Salt form and crystal form of pyridine polysubstituted compound and preparation method of salt form and crystal form

Abstract

The invention discloses a salt form and a crystal form of a pyridine polysubstituted compound and a preparation method of the salt form and the crystal form, and particularly discloses an application of the crystal form of a compound shown as a formula (I) and the preparation method of the crystal form in preparation of medicines for treating related diseases. # imgabs0 #

Description

A salt form, a crystal form and a preparation method of a pyridine polysubstituted compound

[0001] The present invention claims the following priority

[0002] Application number: CN202211740788.0; Application date: December 22, 2022;

[0003] Application number: CN202311689614.0; Application date: December 8, 2023. Technical Field

[0004] The present invention relates to a salt form, a crystal form and a preparation method of a pyridine polysubstituted compound, and particularly to the application of the crystal form of the compound of formula (I) and the preparation method thereof in preparing drugs for treating related diseases. Background Art

[0005] The Janus kinase (JAK) family of non-receptor tyrosine kinases, including JAK1, JAK2, JAK3, and TYK2, is crucial in mediating the signaling of numerous inflammatory cytokines. TYK2 and JAK1 / 2 / 3 typically work in pairs, or "dimers," to transmit extracellular cytokine signals to the cell nucleus. TYK2 selectively participates in the signaling of proinflammatory cytokines such as IL-23, IL-12, and type I interferon (IFN). Therefore, TYK2 inhibitors could be effective treatments for a variety of severe inflammatory and autoimmune diseases.

[0006] JAK1, JAK2, JAK3, and TYK2, members of the JAK family of proteins, all possess a JAK homology domain (JH). The JH1 domain is also known as the kinase domain, while JH2 is a pseudokinase domain. While the JH2 domain of TYK2 closely resembles the JH1 domain and contains an ATP-binding site very similar to that of the JH1 domain, specific residue differences preclude JH2's catalytic function. Although the specific mechanism by which TYK2 achieves allosteric inhibition through the JH2 domain remains undefined, evidence suggests that small molecule ligands binding to JH2 stabilize autoinhibitory interactions between the JH2 domain and the JH1 active site. These JH2-JH1 interactions are thought to restrict the conformational mobility of the JH1 active site, which is required for phosphorus transfer catalysis. Inhibition of TYK2 by binding to its JH2 domain maintains a high level of selectivity against other JAK family members and the entire kinase family.

[0007] Current TYK2 inhibitors mainly include orthosteric inhibitors that inhibit the kinase region (JH1) and allosteric inhibitors that inhibit the pseudokinase region (JH2). Orthosteric inhibitors are represented by Pfizer's PF-06826647, which is used to treat diseases such as plaques and ulcerative colitis and is currently in Phase II clinical trials. Allosteric inhibitors are represented by BMS-986165, and the clinical trials for the treatment of psoriasis vulgaris have advanced to Phase III, with outstanding clinical effects and good safety. At the same time, a variety of autoimmune diseases including Crohn's disease, psoriatic arthritis and systemic lupus erythematosus are in clinical research. In addition to BMS-986165, Nimbus also has a number of TYK2 allosteric inhibitors in preclinical screening. The recently reported TYK2 allosteric inhibitor FTP-637 from Frontera, acquired by Hisun, is preparing to enter Phase I clinical trials.

[0008] Summary of the Invention

[0009] The present invention provides a compound of formula (I),

[0010] The present invention also provides a crystalline form A of the compound of formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 17.56±0.20°, 24.36±0.20°, 25.69±0.20°, and 27.37±0.20°.

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A of compound (I) has characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, and 17.56±0.20°.

[0012] In some embodiments of the present invention, the crystal form A of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the crystal form A, expressed as 2θ angle, contains at least 6, 7 or 8 diffraction peaks selected from the following: 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 24.36±0.20°, 25.69±0.20°, 27.37±0.20°.

[0013] In some embodiments of the present invention, the crystal form A of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the crystal form A, expressed as 2θ angle, contains at least 6, 7 or 8 diffraction peaks selected from the following: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.35±0.20°, 20.44±0.20°.

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A of compound (I) has characteristic diffraction peaks at the following 2θ angles: 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 24.36±0.20°, 25.69±0.20°, and 27.37±0.20°.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A of compound (I) has characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.35±0.20°, 20.44±0.20°.

[0016] Some of the crystal form A of the compound of formula (I) above of the present invention are characterized in that the X-ray powder diffraction pattern of the crystal form A, expressed as 2θ angle, contains at least 10, 11 or 12 diffraction peaks selected from the following: 8.70±0.20°, 10.05±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 24.36±0.20°, 25.69±0.20°, 27.37±0.20°, 29.49±0.20°.

[0017] Some of the crystal forms A of the compounds of formula (I) described above of the present invention are characterized in that the X-ray powder diffraction pattern of the crystal form A, expressed in 2θ angles, comprises at least 10, 11 or 12 diffraction peaks selected from the following: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.35±0.20°, 20.44±0.20°, 22.53±0.20°, 24.51±0.20°, 25.69±0.20°, 27.37±0.20°.

[0018] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A of compound (I) has characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 15.56±0.20°, 17.56±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 24.36±0.20°, 25.69±0.20°, 27.37±0.20°, 29.49±0.20°.

[0019] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A of compound (I) has characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.35±0.20°, 20.44±0.20°, 22.53±0.20°, 24.51±0.20°, 25.69±0.20°, 27.37±0.20°.

[0020] In some embodiments of the present invention, the crystal form A of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the crystal form A, expressed in 2θ angles, comprises at least 12, 13, 14, 15 or 16 diffraction peaks selected from the following: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 15.56±0.20°, 17.56±0 .20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 23.77±0.20°, 24.36±0.20°, 25.69±0.20°, 26.33±0.20°, 27.37±0.20°, 27.83±0.20°, 29.49±0.20°.

[0021] In some embodiments of the present invention, the crystal form A of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the crystal form A, expressed in 2θ angles, comprises at least 12, 13, 14, 15 or 16 diffraction peaks selected from the following: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 14.63±0.20°, 15.56±0 .20°, 17.56±0.20°, 18.76±0.20°, 19.35±0.10°, 19.63±0.10°, 20.44±0.20°, 22.53±0.20°, 22.89±0.10°, 24.51±0.20°, 25.69±0.20°, 26.33±0.20°, 27.37±0.20°.

[0022] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A of compound (I) has characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 14.63±0.20°, 15.56±0.20°, 16.39±0.20°, 17.56±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 23.77±0.20°, 24.36±0.20°, 25.69±0.20°, 26.33±0.20°, 27.37±0.20°, and 29.49±0.20°.

[0023] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A of compound (I) has characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 14.63±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.35±0.10°, 19.63±0.10°, 20.44±0.20°, 22.53±0.20°, 22.89±0.10°, 24.51±0.20°, 25.69±0.20°, 26.33±0.20°, and 27.37±0.20°.

[0024] The present invention provides a crystalline form A of the compound of formula (I), which has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 17.56°±0.20°, 24.36°±0.20°, 27.37°±0.20°, and / or 8.70°±0.20°, and / or 10.05°±0.20°, and / or 12.08°±0.20°, and / or 14.63°±0 .20°, and / or 15.56°±0.20°, and / or 16.39°±0.20°, and / or 18.76°±0.20°, and / or 19.35°±0.20°, and / or 19.63°±0.20°, and / or 20.44°±0.20°, and / or 21.94°±0.20°, and / or 22.53°±0.20°, and / or 22.8 9°±0.20°, and / or 23.23°±0.20°, and / or 23.77°±0.20°, and / or 24.51°±0.20°, and / or 25.69°±0.20°, and / or 26.33°±0.20°, and / or 26.73°±0.20°, and / or 27.83°±0.20°, and / or 28.58°±0.20°, and / or 29.49°±0.20°, and / or 30.42°±0.20°, and / or 31.13°±0.20°, and / or 32.29°±0.20°, and / or 32.88°±0.20°, and / or 34.04°±0.20°, and / or 35.19°±0.20°, and / or 36.30°±0.20°, and / or 38.89°±0.20°.

[0025] The present invention provides a crystalline form A of the compound of formula (I), which has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 17.56°, 24.36°, 27.37°, 8.70°, 10.05°, 12.08°, 14.63°, 15.56°, 16.39°, 18.76°, 19.35°, 19.63°, 20.44°, 21.94°, 22.53°, 22.89°, 23.23°, 23.77°, 24.51°, 25.69°, 26.33°, 26.73°, 27.83°, 28.58°, 29.49°, 30.42°, 31.13°, 32.29°, 32.88°, 34.04°, 35.19°, 36.30°, 38.89°.

[0026] In some embodiments of the present invention, the crystal form A of the compound of formula (I) above,

[0027] Its XRPD pattern is shown in Figure 1.

[0028] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form A are shown in Table 1:

[0029] Table 1: XRPD pattern analysis data of the crystalline form of the compound of formula (I)

[0030] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned crystal form A has a starting point of an endothermic peak at 230.5°C±3.0°C.

[0031] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form A is shown in Figure 2.

[0032] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form A shows a weight loss of 1.02%±0.20% at 175.0°C±3.0°C.

[0033] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form A is shown in Figure 3.

[0034] The present invention also provides the following biological testing method:

[0035] Pharmacokinetic evaluation of compounds in mice

[0036] Experimental purpose: To test the pharmacokinetics of the compound in Balb / c mice

[0037] Experimental materials: Male Balb / c mice, fasted

[0038] Experimental operation:

[0039] The pharmacokinetic characteristics of compound 1 in rodents after intravenous and oral administration were tested using standard protocols.

[0040] Upon arrival at the facility, Balb / c mice undergo at least three days of acclimation / quarantine. Following this period, a veterinarian or designated personnel will examine the animals' health to assess their suitability for the study. All Balb / c mice were fasted overnight prior to dosing and resumed feeding 4 hours after dosing. In this experiment, candidate compounds were formulated as homogenous solutions and administered to Balb / c mice as single intravenous and oral injections. The intravenous injection vehicle consisted of a clear solution of 80% polyethylene glycol 400 / 20% water, while the oral vehicle consisted of a homogenous suspension of ethanol / vitamin E polyethylene glycol succinate / polyethylene glycol 300 at a ratio of 5:5:90. Animals were weighed prior to dosing, and the dosing volume was calculated based on body weight. Whole blood samples were collected over a 24-hour period by jugular venipuncture and immediately transferred to labeled, commercially available centrifuge tubes containing K2-EDTA. After blood sample collection, centrifuge at 3200 g for 10 minutes at 4°C to remove the supernatant plasma, quickly place it on dry ice, and store it at -60°C or colder for LC-MS / MS analysis. A non-compartmental model was used to analyze plasma concentration-time data and calculate pharmacokinetic parameters using the WinNonlin software package (Version 6.3 and above). PK parameters included (if data permit) but were not limited to) peak concentration (Cmax), time to peak concentration (Tmax), elimination half-life (T1 / 2), area under the plasma concentration-time curve (AUC), mean residence time (MRT), and bioavailability.

[0041] Technical Effects

[0042] The compound of the present invention has excellent pharmacokinetic properties and the crystal form of the compound of the present invention has good stability, and is suitable for drug development.

[0043] Definition and Description

[0044] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0045] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0046] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0047] For any given crystalline form, the relative intensity of the diffraction peaks can change due to factors such as the preferred orientation caused by factors such as the crystal morphology, which is well known in the art of crystallography. Where there is a preferred orientation effect, the peak intensity changes, but the position of the diffraction peaks of the crystal form cannot be changed. In addition, for any given crystal form, there may be slight errors in the positions of the peaks, which is also well known in the art of crystallography. For example, due to changes in temperature during sample analysis, movement of the sample, or calibration of the instrument, the position of the peaks can move, and the measurement error of the 2θ value is sometimes about ± 0.20 ° or ± 0.10 °. Therefore, it is well known to those skilled in the art that this error should be taken into account when determining each crystalline structure.

[0048] Unless otherwise stated, X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD pattern may have experimental errors, and the measurement of 2θ of the XRPD pattern may be slightly different between different instruments and different samples, so the numerical value of the 2θ cannot be considered absolute. Depending on the instrument conditions used in this experiment, the diffraction peak has an error tolerance of ±0.20° or ±0.10°.

[0049] DSC measures the transition temperatures of crystals when they absorb or release heat due to changes in their crystalline structure or melting. For the same crystalline form of the same compound, the error in thermal transition temperatures and melting points in consecutive analyses is typically within about 5°C or 3°C. When we say that a compound has a given DSC peak or melting point, this refers to the DSC peak or melting point ±5°C or ±3°C. DSC provides an auxiliary method for distinguishing different crystalline forms. Different crystalline forms can be identified by their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. In addition, since decomposition is associated with the melting process of a substance, the melting temperature is related to the heating rate.

[0050] For the same crystal form, the TGA weight loss temperature may vary due to factors such as the measuring instrument, measuring method / conditions, etc. For any specific crystal form, the weight loss temperature may have an error of about ±5°C, or about ±3°C.

[0051] It should be noted that during the preparation of drug crystal forms, during the contact between drug molecules and solvent molecules, external conditions and internal factors may cause the solvent molecules to form a co-crystal with the compound molecules and remain in the solid material, which is difficult to avoid, thereby forming solvates, specifically including stoichiometric solvates and non-stoichiometric solvates. All such solvates are included within the scope of the present invention.

[0052] Unless otherwise specified, DSC spectra are exothermic upward. The therapeutic dosage of the compounds of the present invention may be determined, for example, based on the specific therapeutic application, the method of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present invention in a pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.

[0053] The term "treatment" means administering the compounds or formulations of the present invention to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0054] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0055] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0056] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their knowledge and this disclosure.

[0057] Unless otherwise required herein, throughout the specification and the claims that follow, the word "comprise" and its English variations such as "comprises" and "comprising" should be interpreted as having an open, inclusive meaning, that is, "including but not limited to".

[0058] Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that the specific referenced elements, structures, or features described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0059] It should be understood that the singular article "a," "an," and "the," as used in the present specification and the appended claims, includes plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a reaction including "a catalyst" includes one catalyst, or two or more catalysts. It should also be understood that the term "or" is generally used in its sense including "and / or," unless the context clearly dictates otherwise.

[0060] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0061] All solvents used in the present invention were commercially available and used without further purification.

[0062] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names.

[0063] The powder X-ray diffractometer (XRPD) method of the present invention

[0064] Instrument model: Empyrean X-ray diffractometer

[0065] Test method: Spread an appropriate amount of sample evenly on a single crystal silicon sample plate and perform XRPD testing using the following parameters.

[0066] The detailed XRPD parameters are as follows:

[0067] Instrument name: X-ray powder diffraction

[0068] Instrument manufacturer: Malvern Panalytical Ltd.

[0069] Method parameters:

[0070] X-ray: Cu, kα, 1.54060; 1.54443; Kα2 / Kα1 intensity ratio: 0.50

[0071] X-ray tube setting: 45kV, 40mA

[0072] Divergence slit: fixed 1 / 8°

[0073] Anti-scatter slit: 1 / 4°

[0074] Detector slit: P7.5

[0075] Scan mode: continuous

[0076] Scanning range (°2Theta): 3-40

[0077] Scan time per step (s): 46.665

[0078] Scan step (°2Theta): 0.0263

[0079] Test time (min): 5

[0080] Differential Scanning Calorimeter (DSC) method of the present invention

[0081] Instrument model: TA Discovery DSC 2500 differential scanning calorimeter

[0082] Test method: Place the sample in an alumina crucible for testing and heat the sample from RT to 320°C at a heating rate of 10°C / min.

[0083] Thermogravimetric analysis (TGA) method of the present invention

[0084] Instrument model: TA Discovery TGA 5500 thermogravimetric analyzer and thermogravimetric analyzer

[0085] Test method: Place the sample in a DSC high-pressure crucible, press and seal it, and then test it. Heat the sample from 25°C to 350°C at a heating rate of 10°C / min. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] FIG1 is an XRPD spectrum of Form A of the compound of formula (I) using Cu-Kα radiation;

[0087] FIG2 is a DSC spectrum of Form A of the compound of formula (I);

[0088] FIG3 is a TGA spectrum of Form A of the compound of formula (I). DETAILED DESCRIPTION

[0089] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0090] Example 1: Preparation of compound of formula (I)

[0091] Synthesis route:

[0092] Step 1: Synthesis of compound 1-2

[0093] To a solution of compound 1-1 (13 g, 67.71 mmol) in dichloromethane (200 mL) were added N,N-diisopropylethylamine (43.75 g, 338.54 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (30.89 g, 81.25 mmol). The mixture was stirred at 20°C for 0.5 hour, and N,O-dimethylhydroxylamine hydrochloride (7.93 g, 81.25 mmol) was added. The mixture was stirred at 20°C for 15.5 hours, and the reaction solution was concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 1-2.

[0094] MS m / z: 235 [M+H] + .

[0095] Step 2: Synthesis of Compounds 1-3

[0096] Under nitrogen protection at 0°C, methylmagnesium bromide (3M, diethyl ether solution, 36.87 mL) was added to a solution of compound 1-2 (13 g, 55.30 mmol) in tetrahydrofuran (130 mL), and the mixture was stirred at 0°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (60 mL), diluted with water (100 mL), and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 15 / 1) to obtain compound 1-3.

[0097] 1 H NMR (400MHz, CDCl3) δ 8.59 (s, 1H), 7.44 (s, 1H), 2.66 (s, 3H).

[0098] Step 3: Synthesis of Compounds 1-4

[0099] To a solution of 1-3 (8 g, 42.10 mmol) in dimethyl carbonate (42.80 g, 475.15 mmol) in tetrahydrofuran (40 mL) was slowly added portionwise 60% sodium hydroxide (5.05 g, 126.30 mmol) at 0°C and stirred at 20°C for 16 hours. The reaction solution was diluted with ethyl acetate (100 mL), quenched with aqueous hydrochloric acid (50 mL 2M), washed with saturated brine (50 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound 1-4.

[0100] MS m / z: 244 [M+H] + .

[0101] Step 4: Synthesis of Compounds 1-5

[0102] To a solution of compound 1-4 (8.2 g, 32.65 mmol) and potassium carbonate (4.96 g, 35.91 mmol) in N,N-dimethylformamide (80 mL) was added deuterated iodomethane (4.97 g, 34.28 mmol) at 0°C, and the mixture was stirred at 20°C for 6 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 4 / 1) to obtain compound 1-5.

[0103] MS m / z: 261[M+H] + .

[0104] Step 5: Synthesis of Compounds 1-6

[0105] To a solution of 1-5 (5.8 g, 18.02 mmol, 81%) in acetic acid (30 mL) was added 35% concentrated hydrochloric acid (61.20 g, 587.48 mmol), and the mixture was stirred at 130°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1) to obtain compound 1-6.

[0106] MS m / z:189[M+H] + .

[0107] Step 6: Synthesis of Compounds 1-7

[0108] To a solution of 1-6 (2.5 g, 12.33 mmol) in acetonitrile (80 mL) was added phosphorus oxychloride (7.56 g, 49.30 mmol) and stirred at 85°C for 1 hour. The reaction solution was concentrated and diluted with ethyl acetate (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to give compound 1-7.

[0109] MS m / z: 207 [M+H] + .

[0110] Step 7: Synthesis of Compounds 1-8

[0111] A solution of compound 1-7 (50 mg, 241.46 μmol), cyclopropylcarboxamide (20.55 mg, 241.46 μmol), potassium carbonate (66.75 mg, 482.92 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27.94 mg, 48.29 μmol), and tris(dibenzylideneacetone)dipalladium chloroform complex (22.11 mg, 24.15 μmol) in dioxane (2 mL) was purged with nitrogen three times and stirred at 80° C. for 2 hours. The reaction solution was concentrated to obtain a crude product, which was then purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound 1-8.

[0112] MS m / z: 256 [M+H] + .

[0113] Step 8: Synthesis of Compounds 1-10

[0114] Compound 1-9 (2 g, 10.34 mmol) was dissolved in dioxane (40 mL), and dimethylsulfenyl imide (1.01 g, 10.86 mmol), cesium carbonate (6.74 g, 20.68 mmol), tris(dibenzylideneacetone)dipalladium (946.85 mg, 1.03 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.20 g, 2.07 mmol) were added. After nitrogen substitution three times, the temperature was raised to 110°C and stirred under nitrogen for 4 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 4). The reaction mixture was concentrated under reduced pressure and then stirred with petroleum ether / ethyl acetate = 5 / 1 (12 mL) at 20°C for 1 hour. The filter cake was collected by filtration and dried to obtain compound 1-10.

[0115] MS m / z: 206 [M+H] + .

[0116] Step 9: Synthesis of Compounds 1-12

[0117] Compound 1-10 (400 mg, 1.94 mmol) was dissolved in dioxane (8 mL) and water (2 mL), and compound 1-11 (532.95 mg, 2.14 mmol), potassium phosphate (825.68 mg, 3.89 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (142.31 mg, 194.49 μmol) were added. After nitrogen substitution three times, the temperature was raised to 100°C and stirred under nitrogen for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1). The mixture was concentrated under reduced pressure and then stirred with petroleum ether / ethyl acetate = 1 / 1 (4 mL) at 20°C for 1 hour. The filter cake was collected by filtration and dried to obtain compound 1-12.

[0118] MS m / z:293[M+H] + .

[0119] Step 10: Synthesis of compound of formula (I)

[0120] Compound 1-12 (635 g) and compound 1-8 (666.5 g) were dissolved in isopropanol (3.175 L), and concentrated hydrochloric acid (22.63 mL) was subsequently added. The internal temperature was 65-70° C. and the reaction was carried out for 16-20 hours. After the reaction was completed, the mixture was filtered while hot, and the filter cake was washed with isopropanol (5 L). The filter cake was collected to obtain the compound of formula (I).

[0121] HNMR: 1H NMR (400MHz, DMSO-d6) δppm 11.91-12.23 (m, 1H) 11.25 (br d, J = 4.77Hz, 1H) 8.89 (d, J = 2.01Hz, 1H) 8.61 (s, 1H) 8.15 (d, J = 1.51Hz, 1H) 7.67 (br d, J=7.78Hz, 1H) 7.15-7.53 (m, 3H) 3.33-3.60 (m, 9H) 3.11 (s, 2H) 1.94 (br d, J=4.77Hz, 1H) 0.77-1.00 (m, 4H)

[0122] Example 2: Preparation of Form A of the compound of formula (I)

[0123] The compound of formula (I) (126 g) was weighed and added to methanol (2900 mL). The reaction mixture was stirred at 55°C for 1.5 hours. Mercaptosilica gel (63 g) was added and stirred at 55°C for 17.5 hours. The mixture was then filtered under reduced pressure. The reaction mixture was concentrated to 2200-2400 mL at ≤50°C. 250 mL of tert-butyl methyl ether was added and stirred at 55°C for 1.5 hours. Seed crystals were added and 2500 mL of tert-butyl methyl ether was added dropwise at 55°C over 8 hours. The temperature was slowly lowered to -20-0°C over 6 hours and stirred at this temperature for 42 hours. The mixture was filtered under reduced pressure. The filter cake was washed with 400 mL of tert-butyl methyl ether and dried at 50-60°C under vacuum (-0.08-0.1 MPa) for 23 hours to obtain Form A of the compound of formula (I).

[0124] Example 3: Solid Stability Test of Form A of the Compound of Formula (I)

[0125] Approximately 1.5 g of Form A of the compound of formula (I) was weighed and placed on the bottom of a glass sample bottle, spreading it into a thin layer. The sample was completely exposed. Samples subjected to high temperature and high humidity were sampled and tested (XRPD) on days 10 and 30. Samples exposed to light were placed in a clean watch glass, spread into a thin layer, covered with a quartz glass lid, and sampled and tested (XRPD) on days 5 and 10. For long-term experiments and accelerated tests (protected from light), each sample was placed in a double-layer LDPE bag, each LDPE bag was sealed with a buckle, and the LDPE bag was then placed in an aluminum foil bag containing a desiccant and heat-sealed. The samples were tested at 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. The test results were compared with the initial test results at day 0. The test results are shown in Table 2 below:

[0126] Table 2: Solid stability test results of Form A of the compound of formula (I)

[0127] Conclusion: Form A of the compound of formula (I) has good stability under the influencing factors of high temperature, high humidity, strong light and long-term accelerated test conditions.

[0128] Biological evaluation

[0129] Experimental Example 1: In vitro enzyme activity evaluation

[0130] Tyk2 JH2 enzyme activity test experimental process

[0131] 0.5 nM TYK2 protein (His-TVMV-TYK2 JH2 (575-869)), 0.2 nM terbium-labeled His antibody, and the related K d The assay system was incubated at room temperature for 90 minutes with a fluorescein-labeled kinase tracer at a specific concentration (e.g., 520 nm) and the test compound. The resulting HTRF (homogeneous time-resolved fluorescence) signal, i.e., the ratio of the fluorescence intensities of the fluorescein acceptor (520 nm) and the terbium donor (495 nm) at the emission wavelength, was then measured on an Envision plate reader, and the IC50 value was calculated based on this. The results of the in vitro enzyme activity assay of the free base of the compounds of the present invention are shown in Table 3:

[0132] Table 3: In vitro enzyme activity assay results of the compounds of the present invention (IC 50 )

[0133] Experimental conclusion: The free base of the compound of the present invention has strong Tyk2 JH2 inhibitory activity.

[0134] Experimental Example 2: In vitro cell activity evaluation

[0135] IFNα-stimulated phosphorylation STAT1 assay

[0136] Human peripheral blood mononuclear cells (hPBMC) were plated at a cell density of 1x10 5 Cells / well were plated and placed in a 37°C incubator for 90 minutes. Compounds of varying concentrations were then added to the cells, with the concentration range of each compound starting from 2 μM and diluted 5-fold for a total of 8 concentration gradients. The compounds and cells were incubated at 37 degrees for 30 minutes. hPBMCs were stimulated with IFN-a (1000 U / ml), and the level of phosphorylated STAT1 in CD4+ T cells was then detected by flow cytometry to evaluate the inhibitory activity of the compound on the IFN-α pathway. The results of the in vitro cell activity assay of the free base of the compound of the present invention are shown in Table 4:

[0137] Table 4: In vitro cell activity assay results of the compounds of the present invention (IC 50 )

[0138] Experimental conclusion: The free base of the compound of the present invention has a strong Tyk2-related IFNα-stimulated cellular activity of phosphorylated STAT1.

[0139] Experimental Example 3: Pharmacokinetic Study (PK)

[0140] Purpose of the experiment:

[0141] The purpose of this study was to investigate the pharmacokinetics of the test article in the plasma of male CD-1 mice, SD rats and pit bulls after intravenous and oral administration.

[0142] Experimental methods:

[0143] The animals were randomly divided into two groups, with 2 males in each group. The compounds were formulated into designated formulations (the vehicle was 5 mg / mL 10% sulfobutyl ether-β-cyclodextrin), and the oral formulations were clear or homogeneous suspensions.

[0144] Whole blood samples were collected from the animals via jugular vein puncture or saphenous vein at 5, 15, and 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Whole blood samples were placed in centrifuge tubes containing anticoagulant and centrifuged at 3000 g for 15 minutes at 4°C. The supernatant plasma was quickly frozen on dry ice and stored at -70 ± 10°C until LC-MS / MS analysis.

[0145] Data processing:

[0146] Using WinNonlin TM Version 6.3.0 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma drug concentration data of the compound using a non-compartmental model. max ) and peak time (T max ) and the quantifiable end time, which can be directly obtained from the plasma concentration-time graph.

[0147] The following pharmacokinetic parameters were calculated using the log-linear trapezoidal method: plasma clearance (CL), volume of distribution (Vd), elimination half-life (T 1 / 2 ), the mean residence time of the drug in the body from time 0 to the end time point (MRT 0-last ), the average residence time of the drug in the body from 0 to infinite time (MRT 0-inf ), the area under the time-plasma concentration curve from point 0 to the terminal time point (AUC 0-last ), the area under the time-plasma concentration curve from point 0 to infinity (AUC 0-inf ) and bioavailability (F). The experimental results of the present invention are shown in Table 5:

[0148] Table 5: Pharmacokinetic test results

[0149] Note: Vd: volume of distribution; Cl: clearance; T 1 / 2 : half-life; AUC: exposure (area under the curve); C max : maximum concentration; T max: time to peak concentration; F%: bioavailability; PO: oral administration

[0150] Experimental conclusion: The compound of the present invention shows excellent pharmacokinetic properties, high in vivo exposure and oral bioavailability.

Claims

1. A compound of formula (I), 2. The crystal form A of the compound of formula (I) according to claim 1, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 17.56±0.20°, 24.36±0.20°, 25.69±0.20°, and 27.37±0.20°.

3. The crystal form A of the compound of formula (I) according to claim 1, characterized in that The X-ray powder diffraction pattern of the A crystal form, expressed by 2θ angle, contains at least 6, 7 or 8 diffraction peaks selected from the following: 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 24.36±0.20°, 25.69±0.20°, and 27.37±0.20°.

4. The crystalline form A of the compound of formula (I) according to claim 1, has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 24.36±0.20°, 25.69±0.20°, and 27.37±0.20°.

5. The crystal form A of the compound of formula (I) according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystal form A, expressed by 2θ angle, comprises at least 10, 11 or 12 diffraction peaks selected from the following: 8.70±0.20°, 10.05±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 24.36±0.20°, 25.69±0.20°, 27.37±0.20°, and 29.49±0.20°.

6. The crystalline form A of the compound of formula (I) according to claim 1, having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.05±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 24.36±0.20°, 25.69±0.20°, 27.37±0.20°, and 29.49±0.20°.

7. The crystal form A of the compound of formula (I) according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystal form A is expressed by 2θ angles and comprises at least 12, 13, 14, 15 or 16 diffraction peaks selected from the following: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 23.77±0.20°, 24.36±0.20°, 25.69±0.20°, 26.33±0.20°, 27.37±0.20°, 27.83±0.20°, and 29.49±0.20°.

8. The crystalline form A of the compound of formula (I) according to claim 1, having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, 15.56±0.20°, 17.56±0.20°, 18.76±0.20°, 19.63±0.20°, 20.44±0.20°, 22.89±0.20°, 23.77±0.20°, 24.36±0.20°, 25.69±0.20°, 26.33±0.20°, 27.37±0.20°, 27.83±0.20°, and 29.49±0.20°.

9. The crystal form A of the compound of formula (I) according to claim 1, wherein its X-ray powder diffraction peak spectrum has characteristic diffraction peaks at the following 2θ angles: 17.56°±0.20°, 24.36°±0.20°, 27.37°±0.20°, and / or 8.70°±0.20°, and / or 10.05°±0.20°, and / or 12.08°±0.20°, and / or 14. 63°±0.20°, and / or 15.56°±0.20°, and / or 16.39°±0.20°, and / or 18.76°±0.20°, and / or 19.35°±0.20°, and / or 19.63°±0.20°, and / or 20.44°±0.20°, and / or 21.94°±0.20°, and / or 22.53°±0.20°, and / or 2 2.89°±0.20°, and / or 23.23°±0.20°, and / or 23.77°±0.20°, and / or 24.51°±0.20°, and / or 25.69°±0.20°, and / or 26.33°±0.20°, and / or 26.73°±0.20°, and / or 27.83°±0.20°, and / or 28.58°±0.20°, and / or Or 29.49°±0.20°, and / or 30.42°±0.20°, and / or 31.13°±0.20°, and / or 32.29°±0.20°, and / or 32.88°±0.20°, and / or 34.04°±0.20°, and / or 35.19°±0.20°, and / or 36.30°±0.20°, and / or 38.89°±0.20°.

10. Crystal form A of the compound of formula (I), Its XRPD pattern is shown in Figure 1.

11. The crystal form A of the compound of formula (I) according to any one of claims 1 to 10, wherein the differential scanning calorimetry curve thereof has an endothermic peak starting point at 230.5°C ± 3.0°C.

12. The crystal form A of the compound of formula (I) according to claim 11, whose DSC spectrum is shown in Figure 2.

13. The crystal form A of the compound of formula (I) according to any one of claims 1 to 10, wherein the thermogravimetric analysis curve thereof shows a weight loss of 1.02%±0.20% at 175.0°C±3.0°C.

14. The crystal form A of the compound of formula (I) according to claim 13, whose TGA spectrum is shown in Figure 3.

15. Use of the compound according to claim 1 or the crystal form A of the compound of formula (I) according to any one of claims 2 to 14 in the preparation of a medicament for treating Tyk2 JH2-related diseases.

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