Patent Description:
Protein kinases are a family of enzymes that catalyze phosphorylation of specific residues in proteins, and are broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activities caused by mutations, overexpression or inappropriate regulation, abnormal regulation or dysregulation, and excessive or insufficient production of growth factors or cytokines are involved in many diseases, including but not limited to cancers, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders and neurological and neurodegenerative disorders (such as Alzheimer's disease). Inappropriate kinase activity triggers a variety of biological cell responses associated with cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility related to the aforementioned diseases and other 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 (<NPL>; <NPL>).

Since the first JAK inhibitor was discovered in the early <NUM>, the development of JAK inhibitors has gone through nearly <NUM> years. JAK is a family of intracellular non-receptor tyrosine kinases, which plays an important role in cytokine receptor signaling pathway by interacting with signal transducer and activator of transcription (STAT). JAK/STAT signaling 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. It is mainly composed of three components, namely tyrosine kinase associated receptor, tyrosine kinase JAK, signal transducer and activator of transcription STAT.

Many cytokines and growth factors transmit signals through the JAK-STAT signal pathway, including interleukins (such as IL-<NUM> to IL-<NUM>, IL-<NUM>, IL-<NUM>, IL-<NUM>, IL-<NUM>, and the like), GM-CSF ( granulocyte/macrophage colony stimulating factor), GH (growth hormone), EGF (epidermal growth factor), PRL (prolactin), EPO (erythropoietin), TPO (thrombopoietin), PDGF (platelet derived factors) and interferons (including IFN-α, IFN-β, IFN-γ and the like) and so on. These cytokines and growth factors have corresponding receptors on the cell membrane. The common feature of these receptors is that the receptor itself does not have kinase activity, but its intracellular segment has a binding site for tyrosine kinase JAK. After the receptor binds to a ligand, tyrosine residues of various target proteins are phosphorylated by activation of JAK that binds to the receptor to realize signal transfer from the extracellular to the intracellular.

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 Janus kinase in English. In Roman mythology, Janus is the double-faced god in charge of the beginning and the end. The reason why it is called Janus kinase is that JAK can phosphorylate cytokine receptors that it binds to, and also phosphorylate multiple signal molecules containing specific SH2 domains. The JAK protein family includes <NUM> members: JAK1, JAK2, JAK3, and TYK2. They have <NUM> JAK homology domains (JH) in structure in which the JH1 domain is a kinase domain having the function of encoding kinase proteins; JH2 domain is a "pseudo" kinase domain, which regulates the activity of JH1; and JH3-JH7 constitute a four-in-one domain, which regulates the binding of JAK proteins to receptors.

STAT is a type of cytoplasmic protein that can bind to DNA in the regulatory region of target genes, and is a downstream substrate of JAK. Seven members of the STAT family have been discovered, namely STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT protein can be divided into the following functional segments in structure including N-terminal conserved sequence, DNA binding region, SH3 domain, SH2 domain and C-terminal transcription activation region. Among them, the segment of the most conserved in sequence and most important in function is the SH2 domain, which has the same core sequence "GTFLLRFSS" as the SH2 domain of tyrosine kinase Src.

JAK-STAT signaling pathway has a wide range of functions and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. At present, the research related to disease and drug innovation mainly focuses on inflammatory diseases and neoplastic diseases in which the inflammatory diseases mainly include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis and Crohn's disease; and the neoplastic diseases mainly involve myelofibrosis, polycythemia vera and primary platelets hyperplasia. In addition, mutations in JAK molecule itself can also cause acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ductal breast carcinoma and non-small cell lung cancer (NSCLC), polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), chronic myeloid leukemia (CML), and the like. In addition, the JAK-STAT signaling pathway has been reported to be closely associated with cytokine storm in Covid-<NUM>.

JAK is a very important drug target. JAK inhibitors developed for this target are mainly used to screen therapeutic drugs for blood system diseases, tumors, rheumatoid arthritis and psoriasis. JAK-<NUM>, JAK-<NUM> and TYK-<NUM> are expressed in various tissue cells of human body. JAK-<NUM> is mainly expressed in various hematopoietic tissue cells, mainly in bone marrow cells, thymocytes, NK cells and activated B lymphocytes and T lymphocytes. Studies have shown that JAK2 inhibitors are suitable for myeloproliferative diseases (<NPL>; <NPL>; <NPL>), and JAK3 inhibitors are suitable as immunosuppressive agents (such as, <CIT>, <CIT>; <NPL>). In addition, JAK inhibitors are considered promising for the treatment of severe pneumonia, such as pneumonia caused by Covid-<NUM>, to suppress inflammatory response, and reduce the risk of cytokine storm, thereby reducing mortality (<NPL>"). There is also literature reporting the efficacy of JAK inhibitors for the treatment of pruritus (<NPL>").

Currently, JAK inhibitors approved by the FDA and EMA include Tofacitinib, Ruxolitinib, and Oclacitinib. JAK inhibitors in the middle and late stages of clinical research include Filgotinib, Peficitinib and so on.

Tofacitinib, a JAK3 inhibitor, was developed by Pfizer and was approved by the FDA in November <NUM> for the treatment of moderate to severe rheumatoid arthritis (RA) due to inadequate response or intolerance to methotrexate in adult patients. It is the first oral JAK inhibitor approved for RA treatment. After that, it was approved by Japan PMDA for listing in March <NUM> under the trade name Xeljanz. On March <NUM>, <NUM>, Pfizer China announced that the CFDA had formally approved Pfizer's application for the marketing of the oral JAK inhibitor. It was reported that the drug was approved for the treatment of adult patients with moderate to severe rheumatoid arthritis having inadequate response or intolerance to methotrexate. At present, Tofacitinib is close to being approved for indications such as psoriasis, ulcerative colitis, juvenile idiopathic arthritis; and clinical trials for the treatment of indications such as Crohn's disease and alopecia areata have also entered the mid- to late-stage. The main side effects of Tofacitinib are serious infection rate and increased low-density lipoprotein level. The most common adverse effects are upper respiratory tract infection, headache, diarrhea, nasal congestion, sore throat and nasopharyngitis. In addition, it has been have reported that Tofacitinib can cause side effects such as anemia and neutropenia in clinical studies.

Filgotinib, a JAK1 inhibitor, passed Phase III clinical trials in September <NUM> for the treatment of rheumatoid arthritis. At the same time, the study of Filgotinib for the treatment of ulcerative colitis and Crohn's disease is currently in clinical phase II/III trials. Filgotinib is a selective JAK1 inhibitor with IC50 of about <NUM>, <NUM>, <NUM> and <NUM> for JAK1, JAK2, JAK3 and TYK2, respectively, as reported. <CHM><CIT>
discloses in example <NUM>(d) a structurally close related compound to present compound of formula (I).

Although some JAK inhibitors have been approved for listing, and some of JAK inhibitors are still in clinical research, these JAK inhibitors are not satisfactory in terms of efficacy or safety. Therefore, there is always a need for JAK inhibitors with better efficacy and/or fewer side effects.

The present application is set out in the appended claims.

The present application provides a novel compound that inhibits JAK, thereby providing additional options for the prevention or treatment of JAK-related diseases. In addition, the present application provides a plurality of solid forms of the compound, including a plurality of crystal forms and amorphous forms, which have different chemical and physical properties as well as different metabolic properties in vivo, thus providing more freedom in the production, storage and selection of different drug dosage forms. Thus, novel drug dosage forms with higher bioavailability and/or better efficacy may be provided.

The following is a specific description of how the technical solutions of the present application are implemented. In these specific descriptions, a number of technical terms are used. In this disclosure, unless otherwise indicated, all terms have the meaning commonly understood by those skilled in the art.

In a first aspect, the present disclosure relates to a solid form of a compound, wherein the compound is the compound of formula (I)
<CHM>
or an isotopically labeled compound of compound of formula (I), or an optical isomer of compound of formula (I), or a geometric isomer of compound of formula (I), or a tautomer of compound of formula (I), a pharmaceutically acceptable salt of compound of formula (I), or a solvate of any one of these compounds and wherein the solid form of a compound is a crystal form.

The compound of formula (I) can be named as (S)-(<NUM>-(<NUM>-(<NUM>-ethyl-<NUM>-fluoro-<NUM>-hydroxyphenyl)-<NUM>-indazol-<NUM>-yl)-<NUM>,<NUM>-dihydropyrrolo[<NUM>,<NUM>-d]imidazol-<NUM>-(<NUM>)-yl)(<NUM>-hydroxy pyrrolidin-<NUM>-yl)ketone.

For simplicity, hereinafter, the term "compound according to the present application " or " compound of the present application" encompasses the compound of Formula (I), or an isotopically labeled compound of compound of formula (I), or an optical isomer of compound of formula (I), or a geometric isomer of compound of formula (I), or a tautomer of compound of formula (I), or a solvate of any one of these compounds.

The term "optical isomer" refers that when a compound has one or more chiral centers, each chiral center may have an R configuration or an S configuration, and the various isomers thus constituted are known as an optical isomer. Optical isomers comprise all diastereomers, enantiomers, meso forms, racemates or mixtures thereof. For example, optical isomers can be separated by a chiral chromatography or by chiral synthesis.

The term "geometric isomer" refers that when a double bond is present in a compound, the compound may exist as a cis isomer, a trans isomer, an E isomer, or a Z isomer. A geometric isomer comprises a cis isomer, trans isomer, E isomer, Z isomer, or a mixture thereof.

The term "tautomer" refers to an isomer that is formed by rapid movement of an atom at two positions in a single molecule. It will be understood by those skilled in the art that tautomers can be mutually transformed, and in a certain state, may coexist by reaching an equilibrium state. As used herein, the term "compound of formula (I)" also encompasses any tautomer of the compound of formula (I).

Unless otherwise indicated, reference to " compound as shown by formula (I)" or " compound of formula (I)" or " compound of the present application" herein also encompasses isotopically-labeled compounds obtained by replacing any atom of the compound with its isotopic atom.

The term "isotopically-labeled compounds" refers to such a compound in which one or more atoms are displaced by atoms having the same atomic number but different atomic mass or mass number than those normally found in nature.

Examples of isotopes suitable for inclusion in the compound of the present application include isotopes of hydrogen, such as <NUM>H (D) and <NUM>H (T), of carbon, such as <NUM>C, <NUM>C and <NUM>C, of chlorine, such as <NUM>C1, of fluorine, such as <NUM>F, of iodine, such as <NUM>I and <NUM>I, of nitrogen, such as <NUM>N and <NUM>N, of oxygen, such as <NUM>O, <NUM>O and <NUM>O, and of sulphur, such as <NUM>S.

Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes deuterium, i.e. <NUM>H, and carbon-<NUM>, i.e. <NUM>C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. <NUM>H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as <NUM>C, <NUM>F, <NUM>O and <NUM>N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of 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 using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

The compound of the present application may be in the form of a pharmaceutically acceptable salt of the compound of formula (I), particularly, an acid addition salt of the compound of formula (I). Suitable acid addition salts are formed from acids that form nontoxic salts. Examples include but are not limited to: muconate, hippurate, ascorbate, succinate, naphthalene-<NUM>-sulfonate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphor sulfonate, citrate, cyclohexamine sulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, <NUM>-(<NUM>-hydroxybenzyl) benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, <NUM>-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthalate, <NUM>-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, tosylate and trifluoroacetate. For a review of suitable salts, please refer to <NPL>). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

Particularly preferred pharmaceutically acceptable salts of the compound of formula (I) are its hydrochloride, phosphate, maleate, L-tartrate, fumarate, mucinate, citrate, p-toluenesulfonate, methanesulfonate, or benzenesulfonate. The most preferred pharmaceutically acceptable salt of the compound of formula (I) is its phosphate, maleate, or methanesulfonate.

The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to mammals, preferably humans. Preferably, the term refers to it is approved by regulatory agencies such as CFDA (China), EMEA (Europe), FDA (United States), and other national regulatory agencies to be suitable for mammals, preferably humans.

As used herein, the term "pharmaceutically acceptable salt of compound of formula (I)" is used to denote a pharmaceutically acceptable salt of compound of formula (I) in any form, encompassing a pharmaceutically acceptable salt of any one of compound of formula (I), an isotopically labeled compound of compound of formula (I), an optical isomer of compound of formula (I), a geometric isomer of compound of formula (I), and a tautomer of compound of formula (I).

Certain compounds of the present application may be present in a nonsolvated form as well as a solvated form, including a hydrated form. In the present disclosure, the terms "compound of formula (I)", "isotopically labeled compound of formula (I)", "optical isomer of compound of formula (I)", "geometric isomer of compound of formula (I)", "tautomer of compound of formula (I)", and "pharmaceutically acceptable salt of compound of formula (I)" all cover their solvates.

In the present application, the terms "solid form of a compound" and "compound in solid form" are understood to have the same meaning and are therefore used interchangeably, indicating that the compound is predominantly in solid form. It is understood by those of ordinary skill in the art that a compound in solid form can exist as a crystal (crystal form), an amorphous substance (non-crystal), or a mixture of both.

The term "crystal" or "crystal form" refers to a solid form as a crystal, which can be determined, for example, by X-ray diffraction. In some embodiments, a crystal form of substance may be substantially free of non-crystalline and/or other crystal forms. In certain embodiments, the crystal form of substance may contain one or more non-crystalline and/or other crystal forms of less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, less than <NUM>%, or less than <NUM>% by weight. In some embodiments, a crystal form of substance may have a purity of about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>%.

A polymorphism phenomenon exists in the compound of the present application. The term "polymorphism phenomenon" refers to a situation in which different crystals having the same molecular structure are formed due to different arrangements or conformations in the crystal lattice. It is known in the art that crystals of a compound with the same molecular structure but having different crystal forms may have different chemical and physical properties such as bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, hygroscopicity, density, and the like.

In a preferred embodiment of the present application, said solid form is a crystal of compound of formula (I) or a crystal of a salt of compound of formula (I) as prepared in the Examples of the present application. For example, in some preferred embodiments of the present application, said solid form is a phosphate crystal form A of compound of formula (I), a maleate crystal form A of compound of formula (I), a methanesulfonate crystal form B of compound of formula (I), a crystal form A of a hydrate of compound of formula (I), a crystal form B of compound of formula (I), and the like.

In a preferred embodiment of the present application, said solid form is a crystal of compound of formula (I) or a crystal of a salt of compound of formula (I) prepared in the "Examples" section of the present disclosure, and said crystal (or crystal form) has a powder X-ray diffraction pattern preferably with one or more characteristic peaks at the same position of the diffraction angle (2θ) as in the corresponding XRPD spectrum measured in the "Examples" section of the present disclosure. By "one or more characteristic peaks" it is meant at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM>, at least <NUM> at least <NUM>, at least <NUM>, or at least <NUM> characteristic peaks. Herein, "characteristic peak" is understood to mean one or more peaks with the greatest relative intensity in an XRPD spectrum. It would be understood by those skilled in the art that the positions of XRPD peaks measured under different conditions may deviate to some extent due to differences in sample purity and test conditions. The expression "same position" is therefore understood herein to mean that there can be a difference of ±<NUM>°, ±<NUM>°, ±<NUM>°, ±<NUM>°, preferably ±<NUM>° with respect to the corresponding diffraction angle (2θ) position given in the "Examples" section of the present disclosure. Most preferably, the powder X-ray diffraction pattern of said crystals (or crystal forms) is substantially the same as the corresponding XRPD pattern measured in the "Examples" section of the present disclosure. By "substantially the same as the corresponding XRPD pattern" it is meant that the two XRPD patterns are identical, or that there are some differences, but those skilled in the art can identify that the differences are immaterial and caused by different sample purities, measurement conditions, instrumentation errors or operating habits, and thus they may confirm that the two XRPD patterns are obtained from the same crystal.

In a preferred embodiment of the present application, said solid form is a crystal of compound of formula (I) or a crystal of a salt of compound of formula (I) prepared in the "Examples" section of the present disclosure, and said crystal (or crystal form) has a TGA or DSC profile preferably with at least one, at least two, at least three, or at least four characteristic peaks at the same position as the corresponding TGA or DSC profile measured in the "Examples" section of the present disclosure. The "characteristic peaks" are understood herein to be heat absorption or exothermic peaks in the TGA/DSC curves. It would be understood by those skilled in the art that the temperature readings indicating the peak positions in the TGA/DSC curves measured under different conditions may deviate to some extent due to differences in sample purity and test conditions. The expression "same position" is therefore understood herein to mean that relative to the corresponding TGA and/or DSC curves given in the "Examples" section of the present disclosure, the temperature at the same position can vary by ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>, ±<NUM>. Most preferably, the TGA/DSC curves of said crystal (or crystal form) are substantially the same as the corresponding TGA/DSC curves measured in the "Examples" section of the present disclosure. By "substantially the same as the corresponding TGA/DSC curves" it is meant that the two TGA and/or DSC curves are identical, or that there are some differences, but those skilled in the art can identify that the differences are immaterial and caused by different sample purities, measurement conditions, instrumentation errors or operating habits, and thus they may confirm that the two TGA and/or DSC curves are obtained from the same crystal.

A preferred embodiment of the present application relates to a crystal form A of a hydrate of compound of formula (I) with a powder X-ray diffraction pattern (XRPD) having one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>° ±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°.

Further preferably, the crystal form A of a hydrate of compound of formula (I) has multiple thermal signals in the range of about <NUM>-<NUM> in its TGA/DSC curve.

A preferred embodiment of the present application relates to a crystal form B of compound of formula (I) with a powder X-ray diffraction pattern (XRPD) having one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° , <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°.

Further preferably, the crystal form B of compound of formula (I) has a heat absorption peak at about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a crystal form C of a hydrate of compound of formula (I) with a powder X-ray diffraction pattern (XRPD) having one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>:<NUM>:<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°.

Further preferably, the crystal form C of a hydrate of compound of formula (I) has a thermal signal at about <NUM> (onset temperature) and thermal signals at about <NUM> (onset temperature) and <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a crystal form G of a hydrate of compound of formula (I) with a powder X-ray diffraction pattern (XRPD) having one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° , <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° , <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°.

Further preferably, the crystal form G of a hydrate of compound of formula (I) has a thermal signal at about <NUM> (onset temperature) and two thermal signals at about <NUM> (onset temperature), and about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a phosphate crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) having one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>° and <NUM> ± <NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° and <NUM>±<NUM>°.

Further preferably, the phosphate crystal form A of compound of formula (I) has a shape heat absorption peak at about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a maleate crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) having one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° <NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

Further preferably, the maleate crystal form A of compound of formula (I) has two thermal signals at about <NUM> and about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a methanesulfonate crystal form B of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) having one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

Further preferably, the methanesulfonate crystal form B of compound of formula (I) has two heat absorption signals at about <NUM> (peak temperature) and about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a hydrochloride crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) having one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>± <NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM> ±<NUM>°, and <NUM>±<NUM>°.

Further preferably, the hydrochloride crystal form A of compound of formula (I) has three heat absorption peaks at about <NUM>, about <NUM> (peak temperature) and about <NUM>° (onset temperature), and an exothermic signal at about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a tartrate crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>± <NUM>°, preferably with one or more characteristic peaks at the diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

Further preferably, the tartarate crystal form A of compound of formula (I) have two thermal signals at about <NUM> and about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a fumarate crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, and <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angel (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°.

Further preferably, the fumarate crystal form A of compound of formula (I) have multiple thermal signals at about <NUM>, about <NUM>, about <NUM>, and about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a mucolate crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, and <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

Further preferably, the mucolate crystal form A of compound of formula (I) has two thermal signals at about <NUM> and about <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a citrate crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, and <NUM> ± <NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM><NUM>°, and <NUM>±<NUM>°.

Further preferably, the citrate crystal form A of compound of formula (I) has three heat absorption peaks at about <NUM> (peak temperature), about <NUM> and <NUM> (onset temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a citrate crystal form B of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

Further preferably, the citrate crystal form B of compound of formula (I) has four heat absorption peaks at about <NUM>, about <NUM>, about <NUM> (onset temperature) and about <NUM> (peak temperature) in its TGA/DSC curve.

A preferred embodiment of the present application relates to a p-toluenesulfonate crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>± <NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

Further preferably, the p-toluenesulfonate crystal form A of compound of formula (I) has two thermal signals at about <NUM> and about <NUM> (onset temperature) in its TGA/DSC curves.

A preferred embodiment of the present application relates to a benzenesulfonate crystal form A of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM> ± <NUM>°, <NUM> ± <NUM>°, <NUM> ± <NUM>°, and <NUM> ± <NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM> ± <NUM> °, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°.

Further preferably, the benzenesulfonate crystal form A of compound of formula (I) has multiple thermal signals at about <NUM>-<NUM> in its TGA/DSC curve.

A preferred embodiment of the present application relates to a benzenesulfonate crystal form B of compound of formula (I) having a powder X-ray diffraction pattern (XRPD) with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM> °, <NUM>±<NUM>°, <NUM>±<NUM>°, and <NUM>±<NUM>°, preferably with one or more characteristic peaks at a diffraction angle (2θ) selected from <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>° <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM>±<NUM>°, <NUM><NUM>°, <NUM>±<NUM>°.

Further preferably, the benzenesulfonate crystal form B of compound of formula (I) has two thermal signals at about <NUM> (peak temperature) and about <NUM> (onset temperature) in its TGA/DSC curve.

In the most preferred embodiment of the present application, said solid form is phosphate crystal form A of compound of formula (I), maleate crystal form A of compound of formula (I), methanesulfonate crystal form B of compound of formula (I), crystal form A of a hydrate of compound of formula (I), and crystal form B of compound of formula (I), each of which has substantially the same XPRD spectrum as the corresponding crystal form described in the "Examples" section of the present disclosure.

In some embodiments of the present application, said solid forms is phosphate crystal form A of compound of formula (I), maleate crystal form A of compound of formula (I), methanesulfonate crystal form B of compound of formula (I), crystal form A of a hydrate of compound of formula (I), crystal form B of compound of formula (I), each of which has substantially the same TGA and/or DSC curves as the corresponding crystal form described in the "Examples" section of the present disclosure.

In a second aspect, the present disclosure provides a pharmaceutical composition comprising the solid form as mentioned in the first aspect of the present disclosure, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

The pharmaceutical composition of the present application may be a solid composition or a liquid composition (e.g., a dispersion).

The pharmaceutical compositions of the invention may be formulated as suitable dosage forms for oral, external (including not limited to external application, spraying, and the like), parenteral (including subcutaneous, intramuscular, intradermal and intravenous), bronchial or nasal administration as desire. Preferably, the pharmaceutical compositions of the invention may be formulated as suitable dosage forms for external administration, or bronchial administration or nasal administration. More preferably, the pharmaceutical compositions of the invention may be formulated as suitable dosage forms for external administration.

If a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, paste, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula (I) according to the invention.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions (such as suspensions or emulsions), and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or dispersing medium include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.

These compositions may also contain excipients such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, <NUM>,<NUM>-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Dosage forms for topical administration of a compound of the application include paste, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments and powders are also contemplated as being within the scope of this invention.

The external dosage form of the compound of the present application may be in the form of a water-in-oil (W/O) or oil-in-water (O/W) emulsion, a multi-emulsion form, such as a water-in-oil-in-water (W/O/W) form or an oil-in-water-oil (O/W/O) emulsion, or in the form of water dispersion or lipid dispersion, gel or aerosol.

The external dosage form of the compound of the present application may contain additives and aids, such as emulsifiers, thickeners, gelling agents, water fixatives, spreading agents, stabilizers, dyes, fragrances, and preservatives. Suitable emulsifiers include stearic acid, triethanolamine and PEG-<NUM>-stearate. Suitable thickeners include glyceryl monostearate, Carbomer and PEG600. Suitable preservatives include propyl paraben and chlorocresol. Suitable spreading agents include dimethicone and polydimethylcyclosiloxane. Suitable water fixatives include polyethylene glycol, preferably polyethylene glycol <NUM>.

The external dosage form of the compound of the present application may include pastes, lotions, gels, emulsions, microemulsions, sprays, skin patches, and the like, which can be applied topically to treat atopic dermatitis, eczema, psoriasis, and scleroderma, itching, vitiligo, hair loss and other skin diseases. In particular, the external dosage form of the compound of the present application is pastes, which can be applied topically to treat skin diseases such as atopic dermatitis, eczema, psoriasis, scleroderma, itching, vitiligo, and hair loss and other skin diseases.

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

In a third aspect, the present disclosure provides the compound in a solid form as described in the first aspect or the pharmacutuial composition as described in the second aspect for use as a medicament for the treatment and/or prevention of JAK-related diseases or disorders.

"Diseases or disorders related to JAK" include but not limited to:.

In order to have the desired effect, a therapeutically effective amount of the solid compound or pharmaceutical composition or dosage form of the present application is usually required to be administered to the patient. The phrase "therapeutically effective amount" is a recognized term in the art. In some embodiments, the term refers to an amount necessary or sufficient to eliminate, reduce, or maintain the target of a particular therapeutic regimen. The effective amount may vary depending on factors such as diseases or conditions being treated, the specific targeting construct being administered, age of the subject, or severity of the diseases or conditions. A person of ordinary skill in the art or a physician may determine the effective amount of a particular compound empirically, without the need for excessive experimentation. In some embodiments, the therapeutically effective amount of a therapeutic agent used in vivo may depend on many factors, including: administration manner and way; and any other materials included in the drug in addition to the active agent. In vitro or in vivo tests may optionally be used to help determine the optimal dose range.

Unexpectedly, the compound of the present application demonstrated in experiments excellent efficacy as a JAK kinase inhibitor that is superior to existing JAK kinase inhibitors, such as Filgotinib or Tofacitinib, and showed good safety potentially.

The present application will be further illustrated and described below in conjunction with the drawings and specific examples.

The compound of the present application can be synthesized by a variety of methods familiar to those skilled in the field of organic synthesis. Exemplary methods well known in the field of synthetic chemistry for the compounds of formula (I) are given in the following examples. Obviously, with reference to the exemplary schemes in the present application, other synthetic routes for the compound of formula (I) or for other compounds can be easily designed by those skilled in the art by suitably adjusting the reactants, reaction conditions and protecting groups.

Suitable crystal or amorphous forms of the compounds of the present application can be obtained using purification, crystallization and/or drying methods familiar to those skilled in the art. Exemplary methods for the preparation of certain crystal forms and amorphous forms are given in the following examples. Obviously, referring to the exemplary embodiments of the present application, those skilled in the art can appropriately adjust solvents, equipment and process conditions to easily design the preparation process for other crystal or amorphous forms.

The following further describes the present application in conjunction with examples. Nevertheless, these examples do not limit the scope of the present disclosure. Unless otherwise stated, all reactants used in the examples were obtained from commercial sources; and the instrumentation and equipment used in the synthesis experiments and product analysis assays were conventional instruments and equipment normally used in organic synthesis.

In order to synthesize the compound of formula (I), intermediate <NUM>-<NUM> to intermediate <NUM>-<NUM> were first synthesized, and then the intermediate <NUM>-<NUM> was used as a raw material to synthesize the compound of formula (I).

Unless otherwise specified, the chemical reagents, solvents and reaction equipment used in each chemical reaction of Example <NUM> were conventional materials and equipment used in chemical synthesis and were readily available through commercial sources.

The intermediate <NUM>-<NUM> was synthesized through the following synthetic route.

<NUM>-pyrroline (<NUM>, <NUM> mol) was dissolved in <NUM> dichloromethane and triethylamine (<NUM>, <NUM> mol), and then cooled to <NUM>. (Boc)<NUM>O (<NUM>, <NUM> mol) was slowly added. The reaction was carried out at room temperature overnight. Water was added and the mixture was extracted twice with dichloromethane. The organic phases was combined, washed with water three times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate <NUM>-<NUM> with a yield of <NUM>%.

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mol) was dissolved in <NUM> of dichloromethane, and then cooled to <NUM>. M-chloroperoxybenzoic acid (<NUM>, <NUM> mol) was slowly added in batches. The reaction was carried out at room temperature overnight. After that, saturated sodium thiosulfate (<NUM>) was added, and then stirred for <NUM> 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 to afford Intermediate <NUM>-<NUM> with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl3) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mol) was dissolved in <NUM> <NUM>,<NUM>-dioxane and <NUM> water, and then sodium azide (<NUM>, <NUM> mol) was added. The mixture was heated to <NUM> and reacted for <NUM> hours, then cooled to room temperature, followed by adding <NUM> of saturated brine. The resulting mixture was extracted with dichloromethane (<NUM> X <NUM>), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford Intermediate <NUM>-<NUM>, with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl3) δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mol) was dissolved in <NUM> of dichloromethane and triethylamine (<NUM>, <NUM> mol), and cooled to <NUM>, followed by slowly adding methanesulfonyl chloride (<NUM>, <NUM> mol) dropwise. After the addition, the reaction was carried out at room temperature for <NUM> hours, the reaction was quenched with water, and the resulting mixture was extracted twice with dichloromethane. The organic phases was combined, washed with saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford Intermediate <NUM>-<NUM>, with a yield of <NUM>%.

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mol) was dissolved in <NUM> DMF, to which sodium azide (<NUM>, <NUM> mol) was added. The mixture was heated to <NUM>, reacted for <NUM> days, and cooled to room temperature, following by adding <NUM> of water. The resulting mixture was extracted with butyl tert-butyl ether (<NUM>*<NUM>), and the organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and purified by silica gel column to afford Intermediate <NUM>-<NUM> with a yield of <NUM>%.

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mol) was dissolved in <NUM> methanol, and <NUM>% Pd/C was added where the atmosphere was displaced with hydrogen <NUM> times. The mixture was heated to <NUM>, and reacted for <NUM> days. The resulting mixture was filtered and concentrated to afford Intermediate <NUM>-<NUM>, with a yield of <NUM> %.

<NUM>H NMR (<NUM>, CDCl3) δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

<NUM>-bromo-<NUM>-fluorophenol (<NUM>, <NUM> mmol) and bis(tri-tert-butylphosphorus) palladium (<NUM>, <NUM> mmol) were dissolved in <NUM> THF. The atmosphere was displaced with nitrogen, which was repeated <NUM> times. The temperature was lowered to <NUM>-<NUM>. <NUM> mol/L diethyl zinc solution (<NUM>, <NUM>. 30mmol) was added dropwise slowly. After the addition was completed, the temperature was heated up to <NUM>. It was allowed to react overnight, and the temperature was cooled to <NUM>. The reaction was quenched with water, and filtered with celite. The celite pad was washed with ethyl acetate. The resulting filtrate was extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After drying, it was concentrated and separated by column chromatography to afford an oily liquid as intermediate <NUM>-<NUM> with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ6. <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J =<NUM>, <NUM>).

Intermediate <NUM>-<NUM> (<NUM>, <NUM>. 43mmol) was dissolved in <NUM> of acetonitrile, to which CuBr<NUM> (<NUM>, <NUM>. 29mmol) was added. The mixture was stirred at room temperature for <NUM> hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil as intermediate <NUM>-<NUM>, with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl3) δ7. <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> DMF, to which potassium carbonate (<NUM>, <NUM> mmol) and benzyl bromide (<NUM>, <NUM> mmol) were added. The mixture was heated to a temperature of <NUM> for reaction. After the reaction was complete, it 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 gave <NUM> of Intermediate <NUM>-<NUM> with a yield of <NUM>%. <NUM>H NMR (<NUM>, CDCl3) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Intermediates <NUM>-<NUM> (<NUM>, <NUM> mmol), pinacol borate (<NUM>, <NUM> mmol), Pd(dppf)Cl2 (<NUM>, <NUM> mmol) and KOAc (<NUM>, <NUM> mmol) were dissolved in <NUM> of <NUM>,<NUM>-dioxaborolane where the atmosphere was displaced with nitrogen <NUM> times. The mixture was heated to <NUM> for reaction. After the reaction was complete, it was quenched with water, extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After concentration, column chromatography gave <NUM> of Intermediate <NUM>-<NUM> with a yield of <NUM>%. <NUM> NMR (<NUM>, CDCl3) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m , <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Intermediate <NUM>-<NUM> was synthesized through the following synthetic route.

Sodium nitrite (<NUM>, <NUM> mmol) was dissolved in <NUM> DMF and <NUM> water, and the solution was cooled to <NUM>. Under nitrogen protection, 3N HCl (<NUM>, <NUM> mmol) was added slowly dropwise and it was allowed to react for <NUM> after dropwise addition. At <NUM>, <NUM>-bromoindole (<NUM>, <NUM> mmol) in DMF (<NUM>) was added to the reaction solution slowly dropwise. After the addition, it was allowed to react at room temperature overnight. The reaction solution was extracted <NUM> times with ethyl acetate, and the resulting organic phases were combined, washed <NUM> times with water, and with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified by silica gel column to give intermediates <NUM>-<NUM> with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, J = <NUM>, <NUM>).

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mmol) was dissolved in dry tetrahydrofuran, and the solution was cooled to <NUM>, to which sodium hydride (<NUM>, <NUM> mmol) was added dropwise slowly. It was allowed to react at room temperature for <NUM> hour. The reaction solution was cooled to <NUM>, and <NUM>-(trimethylsilyl)ethoxymethyl chloride (<NUM>, <NUM> mmol) was add dropwise slowly. It was allowed to react overnight at room temperature after dropwise addition. The reaction was quenched with water, extracted twice with ethyl acetate, and the resulting organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give Intermediates <NUM>-<NUM> with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, J = <NUM> <NUM>), <NUM> (dd, J = <NUM>, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> -<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mmol) and tert-butyl <NUM>,<NUM>-diaminopyrroline-<NUM>-carboxylate (<NUM>, <NUM> mmol) were dissolved in <NUM> of hexafluoroisopropanol, and the solution was heated to <NUM> and allowed to react for <NUM> days. The reaction solution was concentrated and purified by silica gel column to give Intermediate <NUM>-<NUM> with a yield of <NUM>%.

Under nitrogen protection, oxalyl chloride (<NUM>, <NUM> mmol) was dissolved in <NUM> of dry dichloromethane, and the solution was cooled to -<NUM>° C, to which DMSO (<NUM>, <NUM> mmol) was added slowly dropwise. After the addition was completed, it was allowed to react for <NUM>, to which Intermediate <NUM>-<NUM> (<NUM>, <NUM> mmol) in dichloromethane was added slowly dropwise. After the addition was completed, it was allowed to react for <NUM> minutes, to which dry triethyl amine (<NUM>, <NUM> mmol) was added slowly dropwise. After the addition was completed, it was allowed to react for <NUM> minutes. Then, the reaction mixture was slowly increased to room temperature and was allowed to react for <NUM>. The reaction was quenched by adding saturated ammonium chloride solution, extracted twice with dichloromethane, and the resulting organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give Intermediate <NUM>-<NUM> with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mmol) was dissolved in dry tetrahydrofuran, and the solution was cooled to <NUM>, to which sodium hydride (<NUM>, <NUM> mmol) was added. It was allowed to react at room temperature for <NUM>, and the reaction solution was cooled to <NUM>, to which <NUM>-(trimethylsilyl)ethoxymethyl chloride (<NUM>, <NUM> mmol) was added slowly dropwise, it was allowed to react at room temperature for <NUM>. The reaction was quenched by adding water and extracted with ethyl acetate twice and the resulting organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give Intermediates <NUM>-<NUM> with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

The compound of formula (I) was synthesized starting from intermediate <NUM>-<NUM> through the following synthetic route.

Tert-butyl <NUM>-(<NUM>-bromo-<NUM>-((<NUM>-(trimethylsilyl)ethoxy)methyl)-<NUM>-indol-<NUM>-yl)-<NUM>-((<NUM>-(trimethylsilyl)ethoxy)methyl)-<NUM>,<NUM>-dihydropyrrolo[<NUM>,<NUM>-d]imidazole-<NUM>(<NUM>)-carboxylate (<NUM>, <NUM> mmol), <NUM>-(<NUM>-(benzyloxy)-<NUM>-ethyl-<NUM>-fluorophenyl)-<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolane (<NUM>, <NUM> mmol), Pd(dppf)Cl2 (<NUM>, <NUM> mmol) and potassium phosphate (<NUM>, <NUM> mmol) were dissolved in <NUM>,<NUM>-dioxaborolane (<NUM>) and water (<NUM>), where the atmosphere was displaced with nitrogen <NUM> times, and the solution was heated to <NUM>. It was allowed to react for <NUM>. The reaction was cooled to room temperature and quenched with water and extracted with ethyl acetate twice. The resulting organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on silica gel column. The purified product was dissolved in <NUM> of dichloromethane, to which <NUM> of trifluoroacetic acid was added dropwise, and the mixture was stirred for <NUM> at room temperature, and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness (to remove trifluoroacetic acid), which was repeated <NUM> times. The resulting product was purified by silica gel column to afford intermediate <NUM>-<NUM>, totaling <NUM> with a yield of <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>) <NUM> (m, <NUM>), <NUM> (s, <NUM>), -<NUM> (d, J = <NUM>, <NUM>).

Triphosgene (<NUM>, <NUM> mmol) was dissolved in <NUM> of dry dichloromethane and the intermediate <NUM>-(<NUM>-(benzyloxy)-<NUM>-ethyl-<NUM>-fluorophenyl)-<NUM>-((<NUM>-(trimethylsilyl)ethoxy)methyl)-<NUM>-(<NUM>-((<NUM>-(trimethylsilyl)ethoxy)methyl)-<NUM>-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydropyrrolo[<NUM>,<NUM>-d]imidazole (<NUM>, <NUM> mmol) in dichloromethane (<NUM>) was added dropwise at <NUM>. Then dry triethylamine (<NUM>, <NUM> mmol) was added slowly dropwise. The resulting mixture was stirred at room temperature for <NUM>, and was monitored by TLC until the raw material was fully consumed. (S)-pyrrolidin-<NUM>-ol (<NUM>, <NUM> mmol) in dichloromethane (<NUM>) was added at room temperature. The reaction solution was stirred at room temperature for <NUM>, quenched with water, and extracted twice with dichloromethane, and the resulting organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to give <NUM> of Intermediate <NUM>-<NUM> with a yield of <NUM> %.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), -<NUM> (s, <NUM>).

Intermediate <NUM>-<NUM> (<NUM>, <NUM> mmol, <NUM> eq) was added to a three neck flask having a volume of <NUM>, followed by DCM (<NUM>, <NUM> V). After Intermediate <NUM>-<NUM> was dissolved, the solution was cooled to -<NUM> to -<NUM> and stirred magnetically. The atmosphere was displaced three times with N<NUM>. To the reaction solution, BCl<NUM> (<NUM>, <NUM> mmol, <NUM> eq, <NUM> N in DCM) was added in <NUM>, during which, the inner temperature was kept not greater than -<NUM>. After the addition was completed, the mixture was further stirred at -<NUM> to -<NUM> for <NUM>. <NUM> of methanol was added to the reaction system slowly dropwise to quench the reaction, during which the quenching temperature should not exceed -<NUM>, and the dropwise addition was completed in about <NUM>. Then the reaction system was naturally warmed up to <NUM>-<NUM>, and the reaction solution was concentrated under vacuum at <NUM>. To the resulting residue, <NUM> of methanol and ammonia were added, and the mixture was stirred at <NUM> for <NUM> and then subjected to rotary evaporation to remove methanol. A large amount of light yellow solid was precipitated from the system (aqueous phase), which was filtered to give a solid, which was dried to give a crude product (<NUM>). The crude product was purified by Prep-HPLC (normal phase, <NUM>% ammonia alkaline system, ethanol system), and the resulting fraction was concentrated to <NUM> at <NUM> with a large amount of solid precipitation, followed by filtration to give <NUM> of a light yellow solid powder, which is the compound of formula (I).

<NUM>H NMR (<NUM>, DMSO-d6) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>, partially obscured by the solvent peak of DMSO -d6, <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>, partially obscured by the solvent peak of DMSO-d6).

LC-MS: C<NUM>H<NUM>FNgO<NUM> [M+H]+ m/z calculated as <NUM>, and detected as <NUM>.

A drug screening system based on kinases JAK1, JAK2, JAK3, and TYK2 was used to detect the inhibitory ability of compounds on kinase activity. A kinase undergoes an enzymatic reaction with its substrates IRS1, IGF1Rtide, and Poly (<NUM>:<NUM> Glu, Tyr), consuming ATP to produce ADP, wherein the ADP-Glo reagent and luminescence method can be used to detect the amount of the product to reflect the activity of the kinase.

The results of the compound assays are shown in the following table.

The test results show that the inhibitory activity of the compound of formula (I) obtained in Example <NUM> is much higher than that of Filgotinib, in particular by more than two orders of magnitude, and can effectively inhibit JAK1, JAK2, JAK3 and TYK2 at very low concentrations.

The purpose of this example is to assay the activity of the compound in the JAK cell activity assay - human T cell proliferation assay.

The test results show that the compound of formula (I) exhibits superior activity over Tofacitinib in IL-<NUM> induced human T cell proliferation assay.

The polymorphism phenomenon of the compound of formula (I) in Example <NUM> (sometimes referred to as "the free base" because of its basic nature) was investigated by varying crystallization methods, and the various crystal forms were characterized and identified by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), nuclear magnetic resonance hydrogen spectroscopy (<NUM> NMR) and other methods in order to provide a basis for the production and formulation of pharmaceutical preparations.

XRPD patterns were collected on a PANalytical X-ray powder diffraction analyzer using the scanning parameters shown in the table below.

TGA and DSC curves were acquired on a TA Discovery TGA <NUM> thermogravimetric analyzer and a TA Q2000/Discovery DSC <NUM> differential scanning calorimeter, respectively using the test parameters listed in the table below.

The liquid NMR spectra were acquired on a Bruker <NUM> NMR instrument with DMSO-d6 as a solvent.

<NUM> of the compound of formula (I) obtained in Example <NUM> was added to a three-neck flask, to which <NUM> of methanol was added, and was warmed up to <NUM>-<NUM> with stirring. The system became viscous, to which another <NUM> of methanol was added, and the stirring was continued for <NUM>. The product was filtered and the filter cake was rinsed with <NUM> of methanol and dried under vacuum at <NUM> for <NUM>, to finally afford <NUM> of a crystal of the compound of formula (I), named as crystal form A.

The XRPD test results of the crystal form A are shown in <FIG>, and the specific data are as follows.

The TGA/DSC test results of the crystal form A are shown in <FIG>, from which <NUM>% weight loss from the crystal form A by heating to <NUM> could be seen, which is presumed to be caused by the removal of solvent or water from the sample, and multiple thermal signals could be observed in the range of <NUM>-<NUM>.

No corresponding solvent MeOH residue is observed in <NUM>H NMR of the crystal from A, showing that the <NUM>% weight loss in TGA is attributed to the removal of water, and indicating that the crystal from A may be a hydrate.

In order to investigate properties of the crystal from A, heating experiments were carried out on the crystal form A. After the crystal form A was heated to <NUM> and lowered to room temperature under nitrogen protection, the sample was taken out and exposed to air for XRPD. The test results are shown in <FIG>, showing that crystal form of the sample remained unchanged, while a decrease in relative intensity of some diffraction peaks could be observed. Combined with the results of TGA/NMR, it is presumed that the change in crystallinity after heating was caused by the removal of water, and the crystal form A may be a hydrate.

To further determine properties of the crystal form A, a variable temperature XRPD test was carried out on the crystal form A. The results are shown in <FIG>, showing that after the sample was purged with nitrogen for <NUM> at <NUM>, its crystal form remained unchanged; and after the sample was heated to <NUM> and then cooled to <NUM> under nitrogen purging, an anhydrous crystal form D was obtained only under the protection of nitrogen (the shift of diffraction peaks at different temperatures may be related to lattice expansion caused by high temperature). Combined with the above TGA/DSC/NMR results of the crystal form A, it can be concluded that change of the crystal form A after heating to <NUM> is caused by the removal of water from the sample, and crystal form A is a hydrate.

The crystal form A was suspended and stirred in EtOH at room temperature for three days, and then centrifuged for isolation and the solid was dried under vacuum at room temperature for about two hours to give a crystal, named as crystal form B.

The XRPD results of the crystal form B are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the crystal form B are shown in <FIG>, from which <NUM>% weight loss from the crystal form B by heating to <NUM> could be seen, which is presumed to be caused by the removal of solvent or water from the sample, and one heat absorption signal could be observed at <NUM> (onset temperature), which is presumed to come from melting of the sample.

<NUM>H NMR of the crystal form B shows that in the crystal form B, a molar ratio of EtOH to compound (I) is <NUM>:<NUM> (<NUM> wt%).

To investigate properties of the crystal form B, a variable temperature XRPD test was carried out on the crystal from B. The results are shown in <FIG>. After the sample was purged under nitrogen for <NUM>, the crystal form remained unchanged; when the sample was heated to <NUM> under nitrogen purging, the diffraction peaks were slightly shifted compared with those of original crystal form B, which is presumed to be related to lattice expansion at high temperature; after the sample was cooled back to <NUM>, the positions of the diffraction peaks of the sample were the same as those of original crystal form B, and the diffraction peak shift disappeared. Combined with the TGA/DSC results, it is presumed that the TGA weight loss came from moisture or solvent residue on the sample surface, and the crystal form B is determined to be an anhydrous crystal form.

The hydrate crystal form A was suspended and stirred for three days at room temperature in acetone/H<NUM>O (v/v, <NUM>:<NUM>) system containing L-ascorbic acid, and centrifuged for isolation. The solid was dried under vacuum at room temperature for about two hours to give a crystal, named as crystal form C.

The XRPD results for the crystal form C are shown in <FIG>, with the following data.

The TGA/DSC results of the crystal form C are shown in <FIG>, from which it can be seen that, when the sample was heated to <NUM>, it had a weight loss of <NUM>%, and a thermal signal could be observed at <NUM> (onset temperature), which is presumed to come from removal of solvent or water from the sample; and some overlapped thermal signals could be observed at <NUM> and <NUM> (onset temperature).

<NUM>H NMR data of crystal form C show that in the crystal form C, a molar ratio of acetone to compound (I) is <NUM>:<NUM> (<NUM> wt%). Combined with the TGA results, it is speculated that the <NUM>% weight loss in TGA is essentially from removal of water and thus the crystal form C might be a hydrate.

In order to investigate properties of the crystal form C, heating experiments were carried out on the crystal form C. After heating the crystal form C to <NUM> under nitrogen protection and cooling it back to room temperature, the sample was taken out and exposed to air for XRPD. The results are shown in <FIG>, which show that crystallinity of the sample decreased significantly after heating. Combined with the NMR and TGA results, it is speculated that the decrease in crystallinity after heating was caused by the removal of water, and the crystal form C is determined to be a hydrate.

Crystal form D was obtained by heating the crystal form A to <NUM> and lowering the temperature to <NUM> under nitrogen protection, and the XRPD results are shown in <FIG>.

The crystal form D was exposed to air for about <NUM> hours and then was subjected to XRPD. The results in <FIG> show that the crystal form D transformed into the crystal form A. It is assumed that the crystal form D could only exist under nitrogen protection and would rapidly absorb water from the environment and transform into the crystal form A when it is exposed to air. No further studies are conducted because of instability of the crystal form D.

The hydrate crystal form A was suspended and stirred in EtOH at <NUM> for one day, then centrifuged for isolation. The solid was allowed to stand at room temperature and dried overnight in air, thereby giving a crystal, named as crystal form E.

The XRPD results of the crystal form E are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the crystal form E are shown in <FIG>, from which it can be seen that when the sample was heated to <NUM>, it had a weight loss of <NUM>% and a thermal signal could be observed at <NUM> (onset temperature), which is presumed to come from the removal of solvent or water from the sample; and that a heat absorption signal could be observed at <NUM> (onset temperature).

The <NUM>H NMR data of the crystal form E show that a molar ratio of EtOH to compound (I) is <NUM>:<NUM> (<NUM> wt%). Combined with the TGA results, it is presumed that the weight loss in TGA came from the removal of EtOH and water.

In order to investigate properties of the crystal form E, heating experiments were carried out on the crystal form E. After the crystal form E was heated to <NUM> under nitrogen protection and lowered to room temperature, the sample was taken out and exposed to air for XRPD. The results are shown in <FIG>, which show that crystal form of the sample remained unchanged. The NMR results show that a molar ratio of EtOH to compound (I) in the sample after heating is <NUM>:<NUM> (<NUM> wt%).

To further investigate properties of the crystal form E, a variable temperature XRPD test was carried out on the crystal form E. The results are shown in <FIG>, from which it can be seen that when the sample was purged under nitrogen for <NUM>, crystal form of the sample remained unchanged; when the sample was heated to <NUM> under nitrogen purging, the sample had transformed into an anhydrous crystal form D which could only exist under the protection of nitrogen (the positions of a few diffraction peaks are shifted compared with the crystal form D, which might be related to different degrees of expansion of each lattice at different temperatures, wherein the XRPD pattern of the control crystal form D was measured at <NUM>); when the sample was continued to be heated to <NUM>, the sample had transformed into an amorphous form; when the sample was lowered to <NUM>, the sample was still amorphous and was observed to become gelatinous, and it is presumed that the sample had melted. Compared with the result in which when the crystal form E was heated to <NUM> and exposed to air, the crystal form remained unchanged, the result of the experiment in which the sample was heated to <NUM> under nitrogen purging was different. It is speculated that the difference between these two heating results is related to whether the sample was exposed to air after heating. That is, an anhydrous crystal form D could quickly adsorb water in the environment and turn into a crystal form E after being exposed to air and heated, and thus it is speculated that water molecules are involved in the lattice composition of crystal form E.

The hydrate crystal form A and the anhydrous crystal form B, used as the crystal seeds, were suspended and stirred in acetone at <NUM> for one day, then centrifuged for insolation. The solid was allowed to stand in air at room temperature overnight, giving a crystal, named as crystal form F.

The XRPD results of the crystal form F are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the crystal form F (<FIG>) show that when the sample was heated to <NUM>, it had a weight loss of <NUM>%, and a thermal signal was observed at <NUM> (onset temperature), which is presumed to come from the removal of solvent or water from the sample; and that two thermal signals are observed at <NUM> and <NUM> (onset temperature). The <NUM>H NMR data of the crystal form F show that a molar ratio of acetone to compound (I) in crystal form F is <NUM>:<NUM> (<NUM> wt%). Combined with the TGA results, it is assumed that most of the weight loss in TGA came from the removal of acetone.

In order to investigate properties of the crystal form F and to study possible source of the thermal signals in DSC, heating experiments were carried out on crystal form F. After heating the crystal form F to <NUM> under nitrogen protection and lowering it to room temperature, the sample was taken out and exposed to air for XRPD. The results (<FIG>) show that the sample was converted to hydrate crystal form G. The NMR results show that no significant acetone residues could be observed in the heated sample. Combined with the results before and after heating, the change of the crystal form observed in XRPD, and that the component removed after heating was mainly acetone as shown by TGA/NMR, it is concluded that the conversion of the crystal form F to crystal form G after heating may be caused by the removal of acetone, and that the crystal form F is determined to be probably an acetone solvate.

The acetone solvate crystal form F was heated to <NUM> under nitrogen protection and lowered to room temperature, and then the sample was taken out and exposed to air to obtain a crystal, named as crystal form G.

The XRPD results of the crystal form G are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the crystal form G (<FIG>) show that when the crystal form G was heated to <NUM>, it had a weight loss of <NUM>% and one thermal signal could be observed at <NUM> (onset temperature), which is presumed to come from the removal of solvent or water from the sample; and that two thermal signals could be observed at <NUM> and <NUM> (onset temperature). The NMR results of the crystal form G show that no significant acetone residue could be observed in the sample, and thus the crystal form G may be a hydrate or an anhydrous crystal form.

A further study on the crystal form G was carried out by a variable temperature XRPD in which the crystal form F was used as a starting material. The results of <FIG> show that when the crystal form F was purged under nitrogen for <NUM>, the crystal form remained unchanged; when the crystal form F was heated to <NUM> under nitrogen purging, it transformed into an anhydrous crystal form J that existed only under nitrogen protection; and when it was cooled down to <NUM> and exposed to air with the lid open to test XRPD, the results show that it transformed into the crystal form G. It is assumed that the crystal form J would absorb moisture from the environment after it is exposed to air and change to the crystal form G, and that the crystal form G is a hydrate.

A crystal form was obtained by heating the acetone solvate compound crystal form F to <NUM> under nitrogen protection and lowering it to <NUM>, named as crystal form J. The XRPD results of the crystal form J are shown in <FIG>.

The XRPD of the crystal from J was tested again after it was exposed to air, and the results (<FIG>) show that it transformed into the hydrate crystal form G. It is assumed that the crystal form J could only exist under nitrogen protection, and it would rapidly absorb moisture from the environment to shift into the crystal form G when it was exposure to air. Further studies were not carried out because of the instability of the crystal form J.

The crystal form E was heated to <NUM> under nitrogen protection and lowered to room temperature, then the sample was taken out and exposed to air to give a crystal, named as crystal form H. The XRPD results are shown in <FIG>.

The hydrate crystal form C was heated to <NUM> under nitrogen protection and lowered to room temperature by a variable temperature XRPD to give a crystal, named as crystal form I. The XRPD results are shown in <FIG>.

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

The names and abbreviations of the main solvents used in the experiments are shown in the table below.

XRPD patterns were collected on a PANalytical X-ray powder diffraction analyzer, and the scanning parameters are shown in the table below.

TGA and DSC curves were acquired on a TA Q5000/ Discovery TGA <NUM> thermogravimetric analyzer and a TA Discovery DSC <NUM> differential scanning calorimeter, respectively, and the test parameters are listed in the table below.

Dynamic moisture sorption (DVS) curves were collected on the DVS Intrinsic from SMS (Surface Measurement Systems). The relative humidity at <NUM> was calibrated with deliquescence points of LiCl, Mg(NO<NUM>)<NUM> and KCl. Parameters for the DVS test are listed in Table <NUM>.

The pH was collected by Sartorius PB-<NUM> pH meter.

The sample purity and solubility were obtained by HPLC, and the molar ratio of salt-based samples of inorganic acid systems were obtained by HPLC and ion chromatography, with HPLC being collected on an Agilent <NUM> HPL and ion chromatography being collected on a Thermo ICS1100. The specific instrumentation and testing parameters are shown in Table <NUM> and Table <NUM>.

The hydrate crystal form A of compound of formula (I) was used a starting material to prepare the phosphate and the specific steps for preparation are as follows:.

The XRPD diagram of phosphate crystal form A is shown in <FIG>, and the specific data are presented in the following table.

The TGA/DSC results of the phosphate crystal form A are shown in <FIG> from which it can be seen that a weight loss of <NUM>% occurred when the sample was heated to <NUM>, presumably from the removal of water or solvent from the sample, and that a sharp heat absorption peak could be observed at <NUM> (onset temperature), presumably from the sample melting. Based on the fact that a small amount of weight loss occurred before sample melting in TGA and only a single melt heat absorption peak is present in DSC, the phosphate crystal form A is determined to be probably an anhydrous crystal form. The HPLC/IC results show that a molar ratio of compound of formula (I) to phosphate in the sample is <NUM>:<NUM>.

The hydrate crystal form A of compound of formula (I) was used a starting material to prepare the maleate and the specific steps for preparation are as follows:.

The XRPD results of the maleate crystal form A are shown in <FIG>, and the specific data are as follows.

The NMR results show that a molar ratio of compound of formula (I) to maleic acid is <NUM>: <NUM>.

The TGA/DSC results of the maleate crystal form A are shown in <FIG>, and the results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM> and that two thermal signals could be observed at <NUM> and <NUM> (onset temperature).

The hydrate crystal form A of compound of formula (I) was used a starting material to prepare the methanesulfonate and the specific steps for preparation are as follows:.

The XRPD results of the resulting methanesulfonate crystal form B are shown in <FIG>, and the specific data are as follows.

The NMR results of the methanesulfonate crystal form B show that a molar ratio between the compound of formula (I) and methanesulfonic acid in the sample is <NUM>:<NUM>.

The TGA/DSC results of the methanesulfonate crystal form B are shown in <FIG>. A weight loss of <NUM>% occurred when the sample was heated to <NUM>, presumably from the removal of water or solvent from the sample, and two heat absorption signals could be observed at <NUM> (peak temperature) and <NUM> (onset temperature). Based on the fact that a small amount of slow weight loss occurred before sample decomposition in TGA and a smoother curve is showed before <NUM> in DSC, it is assumed that the methanesulfonate crystal form B is an anhydrous crystal form.

The hydrochloride was prepared from the hydrate crystal form A of compound of formula (I) by dispersing and stirring the hydrate crystal form A with hydrochloric acid at a molar ratio of <NUM>:1in EtOAc for about <NUM> days, and then followed by centrifugation for isolation. The solid was transferred to dry at room temperature under vacuum for <NUM> hours to give the hydrochloride crystal form A.

The XRPD results of the hydrochloride crystal form A are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the hydrochloride crystal form A are shown in <FIG>. The results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM>, and three heat absorption peaks could be observed at <NUM>, <NUM> (peak temperature) and <NUM> (onset temperature), and an exothermic signal could be observed at <NUM> (onset temperature). The HPLC/IC results show that a molar ratio of the compound of formula (I) to chloride ion in the hydrochloride crystal form A is <NUM>:<NUM>. Presumably, the sample may not be sufficiently salt-forming.

The tartrate was prepared from the hydrate crystal form A of compound of formula (I) by dispersing and stirring the hydrate crystal form A with tartaric acid at a molar ratio of <NUM>:<NUM> in EtOAc for about <NUM> days, and then followed by centrifugation for isolation. The solid was transferred to dry at room temperature under vacuum for <NUM> hours to give the tartrate crystal form A.

The XRPD results of the tartrate crystal form A are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of tartrate crystal form A are shown in <FIG>. The results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM>, and two thermal signals were observed at <NUM> and <NUM> (onset temperature). The <NUM>H NMR results show that a molar ratio of compound of formula (I) to tartrate in the tartrate crystal form A is <NUM>:<NUM>, in which the <NUM> Hs overlapping with compound of formula (I) have been subtracted.

The fumarate was prepared from the hydrate crystal form A of compound of formula (I) by dispersing and stirring the hydrate crystal form A with fumaric acid at a molar ratio of <NUM>:<NUM> in Acetone/H2O (<NUM>:<NUM>, v/v) for about <NUM> days, and then followed by centrifugation for isolation. The solid was transferred to dry at room temperature under vacuum for <NUM> hours to give the fumarate crystal form A.

The XRPD results of the fumarate crystal form A are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of fumarate crystal form A are shown in <FIG>, and the results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM> and a weight loss of <NUM>% occurred when the heating continued to <NUM>; and that multiple thermal signals could be observed at <NUM>, <NUM>, <NUM> and <NUM> (onset temperature). The <NUM>H NMR results show that a molar ratio of compound of formula (I) to fumaric acid in the fumarate crystal form type A is <NUM>:<NUM>.

The muconate was prepared from the hydrate crystal form A of compound of formula (I) by dispersing and stirring the hydrate crystal form A with muconic acid at a molar ratio of <NUM>:<NUM> in Acetone/H2O (<NUM>:<NUM>, v/v) for about <NUM> days, and then followed by centrifugation for isolation. The solid was transferred to dry at room temperature under vacuum for <NUM> hours to give the fumarate crystal form A.

The XRPD results of the muconate crystal form A are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the muconate crystal form A are shown in <FIG>. The results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM> and a weight loss of <NUM>% occurred when the heating continued to <NUM> and that two thermal signals could be observed at <NUM> and <NUM> (onset temperature). The <NUM>H NMR results show that a molar ratio of compound of formula (I) to muconic acid in the muconate crystal form A is <NUM>:<NUM>.

The citrate was prepared from the hydrate crystal form A of compound of formula (I) by dispersing and stirring the hydrate crystal form A with citric acid at a molar ratio of <NUM>:<NUM> in EtOAc or Acetone/H2O (<NUM>:<NUM>, v/v) for about <NUM> days, and then followed by centrifugation for isolation. The solid was transferred to dry at room temperature under vacuum for <NUM> hours to give the citrate crystal form A or B.

The XRPD results of the citrate crystal form A are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the citrate crystal form A are shown in <FIG>. The results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM>, and three heat absorption peaks could be observed at <NUM> (peak temperature), <NUM> and <NUM> (onset temperature). The <NUM>H NMR results show that a molar ratio of compound of formula (I) to citric acid in the citrate crystal form A was <NUM>:<NUM>.

The XRPD results of the citrate crystal form B are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the citrate crystal form B are shown in <FIG>, and the results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM> and a weight loss of <NUM>% occurred when the heating continued to <NUM>; and that four heat absorption peaks were observed at <NUM>, <NUM>, <NUM> (onset temperature) and <NUM> (peak temperature). The <NUM>H NMR results show that a molar ratio of compound of formula (I) to citric acid in the citrate crystal form B is <NUM>:<NUM>.

The p-toluenesulfonate was prepared from the hydrate crystal form A of compound of formula (I) by dispersing and stirring the hydrate crystal form A with p-toluenesulfonic acid at a molar ratio of <NUM>:<NUM> in Acetone/H2O (<NUM>:<NUM>, v/v) for about <NUM> days, and then followed by centrifugation for isolation. The solid was transferred to dry at room temperature under vacuum for <NUM> hours to give the p-toluenesulfonate crystal form A.

The XRPD results of the p-toluenesulfonate crystal form A are shown in <FIG>, and the specific data are as follows.

The TGA/DSC data of p-toluenesulfonate crystal form A was shown in <FIG>. The results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM>, and two thermal signals could be observed at <NUM> and <NUM> (onset temperature). The <NUM>H NMR results show that a molar ratio of compound of formula (I) to p-toluenesulfonate in the p-toluenesulfonate crystal form A is <NUM>:<NUM>.

The benzenesulfonate was prepared from the hydrate crystal form A of compound of formula (I) by dispersing and stirring the hydrate crystal form A with benzenesulfonic acid at a molar ratio of <NUM>:<NUM> in EtOAc or Acetone/H<NUM>O (<NUM>:<NUM>, v/v) for about <NUM> days, and then followed by centrifugation for isolation. The solid was transferred to dry at room temperature under vacuum for <NUM> hours to give the benzenesulfonate crystal form A or B.

The XRPD results of the benzenesulfonate crystal form A are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the benzenesulfonate crystal form A are shown in <FIG>, and the results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM>, and multiple thermal signals could be observed at <NUM>-<NUM>. The <NUM>H NMR results show that a molar ratio of compound of formula (I) to benzenesulfonic acid in the benzenesulfonate crystal form A is <NUM>:<NUM>.

The XRPD results of the benzenesulfonate crystal form B are shown in <FIG>, and the specific data are as follows.

The TGA/DSC results of the benzenesulfonate crystal form B was shown in <FIG>. The results show that a weight loss of <NUM>% occurred when the sample was heated to <NUM>, and two thermal signals could be observed at <NUM> (peak temperature) and <NUM> (onset temperature). The <NUM>H NMR results show that a molar ratio of compound of formula (I) to benzenesulfonic acid in the benzenesulfonate crystal form B is <NUM>:<NUM>.

Based on the physical characterization data of the above prepared salt crystal forms, phosphate crystal form A, maleate crystal form A and methanesulfonate crystal form B with a higher XRPD diffraction peak intensity (sharp peak), a lower TGA weight loss, a higher DSC melting temperature and a higher safety level of acid were selected for the next study and evaluation.

The evaluation of the three salt crystal forms was carried out in vitro in terms of solubility, solid stability and hygroscopicity.

To assess the solubility of the three salt forms in different media, a dynamic solubility (<NUM>, <NUM>, <NUM>, <NUM>) of three batches of samples in biolysis media (simulated gastric SGF and simulated intestinal fluid FeSSIF) at room temperature, and their solubility in ethanol, water, and pH=<NUM> phosphate buffer for <NUM> were investigated. The specific steps are as follows.

The experimental results are shown in Table <NUM>. At a feeding concentration of <NUM>/mL, the solubilities of the three salt crystal forms in SGF range from <NUM> to <NUM>/mL, among which the solubility of the methanesulfonate crystal form B was relatively high; and the solubilities in FeSSIF range from <NUM> to <NUM>/mL, among which the solubilities of the methanesulfonate crystal form B and the maleate crystal form A are relatively high. For water, ethanol and pH=<NUM> phosphate buffer, the solubilities of the three salt crystal forms in water range from <NUM> to <NUM>/mL, with relatively high solubility of the phosphate crystal form A; the solubilities in ethanol range from <NUM> to <NUM>/mL, with relatively high solubility of the maleate crystal form A, and the solubilities in pH=<NUM> medium range from <NUM> to <NUM>/mL, with relatively high solubility of the methanesulfonate crystal form B.

To evaluate the solid stability of the salt crystal forms, three sample batches were placed at <NUM>/<NUM>% RH and <NUM>/<NUM>% RH (wrapped in sealing film with <NUM> small holes) for <NUM>-week conditioning to assess their physicochemical stability. HPLC tests and XRPD characterization were performed on the conditioned samples to detect changes in sample purity and crystal form. The XRPD results and HPLC results show no significant changes in sample crystal form and purity, and the test results are summarized in Table <NUM>.

In order to evaluate hygroscopicity of the salt crystal forms, DVS tests were conducted on three samples. The results of DVS are shown in <FIG>, <FIG>. Phosphate crystal form A gained <NUM>% by weight after absorbing moisture at <NUM>% RH/<NUM>, maleate crystal form A gained <NUM>% by weight after absorbing moisture at <NUM>% RH/<NUM>, and methanesulfonate crystal form B gained <NUM>% by weight after absorbing moisture at <NUM>% RH/<NUM>, all of which were determined to be slightly hygroscopic. With the further increase of humidity in environment, it could be observed that the weight gains of these three samples after absorbing moisture were relatively more obvious. In addition, the XRPD results show that there was no change in the crystal form of the three batches of samples before and after the DVS test.

A drug screening system based on kinases JAK1, JAK2, JAK3, and TYK2 was used to detect the inhibitory ability of small compounds on kinase activity. A kinase undergoes an enzymatic reaction with its substrates IRS1, IGF1Rtide, and Poly (<NUM>:<NUM> Glu, Tyr), consuming ATP to produce ADP, wherein the ADP-Glo reagent and luminescence method can be used to detect the amount of the product to reflect the activity of the kinase.

The results of the test assays are shown in the following table.

Claim 1:
A solid form of a compound, wherein the compound is the compound of formula (I)
<CHM>
or an isotopically labeled compound of compound of formula (I), or an optical isomer of compound of formula (I), or a geometric isomer of compound of formula (I), or a tautomer of compound of formula (I),a pharmaceutically acceptable salt of compound of formula (I), or a solvate of any one of these compounds,
wherein the solid form of a compound is a crystal form.