JAK inhibitor compounds and their uses

Abstract

This invention relates to a JAK inhibitor compound and its uses. Specifically, the invention discloses compounds of formula (I) in solid form, or isotopically labeled compounds thereof, optical isomers, geometric isomers, tautomers, or mixtures of isomers, pharmaceutically acceptable salts thereof, or solvates thereof. The invention also relates to the medical applications of said compounds in solid form.

Description

TECHNICAL FIELD

[0001] The present application provides a novel compound having pharmaceutical activity, which can be used for inhibiting Janus kinase (JAK). The present application also relates to a composition comprising the compound, and the use of the compound and the composition in the field of medicine. BACKGROUND

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified into tyrosine and serine / threonine kinases. Inappropriate kinase activity due to mutation, overexpression or inappropriate regulation, dysregulation or deregulation, and overproduction or underproduction of growth factors or cytokines is implicated in many diseases, including but not limited to cancer, cardiovascular disease, allergy, asthma and other respiratory diseases, autoimmune disease, inflammatory disease, bone disease, metabolic disorder, and neurological and neurodegenerative disorders (e.g., Alzheimer's disease). Inappropriate kinase activity triggers a variety of biological cellular responses that are related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility involved in the diseases mentioned above and related diseases. Therefore, protein kinases have become an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases plays an important role in cytokine signal transduction (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al., Genome Biology 2004, 5, 253).

[0003] Since the first JAK was discovered in the early 1990s, the development of JAK inhibitors has gone through nearly 30 years. JAK is a family of intracellular non-receptor tyrosine kinases, which plays an important role in the cytokine receptor signal pathway through interaction with signal transducer and activator of transcription (STAT). The JAK / STAT signal pathway is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. Compared with other signal pathways, the transmission process of this signal pathway is relatively simple, which mainly consists of three components, i.e. tyrosine kinase associated receptor, tyrosine kinase JAK and signal transducer and transcriptional activator STAT.

[0004] Many cytokines and growth factors signal through the JAK-STAT pathway, including interleukins (e.g., 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 growth factor), and interferons (including IFN-a, IFN-β, IFN-γ, etc.), among others. These cytokines and growth factors have corresponding receptors on the cell membrane. The common feature of these receptors is that the receptors themselves do not have kinase activity, but the intracellular segment has a binding site for tyrosine kinase JAK. After the receptor binds to the ligand, the activation of JAK bound thereto phosphorylates the tyrosine residues of various target proteins to achieve signal transduction from the extracellular to the intracellular.

[0005] JAK is a cytoplasmic tyrosine kinase that transduces cytokine signals from membrane receptors to STAT transcription factors. As mentioned above, JAK is the abbreviation of English Janus kinase, and Janus is a two-faced god in Roman mythology who governs the beginning and end. It is called two-faced kinase because JAK can phosphorylate both the cytokine receptors bound thereto and multiple signal molecules containing specific SH2 domains. The JAK protein family includes four members: JAK1, JAK2, JAK3, and TYK2, which have seven JAK homology domains (JH) in structure, among which the JH1 domain is the kinase domain, which encodes the kinase protein; the JH2 domain is a "pseudo" kinase domain, which regulates the activity of JH1; and JH3-JH7 form a four-in-one domain, which regulates the binding of JAK to the receptor.

[0006] STAT is a class of cytoplasmic proteins that can bind to the target gene regulatory region DNA, and is the downstream substrate of JAK. Seven members of the STAT family have been found so far, 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 transcription activation region. Among them, the most conserved sequence and the most important functional segment is the SH2 domain, which has the same core sequence "GTFLLRFSS" as the SH2 domain of tyrosine kinase Src.

[0007] JAK-STAT signaling pathway is widely functional, involving cell proliferation, differentiation, apoptosis, and immune regulation in many important biological processes. Current researches on diseases and drug innovation are mostly focused on inflammatory diseases and tumor diseases. Among them, inflammatory diseases mainly include rheumatoid arthritis, atopic dermatitis, psoriasis, ulcerative colitis and Crohn's disease; while tumor diseases mainly involve myelofibrosis, polycythemia vera and essential thrombocytopenia. In addition, mutations in JAK molecules themselves can also cause acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), breast ductal carcinoma, non-small cell lung cancer (NSCLC), polycythemia vera (PV), essential thrombocytopenia (ET), idiopathic myelofibrosis (IMF), chronic myeloid leukemia (CML), etc. In addition, it has been reported that JAK-STAT signaling pathway is closely related to cytokine storm in Covid-19.

[0008] JAK is a very important drug target. JAK inhibitors developed for this target are mainly used for screening therapeutic drugs for hematological diseases, tumors, rheumatoid arthritis, psoriasis, etc. JAK-1, JAK-2 and TYK-2 are expressed in various cells in the human body, and JAK-3 is mainly expressed in various hematopoietic cells, mainly in bone marrow cells, thymus cells, NK cells and activated B lymphocytes, T lymphocytes. Studies have shown that JAK2 inhibitors are suitable for myeloproliferative diseases (Santos et al., Blood, 2010, 115: 1131; Barosi G. and Rosti V., Curr. Opin. Hematol., 2009, 16: 129; Atallah E. and Versotvsek S., 2009 Exp. Rev. Anticancer Ther. 9:663), and JAK3 inhibitors are suitable for immunosuppressants (e.g. U.S. Patent 6,313,129; Borie et al., Curr. Opin. Investigational Drugs, 2003, 4: 1297). In addition, JAK inhibitors are expected to be used to inhibit inflammatory response and reduce the risk of cytokine storm to reduce mortality in the treatment of severe pneumonia such as COVID-19 (Wei Luo et al., Trends in Pharmacological Science, 41(8)·June 2020, “Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19”). Literature also reports that JAK inhibitors have certain curative 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”).

[0009] At present, the JAK inhibitors approved by FDA and EMA include Tofacitinib (Tofacitinib), Ruxolitinib (Ruxolitinib), Oclacitinib (Oclacitinib), etc. JAK inhibitors in the late clinical stage include, for example, Filgotinib, Peficitinib, etc.

[0010] Tofacitinib, a JAK3 inhibitor, developed by Pfizer, was approved by FDA in November 2012 for the treatment of moderate to severe rheumatoid arthritis in adult patients who have had an inadequate response or intolerance to methotrexate. It is the first oral JAK inhibitor approved for the treatment of RA. It was approved by PMDA in Japan in March 2013, and the trade name is Xeljanz. On March 16, 2017, Pfizer China announced that the CFDA had officially approved the marketing application of Pfizer's oral JAK inhibitor. It is reported that the drug has been approved for the treatment of moderate to severe rheumatoid arthritis in adult patients who have had an inadequate response or intolerance to methotrexate. At present, tofacitinib for psoriasis, ulcerative colitis, juvenile idiopathic arthritis and other indications is close to approval; the clinical trials of tofacitinib for the treatment of Crohn's disease, alopecia areata and other indications have entered the middle and late stages of clinical trials. The main side effects of tofacitinib are serious infection rate and low-density lipoprotein level increase, and the most common adverse reactions are upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat and nasopharyngitis. In addition, clinical studies have reported that tofacitinib can cause side effects such as anemia and neutropenia.

[0011]

[0012] Filgotinib, a JAK1 inhibitor, has completed phase III clinical trials in September 2018 for the treatment of rheumatoid arthritis. At the same time, the research of Filgotinib for the treatment of ulcerative colitis and Crohn's disease is currently in the clinical phase II / III trials. Filgotinib is a selective JAK1 inhibitor, and its IC50 for JAK1, JAK2, JAK3 and TYK2 is reported to be about 10 nM, 28 nM, 810 nM and 116 nM, respectively.

[0013]

[0014] Although some JAK inhibitors have been approved for marketing at present, and some JAK inhibitors are in the clinical research stage, these JAK inhibitors are not satisfactory in terms of efficacy or safety. Therefore, there is always a demand for JAK inhibitors with better efficacy and / or fewer side effects. SUMMARY

[0015] An object of the present application is to provide a new type of JAK inhibitor to replace the existing JAK inhibitor, thereby providing more choices for the treatment of JAK-related diseases.

[0016] A further object of the present application is to provide a new type of JAK inhibitor which is more effective and / or safer than the existing JAK inhibitor.

[0017] A further object of the present invention is to provide different solid forms of novel JAK inhibitors that are more suitable for pharmaceutical formulation.

[0018] In a first aspect, the present invention provides a compound in solid form, said compound being a compound of formula (I).

[0019]

[0020] The compound may be an isotopically labeled compound of formula (I), an optical isomer of formula (I), a geometric isomer of formula (I), a tautomer of formula (I), a mixture of isomers of formula (I), a pharmaceutically acceptable salt of formula (I), or a solvate of any of these compounds. Preferably, the solid form of the compound is a crystal.

[0021] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound in solid form as described in the first aspect of the invention and one or more pharmaceutically acceptable carriers, adjuvants, or excipients. For example, the pharmaceutical composition may be in dispersion or solution form.

[0022] In a third aspect, the present invention provides the use of the compounds in solid form described in the first aspect of the invention or the pharmaceutical compositions described in the second aspect of the invention in the preparation of medicaments for treating and / or preventing diseases or conditions related to JAK.

[0023] In a fourth aspect, the present invention provides a method for treating diseases or conditions related to JAK, the method comprising administering a therapeutically effective amount of the compound in solid form described in the first aspect of the invention or the pharmaceutical composition described in the second aspect of the invention to a patient in need. The patient is preferably a mammal, more preferably a human patient. The route of administration may be oral, topical, parenteral, bronchial, or nasal, etc. Oral administration is preferred.

[0024] This invention provides a novel compound that inhibits JAK, thus offering more options for the prevention or treatment of JAK-related diseases. Furthermore, this invention provides the compound in various solid forms, including multiple crystalline and amorphous forms. These different solid forms possess different chemical and physical properties and varying metabolic performance in vivo, thereby providing greater freedom in drug production, storage, and the selection of different drug dosage forms, ultimately enabling the provision of novel drug dosage forms with higher bioavailability and / or better efficacy. Detailed Implementation

[0025] Embodiments of the inventive subject matter are described below with reference to the accompanying drawings. In these descriptions, terminology can be used, and unless specifically called out otherwise, terminology is used by those skilled in the art in accordance with its normal meaning.

[0026] A first aspect of the present invention relates to a solid form of a compound, the compound being a compound of Formula (I)

[0027]

[0028] , an isotopically-labeled compound of Formula (I), an optical isomer of Formula (I), a geometric isomer of Formula (I), a tautomer of Formula (I), an isomer mixture of Formula (I), a pharmaceutically acceptable salt of Formula (I), or a solvate of any of these compounds.

[0029] The compound of Formula (I) can be named as (S)-(2-(6-(2-ethyl-5-fluoro-4- hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3- hydroxypyrrolidin-1-yl)methanone.

[0030] For the sake of brevity, the term "compound of the invention" or "compound of the application" as used herein encompasses a compound of Formula (I), an isotopically-labeled compound of Formula (I), an optical isomer of Formula (I), a geometric isomer of Formula (I), a tautomer of Formula (I), an isomer mixture of Formula (I), or a solvate of any of these compounds.

[0031] The term "optical isomer" means that, when a compound has one or more chiral centers, each chiral center can exist in either the R or S configuration, the various isomers thus constituted being optical isomers. Optical isomers include all diastereomers, enantiomers, meso forms, racemates, or mixtures thereof. Optical isomers can be separated, for example, by a chiral chromatographic column or by chiral synthesis.

[0032] The term "geometric isomer" means that, when a compound has a double bond, the compound can exist as a cis isomer, a trans isomer, an E isomer, and a Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.

[0033] The term "tautomer" refers to isomers of a molecule that can be converted to each other. It is understood by those skilled in the art that tautomers can interconvert and can exist in a state of equilibrium with each other. The compounds of Formula (I) described herein are also meant to encompass any tautomers of the compounds of Formula (I).

[0034] Unless otherwise specified, reference to a "compound of Formula (I)" or "Formula (I) compound" or "compound of the application" or "compound of the present application" is meant to include also isotopically-labeled compounds, which differ by having one or more atoms replaced by an isotope of that atom.

[0035] The term "isotopically-labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number but different atomic mass or mass number.

[0036] Examples of isotopes suitable for inclusion in the compounds of the 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, 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 isotopes of sulfur, such as 35 S.

[0037] Certain isotopically-labeled compounds of Formula (I) (for example, those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. Taking into account the ease of incorporation and the availability of detection means, the radioactive isotopes deuterium (i.e., 2 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose.

[0038] Substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages and can therefore be preferred in some circumstances, for example, when such substitutions improve the metabolic stability and / or the duration of action of the compounds.

[0039] substituted with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N) can be used for Positron Emission Topography (PET) studies for detecting substrate receptor occupancy status.

[0040] Isotopically-labeled compounds of the formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0041] The compounds of the present application can be pharmaceutically acceptable salts of the compounds of formula (I), in particular acid addition salts of the compounds of formula (I). Suitable acid addition salts are formed from acids which form non-toxic salts. Examples of such acids include, but are not limited to, the following: acylate, benzenesulfonate, benzoate, butyrate, citrate, fumarate, glycolate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nitrate, orotate, oxalate, palmitate, phosphate / dihydrogen phosphate / bismonohydrogen phosphate, pyroglutamate, saccharate, stearate, salicylate, tannate, tartrate, tosylate and trifluoroacetate. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of the compounds described herein are known to those of skill in the art.

[0042] Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, the phosphate, the maleate, the L-tartrate, the fumarate, the mucate, the citrate, the p-toluenesulfonate, the methanesulfonate, the benzenesulfonate salts of the compounds of formula (I). Most preferred pharmaceutically acceptable salts of the compounds of formula (I) are the phosphate, the maleate, the methanesulfonate salts of the compounds of formula (I).

[0043] The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is appropriate for administration to a mammal (preferably a human). Preferably, the term means that the compound, carrier or molecule is approved by a regulatory agency such as CFDA (China), EMEA (Europe), FDA (USA) or any other regulatory agency for use in mammals (preferably humans).

[0044] The term "pharmaceutically acceptable salt of a compound of Formula (I)" as used herein is meant to encompass any pharmaceutically acceptable salt of a compound of Formula (I), i.e. a pharmaceutically acceptable salt of a compound of Formula (I), an isotopically-labeled compound of Formula (I), an optical isomer of a compound of Formula (I), a geometric isomer of a compound of Formula (I), a tautomer of a compound of Formula (I), an isomer mixture of a compound of Formula (I).

[0045] Certain compounds of the present application can exist in unsolvated as well as solvated forms (including hydrated forms). In this application, the terms "compound of Formula (I)", "isotopically-labeled compound of Formula (I)", "optical isomer of a compound of Formula (I)", "geometric isomer of a compound of Formula (I)", "tautomer of a compound of Formula (I)", "isomer mixture of a compound of Formula (I)", "pharmaceutically acceptable salt of a compound of Formula (I)" and the like encompass both solvated and unsolvated forms.

[0046] In this application, "solid form of a compound" and "compound in solid form" are understood to have the same meaning and are therefore used interchangeably to mean that the compound exists predominantly in solid form. It is understood by one skilled in the art that the solid form of a compound can exist as a crystal (crystalline form), an amorphous material (non-crystalline), or a mixture of both.

[0047] The term "crystalline form" or "crystal form" refers to a solid form that is crystalline, as can be determined by X-ray diffraction, for example. In certain embodiments, a crystalline form of a substance can be substantially free of amorphous and / or other crystalline forms. In certain embodiments, a crystalline form of a substance can 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. In certain embodiments, a crystalline form of a substance can be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% pure.

[0048] The term "amorphous" or "amorphous form" or "amorphous substance" (sometimes referred to in the prior art as "amorphous material") means a solid form that is not substantially crystalline, as can be determined, for example, by X-ray diffraction. In particular, the term "amorphous" or "amorphous form" or "amorphous substance" describes a disordered solid form, i.e., a solid form that lacks long-range order. In certain embodiments, an amorphous form of a substance can be substantially free of other amorphous and / or crystalline forms of the substance. In certain embodiments, an amorphous form of a substance can 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 other amorphous and / or crystalline forms. In certain embodiments, an amorphous form of a substance can be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% pure.

[0049] The compounds of the present application exist in polymorphic forms. The term "polymorph" refers to different crystalline forms of the same molecular structure, resulting from different arrangements or conformations in the molecular lattice. It is well known in the art that compounds having the same molecular structure but different crystalline forms can have different bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, hygroscopicity, density, and the like.

[0050] In preferred embodiments of the present application, 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. For example, in some preferred embodiments of the present application, the solid form is a phosphate salt Form A of a compound of formula (I), a maleate salt Form A of a compound of formula (I), a mesylate salt Form B of a compound of formula (I), a hydrate Form A of a compound of formula (I), a Form B of a compound of formula (I), and the like.

[0051] In preferred embodiments of the application, the solid form is a crystal of the compound of formula (I) or a crystal of a salt of the compound of formula (I) prepared in the Examples section of the present application, preferably having one or more characteristic peaks in the powder X-ray diffraction pattern at the same diffraction angle (2 theta) positions as the corresponding XRPD pattern determined in the Examples section of the present application. The "one or more characteristic peaks" means 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. Herein "characteristic peaks" are understood to be the one or more peaks in the XRPD pattern having the highest relative intensity. Those skilled in the art understand that due to variations in sample purity and testing conditions, there can be some variation in the position of the XRPD peaks measured under different conditions, and therefore "at the same positions" is understood to mean a difference of ± 0.50°, ± 0.40°, ± 0.30°, ± 0.20°, preferably ± 0.10°, relative to the corresponding diffraction angle (2 theta) positions given in the Examples section of the present application. Most preferably, the powder X-ray diffraction pattern of the crystal (or crystalline form) is substantially the same as the corresponding XRPD pattern determined in the Examples section of the present application. "Substantially the same" means that the two XRPD patterns are identical, or although there are differences, those skilled in the art can confirm that the differences are non-essential, are due to different sample purity, testing conditions, instrument error, or operator habit, and thus can confirm that the two XRPD patterns were obtained from the same crystal.

[0052] In a preferred embodiment of the application, 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 TGA or DSC curve of said crystal (or crystal form) preferably has at least 1, at least 2, at least 3, or at least 4 characteristic peaks which are identical in position to the corresponding TGA or DSC curve as determined in the Examples section of the present application. Herein "characteristic peak" is understood to be an endothermic or exothermic peak in the TGA / DSC curve. The skilled person understands that due to sample purity and testing conditions, there can be some deviation in the temperature readout indicating the position of a peak in a TGA / DSC curve measured under different conditions, and therefore "identical in position" is understood herein to mean that the temperature of the position of the peak can differ by ± 5°C, ± 4°C, ± 3°C, ± 2°C, ± 1 °C relative to the corresponding TGA and / or DSC curve given in the Examples section of the present application. Most preferably, the TGA / DSC curve of said crystal (or crystal form) is substantially identical to the corresponding TGA / DSC curve as determined in the Examples section of the present application. By "substantially identical" TGA / DSC curve it is meant that the two TGA curves and / or DSC curves are identical or, although not identical, the skilled person can confirm that the differences are non-essential, due to different sample purity, testing conditions, instrument error or operator habit, and thus can confirm that the two TGA curves and / or DSC curves were obtained from the same crystal.

[0053] One preferred embodiment of the present application relates to crystalline Form A of a hydrate of a compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks, preferably with at least one, at least two, at least three, or at least four characteristic peaks, selected from the group consisting of 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°

[0054] one or more characteristic peaks at diffraction angles (2Θ) of 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°

[0055] one or more characteristic peaks at diffraction angles (2Θ).

[0056] Further preferably, the TGA / DSC curve of crystalline Form A of a hydrate of a compound of formula (I) exhibits multiple thermal signals in the range of about 50-290°C.

[0057] One preferred embodiment of the present application relates to crystalline Form B of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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° degrees 2-theta, preferably with one or more characteristic peaks 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°, 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° degrees 2-theta.

[0058] Further preferably, the TGA / DSC curve of crystalline Form B of the compound of formula (I) exhibits an endothermic peak at about 319.1 °C (onset temperature).

[0059] One preferred embodiment of the present application relates to crystalline Form C of the hydrate of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks selected from the group consisting of 4.96 ± 0.10°, 7.66 ± 0.10°, 10.18 ± 0.10°, 11.07 ± 0.10°, 14.73 ± 0.10°, 22.87 ± 0.10° degrees 2-theta, preferably with one or more characteristic peaks selected from the group consisting of 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° degrees 2-theta.

[0060] Further preferably, the TGA / DSC curve of crystalline Form C of the hydrate of the compound of formula (I) exhibits one thermal signal at about 78.1 °C (onset temperature), thermal signals at about 279.4 (onset temperature) and 303.8 °C (onset temperature).

[0061] One preferred embodiment of the present application relates to crystalline Form G of the hydrate of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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°, preferably with one or more characteristic peaks selected from the group consisting of 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°, at diffraction angles 2Θ.

[0062] Further preferably, the TGA / DSC curve of crystalline Form G of the hydrate of the compound of formula (I) has one thermal signal at about 81.2 °C (onset temperature) and two thermal signals at about 209.6 °C (onset temperature), at about 314.0 °C (onset temperature).

[0063] One preferred embodiment of the present application relates to crystalline Form A of the phosphate salt of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks selected from the group consisting of 5.29 ± 0.10°, 7.47 ± 0.10°, 10.61 ± 0.10°, 19.16 ± 0.10° and 21.32 ± 0.10°, preferably with one or more characteristic peaks 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°, at diffraction angles 2Θ.

[0064] Further preferably, the TGA / DSC curve of crystalline Form A of the phosphate salt of the compound of formula (I) has a sharp endothermic peak at about 279.3 °C (onset temperature).

[0065] One preferred embodiment of the present application relates to a maleate salt crystalline Form A of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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° degrees 2-theta, preferably with one or more characteristic peaks selected from the group consisting of 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° degrees 2-theta.

[0066] Further preferably, the TGA / DSC curve of the maleate salt crystalline Form A of the compound of formula (I) has two thermal signals at about 211.2 °C and about 278.1 °C (onset temperature).

[0067] One preferred embodiment of the present application relates to a mesylate salt crystalline Form B of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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° degrees 2-theta, preferably with one or more characteristic peaks 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°, 20.61 ± 0.10°, 21.36 ± 0.10°, 23.18 ± 0.10°, 25.01 ± 0.10° degrees 2-theta.

[0068] Further preferably, the TGA / DSC curve of the mesylate salt crystalline 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).

[0069] One preferred embodiment of the present application relates to a hydrochloride salt crystalline Form A of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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° degrees 2-theta, 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° degrees 2-theta.

[0070] Further preferably, the TGA / DSC curve of the hydrochloride salt crystalline 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 an exothermic signal at about 231.5 °C (onset temperature).

[0071] One preferred embodiment of the present application relates to a tartrate salt crystalline Form A of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks selected from the group consisting of 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° degrees 2-theta, preferably with one or more characteristic peaks selected from the group consisting of 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° degrees 2-theta.

[0072] Further preferably, the TGA / DSC curve of the tartrate salt crystalline Form A of the compound of formula (I) has two thermal signals at about 125.2 °C and about 168.8 °C (onset temperature).

[0073] One preferred embodiment of the present application relates to a fumarate salt crystalline Form A of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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° degrees 2-theta, preferably with one or more characteristic peaks selected from the group consisting of 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° degrees 2-theta.

[0074] Further preferably, the TGA / DSC curve of the fumarate salt Form A of the compound of formula (I) shows two thermal signals at about 71.1 °C and about 205.3 °C (onset temperatures).

[0075] One preferred embodiment of the present application relates to a mucate salt crystalline Form A of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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° degrees 2-theta, preferably with one or more characteristic peaks selected from the group consisting of 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° degrees 2-theta.

[0076] Further preferably, the TGA / DSC curve of the mucate salt Form A of the compound of formula (I) shows two thermal signals at about 69.8 °C and about 210.4 °C (onset temperatures).

[0077] One preferred embodiment of the present application relates to citrate Form A of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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°, preferably with one or more characteristic peaks selected from the group consisting of 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°, at diffraction angles 2Θ.

[0078] Further preferably, the TGA / DSC curve of citrate 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 temperatures).

[0079] One preferred embodiment of the present application relates to citrate Form B of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks selected from the group consisting of 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°, preferably with one or more characteristic peaks selected from the group consisting of 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°, at diffraction angles 2Θ.

[0080] Further preferably, the TGA / DSC curve of citrate Form B of the compound of formula (I) has four endothermic peaks at about 73.1 °C, about 280.2 °C, about 301.6 °C (onset temperatures) and about 179.7 °C (peak temperature).

[0081] One preferred embodiment of the present application relates to the p-toluenesulfonic acid salt Form A of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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° degrees 2-theta, preferably with one or more characteristic peaks selected from the group consisting of 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° degrees 2-theta.

[0082] Further preferably, the TGA / DSC curve of the p-toluenesulfonic acid Form A of the compound of formula (I) has two thermal signals at about 121.2 °C and at about 222.3 °C (onset temperature).

[0083] One preferred embodiment of the present application relates to the p-toluenesulfonic acid salt Form A of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks 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° degrees 2-theta, preferably with one or more characteristic peaks selected from the group consisting of 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° degrees 2-theta.

[0084] Further preferably, the TGA / DSC curve of the p-toluenesulfonic acid Form A of the compound of formula (I) has two thermal signals at about 121.2 °C and at about 222.3 °C (onset temperature).

[0085] One preferred embodiment of the present application relates to a benzenesulfonic acid salt crystalline Form B of the compound of formula (I), having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks selected from the group consisting of diffraction angles (2 theta) at 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°, preferably one or more characteristic peaks selected from the group consisting of diffraction angles (2 theta) at 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°.

[0086] Further preferably, the TGA / DSC curve of the benzenesulfonic acid salt crystalline 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).

[0087] In the most preferred embodiments of the present application, the solid form is the phosphate salt crystalline Form A of the compound of formula (I), the maleate salt crystalline Form A of the compound of formula (I), the mesylate salt crystalline Form B of the compound of formula (I), the crystalline Form A of the compound of formula (I) hydrate, the crystalline Form B of the compound of formula (I), each having substantially the same XPRD pattern as the corresponding crystalline form described in the Examples section of the present application.

[0088] In some embodiments of the present application, the solid form is the phosphate salt crystalline Form A of the compound of formula (I), the maleate salt crystalline Form A of the compound of formula (I), the mesylate salt crystalline Form B of the compound of formula (I), the crystalline Form A of the compound of formula (I) hydrate, the crystalline Form B of the compound of formula (I), each having substantially the same TGA and / or DSC curve as the corresponding crystalline form described in the Examples section of the present application.

[0089] In a second aspect, the present application provides a pharmaceutical composition comprising a solid form of the compound according to the first aspect of the present application and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

[0090] The pharmaceutical composition of the present application can be a solid composition or a liquid composition (e.g. a dispersion or a solution).

[0091] The pharmaceutical compositions of the present invention can be formulated as needed into dosage forms suitable for oral, topical (including but not limited to poultices, sprays, etc.), parenteral (including subcutaneous, intramuscular, dermal, and intravenous) administration, bronchial administration, or nasal administration. Preferably, the pharmaceutical compositions of the present invention are formulated into dosage forms (formulations) suitable for topical, bronchial, or nasal administration. More preferably, the pharmaceutical compositions of the present invention are formulated into dosage forms (formulations) suitable for topical application.

[0092] If a solid carrier is used, the formulation can be in tablet form, in powder or granule form within a hard gel capsule, or in the form of tablets or lozenges. Solid carriers can include conventional excipients such as binders, fillers, tablet lubricants, disintegrants, wetting agents, etc. If necessary, the tablet can be film-coated using conventional techniques. If a liquid carrier is used, the formulation can be in the form of syrup, emulsion, ointment, soft gel capsule, sterile carrier for injection, aqueous or non-aqueous liquid suspension, or a dry product reconstituted with water or other suitable carrier before use. Liquid formulations can contain conventional additives such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including edible oils), preservatives, and flavoring and / or coloring agents. For parenteral administration, the carrier typically comprises at least a majority of sterile water, but saline solutions, glucose solutions, etc., can also be used. Injectable suspensions can also be used, in which case conventional suspending agents can be used. Conventional preservatives, buffers, etc., can also be added to parenteral dosage forms. The pharmaceutical composition is prepared by suitable conventional techniques for a desired formulation containing an appropriate amount of the active ingredient (i.e., the compound of formula (I) of the present invention).

[0093] Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions (e.g., suspensions or emulsions), and sterile powders for sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, and dispersants include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate).

[0094] These compositions may also contain various excipients, such as preservatives, wetting agents, emulsifiers, and dispersants. Inhibition of microbial activity can be ensured by various antimicrobial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, etc.). Isotonic agents, such as sugars and sodium chloride, may also be included. Absorption of injectable pharmaceutical dosage forms can be prolonged by using delayed absorption agents (e.g., aluminum monostearate and gels).

[0095] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), which may further include: (a) a filler or mixture (e.g., starch, lactose, sucrose, glucose, mannitol, and silica); (b) a binder (e.g., carboxymethyl cellulose, alginate, gel, polyvinylpyrrolidone, sucrose, and gum arabic); (c) a humectant (e.g., glycerol); and (d) a disintegrant (e.g., agar). (e) a mixture of lipid-agar, calcium carbonate, potato or cassava starch, alginic acid, certain synthetic silicates, sodium carbonate; (f) a solution barrier (e.g., paraffin); (g) an absorption enhancer (e.g., quaternary ammonium compounds); (h) a wetting agent (e.g., hexadecyl alcohol and glycerol monostearate); (i) an adsorbent (e.g., kaolin and bentonite); and (v) a lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.

[0096] Similar solid compositions can also be used as fillers in soft-filled and hard-filled gel capsules that use excipients such as lactose and high molecular weight polyethylene glycol.

[0097] Solid dosage forms (e.g., tablets, sugar-coated pills, capsules, pellets, and granules) can be prepared using coatings and shells (e.g., intestinal coatings and others known in the art). They may contain light-blocking agents, and they may also be compositions of various active compounds that release the active compound in a delayed manner within a portion of the intestine. Examples of available encapsulation compositions are polymeric substances and waxes. The active component may also be in microencapsulated form and, where appropriate, may contain one or more of the excipients described above.

[0098] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents (e.g., water or other solvents) commonly used in the art, solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide), oils (specifically, cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitan, or mixtures thereof.

[0099] In addition to these inert diluents, the composition may also include, for example, wetting agents, emulsifiers and suspending agents, flavoring agents, flavoring agents and fragrances.

[0100] In addition to active compounds, suspensions may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyethylene glycol, sorbitol, sorbitan esters, microcrystalline fibers, aluminum hydroxide, bentonite, agar-agar and astragalus gum, or mixtures of these substances.

[0101] Topical dosage forms of the compounds of this invention include ointments, powders, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any desired preservatives, buffers, or propellants. Ophthalmic formulations, ointments, powders, and solutions are also included within the scope of this invention.

[0102] The topical formulations of the compounds of the present invention can 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-water-in-oil (O / W / O) emulsions, or prepared as aqueous dispersions or lipid dispersions, gels or aerosols.

[0103] The topical dosage forms of the compounds of this invention may include additives and formulation auxiliaries, such as emulsifiers, thickeners, gelling agents, water-fixing agents, spreading agents, stabilizers, dyes, fragrances, and preservatives. Suitable 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 dimethylpolysiloxane and polydimethylcyclosiloxane. Suitable water-fixing agents include polyethylene glycol, preferably polyethylene glycol 600.

[0104] The topical dosage forms of the compounds of the present invention may include ointments, lotions, gels, emulsions, microemulsions, sprays, skin patches, etc., which can be applied topically to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo, and hair loss. In particular, the topical dosage form of the compounds of the present invention is an ointment, which can be applied topically to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, pruritus, vitiligo, and hair loss.

[0105] The amount of compound of formula (I) in a pharmaceutical composition and dosage form may be appropriately determined by those skilled in the art as needed, for example, the compound of formula (I) may be present in a therapeutically effective amount in the pharmaceutical composition or dosage form.

[0106] In a third aspect, the present invention provides the use of the compounds in solid form described in the first aspect of the invention, or the pharmaceutical compositions described in the second aspect of the invention, in the preparation of medicaments for treating and / or preventing diseases or conditions related to JAK.

[0107] "Diseases or conditions related to JAK" include, but are not limited to:

[0108] Arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis;

[0109] Autoimmune diseases or conditions, including single-organ or single-cell type autoimmune diseases, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis with pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasseur's disease, autoimmune thrombocytopenic purpura, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic invasive hepatitis, ulcerative colitis and membranous glomerulonephritis, those involving systemic autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, Leter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid), and other O-cell (humoral) or T-cell autoimmune diseases (including Kurgan's syndrome), ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I diabetes or juvenile-onset diabetes or thyroiditis;

[0110] Cancers or tumors, including gastrointestinal cancers, colorectal cancers, liver cancers, skin cancers (including mast cell tumors and squamous cell carcinomas), breast and breast cancers, ovarian cancers, prostate cancers, lymphomas, leukemias (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancers, lung cancers, myomas, bone cancers, bladder cancers, brain cancers, melanomas (including oral and metastatic melanomas), Kaposi's sarcoma, myelomas (including multiple myelomas), myeloproliferative disorders, proliferative diabetic retinopathy, or angiogenesis-related conditions (including solid tumors);

[0111] Diabetes, including type 1 diabetes or complications of diabetes;

[0112] Eye diseases, conditions, or illnesses, including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis (including uveitis associated with Bechette's disease and lenticulouveitis), keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoma, ocular pemphigoid, Moren's ulcer, scleritis, Graves' eye disease, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye syndrome), bullae, iridocyclitis, sarcoidosis, endocrine eye diseases, sympathetic ophthalmia, allergic conjunctivitis, or ocular neovascularization;

[0113] Intestinal inflammation, allergic reactions, or conditions, including Crohn's disease and / or ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis;

[0114] Neurodegenerative diseases, including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative diseases caused by ischemic or traumatic brain injury, stroke, glutamate neurotoxicity or hypoxia; ischemic / reperfusion injury of stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia or platelet aggregation;

[0115] Skin diseases, conditions, or symptoms, including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other pruritus conditions, vitiligo, and hair loss;

[0116] Allergic reactions include allergic dermatitis in mammals (including allergic diseases such as bite allergies), summer eczema, sweet itch syndrome, emphysema, inflammatory airway disease, recurrent airway obstruction, airway hyperresponsiveness, or chronic obstructive pulmonary disease.

[0117] Asthma and other obstructive airway diseases, including chronic or refractory asthma, advanced asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, or dust asthma.

[0118] Transplant rejection includes 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, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine or trachea) or xenotransplantation;

[0119] Severe pneumonia caused by influenza virus or coronavirus infection, including SARS, MERS and Covid-19 (COVID-19), especially in COVID-19, suppressing the inflammatory response and inhibiting or preventing cytokine storm.

[0120] In a fourth aspect, the present invention provides a method for treating diseases or conditions related to JAK, the method comprising administering a therapeutically effective amount of the compound in solid form described in the first aspect of the invention, or the pharmaceutical composition described in the second aspect of the invention, to a patient in need. The patient is preferably a mammal, more preferably a human patient. The route of administration may be oral, topical (including but not limited to poultices, sprays, etc.), parenteral (including subcutaneous, intramuscular, dermal, and intravenous) administration, bronchial administration, or nasal administration. Preferably, administration is via nasal or topical application. More preferably, administration is via topical application.

[0121] To achieve the desired effect, a therapeutically effective amount of the solid compound or pharmaceutical composition or dosage form of the present invention is typically administered to the patient. The phrase "therapeutically effective amount" is a recognized term in the art. In some embodiments, this term refers to the amount necessary or sufficient to eliminate, reduce, or maintain the target of a particular treatment regimen. The effective amount can vary depending on factors such as the disease or condition being treated, the specific targeted construct being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art or physicians can determine the effective amount of a particular compound empirically without extensive experimentation. In some embodiments, the therapeutically effective amount of a therapeutic agent used in vivo may depend on many factors, including: the manner and method of administration; any other materials contained in the drug besides the agent. In vitro or in vivo studies may be used to help determine the optimal dosage range.

[0122] Surprisingly, the compounds of the present invention have demonstrated superior efficacy as JAK kinase inhibitors in experiments (superior to existing JAK kinase inhibitors such as Filgotinib or Tofacitinib), and have the potential for good safety.

[0123] The present invention will be further described and illustrated below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0124] Figure 1 The XRPD diagram of crystal form A of compound (I) is shown;

[0125] Figure 2 The TGA / DSC curves of crystal form A of compound (I) are shown;

[0126] Figure 3 The XRPD comparison diagrams of crystal form A of compound (I) before and after heating are shown;

[0127] Figure 4 The temperature-varying XRPD plot of crystal form A of compound (I) is shown;

[0128] Figure 5 The XRPD diagram of crystal form B of compound (I) is shown;

[0129] Figure 6 The TGA / DSC curves of crystal form B of compound (I) are shown;

[0130] Figure 7 The temperature-varying XRPD plot of crystal form B of compound (I) is shown;

[0131] Figure 8 The XRPD diagram of crystal form C of compound (I) is shown;

[0132] Figure 9 The TGA / DSC curves of crystal form C of compound (I) are shown;

[0133] Figure 10 The XRPD comparison diagrams of crystal form C of compound (I) before and after heating are shown;

[0134] Figure 11 The XRPD diagram of crystal form D of compound (I) is shown;

[0135] Figure 12 XRPD comparison diagrams of crystal form D of compound (I) are shown;

[0136] Figure 13 The XRPD diagram of crystal form E of compound (I) is shown;

[0137] Figure 14 The TGA / DSC curves of crystal form E of compound (I) are shown;

[0138] Figure 15 The XRPD comparison diagrams of crystal form E of compound (I) before and after heating are shown;

[0139] Figure 16 The temperature-varying XRPD plot of crystal form E of compound (I) is shown;

[0140] Figure 17 The XRPD plot of crystal form F of compound (I) is shown;

[0141] Figure 18 The TGA / DSC curves of crystal form F of compound (I) are shown;

[0142] Figure 19 The XRPD comparison diagrams of crystal form F of compound (I) before and after heating are shown;

[0143] Figure 20 The XRPD diagram of crystal form G of compound (I) is shown;

[0144] Figure 21 The TGA / DSC curves of crystal form G of compound (I) are shown;

[0145] Figure 22 The temperature-varying XRPD plot of crystal form G of compound (I) is shown;

[0146] Figure 23 The XRPD diagram of crystal form J of compound (I) is shown;

[0147] Figure 24 The XRPD comparison diagram of crystal form J of compound (I) is shown;

[0148] Figure 25 The XRPD diagram of crystal form H of compound (I) is shown;

[0149] Figure 26 The XRPD diagram of crystal form I of compound (I) is shown;

[0150] Figure 27 The XRPD diagram of phosphate crystal form A of compound (I) is shown;

[0151] Figure 28 The TGA / DSC curves of phosphate crystal form A of compound (I) are shown;

[0152] Figure 29 The XRPD diagram of maleate crystal form A of compound (I) is shown;

[0153] Figure 30 The TGA / DSC curves of maleate crystal form A of compound (I) are shown;

[0154] Figure 31 The XRPD diagram of the methanesulfonate crystal form B of compound (I) is shown;

[0155] Figure 32 The TGA / DSC curves of the methanesulfonate crystal form B of compound (I) are shown;

[0156] Figure 33 The XRPD plot of the hydrochloride crystal form A of compound (I) is shown;

[0157] Figure 34 The TGA / DSC curves of the hydrochloride crystal form A of compound (I) are shown;

[0158] Figure 35 The XRPD diagram of tartrate crystal form A of compound (I) is shown;

[0159] Figure 36 The TGA / DSC curves of tartrate crystal form A of compound (I) are shown;

[0160] Figure 37 The XRPD diagram of fumarate crystal form A of compound (I) is shown;

[0161] Figure 38 The TGA / DSC curves of fumarate form A of compound (I) are shown.

[0162] Figure 39 The XRPD diagram of the mucilage crystal form A of compound (I) is shown;

[0163] Figure 40The TGA / DSC curves of the mucilage crystal form A of compound (I) are shown;

[0164] Figure 41 The XRPD diagram of citrate crystal form A of compound (I) is shown;

[0165] Figure 42 The TGA / DSC curves of citrate form A of compound (I) are shown;

[0166] Figure 43 The XRPD diagram of citrate crystal form B of compound (I) is shown;

[0167] Figure 44 The TGA / DSC curves of citrate form B of compound (I) are shown;

[0168] Figure 45 The XRPD diagram of p-toluenesulfonate crystal form A of compound (I) is shown;

[0169] Figure 46 The TGA / DSC curves of p-toluenesulfonate crystal form A of compound (I) are shown;

[0170] Figure 47 The XRPD diagram of benzenesulfonate crystal form A of compound (I) is shown;

[0171] Figure 48 The TGA / DSC curves of benzenesulfonate crystal form A of compound (I) are shown;

[0172] Figure 49 The XRPD diagram of the benzenesulfonate crystal form B of compound (I) is shown;

[0173] Figure 50 The TGA / DSC curves of benzenesulfonate crystal form B of compound (I) are shown;

[0174] Figure 51 The DVS diagram of phosphate crystal form A of compound (I) is shown;

[0175] Figure 52 The DVS diagram of maleate crystal form A of compound (I) is shown;

[0176] Figure 53 The DVS diagram of the methanesulfonate crystal form B of compound (I) is shown.

[0177] Example

[0178] The compounds of this invention can be synthesized using 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. Clearly, by referring to the exemplary schemes in this application, those skilled in the art can readily design other synthetic routes for compounds of formula (I) or other compounds by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0179] Suitable crystalline or amorphous forms of the compounds of the present invention can be obtained using purification, crystallization, and / or drying methods familiar to those skilled in the art. Exemplary methods for preparing certain crystalline and amorphous forms are given in the following specific examples. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design methods for preparing other crystalline or amorphous forms by appropriately adjusting the solvents, equipment, and process conditions.

[0180] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0181] Example 1: Synthesis of (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6- dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidin-1-yl)methanone (I) Example 2: Pharmacological activity evaluation I of compounds of formula (I)

[0182]

[0183] In order to synthesize compound (I), intermediates 1-1 to 1-15 were first synthesized, and then compound (I) was synthesized using intermediate 1-15 as a starting material.

[0184] Unless otherwise specified, the chemical reagents, solvents and reaction equipment used in each chemical reaction in Example 1 are all conventional raw materials and equipment used in chemical synthesis and can be easily obtained through commercial means.

[0185] I. Synthetic Intermediates 1-6: tert-butyl 3,4-diaminopyrrolidinyl-1-carboxylate

[0186] Intermediates 1-6 were synthesized using the following synthetic route:

[0187]

[0188] 1. Synthetic intermediate 1-1: tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate

[0189] 3-Pyrrolidine (10.0 g, 0.15 mol) was dissolved in 400 mL of dichloromethane and triethylamine (40.6 mL, 0.29 mol), cooled to 0°C, and (Boc)₂O (37.9 g, 0.17 mol) was slowly added. The mixture was reacted overnight at room temperature, water was added, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed three times with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give intermediate 1-1, with a yield of 91.0%.

[0190] 2. Synthetic intermediates 1-2: tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0191] Intermediate 1-1 (24.5 g, 0.15 mol) was dissolved in 450 mL of dichloromethane and cooled to 0°C. Then, m-chloroperoxybenzoic acid (37.5 g, 0.22 mol) was slowly added in portions. The mixture was reacted overnight at room temperature. Saturated sodium thiosulfate (40 mL) was added, and the mixture was stirred for 30 minutes. The aqueous phase was extracted twice with dichloromethane, washed with saturated potassium carbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain intermediate 1-2 in 84.9% yield.

[0192] 1 H NMR (400MHz, CDCl3) 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).

[0193] 3. Synthetic intermediates 1-3: tert-butyl 3-azido-4-hydroxypyrrolyl-1-carboxylate

[0194] Intermediate 1-2 (20.8 g, 0.12 mol) was dissolved in 150 ml of 1,4-dioxane and 50 ml of water. Sodium azide (24.0 g, 0.37 mol) was added, and the mixture was heated to 106°C and reacted for 18 hours. After cooling to room temperature, 100 ml of saturated brine was added, and the mixture was extracted with dichloromethane (250 ml x 4). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give intermediate 1-3 in 100% yield.

[0195] 1 H 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).

[0196] 4. Synthetic intermediates 1-4: 3-Azide-4-((methanesulfonyl)oxy)pyrrolidinyl-1-carboxylic acid tert-butyl ester

[0197] Intermediate 1-3 (28.0 g, 0.12 mol) was dissolved in 350 mL of dichloromethane and triethylamine (37.3 g, 0.37 mol), cooled to 0°C, and methanesulfonyl chloride (16.9 g, 0.15 mol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with water, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give intermediate 1-4, with a yield of 98.0%.

[0198] 5. Synthetic intermediates 1-5: tert-butyl 3,4-diazidopyrrolidinyl-1-carboxylate

[0199] Intermediate 1-4 (36.9 g, 0.12 mol) was dissolved in 250 ml of DMF, and sodium azide (23.5 g, 0.36 mol) was added. The mixture was heated to 90°C and reacted for 2 days. After cooling to room temperature, 750 ml of water was added, and the mixture was extracted with methyl tert-butyl ether (400 ml x 4). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to give intermediate 1-5 in 62.2% yield.

[0200] 6. Synthetic intermediates 1-6: tert-butyl 3,4-diaminopyrrolidinyl-1-carboxylate

[0201] Intermediate 1-5 (18.9 g, 0.08 mol) was dissolved in 200 ml of methanol, 10% Pd / C was added, hydrogen was added three times, the mixture was heated to 40 degrees Celsius, and the reaction was carried out for 2 days. The mixture was then filtered and concentrated to obtain intermediate 1-6 with a yield of 78%.

[0202] 1 H NMR (400MHz, CDCl3) δ3.51-3.49(m,2H),3.40-3.36(m,2H),3.21-3.11(m,2H),1.47(s,9H).

[0203] II. Synthetic Intermediates 1-10: 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0204] Intermediates 1-10 are synthesized using the following synthetic route:

[0205]

[0206] 1. Synthetic intermediate 1-7: 5-ethyl-2-fluorophenol

[0207] 5-Bromo-2-fluorophenol (200.0 mg, 1.05 mmol) and di(tri-tert-butylphosphine)palladium (10.7 mg, 0.02 mmol) were dissolved in 10 mL of THF. The mixture was purged with nitrogen three times, cooled to 10–20 °C, and a 1 mol / L diethylzinc solution (2.3 mL, 2.30 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 50 °C. The reaction was allowed to proceed overnight, cooled to 0 °C, quenched with water, filtered through diatomaceous earth, washed with ethyl acetate, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After drying, the solution was concentrated and separated by column chromatography to obtain an oily liquid intermediate 1-7, in 65.1% yield. 1 H NMR (400MHz, CDCl3) 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).

[0208] 2. Synthetic intermediate 1-8: 4-bromo-5-ethyl-2-fluorophenol

[0209] Intermediates 1-7 (200.1 mg, 1.43 mmol) were dissolved in 6 mL of acetonitrile, and CuBr2 (957.5 mg, 4.29 mmol) was added. The mixture was stirred at room temperature for 3 hours, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Concentration column chromatography yielded a colorless oily intermediate 1-8, in 78.1% of the product. 1 H NMR (400MHz, CDCl3) 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).

[0210] 3. Synthetic intermediates 1-9: 1-(benzyloxy)-4-bromo-5-ethyl-2-fluorobenzene

[0211] Intermediate 1-8 (15.5 g, 70.8 mmol) was dissolved in 200 mL of DMF, and potassium carbonate (19.5 g, 141.5 mmol) and benzyl bromide (14.5 g, 84.9 mmol) were added. The mixture was heated to 60 °C. After the reaction was complete, the mixture was quenched with water, extracted with EA, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After concentration, column chromatography yielded 19.0 g of intermediate 1-9, yield: 86.8%. 1H NMR (400MHz, CDCl3) 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).

[0212] 4. Synthetic intermediates 1-10: 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0213] Intermediate 1-9 (1.0 g, 3.23 mmol), pinacol borate (0.82 g, 3.23 mmol), Pd(dppf)Cl2 (0.24 g, 0.32 mmol), and KOAc (0.95 g, 9.70 mmol) were dissolved in 15 mL of 1,4-dioxane and purged three times with nitrogen. The reaction was heated to 100 °C. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentration and column chromatography yielded 0.98 g of intermediate 1-10, yield: 85.1%. 1 H NMR (400MHz, CDCl3) 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).

[0214] III. Synthetic Intermediate 1-15: 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylic acid tert-butyl ester

[0215] Intermediates 1-15 were synthesized using the following synthetic route:

[0216]

[0217] 1. Synthetic intermediate 1-11: 6-bromo-1H-indazole-3-carboxaldehyde

[0218] Sodium nitrite (14.00 g, 200 mmol) was dissolved in 75 mL of DMF and 100 mL of water. The solution was cooled to 0°C, and under nitrogen protection, 23 mL of 3N HCl (68.9 mmol) was slowly added dropwise over 10 minutes after the addition was complete. At 0°C, a DMF solution of 5.00 g, 25.5 mmol, containing 6-bromoindole (35 mL) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with water and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give intermediate 1-11 in 83.6% yield.

[0219] 1 H NMR (400MHz, CDCl3) 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).

[0220] 2. Synthetic intermediate 1-12: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxaldehyde

[0221] Intermediate 1-11 (1.56 g, 6.93 mmol) was dissolved in dry tetrahydrofuran, cooled to 0°C, and sodium hydride (0.33 g, 8.32 mmol) was slowly added. The reaction was carried out at room temperature for 1 hour, cooled to 0°C, and 2-(trimethylsilyl)ethoxymethyl chloride (1.73 g, 10.40 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature overnight. The reaction was quenched with water, extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give intermediate 1-12 in 49.2% yield.

[0222] 1 H NMR (400MHz, CDCl3) 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).

[0223] 3. Synthetic intermediate 1-13: 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-3,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylic acid tert-butyl ester

[0224] Intermediate 1-12 (1.56 g, 6.93 mmol) and tert-butyl 3,4-diaminopyrrololine-1-carboxylate (1.56 g, 6.93 mmol) were dissolved in 5 ml of hexafluoroisopropanol, heated to 40 degrees Celsius and reacted for 2 days. The mixture was then concentrated and purified by silica gel column chromatography to obtain intermediate 1-13, with a yield of 54.7%.

[0225] 4. Synthetic intermediate 1-14: 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylic acid tert-butyl ester

[0226] Oxaloyl chloride (0.53 g, 4.20 mmol) was dissolved in 15 mL of dry dichloromethane. Under nitrogen protection, the mixture was cooled to -78°C, and DMSO (0.61 g, 7.84 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 30 minutes. Then, a dichloromethane solution of intermediate 1-13 (1.00 g, 1.87 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 30 minutes. Then, dry triethylamine (1.89 g, 18.66 mmol) was slowly added dropwise. The reaction was allowed to proceed for 10 minutes, and the temperature was slowly increased to room temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride solution. The mixture was extracted twice with dichloromethane, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give intermediate 1-14 in 36.3% yield.

[0227] 1 H NMR (400MHz, CDCl3) 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).

[0228] 5. Synthetic intermediate 1-15: 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylic acid tert-butyl ester

[0229] Intermediate 1-14 (110 mg, 0.21 mmol) was dissolved in dry tetrahydrofuran, cooled to 0°C, and sodium hydride (12.3 mg, 0.31 mmol) was added. The mixture was reacted at room temperature for 30 minutes, cooled to 0°C, and 2-(trimethylsilyl)ethoxymethyl chloride (41.2 mg, 0.25 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 4 hours, and the reaction was quenched with water. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give intermediate 1-15 in 73.1% yield.

[0230] 1 H NMR (400MHz, CDCl3) δ8.41-8.36(m,1H),7.79(s,1H),7.44(dd,J=8.0Hz,J=4.0Hz,1H),5.94(d,J=12.0H z,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).

[0231] IV. Synthetic Compounds (I)

[0232] The following synthetic route was used to synthesize compound (I) starting from intermediates 1-15:

[0233]

[0234] 1. Synthetic intermediate 1-16: 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

[0235] The following ingredients were added: 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazolium-5(1H)-carboxylic acid tert-butyl ester (500 mg, 0.75 mmol), 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (401 mg, 1.13 mmol), Pd(dppf)Cl2 (75 mg, 0.075 mmol), and phosphoric acid. Potassium (495 mg, 2.25 mmol) was dissolved in 1,4-dioxane (30 ml) and water (6 ml), purged three times with nitrogen, heated to 100 °C, and reacted for 16 h. After cooling to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography. The purified product was dissolved in 25 ml of dichloromethane, and 5 ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 30 min, concentrated, and then purified three times with dichloromethane to remove trifluoroacetic acid. The concentration was repeated, and the mixture was purified by silica gel column chromatography to give 210 mg of intermediates 1-16, with a yield of 39.2%.

[0236] 1 H NMR(400MHz, CDCl3)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).

[0237] 2. Synthetic intermediate 1-17: (S)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidine-1-yl)methyl ketone

[0238] Dissolve triphosgene (91.5 mg, 0.31 mmol) in 10 ml of dry dichloromethane, and add dropwise a solution of intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (220.0 mg, 0.31 mmol) in 5 ml of dichloromethane at 0°C. After the initial addition of the solution, dry triethylamine (312.2 mg, 3.09 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes. The reaction was monitored by TLC until the starting material disappeared. Then, a solution of (S)-pyrrolidine-3-ol (40.3 mg, 0.46 mmol) in dichloromethane (2 ml) was added at room temperature. The mixture was stirred at room temperature for 20 minutes until the reaction was complete. The reaction was quenched with water and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give 192 mg of intermediate 1-17, with a yield of 75.3%.

[0239] 1 H NMR(400MHz, CDCl3)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).

[0240] 3. Synthetic compound (I): (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidine-1-yl) methyl ketone

[0241] Intermediate 1-17 (22.00 g, 26.60 mmol, 1.00 eq) was added to a 1 L three-necked flask, followed by the addition of DCM (330 mL, 15 V) to dissolve it. The mixture was then cooled to -70 °C to -60 °C and magnetically stirred. The mixture was then replaced three times with N2, and BCl3 (133 mL, 132.99 mmol, 5.00 eq, 1 N in DCM) was slowly added dropwise over approximately 15 min. During the addition process, the internal temperature was kept below -55 °C. After the addition was complete, the mixture was stirred at -70 °C to -60 °C for 1 h. The reaction was quenched by slowly adding 50 mL of methanol dropwise to the reaction system at a temperature not exceeding -50°C. The addition was completed in about 15 minutes. The system was then allowed to naturally warm to 15-20°C. The reaction solution was concentrated under vacuum at 38°C. The residue was added to 200 mL of methanol and ammonia. The mixture was stirred at 40°C for 30 minutes, and then the methanol was removed by rotary evaporation. A large amount of light yellow solid precipitated in the aqueous phase. The system was filtered to obtain the solid, which was then dried to obtain the crude product (15.00 g). The crude product was sent for Prep-HPLC purification (normal phase, 0.1% ammonia alkaline system, ethanol system). When the obtained fraction was concentrated to 200 mL at 40°C, a large amount of solid precipitated. The solid was filtered to obtain 5.90 g of light yellow solid powder, which is compound (I).

[0242] 1 H 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, partially obscured by the solvent peak of DMSO-d6), 1.92–1.71 (m, 2H), 1.02 (t, J = 7.6 Hz, 3H)

[0243] LC-MS:C 25 H 26 FN6O3[M+H] + The calculated m / z value is 477.2, and the detected value is 477.1. Serial number Name

[0244] 1. Experimental Principle

[0245] A drug screening system based on JAK1, JAK2, JAK3, and TYK2 kinases was used to detect the inhibitory effects of compounds on kinase activity. The kinases react enzymatically with their substrates IRS1, IGF1Rtide, and Poly(4:1Glu,Tyr), consuming ATP to produce ADP. The amount of product was detected using ADP-Glo ​​reagent and luminescence methods to reflect the kinase activity.

[0246] 2. Experimental Design

[0247] 2.1 Experimental Materials and Instruments

[0248] Source Article number HEPES Life Technologies 1 BRIJ 35 detergent (10%) Sigma 15630-080 2 MgCl2 Sigma 1018940100 3 EGTA Sigma M1028 4 ADP-Glo Kinase Assay Promega E3889 5 JAK1 Carna V9101 6 JAK2 Carna 08-144 7 JAK3 Carna 08-045 8 TYK2 Carna 08-046 9 ATP Promega 08-147 10 V915B IRS1 Signalchem 11 IGF1R tide Signalchem I40-58-1000 12 Poly(4:1 Glu, Tyr) Sigma I15-58 13 384 polystyrene shallow flat white Greiner P0275 15 384-Well Polypropylene microplate labcyte 784075 16 PP-0200 Biotek microplate reader Biotek 17 Synergy 4 Microplate low speed centrifuge Xiangzhi 18 TD5B Name Stock concentration

[0249] 2.2 Experimental Methods

[0250] 2.2.1 Kinase Reaction Reagent Formulation

[0251] 2.2.1.1 1X kinase reaction buffer (400 mL)

[0252] Volume Final concentration HEPES 1M (20X) 20 mL 50 mM 1M (100X) 4 mL MgCl2 10 mM BRIJ-35 400 μL EGTA 10％(1000X) Powder 0.01％ 152 mg 1 mM 375.6 mL Compound name ddH2O Mass / mg

[0253] 2mM DTT, prepare fresh before use.

[0254] 2.2.1.2 2X Kinase Formulation

[0255]

[0256]

[0257] 2.2.1.3 Formulation of 4X substrate mixture

[0258]

[0259]

[0260] 2.2.1.4 Test Compound

[0261] Molecular weight Concentration / mM Filgotinib Compound of formula (I) Example 3: Pharmacological activity evaluation II of compounds of formula (I) 5.0 420.5 10 Compound 1.5 476.51 10

[0262] 2.2.2 Kinase Reaction Experimental Procedure

[0263] 2.2.2.1 Experimental Procedure for JAK1 & JAK2 Kinase Reaction

[0264] a) Dilute the 10 mM stock solution of Filgotinib (10 mM) undiluted with 100% DMSO, and dilute the test compound 5 times. Perform a 4-fold serial dilution in a 96-well dilution plate. Add 1 μL of the compound to 49 μL of kinase reaction buffer and shake on a microplate shaker for 20 min.

[0265] b) Transfer 2 μL of kinase (prepared in step 2.2.1.2) to a 384 reaction plate, add 1 μL of the test compound (prepared in step a) to the 384 reaction plate (Greiner, 784075), centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 10 min.

[0266] c) Transfer 1 μL 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 Filgotinib in the reaction system were 50, 12.5, 3.125, 0.7812, 0.1953, 0.0488, 0.0122, 0.003, and 0.00076.

[0267] 0.00019, 0.000047 μM. Final concentrations of the analyte: 10, 2.5, 0.625, 0.15625, 0.039.

[0268] 0.0097, 0.0024, 0.0006, 0.0015, 0.000038, 0.0000095 μM. The final concentration of DMSO was 0.5% for all values.

[0269] d) Transfer 4 μL of LADP-Glo ​​to a 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C.

[0270] Incubate for 40 minutes.

[0271] e) Transfer 8 μL of Detection solution to a 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 40 min.

[0272] f) Use a Biotek multi-function plate reader to read the RLU (Relative Luminescence Unit) signal. The signal intensity is used to characterize the activity level of the kinase.

[0273] 2.2.2.2 JAK3 & TYK2 kinase reaction experimental procedure

[0274] a) Dilute the 10 mM stock solution of Filgotinib (10 mM) to 100% DMSO, dilute the compound to be tested 5 times, perform 3-fold serial dilutions in a 96-well dilution plate, add 1 μL of the compound to 49 μL of kinase reaction buffer, and shake on a microplate shaker for 20 min.

[0275] b) Transfer 2 μL of the kinase (prepared in step 2.2.1.2) to a 384 reaction plate, and add 1 μL of the test compound (prepared in step a) to the 384 reaction plate (Greiner, 784075).

[0276] Centrifuge at 1000 rpm for 1 min, then incubate at 25°C for 10 min.

[0277] c) Transfer 1 μL of the substrate mixture (prepared in step 2.2.1.3) to a 384 reaction plate, and incubate at 1000 mL / min.

[0278] Centrifuge at rpm / min for 1 min, then incubate at 25℃ for 60 min. The final concentrations of Filgotinib in the reaction system were 50, 16.67, 5.555, 1.851, 0.617, 0.205, 0.0686, 0.0228, 0.00762, and 0.0025 μM. The final concentrations of the analyte were 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, and 0.0005 μM. The final concentration of DMSO was 0.5% for all reactions.

[0279] d) Transfer 4 μL of LADP-Glo ​​to a 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 40 min.

[0280] e) Transfer 8 μL of Detection solution to a 384 reaction plate and centrifuge at 1000 rpm for 1 min.

[0281] Incubate at 25℃ for 40 minutes.

[0282] f) Use a Biotek multi-function plate reader to read the RLU (Relative Luminescence Unit) signal. The signal intensity is used to characterize the activity level of the kinase.

[0283] 2.2.3 Experimental Data Processing Methods

[0284] Compound inhibition rate (%inh) = (Negative control - Compound) / (Negative control - Positive control) × 100%

[0285] Negative control: DMSO

[0286] Positive control: 10uM / 100uM / 30uM Filgotinib

[0287] The IC50 (half-maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:

[0288] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0289] X: Log value of compound concentration

[0290] Y: Compound inhibition rate (%inh)

[0291] Z' factor calculation equation:

[0292] Z'=1-3(SDmin+SDmax) / (AVEmax-AVEmin)

[0293] in:

[0294] Min represents the RLU value of 10uM / 100uM / 30uM Filgotinib in the positive control group, and Max represents the RLU value of DMSO in the negative control group.

[0295] SD is the standard error, and AVE is the average RLU value.

[0296] 3. Results

[0297] The results of the compound detection are shown in the table below:

[0298]

[0299] 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 it can effectively inhibit JAK1, JAK2, JAK3 and TYK2 at extremely low concentrations.

[0300] IC50 (nM)

[0301] 1. Experimental Objective

[0302] This embodiment aims to detect the activity of the compound in the JAK cell activity assay-human T cell proliferation assay.

[0303] 2. Experimental Design

[0304] 2.1 Experimental Materials and Instruments

[0305]

[0306] 2.2 Experimental Methods

[0307] 2.2.1 Preparation of the test compound storage solution

[0308] 2.2.2 Kinase Reaction Experimental Procedure

[0309] a) T cells were sorted from human PBMCs using a human total T cell sorting kit.

[0310] b) Stimulate T cells with anti-CD3 antibody and anti-CD28 antibody and incubate at 37°C in a 5% CO2 incubator for 72 hours.

[0311] c) Collect T cells and wash them with PBS.

[0312] d) Transfer 40 nL of the diluted test compound to a 384-well plate using an Echo 550.

[0313] e) Seed T cells (prepared in step c) into 384-well reaction plates (prepared in step d), 35 μL / well, centrifuged at 1000 rpm for 1 min, and incubated at 37°C with 5% CO2.

[0314] f) Add 5 μL / well of recombinant human IL-2 protein to a final concentration of 10 ng / mL, centrifuge at 1000 rpm for 1 min, and incubate at 37°C and 5% CO2 for 72 h.

[0315] g) Add 20 μL / well Celltiter Glo buffer, centrifuge at 1000 rpm for 1 min, mix at 350 g for 2 min, and incubate at room temperature for 30 min.

[0316] h) Read the lumilencence signal value on the EnVision multifunction reader.

[0317] 2.2.3 Experimental Data Processing Methods

[0318] Compound inhibition rate (%inh) = (Negative control - Compound) / (Negative control - Positive control) × 100%

[0319] Negative control: DMSO reading

[0320] Positive control: 10 μM Tofacitinib reading

[0321] The IC50 (half-maximal inhibitory concentration) of the compound is obtained using the following nonlinear fitting formula:

[0322] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0323] X: Log value of compound concentration

[0324] Y: Compound inhibition rate (%inh)

[0325] 3. Results

[0326] The results of the compound detection are shown in the table below:

[0327] Tofacitinib Compound of formula (I) Example 4: Crystal form study of compounds of formula (I) 21.74 Parameter 13.01

[0328] The above results indicate that compound (I) showed superior activity to tofacitinib in the activity assay - IL-2-induced human T cell proliferation assay.

[0329] TGA

[0330] The polymorphism of compound (I) in Example 1 (sometimes referred to as "free base" hereinafter) was studied using different crystallization methods. The various crystal forms obtained were characterized and identified by methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and 1H nuclear magnetic resonance spectroscopy (1H NMR) to provide a basis and reference for the production and formulation of pharmaceutical preparations.

[0331] I. Instruments and Measurement Methods

[0332] 1) X-ray powder diffraction (XRPD)

[0333] The XRPD images were acquired using a PANalytical X-ray powder diffractometer, and the scanning parameters are shown in the table below.

[0334] Table 1: XRPD Test Parameters

[0335]

[0336]

[0337] 2) Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0338] The TGA and DSC plots were acquired using a TA Discovery TGA 5500 thermogravimetric analyzer and a TA Q2000 / DiscoveryDSC 2500 differential scanning calorimeter, respectively. The test parameters are listed in the table below.

[0339] Table 2: TGA and DSC Test Parameters

[0340] DSC Method Linear temperature increase Linear temperature increase Sample pan Aluminum pan, open Aluminum pan, crimped / uncrimped Temperature range Room temperature - set endpoint temperature Room temperature / 25°C - set endpoint temperature Scan rate (°C / min) Protective gas Nitrogen 10 10 Nitrogen Figure 1 Figure 2

[0341] 3) Liquid NMR ( 1 H NMR)

[0342] Liquid NMR spectra were acquired using a Bruker 400M NMR spectrometer with DMSO-d6 as the solvent.

[0343] II. Specific Experimental Procedures and Results

[0344] 1. Preparation and characterization of crystal form A

[0345] 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, and the temperature was raised to 50–55 °C and stirred. The system became viscous, and another 50 mL of methanol was added, and stirring was continued for 5 h. The mixture was filtered, and the filter cake was washed 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 crystal form A.

[0346] The XRPD test results for crystal form A are shown below. Figure 3 The specific data is as follows:

[0347] Table 3: XRPD data of free alkali crystal form A

[0348]

[0349] The TGA / DSC test results for crystal form A are shown below. Figure 4 As can be seen from the figure, when crystal form A is heated to 200℃, it loses 4.4% of its weight, which is presumably due to the removal of solvent or water from the sample. Multiple thermal signals can be observed in the range of 50-290℃.

[0350] Crystal form A 1 No residual MeOH solvent was observed in the 1H NMR, indicating that the 4.4% weight loss in the TGA came from the removal of water, suggesting that crystal form A may be a hydrate.

[0351] To investigate the properties of crystal form A, a heating experiment was conducted on crystal form A. Crystal form A was heated to 190°C under nitrogen protection and then cooled to room temperature. The sample was then exposed to air for XRPD testing. The test results are shown below. Figure 5 The results show that the crystal form of the sample remained unchanged, while a decrease in the relative intensity of some diffraction peaks was observed. Combined with the TGA / NMR results, the change in crystallinity after heating is presumably caused by the removal of water, and crystal form A may be a hydrate.

[0352] To further determine the properties of crystal form A, variable-temperature XRPD testing was performed on crystal form A. The results are shown in [Figure number missing]. Figure 6 The results showed that the crystal form of the sample remained unchanged after purging with nitrogen for 20 minutes at 30℃. Heating to 190℃ and then cooling to 30℃ under nitrogen purging yielded crystal-amorphous form D, which only existed under nitrogen protection (the shift in diffraction peak positions at different temperatures may be related to lattice expansion caused by high temperature). Based on the TGA / DSC / NMR results of crystal form A, it can be concluded that the crystal form change of crystal form A after heating to 190℃ was caused by the removal of water from the sample, and crystal form A is a hydrate.

[0353] 2. Preparation and characterization of crystal form B

[0354] After suspending and stirring crystal form A in EtOH at room temperature for three days, centrifuge the solid and then vacuum dry it at room temperature for about two hours to obtain crystal form B.

[0355] XRPD results for crystal form B are as follows: Figure 7 As shown, the specific data is as follows:

[0356] Table 4: XRPD data of free alkali crystal form B

[0357]

[0358] The TGA / DSC results for crystal form B are as follows: Figure 8 As shown, crystal form B loses 6.0% of its weight when heated to 150℃, presumably due to the removal of solvent or water from the sample; an endothermic signal is observed at 319.1℃ (initial temperature), presumably from the melting of the sample.

[0359] Crystal form B 1 1H NMR showed that the molar ratio of EtOH to compound (I) in crystal form B was 0.12:1.00 (1.1 wt%).

[0360] To investigate the properties of crystal form B, variable-temperature XRPD testing was conducted on crystal form B, and the results are as follows: Figure 9 As shown. After purging with nitrogen for 20 minutes, the crystal form of sample B remained unchanged. When heated to 150℃ under nitrogen purging, the diffraction peak positions of the sample were slightly shifted compared to crystal form B, which is presumably related to lattice expansion at high temperature. After cooling to 30℃, the diffraction peak positions of the sample were consistent with those of crystal form B, and the shift in diffraction peaks disappeared. Based on the TGA / DSC results, it is presumed that the TGA weight loss comes from moisture or solvent residue on the sample surface, and crystal form B is determined to be an amorphous form.

[0361] 3. Preparation and characterization of crystal form C

[0362] Hydrate crystal form A was suspended and stirred at room temperature for three days in an acetone / H2O (v / v, 19:1) system containing L-ascorbic acid. After centrifugation, the solid was vacuum dried at room temperature for about two hours to obtain crystals, which were named crystal form C.

[0363] XRPD results for crystal form C are as follows Figure 10 As shown, the specific data is as follows:

[0364] Table 5: XRPD data of free alkali crystal form C

[0365]

[0366] TGA / DSC results for crystal form C are as follows Figure 11As shown: the sample lost 6.4% of its weight when heated to 100℃, and a thermal signal was observed at 78.1℃ (initial temperature), presumably from the removal of solvent or water from the sample; overlapping thermal signals were observed at 279.4℃ and 303.8℃ (initial temperature).

[0367] Crystal form C 1 ¹H NMR showed that the molar ratio of acetone to compound (I) in crystal form C was 0.06:1.00 (0.7 wt%). Combined with the TGA results, it is speculated that the 6.4% weight loss in the TGA mainly came from the removal of water, and crystal form C may be a hydrate.

[0368] To investigate the properties of crystalline C, heating experiments were conducted. Crystalline C was heated to 150°C under nitrogen protection and then cooled to room temperature. The sample was then exposed to air for XRPD testing. The results were... Figure 12 The results showed a significant decrease in crystallinity after heating. Based on the NMR and TGA results, it is inferred that the decrease in crystallinity after heating was caused by the removal of water, and crystal form C was determined to be a hydrate.

[0369] 4. Preparation and characterization of crystal form D

[0370] Crystal form A was obtained by heating to 190°C and then cooling to 30°C under nitrogen protection. The XRPD results are as follows. Figure 13 As shown.

[0371] XRPD was tested after exposing crystal form D to air for approximately 2 hours, and the results were ( Figure 14 The result showed that it had transformed into crystal form A. It is speculated that crystal form D can only exist under nitrogen protection, and when exposed to air, it will rapidly absorb moisture from the environment and transform into crystal form A. Due to the instability of crystal form D, no further research was conducted.

[0372] 5. Preparation and characterization of crystal form E

[0373] After suspending and stirring the hydrate crystal form A in EtOH at 50°C for one day, centrifuge to separate the solid and place it at room temperature. After drying it overnight in an open container, the crystal was obtained and named crystal form E.

[0374] XRPD results for crystal form E are as follows Figure 15 As shown, the specific data is as follows:

[0375] Table 6: XRPD data of free alkali crystal form E

[0376]

[0377] The TGA / DSC results for crystal form E are as follows: Figure 16As shown: the sample lost 7.9% of its weight when heated to 150℃, and a thermal signal was observed at 43.5℃ (initial temperature), presumably from the removal of solvent or water from the sample; an endothermic signal was observed at 187.1℃ (initial temperature).

[0378] Crystal form E 1 1H NMR showed that the molar ratio of EtOH to compound (I) was 0.62:1.00 (5.7wt%). Combined with the TGA results, it is speculated that the weight loss in the TGA was due to the removal of EtOH and water.

[0379] To investigate the properties of crystal form E, a heating experiment was conducted on crystal form E. Crystal form E was heated to 120°C under nitrogen protection and then cooled to room temperature. The sample was then exposed to air for XRPD testing, and the results are as follows: Figure 17 As shown, the results indicate that the crystal form of the sample remained unchanged. 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%).

[0380] To further investigate the properties of crystal form E, variable-temperature XRPD testing was conducted on crystal form E. The results are as follows: Figure 18 As shown: After purging the sample with nitrogen for 20 minutes, the crystal form remained unchanged. Upon heating to 120℃ under nitrogen purging, the sample transformed into amorphous form D, existing only under nitrogen protection (a few diffraction peaks shifted compared to crystal form D, possibly related to different lattice expansion at different temperatures; the XRPD pattern of the reference crystal form D was measured at 30℃). Further heating to 210℃ resulted in the sample becoming amorphous. Cooling to 30℃ maintained the amorphous state, and gel formation was observed, suggesting the sample had melted. Compared to the results of heating crystal form E to 120℃ and then exposing it to air (where the crystal form remained unchanged), the difference in the two heating results is presumably related to whether the sample was exposed to air after heating. Specifically, amorphous form D, when exposed to air and heated, rapidly adsorbs moisture from the environment and transforms into crystal form E, suggesting that water molecules participate in the lattice composition of crystal form E.

[0381] 6. Preparation and characterization of crystal form F

[0382] After suspending and stirring the hydrate crystal form A and the amorphous crystal form B in acetone at 50°C for one day, centrifuge them, and then dry the solids in an open container at room temperature overnight to obtain crystals, which are named crystal form F.

[0383] XRPD results for crystal form F are shown in Figure 19 The specific data is as follows:

[0384] Table 7: XRPD data of free alkali crystal form F

[0385]

[0386] TGA / DSC results of crystal form F ( Figure 20 The data showed that the sample lost 10.5% of its weight when heated to 170℃, and a corresponding thermal signal was observed at 119.7℃ (initial temperature), presumably from the removal of solvent or water from the sample; two thermal signals were observed at 209.3℃ and 316.3℃ (initial temperatures). Crystal form F... 1 1H NMR showed that the molar ratio of acetone to compound (I) in crystal form F was 0.68:1.00 (7.7wt%). Combined with the TGA results, it is speculated that most of the weight loss in the TGA was due to the removal of acetone.

[0387] To investigate the properties of crystal form F and the possible source of thermal signals in DSC, heating experiments were conducted on crystal form F. Crystal form F was heated to 170℃ under nitrogen protection and then cooled to room temperature. The sample was then exposed to air for XRPD testing. The results (…) Figure 21 The results showed that the sample had transformed into hydrate crystal form G, and NMR results showed no obvious acetone residue in the heated sample. Combining the data before and after heating, XRPD showed a change in crystal form, and TGA / NMR showed that the component removed after heating was mainly acetone. The transformation of crystal form F to crystal form G after heating may have been caused by the removal of acetone, and it is determined that crystal form F is likely an acetone solvate.

[0388] 7. Preparation and characterization of crystal form G

[0389] After heating the acetone solvate crystal form F to 170°C under nitrogen protection and then cooling it to room temperature, the sample was removed and exposed to air to obtain crystals, which were named crystal form G.

[0390] XRPD results for crystal form G are as follows Figure 22 As shown, the specific data is as follows:

[0391] Table 8: XRPD data of free alkali crystal form G

[0392]

[0393] TGA / DSC results for crystal form G ( Figure 23 The results showed that crystalline form G lost 4.7% of its weight when heated to 100℃, and a thermal signal was observed at 81.2℃ (initial temperature), presumably from the removal of solvent or water from the sample; two thermal signals were observed at 209.6℃ and 314.0℃ (initial temperatures). NMR results for crystalline form G showed no obvious acetone residue in the sample, suggesting that crystalline form G may be a hydrated or amorphous form.

[0394] Further research was conducted on crystal form G using variable-temperature XRPD (using crystal form F as the starting material). Results ( Figure 24The results showed that after purging crystal form F under nitrogen for 20 minutes, the crystal form remained unchanged; after heating to 170°C under nitrogen purging, it transformed into amorphous form J, which only exists under nitrogen protection; after cooling to 30°C, the sample was exposed to air and tested for XRPD, and the results showed that it had transformed into crystal form G. It is speculated that crystal form J absorbs moisture from the environment after being exposed to air and transforms into crystal form G, which is a hydrate.

[0395] 8. Preparation and characterization of crystal form J

[0396] Crystals, named crystal form J, were obtained by heating acetone solvate crystal form F to 170°C and then cooling to 30°C under nitrogen protection. The XRPD results for crystal form J are shown below. Figure 25 As shown.

[0397] Crystal form J was exposed to air, and XRPD was tested again. The results were as follows: Figure 26 The results showed that it had transformed into hydrate crystal form G. It is speculated that crystal form J can only exist under nitrogen protection, and when exposed to air, it will rapidly absorb moisture from the environment and transform into crystal form G. Due to the instability of crystal form J, no further research was conducted.

[0398] 9. Preparation and characterization of crystal form H

[0399] Crystal form E was heated to 150°C under nitrogen protection and then cooled to room temperature. The sample was then exposed to air to obtain crystals, which were named crystal form H. The XRPD results are as follows: Example 5: Salt form study of compounds of formula (I) As shown.

[0400] 10. Preparation and characterization of crystal form I

[0401] Crystal form C of the hydrate was obtained by variable-temperature XRPD by heating it to 150°C under nitrogen protection and then cooling it to room temperature. This crystal was named crystal form I. The XRPD results are as follows: Abbreviation As shown.

[0402] Chinese

[0403] Using the compound of formula (I) obtained in Example 1 as the starting material, different acids were selected to study its salt formation, and crystallization was carried out under different conditions to study the polymorphism of each salt. The various crystal forms obtained were characterized and identified by methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), 1H nuclear magnetic resonance spectroscopy (1H NMR), and high performance liquid chromatography / ion chromatography (HPLC / IC) to provide a basis and reference for the production and formulation of pharmaceutical preparations.

[0404] I. Main reagents, instruments and measurement methods used in the study

[0405] 1. The abbreviations and corresponding Chinese names of the main solvents used in the experiment are shown in the table below.

[0406] Table 9: Comparison of Chinese and English Names of Solvents Used in the Experiment

[0407] Abbreviation Chinese MeOH Methanol MTBE Methyl tert-butyl ether EtOH Ethanol Anisole Anisole IPA Isopropyl alcohol ​ ​ n-Heptane n-Heptane Acetone Acetone Toluene Toluene MIBK MIBK DCM DCM EtOAc EtOAc ACN ACN IPAc IPAc DMSO DMSO THF THF CHCl3 Chloroform Chloroform 2-MeTHF 2-MeTHF DMF DMF 1,4-Dioxane H2O 1,4-Dioxane

[0408] 2. X-ray powder diffraction (XRPD)

[0409] XRPD images were acquired using a PANalytical X-ray powder diffractometer, and the scanning parameters are shown in Table 10.

[0410] Table 10: XRPD Test Parameters

[0411]

[0412] 3. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0413] The TGA and DSC plots were acquired using a TA Q5000 / Discovery TGA 5500 thermogravimetric analyzer and a TA DiscoveryDSC 2500 differential scanning calorimeter, respectively. The test parameters are listed in Table 11.

[0414] Table 11: TGA and DSC Test Parameters

[0415] Water Parameters TGA DSC Method Linear Ramp Linear Ramp Sample Pan Aluminum pan, open Aluminum pan, crimped Temperature Range Room temperature - set endpoint temperature 25 °C - set endpoint temperature 10 10 Scan Rate (°C / min) Protective Gas Nitrogen

[0416] 4. Dynamic Moisture Adsorption (DVS)

[0417] Dynamic moisture adsorption (DVS) curves were acquired using the DVSIntrinsic instrument of SMS (Surface Measurement Systems). 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.

[0418] Table 12: DVS Test Parameters

[0419]

[0420] 5. Liquid NMR ( 1 H NMR)

[0421] Liquid NMR spectra were acquired using a Bruker 400M NMR spectrometer, with DMSO-d6 as the NMR solvent.

[0422] 6. pH meter (pH)

[0423] pH was collected using a Sartorius PB-10 pH meter.

[0424] 7. High-performance liquid chromatography (HPLC) and ion chromatography (IC)

[0425] Sample purity and solubility were determined by high-performance liquid chromatography (HPLC). The molar ratio of salt-type samples in inorganic acid systems was determined by HPLC and ion chromatography. HPLC was performed on an Agilent 1290HPL, and ion chromatography was performed on a Thermo ICS 1100. Specific instruments and test parameters are shown in Tables 13 and 14.

[0426] Table 13: HPLC test parameters for solubility, molar ratio and purity

[0427]

[0428] *: Add sulfuric acid to aid dissolution during preparation.

[0429] Table 14: IC Test Parameters

[0430] Nitrogen Parameters Set Value Chromatography Column IonPac AS18 Analytical Column (4 x 250 mm) Mobile Phase 20 mM Sodium Hydroxide Injection Volume 25 microliters Flow Rate 1.0 milliliter / minute 35℃ Sample Chamber Temperature 35℃ Column Temperature Current 80 mA Run Time

[0431] II. Salt Preparation and Characterization

[0432] 1. Preparation and characterization of phosphate crystal form A

[0433] The preparation of phosphate using hydrate crystal form A of compound (I) as raw material is as follows:

[0434] 1) Measure 24 μL of concentrated phosphoric acid (approximately 85%) into a 20 mL glass vial;

[0435] 2) Weigh about 200 mg of the hydrate crystal form A of compound (I) into a 20 mL glass vial and add 10 mL of Lacetone / H2O (v / v, 19:1);

[0436] 3) After suspending and stirring at 25℃ for about 3 days, a milky white suspension was obtained. The solid was obtained by vacuum filtration at room temperature. The solid was transferred to room temperature and vacuum dried for 3 hours to obtain a white powder sample. XRPD results showed that the sample was crystallized. At the same time, HPLC / IC results showed that the molar ratio of compound (I) to phosphate was 1.00:1.25 (it is speculated that the high phosphate content may be due to unreacted phosphate residue).

[0437] 4) To remove any possible residual phosphoric acid, a total of 2 mL of EtOAc was added to the sample obtained in step 3 at room temperature and stirred. After about 5 hours, the sample was centrifuged and the solid was dried under vacuum at room temperature for about 13 hours to obtain phosphate crystal form A.

[0438] The XRPD diagram of phosphate crystal form A is shown below. 40 minutes As shown, the specific data is shown in the table below:

[0439] Table 15: XRPD data for phosphate crystal form A

[0440]

[0441] TGA / DSC data for phosphate crystal form A are as follows: Figure 27 As shown, the sample lost 1.8% weight when heated to 190℃, presumably due to the removal of water or solvent from the sample. A sharp endothermic peak was observed at 279.3℃ (initial temperature), presumably from sample melting. Based on the small weight loss before melting in TGA and the single endothermic melting peak in DSC, it is determined that phosphate crystal form A is likely amorphous. HPLC / IC results show that the molar ratio of compound (I) to phosphate in the sample is 1:1.

[0442] 2. Preparation and characterization of maleate crystal form A

[0443] Maleate salts were prepared using hydrate crystal form A of compound (I) as a raw material. The specific preparation steps are as follows:

[0444] 1) Weigh approximately 200 mg of the hydrate crystal form A of compound (I) into a 20 mL glass vial;

[0445] 2) Add 53 mg of maleic acid to a 20 mL glass vial, and add 10 mL of Acetone / H2O (v / v, 19:1);

[0446] 3) After suspending and stirring at 25℃ for about 3 days, a milky white suspension was obtained. The solid was obtained by vacuum filtration at room temperature. The solid was transferred to room temperature and vacuum dried for 3 hours to obtain a white powder sample. XRPD results showed that the sample was crystalline. At the same time, NMR results showed that the molar ratio of compound (I) to maleic acid in the sample was 1.00:0.86. It is speculated that there is a small amount of unreacted compound (I) in the sample, and the salt formation of the sample may be insufficient.

[0447] 4) To promote complete salt formation of the sample, 10 mg of maleic acid was added to the 163 mg sample obtained in step 3. After stirring in 2 mL of LEtOAc at 50 °C for about 14 hours, the solid was transferred to room temperature and vacuum dried for about 2 hours. After drying, crystals were obtained and named maleate crystal form A. XRPD and NMR tests were performed.

[0448] XRPD results for maleate crystal form A are shown in [reference needed]. Figure 28 The specific data is as follows:

[0449] Table 16: XRPD data of maleate crystal form A

[0450]

[0451] The NMR results showed that the molar ratio of compound (I) to maleic acid was 1:1.

[0452] For the TGA / DSC of maleate crystal form A, see [link to TGA / DSC]. Figure 29 The results showed that the sample lost 3.3% of its weight when heated to 150℃, and two thermal signals were observed at 211.2℃ and 278.1℃ (initial temperature).

[0453] 3. Preparation and characterization of methanesulfonate crystal form B

[0454] The preparation of methanesulfonate using hydrate crystal form A of compound (I) as raw material is as follows:

[0455] 1) Weigh approximately 200 mg of the hydrate crystal form A of compound (I) into a 20 mL glass vial;

[0456] 2) Add 54 mg of mesylate to a 20 mL glass vial, and add 10 mL of EtOAc;

[0457] 3) After suspending and stirring at 25℃ for about 3 days, a milky white suspension was obtained. The solid was obtained by vacuum filtration at room temperature. The solid was then transferred to room temperature and vacuum dried for 3 hours to obtain a white powder sample, namely methanesulfonate crystal form B.

[0458] The XRPD results of methanesulfonate crystal form B obtained thus are as follows: Figure 30 As shown, the specific data is as follows:

[0459] Table 17: XRPD data for methanesulfonate crystal form B

[0460]

[0461] The NMR results of methanesulfonate crystal form B showed that the molar ratio of compound (I) to methanesulfonic acid in the sample was 1:1.

[0462] TGA / DSC data for mesylate crystal form B are as follows: Figure 31 As shown, the sample lost 2.2% of its weight when heated to 190℃, presumably due to the removal of water or solvent from the sample. Two endothermic signals were observed at 234.4℃ (peak temperature) and 264.1℃ (initial temperature). Based on the small, slow weight loss before sample decomposition in TGA and the relatively smooth curve before 190℃ in DSC, it is speculated that methanesulfonate crystal form B is the amorphous form.

[0463] 4. Preparation and characterization of hydrochloride crystal form A

[0464] Hydrochloride was prepared using the hydrate crystal form A of compound (I) as a raw material. The specific preparation steps were as follows: the hydrate crystal form A of compound (I) and hydrochloric acid were suspended and stirred in EtOAc at room temperature for about 3 days at a molar ratio of 1:1. After centrifugation, the solid was transferred to room temperature and vacuum dried for 2 hours to obtain hydrochloride crystal form A.

[0465] XRPD results for hydrochloride crystal form A are as follows: Figure 32 As shown, the specific data is as follows:

[0466] Table 18: XRPD data for hydrochloride crystal form A

[0467]

[0468] TGA / DSC of hydrochloride crystal form A is shown in [reference]. Figure 33 The results showed that the sample lost 13.7% of its weight when heated to 240℃. Three endothermic peaks were observed at 80.1℃, 118.0℃ (peak temperature), and 224.5℃ (initial temperature), while an exothermic signal was observed at 231.5℃ (initial temperature). HPLC / IC results showed that the molar ratio of the hydrochloride crystal form A (formula (I)) compound to chloride ions was 1:0.7 (it is speculated that the salt formation of the sample may be incomplete).

[0469] 5. Preparation and characterization of tartrate crystal form A

[0470] Tartrate was prepared using hydrate crystal form A of compound (I) as raw material. The specific preparation steps were as follows: hydrate crystal form A of compound (I) and tartaric acid were suspended and stirred in EtOAc at room temperature for about 3 days at a molar ratio of 1:1. After centrifugation, the solid was transferred to room temperature and vacuum dried for 2 hours to obtain tartrate crystal form A.

[0471] XRPD results for tartrate crystal form A are as follows: Figure 34 As shown, the specific data is as follows:

[0472] Table 19: XRPD data for tartrate crystal form A

[0473]

[0474] TGA / DSC of tartaric acid crystal form A is shown in [reference needed]. Figure 35 The results showed that the sample lost 9.1% of its weight when heated to 200℃, and two thermal signals were observed at 125.2℃ and 168.8℃ (initial temperature). 1 1H NMR results showed that the molar ratio of compound (I) to tartaric acid in tartrate crystal form A was 1:1 (after deducting the 5 H atoms that overlap with compound (I)).

[0475] 6. Preparation and characterization of fumarate crystal form A

[0476] Fumarate was prepared using the hydrate crystal form A of compound (I) as a raw material. The specific preparation steps were as follows: the hydrate crystal form A of compound (I) and fumaric acid were suspended and stirred at room temperature in Acetone / H2O (19:1, v / v) at a molar ratio of 1:1 for about 3 days. After centrifugation, the solid was transferred to room temperature and vacuum dried for 2 hours to obtain fumarate crystal form A.

[0477] XRPD results for fumarate crystal form A are as follows: Figure 36 As shown, the specific data is as follows:

[0478] Table 20: XRPD data for fumarate crystal form A

[0479]

[0480] TGA / DSC of fumarate crystal form A is shown in [link to TGA / DSC]. Figure 37 The results showed that the sample lost 7.5% of its weight when heated to 110℃ and 8.0% when heated to 250℃. Multiple thermal signals were observed at 71.1, 205.3, 273.7 and 299.4℃ (initial temperature). 1 1H NMR results showed that the molar ratio of the fumarate crystal form A, compound of formula (I), to fumaric acid was 1:0.6.

[0481] 7. Preparation and characterization of mucilage crystal form A

[0482] The hydrate crystal form A of compound (I) was used as a raw material to prepare a viscous acid salt. The specific preparation steps were as follows: hydrate crystal form A of compound (I) and viscous acid were suspended and stirred at room temperature in Acetone / H2O (19:1, v / v) at a molar ratio of 1:1 for about 3 days. After centrifugation, the solid was transferred to room temperature and vacuum dried for 2 hours to obtain viscous acid salt crystal form A.

[0483] XRPD results of mucilage crystal form A are as follows Figure 38 As shown, the specific data is as follows:

[0484] Table 21: XRPD data of mucilage crystal form A

[0485]

[0486]

[0487] TGA / DSC of mucilage crystal form A is shown in [reference]. Figure 39 The results showed that the sample lost 4.4% of its weight when heated to 100℃ and 26.4% when heated to 260℃. Two thermal signals were observed at 69.8℃ and 210.4℃ (initial temperature). 1 1H NMR results showed that the molar ratio of the viscous acid in the A crystal form of the viscous acid compound of formula (I) was 1:1.4.

[0488] 8. Preparation and characterization of citrate crystal forms A / B

[0489] Citrate was prepared using hydrate crystal form A of compound (I) as raw material. The specific preparation steps were as follows: hydrate crystal form A of compound (I) and citric acid were suspended and stirred at room temperature for about 3 days in EtOAc and Acetone / H2O (19:1, v / v) at a molar ratio of 1:1. After centrifugation, the solid was transferred to room temperature and vacuum dried for 2 hours to obtain citrate crystal form A / B.

[0490] XRPD results for citrate crystal form A are as follows: Figure 40 As shown, the specific data is as follows:

[0491] Table 22: XRPD data for citrate crystal form A

[0492]

[0493] TGA / DSC of citrate crystal form A is shown in [link to TGA / DSC]. Figure 41 The results showed that the sample lost 9.1% of its weight when heated to 150℃, and three endothermic peaks were observed at 68.2℃ (peak temperature), 154.4℃ and 164.0℃ (initial temperature). 1 1H NMR results showed that the molar ratio of citrate crystal form A, compound of formula (I), to citric acid was 1:0.5.

[0494] XRPD results for citrate crystal form B are as follows: Figure 42 As shown, the specific data is as follows:

[0495] Table 23: XRPD data for citrate crystal form B

[0496]

[0497] TGA / DSC of citrate crystal form B is shown below. Figure 43 The results showed that the sample lost 7.1% of its weight when heated to 100℃ and 6.8% when heated to 250℃. Four endothermic peaks were observed at 73.1℃, 280.2℃, 301.6℃ (initial temperature) and 179.7℃ (peak temperature). 1 1H NMR results showed that the molar ratio of citrate crystal form B, compound (I) to citric acid was 1:0.5.

[0498] 9. Preparation and characterization of p-toluenesulfonate crystal form A

[0499] p-Toluenesulfonate was prepared using the hydrate crystal form A of compound (I) as a raw material. The specific preparation steps were as follows: the hydrate crystal form A of compound (I) and p-toluenesulfonic acid were suspended and stirred at room temperature in Acetone / H2O (19:1, v / v) at a molar ratio of 1:1 for about 3 days. After centrifugation, the solid was transferred to room temperature and vacuum dried for 2 hours to obtain p-toluenesulfonate crystal form A.

[0500] XRPD results for p-toluenesulfonate crystal form A are as follows: Figure 44 As shown, the specific data is as follows:

[0501] Table 24: XRPD data for p-toluenesulfonate crystal form A

[0502]

[0503] TGA / DSC of p-toluenesulfonic acid crystal form A is shown in [reference needed]. Figure 45 The results showed that the sample lost 5.1% of its weight when heated to 150℃, and two thermal signals were observed at 121.2℃ and 222.3℃ (initial temperature). 1 1H NMR results showed that the molar ratio of compound (I) in crystal form A of p-toluenesulfonate to p-toluenesulfonic acid was 1:1.

[0504] 10. Preparation and characterization of benzenesulfonate crystal forms A / B

[0505] Benzenesulfonate was prepared using hydrate crystal form A of compound (I) as raw material. The specific preparation steps were as follows: hydrate crystal form A of compound (I) and benzenesulfonic acid were suspended and stirred at room temperature for about 3 days in EtOH and Acetone / H2O (v / v, 19:1) at a molar ratio of 1:1. After centrifugation, the solid was transferred to room temperature and vacuum dried for 2 hours to obtain benzenesulfonate crystal form A / B.

[0506] The XRPD results of benzenesulfonic acid crystal form A are as follows: Figure 46 As shown, the specific data is as follows:

[0507] Table 25: XRPD data for benzenesulfonate crystal form A

[0508]

[0509] TGA / DSC of benzenesulfonic acid crystal form A is shown in [link to TGA / DSC]. Figure 47 The results showed that the sample lost 9.0% of its weight when heated to 150℃, and multiple thermal signals could be observed in the range of 60-200℃. 1 The H NMR results showed that the molar ratio of compound (I) in benzenesulfonic acid crystal form A to benzenesulfonic acid was 1:1.

[0510] The XRPD results of benzenesulfonic acid crystal form B are as follows: Figure 48 As shown, the specific data is as follows:

[0511] Table 26: XRPD data for benzenesulfonate crystal form B

[0512]

[0513] TGA / DSC of benzenesulfonic acid crystal form B is shown in [link to TGA / DSC]. Figure 49 The results showed that the sample lost 4.6% of its weight when heated to 100℃, and two thermal signals were observed at 90.1℃ (peak temperature) and 236.7℃ (initial temperature). 1 1H NMR results showed that the molar ratio of compound (I) of benzenesulfonic acid crystal form B to benzenesulfonic acid was 1:0.5.

[0514] III. Salt type screening

[0515] Based on the physical characterization data of the salt forms prepared above, phosphate crystal form A, maleate crystal form A, and methanesulfonate crystal form B, which have high XRPD diffraction peak intensity (sharp peak shape), small TGA weight loss, high DSC melting temperature, and high ligand acid safety level, were selected for further research and evaluation.

[0516] Table 27: Summary of Characterization Data for Salt-Type Samples

[0517]

[0518] *: Peak temperature;

[0519] # : Determined by IC and HPLC.

[0520] IV. Salt type assessment

[0521] In vitro evaluations were conducted on the three salt types of samples in terms of solubility, solid stability, and hygroscopicity.

[0522] 1. Reagents and Consumables

[0523] Table 28: Reagents used in the solubility experiment

[0524]

[0525] 2. Solubility

[0526] To evaluate the solubility of the three salt forms in different media, the dynamic solubility (1, 2, 4, and 24 hours) of three batches of samples in biological solvents (simulated gastric juice SGF and simulated intestinal juice FeSSIF) at room temperature was investigated, as well as their 24-hour solubility in ethanol, water, and phosphate buffer at pH 7.4. The specific steps were as follows:

[0527] 1) Weigh approximately 10 mg of the salt sample into an HPLC vial and add 1 mL each of ethanol, water, and pH 7.4 phosphate buffer.

[0528] 2) Weigh approximately 40 mg of the salt-type sample into a 5 mL centrifuge tube, and add 4 mL of SGF and FeSSIF respectively;

[0529] 3) Stir with magnetic levitation at a speed of ~750 rpm at 25°C;

[0530] 4) After equilibration for the appropriate time, centrifuge at room temperature to separate the solid and supernatant. The supernatant is used for pH and solubility testing.

[0531] The experimental results are shown in Table 29. At a salt concentration of 10 mg / mL, the solubility of the three salt forms in SGF and FeSSIF ranged from 0.05 to 0.30 mg / mL, with methanesulfonate form B showing relatively high solubility. In FeSSIF, the solubility ranged from 0.08 to 6.21 mg / mL, with methanesulfonate form B and maleate form A showing relatively high solubility. In water, ethanol, and pH 7.4 phosphate buffer, the solubility of the three salt forms in water ranged from 0.04 to 1.30 mg / mL, with phosphate form A showing relatively high solubility; in ethanol, the solubility ranged from 1.14 to 2.14 mg / mL, with maleate form A showing relatively high solubility; and in pH 7.4, the solubility ranged from 0.02 to 0.15 mg / mL, with methanesulfonate form B showing relatively high solubility.

[0532] Table 29: Summary of solubility of three salt forms in different media at 25°C

[0533]

[0534] S: API solubility (mg / mL);

[0535] NA: pH not tested.

[0536] Table 30: Summary of solubility of three salt forms in different media at 25℃

[0537]

[0538] S: API solubility (mg / mL);

[0539] NA: pH not tested.

[0540] 3. Solid stability

[0541] To assess the solid stability of the salt form, three batches of samples were placed at 25℃ / 60%RH and 40℃ / 75%RH (sealed with film and punctured with 6 small holes) for one week to evaluate their physicochemical stability. The samples were then subjected to HPLC and XRPD characterization to detect changes in purity and crystal form. The XRPD and HPLC results showed no significant changes in crystal form or purity. The test results are summarized in Table 31.

[0542] Table 31: Summary of stability test results for the three salt forms

[0543]

[0544] # Relative purity is the ratio of the purity of the stable sample to the purity of the initial sample.

[0545] 4. Hygroscopicity

[0546] To evaluate the hygroscopicity of the salt form, DVS testing was performed on three batches of samples. The DVS test results are as follows: Figure 50 , Figure 51 and Figure 52 As shown, phosphate crystal form A increased in weight by 0.6% upon moisture absorption at 80% RH / 25℃, maleate crystal form A increased by 0.8% upon moisture absorption at 80% RH / 25℃, and methanesulfonate crystal form B increased by 1.3% upon moisture absorption at 80% RH / 25℃. All three batches of samples showed slight hygroscopicity. With further increases in humidity, the weight gain from moisture absorption became more pronounced in all three batches. Furthermore, XRPD results showed no change in crystal form before and after DVS testing for all three batches of samples.

[0547] V. Conclusion

[0548] 1) Salt formation and salt form screening tests were conducted on (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxypyrrolidine-1-yl) methyl ketone of formula (I). Based on the characterization results of XRPD, TGA, DSC, NMR or HPLC / IC, a total of 10 different salt forms (involving 12 crystal forms) were found.

[0549] 2) Based on the criteria of high XRPD diffraction peak intensity, low TGA weight loss, high DSC melting temperature, and high ligand acid safety level, the phosphate crystal form A, maleate crystal form A, and methanesulfonate crystal form B of compound (I) were selected for in vitro evaluation of hygroscopicity, solubility, and solid stability.

[0550] 3) The solubility of phosphate form A, maleate form A, and methanesulfonate form B in SGF is 0.05-0.30 mg / mL, in FeSSIF is 0.08-6.21 mg / mL, in water is 0.04-1.30 mg / mL, in ethanol is 1.14-2.14 mg / mL, and in phosphate buffer at pH 7.4 is 0.02-0.15 mg / mL. After being stored at 40℃ / 75%RH and 25℃ / 60%RH for one week, the purity and crystal form of the three samples did not change significantly. DVS results for the three samples showed a moisture absorption weight gain of 0.6-1.3%, indicating slight hygroscopicity. The crystal forms remained unchanged after the DVS test. In conclusion, all three salt forms exhibit good properties in terms of hygroscopicity and solid stability.

[0551] Figure 53

[0552] 1. Experimental Principle

[0553] This study employed a drug screening system based on JAK1, JAK2, JAK3, and TYK2 kinases to assess the inhibitory effects of small molecule compounds on kinase activity. The kinases underwent an enzymatic reaction with their substrates IRS1, IGF1Rtide, and Poly(4:1Glu,Tyr), consuming ATP to produce ADP. The amount of product was detected using ADP-Glo ​​reagent and luminescence methods to reflect the kinase activity.

[0554] 2. Experimental Design

[0555] 2.1 Experimental Materials and Instruments

[0556] Example 6: Pharmacological Activity Evaluation of Salts of the Compound of Formula (I) Serial Number Name Source 1 Catalog Number Tris 30188336 2 National Pharmaceutical DTT 43816 3 Sigma MgCl2 M1028 4 Sigma BSA PE 5 CR84-100 ADP-Glo Kinase Assay V9101 6 Promega JAK1 Thermofisher 7 PV4774 JAK2 08-045 8 Carna JAK3 08-046 9 Carna TYK2 08-147 10 Carna ATP Promega 11 V915B IRS1 I40-58-1000 12 Signalchem IGF1Rtide I15-58 13 Signalchem Poly(4:1 Glu, Tyr) P0275 15 Sigma 384 polystyrene shallow flat white 784075 16 Greiner 384-Well Polypropylene microplate labcyte 17 PP-0200 Biotek microplate reader Biotek 18 Synergy 4 Microplate low speed centrifuge Xiangzhi

[0557] 2.2 Experimental Methods

[0558] 2.2.1 Kinase Reaction Reagent Formulation

[0559] 2.1.1.1 1X kinase reaction buffer (6 mL)

[0560] TD5B Name Stock Concentration Volume Final Concentration Tris 1 M (25X) 240 μL 40 mM MgCl2 1 M (50X) 120 μL 20 mM 7.5％(75X) BSA 0.1％ 80 μL DTT 1 M (500X) 3 μL 0.5 mM ddH2O 5557 μL

[0561] 2.2.1.2 2X Kinase Formulation

[0562]

[0563] 2.2.1.3 Formulation of 4X substrate mixture

[0564]

[0565] 2.2.1.4 Test Compound

[0566]

[0567] 2.2.2 Kinase Reaction Experimental Procedure

[0568] 2.2.2.1 Kinase Reaction Experimental Procedure

[0569] a) Dilute Tofacitinib and the test compound (10 mM stock solution) 50 times with 100% DMSO.

[0570] The compound was serially diluted 4-fold in a 96-well plate to obtain 10 concentrations. 1 μL of the compound was added to 49 μL of kinase reaction buffer and the plate was shaken for 20 min on a microplate shaker.

[0571] b) Transfer 2 μL of kinase (prepared in step 2.2.1.2) to a 384 reaction plate, add 1 μL of the test compound (prepared in step a) to the 384 reaction plate (Greiner, 784075), centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 10 min.

[0572] c) Transfer 1 μL 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 analyte in the reaction system were 1000, 250, 62.5, 15.625, 3.906, 0.977, 0.244, 0.061, 0.015, and 0.0038 nM. The final concentration of DMSO was 0.5%.

[0573] d) Transfer 4 μL of ADP-Glo ​​to a 384 reaction plate, centrifuge at 1000 rpm / min for 1 min, and incubate at 25 °C for 40 min.

[0574] e) Transfer 8 μL of Detection solution to a 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 40 min.

[0575] f) Use a Biotek multi-function plate reader to read the luminescence signal. The signal intensity is used to characterize the activity level of the kinase.

[0576] 2.2.3 Experimental Data Processing Methods

[0577] Compound inhibition rate (%inh) = (Negative control - Compound) / (Negative control - Positive control) × 100%

[0578] Negative control: DMSO

[0579] Positive control: 1000 nM Tofacitinib

[0580] The IC50 (half-maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:

[0581] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0582] X: Log value of compound concentration

[0583] Y: Compound inhibition rate (%inh)

[0584] Z' factor calculation equation:

[0585] Z'=1-3(SDmin+SDmax) / (AVEmax-AVEmin)

[0586] in:

[0587] Min represents the RLU value of 10uM / 100uM / 30uM Filgotinib in the positive control group, and Max represents the RLU value of DMSO in the negative control group.

[0588] SD is the standard error, and AVE is the average RLU value.

[0589] 3. Results

[0590] The results of the compound detection are shown in the table below:

[0591]

[0592] Test results show that, similar to compound (I), the mesylate of compound (I) also has JAK inhibitory activity, and its inhibitory activity is much higher than that of Tofacitinib (the inhibition of JAK1 and TYK2 is one to one order of magnitude higher), and it can effectively inhibit JAK1, JAK2, JAK3 and TYK2 at extremely low concentrations.

[0593] While specific embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the language used in this specification is merely descriptive and not restrictive. It will be apparent to those skilled in the art that various other changes and modifications can be made without departing from the general scope of this disclosure. Therefore, all such changes and modifications within the scope of the invention are intended to be included in the appended claims.

Claims

1. A solid form of a compound of formula (I), （I） which is any one of the following crystalline forms: 1) a phosphate salt Form A of a compound of formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks selected from the diffraction angles 2Θ of 5.29 ± 0.10º, 7.47 ± 0.10º, 10.61 ± 0.10º, 19.16 ± 0.10º and 21.32 ± 0.10º; 1) a phosphate salt Form A of a compound of formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks selected from the diffraction angles 2Θ of 5.29 ± 0.10º, 7.47 ± 0.10º, 10.61 ± 0.10º, 19.16 ± 0.10º and 21.32 ± 0.10º; 2) a maleate salt crystalline Form A of the compound of formula (I), having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.55 ± 0.10º, 8.78 ± 0.10º, 12.69 ± 0.10º, 13.96 ± 0.10º, 16.62 ± 0.10º, 17.61 ± 0.10º, 18.32 ± 0.10º, 25.39 ± 0.10º, 26.53 ± 0.10º ; 3) a mesylate salt crystalline Form B of a compound of formula (I), having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 5.91 ± 0.10º, 9.22 ± 0.10º, 15.83 ± 0.10º, 17.73 ± 0.10º, 19.02 ± 0.10º, 25.01 ± 0.10º ; 4) a hydrochloride salt Form A of the compound of formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 8.05 ± 0.10º, 17.11 ± 0.10º, 18.02 ± 0.10º, 20.84 ± 0.10º, 21.09 ± 0.10º, 22.77 ± 0.10º, 23.14 ± 0.10º; or a hydrochloride salt Form B of the compound of formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 7.62 ± 0.10º, 8.05 ± 0.10º, 17.11 ± 0.10º, 18.02 ± 0.10º, 20.84 ± 0.10º, 21.09 ± 0.10º, 22.77 5) a tartrate salt Form A of the compound of formula (I) having a powder X- ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 7.90 ± 0.10º, 8.69 ± 0.10º, 13.12 ± 0.10º, 13.43 ± 0.10º, 18.11 ± 0.10º, 21.28 ± 0.10º, 22.90 ± 0.10º ; 6) a fumarate salt crystalline Form A of a compound of formula (I) having a powder X- ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.96 ± 0.10º, 7.66 ± 0.10º, 10.21 ± 0.10º, 11.06 ± 0.10º, 14.74 ± 0.10º, 16.11 ± 0.10º, 22.87 ± 0.10º, 25.10 ± 0.10º ; 7) a mucate salt crystalline Form A of a compound of Formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.98 ± 0.10º, 10.22 ± 0.10º, 11.07 ± 0.10º, 14.75 ± 0.10º, 14.94 ± 0.10º, 16.13 ± 0.10º, 19.65 ± 0.10º, 30.79 ± 0.10º ; 8) a citrate salt crystalline Form A of the compound of formula (I), having a powder X- ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.85 ± 0.10º, 6.42 ± 0.10º, 14.63 ± 0.10º, 17.12 ± 0.10º, 20.75 ± 0.10º, 25.34 ± 0.10º ; 9) a citrate salt Form B of a compound of formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.96 ± 0.10º, 7.67 ± 0.10º, 10.20 ± 0.10º, 11.04 ± 0.10º, 14.73 ± 0.10º, 19.23 ± 0.10º, 22.86 ± 0.10º, 23.54 ± 0.10º, 24.28 ± 0.10º, 25.08 ± 0.10º ; 10) A p-toluenesulfonic acid salt crystalline Form A of a compound of formula (I), having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 5.90 ± 0.10º, 9.34 ± 0.10º, 14.87 ± 0.10º, 15.33 ± 0.10º, 17.88 ± 0.10º, 18.76 ± 0.10º, 19.71 ± 0.10º, 24.26 ± 0.10º characteristic peaks at diffraction angles 2Θ selected from 5.90 ± 0.10º, 9.34 ± 0.10º, 14.87 ± 0.10º, 15.33 ± 0.10º, 17.88 ± 0.10º, 18.76 ± 0.10º, 19.71 ± 0.10º, 24.26 ± 0.10º 11) a crystalline form A of a benzenesulfonic acid salt of a compound of formula (I), having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 5.82 ± 0.10º, 6.74 ± 0.10º, 11.85 ± 0.10º, 16.38 ± 0.10º ; 12) a benzenesulfonic acid salt Form B of a compound of Formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks selected from the diffraction angles 2Θ of 4.93 ± 0.10º, 5.63 ± 0.10º, 9.02 ± 0.10º, 10.89 ± 0.10º, 14.84 ± 0.10º, 17.55 ± 0.10º, 18.84 ± 0.10º, 23.12 ± 0.10º, 25.55 ± 0.10º, 26.14 ± 0.10º. characteristic peaks selected from the diffraction angles 2Θ of 4.93 ± 0.10º, 5.63 ± 0.10º, 9.02 ± 0.10º, 10.89 ± 0.10º, 14.84 ± 0.10º, 17.55 ± 0.10º, 18.84 ± 0.10º, 23.12 ± 0.10º, 25.55 ± 0.10º, 26.14 ± 0.10º.

2. The solid form of a compound according to claim 1, which is any one of the following crystalline forms: 1) a phosphate salt Form A of a compound of Formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks selected from diffraction angles 2Θ of 5.29 ± 0.10º, 7.47 ± 0.10º, 10.61 ± 0.10º, 15.94 ± 0.10º, 16.77 ± 0.10º, 18.68 ± 0.10º, 19.16 ± 0.10º, 21.32 ± 0.10º, and 25.36 ± 0.10º; characteristic peaks selected from diffraction angles 2Θ of 5.29 ± 0.10º, 7.47 ± 0.10º, 10.61 ± 0.10º, 15.94 ± 0.10º, 16.77 ± 0.10º, 18.68 ± 0.10º, 19.16 ± 0.10º, 21.32 ± 0.10º, and 25.36 ± 0.10º; 2) a maleate salt crystalline Form A of the compound of formula (I), having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.55 ± 0.10º, 8.78 ± 0.10º, 12.69 ± 0.10º, 13.74 ± 0.10º, 13.96 ± 0.10º, 16.62 ± 0.10º, 17.61 ± 0.10º, 18.32 ± 0.10º, 21.72 ± 0.10º, 25.39 ± 0.10º, 26.53 ± 0.10º ; 3) a mesylate salt crystalline Form B of a compound of Formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 5.91 ± 0.10º, 9.22 ± 0.10º, 15.83 ± 0.10º, 17.73 ± 0.10º, 19.02 ± 0.10º, 20.61 ± 0.10º, 21.36 ± 0.10º, 23.18 ± 0.10º, 25.01 ± 0.10º characteristic peaks at diffraction angles 2Θ selected from 5.91 ± 0.10º, 9.22 ± 0.10º, 15.83 ± 0.10º, 17.73 ± 0.10º, 19.02 ± 0.10º, 20.61 ± 0.10º, 21.36 ± 0.10º, 23.18 ± 0.10º, 25.01 ± 0.10º 4) a hydrochloride salt Form A of the compound of formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 8.05 ± 0.10º, 15.04 ± 0.10º, 17.11 ± 0.10º, 18.02 ± 0.10º, 20.44 ± 0.10º, 20.84 ± 0.10º, 21.09 ± 0.10º, 22.07 ± 0.10º, 22.77 ± 0.10º, 23.14 ± 0.10º ; 5) a tartrate salt crystalline Form A of the compound of formula (I) having a powder X- ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 7.90 ± 0.10º, 8.69 ± 0.10º, 13.12 ± 0.10º, 13.43 ± 0.10º, 15.08 ± 0.10º, 17.17 ± 0.10º, 17.44 ± 0.10º, 18.11 ± 0.10º, 19.40 ± 0.10º, 20.74 ± 0.10º, 21.28 ± 0.10º, 22.90 ± 0.10º, 24.15 ± 0.10º, 24.95 ± 0.10º ; 6) a fumarate salt crystalline Form A of a compound of formula (I) having a powder X- ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.96 ± 0.10º, 7.66 ± 0.10º, 10.21 ± 0.10º, 11.06 ± 0.10º, 12.44 ± 0.10º, 14.74 ± 0.10º, 16.11 ± 0.10º, 19.25 ± 0.10º, 22.87 ± 0.10º, 23.54 ± 0.10º, 24.27 ± 0.10º, 25.10 ± 0.10º, 25.37 ± 0.10º ; 7) a mucate salt crystalline Form A of a compound of Formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.98 ± 0.10º, 7.69 ± 0.10º, 10.22 ± 0.10º, 11.07 ± 0.10º, 14.75 ± 0.10º, 14.94 ± 0.10º, 16.13 ± 0.10º, 19.65 ± 0.10º, 21.51 ± 0.10º, 22.92 ± 0.10º, 30.79 ± 0.10º ; 8) a citrate salt crystalline Form A of the compound of formula (I), having a powder X- ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.85 ± 0.10º, 6.42 ± 0.10º, 7.64 ± 0.10º, 14.63 ± 0.10º, 15.40 ± 0.10º, 17.12 ± 0.10º, 18.12 ± 0.10º, 18.84 ± 0.10º, 19.37 ± 0.10º, 20.75 ± 0.10º, 25.34 ± 0.10º ; 9) The citrate crystal form B of compound (I) has a powder X-ray diffraction (XRPD) pattern with diffraction angles selected from 4.96±0.10º, 7.67±0.10º, 10.20±0.10º, 11.04±0.10º, 12.42±0.10º, 14.73±0.10º, 16.09±0.10º, 17.55±0.10º, 19.23±0.10º, 22.86±0.10º, 23.54±0.10º, 24.28±0.10º, 25.08±0.10º, and 27.91±0.10º. Characteristic peaks at the location; 10) a p-toluenesulfonic acid salt crystalline Form A of a compound of Formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 5.90 ± 0.10º, 9.34 ± 0.10º, 12.99 ± 0.10º, 14.87 ± 0.10º, 15.33 ± 0.10º, 16.10 ± 0.10º, 17.88 ± 0.10º, 18.76 ± 0.10º, 19.34 ± 0.10º, 19.71 ± 0.10º, 20.39 ± 0.10º, 24.26 ± 0.10º, 24.99 ± 0.10º; 2 characteristic peaks at diffraction angles 2Θ selected from 5.90 ± 0.10º, 9.34 ± 0.10º, 12.99 ± 0.10º, 14.87 ± 0.10º, 15.33 ± 0.10º, 16.10 ± 0.10º, 17.88 ± 0.10º, 18.76 ± 0.10º, 19.34 ± 0.10º, 19.71 ± 0.10º, 20.39 ± 0.10º, 24.26 ± 0.10º, 24.99 ± 11) a crystalline form A of a benzenesulfonic acid salt of a compound of formula (I), having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 5.82 ± 0.10º, 6.74 ± 0.10º, 11.85 ± 0.10º, 16.38 ± 0.10º, 19.46 ± 0.10º, 20.20 ± 0.10º ; 12) a benzenesulfonic acid salt crystalline Form B of a compound of Formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 4.93 ± 0.10º, 5.63 ± 0.10º, 9.02 ± 0.10º, 10.30 ± 0.10º, 10.89 ± 0.10º, 11.43 ± 0.10º, 14.23 ± 0.10º, 14.84 ± 0.10º, 17.04 ± 0.10º, 17.55 ± 0.10º, 18.84 ± 0.10º, 19.66 ± 0.10º, 20.24 ± 0.10º, 22.71 ± 0.10º, 23.12 ± 0.10º, 24.91 ± 0.10º, 25.55 ± 0.10º, 26.14 ± 0.10º.2 characteristic peaks at diffraction angles 2Θ selected from 4.93 ± 0.10º, 5.63 ± 0.10º, 9.02 ± 0.10º, 10.30 ± 0.10º, 10.89 ± 0.10º, 11.43 ± 0.10º, 14.23 ± 0.10º, 14.84 ± 0.10º, 17.04 ± 0.10º, 17.55 ± 0.10º, 18.84 ± 0.10º, 19.66 ± 0.10º, 20.24 ± 0.10º, 22.71 ± 0.10º, 23.12 ± 0.10º, 24.91 ± 0 3. A solid form of a compound of formula (I), （I） which is any one of the following crystalline forms: 1) a crystalline form A of a hydrate of a compound of formula (I), having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 8.67 ± 0.10º, 13.39 ± 0.10º, 15.05 ± 0.10º, 17.38 ± 0.10º, 21.24 ± 0.10º, 22.86 ± 0.10º, 24.89 ± 0.10º; 2) a crystalline form B of a hydrate of a compound of formula (I), having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 8.67 ± 0.10º, 13.39 ± 0.10º, 15.05 ± 0.10º, 17.38 ± 0.10º, 21.24 ± 0.10º, 22.86 ± 0 2) a crystalline Form B of the compound of formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 7.70 ± 0.10º, 11.20 ± 0.10º, 12.46 ± 0.10º, 15.44 ± 0.10º, 18.17 ± 0.10º, 18.48 ± 0.10º, 19.27 ± 0.10º, 21.84 ± 0.10º, 22.94 ± 0.10º, 24.29 ± 0.10º, 25.40 ± 0.10º, 27.92 ± 0.10º ; 3)(I) The crystal form C of the compound hydrate, its powder X-ray diffraction (XRPD) pattern has diffraction angles selected from 4.96±0.10º, 7.66±0.10º, 10.18±0.10º, 11.07±0.10º, 14.73±0.10º, and 22.87±0.10º. Characteristic peaks at the location; 4) a crystalline form G of a hydrate of the compound of formula (I), having a powder X- ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Θ selected from 6.42 ± 0.10º, 7.04 ± 0.10º, 7.69 ± 0.10º, 12.52 ± 0.10º, 15.81 ± 0.10º, 18.83 ± 0.10º, 22.85 ± 0.10º, 23.40 ± 0.10º .

4. The solid form of a compound according to claim 3, which is any one of the following crystalline forms: 1) Crystal form A of the hydrate of compound (I) has a powder X-ray diffraction (XRPD) pattern with diffraction angles selected from 8.67±0.10º, 11.53±0.10º, 13.39±0.10º, 15.05±0.10º, 17.38±0.10º, 21.24±0.10º, 21.63±0.10º, 22.19±0.10º, 22.86±0.10º, 23.43±0.10º, and 24.89±0.10º. Characteristic peaks at the location; 2) a crystalline Form B of the compound of formula (I) having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 20 selected from 7.70 ± 0.10º, 11.20 ± 0.10º, 12.46 ± 0.10º, 15.44 ± 0.10º, 18.17 ± 0.10º, 18.48 ± 0.10º, 18.93 ± 0.10º, 19.27 ± 0.10º, 19.50 ± 0.10º, 20.83 ± 0.10º, 21.84 ± 0.10º, 22.94 ± 0.10º, 23.22 ± 0.10º, 24.29 ± 0.10º, 25.40 ± 0.10º, 26.74 ± 0.10º, 27.92 ± 0.10º characteristic peaks at diffraction angles 20 selected from 7.70 ± 0.10º, 11.20 ± 0.10º, 12.46 ± 0.10º, 15.44 ± 0.10º, 18.17 ± 0.10º, 18.48 ± 0.10º, 18.93 ± 0.10º, 19.27 ± 0.10º, 19.50 ± 0.10º, 20.83 ± 0.10º, 21.84 ± 0.10º, 22.94 ± 0.10º, 23.22 ± 0.10º, 24.29 ± 0.10º, 25.40 ± 0. 3) a crystalline Form C of a hydrate of the (I) compound having a powder X-ray diffraction pattern XRPD with characteristic peaks at diffraction angles 2Q selected from 4.96 ± 0.10º, 7.66 ± 0.10º, 10.18 ± 0.10º, 11.07 ± 0.10º, 12.43 ± 0.10º, 14.73 ± 0.10º, 16.10 ± 0.10º, 19.24 ± 0.10º, 22.87 ± 0.10º, 23.52 ± 0.10º, 24.27 ± 0.10º, 25.09 ± 0.10º ; 4) The crystal form G of the hydrate of compound (I) has a powder X-ray diffraction (XRPD) pattern with diffraction angles selected from 6.42±0.10º, 7.04±0.10º, 7.69±0.10º, 11.48±0.10º, 12.52±0.10º, 15.81±0.10º, 18.83±0.10º, 19.58±0.10º, 22.85±0.10º, 23.40±0.10º, 25.31±0.10º, and 27.85±0.10º. The characteristic peak at that location.

5. A pharmaceutical composition which is a dispersion comprising a pharmaceutically acceptable liquid dispersant and a solid form of a compound according to any one of claims 1-4 dispersed in the liquid dispersant.

6. Use of a solid form of a compound according to any one of claims 1-4, or of a composition according to claim 5, for the manufacture of a medicament for the treatment and / or prevention of a JAK-associated disease.

7. The use according to claim 6, wherein the JAK-associated disease is selected from the group consisting of arthritis, autoimmune diseases, tumors, diabetes, ocular diseases, intestinal inflammation, intestinal allergy, neurodegenerative diseases, skin diseases, asthma and other obstructive airway diseases, transplant rejection, severe pneumonia caused by coronavirus infection.

8. The use according to claim 6, wherein the JAK-associated disease is selected from the group consisting of allergy.

9. The use according to claim 6, wherein the JAK-associated disease is selected from the group consisting of cancer, pruritus.

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