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

Abstract

The application discloses a salt type and crystal form of a pyridine polysubstituted compound and a preparation method thereof, and particularly discloses a crystal form of a compound of formula (I) and application of the crystal form and a preparation method thereof in preparation of a medicine for treating related diseases.

Description

[0001] This 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] This invention relates to a salt form, crystal form, and preparation method of a polysubstituted pyridine compound, specifically to the crystal form of compound (I), its preparation method, and its application in the preparation of medicaments for treating related diseases. Background Technology

[0005] The Janus kinase (JAK) family of non-receptor tyrosine kinases plays a crucial role in mediating the signaling of numerous cytokines that induce inflammation. The JAK family includes JAK1, JAK2, JAK3, and TYK2. 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 pro-inflammatory cytokines such as IL-23, IL-12, and type I IFN. Therefore, TYK2 inhibitors could be an effective treatment for various severe inflammatory and autoimmune diseases.

[0006] JAK1, JAK2, JAK3, and TYK2, all members of the JAK protein family, possess a JAK homology domain (JH). The JH1 domain is also known as the kinase domain, while JH2 is a pseudokinase domain. Although the JH2 domain of TYK2 is very similar to the JH1 domain and contains an ATP-binding site very similar to the JH1 domain, specific residue differences preclude the catalytic function of JH2. While the specific mechanism by which TYK2 achieves allosteric inhibition through the JH2 domain is not fully elucidated, there is evidence that small ligands binding to JH2 stabilize the self-inhibitory interaction between the JH2 domain and the JH1 active site. These interactions between JH2 and JH1 are believed to limit the conformational migration rate of the JH1 active site required for phosphorus transfer catalysis. Inhibiting TYK2 by binding to its JH2 domain maintains a high level of selectivity for other JAK family members and the entire kinase family.

[0007] Current TYK2 inhibitors mainly include orthoform inhibitors that inhibit the kinase domain (JH1) and allosteric inhibitors that inhibit the pseudokinase domain (JH2). Orthoform inhibitors, exemplified by Pfizer's PF-06826647, are used to treat diseases such as plaque psoriasis and ulcerative colitis and are currently in phase II clinical trials. Allosteric inhibitors, represented by BMS-986165, have progressed to phase III clinical trials for the treatment of plaque psoriasis, demonstrating significant clinical efficacy and good safety. They are also under clinical investigation for various autoimmune diseases, including Crohn's disease, psoriatic arthritis, and systemic lupus erythematosus. Besides BMS-986165, Nimbus also has several TYK2 allosteric inhibitors in preclinical screening, and the recently reported TYK2 allosteric inhibitor FTP-637 from Frontera, acquired by Hisun Pharmaceuticals, is preparing to enter phase I clinical trials. Summary of the Invention

[0008] This invention provides a compound of formula (I),

[0009]

[0010] The present invention also provides a crystal 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°, 27.37±0.20°.

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

[0012] In some embodiments of the present invention, the A crystal form of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the A crystal form, represented by a 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 A crystal form of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the A crystal form, represented by a 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 A-type of the above-mentioned (I) compound 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°, 27.37±0.20°.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of the A-crystal form of the above-mentioned (I) compound 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 compounds of formula (I) of the present invention, in crystal form A, are characterized in that the X-ray powder diffraction pattern of crystal form A, represented by a 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 compounds of formula (I) of the present invention, in crystal form A, are characterized in that the X-ray powder diffraction pattern of crystal form A, represented by a 2θ angle, contains 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 A-crystal form of the above-mentioned (I) compound 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 A-crystal form of the above-mentioned (I) compound 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 A-type crystal form of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the A-type crystal form, expressed in terms of 2θ angle, contains 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°. 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 A-type crystal form of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the A-type crystal form, expressed in terms of 2θ angle, contains 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°. 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 A-crystal form of the above-mentioned (I) compound 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°, 29.49±0.20°.

[0023] In some embodiments of the present invention, the X-ray powder diffraction pattern of the A-crystal form of the above-mentioned (I) compound 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°, 27.37±0.20°.

[0024] This invention provides crystal form A of the compound of formula (I), whose X-ray powder diffraction pattern 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°. 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 crystal form A of the compound of formula (I), whose X-ray powder diffraction pattern has 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 A crystal form of the compound of formula (I) above,

[0027]

[0028] Its XRPD map is as follows Figure 1 As shown.

[0029] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned A-type crystal form are shown in Table 1:

[0030] Table 1: XRPD spectrum analysis data of the crystal form of compound (I)

[0031]

[0032]

[0033] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned A crystal form has an endothermic peak starting point at 230.5℃±3.0℃.

[0034] In some embodiments of the present invention, the DSC spectrum of the above-mentioned A-type crystal is as follows: Figure 2 As shown.

[0035] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned A crystal form shows a weight loss of 1.02% ± 0.20% at 175.0℃ ± 3.0℃.

[0036] In some embodiments of the present invention, the TGA pattern of the above-mentioned A-type crystal is as follows: Figure 3 As shown.

[0037] This invention also provides the following biological testing methods:

[0038] Pharmacokinetic evaluation of the compound in mice

[0039] Experimental objective: To test the pharmacokinetics of the compound in Balb / c mice.

[0040] Experimental materials: Male Balb / c mice, fasted

[0041] Experimental procedure:

[0042] The pharmacokinetic characteristics of compound 1 in rodents after intravenous and oral administration were tested using a standard protocol.

[0043] After arriving at the facility, Balb / c mice will undergo at least 3 days of acclimatization / quarantine. Following acclimatization / quarantine, a veterinarian or designated personnel will examine the mice's health to assess their suitability for the experimental study. All Balb / c mice will be fasted overnight before administration and resumed feeding 4 hours after administration. The candidate compounds will be prepared into homogeneous solutions and administered to Balb / c mice via a single intravenous injection and oral administration. The intravenous solvent will be a clear solution of 80% polyethylene glycol 400 / 20% water, and the oral solvent will be a homogeneous suspension of ethanol / vitamin E polyethylene glycol succinate / polyethylene glycol 300 = 5 / 5 / 90. Animals will be weighed before administration, and the volume of medication will be calculated based on body weight. Whole blood samples will be collected within 24 hours via jugular vein puncture, and all samples will be immediately transferred to labeled commercially available centrifuge tubes containing K2-EDTA. After blood sample collection, the supernatant plasma was centrifuged at 3200g for 10 minutes at 4℃, and immediately placed on dry ice. It was then stored at -60℃ or lower for LC-MS / MS analysis. A non-compartmental model was used, and the drug concentration-time data were analyzed and pharmacokinetic parameters were calculated using the WinNonlin software package (Version 6.3 and above). PK parameters included (if data allowed) 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.

[0044] Technical effect

[0045] The compounds of this invention have excellent pharmacokinetic properties and their crystal forms exhibit good stability, making them suitable for drug development.

[0046] Definitions and Explanations

[0047] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0048] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0049] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0050] For any given crystal form, the relative intensity of diffraction peaks can change due to preferred orientations caused by factors such as crystal morphology, which is well known in the field of crystallography. Where preferred orientations have an effect, the peak intensity changes, but the positions of the diffraction peaks of the crystal form cannot be altered. Furthermore, for any given crystal form, the peak positions may have slight errors, which is also well known in the field of crystallography. For example, due to temperature changes during sample analysis, sample movement, or instrument calibration, the peak positions can shift, and the measurement error of the 2θ value is sometimes approximately ±0.20° or ±0.10°. Therefore, it is known to those skilled in the art that this error should be taken into account when determining each crystal structure.

[0051] Unless otherwise stated, X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD patterns depend primarily on the structure of the crystal form and are relatively insensitive to experimental details, while their relative peak heights depend 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 essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD pattern can be subject to experimental error; the measurement of 2θ in the XRPD pattern may vary slightly between different instruments and different samples, therefore the value of 2θ should not be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±0.20° or ±0.10° for the diffraction peaks.

[0052] DSC determines the transition temperature when crystals absorb or release heat due to changes in their crystalline structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point is typically within about 5°C or 3°C in consecutive analyses. When we say a compound has a given DSC peak or melting point, we mean that the DSC peak or melting point is ±5°C or ±3°C. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0053] For the same crystal form, the weight loss temperature of TGA may vary due to factors such as the measuring instrument, measurement method / conditions, etc. For any specific crystal form, the weight loss temperature may have an error, which may be approximately ±5℃ or approximately ±3℃.

[0054] It should be noted that during the preparation of drug crystals, it is difficult to avoid situations where external conditions and internal factors cause solvent molecules to form eutectic residues in the solid substance during the contact between drug molecules and solvent molecules, thus forming solvates. These solvates include stoichiometric solvates and non-stoichiometric solvates. All solvates mentioned are included within the scope of this invention.

[0055] Unless otherwise specified, the exothermic direction of the DSC spectrum is upward. The therapeutic dose of the compounds of the present invention may be determined based on, for example, the specific therapeutic use, the manner of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present invention in the pharmaceutical composition may not be fixed and may depend on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.

[0056] The term "treatment" means administering the compounds or preparations described in this invention to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0057] (i) Suppress the disease or disease state, that is, curb its development;

[0058] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0059] The term "therapeutic effective amount" means the amount of the compound of the present invention used to treat a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present invention constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by those skilled in the art based on their own knowledge and the content of this disclosure.

[0060] Unless otherwise required by the present invention, throughout the specification and the following claims, the word “comprise” and its English variations such as “comprises” and “comprising” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”.

[0061] Throughout this specification, the terms "an embodiment," "an embodiment," "in another embodiment," or "in some embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in an embodiment," "in another embodiment," or "in some embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0062] It should be understood that the singular article “a” (corresponding to the English words “a,” “an,” and “the”) used in this specification and appended claims includes plural objects unless otherwise expressly stated herein. Thus, a reaction involving “catalyst,” for example, includes one catalyst, or two or more catalysts. It should also be understood that the term “or” is generally used in its meaning including “and / or” unless otherwise expressly stated herein.

[0063] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0064] All solvents used in this invention are commercially available and can be used without further purification.

[0065] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds are named according to the supplier's catalog. This invention relates to a powder X-ray diffractometer (XRPD) method.

[0066] Instrument Model: Empyrean X-ray Diffractometer

[0067] Test method: Spread an appropriate amount of sample evenly on a single-crystal silicon sample disk and perform XRPD testing using the parameters described below.

[0068] The detailed XRPD parameters are as follows:

[0069] Instrument Name: X-ray Powder Diffraction

[0070] Instrument manufacturer: Malvern Panaco Ltd.

[0071] Method parameters:

[0072] X-rays: Cu, kα, Kα1 1.54060; Kα2 1.54443; Kα2 / Kα1 intensity ratio: 0.50

[0073] X-ray tube settings: 45kV, 40mA

[0074] Diverging slit: Fixed at 1 / 8°

[0075] Anti-scattering slit: 1 / 4°

[0076] Detector slit: P7.5

[0077] Scanning mode: Continuous

[0078] Scan range (°2Theta): 3-40

[0079] Scan time per step (s): 46.665

[0080] Scan step size (°2Theta): 0.0263

[0081] Test time (min): 5

[0082] This invention relates to a differential scanning calorimeter (DSC) method.

[0083] Instrument Model: TA Discovery DSC 2500 Differential Scanning Calorimeter

[0084] Test method: The sample is placed in an alumina crucible for testing, and heated from RT to 320℃ at a heating rate of 10℃ / min.

[0085] The present invention relates to a thermogravimetric analysis (TGA) method.

[0086] Instrument Model: TA Discovery TGA 5500 Thermogravimetric Analyzer and Thermogravimetric Analyzer

[0087] Test method: The sample was placed in the DSC high-pressure crucible and sealed before testing. The sample was heated from 25℃ to 350℃ at a heating rate of 10℃ / min. Attached Figure Description

[0088] Figure 1 XRPD spectrum of Cu-Kα radiation for the A crystal form of compound (I);

[0089] Figure 2 The DSC spectrum of the A crystal form of compound (I) is shown.

[0090] Figure 3 The TGA spectrum is for the A crystal form of compound (I). Detailed Implementation

[0091] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, 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 thereof.

[0092] Example 1: Preparation of compound (I)

[0093]

[0094] Synthesis route:

[0095]

[0096] Step 1: Synthesis of Compounds 1-2

[0097] To a solution of compound 1-1 (13 g, 67.71 mmol) in dichloromethane (200 mL), N,N-diisopropylethylamine (43.75 g, 338.54 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (30.89 g, 81.25 mmol) were added. The mixture was stirred at 20 °C for 0.5 h, followed by the addition of N,O-dimethylhydroxylamine hydrochloride (7.93 g, 81.25 mmol). The mixture was stirred at 20 °C for 15.5 h, 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 give compound 1-2.

[0098] MSm / z:235[M+H] + .

[0099] Step 2: Synthesis of compounds 1-3

[0100] Under nitrogen protection at 0°C, methyl magnesium bromide (3M, diethyl ether solution, 36.87 mL) was added to a tetrahydrofuran (130 mL) solution of compounds 1-2 (13 g, 55.30 mmol), and the mixture was stirred at 0°C for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (60 mL), diluted with water (100 mL), and then extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 15 / 1) to obtain compounds 1-3.

[0101] 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),7.44(s,1H),2.66(s,3H).

[0102] Step 3: Synthesis of compounds 1-4

[0103] At 0 °C, 60% sodium hydroxide (5.05 g, 126.30 mmol) was slowly added in portions to a solution of dimethyl carbonate (42.80 g, 475.15 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at 20 °C for 16 hours. The reaction solution was diluted with ethyl acetate (100 mL), quenched with hydrochloric acid aqueous solution (50 mL, 2 M), washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compounds 1-4.

[0104] MSm / z:244[M+H] + .

[0105] Step 4: Synthesis of compounds 1-5

[0106] At 0 °C, deuterated iodomethane (4.97 g, 34.28 mmol) was added to a solution of compounds 1-4 (8.2 g, 32.65 mmol) and potassium carbonate (4.96 g, 35.91 mmol) in N,N-dimethylformamide (80 mL), 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 combined organic phases were washed with saturated brine (100 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 4 / 1) to obtain compounds 1-5.

[0107] MSm / z:261[M+H] + .

[0108] Step 5: Synthesis of compounds 1-6

[0109] To a solution of 1-5 (5.8 g, 18.02 mmol, 81%) in acetic acid (30 mL), 35% concentrated hydrochloric acid (61.20 g, 587.48 mmol) was added, 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 purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1) to give compounds 1-6.

[0110] MSm / z:189[M+H] + .

[0111] Step 6: Synthesis of compounds 1-7

[0112] To a solution of 1-6 (2.5 g, 12.33 mmol) in acetonitrile (80 mL), phosphorus oxychloride (7.56 g, 49.30 mmol) was added, and the mixture was 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 sodium bicarbonate aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to obtain compounds 1-7.

[0113] MSm / z:207[M+H] + .

[0114] Step 7: Synthesis of compounds 1-8

[0115] A solution of compounds 1-7 (50 mg, 241.46 μmol), cyclopropylformamide (20.55 mg, 241.46 μmol), potassium carbonate (66.75 mg, 482.92 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (27.94 mg, 48.29 μmol), and tris(dibenzylacetone)dipalladium chloroform complex (22.11 mg, 24.15 μmol) in dioxane (2 mL) was purged three times with nitrogen and stirred at 80 °C for 2 hours. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compounds 1-8.

[0116] MSm / z:256[M+H] + .

[0117] Step 8: Synthesis of compounds 1-10

[0118] Compounds 1-9 (2 g, 10.34 mmol) were dissolved in dioxane (40 mL), and dimethylsulfinylimide (1.01 g, 10.86 mmol), cesium carbonate (6.74 g, 20.68 mmol), tris(dibenzylacetone)dipalladium (946.85 mg, 1.03 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (1.20 g, 2.07 mmol) were added. After purging with nitrogen three times, the mixture was heated to 110 °C and stirred for 4 hours under nitrogen protection. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 4). The crude product was concentrated under reduced pressure and then stirred for 1 hour at 20 °C with petroleum ether / ethyl acetate = 5 / 1 (12 mL). The filter cake was collected by filtration and dried to obtain compounds 1-10.

[0119] MSm / z:206[M+H] + .

[0120] Step 9: Synthesis of compounds 1-12

[0121] Compound 1-10 (400 mg, 1.94 mmol) was dissolved in dioxane (8 mL) and water (2 mL). Compound 1-11 (532.95 mg, 2.14 mmol), potassium phosphate (825.68 mg, 3.89 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (142.31 mg, 194.49 μmol) were added. After purging with nitrogen three times, the mixture was heated to 100 °C and stirred for 2 hours under nitrogen protection. 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 crude product was concentrated under reduced pressure and then stirred for 1 hour at 20 °C with petroleum ether / ethyl acetate = 1 / 1 (4 mL). The filter cake was collected by filtration and dried to obtain compound 1-12.

[0122] MSm / z:293[M+H] + .

[0123] Step 10: Synthesis of compound (I)

[0124] Compounds 1-12 (635 g) and 1-8 (666.5 g) were dissolved in isopropanol (3.175 L), followed by the addition of concentrated hydrochloric acid (22.63 mL). The reaction was carried out at an internal temperature of 65–70 °C for 16–20 hours. After the reaction was complete, the mixture was filtered while hot. The filter cake was washed with isopropanol (5 L) and collected to obtain compound (I).

[0125] 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)

[0126] Example 2: Preparation of Crystal Form A of Compound (I)

[0127] 126 g of compound (I) was weighed and added to 2900 mL of methanol. The reaction mixture was stirred at 55 °C for 1.5 hours. 63 g of mercaptosilica gel was added, and the mixture was 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 the mixture was 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 a period exceeding 8 hours. The mixture was then slowly cooled to -20–0 °C over a period exceeding 6 hours, and stirred at this temperature for 42 hours. The mixture was then filtered under reduced pressure. The filter cake was washed with 400 mL of tert-butyl methyl ether and dried under vacuum (-0.08–0.1 MPa) at 50–60 °C for 23 hours to obtain crystal form A of compound (I).

[0128] Example 3: Solid stability test of crystal form A of compound (I)

[0129] Approximately 1.5 g of crystal form A of compound (I) was weighed and placed at the bottom of a glass sample vial, spreading it into a thin layer. The sample was placed in complete exposure. Samples placed under high temperature and humidity were sampled and tested on day 10 and day 30 (XRPD). Samples exposed to light were placed in a clean petri dish, spread into a thin layer, covered with a quartz glass lid, and sampled and tested on day 5 and day 10 (XRPD). For long-term and accelerated tests (protected from light), each sample was placed in a double-layered LDPE bag, each layer of LDPE bag was sealed, and then the LDPE bag was placed in an aluminum foil bag containing a desiccant and heat-sealed. The samples were then tested under conditions of 25℃ / 60%RH, 30℃ / 65%RH, and 40℃ / 75%RH. The test results were compared with the initial test results at day 0. The test results are shown in Table 2 below.

[0130] Table 2: Solid stability test results of crystal form A of compound (I)

[0131]

[0132] Conclusion: The A crystal form of compound (I) exhibits good stability under the influencing factors of high temperature, high humidity, strong light, and long-term accelerated experimental conditions.

[0133] Bioevaluation

[0134] Experimental Example 1: Evaluation of In Vitro Enzyme Activity

[0135] Tyk2 JH2 enzyme activity test procedure

[0136] Add 0.5 nM TYK2 protein (His-TVMV-TYK2 JH2(575-869)) and 0.2 nM terbium-labeled His antibody to a buffer solution containing 20 mM Hepes pH 7.5, 10 mM MgCl2, 0.015% Brij-35, 2 mM DTT, and 50 μg / mL BSA. d The luciferin-labeled kinase tracer and the test compound were incubated at room temperature for 90 minutes. Subsequently, the generated HTRF (homogeneous time-resolved fluorescence) signal, i.e., the ratio of fluorescence intensity at the emission wavelength of the luciferin acceptor (520 nm) to that of the terbium donor (495 nm), was 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 this invention are shown in Table 3:

[0137] Table 3: Results of in vitro enzyme activity assay of the compounds of the present invention (IC50) 50 )

[0138] serial number <![CDATA[Tyk2 JH2(IC 50 nM)]]> Free base of compound (I) 0.04

[0139] Experimental conclusion: The free base of the compound of this invention has strong inhibitory activity against Tyk2 JH2.

[0140] Experimental Example 2: Evaluation of In Vitro Cell Viability

[0141] IFNα-stimulated phosphorylation of STAT1 experiment

[0142] Human peripheral blood mononuclear cells (hPBMCs) were seeded into plates at a cell density of 1×10⁻⁶. 5 Cells / well were incubated at 37°C for 90 minutes. Then, different concentrations of the compound were added to the cells, starting at 2 μM and serially diluted 5-fold for a total of 8 concentration gradients. The compounds and cells were incubated at 37°C for 30 minutes. hPBMCs were stimulated with IFN-α (1000 U / ml), and the level of phosphorylated STAT1 in CD4+ T cells was detected by flow cytometry to evaluate the inhibitory activity of the compounds on the IFN-α pathway. The results of the in vitro cell activity assays of the free bases of the compounds of this invention are shown in Table 4.

[0143] Table 4: Results of in vitro cell activity assays of the compounds of this invention (IC50) 50 )

[0144] serial number <![CDATA[IFNα-stimulated phosphorylated STAT1 (IC 50 nM)]]> Free base of compound (I) 1.1

[0145] Experimental conclusion: The free base of the compound of this invention has strong Tyk2-related IFNα-stimulated cellular activity against phosphorylated STAT1.

[0146] Experimental Example 3: Pharmacokinetic Study (PK)

[0147] Experimental objective:

[0148] This study aimed to investigate the pharmacokinetics of the test sample in the plasma of male CD1 mice, SD rats, and pit bulls after intravenous and oral administration.

[0149] Experimental methods:

[0150] Animals were randomly divided into two groups of two males each. The compound was formulated into a specified preparation (solvent: 5 mg / mL 10% sulfobutyl ether-β-cyclodextrin), and the oral preparation was a clear or homogeneous suspension.

[0151] Whole blood samples were collected from animals via jugular vein puncture or saphenous vein at 5, 15, 30 minutes, 1, 2, 4, 8, and 24 hours after drug administration. The whole blood samples were added to centrifuge tubes containing anticoagulant, centrifuged at 3000g for 15 min at 4°C, and the supernatant plasma was rapidly frozen on dry ice and then stored at -70±10°C until LC-MS / MS analysis.

[0152] Data processing:

[0153] Using WinNonlin TM Version 6.3.0 (Pharsight, Mountain View, CA) pharmacokinetic software processes plasma drug concentration data of compounds using a non-compartmental model. Peak concentration (C) max ) and peak time (T) max The quantifiable end time can be obtained directly from the blood drug concentration-time graph.

[0154] The following pharmacokinetic parameters were calculated using the logarithmic linear trapezoidal rule: plasma clearance (CL), volume of distribution (Vd), and elimination phase half-life (T). 1 / 2 Mean time of residence of the drug in the body from 0:00 to the end of the time point (MRT) 0-last Mean Time Retention (MRT) of a drug in the body from 0:00 to infinity. 0-inf The area under the time-plasma concentration curve from 0 to the end of the time period (AUC) 0-last ), Area under the plasma concentration curve from 0 to infinity (AUC) 0-inf ) and bioavailability (F). The experimental results of this invention are shown in Table 5:

[0155] Table 5: Pharmacokinetic Test Results

[0156]

[0157] Note: Vd: Volume of distribution; Cl: Scavenging rate; 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 concentration.

[0158] Experimental conclusion: The compounds of this invention exhibit excellent pharmacokinetic properties, with high in vivo exposure and oral bioavailability.

Claims

1. Compound of formula (I), 。 2. The A crystal form 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 A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by the 2θ angle, contains at least six 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 A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by the 2θ angle, contains at least seven 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°.

5. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by a 2θ angle, contains at least eight 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°.

6. The A crystal form of the compound of formula (I) according to claim 1, wherein the X-ray powder diffraction pattern 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°, 27.37±0.20°.

7. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by a 2θ angle, contains at least 10 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°.

8. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by the 2θ angle, contains at least 11 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°.

9. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by a 2θ angle, contains at least 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°.

10. The A crystal form of the compound of formula (I) according to claim 1, wherein the X-ray powder diffraction pattern has 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°, 29.49±0.20°.

11. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by a 2θ angle, contains at least 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°, 19.63±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°.

12. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by a 2θ angle, contains at least 13 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°.

13. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by the 2θ angle, contains at least 14 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°.

14. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by a 2θ angle, contains at least 15 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°.

15. The A crystal form of the compound of formula (I) according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal, represented by the 2θ angle, contains at least 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°.

16. The A crystal form of the compound of formula (I) according to claim 1, wherein the X-ray powder diffraction pattern 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°, 19.63±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°.

17. The A-type of the compound of formula (I) according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 17.56°±0.20°, 24.36°±0.20°, 27.37°±0.20°, 8.70°±0.20°, 10.05°±0.20°, 12.08°±0.20°, 14.63°±0.20°, 15.56°±0.20°, 16.39°±0.20°, 18.76°±0.20°, 19.35°±0.20°, 19.63°±0.20°, 20.44°±0.20°, 21.94°±0.20°, 22.53°± 0.20°, 22.89°±0.20°, 23.23°±0.20°, 23.77°±0.20°, 24.51°±0.20°, 25.69°±0.20°, 26.33°±0.20°, 26.73°±0.20°, 27.83°±0.20°, 28.58°±0.20°, 29.49°±0.20°, 30.42°±0.20°, 31.13°±0.20°, 32.29°±0.20°, 32.88°±0.20°, 34.04°±0.20°, 35.19°±0.20°, 36.30°±0.20°, 38.89°±0.20°.

18. The A-crystal form of compound (I), Its XRPD map is shown in Figure 1.

19. The A crystal form of the compound of formula (I) according to any one of claims 2 to 18, wherein the differential scanning calorimetry curve has an endothermic peak at the starting point of 230.5°C ± 3.0°C.

20. The A crystal form of the compound of formula (I) according to claim 19, the DSC spectrum of which is shown in Figure 2.

21. The A crystal form of the compound of formula (I) according to any one of claims 2 to 18, wherein the thermogravimetric analysis curve shows a weight loss of 1.02% ± 0.20% at 175.0°C ± 3.0°C.

22. The A crystal form of the compound of formula (I) according to claim 19, the thermogravimetric analysis curve shows a weight loss of 1.02% ± 0.20% at 175.0°C ± 3.0°C.

23. The A crystal form of the compound of formula (I) according to claim 20, wherein the thermogravimetric analysis curve shows a weight loss of 1.02% ± 0.20% at 175.0°C ± 3.0°C.

24. The TGA spectrum of the A crystal form of the compound of formula (I) according to claim 21 is shown in Figure 3.

25. The TGA spectrum of the compound of formula (I) according to claim 22 is shown in Figure 3.

26. The TGA spectrum of the A crystal form of the compound of formula (I) according to claim 23 is shown in Figure 3.

27. Use in the preparation of a medicament for treating Tyk2 JH2-related diseases from the A crystal form of the compound according to claim 1 or any one of claims 2 to 26.

28. A medicament comprising crystal form A of the compound according to claim 1 or the compound of formula (I) according to any one of claims 2 to 26.

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