Salt and crystalline forms of polysubstituted pyridine compounds and methods for producing them

Abstract

The present invention discloses salt forms and crystalline forms of polysubstituted pyridine compounds and methods for their preparation, and in particular, discloses the use of crystalline forms of the compound of formula (I) and methods for their preparation in the manufacture of medicaments for treating related diseases. JPEG2026500384000013.jpg70170

Description

[Technical Field]

[0001] This invention claims priority to the following: Application number: CN202211740788.0, application date: December 22, 2022 Application number: CN202311689614.0, application date: December 8, 2023

[0002] The present invention relates to salt forms and crystalline forms of polysubstituted pyridine compounds and methods for their preparation, in particular to crystalline forms of the compound of formula (I) and methods for their preparation and use in the manufacture of medicaments for treating related diseases. [Background technology]

[0003] The Janus kinase (JAK) family of non-receptor tyrosine kinases is important in mediating the signal transduction of numerous cytokines that cause inflammation. The JAK family includes JAK1, JAK2, JAK3, and TYK2. TYK2 and JAK1 / 2 / 3 normally function as pairs or "dimers" to transmit extracellular cytokine signals to the cell nucleus. TYK2 is selectively involved in the signal transduction of proinflammatory cytokines such as IL-23, IL-12, and type I IFN. Therefore, TYK2 inhibitors may be an effective therapeutic approach for a variety of severe inflammatory and autoimmune diseases.

[0004] JAK1, JAK2, JAK3, and TYK2 all contain JAK homology domains (JHs). The JH1 domain is also called the kinase domain, and the JH2 domain is a pseudokinase domain. The JH2 domain of TYK2 is highly similar to the JH1 domain and contains an ATP-binding site highly similar to the JH1 domain, but differences in certain residues eliminate the catalytic function of JH2. Although the specific mechanism by which TYK2 achieves allosteric inhibition via the JH2 domain remains unclear, it has been shown that small molecule ligands binding to JH2 stabilize the autoinhibitory interaction between the JH2 domain and the JH1 active site. These interactions between JH2 and JH1 are thought to restrict the conformational mobility of the JH1 active site required for catalysis of phosphoryl transfer. Binding to the JH2 domain of TYK2 and inhibiting TYK2 maintains a high level of selectivity over other JAK family members and the entire kinase family.

[0005] Current TYK2 inhibitors primarily include orthosteric inhibitors that inhibit the kinase domain (JH1) and allosteric inhibitors that inhibit the pseudokinase domain (JH2). Orthosteric inhibitors are used to treat diseases such as plaques and ulcerative colitis, and are exemplified by Pfizer's PF-06826647, which is currently undergoing Phase II clinical trials. Allosteric inhibitors include BMS-986165, which has progressed to Phase III clinical trials for the treatment of psoriasis vulgaris and has demonstrated excellent clinical efficacy and safety. It is also being studied for the treatment of various autoimmune diseases, such as Crohn's disease, psoriatic arthritis, and systemic lupus erythematosus. In addition to BMS-986165, Nimbus also has several TYK2 allosteric inhibitors in the preclinical screening stage. Fronthera's TYK2 allosteric inhibitor FTP-637, acquired by Heisenberg Pharmaceutical Group Co., Ltd., was recently reported to be preparing for Phase I clinical trials. Summary of the Invention

[0006] The present invention provides compounds of formula (I): [ka]

[0007] The present invention further provides crystalline form A of the compound of formula (I), characterized in that the powder X-ray diffraction pattern has characteristic diffraction peaks at 2θ angles of 17.56±0.20°, 24.36±0.20°, 25.69±0.20°, and 27.37±0.20°.

[0008] In some embodiments of the present invention, the powder X-ray diffraction pattern of crystalline form A of the compound of formula (I) has characteristic diffraction peaks at 2θ angles of 8.70±0.20°, 10.05±0.20°, 12.08±0.20°, and 17.56±0.20°.

[0009] In some embodiments of the present invention, the crystalline form A of the compound of formula (I) is characterized in that the powder X-ray diffraction pattern contains at least diffraction peaks at six, seven, or eight positions selected from 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°, expressed in terms of 2θ angles.

[0010] In some embodiments of the present invention, the crystalline form A of the compound of formula (I) is characterized in that the powder X-ray diffraction pattern contains at least diffraction peaks at six, seven, or eight positions selected from the group consisting of 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°, and 20.44±0.20°, expressed in terms of 2θ angles.

[0011] In some embodiments of the present invention, the powder X-ray diffraction pattern of crystalline form A of the compound of formula (I) has characteristic diffraction peaks at 2θ angles of 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°.

[0012] In some embodiments of the present invention, the powder X-ray diffraction pattern of crystalline form A of the compound of formula (I) has characteristic diffraction peaks at 2θ angles of 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°, and 20.44±0.20°.

[0013] In some embodiments of the present invention, the crystalline form A of the compound of formula (I) is characterized in that the powder X-ray diffraction pattern contains at least diffraction peaks at 10, 11, or 12 positions selected from the group consisting of 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°, expressed in terms of 2θ angles.

[0014] In some embodiments of the present invention, the crystalline form A of the compound of formula (I) is characterized in that the powder X-ray diffraction pattern contains at least diffraction peaks at 10, 11, or 12 positions selected from the group consisting of 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°, and 27.37±0.20°, expressed in terms of 2θ angles.

[0015] In some embodiments of the present invention, the powder X-ray diffraction pattern of crystalline form A of the compound of formula (I) has characteristic diffraction peaks at 2θ angles of 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°, and 29.49±0.20°.

[0016] In some embodiments of the present invention, the powder X-ray diffraction pattern of crystalline form A of the compound of formula (I) has characteristic diffraction peaks at 2θ angles of 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°, and 27.37±0.20°.

[0017] In some embodiments of the present invention, the crystalline form A of the compound of formula (I) has a powder X-ray diffraction pattern with 2θ angles of 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°, and 21.06±0.20°. The diffraction peaks are characterized by having at least diffraction peaks at 12, 13, 14, 15, or 16 positions selected from 0°, 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°.

[0018] In some embodiments of the present invention, the crystalline form A of the compound of formula (I) has a powder X-ray diffraction pattern with 2θ angles of 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±0.1°, and 20.05±0.20°. The diffraction peaks are characterized by having at least 12, 13, 14, 15, or 16 positions selected from 0°, 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°.

[0019] In some embodiments of the present invention, the powder X-ray diffraction pattern of crystalline form A of the compound of formula (I) has characteristic diffraction peaks at 2θ angles of 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°.

[0020] In some embodiments of the present invention, the powder X-ray diffraction pattern of crystalline form A of the compound of formula (I) has characteristic diffraction peaks at 2θ angles of 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°.

[0021] The present invention relates to a compound having an X-ray powder diffraction pattern of 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 22.89° ± 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 29.49°±0.20°, and / or 30.42°±0.20°, and / or 3 Provided is crystalline form A of compound of formula (I) having characteristic diffraction peaks at 2θ angles of 1.13°±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°.

[0022] The present invention relates to a powder X-ray diffraction pattern of 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°, 24.63°, 25.56°, 26.39°, 27.56°, 28.76°, 29.35°, 30.63°, 31.94°, 32.53°, 32.89°, 33.23°, 33.77°, 34.63°, 35.56°, 36.39°, 37.76°, 38.76°, 39.35°, 40.63°, 41.94°, 42.53°, 42.89°, 43.23°, 43.77°, 44.63°, 45.56°, 46.39°, 47.37°, 48.70°, 49.37°, 50.63°, 51.56°, 52.56°, 53.56°, 54.56°, 55.56°, 56.39°, 57.76°, 58.76°, 59.35°, 60.63°, 61.56°, 62.53°, 63.23°, 64 Provided is crystalline form A of compound of formula (I) having characteristic diffraction peaks at 2θ angle positions of 4.51°, 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°, and 38.89°.

[0023] In some embodiments of the present invention, the XRPD pattern of crystalline form A of the compound of formula (I) above is as shown in FIG. [ka]

[0024] In some embodiments of the present invention, the XRPD pattern analysis data of the crystalline form A is as shown in Table 1.

[0025] Table 1: XRPD pattern analysis data of crystalline forms of the compound of formula (I) [Table 1]

[0026] In some embodiments of the present invention, the differential scanning calorimetry curve of crystalline form A has an endothermic peak onset at 230.5°C ± 3.0°C.

[0027] In some embodiments of the present invention, the DSC pattern of the crystalline form A is as shown in FIG.

[0028] In some embodiments of the present invention, the thermogravimetric analysis curve of the crystalline form A shows a weight loss of 1.02%±0.20% at 175.0°C±3.0°C.

[0029] In some embodiments of the present invention, the TGA pattern of the crystalline form A is as shown in FIG.

[0030] The present invention further provides the following biological test methods.

[0031] Pharmacokinetic evaluation of compounds in mice Experimental objective: Pharmacokinetics of test compounds in Balb / c mice Experimental materials: Male Balb / c mice, fasted Testing Procedure: Compound 1 was characterized for pharmacokinetics in rodents after intravenous and oral administration according to standard protocols.

[0032] After arrival at the facility, Balb / c mice underwent at least three days of adaptation / quarantine. After completion of the adaptation / quarantine period, a veterinarian or designated personnel inspected the health of the Balb / c mice to assess their suitability for experimental studies. All Balb / c mice were fasted overnight before administration and resumed feeding 4 hours after administration. For the experiments, candidate compounds were prepared into homogeneous solutions and administered intravenously and orally to Balb / c mice in a single dose. The intravenous vehicle was a clear solution of 80% polyethylene glycol 400 / 20% water, and the oral vehicle was a homogeneous suspension of ethanol / vitamin E polyethylene glycol succinate / polyethylene glycol 300 = 5 / 5 / 90. Animals were weighed before administration, and the administration volume was calculated based on body weight. Whole blood samples were collected within 24 hours by jugular vein puncture, and all blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood samples were collected, they were centrifuged at 3200 g for 10 minutes at 4°C, and the supernatant plasma was aspirated and quickly placed on dry ice, maintained at a temperature of -60°C or lower, and used for LC-MS / MS analysis. Using a non-compartmental model, the drug concentration-time data were analyzed using the WinNonlin software package (Version 6.3 or higher) to calculate pharmacokinetic parameters, including, but not limited to, peak concentration (Cmax), time to peak (Tmax), elimination half-life (T1 / 2), area under the plasma concentration-time curve (AUC), mean residence time (MRT), and bioavailability (if data permitted).

[0033] Technical effects The compounds of the present invention have excellent pharmacokinetic properties, and the crystalline forms of the compounds of the present invention have high stability and are suitable for drug development.

[0034] Definitions and Explanations Unless otherwise specified, the following terms and phrases used herein are intended to include the meanings set forth below. A particular phrase or term, unless specifically defined, should not be considered unclear or ambiguous and should be understood in its general sense. When trade names appear herein, it is intended to refer to the corresponding product name or its active ingredient.

[0035] The intermediate compounds of the present invention can be prepared by a number of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthetic methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0036] The chemical reactions in specific embodiments of the present invention are carried out in solvents suitable for the chemical transformations of the present invention and the reagents and materials required therefor. To obtain compounds of the present invention, one skilled in the art may need to modify or select synthetic steps or reaction flows based on existing embodiments.

[0037] It is well known in the field of crystallography that for any given crystalline form, the relative intensities of diffraction peaks may vary depending on factors such as preferred orientation due to crystal morphology. When preferred orientation is present, peak intensities change, but the diffraction peak positions of the crystalline form do not. It is also well known in the field of crystallography that for any given crystalline form, there may be slight errors in the peak positions. For example, peak positions may shift due to temperature changes during sample analysis, sample movement, instrument calibration, etc., and the measurement error in 2θ values ​​may be approximately ±0.20° or ±0.10°. Therefore, those skilled in the art should take such errors into account when determining various crystalline structures.

[0038] Unless otherwise specified, X-ray powder diffraction (XRPD) can detect information such as crystalline form changes, crystallinity, and crystalline structure state, and is a common means of identifying crystalline forms. The peak positions in an XRPD pattern primarily depend on the structure of the crystalline form and are relatively insensitive to experimental details, and their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline forms of the present invention are characterized by an XRPD pattern having several peak positions, which are substantially as shown in the XRPD patterns provided in the drawings of the present invention. Furthermore, since there may be experimental error in measuring 2θ in an XRPD pattern, and measurements of 2θ in XRPD patterns using different instruments and different samples may vary slightly, the above 2θ values ​​cannot be considered absolute. Depending on the instrument conditions used in this test, the allowable error for diffraction peaks is ±0.20°C or ±0.10°C.

[0039] DSC measures the transition temperatures of crystals when heat is absorbed or released due to changes in the crystal structure or melting of the crystal. For the same crystalline form of the same compound, the error in thermal transition temperatures and melting points is typically within about ±5°C or ±3°C in consecutive analyses. When a compound is said to have a given DSC peak or melting point, this means that the DSC peak or melting point can vary within ±5°C or ±3°C. DSC provides an auxiliary method for distinguishing between different crystalline forms. Different crystalline forms can be distinguished by their distinct transition temperatures. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. Furthermore, due to the decomposition that occurs during the melting process, the melting temperature and the heating rate are interrelated.

[0040] For the same type of crystalline form, the TGA weight loss temperature may vary depending on factors such as the measurement instrument, measurement method / conditions, etc. For any particular crystalline form, there may be an error in the weight loss temperature, and the error may be about ±5°C or about ±3°C.

[0041] In addition, during the preparation of a crystalline form of a drug, in the process of contacting the drug molecules with the solvent molecules, due to external conditions and internal factors, the solvent molecules and the compound molecules will inevitably form a eutectic that remains in the solid material, thereby forming solvates, specifically including stoichiometric solvates and non-stoichiometric solvates, all of which are included in the scope of the present invention.

[0042] Unless otherwise specified, an exotherm is indicated upward in a DSC pattern. The therapeutic dosage of a compound of the invention will depend, for example, on the particular therapeutic application, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on a number of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.

[0043] The term "treatment" means administering a compound or formulation according to the present invention to improve or eliminate a disease or one or more symptoms associated with said disease; (i) inhibiting the disease or disease state, i.e., inhibiting its progression; (ii) alleviating the disease or disease state, i.e., eliminating the disease or disease state.

[0044] The term "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder, (ii) reduces, 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 described herein. The "therapeutically effective amount" of a compound of the present invention will vary depending on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal being treated, but can be determined routinely by one of ordinary skill in the art based on their own knowledge and the present disclosure.

[0045] In the present invention, unless otherwise specified, throughout the specification and the appended claims, the term "comprise" and its English variants, such as "comprises" and "comprising," are to be understood in their open and non-exclusive sense, meaning "including, but not limited to."

[0046] As used throughout the specification, the terms "in one embodiment," "in an embodiment," "in another embodiment," or "in some embodiments" mean that at least one embodiment includes the relevant referenced particular element, structure, or feature described in the embodiment. Thus, the appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in some embodiments" in different places throughout the specification do not necessarily refer to the same embodiment. Furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0047] As used in this specification and the appended claims, the singular article "a" (corresponding to the English words "a," "an," and "the") includes the plural unless the context clearly dictates otherwise. Thus, for example, reference to a reaction containing a "catalyst" includes one 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.

[0048] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0049] All solvents used in this invention are commercially available and can be used without further purification.

[0050] Compounds are named according to general naming principles in the field or using ChemDraw® software; commercially available compounds use the supplier's catalog name.

[0051] X-ray powder diffractometer (XRPD) method of the present invention Model number: Empyrean type X-ray diffraction instrument Test method: An appropriate amount of sample is evenly spread on a single crystal silicon sample disc, and XRPD testing is carried out using the following descriptive parameters:

[0052] The detailed XRPD parameters are as follows:

[0053] Equipment name: Powder X-ray diffraction Equipment manufacturer: Malvern Panalytical Method parameters: X-rays: Cu, kα, Kα1(Å): 1.54060, Kα2(Å): 1.54443, Kα2 / Kα1 intensity ratio: 0.50 X-ray tube settings: 45kV, 40mA Divergence slit: fixed, 1 / 8° Anti-scatter slit: 1 / 4° Detector slit: P7.5 Scanning mode: Continuous Scanning range (2θ) (°): 3 to 40 Scanning time for each step (s): 46.665 Scan step width (2θ)(°): 0.0263 Test time (min): 5

[0054] Differential Scanning Calorimetry (DSC) Method of the Present Invention Model number: TA Discovery DSC 2500 Differential Scanning Calorimeter Test method: The sample is placed in an alumina crucible and heated from RT to 320°C at a rate of 10°C / min.

[0055] The Thermogravimetric Analysis (TGA) Method of the Present Invention Instrument model: TA Discovery TGA 5500 Thermogravimetric Analyzer and Thermogravimetric Analyzer Test method: The sample is placed in a DSC high-pressure crucible and sealed with a laminate before testing. The sample is heated from 25°C to 350°C at a heating rate of 10°C / min. [Brief explanation of the drawings]

[0056] [Figure 1] 1 is an XRPD pattern of Cu-Kα radiation of crystalline form A of compound of formula (I). [Figure 2] 1 is a DSC pattern of crystalline form A of the compound of formula (I). [Figure 3] 1 is a TGA pattern of crystalline form A of the compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0057] The present invention will be described in detail below with reference to examples, but these examples are not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments have been disclosed therein. 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.

[0058] Example 1: Preparation of compounds of formula (I) [ka]

[0059] Synthetic Route: [ka]

[0060] Step 1: Synthesis of Compound 1-2 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'-tetramethyluronium hexafluorophosphate (30.89 g, 81.25 mmol) were added, and the mixture was stirred at 20 °C for 0.5 h. N,O-dimethylhydroxylamine hydrochloride (7.93 g, 81.25 mmol) was added. After stirring at 20 °C for 15.5 h, the reaction mixture was concentrated, and the resulting crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain compound 1-2. MS m / z: 235 [M+H] + .

[0061] Step 2: Synthesis of Compounds 1-3 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) under nitrogen gas protection at 0 ° C. and stirred for 2 hours at 0 ° C. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (60 mL), diluted with water (100 mL), and then extracted with ethyl acetate (100 mL × 2). The combined organic phase was 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 compound 1-3. 1 H NMR (400MHz, CDCl3) δ 8.59 (s,1H), 7.44 (s,1H), 2.66 (s,3H).

[0062] Step 3: Synthesis of Compounds 1-4 To a solution of compound 1-3 (8 g, 42.10 mmol) in dimethyl carbonate (42.80 g, 475.15 mmol) in tetrahydrofuran (40 mL) was added 60% sodium hydride (5.05 g, 126.30 mmol) in small portions at 0 °C and stirred for 16 h at 20 °C. The reaction mixture was diluted with ethyl acetate (100 mL) and quenched by the addition of aqueous hydrochloric acid (50 mL, 2 M). The mixture was washed with saturated brine (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound 1-4. MS m / z: 244 [M+H] + .

[0063] Step 4: Synthesis of Compounds 1-5 Iodomethane-D3 (4.97 g, 34.28 mmol) was added 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) at 0 °C, and the mixture was stirred for 6 hours at 20 °C. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phase was 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 4 / 1) to obtain compound 1-5. MS m / z: 261 [M+H] + .

[0064] Step 5: Synthesis of Compounds 1-6 To a solution of compound 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 mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1) to give compound 1-6. MS m / z: 189 [M+H] + .

[0065] Step 6: Synthesis of Compounds 1-7 Phosphoryl chloride (7.56 g, 49.30 mmol) was added to a solution of compound 1-6 (2.5 g, 12.33 mmol) in acetonitrile (80 mL) and stirred at 85° C. for 1 hour. The reaction mixture was concentrated and then diluted with ethyl acetate (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to obtain compound 1-7. MS m / z: 207 [M+H] + .

[0066] Step 7: Synthesis of Compounds 1-8 A solution of compound 1-7 (50 mg, 241.46 μmol), cyclopropanecarboxamide (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(0)-chloroform adduct (22.11 mg, 24.15 μmol) in dioxane (2 mL) was purged with nitrogen gas three times and stirred at 80 °C for 2 h. The reaction mixture was concentrated to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give compound 1-8. MS m / z: 256 [M+H] + .

[0067] Step 8: Synthesis of Compounds 1-10 Compound 1-9 (2 g, 10.34 mmol) was dissolved in dioxane (40 mL) and dimethyl sulfoximine (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. The mixture was purged with nitrogen gas three times, then heated to 110 °C and stirred under nitrogen gas protection for 4 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 4). The mixture was concentrated under reduced pressure and further stirred at 20 °C with petroleum ether / ethyl acetate = 5 / 1 (12 mL) for 1 h. The filter cake was collected and dried to give compound 1-10. MS m / z: 206 [M+H] + .

[0068] Step 9: Synthesis of Compounds 1-12 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(diphenylphosphino)ferrocene]dichloropalladium (142.31 mg, 194.49 μmol) were added. The mixture was purged with nitrogen gas three times, then heated to 100 °C and stirred under nitrogen gas protection for 2 h. The reaction mixture was concentrated under reduced pressure to give the 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 further stirred at 20 °C with petroleum ether / ethyl acetate = 1 / 1 (4 mL) for 1 h. The filter cake was collected and dried to give compound 1-12. MS m / z: 293 [M+H] + .

[0069] Step 10: Synthesis of Compounds of Formula (I) Compound 1-12 (635 g) and compound 1-8 (666.5 g) were dissolved in isopropyl alcohol (3.175 L), and then concentrated hydrochloric acid (22.63 mL) was added. The mixture was reacted at a temperature of 65-70°C for 16-20 hours. After the reaction was completed, the mixture was filtered while still hot. The filter cake was washed with isopropyl alcohol (5 L), and the filter cake was collected to obtain the compound of formula (I). HNMR: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 - 12.23 (m, 1H) 11.25 (br d, J=4.77 Hz, 1H) 8.89 (d, J=2.01Hz, 1H) 8.61 (s, 1H) 8.15 (d, J=1.51Hz, 1H) 7.67 (br d, J=7.78 Hz, 1H) 7.15 - 7.53 (m, 3 H) 3.33 - 3.60 (m, 9H) 3.11 (s, 2H) 1.94 (br d, J=4.77 Hz, 1H) 0.77 - 1.00 (m, 4H)

[0070] Example 2: Preparation of crystalline form A of the compound of formula (I) Compound (I) (126 g) was added to methanol (2900 mL), and the reaction mixture was stirred at 55°C for 1.5 hours. Silicon dioxide (63 g) 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 or less, and 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 over 8 hours at 55°C. The mixture was then slowly cooled to -20 to 0°C over 6 hours and stirred at that 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 the filter cake was dried at 50-60°C under vacuum (-0.08 to 0.1 MPa) for 23 hours to obtain crystalline form A of compound (I).

[0071] Example 3: Solid state stability test of crystalline form A of the compound of formula (I) Approximately 1.5 g of crystalline Form A of compound of formula (I) was weighed and placed at the bottom of a glass vial, spread into a thin layer, and left completely exposed. Samples were sampled and analyzed (XRPD) on the 10th and 30th days after exposure to high temperature and humidity. The light-exposed samples were placed in a clean watch glass, spread into a thin layer, and covered with a quartz glass cover. Samples were sampled and analyzed (XRPD) on the 5th and 10th days after exposure to light. Each sample in the long-term test and accelerated test (light-shielded) was placed in a two-layer LDPE bag, each of which was tied and sealed. The LDPE bag was then placed in an aluminum foil bag containing a desiccant and heat-sealed. The samples were then observed under conditions of 25°C / 60%RH, 30°C / 65%RH, and 40°C / 75%RH. The results were compared with the initial results on day 0. The test results are shown in Table 2 below.

[0072] Table 2: Solid state stability test results for crystalline form A of the compound of formula (I) [Table 2] Conclusion: Form A of compound of formula (I) has high stability under the influence of high temperature, high humidity, and strong light, as well as under long-term and accelerated experimental conditions.

[0073] Biological evaluation Experimental Example 1: In vitro enzyme activity evaluation Tyk2 JH2 enzyme activity measurement experiment process 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 was added to 0.5 nM TYK2 protein (His-TVMV-TYK2 JH2(575-869)), 0.2 nM terbium-labeled His antibody, and the appropriate K dA fluorescein-labeled kinase tracer (amount) and a test compound were added, and the test system was incubated at room temperature for 90 minutes. Subsequently, the generated HTRF (homogeneous time-resolved fluorescence) signal, i.e., the ratio of the fluorescence intensity at the emission wavelengths of the fluorescein acceptor (520 nm) and the terbium donor (495 nm), was measured using an Envision plate reader, and the IC50 value was calculated based on this. The in vitro enzyme activity measurement results of the free base of the compounds of the present invention are shown in Table 3.

[0074] Table 3: In vitro enzyme activity measurement results (IC 50 ) [Table 3] Experimental conclusion: The free base of the compound of the present invention has strong Tyk2 JH2 inhibitory activity.

[0075] Experimental Example 2: In vitro cell activity evaluation STAT1 phosphorylation experiment by IFNα stimulation 1 × 10 human peripheral blood mononuclear cells (hPBMCs) 5 Cells were seeded at a cell density of 1000 cells / well and placed in a 37°C incubator for 90 minutes. Different concentrations of compounds were then added to the cells, and each compound was diluted 5-fold starting from 2 μM, resulting in a total of eight concentration gradients. The compounds and cells were incubated at 37°C for 30 minutes. After stimulating hPBMCs with IFN-α (1000 U / ml), the STAT1 phosphorylation level in CD4+ T cells was detected by flow cytometry to evaluate the inhibitory activity of the compounds against the IFN-α pathway. The in vitro cellular activity assay results for the free base of the compounds of the present invention are shown in Table 4.

[0076] Table 4: In vitro cellular activity assay results for compounds of the present invention (IC 50 ) [Table 4] Experimental Conclusion: The free base of the compound of the present invention has strong cellular activity in IFNα-stimulated STAT1 phosphorylation, which is associated with Tyk2.

[0077] Experimental Example 3: Pharmacokinetic study (PK) Objective of the experiment: This study aims to study the pharmacokinetics of the test article in the plasma of male CD-1 mice, SD rats and pit bulls after intravenous and oral administration.

[0078] Experimental Method: The animals were randomly divided into two groups, with two males in each group. The compounds were prepared in a given formulation (solvent was 10% sulfobutylether-β-cyclodextrin at 5 mg / mL) and orally administered when the formulation was clear or a uniform suspension.

[0079] Whole blood samples were collected from the animals via jugular vein puncture or saphenous vein at 5, 15, 30, 1, 2, 4, 8, and 24 hours after administration. The whole blood samples were placed in centrifuge tubes containing anticoagulant and centrifuged at 3000 g for 15 min at 4°C. The supernatant plasma was quickly frozen on dry ice and stored in a refrigerator at -70±10°C until LC-MS / MS analysis.

[0080] Data Processing: The plasma drug concentration data of the compounds were processed using a non-compartmental model using WinNonlin® Version 6.3.0 (Pharsight, Mountain View, CA) pharmacokinetic software. max ), peak arrival time (T max ) and a quantifiable end time can be obtained directly from the blood concentration-time curve.

[0081] The log-linear trapezoidal method was used to calculate plasma clearance (CL), volume of distribution (Vd), and elimination half-life (T 1 / 2 ), mean residence time of the drug in the body from 0 to the end time (MRT 0-last ), mean residence time of the drug in the body from 0 to infinity (MRT 0-inf ), the area under the time-plasma concentration curve from 0 to the end time (AUC 0-last ), the area under the time-plasma concentration curve from 0 to infinity (AUC0-inf The pharmacokinetic parameters of the drug (D) and bioavailability (F) were calculated. The experimental results of the present invention are shown in Table 5.

[0082] Table 5: Pharmacokinetic study results [Table 5] 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 Experimental Conclusion: The compounds of the present invention exhibit excellent pharmacokinetic properties, with high systemic exposure and oral bioavailability.

Claims

1. A compound of formula (I). 【Chemistry 1】

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

3. 2. The crystalline form A of the compound of formula (I) according to claim 1, characterized in that the powder X-ray diffraction pattern contains at least diffraction peaks at 6, 7 or 8 positions selected from the group consisting of 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°, expressed in terms of 2θ angles.

4. 2. The crystalline form A of the compound of formula (I) according to claim 1, wherein the powder X-ray diffraction pattern has characteristic diffraction peaks at 2θ angle positions of 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. 2. The crystalline form A of the compound of formula (I) according to claim 1, characterized in that the powder X-ray diffraction pattern contains at least diffraction peaks at 10, 11 or 12 positions selected from the group consisting of 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°, when expressed in terms of 2θ angles.

6. 2. The crystalline form A of compound of formula (I) according to claim 1, wherein the powder X-ray diffraction pattern has characteristic diffraction peaks at 2θ angle positions of 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. In the powder X-ray diffraction pattern, the 2θ angles are 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°, 24.09±0.20°, 25.09±0.20°, 26.09±0.20°, 27.09±0.20°, 28.09±0.20°, 29.09±0.20°, 30.09±0.20°, 31.09±0.20°, 32.09±0.20°, 33.09±0.20°, 34.09±0.20°, 35.09±0.20°, 36.09±0.20°, 37.09±0.20°, 38.09±0.20°, 39.09±0.20°, 40.09±0.20°, 41.09±0.20°, 42.09±0.20°, 43.09±0.20°, 44.09±0.20°, 45.09±0.20°, 46.09±0.20°, 47.09±0.20°, 48.09±0.20°, 49.09±0.20°, 50.09±0.20°, 51.09±0.20°, 52 2. The crystalline form A of compound of formula (I) according to claim 1, characterized in that it contains at least diffraction peaks at 12, 13, 14, 15 or 16 positions selected from 4.36±0.20°, 25.69±0.20°, 26.33±0.20°, 27.37±0.20°, 27.83±0.20°, 29.49±0.20°.

8. 2. The crystalline form A of compound of formula (I) according to claim 1, wherein the powder X-ray diffraction pattern has characteristic diffraction peaks at 2θ angle positions of 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 powder X-ray diffraction peak pattern is 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 22.89°±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 29.49°±0.20°, and / or 30.42°±0.20°, and / or 31.13°±0.20° 2. The crystalline form A of compound of formula (I) according to claim 1, having characteristic diffraction peaks at 2θ angles of 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. Crystalline form A of the compound of formula (I), whose XRPD pattern is as shown in Figure 1. 【Chemistry 2】

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

12. 12. The crystalline form A of the compound of formula (I) according to claim 11, having a DSC pattern as shown in Figure 2.

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

14. 14. The crystalline form A of the compound of formula (I) according to claim 13, having a TGA pattern as shown in Figure 3.

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

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