自然界中所发现的原子相同原子序数但是不同原子质量或者质量数的原子所替换。
适用于包含在本申请的化合物中的同位素的实例包括氢的同位素，诸如 2H(D)和 3H(T)，碳的同位素，诸如 11C、 13C和 14C，氯的同位素，诸如 36Cl，氟的同位素，诸如 18F，碘的同位素，诸如 123I和 125I，氮的同位素，诸如 13N和 15N，氧的同位素，诸如 15O、 17O和 18O，以及硫的同位素，诸如 35S。
式(I)化合物的某些同位素标记化合物(例如包含放射性同位素的那些)可用于药物和/或底物组织分布研究。考虑到引入的容易性和检测手段的方便性，放射性同位素氘(即 2H)和碳-14(即 14C)对于该目的是特别有用的。
利用诸如氘(即 2H)的较重同位素进行取代可以提供某些治疗方面的好处并且因此在某些情况下可能是优选的，所述治疗方面的好处是由更大的代谢作用稳定性(例如，增长的体内半衰期或者减小的剂量要求)带来的。
利用正电子放射同位素(诸如 11C、 18F、 15O和 13N)进行取代可以用于正电子放射受体图像(Positron Emission Topography(PET))研究，用于检测底物受体占用状态。
式(I)化合物的同位素标记化合物一般可以通过本领域技术人员已知的常规技术或者通过使用合适的同位素标记试剂代替先前使用的非标记试剂以类似于在本文所附的实例和制备中所描述的方法，来进行制备。
本申请的化合物可以是式(I)化合物的药学上可接受的盐，具体是式(I)化合物的酸加成盐。适当的酸加成盐是由形成无毒性盐的酸所形 成的。其实例包括但不限于：粘酸盐、马尿酸盐、抗坏血酸盐、琥珀酸盐、萘-2-磺酸盐、乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。关于合适的盐的综述，可以参见Handbook of Pharmaceutical Salts：Properties，Selection and Use by Stahl and Wermuth(Wiley-VCH，2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
特别优选的式(I)化合物的药学上可接受的盐是其盐酸盐、磷酸盐、马来酸盐、L-酒石酸盐、富马酸盐、粘酸盐、柠檬酸盐、对甲苯磺酸盐、甲磺酸盐、苯磺酸盐。最优选的式(I)化合物的药学上可接受的盐是其磷酸盐、马来酸盐、甲磺酸盐。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予哺乳动物(优选人)。优选地，该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物(优选人)。
本文所使用的术语“式(I)化合物的药学上可接受的盐”用于表示任意形式的式(I)化合物的药学上可接受的盐，即涵盖了式(I)化合物、式(I)化合物的同位素标记化合物、式(I)化合物的光学异构体、式(I)化合物的几何异构体、式(I)化合物的互变异构体、式(I)化合物的异构体混合物中任意一种的药学上可接受的盐。
本申请的某些化合物可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在。在本申请中，“式(I)化合物”、“式(I)化合物的同位素标记化合物”、“式(I)化合物的光学异构体”、“式(I)化 合物的几何异构体”、“式(I)化合物的互变异构体”、“式(I)化合物的异构体混合物”、“式(I)化合物的药学上可接受的盐”等术语均涵盖其溶剂化物。
在本申请中，“化合物的固体形式”与“固体形式的化合物”被理解为具有相同的含义并因此可以互换使用，表示化合物主要以固体形式存在。本领域技术人员可以理解，固体形式的化合物的存在形式可以为晶体(晶型)、无定形物(非晶体)、或者两者的混合物。
术语“晶型”或“晶体形式”是指作为晶体的固体形式，例如可以通过X射线衍射测定。在某些实施方案中，物质的晶型可基本上不含非晶形和/或其它晶型。在某些实施方案中，物质的晶型可含有小于约1％、小于约2％、小于约3％、小于约4％、小于约5％、小于约6％、小于约7％、小于约8％、小于约9％、小于约10％重量的一种或多种非晶形和/或其它晶型。在某些实施方案中，在某些实施方案中，物质的晶型可为约99％、约98％、约97％、约96％、约95％、约94％、约93％、约92％、约91％或约90％纯的。
术语“非晶形体”或“非晶形式”或“无定形物”(有些现有技术文献称之为“无定型物”)意指基本上不是晶体的固体形式，例如可以通过X射线衍射测定。具体地说，术语“非晶形体”或“非晶形式”或“无定形物”描述无序的固体形式，即固体形式缺乏长程有序性。在某些实施方案中，物质的非晶形式可基本上不含其它非晶形和/或晶型。在某些实施方案中，物质的非晶形式可含有以重量计小于约1％、小于约2％、小于约3％、小于约4％、小于约5％、小于约6％、小于约7％、小于约8％、小于约9％、小于约10％重量的一种或多种其它的非晶形和/或晶型。在某些实施方案中，物质的非晶形式可为约99％、约98％、约97％、约96％、约95％、约94％、约93％、约92％、约91％或约90％纯的。
本申请的化合物存在多晶型现象。术语“多晶型”是指具有相同分子结构、但由于分子晶格中的排列或构象不同而形成的不同晶体。本领域公知，分子结构相同但晶形不同的化合物晶体，有可能具有不同的生 物利用度、溶解度、溶解速率、化学物理稳定性、熔点、颜色、可滤性、吸湿性、密度等化学物理性质。
在本申请的优选实施方案中，所述固体形式是本申请实施例部分所制备的式(I)化合物的晶体或式(I)化合物的盐的晶体。例如，在本申请的一些优选实施方案中，所述固体形式式(I)化合物的磷酸盐晶型A、式(I)化合物的马来酸盐晶型A、式(I)化合物的甲磺酸盐晶型B、式(I)化合物水合物的晶型A、式(I)化合物的晶型B等。
在本申请的优选实施方案中，所述固体形式是本申请实施例部分所制备的式(I)化合物的晶体或式(I)化合物的盐的晶体，所述晶体(或晶型)的粉末X-射线衍射图谱优选地具有与本申请实施例部分所测定的对应XRPD谱中衍射角(2θ)位置相同的一个或多个特征峰。所述“一个或多个特征峰”是指至少1个、至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个、至少11个、至少12个、至少13个、至少14个、至少15个、至少16个、至少17个、至少18个、至少19个或至少20个特征峰。这里“特征峰”被理解为XRPD谱中相对强度最大的1个或多个峰。本领域技术人员理解，由于样品纯度和测试条件的差异，不同条件下测得的XRPD峰位置可能有一定的偏离，因此这里“位置相同”被理解为相对于本申请实施例中给出的对应的衍射角(2θ)位置可以有±0.50°、±0.40°、±0.30°、±0.20°、优选±0.10°的差异。最优选地，所述晶体(或晶型)的粉末X-射线衍射图谱与本申请实施例部分所测定的对应XRPD图谱基本相同。所述“XRPD图谱基本相同”是指：两个XRPD图谱完全相同，或者虽然有所差异，但是本领域技术人员可以确认所述差异是非实质性的、是由不同的样品纯度、测定条件、仪器误差或操作习惯导致的，并由此可以确认两个XRPD图谱是由同样的晶体获得的。
在本申请的优选实施方案中，所述固体形式是本申请实施例部分所制备的式(I)化合物的晶体或式(I)化合物的盐的晶体，所述晶体(或晶型)的TGA或DSC曲线优选地具有与本申请实施例部分所测定的对应TGA或DSC曲线位置相同的至少1个、至少2个、至少3个、或 至少4个特征峰。这里“特征峰”被理解为TGA/DSC曲线中的吸热峰或放热峰。本领域技术人员理解，由于样品纯度和测试条件的差异，不同条件下测得的TGA/DSC曲线中表示峰位置的温度读数可能有一定的偏离，因此这里“位置相同”被理解为相对于本申请实施例中给出的对应的TGA和/或DSC曲线，峰位置的温度可以有±5℃、±4℃、±3℃、±2℃、±1℃的差异。最优选地，所述晶体(或晶型)的TGA/DSC曲线与本申请实施例部分所测定的对应TGA/DSC曲线基本相同。所述“TGA/DSC曲线基本相同”是指：两个TGA曲线和/或DSC曲线完全相同，或者虽然有所差异，但是本领域技术人员可以确认所述差异是非实质性的、是由不同的样品纯度、测定条件、仪器误差或操作习惯导致的，并由此可以确认两个TGA曲线和/或DSC曲线是由同样的晶体获得的。
本申请的一个优选实施方案涉及式(I)化合物水合物的晶型A，其粉末X-射线衍射图谱(XRPD)具有选自8.67±0.10°、13.39±0.10°、15.05±0.10°、17.38±0.10°、21.24±0.10°、22.86±0.10°、24.89±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自8.67±0.10°、11.53±0.10°、13.39±0.10°、15.05±0.10°、17.38±0.10°、21.24±0.10°、21.63±0.10°、22.19±0.10°、22.86±0.10°、23.43±0.10°、24.89±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物水合物的晶型A的TGA/DSC曲线在约50-290℃范围内存在多个热信号。
本申请的一个优选实施方案涉及式(I)化合物的晶型B，其粉末X-射线衍射图谱(XRPD)具有选自7.70±0.10°、11.20±0.10°、12.46±0.10°、15.44±0.10°、18.17±0.10°、18.48±0.10°、19.27±0.10°、21.84±0.10°、22.94±0.10°、24.29±0.10°、25.40±0.10°、27.92±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自7.70±0.10°、11.20±0.10°、12.46±0.10°、15.44±0.10°、18.17±0.10°、18.48±0.10°、18.93±0.10°、19.27±0.10°、19.50±0.10°、20.83±0.10°、21.84±0.10°、22.94±0.10°、23.22±0.10°、24.29±0.10°、25.40±0.10°、26.74±0.10°、27.92±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的晶型B的TGA/DSC曲线在约319.1℃(起始温度)处存在吸热峰。
本申请的一个优选实施方案涉及式(I)化合物水合物的晶型C，其粉末X-射线衍射图谱(XRPD)具有选自4.96±0.10°、7.66±0.10°、10.18±0.10°、11.07±0.10°、14.73±0.10°、22.87±0.10°衍衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.96±0.10°、7.66±0.10°、10.18±0.10°、11.07±0.10°、12.43±0.10°、14.73±0.10°、16.10±0.10°、19.24±0.10°、22.87±0.10°、23.52±0.10°、24.27±0.10°、25.09±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物水合物的晶型C的TGA/DSC曲线在约78.1℃(起始温度)处存在一个热信号，在约279.4(起始温度)处和303.8℃(起始温度)处存在热信号。
本申请的一个优选实施方案涉及式(I)化合物水合物的晶型G，其粉末X-射线衍射图谱(XRPD)具有选自6.42±0.10°、7.04±0.10°、7.69±0.10°、12.52±0.10°、15.81±0.10°、18.83±0.10°、22.85±0.10°、23.40±0.10°、衍射角(2θ)处的一个或多个特征峰，优选地具有选自6.42±0.10°、7.04±0.10°、7.69±0.10°、11.48±0.10°、12.52±0.10°、15.81±0.10°、18.83±0.10°、19.58±0.10°、22.85±0.10°、23.40±0.10°、25.31±0.10°、27.85±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物水合物的晶型G的TGA/DSC曲线在约81.2℃(起始温度)处存在一个热信号，在约209.6℃(起始温度)处、约314.0℃(起始温度)处存在两个热信号。
本申请的一个优选实施方案涉及式(I)化合物的磷酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自5.29±0.10°、7.47±0.10°、10.61±0.10°、19.16±0.10°和21.32±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自5.29±0.10°、7.47±0.10°、10.61±0.10°、15.94±0.10°、16.77±0.10°、18.68±0.10°、19.16±0.10°、21.32±0.10°及25.36±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的磷酸盐晶型A的TGA/DSC曲线在 约279.3℃(起始温度)处有尖锐吸热峰数。
本申请的一个优选实施方案涉及式(I)化合物的马来酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自4.55±0.10°、8.78±0.10°、12.69±0.10°、13.96±0.10°、16.62±0.10°、17.61±0.10°、18.32±0.10°、25.39±0.10°、26.53±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.55±0.10°、8.78±0.10°、12.69±0.10°、13.74±0.10°、13.96±0.10°、16.62±0.10°、17.61±0.10°、18.32±0.10°、21.72±0.10°、25.39±0.10°、26.53±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的马来酸盐晶型A的TGA/DSC曲线在约211.2℃和约278.1℃(起始温度)处有两个热信号。
本申请的一个优选实施方案涉及式(I)化合物的甲磺酸盐晶型B，其粉末X-射线衍射图谱(XRPD)具有选自5.91±0.10°、9.22±0.10°、15.83±0.10°、17.73±0.10°、19.02±0.10°、25.01±0.10°、衍射角(2θ)处的一个或多个特征峰，优选地具有选自5.91±0.10°、9.22±0.10°、15.83±0.10°、17.73±0.10°、19.02±0.10°、20.61±0.10°、21.36±0.10°、23.18±0.10°、25.01±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的甲磺酸盐晶型B的TGA/DSC曲线在约234.4℃(峰值温度)和约264.1℃(起始温度)有两个吸热信号。
本申请的一个优选实施方案涉及式(I)化合物的盐酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自8.05±0.10°、17.11±0.10°、18.02±0.10°、20.84±0.10°、21.09±0.10°、22.77±0.10°、23.14±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自8.05±0.10°、15.04±0.10°、17.11±0.10°、18.02±0.10°、20.44±0.10°、20.84±0.10°、21.09±0.10°、22.07±0.10°、22.77±0.10°、23.14±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的盐酸盐晶型A的TGA/DSC曲线在约80.1℃、约118.0℃(峰值温度)和约224.5℃(起始温度)处有三个吸热峰，在约231.5℃(起始温度)处有放热信号。
本申请的一个优选实施方案涉及式(I)化合物的酒石酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自7.90±0.10°、8.69±0.10°、13.12±0.10°、13.43±0.10°、18.11±0.10°、21.28±0.10°、22.90±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自7.90±0.10°、8.69±0.10°、13.12±0.10°、13.43±0.10°、15.08±0.10°、17.17±0.10°、17.44±0.10°、18.11±0.10°、19.40±0.10°、20.74±0.10°、21.28±0.10°、22.90±0.10°、24.15±0.10°、24.95±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的酒石酸晶型A的TGA/DSC曲线在约125.2℃和约168.8℃(起始温度)处有两个热信号。
本申请的一个优选实施方案涉及式(I)化合物的富马酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自4.96±0.10°、7.66±0.10°、10.21±0.10°、11.06±0.10°、14.74±0.10°、16.11±0.10°、22.87±0.10°、25.10±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.96±0.10°、7.66±0.10°、10.21±0.10°、11.06±0.10°、12.44±0.10°、14.74±0.10°、16.11±0.10°、19.25±0.10°、22.87±0.10°、23.54±0.10°、24.27±0.10°、25.10±0.10°、25.37±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的富马酸晶型A的TGA/DSC曲线在约71.1℃、约205.3℃、约273.7℃和约299.4℃(起始温度)处有多个热信号。
本申请的一个优选实施方案涉及式(I)化合物的粘酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自4.98±0.10°、10.22±0.10°、11.07±0.10°、14.75±0.10°、14.94±0.10°、16.13±0.10°、19.65±0.10°、30.79±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.98±0.10°、7.69±0.10°、10.22±0.10°、11.07±0.10°、14.75±0.10°、14.94±0.10°、16.13±0.10°、19.65±0.10°、21.51±0.10°、22.92±0.10°、30.79±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的粘酸盐晶型A的TGA/DSC曲线在 约69.8℃和约210.4℃(起始温度)处可观察到两个热信号。
本申请的一个优选实施方案涉及式(I)化合物的柠檬酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自4.85±0.10°、6.42±0.10°、14.63±0.10°、17.12±0.10°、20.75±0.10°、25.34±0.10°、衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.85±0.10°、6.42±0.10°、7.64±0.10°、14.63±0.10°、15.40±0.10°、17.12±0.10°、18.12±0.10°、18.84±0.10°、19.37±0.10°、20.75±0.10°、25.34±0.10°、衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的柠檬酸盐晶型A的TGA/DSC曲线在约68.2℃(峰值温度)、约154.4℃和164.0℃(起始温度)处有三个吸热峰。
本申请的一个优选实施方案涉及式(I)化合物的柠檬酸盐晶型B，其粉末X-射线衍射图谱(XRPD)具有选自4.96±0.10°、7.67±0.10°、10.20±0.10°、11.04±0.10°、14.73±0.10°、19.23±0.10°、22.86±0.10°、23.54±0.10°、24.28±0.10°、25.08±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.96±0.10°、7.67±0.10°、10.20±0.10°、11.04±0.10°、12.42±0.10°、14.73±0.10°、16.09±0.10°、17.55±0.10°、19.23±0.10°、22.86±0.10°、23.54±0.10°、24.28±0.10°、25.08±0.10°、27.91±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的柠檬酸盐晶型B的TGA/DSC曲线在约73.1℃、约280.2℃、约301.6℃(起始温度)和约179.7℃(峰值温度)处有四个吸热峰。
本申请的一个优选实施方案涉及式(I)化合物的对甲苯磺酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自5.90±0.10°、9.34±0.10°、14.87±0.10°、15.33±0.10°、17.88±0.10°、18.76±0.10°、19.71±0.10°、24.26±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自5.90±0.10°、9.34±0.10°、12.99±0.10°、14.87±0.10°、15.33±0.10°、16.10±0.10°、17.88±0.10°、18.76±0.10°、19.34±0.10°、1971 ±0.10°、20.39±0.10°、24.26±0.10°、24.99±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的对甲苯磺酸晶型A的TGA/DSC曲线在约121.2℃和约222.3℃(起始温度)处由两个热信号。
本申请的一个优选实施方案涉及式(I)化合物的苯磺酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自5.82±0.10°、6.74±0.10°、11.85±0.10°、16.38±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自5.82±0.10°、6.74±0.10°、11.85±0.10°、16.38±0.10°、19.46±0.10°、20.20±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的苯磺酸晶型A的TGA/DSC曲线在约60-200℃处有多个热信号。
本申请的一个优选实施方案涉及式(I)化合物的苯磺酸盐晶型B，其粉末X-射线衍射图谱(XRPD)具有选自4.93±0.10°、5.63±0.10°、9.02±0.10°、10.89±0.10°、14.84±0.10°、17.55±0.10°、18.84±0.10°、23.12±0.10°、25.55±0.10°、26.14±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.93±0.10°、5.63±0.10°、9.02±0.10°、10.30±0.10°、10.89±0.10°、11.43±0.10°、14.23±0.10°、14.84±0.10°、17.04±0.10°、17.55±0.10°、18.84±0.10°、19.66±0.10°、20.24±0.10°、22.71±0.10°、23.12±0.10°、24.91±0.10°、25.55±0.10°、26.14±0.10°衍射角(2θ)处的一个或多个特征峰。
进一步优选地，式(I)化合物的苯磺酸晶型B的TGA/DSC曲线在约90.1℃(峰值温度)和约236.7℃(起始温度)处有两个热信号。
在本申请的最优选实施方案中，所述固体形式是式(I)化合物的磷酸盐晶型A、式(I)化合物的马来酸盐晶型A、式(I)化合物的甲磺酸盐晶型B、式(I)化合物水合物的晶型A、式(I)化合物的晶型B，它们各自具有与本申请实施例部分所述对应晶型基本上相同的XPRD谱。
在本申请的一些实施方案中，所述固体形式是式(I)化合物的磷酸盐晶型A、式(I)化合物的马来酸盐晶型A、式(I)化合物的甲磺酸盐晶型B、式(I)化合物水合物的晶型A、式(I)化合物的晶型B，它们 各自具有与本申请实施例部分所述对应晶型基本上相同的TGA和/或DSC曲线。
在第二个方面，本申请提供了一种药物组合物，其含有本申请第一方面所述固体形式的化合物和一种或多种药学上可接受的载体、佐剂或赋形剂。
本申请的药物组合物可以是固体组合物或液体组合物(例如分散液或溶液)。
本申请的药物组合物可根据需要配制成适用于口服、外用(包括但不限于外敷、喷涂等)、胃肠外(包括皮下、肌肉、皮层和静脉)施予、支气管施予或鼻施予的剂型。其中，优选地，本申请的药物组合物被配制成适用于外用或支气管施予或鼻施予的剂型(制剂)。更优选地，本申请的药物组合物被配制成适用于外用的剂型(制剂)。
如果使用固体载剂，则该制剂可以成片，以粉末或颗粒形式置于硬质凝胶胶囊中，或以糖锭或锭剂形式。固体载剂可以包括常规的赋形剂，诸如粘合剂、填料、成片润滑剂、崩解剂、润湿剂等等。如果需要可以通过常规技术膜包衣该片剂。如果使用液体载剂，则该制剂可以是糖浆、乳液、膏剂、软凝胶胶囊、用于注射的无菌载体、水性或非水性液体悬浮液形式的，或者可以是在使用前用水或其他适当载体复原的干品。液体制剂可以包含常规添加剂，诸如悬浮剂、乳化剂、润湿剂、非水性载体(包括可食用油)、防腐剂以及香味剂和/或着色剂。为了胃肠外施予，通常载体至少大部分包括无菌水，但也可以使用盐水溶液、葡萄糖溶液等。也可以使用可注射悬浮液，在这种情况下，可以使用常规悬浮剂。常规防腐剂、缓冲试剂等也可以添加到胃肠外剂型中。药物组合物通过对包含适量的活性成分(即本申请的式(I)化合物)的所需制剂合适的常规技术制备。
适于非肠道注射的组合物可以包括生理学上可接受无菌水性或非水性溶液、分散液(例如悬浮液或乳液)和用于无菌可注射溶液或分散液的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂、分散剂的实例 包括水、乙醇、多元醇(丙二醇、聚乙二醇、丙三醇等)、其合适的混合物、植物油(例如，橄榄油)和可注射有机酯(例如，油酸乙酯)。
这些组合物还可以包含各种赋形剂，例如，防腐剂、润湿剂、乳化剂和分散剂。可以通过各种抗菌剂和抗真菌剂(例如，对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等)来确保对微生物的作用的抑制。还可以包括等渗剂，例如，糖、氯化钠等。可以通过使用延迟吸收试剂(例如，单硬脂酸铝和凝胶)来延长可注射药学剂型的吸收。
用于口服的固体剂型包括胶囊、药片、药丸、粉末和颗粒。在这种固体剂型中，将活性化合物与至少一种惰性赋型剂(或载体)(例如，柠檬酸钠或磷酸二钙)混合，其中还可以包括：(a)填料或混合剂(例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸)；(b)粘结剂(例如，羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树胶)；(c)保湿剂(例如，丙三醇)；(d)崩解剂(例如，琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠)；(e)溶液阻滞剂(例如，石蜡)；(f)吸收促进剂(例如，季铵化合物)；(g)润湿剂(例如，十六烷醇和单硬脂酸丙三醇酯)；(h)吸附剂(例如，高岭土和斑脱土)和(i)润滑剂(例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
类似类型的固体组合物还可以在使用例如乳糖以及高分子量聚乙二醇等作为赋型剂的软填充和硬填充凝胶胶囊中作为填料。
固体剂型(例如，药片、糖衣丸、胶囊、药丸和颗粒)可以采用涂层和外壳(例如，肠道涂层和本领域已知的其它)来制备。它们可以包含遮光剂，它们还可以是以延迟方式在肠道的某一部分中释放活性化合物或各种活性化合物的组合物。可用的包埋组合物的实例是聚合物质和蜡。活性组分还可以以微胶囊化形式，如果适当的话，可以具有一种或更多种上述赋型剂。
用于口服的液体剂型包括药学上可接受乳液、溶液、分散液、糖浆和酏剂。除了活性化合物以外，液体剂型可以包含本领域中通常所用的惰性稀释剂(例如，水或其它溶剂)、增溶剂和乳化剂(例如，乙醇、 异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1，3丁二醇、二甲基甲酰铵)、油(具体为，棉花子油、落花生油、玉米油、橄榄油、蓖麻油、芝麻油)、丙三醇、四氢呋喃醇、聚乙二醇和山梨聚糖的脂肪酸酯或这些物质的混合物等。
除了这些惰性稀释剂，组合物还可以包括，例如，润湿剂、乳化和悬浮剂、香化剂、调味剂和加香剂。
除了活性化合物，悬浮液可以包含悬浮剂，例如乙氧基化异十八烷醇、聚氧化乙烯山梨醇、山梨聚糖酯、微晶纤维、偏氢氧化铝、斑脱土、琼脂-琼脂和黄芪胶或这些物质的混合物等。
本申请的化合物的局部给药用剂型包括膏剂、粉末、喷雾和吸入剂。该活性组分在无菌条件下与生理学上可接受载体和任何所需要的防腐剂、缓冲剂或推进剂混合。眼用配方、眼药膏、粉末和溶液也包括在本申请的范围内。
本申请的化合物的外用剂型可以呈油包水(W/O)或水包油(O/W)乳液的形式，多乳液形式，如水包油包水(W/O/W)形式或油包水包油(O/W/O)乳液形式，或者以水分散体或脂分散体、凝胶或气溶胶形式制得。
本申请的化合物的外用剂型可以包含添加剂和制剂助剂，如乳化剂、增稠剂、胶凝剂、水固定剂、铺展剂、稳定剂、染料、香料和防腐剂。合适的乳化剂包括硬脂酸、三乙醇胺和PEG-40-硬脂酸酯。合适的增稠剂包括单硬脂酸甘油酯，卡波姆和PEG600。合适的防腐剂包括对羟苯甲酸丙酯和氯甲酚。适的铺展剂包括二甲聚硅氧烷和聚二甲基环硅氧烷。合适的水固定剂包括聚乙二醇，优选聚乙二醇600。
本申请的化合物的外用剂型可以包括膏剂、洗剂、凝胶、乳液、微乳剂、喷雾剂、皮肤贴剂等，其可局部施用，以治疗特应性皮炎、湿疹、银屑病、硬皮病、瘙痒、白癜风、脱发等皮肤疾病。特别地，本申请的化合物的外用剂型是膏剂，其可局部外敷施用，以治疗特应性皮炎、湿疹、银屑病、硬皮病、瘙痒、白癜风、脱发等皮肤疾病。
在药物组合物和剂型中式(I)化合物的量可以由本领域技术人员根据需要适当地确定，例如式(I)化合物可以治疗有效量存在于药物组合物或剂型中。
在第三个方面，本申请提供了本申请第一方面所述固体形式的化合物、或本申请第二方面所述药物组合物在制备用于治疗和/或预防与JAK相关的疾病或病症的药物中的用途。
“与JAK相关的疾病或病症”包括但不限于：
关节炎，包括类风湿性关节炎、幼年型关节炎和银屑病关节炎；
自身免疫疾病或病症，包括单一器官或单一细胞类型自身免疫病症，例如桥本甲状腺炎、自身性免疫溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、古德帕斯彻病、自身免疫性血小板减少症、交感性眼炎、重症肌无力、格雷夫斯病、原发性胆汁性肝硬变、慢性侵袭性肝炎、溃疡性结肠炎和膜性肾小球病、涉及全身性自身免疫病症的那些(例如全身性红斑狼疮、类风湿性关节炎、干燥综合征、莱特尔综合征、多肌炎-皮肌炎、系统性硬化病、结节性多动脉炎、多发性硬化和大疱性类天疱疮)以及其它O-细胞(体液)型或T细胞型自身免疫病(包括寇甘综合征)、强直性脊椎炎、Wegener’s氏肉芽肿、自身免疫性脱发、I型糖尿病或幼年发病型糖尿病或甲状腺炎；
癌症或肿瘤，包括消化道/胃肠道癌、结直肠癌、肝癌、皮肤癌(包括肥大细胞瘤和鳞状细胞癌)、乳房和乳腺癌、卵巢癌、前列腺癌、淋巴瘤、白血病(包括急性髓性白血病和慢性髓性白血病)、肾癌、肺癌、肌癌、骨癌、膀胱癌、脑癌、黑色素瘤(包含口腔和转移性黑色素瘤)、卡波西肉瘤、骨髓瘤(包括多发性骨髓瘤)、骨髓增殖性病症、增生型糖尿病视网膜病变或与血管生成相关的病症(包括实体瘤)；
糖尿病，包括I型糖尿病或糖尿病并发症；
眼疾病、病症或病况，包括眼的自身免疫病、角膜结膜炎、春季结膜炎、葡萄膜炎(包括与贝切特病相关的葡萄膜炎和晶状体性葡萄膜炎)、角膜炎、疱疹性角膜炎、圆锥形角膜炎、角膜上皮营养障碍、角 膜白斑、眼天疱疮、莫伦溃疡、巩膜炎、格雷夫眼病、Vogt-Koyanagi-Harada综合征、干燥性角结膜炎(干眼症)、水疱、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎、变应性结膜炎或眼部新生血管形成；
肠炎症、变态反应或病况，包括克罗恩氏病和/或溃疡性结肠炎、炎性肠病、乳糜泻、直肠炎、嗜酸细胞性胃肠炎或肥大细胞增多症；
神经变性疾病，包括运动神经元病、阿尔茨海默病、帕金森病、肌萎缩侧索硬化、亨廷顿病、脑缺血或创伤性损伤引发的神经变性疾病、卒中、谷氨酸神经毒性或缺氧；卒中的缺血/再灌注损伤、心肌缺血、肾缺血、心脏病发作、心脏肥大、动脉粥样硬化和动脉硬化、器官缺氧或血小板聚集；
皮肤疾病、病况或病症，包括特应性皮炎、湿疹、银屑病、硬皮病、瘙痒症或其它瘙痒病况、白癜风、脱发；
变态反应，包括哺乳动物的变应性皮炎(包括变应性疾病，例如叮咬过敏)、夏季湿疹、库蚊叮痒综合症(sweet itch)、肺气肿、炎症性气道疾病、复发性气道阻塞、气道反应过度或慢性阻塞性肺疾病；
哮喘和其它阻塞性气道疾病，包括慢性或顽固型哮喘、晚期哮喘、支气管炎、支气管性哮喘、变应性哮喘、内源性哮喘、外源性哮喘或粉尘性哮喘；
移植排斥，包括胰岛移植排斥、骨髓移植排斥、移植物抗宿主病、器官和细胞移植排斥(例如骨髓、软骨、角膜、心脏、椎间盘、胰岛、肾、四肢、肝、肺、肌肉、成肌细胞、神经、胰脏、皮肤、小肠或气管)或者异种移植；
流感病毒或者冠状病毒感染导致的重症肺炎，包括Sars、Mers和Covid-19(新冠肺炎)，尤其是在新冠肺炎中抑制炎症反应、抑制或防止细胞因子风暴。
在第四个方面，本申请提供了一种治疗与JAK相关的疾病或病症的方法，所述方法包括将治疗有效量的本申请第一方面所述固体形式的化合物、或本申请第二方面所述药物组合物给予有需要的患者。其中，所述患者优选是哺乳动物，更优选是人类患者。其中给药途径可以是口服、 外用(包括但不限于外敷、喷涂等)、胃肠外(包括皮下、肌肉、皮层和静脉)施予、支气管施予或鼻施予等。其中，优选地通过鼻施予或外用施予。更优选地通过外用施予。
为了起到预期效果，通常需要将治疗有效量的本申请的固体化合物或药物组合物或剂型给予患者。短语“治疗有效量”是本领域公认的术语。在某些实施方案中，该术语是指消除、减少或维持特定治疗方案的目标所必需或足够的量。有效量可以根据诸如所治疗的疾病或病症、所施用的特定靶向构建体、受试者的大小或疾病或病症的严重性等因素而变化。本领域普通技术人员或医生可凭经验确定特定化合物的有效量，而无需过多的实验。在某些实施方案中，体内使用的治疗剂的治疗有效量可能取决于许多因素，包括：施用的方式和方法；除了药剂之外还包含在药物中的任何其他材料。可选使用体外或体内试验来帮助确定最佳剂量范围。
出人意料地，本申请的化合物在实验中展示出作为JAK激酶抑制剂的优异功效(优于现有的JAK激酶抑制剂，例如Filgotinib或Tofacitinib)，而且潜在具有良好的安全性。
下面结合附图和具体实施例对本申请做进一步的说明和描述。
附图说明
图1示出了式(I)化合物的晶型A的XRPD图；
图2示出了式(I)化合物的晶型A的TGA/DSC曲线；
图3示出了式(I)化合物的晶型A的加热前、后的XRPD对比图；
图4示出了式(I)化合物的晶型A的变温XRPD图；
图5示出了式(I)化合物的晶型B的XRPD图；
图6示出了式(I)化合物的晶型B的TGA/DSC曲线；
图7示出了式(I)化合物的晶型B的变温XRPD图；
图8示出了式(I)化合物的晶型C的XRPD图；
图9示出了式(I)化合物的晶型C的TGA/DSC曲线；
图10示出了式(I)化合物的晶型C的加热前、后的XRPD对比图；
图11示出了式(I)化合物的晶型D的XRPD图；
图12示出了式(I)化合物的晶型D的XRPD对比图；
图13示出了式(I)化合物的晶型E的XRPD图；
图14示出了式(I)化合物的晶型E的TGA/DSC曲线；
图15示出了式(I)化合物的晶型E的加热前、后的XRPD对比图；
图16示出了式(I)化合物的晶型E的变温XRPD图；
图17示出了式(I)化合物的晶型F的XRPD图；
图18示出了式(I)化合物的晶型F的TGA/DSC曲线；
图19示出了式(I)化合物的晶型F的加热前、后的XRPD对比图；
图20示出了式(I)化合物的晶型G的XRPD图；
图21示出了式(I)化合物的晶型G的TGA/DSC曲线；
图22示出了式(I)化合物的晶型G的变温XRPD图；
图23示出了式(I)化合物的晶型J的XRPD图；
图24示出了式(I)化合物的晶型J的XRPD对比图；
图25示出了式(I)化合物的晶型H的XRPD图；
图26示出了式(I)化合物的晶型I的XRPD图；
图27示出了式(I)化合物的磷酸盐晶型A的XRPD图；
图28示出了式(I)化合物的磷酸盐晶型A的TGA/DSC曲线；
图29示出了式(I)化合物的马来酸盐晶型A的XRPD图；
图30示出了式(I)化合物的马来酸盐晶型A的TGA/DSC曲线；
图31示出了式(I)化合物的甲磺酸盐晶型B的XRPD图；
图32示出了式(I)化合物的甲磺酸盐晶型B的TGA/DSC曲线；
图33示出了式(I)化合物的盐酸盐晶型A的XRPD图；
图34示出了式(I)化合物的盐酸盐晶型A的TGA/DSC曲线；
图35示出了式(I)化合物的酒石酸盐晶型A的XRPD图；
图36示出了式(I)化合物的酒石酸盐晶型A的TGA/DSC曲线；
图37示出了式(I)化合物的富马酸盐晶型A的XRPD图；
图38示出了式(I)化合物的富马酸盐晶型A的TGA/DSC曲线；
图39示出了式(I)化合物的粘酸盐晶型A的XRPD图；
图40示出了式(I)化合物的粘酸盐晶型A的TGA/DSC曲线；
图41示出了式(I)化合物的柠檬酸盐晶型A的XRPD图；
图42示出了式(I)化合物的柠檬酸盐晶型A的TGA/DSC曲线；
图43示出了式(I)化合物的柠檬酸盐晶型B的XRPD图；
图44示出了式(I)化合物的柠檬酸盐晶型B的TGA/DSC曲线；
图45示出了式(I)化合物的对甲苯磺酸盐晶型A的XRPD图；
图46示出了式(I)化合物的对甲苯磺酸盐晶型A的TGA/DSC曲线；
图47示出了式(I)化合物的苯磺酸盐晶型A的XRPD图；
图48示出了式(I)化合物的苯磺酸盐晶型A的TGA/DSC曲线；
图49示出了式(I)化合物的苯磺酸盐晶型B的XRPD图；
图50示出了式(I)化合物的苯磺酸盐晶型B的TGA/DSC曲线；
图51示出了式(I)化合物的磷酸盐晶型A的DVS图；
图52示出了式(I)化合物的马来酸盐晶型A的DVS图；
图53示出了式(I)化合物的甲磺酸盐晶型B的DVS图。
实施例
本申请的化合物可以用有机合成领域的技术人员所熟悉的多种方法合成。以下具体实施例中给出了示例性的式(I)化合物的合成方法。显然，参照本申请中的示例性方案，本领域技术人员可以适当调整反应物、反应条件和保护基团而容易地设计式(I)化合物的其他合成路线或其它化合物的合成路线。
本申请的化合物的适当的晶型或无定形物可以采用本领域技术人员所熟悉的纯化、结晶和/或干燥方法得到。以下具体实施例中给出了示例性的某些晶型和无定形物的制备方法。显然，参照本专利中的示例性方案，本领域技术人员可以适当调整溶剂、设备和工艺条件而容易地设计其它晶型或无定形物的制备方法。
下面进一步结合实施例来阐述本发明；但这些实施例并不限制本发明的范围。除非另有声明，各实施例中所用的所有反应物均从商业途径 获得；合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。
实施例1：(S)-(2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-4，6-二氢吡 咯并[3，4-d]咪唑-5-(1H)-基)(3-羟基吡咯烷-1-基)甲酮(I)的合成
Figure PCTCN2021112352-appb-000005
为了合成式(I)化合物，首先合成了化合物中间体1-1至中间体1-15，然后以中间体1-15为原料来合成式(I)化合物。
除特别指明外，实施例1的各化学反应中所使用的化学试剂、溶剂和反应设备等均为化学合成中的常规原料和设备，可通过商业途径方便地获得。
一、合成中间体1-6：3，4-二氨基吡咯烷基-1-甲酸叔丁酯
通过以下合成路线来合成中间体1-6：
Figure PCTCN2021112352-appb-000006
1.合成中间体1-1：2，5-二氢-1H-吡咯-1-甲酸叔丁酯
将3-吡咯啉(10.0g，0.15mol)溶于400ml二氯甲烷和三乙胺(40.6ml，0.29mol)中，冷却到0度，缓慢加入(Boc) 2O(37.9g，0.17mol)，室温反应 过夜，加入水，用二氯甲烷萃取2次，合并有机相，用水洗3次，饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-1，收率91.0％。
2.合成中间体1-2：6-氧杂-3-氮杂双环并[3.1.0]己烷-3-甲酸叔丁酯
将中间体1-1(24.5g，0.15mol)溶于450ml二氯甲烷中，冷却到0度，分批缓慢加入间氯过氧苯甲酸(37.5g，0.22mol)，室温反应过夜，加入饱和硫代硫酸钠(40ml)，搅拌30分钟，水相用二氯甲烷萃取2次，用饱和碳酸钾溶液，水和饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-2，收率84.9％。
1H NMR(400MHz，CDCl 3)δ3.85(d，J＝12.0Hz，1H)，3.77(d，J＝12.0Hz，1H)，3.69-3.67(m，2H)，3.36-3.30(m，2H)，1.45(s，9H).
3.合成中间体1-3：3-叠氮基-4-羟基吡咯烷基-1-甲酸叔丁酯
将中间体1-2(20.8g，0.12mol)溶于150ml 1，4-二氧六环和50ml水中，加入叠氮化钠(24.0g，0.37mol)，加热到106度反应18小时，冷却到室温，加入饱和食盐水100ml，用二氯甲烷萃取(250ml X 4)，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，浓缩，得中间体1-3，收率100％。
1H NMR(400MHz，CDCl3)δ4.27-4.24(m，1H)，3.94(s，1H)，3.73-3.59(m，2H)，3.41-3.36(m，2H)，1.47(s，9H).
4.合成中间体1-4：3-叠氮基-4-((甲磺酰基)氧基)吡咯烷基-1-甲酸叔丁酯
将中间体1-3(28.0g，0.12mol)溶于350ml二氯甲烷和三乙胺(37.3g，0.37mol)中，冷却到0度，缓慢滴加甲磺酰氯(16.9g，0.15mol)，滴加完后，室温反应2小时，加入水淬灭反应，用二氯甲烷萃取2次，合并有机相，用饱和碳酸氢钠溶液，水和饱和食盐水洗，无水硫酸钠干燥，浓缩，得中间体1-4，收率98.0％。
5.合成中间体1-5：3，4-二叠氮基吡咯烷基-1-甲酸叔丁酯
将中间体1-4(36.9g，0.12mol)溶于250ml DMF中，加入叠氮化钠(23.5g，0.36mol)，加热到90度，反应2天，冷却到室温，加入750ml水，用甲基叔丁基醚萃取(400ml*4)，合并有机相，用饱和食盐水洗，无水硫 酸钠干燥，硅胶柱纯化，得中间体1-5，收率62.2％。
6.合成中间体1-6：3，4-二氨基吡咯烷基-1-甲酸叔丁酯
将中间体1-5(18.9g，0.08mol)溶于200ml甲醇中，加入10％Pd/C，氢气置换3次，加热到40度，反应2天，过滤，浓缩，得中间体1-6，收率78％。
1H NMR(400MHz，CDCl 3)δ3.51-3.49(m，2H)，3.40-3.36(m，2H)，3.21-3.11(m，2H)，1.47(s，9H).
二、合成中间体1-10：2-(4-(苄氧基)-2-乙基-5-氟苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷
通过以下合成路线来合成中间体1-10：
Figure PCTCN2021112352-appb-000007
1.合成中间体1-7：5-乙基-2-氟苯酚
将5-溴-2-氟苯酚(200.0mg，1.05mmol)和二(三叔丁基磷)钯(10.7mg，0.02mmol)溶于10ml THF。氮气置换3次，降温至10～20℃，缓慢滴加1mol/L的二乙基锌溶液(2.3ml，2.30mmol)，滴加完毕，升温至50℃。反应过夜，降温至0℃，加水淬灭，用硅藻土过滤，硅藻土垫用乙酸乙酯洗涤，用乙酸乙酯萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥。干燥后浓缩柱层析分离得到油状液体中间体1-7，收率65.1％。 1H NMR(400MHz，CDCl 3)δ6.97(d，J＝8.0Hz，1H)，6.85(d，J＝12.0Hz，1H)，6.69-6.65(m，1H)，2.61-2.55(m，2H)，1.21(t，J＝8.0Hz，3H).
2.合成中间体1-8：4-溴-5-乙基-2-氟苯酚
将中间体1-7(200.1mg，1.43mmol)溶于6ml乙腈中，加入CuBr 2(957.5mg，4.29mmol)，室温搅拌3小时，加水淬灭，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到无色油状物中间体1-8，收率：78.1％。 1H NMR(400MHz，CDCl 3)δ7.25(d，J＝12.0Hz，1H)，6.89(d，J＝12.0Hz，1H)，2.69-2.63(m，2H)，1.19(t，J＝12.0Hz，3H).
3.合成中间体1-9：1-(苄氧基)-4-溴-5-乙基-2-氟苯
将中间体1-8(15.5g，70.8mmol)溶于200ml DMF中，加入碳酸钾(19.5g，141.5mmol)，溴化苄(14.5g，84.9mmol)，升温到60℃反应。反应完成后，加水淬灭，用EA萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩后柱层析得到19.0g中间体1-9，收率：86.8％。 1H NMR(400MHz，CDCl 3)δ7.44-7.31(m，5H)，7.27(d，J＝8.0Hz，1H)，6.87(d，J＝8.0Hz，1H)，5.12(s，2H)，2.68-2.63(m，2H)，1.16(t，J＝8.0Hz，3H).
4.合成中间体1-10：2-(4-(苄氧基)-2-乙基-5-氟苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷
将中间体1-9(1.0g，3.23mmol)，频哪醇硼酸酯(0.82g，3.23mmol)，Pd(dppf)Cl 2(0.24g，0.32mmol)和KOAc(0.95g，9.70mmol)溶于15ml 1，4-二氧六环中，氮气置换3次。加热到100℃反应。反应完成后加水淬灭，用乙酸乙酯萃取，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩柱层析得到0.98g中间体1-10，收率：85.1％。 1H NMR(400MHz，CDCl 3)δ7.50-7.30(m，6H)，7.82(d，J＝8.0Hz，1H)，5.16(s，2H)，2.87-2.81(m，2H)，1.32(s，12H)，1.14(t，J＝8.0Hz，3H).
三、合成中间体1-15：2-(6-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅基)乙氧基)甲基)-4，6-二氢吡咯并[3，4-d]咪唑-5(1H)-甲酸叔丁酯
通过以下合成路线来合成中间体1-15：
Figure PCTCN2021112352-appb-000008
1.合成中间体1-11：6-溴-1H-吲唑-3-甲醛
将亚硝酸钠(14.00g，200mmol)溶于75ml DMF和100ml水中，冷却到0度，氮气保护下，缓慢滴加3N HCl(23ml，68.9mmol)，滴加完反应10分钟。在0度下，向反应液中缓慢滴加6-溴吲哚(5.00g，25.5mmol)的DMF(35ml)溶液，滴加完，室温反应过夜。用乙酸乙酯萃取3次，合并有机相，用水洗3次，饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-11，收率83.6％。
1H NMR(400MHz，CDCl 3)δ10.29(s，1H)，8.24(d，J＝8.0Hz，1H)，7.80(d，J＝4.0Hz，1H)，7.52(dd，J＝8.0Hz，J＝4.0Hz，1H).
2.合成中间体1-12：6-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲唑-3-甲醛
将中间体1-11(1.56g，6.93mmol)溶于干燥的四氢呋喃中，冷却到0度，缓慢加入氢化钠(0.33g，8.32mmol)，室温反应1小时，冷却到0度，缓慢滴加2-(三甲基硅烷基)乙氧甲基氯(1.73g，10.40mmol)，滴加完室温反应过夜，加入水淬灭反应，用乙酸乙酯萃取2次，合并有机相，用水和饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-12，收率49.2％。
1H NMR(400MHz，CDCl 3)δ10.25(s，1H)，8.22(dd，J＝8.0Hz，J＝4.0Hz 1H)，7.88(dd，J＝4.0Hz，J＝4.0Hz，1H)，7.52(dd，J＝4.0Hz，J＝4.0Hz，1H)，5.81(s，2H)，3.63-3.58(m，2H)，0.97-0.93(m，2H)，0.04(s，9H).
3.合成中间体1-13：2-(6-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲唑-3-基)-3，4，6，6a-四氢吡咯并[3，4-d]咪唑-5(1H)-甲酸叔丁酯
将中间体1-12(1.56g，6.93mmol)和3，4-二氨基吡咯啉-1-甲酸叔丁酯(1.56g，6.93mmol)溶于5ml六氟异丙醇中，加热到40度反应2天，浓缩，硅胶柱纯化，得中间体1-13，收率54.7％。
4.合成中间体1-14：2-(6-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲唑-3-基)-4，6-二氢吡咯并[3，4-d]咪唑-5(1H)-甲酸叔丁酯
将草酰氯(0.53g，4.20mmol)溶于干燥的15ml二氯甲烷中，氮气保护下，冷却到-78度，缓慢滴加DMSO(0.61g，7.84mmol)，滴加完，反应30分钟，缓慢滴加中间体1-13(1.00g，1.87mmol)的二氯甲烷溶液，滴加完后，反应30分钟，缓慢滴加干燥的三乙胺(1.89g，18.66mmol)，反应10分钟，缓慢升温室温反应2小时，加入饱和氯化铵溶液淬灭反应，用二氯甲烷萃取2次，合并有机层，用水和饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-14，收率36.3％。
1H NMR(400MHz，CDCl 3)δ8.36(d，J＝4.0Hz，1H)，7.78(d，J＝4.0Hz，1H)，7.44(dd，J＝8.0Hz，J＝4.0Hz，1H)，5.69(s，2H)，4.64-4.52(m，4H)，3.67-3.56(m，2H)，1.56(s，9H)，0.95-0.89(m，2H)，0.03(s，9H).
5.合成中间体1-15：2-(6-溴-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基硅基)乙氧基)甲基)-4，6-二氢吡咯并[3，4-d]咪唑-5(1H)-甲酸叔丁酯
将中间体1-14(110mg，0.21mmol)溶于干燥的四氢呋喃中，冷却到0，加入氢化钠(12.3mg，0.31mmol)，室温反应30分钟，冷却到0度，缓慢滴加2-(三甲基硅烷基)乙氧甲基氯(41.2mg，0.25mmol)，室温反应4小时，加入水淬灭反应，用乙酸乙酯萃取2次，合并有机相，用水和饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，得中间体1-15，收率73.1％。
1H NMR(400MHz，CDCl 3)δ8.41-8.36(m，1H)，7.79(s，1H)，7.44(dd，J＝8.0Hz，J＝4.0Hz，1H)，5.94(d，J＝12.0Hz，2H)，5.73(s，2H)，4.65-4.52(m，4H)，3.63-3.57(m，4H)，1.56(s，9H)，0.96-0.91(m，4H)，0.03(s，18H).
四、合成式(I)化合物
通过以下合成路线，从中间体1-15出发来合成式(I)化合物：
Figure PCTCN2021112352-appb-000009
1.合成中间体1-16：6-(4-(苄氧基)-2-乙基-5-氟苯基)-1-((2-(三甲基硅基)乙氧基)甲基)-3-(1-((2-(三甲基硅基)乙氧基)甲基)-1，4，5，6-四氢吡咯并[3，4-d]咪唑-2-基)-1H-吲唑
将2-(6-溴1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲哚-3-基)-1-((2-(三甲基硅基)乙氧基)甲基)-4，6-二氢吡咯并[3，4-d]咪唑-5(1H)-甲酸叔丁酯(500mg，0.75mmol)，2-(4-(苄氧基)-2-乙基-5-氟苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷(401mg，1.13mmol)，Pd(dppf)Cl2(75mg，0.075mmol)和磷酸钾(495mg，2.25mmol)溶于1，4-二氧六环(30ml)和水(6ml)中，氮气置换3次，加热到100度，反应16h，冷却到室温，加入水，用乙酸乙酯萃取2次，合并有机相，用水和饱和食盐水洗，无水硫酸钠干燥，浓缩，硅胶柱纯化，纯化所得产品溶于25ml二氯甲烷，滴加5ml三氟乙酸，室温 搅拌30分钟，浓缩，用二氯甲烷带3次三氟乙酸，浓缩，硅胶柱纯化，得中间体1-16共210mg，收率39.2％。
1H NMR(400MHz，CDCl 3)δ8.48(d，J＝8.3Hz，1H)，7.52(d，J＝7.4Hz，1H)，7.49-7.37(m，5H)，7.25(d，J＝8.4Hz，1H)，7.23-6.96(m，2H)，5.93(s，2H)，5.77(s，2H)，5.23(s，2H)，4.21(d，J＝35.1Hz，4H)，3.66-3.52(m，4H)，2.54(q，J＝7.6Hz，2H)，1.05(t，J＝7.5Hz，3H)，0.95-0.89(m，4H)，0.02(s，9H)，-0.05(d，J＝3.4Hz，9H).
2.合成中间体1-17：(S)-(2-(6-(4-(苄氧基)-2-乙基-5-氟苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4，6-二氢吡咯并[3，4-d]咪唑-5-(1H)-基)(3-羟基吡咯烷-1-基)甲酮
将三光气(91.5mg，0.31mmol)溶于10ml干燥二氯甲烷中，0度滴加中间体6-(4-(苄氧基)-2-乙基-5-氟苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1-1，4，5，6-四氢吡咯并[3，4-d]咪唑-2-基)-1H-吲唑(220.0mg，0.31mmol)的二氯甲烷(5ml)溶液，加完后缓慢滴加干燥三乙胺(312.2mg，3.09mmol)，室温搅拌10分钟，TLC监测原料消失，室温加入(S)-吡咯烷-3-醇(40.3mg，0.46mmol)的二氯甲烷(2ml)溶液，室温搅拌20分钟反应完毕，加水淬灭，用二氯甲烷萃取2次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱纯化，得192mg中间体1-17，收率75.3％。
1H NMR(400MHz，CDCl 3)δ8.47(d，J＝8.3Hz，1H)，7.53-7.51(m，2H)，7.47-7.35(m，4H)，7.25(d，J＝8.4Hz，1H)，7.06-6.96(m，2H)，5.96(s，2H)，5.78(s，2H)，5.23(s，2H)，4.79-4.56(m，4H)，4.49-4.45(m，1H)，3.81-3.72(m，2H)，3.68-3.58(m，5H)，3.46-3.43(m，1H)，2.56(q，J＝7.6Hz，2H)，2.09-1.96(m，2H)，1.16(t，J＝7.5Hz，3H)，0.99-0.89(m，4H)，0.02(s，9H)，-0.05(s，9H).
3.合成式(I)化合物：(S)-(2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-4，6-二氢吡咯并[3，4-d]咪唑-5-(1H)-基)(3-羟基吡咯烷-1-基)甲酮
将中间体1-17(22.00g，26.60mmol，1.00eq)加入到1L的三口瓶中，然后再加入DCM(330mL，15V)溶解后降温到-70℃至-6()℃， 磁力搅拌，用N 2置换三次，缓慢滴加BCl 3(133mL，132.99mmol，5.00eq，1N in DCM)，约15min滴加完毕，滴加过程保持内温不超过-55℃，滴加完之后继续在-70℃至-60℃搅拌反应1h。向反应体系缓慢滴加50mL甲醇淬灭反应，淬灭温度不超过-50℃，约15min滴加完毕，体系自然回温至15-20℃，反应液在38℃真空下浓缩，残渣加入200mL甲醇和氨水，在40℃搅拌反应30min后，旋蒸除去甲醇，体系(水相)中有大量浅黄色固体析出，将体系过滤得到固体，固体烘干得到粗品(15.00g)。粗品送Prep-HPLC纯化(正相，0.1％氨水碱性体系，乙醇体系)，所得馏分在40℃浓缩至200mL时有大量固体析出，过滤，得到浅黄色固体粉末5.90g，即式(I)化合物。
1H NMR(400MHz，DMSO-d6)δ13.25(s，1H)，12.69(s，1H)，9.84(s，1H)，8.32(d，J＝8.4Hz，1H)，7.39(s，1H)，7.11(d，J＝9.2Hz，1H)，7.03(d，J＝12Hz，1H)，6.92(d，J＝9.2Hz，1H)，4.92(s，1H)，4.74-4.53(m，2H)，4.51-4.35(m，2H)，4.27(s，1H)，3.58-3.49(m，2H)，3.45-3.37(m，1H)，3.23(m，1H)，2.49-2.45(m，2H，被DMSO-d6的溶剂峰部分遮挡)，1.92-1.71(m，2H)，1.02(t，J＝7.6Hz，3H)
LC-MS：C 25H 26FN 6O 3[M+H] +m/z计算值为477.2，检测值为477.1.
实施例2：式(I)化合物的药理学活性评价I
1.实验原理
通过基于JAK1、JAK2、JAK3、TYK2激酶的药物筛选体系来检测化合物分别对于激酶活性的抑制能力。激酶与其底物IRS1，IGF1Rtide，Poly(4∶1Glu，Tyr)进行酶学反应，消耗ATP产生ADP，利用ADP-Glo试剂和发光的方法检测产物的量用以反映激酶的活性。
2.实验方案
2.1实验材料和仪器
序号 名称 来源 货号
1 HEPES Life Technologies 15630-080
2 BRIJ 35 detergent(10％) Sigma 1018940100
3 MgCl2 Sigma M1028
4 EGTA Sigma E3889
5 ADP-Glo Kinase Assay Promega V9101
6 JAK1 Carna 08-144
7 JAK2 Carna 08-045
8 JAK3 Carna 08-046
9 TYK2 Carna 08-147
10 ATP Promega V915B
11 IRS1 Signalchem I40-58-1000
12 IGF1Rtide Signalchem I15-58
13 Poly(4∶1 Glu，Tyr) Sigma P0275
15 384 polystyrene shallow flat white Greiner 784075
16 384-Well Polypropylene microplate labcyte PP-0200
17 Biotek酶标仪 Biotek Synergy 4
18 微孔板低速离心机 湘智 TD5B
2.2实验方法
2.2.1激酶反应试剂配方
2.2.1.1 1X激酶反应缓冲液(400mL)
名称 储液浓度 体积 终浓度
HEPES 1M(20X) 20mL 50mM
MgCl 2 1M(100X) 4mL 10mM
BRIJ-35 10％(1000X) 400μL 0.01％
EGTA 粉末 152mg 1mM
ddH 2O   375.6mL  
2mM DTT，现用现配
2.2.1.2 2X激酶配方
Figure PCTCN2021112352-appb-000010
Figure PCTCN2021112352-appb-000011
Figure PCTCN2021112352-appb-000012
Figure PCTCN2021112352-appb-000013
2.2.1.3 4X底物混合物配方
Figure PCTCN2021112352-appb-000014
Figure PCTCN2021112352-appb-000015
Figure PCTCN2021112352-appb-000016
Figure PCTCN2021112352-appb-000017
2.2.1.4待测化合物
化合物名称 质量/mg 分子量 浓度/mM
Filgotinib 5.0 420.5 10
式(I)化合物 1.5 476.51 10
2.2.2激酶反应实验步骤
2.2.2.1 JAK1&JAK2激酶反应实验步骤
a)用100％DMSO将Filgotinib(10mM储液)原倍，待测化合物稀释5倍，在96孔稀释板中进行4倍等比稀释，取1μL的化合物加入49μL的激酶反应缓冲液中，在微孔板振荡器上震荡20min。
b)转移2μL的激酶(2.2.1.2步骤中制备)到384反应板中，加入1μL的待测化合物(a步骤中准备)到384反应板中(Greiner，784075)，1000rpm/min，离心1min，25℃孵育10min。
c)转移1μL底物混合物(2.2.1.3步骤中制备)到384反应板中，1000rpm/min，离心1min，25℃孵育60min。在反应体系中，Filgotinib终浓度50，12.5，3.125，0.7812，0.1953，0.0488，0.0122，0.003，0.00076，0.00019，0.000047μM。待测化合物终浓度：10，2.5，0.625，0.15625，0.039，0.0097，0.0024，0.0006，0.0015，0.000038，0.0000095μM。DMSO终浓度均为0.5％。
d)转移4μL ADP-Glo到384反应板中1000rpm/min，离心1min，25℃孵育40min。
e)转移8μL Detection溶液到384反应板中1000rpm/min，离心1min，25℃孵育40min。
f)使用Biotek多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。
2.2.2.2 JAK3&TYK2激酶反应实验步骤
a)用100％DMSO将Filgotinib(10mM储液)原倍，待测化合物稀释5倍，在96孔稀释板中进行3倍等比稀释，取1μL的化合物加入49μL的激酶反应缓冲液中，在微孔板振荡器上震荡20min。
b)转移2μL的激酶(2.2.1.2步骤中制备)到384反应板中，加入1μL的待测化合物(a步骤中准备)到384反应板中(Greiner，784075)，1000rpm/min，离心1min，25℃孵育10min。
c)转移1μL底物混合物(2.2.1.3步骤中制备)到384反应板中，1000rpm/min，离心1min，25℃孵育60min。在反应体系中，Filgotinib终浓度50，16.67，5.555，1.851，0.617，0.205，0.0686，0.0228，0.00762，0.0025μM。待测化合物终浓度：10，3.33，1.11，0.37，0.12，0.04，0.014，0.0046，0.0015，0.0005μM。DMSO终浓度均为0.5％。
d)转移4μL ADP-Glo到384反应板中1000rpm/min，离心1min，25℃孵育40min。
e)转移8μL Detection溶液到384反应板中1000rpm/min，离心1min，25℃孵育40min。
f)使用Biotek多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。
2.2.3实验数据处理方法
化合物抑制率(％inh)＝(阴性对照-化合物)/(阴性对照-阳性对照)×100％
阴性对照：DMSO
阳性对照：10uM/100uM/30uM Filgotinib
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度)：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X：化合物浓度log值
Y：化合物抑制率(％inh)
Z’因子计算方程：
Z’＝1-3(SDmin+SDmax)/(AVEmax-AVEmin)
其中：
Min为阳性对照10uM/100uM/30uMFilgotinib RLU值，Max为阴性对照DMSO RLU值。
SD为标准误差，AVE为RLU平均值。
3.结果
化合物检测结果见下表：
Figure PCTCN2021112352-appb-000018
测试结果表明：实施例1得到的式(I)化合物的抑制活性远远高于Filgotinib(高两个数量级以上)，能够在极低的浓度下有效抑制JAK1、JAK2、JAK3、TYK2。
实施例3：式(I)化合物的药理学活性评价II
1.实验目的
本实施例旨在检测化合物在JAK细胞活性实验-人T细胞增殖实验中的活性。
2.实验方案
2.1实验材料和仪器
Figure PCTCN2021112352-appb-000019
2.2实验方法
2.2.1待测化合物储液的配制
化合物储液的配制
Figure PCTCN2021112352-appb-000020
2.2.2激酶反应实验步骤
a)根据人总T细胞分选试剂盒从人PBMC中分选出T细胞。
b)用anti-CD3抗体和anti-CD28抗体刺激T细胞，在37℃、5％CO 2培养箱中孵育72h。
c)收集T细胞，并用PBS洗涤细胞。
d)用Echo 550转移40nL稀释好的待测化合物至384孔板。
e)将T细胞(c步骤中准备)种植到384孔反应板(d步骤中准备)，35μL/孔，1000rpm离心1min，37℃、5％CO 2孵育。
f)加入5μL/孔人重组IL-2蛋白，终浓度为10ng/mL，1000rpm离心1min，37℃、5％CO2孵育72h。
g)加入20μL/孔Celltiter Glo缓冲液，1000rpm离心1min，350g混匀2min，在室温孵育30min。
h)在EnVision多功能读板机上读取lumilencence信号值。
2.2.3实验数据处理方法
化合物抑制率(％inh)＝(阴性对照-化合物)/(阴性对照-阳性对照)×100％
阴性对照：DMSO的读值
阳性对照：10uM Tofacitinib的读值
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度)：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X：化合物浓度log值
Y：化合物抑制率(％inh)
3.结果
化合物检测结果见下表：
化合物 IC50(nM)
Tofacitinib 21.74
式(I)化合物 13.01
以上结果表明：式(I)化合物在活性实验-IL-2诱导的人T细胞增殖实验中显示出优于Tofacitinib的活性。
实施例4：式(I)化合物的晶型研究
通过不同的结晶方法来研究实施例1中的式(I)化合物(因为其为碱性化合物，在后文有时也称为“游离碱”)的多晶型现象，通过X射线粉末衍射(XRPD)、热重分析(TGA)、差示扫描量热(DSC)、核磁共振氢谱(1H NMR)等方法对得到各种晶型进行表征和鉴定，以便为药物制剂的生产和配制提供基础和依据。
一、仪器和测定方法
1)X射线粉末衍射(XRPD)
XRPD图在PANalytical X射线粉末衍射分析仪上采集，扫描参数如下表所示。
表1：XRPD测试参数
Figure PCTCN2021112352-appb-000021
Figure PCTCN2021112352-appb-000022
2)热重分析(TGA)和差示扫描量热(DSC)
TGA和DSC图分别在TA Discovery TGA 5500热重分析仪和TA Q2000/Discovery DSC 2500差示扫描量热仪上采集，下表列出了测试参数。
表2：TGA和DSC测试参数
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铝盘，敞开 铝盘，压盖/不压盖
温度范围 室温-设置终点温度 室温/25℃-设置终点温度
扫描速率(℃/分钟) 10 10
保护气体 氮气 氮气
3)液态核磁( 1H NMR)
液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d6作为溶剂。
二、具体实验过程和结果
1.晶型A的制备和表征
将实施例1获得的式(I)化合物5.00g加入到三口瓶中，加入100mL甲醇升温至50～55℃搅拌，体系变得粘稠，又加入50mL甲醇，继续搅拌5h。过滤，滤饼用20mL甲醇淋洗，45℃下真空干燥8h，最终得到3.7g式(I)化合物的一种晶体，命名为晶型A。
晶型A的XRPD测试结果见图1，具体数据如下：
表3：游离碱晶型A的XRPD数据
Figure PCTCN2021112352-appb-000023
晶型A的TGA/DSC测试结果见图2，从图中可知，将晶型A加热至200℃失重4.4％，推测来自样品中溶剂或水的脱除，在50-290℃范围内可观察到多个热信号。
晶型A的 1H NMR中未观察到相应溶剂MeOH残留，说明TGA中4.4％的失重来自水的脱除，提示晶型A可能为水合物。
为了研究晶型A的属性，对晶型A开展了加热实验。氮气保护下将晶型A加热至190℃并降至室温后，取出样品暴露在空气中用于XRPD测试，测试结果见图3，显示样品晶型未变，同时可观察到部分衍射峰相对强度降低。结合TGA/NMR结果，加热后结晶度的变化推测由水的脱除引起，晶型A可能为水合物。
为进一步确定晶型A的属性，对晶型A开展了变温XRPD测试，结果见图4。显示在30℃条件下，样品经过氮气吹扫20分钟后晶型未变；在氮气吹扫下加热至190℃并降至30℃后，均得到仅在氮气保护下存在的无水晶型D(不同温度下衍射峰位置的偏移可能与高温引起的晶格膨 胀相关)。综合以上晶型A的TGA/DSC/NMR结果，可以认定晶型A加热至190℃后的晶型变化由样品中水的脱除引起，晶型A为水合物。
2.晶型B的制备和表征
将晶型A在EtOH中室温悬浮搅拌三天后，离心分离并将固体置于室温下真空干燥约两小时后得到晶体，命名为晶型B。
晶型B的XRPD结果如图5所示，具体数据如下：
表4：游离碱晶型B的XRPD数据
Figure PCTCN2021112352-appb-000024
晶型B的TGA/DSC结果如图6所示。晶型B加热至150℃失重6.0％，推测来自样品中溶剂或水的脱除；在319.1℃(起始温度)处可观察到一个吸热信号，推测来自样品熔融。
晶型B的 1H NMR显示晶型B中EtOH与化合物(I)的摩尔比为 0.12∶1.00(1.1wt％)。
为研究晶型B的属性，对晶型B开展了变温XRPD测试，结果如图7所示。晶型B样品在氮气下吹扫20分钟后晶型未变；在氮气吹扫下加热至150℃，与晶型B相比，样品衍射峰位置略有偏移，推测与高温下晶格膨胀相关；降温至30℃后，样品的衍射峰位置与晶型B一致，且衍射峰的偏移消失，结合TGA/DSC结果，推测TGA失重来自样品表面的水分或溶剂残留，判断晶型B为无水晶型。
3.晶型C的制备和表征
将水合物晶型A在含有L-抗坏血酸的丙酮/H 2O(v/v，19∶1)体系中室温悬浮搅拌三天，离心分离并将固体置于室温下真空干燥约两小时后得到晶体，命名为晶型C。
晶型C的XRPD结果如图8所示，具体数据如下：
表5：游离碱晶型C的XRPD数据
Figure PCTCN2021112352-appb-000025
晶型C的TGA/DSC结果如图9所示：样品加热至100℃失重6.4％，相应地在78.1℃(起始温度)处可观察到一个热信号，推测来自样品中溶剂或水的脱除；在279.4和303.8℃(起始温度)处可观察到重叠的热 信号。
晶型C的 1H NMR显示晶型C中丙酮与化合物(I)的摩尔比为0.06∶1.00(0.7wt％)。结合TGA结果，推测TGA中6.4％的失重基本来自水的脱除，晶型C可能为水合物。
为了研究晶型C的属性，对晶型C开展了加热实验。氮气保护下将晶型C加热至150℃并降至室温后，取出样品暴露在空气中用于XRPD测试，结果(图10)，显示加热后样品结晶度明显降低。结合核磁及TGA结果，推测加热后结晶度的降低由水的脱除引起，判断晶型C为水合物。
4.晶型D的制备和表征
将晶型A在氮气保护下加热至190℃并降至30℃后得到，XRPD结果如图11所示。
将晶型D暴露在空气中约2小时后测试XRPD，结果(图12)显示已转变为晶型A。推测晶型D仅能在氮气保护下存在，暴露在空气中将快速吸收环境中的水份转为晶型A。由于晶型D不稳定，未开展进一步研究。
5.晶型E的制备和表征
将水合物晶型A在EtOH中50℃悬浮搅拌一天后，离心分离并将固体置于室温，敞口干燥过夜后得到晶体，命名为晶型E。
晶型E的XRPD结果如图13所示，具体数据如下：
表6：游离碱晶型E的XRPD数据
Figure PCTCN2021112352-appb-000026
晶型E的TGA/DSC结果如图14所示：样品加热至150℃失重7.9％，相应地在43.5℃(起始温度)处可观察到一个热信号，推测来自样品中溶剂或水的脱除；在187.1℃(起始温度)处可观察到一个吸热信号。
晶型E的 1H NMR显示EtOH与化合物(I)的摩尔比为0.62∶1.00(5.7wt％)，结合TGA结果，推测TGA中失重来自EtOH和水的脱除。
为了研究晶型E的属性，对晶型E开展了加热实验。氮气保护下将晶型E加热至120℃并降至室温后，取出样品暴露在空气中用于XRPD测试，结果如图15所示，结果显示样品晶型未变。核磁结果显示：加热后样品中EtOH与化合物(I)的摩尔比为0.65∶1.00(5.7wt％)。
为进一步研究晶型E的属性，对晶型E开展了变温XRPD测试。结果如图16所示：样品在氮气下吹扫20分钟后，晶型未变；在氮气吹扫下加热至120℃，样品已转变为仅在氮气保护下存在的无水晶型D(少数衍射峰位置与晶型D相比有偏移，可能与不同温度下晶格膨胀程度不同相关，参比晶型D的XRPD图谱为30℃测得)；继续加热至210℃，样品已转为无定形；降温至30℃后，样品仍为无定形，且观察到样品成胶，推测样品已熔融。与将晶型E加热至120℃后暴露在空气中的实验结果(晶型未变)相比，推测两次加热结果的差异与样品加热后是否暴露在空气中相关，即无水晶型D暴露在空气中加热后能快速吸附环境中的水份转为晶型E，推测水分子参与晶型E的晶格组成。
6.晶型F的制备和表征
将水合物晶型A及无水晶型B的晶种在丙酮中50℃悬浮搅拌一天后，离心分离并将固体置于室温敞口干燥过夜后，得到晶体，命名为晶型F。
晶型F的XRPD结果见图17，具体数据如下：
表7：游离碱晶型F的XRPD数据
Figure PCTCN2021112352-appb-000027
晶型F的TGA/DSC结果(图18)显示，样品加热至170℃失重10.5％，相应地在119.7℃(起始温度)处可观察到一个热信号，推测来自样品中溶剂或水的脱除；在209.3、316.3℃(起始温度)处可观察两个热信号。晶型F的 1H NMR显示，晶型F中丙酮与化合物(I)的摩尔比为0.68∶1.00(7.7wt％)，结合TGA结果，推测TGA中失重大部分来自丙酮的脱除。
为了研究晶型F的属性并研究DSC中热信号可能的来源，对晶型F开展了加热实验。氮气保护下将晶型F加热至170℃并降至室温后，取出样品暴露在空气中用于XRPD测试，结果(图19)显示样品已转为水合物晶型G，核磁结果显示加热后的样品中未观察到明显丙酮残留。综合加热前、后的数据，XRPD中可观察到晶型的变化，TGA/NMR显示加热后脱除的组分主要为丙酮，加热后晶型F转为晶型G可能由丙酮的脱除引起，判断晶型F可能为丙酮溶剂合物。
7.晶型G的制备和表征
将丙酮溶剂合物晶型F在氮气保护下加热至170℃并降至室温后，取出样品暴露在空气中，得到晶体，命名为晶型G。
晶型G的XRPD结果如图20所示，具体数据如下：
表8：游离碱晶型G的XRPD数据
Figure PCTCN2021112352-appb-000028
晶型G的TGA/DSC结果(图21)显示：晶型G加热至100℃失重4.7％，相应地在81.2℃(起始温度)处可观察到一个热信号，推测来自样品中溶剂或水的脱除；在209.6、314.0℃(起始温度)处可观察到两个热信号。晶型G的核磁结果显示，样品中未观察到明显丙酮残留，晶型G可能为水合物或无水晶型。
通过变温XRPD对晶型G开展了进一步研究(以晶型F为起始原料进行研究)。结果(图22)显示：将晶型F在氮气下吹扫20分钟后，晶型未变；在氮气吹扫下加热至170℃，已转变为仅在氮气保护下存在的无水晶型J；降温至30℃后将样品开盖暴露在空气中测试XRPD，结果显示已转为晶型G，推测晶型J暴露在空气中后吸收环境中的水份转为晶型G，晶型G为水合物。
8.晶型J的制备和表征
通过将丙酮溶剂合物晶型F在氮气保护下加热至170℃并降至30℃， 得到晶体，命名为晶型J。晶型J的XRPD结果如图23所示。
将晶型J暴露在空气中，再次测试XRPD，结果(图24)显示已转变为水合物晶型G，推测晶型J仅能在氮气保护下存在，暴露在空气中将快速吸收环境中的水份转为晶型G。由于晶型J不稳定，未开展进一步研究。
9.晶型H的制备和表征
将晶型E在氮气保护下加热至150℃并降至室温后，取出样品暴露在空气中，得到晶体，命名为晶型H，其XRPD结果如图25所示。
10.晶型I的制备和表征
通过变温XRPD将水合物晶型C在氮气保护下加热至150℃并降至室温后得到晶体，命名为晶型I，其XRPD结果如图26所示。
实施例5：式(I)化合物的盐型研究
以实施例1得到的式(I)化合物为起始物料，选用不同的酸对其进行成盐研究，并在不同条件下进行结晶，研究各盐的多晶型现象，通过X射线粉末衍射(XRPD)、热重分析(TGA)、差示扫描量热(DSC)、核磁共振氢谱(1H NMR)、高效液相色谱/离子色谱(HPLC/IC)等方法对得到各种晶型进行表征和鉴定，以便为药物制剂的生产和配制提供基础和依据。
一、研究中所用的主要试剂、仪器和测定方法
1.实验中所用主要溶剂的缩写与相应中文名称对照如下表所示。
表9：试验中选用溶剂的中英文名称对照表
简写 中文 简写 中文
MeOH 甲醇 MTBE 甲基叔丁基醚
EtOH 乙醇 Anisole 苯甲醚
IPA 异丙醇 n-Heptane 正庚烷
Acetone 丙酮 Toluene 甲苯
MIBK 甲基异丁基酮 DCM 二氯甲烷
EtOAc 乙酸乙酯 ACN 乙腈
IPAc 乙酸异丙酯 DMSO 二甲基亚砜
THF 四氢呋喃 CHCl 3 氯仿
2-MeTHF 2-甲基四氢呋喃 DMF N，N-二甲基甲酰胺
1，4-Dioxane 1，4-二氧六环 H 2O 水
2.X射线粉末衍射(XRPD)
XRPD图在PANalytical X射线粉末衍射分析仪上采集，扫描参数如表10所示。
表10：XRPD测试参数
Figure PCTCN2021112352-appb-000029
3.热重分析(TGA)和差示扫描量热(DSC)
TGA和DSC图分别在TA Q5000/Discovery TGA 5500热重分析仪和TA Discovery DSC 2500差示扫描量热仪上采集，表11列出了测试参数。
表11：TGA和DSC测试参数
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铝盘，敞开 铝盘，压盖
温度范围 室温-设置终点温度 25℃-设置终点温度
扫描速率(℃/分钟) 10 10
保护气体 氮气 氮气
4.动态水分吸附(DVS)
动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl，Mg(NO 3)2和KCl的潮解点校正。DVS测试参数列于表12。
表12：DVS测试参数
Figure PCTCN2021112352-appb-000030
5.液态核磁( 1H NMR)
液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d6作为核磁溶剂。
6.pH计(pH)
pH通过Sartorius PB-10pH计采集。
7.高效液相色谱(HPLC)及离子色谱(IC)
样品纯度及溶解度通过高效液相色谱采集，无机酸体系的盐型样品摩尔比通过高效液相色谱及离子色谱采集，高效液相色谱在Agilent 1290 HPL上测试，离子色谱在Thermo ICS1100上采集。具体仪器和测试参数见表13及表14。
表13：溶解度，摩尔比及纯度HPLC测试参数
Figure PCTCN2021112352-appb-000031
*：配置时加硫酸助溶。
表14：IC测试参数
参数 设定值
色谱柱 IonPac AS18 Analytical Column(4×250mm)
流动相 20mM氢氧化钠
进样量 25微升
流速 1.0毫升/分钟
样品室温度 35℃
柱温 35℃
电流 80mA
运行时间 40分钟
二、盐的制备和表征
1.磷酸盐晶型A的制备和表征
以式(I)化合物水合物晶型A为原料制备磷酸盐，制备具体步骤为：
1)量取24μL浓磷酸(约85％)至20mL玻璃小瓶中；
2)称取约200mg的式(I)化合物水合物晶型A至20mL玻璃小瓶中，并加入10mL Acetone/H 2O(v/v，19∶1)；
3)25℃悬浮搅拌约3天后得到乳白色悬浊液，室温减压抽滤得到固体，将固体转移至室温真空干燥3小时得到白色粉末状样品，XRPD结果显示样品为晶体，同时HPLC/IC结果显示式(I)化合物与磷酸根的摩尔比为1.00∶1.25(推测磷酸根含量偏高可能由未反应的磷酸残留导致)；
4)为除去可能残留的磷酸，室温下向第3步得到的样品中加入总计2mL EtOAc进行悬浮搅拌，约5小时后离心分离，固体转至室温真空干燥约13小时，得到磷酸盐晶型A。
磷酸盐晶型A的XRPD图如图27所示，具体数据见下表：
表15：磷酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000032
磷酸盐晶型A的TGA/DSC数据如图28所示：样品加热至190℃时失重为1.8％，推测来自样品中水或溶剂的脱除，在279.3℃(起始温度)处可观察到一个尖锐吸热峰，推测来自样品熔融。基于TGA中样品熔融前少量的失重以及DSC中仅有单一熔融吸热峰，判断磷酸盐晶型A可能为无水晶型。HPLC/IC结果显示，样品中式(I)化合物与磷酸根的摩尔比为1∶1。
2.马来酸盐晶型A的制备和表征
以式(I)化合物水合物晶型A为原料制备马来酸盐，制备具体步骤为：
1)称取约200mg式(I)化合物水合物晶型A至20mL玻璃小瓶中；
2)加入53mg马来酸至20mL玻璃小瓶中，并加入10mL Acetone/H 2O(v/v，19∶1)；
3)25℃悬浮搅拌约3天后得到乳白色悬浊液，室温减压抽滤得到固体，将固体转移至室温真空干燥3小时得到白色粉末状样品，XRPD结果显示样品为晶体，同时核磁结果显示样品中式(I)化合物与马来酸的摩尔比为1.00∶0.86，推测样品中存在少量未反应的式(I)化合物，样品成盐可能不充分；
4)为促进样品充分成盐，向第3步得到的163mg样品中加入10mg马来酸，在2mL EtOAc中50℃搅拌约14小时后，固体转至室温真空干燥约2小时，干燥后得到晶体，命名为马来酸盐晶型A，进行XRPD及核磁测试。
马来酸盐晶型A的XRPD结果见图29，具体数据如下：
表16：马来酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000033
核磁结果显示式(I)化合物与马来酸的摩尔比为1∶1。
马来酸盐晶型A的TGA/DSC见图30，结果显示样品加热至150℃失重3.3％，在211.2和278.1℃(起始温度)处可观察到两个热信号。
3.甲磺酸盐晶型B的制备和表征
以式(I)化合物水合物晶型A为原料制备甲磺酸盐，制备具体步骤 为：
1)称取约200mg式(I)化合物水合物晶型A至20mL玻璃小瓶中；
2)加入54mg甲磺酸至20mL玻璃小瓶中，并加入10mL EtOAc；
3)25℃悬浮搅拌约3天后得到乳白色悬浊液，室温减压抽滤得到固体，将固体转移至室温真空干燥3小时得到白色粉末状样品，即甲磺酸盐晶型B。
由此获得的甲磺酸盐晶型B的XRPD结果如图31所示，具体数据如下：
表17：甲磺酸盐晶型B的XRPD数据
Figure PCTCN2021112352-appb-000034
甲磺酸盐晶型B的核磁结果显示样品中式(I)化合物与甲磺酸的摩尔比为1∶1。
甲磺酸盐晶型B的TGA/DSC数据如图32所示，样品加热至190℃时失重为2.2％，推测来自样品中水或溶剂的脱除，在234.4℃(峰值温度)和264.1℃(起始温度)处可观察到两个吸热信号。基于TGA中样品分解前少量缓慢的失重以及DSC中190℃之前较平滑的曲线，推测甲 磺酸盐晶型B为无水晶型。
4.盐酸盐晶型A的制备和表征
以式(I)化合物水合物晶型A为原料制备盐酸盐，制备具体步骤为：将式(I)化合物水合物晶型A与盐酸按照摩尔比1∶1在EtOAc中室温悬浮搅拌约3天后，离心分离，将固体转移至室温真空干燥2小时后获得盐酸盐晶型A。
盐酸盐晶型A的XRPD结果如图33所示，具体数据如下：
表18：盐酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000035
盐酸盐晶型A的TGA/DSC见图34，结果显示样品加热至240℃失重13.7％，在80.1、118.0℃(峰值温度)和224.5℃(起始温度)处可观察到三个吸热峰，在231.5℃(起始温度)处可观察到一个放热信号。HPLC/IC结果显示，盐酸盐晶型A中式(I)化合物与氯离子的摩尔比为1∶0.7(推测样品成盐可能不充分)。
5.酒石酸盐晶型A的制备和表征
以式(I)化合物水合物晶型A为原料制备酒石酸盐，制备具体步骤为：将式(I)化合物水合物晶型A与酒石酸按照摩尔比1∶1在EtOAc中室温悬浮搅拌约3天后，离心分离，将固体转移至室温真空干燥2小时后获得酒石酸盐晶型A。
酒石酸盐晶型A的XRPD结果如图35所示，具体数据如下：
表19：酒石酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000036
酒石酸晶型A的TGA/DSC见图36，结果显示样品加热至200℃失 重9.1％，在125.2和168.8℃(起始温度)处可观察到两个热信号。 1H NMR结果显示，酒石酸盐晶型A中式(I)化合物与酒石酸的摩尔比为1∶1(已扣除与式(I)化合物重叠的5个H)。
6.富马酸盐晶型A的制备和表征
以式(I)化合物水合物晶型A为原料制备富马酸盐，制备具体步骤为：将式(I)化合物水合物晶型A与富马酸按照摩尔比1∶1在Acetone/H 2O(19∶1，v/v)中室温悬浮搅拌约3天后，离心分离，将固体转移至室温真空干燥2小时后获得富马酸盐晶型A。
富马酸盐晶型A的XRPD结果如图37所示，具体数据如下：
表20：富马酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000037
富马酸晶型A的TGA/DSC见图38，结果显示样品加热至110℃失重7.5％，继续加热至250℃失重8.0％；样品在71.1、205.3、273.7和 299.4℃(起始温度)处可观察到多个热信号。 1H NMR结果显示，富马酸盐晶型A中式(I)化合物与富马酸的摩尔比为1∶0.6。
7.粘酸盐晶型A的制备和表征
以式(I)化合物水合物晶型A为原料制备粘酸盐，制备具体步骤为：将式(I)化合物水合物晶型A与粘酸按照摩尔比1∶1在Acetone/H 2O(19∶1，v/v)中室温悬浮搅拌约3天后，离心分离，将固体转移至室温真空干燥2小时后获得粘酸盐晶型A。
粘酸盐晶型A的XRPD结果如图39所示，具体数据如下：
表21：粘酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000038
Figure PCTCN2021112352-appb-000039
粘酸盐晶型A的TGA/DSC见图40，结果显示样品加热至100℃失重4.4％，继续加热至260℃失重26.4％，在69.8和210.4℃(起始温度)处可观察到两个热信号。 1H NMR结果显示，粘酸盐晶型A中式(I)化合物与粘酸的摩尔比为1∶1.4。
8.柠檬酸盐晶型A/B的制备和表征
以式(I)化合物水合物晶型A为原料制备柠檬酸盐，制备具体步骤为：将式(I)化合物水合物晶型A与柠檬酸按照摩尔比1∶1分别在EtOAc、Acetone/H 2O(19∶1，v/v)中室温悬浮搅拌约3天后，离心分离，将固体转移至室温真空干燥2小时后获得柠檬酸盐晶型A/B。
柠檬酸盐晶型A的XRPD结果如图41所示，具体数据如下：
表22：柠檬酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000040
柠檬酸盐晶型A的TGA/DSC见图42，结果显示样品加热至150℃ 失重9.1％，在68.2℃(峰值温度)、154.4和164.0℃(起始温度)处可观察到三个吸热峰。 1H NMR结果显示，柠檬酸盐晶型A中式(I)化合物与柠檬酸的摩尔比为1∶0.5。
柠檬酸盐晶型B的XRPD结果如图43所示，具体数据如下：
表23：柠檬酸盐晶型B的XRPD数据
Figure PCTCN2021112352-appb-000041
柠檬酸盐晶型B的TGA/DSC见图44，结果显示样品加热至100℃失重7.1％，继续加热至250℃失重6.8％；在73.1、280.2、301.6℃(起始温度)和179.7℃(峰值温度)处可观察到四个吸热峰。 1H NMR结果显示，柠檬酸盐晶型B中式(I)化合物与柠檬酸的摩尔比为1∶0.5。
9.对甲苯磺酸盐晶型A的制备和表征
以式(I)化合物水合物晶型A为原料制备对甲苯磺酸盐，制备具体步骤为：将式(I)化合物水合物晶型A与对甲苯磺酸按照摩尔比1∶1在Acetone/H 2O(19∶1，v/v)中室温悬浮搅拌约3天后，离心分离，将固体 转移至室温真空干燥2小时后获得对甲苯磺酸盐晶型A。
对甲苯磺酸盐晶型A的XRPD结果如图45所示，具体数据如下：
表24：对甲苯磺酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000042
对甲苯磺酸晶型A的TGA/DSC见图46，结果显示样品加热至150℃失重5.1％，在121.2和222.3℃(起始温度)处可观察到两个热信号。 1H NMR结果显示，对甲苯磺酸盐晶型A中式(I)化合物与对甲苯磺酸的摩尔比为1∶1。
10.苯磺酸盐晶型A/B的制备和表征
以式(I)化合物水合物晶型A为原料制备苯磺酸盐，制备具体步骤为：将式(I)化合物水合物晶型A与苯磺酸按照摩尔比1∶1分别在EtOH、Acetone/H 2O(v/v，19∶1)中室温悬浮搅拌约3天后，离心分离，将固体 转移至室温真空干燥2小时后获得苯磺酸盐晶型A/B。
苯磺酸晶型A的XRPD结果如图47所示，具体数据如下：
表25：苯磺酸盐晶型A的XRPD数据
Figure PCTCN2021112352-appb-000043
苯磺酸晶型A的TGA/DSC见图48，结果显示样品加热至150℃失重9.0％，在60-200℃处可观察到多个热信号。 1H NMR的结果显示，苯磺酸晶型A中式(I)化合物与苯磺酸的摩尔比为1∶1。
苯磺酸晶型B的XRPD结果如图49所示，具体数据如下：
表26：苯磺酸盐晶型B的XRPD数据
Figure PCTCN2021112352-appb-000044
苯磺酸晶型B的TGA/DSC见图50，结果显示样品加热至100℃失重4.6％，在90.1℃(峰值温度)和236.7℃(起始温度)处可观察到两个热信号。 1H NMR结果显示，苯磺酸晶型B中式(I)化合物与苯磺酸的摩尔比为1∶0.5。
三、盐型的筛选
根据以上制备所得盐型的物理表征数据，选择XRPD衍射峰强度较高(峰形尖锐)、TGA失重较小、DSC熔融温度较高、配体酸安全等级较高的磷酸盐晶型A、马来酸盐晶型A和甲磺酸盐晶型B进行下一步研究和评估。
表27：盐型样品表征数据汇总
Figure PCTCN2021112352-appb-000045
*：峰值温度；
#：通过IC及HPLC测定。
四、盐型的评估
对三种盐型样品从溶解度、固体稳定性、引湿性三个方面开展了体外评估。
1.试剂与耗材
表28：溶解度实验所用试剂
Figure PCTCN2021112352-appb-000046
2.溶解度
为评估三种盐型在不同介质中的溶解度，考察了室温条件下三批样品在生物溶媒(模拟胃液SGF和模拟肠液FeSSIF)中的动态溶解度(1、2、4、24小时)，以及它们在乙醇、水、pH＝7.4磷酸盐缓冲液中的24小时的溶解度。。具体步骤为：
1)称取约10mg盐型样品至HPLC小瓶中，分别加入1mL乙醇、水、pH＝7.4磷酸盐缓冲液。
2)另外称取约40mg盐型样品至5mL离心管中，分别加入4mL SGF、FeSSIF；
3)以～750rpm转速在25℃条件下磁力悬浮搅拌；
4)平衡相应时间后，室温离心分离固体及上清液，上清液用于pH及溶解度测试。
实验结果如表29所示，按照10mg/mL的盐型投料浓度，在SGF及FeSSIF中，三种盐型在SGF中的溶解度在0.05-0.30mg/mL之间，其中甲磺酸盐晶型B的溶解度相对较高；在FeSSIF中的溶解度在0.08-6.21mg/mL之间，其中甲磺酸盐晶型B、马来酸盐晶型A的溶解度相对较高。在水、乙醇及pH＝7.4磷酸盐缓冲液中，三种盐型在水中的溶解度在0.04-1.30mg/mL之间，其中磷酸盐晶型A溶解度相对较高；在乙醇中的溶解度在1.14-2.14mg/mL之间，其中马来酸盐晶型A溶解度相对较高；在pH＝7.4介质中的溶解度在0.02-0.15mg/mL之间，其中甲磺酸盐晶型B溶解度相对较高。
表29：三种盐型在不同介质中25℃溶解度汇总1
Figure PCTCN2021112352-appb-000047
S：API溶解度(mg/mL)；
NA：未测试pH。
表30：三种盐型在不同介质中25℃溶解度汇总2
Figure PCTCN2021112352-appb-000048
S：API溶解度(mg/mL)；
NA：未测试pH。
3.固体稳定性
为评估盐型的固体稳定性，将三批样品分别在25℃/60％RH和40℃/75％RH(封口膜包裹并扎6个小孔)条件下放置1周以评估其物理化学稳定性。对放置后的样品进行HPLC测试和XRPD表征，以检测样品纯度及晶型的变化，XRPD结果及HPLC结果显示，样品晶型及纯度均无明显变化，测试结果汇总在表31。
表31：三种盐型的稳定性测试结果小结
Figure PCTCN2021112352-appb-000049
#：相对纯度为稳定性样品纯度与起始样品纯度的比值。
4.引湿性
为评估盐型的引湿性，对三批样品开展DVS测试。DVS测试结果如图51、图52和图53所示，磷酸盐晶型A在80％RH/25℃吸湿增重0.6％，马来酸盐晶型A在80％RH/25℃下吸湿增重0.8％，甲磺酸盐晶型B在80％RH/25℃下吸湿增重1.3％，三批样品均略有引湿性。随着湿度进一步提高，可观察到三批样品吸湿增重相对更明显。另外，XRPD结果显示，三批样品测试DVS前、后晶型均无变化。
五、结论
1)对(S)-(2-(6-(2-乙基-5-氟-4-羟基苯基)-1H-吲唑-3-基)-4，6-二氢吡咯并[3，4-d]咪唑-5-(1H)-基)(3-羟基吡咯烷-1-基)甲酮的式(I)化合物进行了成盐和盐型筛选试验，基于XRPD、TGA、DSC、NMR或HPLC/IC表征结果，共发现10种不同的盐型(涉及12种晶型)。
2)根据XRPD衍射峰强度较高、TGA失重较小、DSC熔融温度较高、配体酸安全等级较高等标准，选择了式(I)化合物的磷酸盐晶型A、马来酸盐晶型A和甲磺酸盐晶型B进行了引湿性、溶解度、固体稳定性等方面的体外评估。
3)磷酸盐晶型A、马来酸盐晶型A和甲磺酸盐晶型B在SGF中溶解度为0.05-0.30mg/mL，在FeSSIF中溶解度为0.08-6.21mg/mL；在水 中溶解度为0.04-1.30mg/mL，在乙醇中溶解度为1.14-2.14mg/mL，在pH＝7.4磷酸盐缓冲液中溶解度为0.02-0.15mg/mL。三种样品在40℃/75％RH、25℃/60％RH条件下放置1周后，纯度及晶型均未发生明显变化。三种样品DVS结果显示吸湿增重0.6-1.3％，样品均略有引湿性，完成DVS测试后晶型均未变。综上所述，三批盐型在引湿性及固体稳定性方面均具有较好的性质。
实施例6：式(I)化合物的盐的药理学活性评价
1.实验原理
通过基于JAK1、JAK2、JAK3、TYK2激酶的药物筛选体系来检测小分子化合物分别对于激酶活性的抑制能力。激酶与其底物IRS1，IGF1Rtide，Poly(4∶1Glu，Tyr)进行酶学反应，消耗ATP产生ADP，利用ADP-Glo试剂和发光的方法检测产物的量用以反映激酶的活性。
2.实验方案
2.1实验材料和仪器
序号 名称 来源 货号
1 Tris 国药 30188336
2 DTT Sigma 43816
3 MgCl2 Sigma M1028
4 BSA PE CR84-100
5 ADP-Glo Kinase Assay Promega V9101
6 JAK1 Thermofisher PV4774
7 JAK2 Carna 08-045
8 JAK3 Carna 08-046
9 TYK2 Carna 08-147
10 ATP Promega V915B
11 IRS1 Signalchem I40-58-1000
12 IGF1Rtide Signalchem I15-58
13 Poly(4∶1 Glu，Tyr) Sigma P0275
15 384 polystyrene shallow flat white Greiner 784075
16 384-Well Polypropylene microplate labcyte PP-0200
17 Biotek酶标仪 Biotek Synergy 4
18 微孔板低速离心机 湘智 TD5B
2.2实验方法
2.2.1激酶反应试剂配方
2.1.1.1 1X激酶反应缓冲液(6mL)
名称 储液浓度 体积 终浓度
Tris 1M(25X) 240μL 40mM
MgCl2 1M(50X) 120μL 20mM
BSA 7.5％(75X) 80μL 0.1％
DTT 1M(500X) 3μL 0.5mM
ddH2O   5557μL  
2.2.1.2 2X激酶配方
Figure PCTCN2021112352-appb-000050
Figure PCTCN2021112352-appb-000051
Figure PCTCN2021112352-appb-000052
Figure PCTCN2021112352-appb-000053
2.2.1.3 4X底物混合物配方
Figure PCTCN2021112352-appb-000054
Figure PCTCN2021112352-appb-000055
Figure PCTCN2021112352-appb-000056
2.2.1.4待测化合物
Figure PCTCN2021112352-appb-000057
2.2.2激酶反应实验步骤
2.2.2.1激酶反应实验步骤
a)用100％DMSO将Tofacitinib及待测化合物(10mM储液)50倍稀释，在96孔稀释板中进行4倍等比稀释，共10个浓度，取1μL的化合物加入49μL的激酶反应缓冲液中，在微孔板振荡器上震荡20min。
b)转移2μL的激酶(2.2.1.2步骤中制备)到384反应板中，加入1μL的待测化合物(a步骤中准备)到384反应板中(Greiner，784075)，1000rpm/min，离心1min，25℃孵育10min。
c)转移1μL底物混合物(2.2.1.3步骤中制备)到384反应板中，1000rpm/min，离心1min，25℃孵育60min。在反应体系中，Tofacitinib及待测化合物的终浓度1000，250，62.5，15.625，3.906，0.977，0.244，0.061，0.015，0.0038，nM。DMSO终浓度均为0.5％。
d)转移4μL ADP-Glo到384反应板中1000rpm/min，离心1min，25℃孵育40min。
e)转移8μL Detection溶液到384反应板中1000rpm/min，离心1min，25℃孵育40min。
f)使用Biotek多功能读板机读取luminescence信号。信号强度用于表征激酶的活性程度。
2.2.3实验数据处理方法
化合物抑制率(％inh)＝(阴性对照-化合物)/(阴性对照-阳性对照)×100％
阴性对照：DMSO
阳性对照：1000nM Tofacitinib
利用以下非线性拟合公式来得到化合物的IC50(半数抑制浓度)：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X：化合物浓度log值
Y：化合物抑制率(％inh)
Z’因子计算方程：
Z’＝1-3(SDmin+SDmax)/(AVEmax-AVEmin)
其中：
Min为阳性对照10uM/100uM/30uMFilgotinib RLU值，Max为阴性对照DMSO RLU值。
SD为标准误差，AVE为RLU平均值。
3.结果
化合物检测结果见下表：
Figure PCTCN2021112352-appb-000058
测试结果表明：与式(I)化合物类似，与式(I)化合物的甲磺酸盐也具有JAK抑制活性，且其抑制活性远高于Tofacitinib(对JAK1和TYK2的抑制高一到个数量级以上)，能够在极低的浓度下有效抑制JAK1、JAK2、JAK3、TYK2。
虽然已经阐明并描述了本发明的特定实施方式，但并不意味着这些实施方式阐明了并描述了本发明的所有可能形式。更确切地，用在本说明书中的文字仅仅是描述性的文字并非限制性的。对于本领域技术人员明显的是，在不脱离本公开的一般范围的情况下，可以进行各种其他改变和修改。因此，在所附权利要求中，旨在包括在本申请范围内的所有这些改变和修改。

Claims (11)

  1. 一种化合物的固体形式，所述化合物是式(I)化合物
    Figure PCTCN2021112352-appb-100001
    、式(I)化合物的同位素标记化合物、式(I)化合物的光学异构体、式(I)化合物的几何异构体、式(I)化合物的互变异构体、式(I)化合物的异构体混合物、式(I)化合物的药学上可接受的盐、或这些化合物中任意一种的溶剂化物。
  2. 根据权利要求1所述的化合物的固体形式，其是晶体、无定形物或两者的混合物。
  3. 根据权利要求1或2所述的化合物的固体形式，其中所述化合物是式(I)化合物的药学上可接受的盐或其溶剂化物。
  4. 根据权利要求3所述的化合物的固体形式，其中所述化合物是式(I)化合物的盐酸盐、磷酸盐、马来酸盐、L-酒石酸盐、富马酸盐、粘酸盐、柠檬酸盐、对甲苯磺酸盐、甲磺酸盐、苯磺酸盐、或这些盐中任意一种的溶剂化物，优选是磷酸盐、马来酸盐、甲磺酸盐或其中任意一种的溶剂化物。
  5. 根据权利要求1所述的化合物的固体形式，其是以下晶型中的任意一种：
    1)式(I)化合物的磷酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自5.29±0.10°、7.47±0.10°、10.61±0.10°、19.16±0.10°和21.32 ±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自5.29±0.10°、7.47±0.10°、10.61±0.10°、15.94±0.10°、16.77±0.10°、18.68±0.10°、19.16±0.10°、21.32±0.10°及25.36±0.10°衍射角(2θ)处的一个或多个特征峰；
    2)式(I)化合物的马来酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自4.55±0.10°、8.78±0.10°、12.69±0.10°、13.96±0.10°、16.62±0.10°、17.61±0.10°、18.32±0.10°、25.39±0.10°、26.53±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.55±0.10°、8.78±0.10°、12.69±0.10°、13.74±0.10°、13.96±0.10°、16.62±0.10°、17.61±0.10°、18.32±0.10°、21.72±0.10°、25.39±0.10°、26.53±0.10°衍射角(2θ)处的一个或多个特征峰；
    3)式(I)化合物的甲磺酸盐晶型B，其粉末X-射线衍射图谱(XRPD)具有选自5.91±0.10°、9.22±0.10°、15.83±0.10°、17.73±0.10°、19.02±0.10°、25.01±0.10°、衍射角(2θ)处的一个或多个特征峰，优选地具有选自5.91±0.10°、9.22±0.10°、15.83±0.10°、17.73±0.10°、19.02±0.10°、20.61±0.10°、21.36±0.10°、23.18±0.10°、25.01±0.10°衍射角(2θ)处的一个或多个特征峰；
    4)式(I)化合物的盐酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自8.05±0.10°、17.11±0.10°、18.02±0.10°、20.84±0.10°、21.09±0.10°、22.77±0.10°、23.14±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自8.05±0.10°、15.04±0.10°、17.11±0.10°、18.02±0.10°、20.44±0.10°、20.84±0.10°、21.09±0.10°、22.07±0.10°、22.77±0.10°、23.14±0.10°衍射角(2θ)处的一个或多个特征峰；
    5)式(I)化合物的酒石酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自7.90±0.10°、8.69±0.10°、13.12±0.10°、13.43±0.10°、18.11±0.10°、21.28±0.10°、22.90±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自7.90±0.10°、8.69±0.10°、13.12±0.10°、13.43±0.10°、15.08±0.10°、17.17±0.10°、17.44±0.10°、18.11 ±0.10°、19.40±0.10°、20.74±0.10°、21.28±0.10°、22.90±0.10°、24.15±0.10°、24.95±0.10°衍射角(2θ)处的一个或多个特征峰；
    6)式(I)化合物的富马酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自4.96±0.10°、7.66±0.10°、10.21±0.10°、11.06±0.10°、14.74±0.10°、16.11±0.10°、22.87±0.10°、25.10±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.96±0.10°、7.66±0.10°、10.21±0.10°、11.06±0.10°、12.44±0.10°、14.74±0.10°、16.11±0.10°、19.25±0.10°、22.87±0.10°、23.54±0.10°、24.27±0.10°、25.10±0.10°、25.37±0.10°衍射角(2θ)处的一个或多个特征峰；
    7)式(I)化合物的粘酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自4.98±0.10°、10.22±0.10°、11.07±0.10°、14.75±0.10°、14.94±0.10°、16.13±0.10°、19.65±0.10°、30.79±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.98±0.10°、7.69±0.10°、10.22±0.10°、11.07±0.10°、14.75±0.10°、14.94±0.10°、16.13±0.10°、19.65±0.10°、21.51±0.10°、22.92±0.10°、30.79±0.10°衍射角(2θ)处的一个或多个特征峰；
    8)式(I)化合物的柠檬酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自4.85±0.10°、6.42±0.10°、14.63±0.10°、17.12±0.10°、20.75±0.10°、25.34±0.10°、衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.85±0.10°、6.42±0.10°、7.64±0.10°、14.63±0.10°、15.40±0.10°、17.12±0.10°、18.12±0.10°、18.84±0.10°、19.37±0.10°、20.75±0.10°、25.34±0.10°、衍射角(2θ)处的一个或多个特征峰；
    9)式(I)化合物的柠檬酸盐晶型B，其粉末X-射线衍射图谱(XRPD)具有选自4.96±0.10°、7.67±0.10°、10.20±0.10°、11.04±0.10°、14.73±0.10°、19.23±0.10°、22.86±0.10°、23.54±0.10°、24.28±0.10°、25.08±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.96±0.10°、7.67±0.10°、10.20±0.10°、11.04±0.10°、12.42±0.10°、14.73±0.10°、16.09±0.10°、17.55±0.10°、19.23±0.10°、22.86 ±0.10°、23.54±0.10°、24.28±0.10°、25.08±0.10°、27.91±0.10°衍射角(2θ)处的一个或多个特征峰；
    10)式(I)化合物的对甲苯磺酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自5.90±0.10°、9.34±0.10°、14.87±0.10°、15.33±0.10°、17.88±0.10°、18.76±0.10°、19.71±0.10°、24.26±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自5.90±0.10°、9.34±0.10°、12.99±0.10°、14.87±0.10°、15.33±0.10°、16.10±0.10°、17.88±0.10°、18.76±0.10°、19.34±0.10°、19.71±0.10°、20.39±0.10°、24.26±0.10°、24.99±0.10°衍射角(2θ)处的一个或多个特征峰；
    11)式(I)化合物的苯磺酸盐晶型A，其粉末X-射线衍射图谱(XRPD)具有选自5.82±0.10°、6.74±0.10°、11.85±0.10°、16.38±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自5.82±0.10°、6.74±0.10°、11.85±0.10°、16.38±0.10°、19.46±0.10°、20.20±0.10°衍射角(2θ)处的一个或多个特征峰；
    12)式(I)化合物的苯磺酸盐晶型B，其粉末X-射线衍射图谱(XRPD)具有选自4.93±0.10°、5.63±0.10°、9.02±0.10°、10.89±0.10°、14.84±0.10°、17.55±0.10°、18.84±0.10°、23.12±0.10°、25.55±0.10°、26.14±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.93±0.10°、5.63±0.10°、9.02±0.10°、10.30±0.10°、10.89±0.10°、11.43±0.10°、14.23±0.10°、14.84±0.10°、17.04±0.10°、17.55±0.10°、18.84±0.10°、19.66±0.10°、20.24±0.10°、22.71±0.10°、23.12±0.10°、24.91±0.10°、25.55±0.10°、26.14±0.10°衍射角(2θ)处的一个或多个特征峰。
  6. 根据权利要求1所述的化合物的固体形式，其是以下晶型中的任意一种：
    1)式(I)化合物水合物的晶型A，其粉末X-射线衍射图谱(XRPD)具有选自8.67±0.10°、13.39±0.10°、15.05±0.10°、17.38±0.10°、21.24±0.10°、22.86±0.10°、24.89±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自8.67±0.10°、11.53±0.10°、13.39±0.10°、 15.05±0.10°、17.38±0.10°、21.24±0.10°、21.63±0.10°、22.19±0.10°、22.86±0.10°、23.43±0.10°、24.89±0.10°衍射角(2θ)处的一个或多个特征峰；
    2)式(I)化合物的晶型B，其粉末X-射线衍射图谱(XRPD)具有选自7.70±0.10°、11.20±0.10°、12.46±0.10°、15.44±0.10°、18.17±0.10°、18.48±0.10°、19.27±0.10°、21.84±0.10°、22.94±0.10°、24.29±0.10°、25.40±0.10°、27.92±0.10°衍射角(2θ)处的一个或多个特征峰，优选地具有选自7.70±0.10°、11.20±0.10°、12.46±0.10°、15.44±0.10°、18.17±0.10°、18.48±0.10°、18.93±0.10°、19.27±0.10°、19.50±0.10°、20.83±0.10°、21.84±0.10°、22.94±0.10°、23.22±0.10°、24.29±0.10°、25.40±0.10°、26.74±0.10°、27.92±0.10°衍射角(2θ)处的一个或多个特征峰；
    3)(I)化合物水合物的晶型C，其粉末X-射线衍射图谱(XRPD)具有选自4.96±0.10°、7.66±0.10°、10.18±0.10°、11.07±0.10°、14.73±0.10°、22.87±0.10°衍衍射角(2θ)处的一个或多个特征峰，优选地具有选自4.96±0.10°、7.66±0.10°、10.18±0.10°、11.07±0.10°、12.43±0.10°、14.73±0.10°、16.10±0.10°、19.24±0.10°、22.87±0.10°、23.52±0.10°、24.27±0.10°、25.09±0.10°衍射角(2θ)处的一个或多个特征峰；
    4)式(I)化合物水合物的晶型G，其粉末X-射线衍射图谱(XRPD)具有选自6.42±0.10°、7.04±0.10°、7.69±0.10°、12.52±0.10°、15.81±0.10°、18.83±0.10°、22.85±0.10°、23.40±0.10°、衍射角(2θ)处的一个或多个特征峰，优选地具有选自6.42±0.10°、7.04±0.10°、7.69±0.10°、11.48±0.10°、12.52±0.10°、15.81±0.10°、18.83±0.10°、19.58±0.10°、22.85±0.10°、23.40±0.10°、25.31±0.10°、27.85±0.10°衍射角(2θ)处的一个或多个特征峰。
  7. 一种药物组合物，其包含如权利要求1-6中任意一项所述的化合物的固体形式和一种或多种药学上可接受的载体、佐剂或赋形剂。
  8. 根据权利要求7所述的药物组合物，其是分散液，包含药学上可接受的液体分散剂和分散于所述液体分散剂中的如权利要求1-6中任意一项所述的化合物的固体形式。
  9. 根据权利要求8所述的药物组合物，其是溶液，包含药学上可接受的溶剂和溶解在所述溶剂中的如权利要求1-6中任意一项所述的化合物的固体形式。
  10. 如权利要求1-6中任意一项所述的化合物的固体形式、或如权利要求7-9中任意一项所述所述的组合物在制备用于治疗和/或预防与JAK相关的疾病或病症的药物中的用途。
  11. 根据权利要求10所述的用途，其中所述与JAK相关的疾病或病症选自：关节炎，自身免疫疾病或病症，癌症或肿瘤，糖尿病，眼疾病、病症或病况，肠炎症、变态反应或病况，神经变性疾病，皮肤疾病、病况或病症(包括瘙痒症)，变态反应，哮喘和其它阻塞性气道疾病，移植排斥，流感病毒或者冠状病毒感染导致的重症肺炎。
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