Macrocycles of tyk2 inhibitors, pharmaceutical compositions and uses thereof

Abstract

The present application provides a macrocyclic compound of TYK2 inhibitor and its pharmaceutical composition and application, which can be used for regulating TYK2-mediated related diseases, wherein the compound has a structure shown in formula (II).

Description

Technical Field

[0001] This application relates to the pharmaceutical field, specifically to a macrocyclic compound of a TYK2 inhibitor, a pharmaceutical composition thereof, and its application, which can be used to regulate TYK2-mediated diseases. Background Technology

[0002] TYK2 is one of the four members of the JAK kinase family (JAK1, JAK2, JAK3, TYK2), belonging to the non-receptor tyrosine kinase family. JAK family kinases are key mediators of cytokine signaling from cell membrane receptors to the cell nucleus. Their classic mode of action is as follows: when a cytokine (such as interferon or interleukin) binds to its specific receptor, it causes receptor dimerization or conformational changes, thereby recruiting and activating the associated JAK kinase. The activated JAK kinase further phosphorylates tyrosine residues in the receptor's intracellular domain through autophosphorylation and cross-phosphorylation, creating docking sites for signal transduction and activating transcription factor (STAT) proteins. Subsequently, the STAT protein is phosphorylated by JAK kinase, forming a dimer and translocating to the cell nucleus, where it acts as a transcription factor to regulate the expression of downstream target genes. TYK2 specifically participates in signal transduction in multiple key cytokine pathways, primarily by regulating downstream signaling pathways of type I interferon, IL-12, IL-23, and IL-10, thus playing a role in various autoimmune and inflammatory diseases. This also makes it a highly attractive target for drug development.

[0003] With the convergence of neuroscience and immunology, neuroimmunology has become one of the most dynamic frontiers in understanding and treating central nervous system (CNS) diseases. Traditionally, the CNS was considered an "immune privileged" region, relatively isolated from the peripheral immune system. However, modern research has clearly demonstrated the existence of a complex innate immune system within the CNS, and its dynamic interaction with the peripheral immune system plays a central role in maintaining CNS homeostasis and driving disease progression. TYK2 is expressed in key CNS cell types, including microglia, astrocytes, and specific neuronal subsets, making it a key node in regulating neuroinflammation. Primarily through the classical JAK-STAT pathway, it responds to upstream cytokine signals such as type I interferon (IFN), IL-12, and IL-23, thereby driving the neuroinflammatory cascade and playing a crucial role in regulating neuronal survival and apoptosis. TYK2 has become a key player in various neurological diseases, especially those characterized by neuroinflammation and neurodegeneration.

[0004] Deucravacitinib, a TYK2 inhibitor currently approved for the treatment of psoriasis, achieves high selectivity for other JAK family members and the entire kinase family through allosteric inhibition targeting the pseudokinase domain. This reduces the risk of adverse events such as cardiovascular events or venous thromboembolism, making it the only marketed JAK drug without a black box warning, unlike traditional JAK inhibitors that act on the kinase domain. However, because it only acts on the periphery and has limited ability to cross the blood-brain barrier, transforming a successful target for systemic autoimmune diseases into an effective target for CNS diseases presents a significant challenge: the blood-brain barrier. Drugs must be able to efficiently cross the blood-brain barrier and directly act on microglia, astrocytes, and neurons in the brain to exert ideal therapeutic effects on diseases within the CNS. Furthermore, CNS neurodegenerative diseases, such as Alzheimer's and Parkinson's, are chronic and require long-term medication. Therefore, developing TYK2 inhibitors with high central nervous system penetration (CNS-penetrant) and high safety (e.g., no cardiotoxicity) has become the focus of current CNS disease treatment. Summary of the Invention

[0005] The first aspect of this application provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof. (I).

[0006] A second aspect of this application provides a pharmaceutical composition comprising the compound provided in the first aspect or a pharmaceutically acceptable salt, solvate or isomer thereof, and a pharmaceutically acceptable carrier.

[0007] A third aspect of this application provides the above-described compound or its pharmaceutically acceptable salts, solvates, or isomers, and the use of the above-described pharmaceutical compositions in the preparation of a medicament for treating tyrosine kinase-mediated diseases. The tyrosine kinase-mediated diseases include inflammatory autoimmune diseases, tumors, or neurodegenerative diseases. Detailed Implementation

[0008] The present application will be further described in detail below through embodiments. Through these descriptions, the features and advantages of the present application will become clearer and more apparent.

[0009] The term “exemplary” as used herein means “serving as an example, embodiment, or illustration.” Any embodiment illustrated herein as “exemplary” is not necessarily to be construed as superior to or better than other embodiments.

[0010] Furthermore, the technical features involved in the different embodiments of this application described below can be combined with each other as long as they do not conflict with each other.

[0011] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions of exemplary embodiments of this application will be further described below.

[0012] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains.

[0013] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention herein. In this application, it must be noted that, unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “comprising” are not limiting.

[0014] This application provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof. (I), R1 is selected from -NR a R b R a R b Each independently is hydrogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl groups; R3 and R4 are each independently hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Haloalkyl; or R3, R4 together with the attached carbon atom to form C 3-6 cycloalkyl; Y and Z are each independently selected from C or N; Ring A is selected from phenyl, 5-6 membered monocyclic heteroaryl, and 7-10 membered bicyclic heteroaryl, wherein the heteroatom is one or more of O, N, and S; wherein ring A is optionally substituted by 1, 2, or 3 R2 atoms. R2 is selected from C 1-3 Alkyl, C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups, wherein the heteroatom is one or more of O, N, and S; “ " indicates a single or double bond.

[0015] In some embodiments, ring A is selected from 7-10 membered bicyclic heteroaryl groups, wherein the heteroatom is one or more of O, N, and S.

[0016] In some embodiments, ring A is selected from any of the following groups: , , .

[0017] This application provides a compound of formula (II) or a pharmaceutically acceptable salt, solvate, or isomer thereof: (II) R1 is selected from -NR a R b R a R b Each is independently hydrogen or C 1-3 alkyl; R2 is selected from C 1-3 Alkyl or C 3-6 cycloalkyl; R3 and R4 are each independently hydrogen or C. 1-6 Alkyl group; or R3, R4, and the attached carbon atom together form a C12 group. 3-6 cycloalkyl; X, Y, and Z are each independently selected from C or N; “ " indicates a single or double bond.

[0018] In this application, C 1-6 Alkyl groups are alkyl groups containing 1 to 6 carbon atoms, meaning they are selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl. For alkyl groups with 3 or more carbon atoms, including their isomers such as isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., they are not listed here. Numerical ranges in this document, such as "1-6," refer to integers within a given range; for example, "1-6 carbon atoms" means the group can have 1, 2, 3, 4, 5, or 6 carbon atoms. An alkyl group is an optionally substituted straight-chain or optionally substituted branched saturated aliphatic hydrocarbon group connected to the rest of the molecule by a single bond.

[0019] Similarly, C 1-3 Alkyl refers to an alkyl group containing 1 to 3 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl and propyl.

[0020] C 1-3 Deuterated alkyl refers to a C-shaped alkyl group substituted with one or more deuterium atoms. 1-3 Alkyl groups, such as -CH2D, -CH2CH2D, -CH2CH2DCH2D, -CHD2, -CD3, etc.

[0021] In this application, cycloalkyl refers to a non-aromatic carbon-containing ring, including saturated carbon rings (such as cycloalkyl) or unsaturated carbon rings (such as cycloalkenyl). C3-6 Cycloalkyl refers to a carbon ring containing 3 to 6 carbon atoms, such as a carbon ring containing 3 carbon atoms, a carbon ring containing 4 carbon atoms, a carbon ring containing 5 carbon atoms, and a carbon ring containing 6 carbon atoms.

[0022] In the structure of this application, " The symbol "" indicates a single or double bond. However, those skilled in the art should understand that this notation is merely a descriptive convenience and does not limit the actual physical form of the chemical bonds in the compound. In fact, when this symbol is used in aromatic or heteroaromatic ring systems, such as benzene rings or five-membered heteroaromatic rings (e.g., pyrrole, furan, thiophene, imidazole, oxazole, pyrazole, etc.), there are no isolated single or double bonds within the ring; instead, a delocalized π-electron conjugated system is formed, i.e., a large π bond (also known as an aromatic conjugated structure). This application uses "". When the symbol "or similar" is used to describe a ring structure, it should be understood as intended to cover all aromatic or partially aromatic structures described by conjugated π electrons.

[0023] C 1-6 Haloalkyl refers to a C-shaped alkyl group substituted with one or more halogen groups. 1-6 Alkyl groups, such as -CH2F, -CHF2, -CF3, -CH2CH2Cl, -CH2CHF2, -CH2CH2CHFCH3, -(CH2)5CH2F, etc., and halogen groups as defined above.

[0024] In some implementations, R1 is -NR a R b R a R b Each is independently hydrogen or C 1-3 alkyl.

[0025] In some implementations, R1 is -NHCH3.

[0026] In some implementations, R2 is -CH3, cyclopropyl.

[0027] In some embodiments, R3 and R4 are each independently hydrogen or C. 1-3 Alkyl group; or R3, R4, and the attached carbon atom together form a C12 group. 4-5 Cycloalkyl.

[0028] In some embodiments, the compound is selected from the following compounds: .

[0029] Pharmaceutically acceptable salts are those that retain the biological potency of the free acid and free base of the specified compound and have no adverse effects in biological or other respects. Unless otherwise specified, the term "salt" in this disclosure may refer to metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with basic or acidic amino acids, etc. Non-limiting examples of metal salts include, but are not limited to, salts of alkali metals, such as sodium and potassium salts; salts of alkaline earth metals, such as calcium, magnesium, and barium salts; and aluminum salts. Non-limiting examples of salts formed with organic bases include, but are not limited to, salts formed with trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, and dicyclohexylamine. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, and ornithine. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid and glutamic acid.

[0030] Pharmaceutically acceptable salts can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0031] The term "solvent" refers to an associated complex formed by the compound of this application and one or more solvent molecules through intermolecular non-covalent bonds (such as hydrogen bonds, van der Waals forces, ionic dipole interactions, etc.). When the solvent is water, the resulting solvate is also called a "hydrate". Solvents include, but are not limited to, stoichiometric or non-stoichiometric solvates, such as monohydrates, dihydrates, hemihydrates, ethanolates, acetone compounds, isopropanol compounds, etc. This application covers all solvate forms of the compound.

[0032] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. The compounds disclosed herein contain asymmetric or chiral centers, double bonds, and other structures; therefore, the compounds disclosed herein may include various isomer forms such as optical isomers, geometric isomers, tautomers, and blocked transisomers. These isomers, as well as their single isomers, racemates, etc., are all included within the scope of this disclosure. For example, optical isomers can be prepared by chiral resolution, chiral synthesis, or chiral reagents or other conventional techniques. R )-and( S )-Isomers and D and L Isomers. For example, they can be converted to diastereomers by reacting with suitable optically active substances (such as chiral alcohols or Mosher's chloride), separated, and converted (e.g., hydrolyzed) to the corresponding single isomers. Alternatively, they can be separated by chromatographic column chromatography.

[0033] Pharmaceutical Compositions and Applications This application also provides a pharmaceutical composition comprising the above-described compound of this application or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof, and a pharmaceutically acceptable carrier.

[0034] A pharmaceutical composition refers to a bioactive compound optionally mixed with at least one pharmaceutically acceptable chemical component or reagent, which is a "carrier" that facilitates the introduction of the compound into cells or tissues. This includes, but is not limited to, stabilizers, diluents, suspending agents, thickeners, and / or excipients. The carrier is a common pharmaceutical carrier in the art, such as lactose, microcrystalline cellulose, magnesium stearate, or physiological saline.

[0035] The “pharmaceutical compositions” described herein may be prepared in a manner well known in the pharmaceutical field and may be administered or applied via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. They may be administered topically (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonaryly (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal), or orally or parenterally. Parenterally administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenterally administration may be in the form of a single large dose or via, for example, a continuous infusion pump. The pharmaceutical compositions described herein include, but are not limited to, the following forms: tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in liquid solvents); ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders containing, for example, up to 10% by weight of an active compound.

[0036] The pharmaceutical compositions described herein can be formulated in unit dosage forms, each containing approximately 0.1 to 1000 mg, typically approximately 5 to 1000 mg of active ingredient, and more typically approximately 100 to 500 mg of active ingredient. The term "unit dosage form" refers to a physically isolated single-dose unit suitable for use in human patients and other mammals, each unit containing a predetermined amount of active substance, calculated to produce the desired therapeutic effect, when mixed with a suitable drug carrier.

[0037] As demonstrated in this application, the compounds of this application possess excellent TYK2 inhibitory activity, particularly acting on the TYK2 JH2 pseudokinase domain. They are high- and medium-thickness central nervous system penetrating TYK2 allosteric inhibitors and can be used to regulate TYK2-mediated diseases. Therefore, this application also relates to the above-mentioned compounds or their pharmaceutically acceptable salts, hydrates, solvates, or isomers, and the use of pharmaceutical compositions in the preparation of treatments for diseases mediated by tyrosine kinases.

[0038] In some embodiments, the tyrosine kinase is selected from TYK2 kinase.

[0039] In some embodiments, the tyrosine kinase-mediated disease is a TYK2 kinase-mediated disease.

[0040] In some embodiments, the diseases mediated by the tyrosine kinase include inflammatory autoimmune diseases, tumors, neurodegenerative diseases, etc. These diseases exhibit dysregulation of neuroimmune and inflammatory responses, including activation of neurons and glial cells, damage to neurovascular units associated with excessive release of pro-inflammatory cytokines, chemokines, and neurotoxic mediators, infiltration of peripheral immune cells into the brain, and entry of inflammatory cells. TYK2 is a STAT pathway activator targeting a range of pro-inflammatory cytokines, and inhibition of TYK2 may play an important role in reducing inflammation in the aforementioned neurodegenerative diseases.

[0041] The proportion or concentration of the disclosed compound in a pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), route of administration, etc. For example, the disclosed compound may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration.

[0042] The compounds described herein can be prepared using the methods described below. The following methods and examples are for illustrative purposes. These procedures and examples should not be construed as limiting the scope of this application in any way. The compounds described herein can also be synthesized using standard synthetic techniques known to those skilled in the art, or in combination with methods known in the art.

[0043] The chemical reactions in the embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0044] A crucial consideration in planning any synthetic route in this field is selecting appropriate protecting groups for reactive functional groups, such as the amino groups in this application. For trained practitioners, Greene and Wuts's (Protective Groups in Organic Synthesis, Wiley and Sons, 1991) is the authority on this matter. All references cited in this application are incorporated herein by reference in their entirety.

[0045] The reactions described herein can be monitored using any suitable method known in the art. For example, they can be monitored using broad-spectrum methods such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or monitoring of product formation by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0046] The compounds of general formula (I) of this application can be prepared by those skilled in the art of organic synthesis using standard methods in the art through the following procedures.

[0047] This application is illustrated in more detail by way of specific embodiments. The following embodiments are provided for illustrative purposes and are not intended to limit this application in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to obtain substantially the same results. Following one or more assays described herein, the compounds in the following examples were found to be TYK2 allosteric inhibitors.

[0048] Example 1: ( R ,1 3 E ,1 4 E )-2 1 ,6-Dimethyl-1 7 -(methylamino)-2 1 H-4,7-dioxa-1(5,3)-pyrazolo[1,5- a ]Pyrimidine-2(3,5)-pyrrolo[2,3- b ]Pyridine acyclic tribenzothiophene-8-one

[0049] Synthesis route:

[0050]

[0051] Step A: 3-Bromo-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate

[0052] In a 500 mL single-necked bottle, put 1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate (25 g, 142 mmol) dissolved in N,N In dimethylformamide (150 mL), cool to 0°C using an ice-water bath, then... N 3-Bromosuccinimide (27.8 g, 157 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was brought back to room temperature and stirred for 2 hours. LC-MS confirmed that the reactants had reacted completely. The reaction solution was then slowly poured into ice water (1 L), resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with water and dried under vacuum to obtain 3-bromo-1-bromosuccinimide. H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate (36 g, yield = 98%), pale yellow solid.

[0053] LC-MS: (M+1) + m / z=255.02; Step B: 3-Bromo-1-methyl-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate

[0054] In a 500 mL single-necked flask, 3-bromo-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate (36 g, 141 mmol) dissolved in N,NIn 150 mL of dimethylformamide, potassium carbonate (70 g, 212 mmol) was slowly added. After cooling to 0 °C in an ice-water bath, methyl iodoformane (26 g, 183 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was brought to room temperature and stirred for 2 hours. LC-MS confirmed the reaction was complete. The reaction solution was slowly poured into ice water (1 L), resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with water and dried under vacuum to obtain 3-bromo-1-methyl-1-dimethylformamide. H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate (36 g, yield = 94%), pale yellow solid.

[0055] LC-MS: (M+1) + m / z=269.02; Step C: (3-bromo-1-methyl-1) H -pyrrolo[2,3- b ]pyridin-5-yl)methanol

[0056] In a 1 L single-necked flask, 3-bromo-1-methyl-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate (36 g, 133.8 mmol) was dissolved in tetrahydrofuran (360 mL). The system was placed under nitrogen protection and cooled to 0 °C using an ice-water bath. Then, diisobutylaluminum hydride (1.5 M / toluene solution) (357 mL) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was maintained at 0 °C and stirred for 1 hour. LC-MS confirmed that the reactants had reacted completely. The reaction solution was slowly poured into 1.5 L of ice water, followed by the addition of 1.5 L of ethyl acetate. After thorough stirring, the aqueous and organic phases were filtered through diatomaceous earth. The two phases were separated, and the aqueous layer was extracted with ethyl acetate (2 × 500 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain (3-bromo-1-methyl-1-carboxylate). H -pyrrolo[2,3- b Pyridin-5-yl)methanol (25 g, yield = 74%), pale yellow solid.

[0057] LC-MS: (M+1) + m / z=241.06; Step D: 3-Bromo-5-(chloromethyl)-1-methyl-1 H -pyrrolo[2,3- b ]Pyridine

[0058] In a 1 L single-necked flask, (3-bromo-1-methyl-1 H -pyrrolo[2,3- b 15 g (62.2 mmol) of pyridin-5-yl)methanol was dissolved in 150 mL of dichloromethane. The system was placed under nitrogen protection and cooled to 0 °C using an ice-water bath. Then, 22.6 mL of thionyl chloride was slowly added dropwise to the reaction system. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. LC-MS confirmed the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure to give the crude product 3-bromo-5-(chloromethyl)-1-methyl-1-yl)-1-methyl H -pyrrolo[2,3- b Pyridine (17 g, yield = 96%), off-white solid.

[0059] LC-MS: (M+1) + m / z=259.00; Step E: ( R )-1-((3-bromo-1-methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)methoxy)prop-2-ol

[0060] In a 500 mL single-necked flask, 3-bromo-5-(chloromethyl)-1-methyl-1 H -pyrrolo[2,3- b Pyridine (7 g, 27 mmol) was dissolved in anhydrous acetonitrile (100 mL), and then cesium carbonate (17.6 g, 54 mmol) and ( R )-Propane-1,2-diol (6.2 g, 81 mmol) was added to the reaction system, and after purging with nitrogen three times, the mixture was refluxed at 80 °C for 16 hours. The reaction was confirmed to be complete by LC-MS. Water (500 mL) was added for dilution, followed by extraction with ethyl acetate (3 × 500). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product. The residue was purified by preparative chromatography (mobile phase A: 0.1% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 20%-70% B, 55 min; flow rate: 70 mL / min) to obtain ( R )-1-((3-bromo-1-methyl-1 H -pyrrolo[2,3- b Pyridin-5-yl)methoxy)prop-2-ol (2 g, yield = 24%) is a pale yellow liquid.

[0061] LC-MS: (M+1) + m / z=299.1; Step F: ( R )-1-((3-bromo-1-methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)methoxy)propyl-2-yl7-((tert-butyloxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5- a Pyrimidine-3-carboxylic acid ester

[0062] In a 50 mL Shrek tube, put ( R )-1-((3-bromo-1-methyl-1 H -pyrrolo[2,3- b Pyridin-5-yl)methoxy)prop-2-ol (1 g, 3.3 mmol) dissolved in anhydrous N,N Add 7-((tert-butyloxycarbonyl)(methyl)amino)-5-chloropyrazol [1,5- a Pyrimidine-3-carboxylic acid (1.1 g, 3.3 mmol), N,N,N',N' -Tetramethylchloroformamidine hexafluorophosphate (1.88 g, 6.68 mmol), cooled to 0 °C in an ice-water bath under a nitrogen atmosphere, and then... N 1-Methylimidazole (1.1 g, 13.4 mmol) was added dropwise to the reaction system, and after the addition was complete, the mixture was heated to room temperature and stirred for 2 hours. The reaction was confirmed to be complete by LC-MS. The mixture was diluted with water (200 mL) and then extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by preparative chromatography (mobile phase A: 0.1% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 40%-95% B, 55 min; flow rate: 70 mL / min) to obtain (… R )-1-((3-bromo-1-methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)methoxy)propyl-2-yl7-((tert-butyloxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5- a Pyrimidine-3-carboxylic acid ester (0.96 g, yield = 45%), pale yellow liquid.

[0063] LC-MS: (M+1) + m / z=607.4; Step G: ( R ,1 3 E ,1 4 E )-2 16-Dimethyl-8-oxo-2 1 H -4,7-dioxo-1(5,3)-pyrazolo[1,5- a ]Pyrimidine-2(3,5)-pyrrolo[2,3- b ]Pyridine acyclopentane-1 7 -yl)(methyl)carbamate

[0064] Will( R )-1-((3-bromo-1-methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)methoxy)propyl-2-yl7-((tert-butyloxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5- a Methyl pyrimidine-3-carboxylate (960 mg, 1.60 mmol) was dissolved in 1,4-dioxane (50 mL), and then hexa-n-butyltin (1.83 g, 3.15 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (301 mg, 0.63 mmol), and tris(dibenzylideneacetone)palladium (289 mg, 0.32 mmol) were added to the reaction system. After purging with nitrogen three times, the temperature was raised to 100 °C and the reaction was stirred for 6 hours. LC-MS confirmed the reaction was complete. After cooling the system to room temperature, the crude product was evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to obtain crude product (800 mg). The residue was purified by preparative chromatography (mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to obtain ( R 1 3 E 1 4 E )-2 1 6-Dimethyl-8-oxo-2 1 H -4,7-dioxo-1(5,3)-pyrazolo[1,5- a ]Pyrimidine-2(3,5)-pyrrolo[2,3- b ]Pyridine acyclopentane-1 7 -yl)(methyl)carbamate (100 mg, yield = 12%), white solid.

[0065] LC-MS: (M+1) + m / z=492.88; Step H: ( R ,1 3E ,1 4 E )-2 1 ,6-Dimethyl-1 7 -(methylamino)-2 1 H -4,7-dioxa-1(5,3)-pyrazolo[1,5- a ]Pyrimidine-2(3,5)-pyrrolo[2,3- b ]Pyridine acyclic tribenzothiophene-8-one

[0066] In a 50 mL Shrek tube, put ( R ,1 3 E ,1 4 E )-2 1 6-Dimethyl-8-oxo-2 1 H -4,7-dioxo-1(5,3)-pyrazolo[1,5- a ]Pyrimidine-2(3,5)-pyrrolo[2,3- b ]Pyridine acyclopentane-1 7 100 mg (0.19 mmol) of methyl carbamate was dissolved in dichloromethane (2 mL). After cooling to 0 °C in an ice-water bath under nitrogen atmosphere, trifluoroacetic acid (220 mg, 2.0 mmol) was added to the reaction system, and the mixture was allowed to react at room temperature for 1 hour. LC-MS confirmed the complete reaction. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative chromatography (mobile phase A: 0.1% ammonium bicarbonate; mobile phase B: acetonitrile; gradient: 30%-70% B, 55 min; flow rate: 70 mL / min) to obtain ( R 1 3 E 1 4 E )-2 1 ,6-Dimethyl-1 7 -(methylamino)-2 1 H -4,7-dioxa-1(5,3)-pyrazolo[1,5- a ]Pyrimidine-2(3,5)-pyrrolo[2,3- b Pyridine acyclic tribenzothiophene-8-one (10.37 mg, yield = 13%), white solid.

[0067] LC-MS: (M+1) + m / z=393.3; 1 H-NMR (400 MHz, DMSO- d 6) δ 10.22 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 1.3Hz, 2H), 8.16 (d, J = 2.2 Hz, 1H), 8.10 (q, J = 4.9 Hz, 1H), 6.71 (s, 1H), 5.09– 5.01 (m, 1H), 4.95 (d, J = 16.3 Hz, 1H), 4.74 (d, J = 15.6 Hz, 1H), 4.00 –3.92 (m, 2H), 3.91 (s, 3H), 3.06 (d, J = 5.0 Hz, 3H), 1.45 (d, J = 6.4 Hz, 3H).

[0068] The following examples were prepared according to the experimental route and method in Example 1:

[0069] Bioactivity and pharmacokinetic experiments 1. Enzymatic activity (IC50) of compound TYK2-JH2 50 ) Detection experiment The control and test compounds were diluted from the 10 mmol / L stock solution to 0.2 mmol / L by adding 1.2 μL of the compound to 58.8 μL of DMSO, followed by 4-fold dilutions to obtain 10 concentrations. 50 nL of the test compound was transferred to a 384 plate using an Echo transducer, with two replicates per compound. The plates were centrifuged at 1000 rpm for 1 minute, with a final DMSO concentration of 0.5%. 5 μL of TYK2 was added to the 384 plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 5 μL of JH2 probe1 was added to the 384 plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. The FP520 / 48 signal was read using a BMG high-throughput microplate reader.

[0070] The experimental data of TYK2-JH2 were analyzed using GraphPad Prism 8 software. The readings of the negative control (0.5% DMSO wells) were set to 0% inhibition rate, and the readings of the positive control (wells with the highest concentration of the control compound) were set to 100% inhibition rate. After calculating the inhibition rate, the IC50 values ​​of the control compound and the test compound were obtained using the software's nonlinear fitting formula. 50 Value (half-maximal inhibitory concentration);

[0071] Average value of positive control wells Average value of negative control wells Specific IC 50 The test results are shown in Table 1 below: Table 1: IC50 of the compounds in the examples 50 Test results

[0072] As can be seen from the data in the table, the compounds in the examples of this application all have good enzymatic inhibitory activity against TYK2-JH2, and some compounds have an IC50 concentration. 50 Even at <5 nM, the compound in this application is a potent allosteric inhibitor of TYK2 (tyrosine kinase 2).

[0073] 2. Blood-brain distribution experiment Male SD rats were divided into groups of three, and each group received a single intravenous injection of either the compound used in the examples or the control compound. Animals were fasted overnight before the experiment, from 10 hours before administration to 4 hours after administration. Each rat was sacrificed 0.5 hours after administration, and blood, brain tissue, and cerebrospinal fluid were collected. Samples were centrifuged at 4°C, and plasma was transferred to centrifuge tubes and stored at -80°C until sample analysis. Protein precipitation was used to extract the samples, and the extracts were analyzed by LC / MS / MS. Data showed that the compounds in the examples of this application can efficiently cross the blood-brain barrier and have penetrating properties of the high and medium central nervous systems.

[0074] Table 2: Blood-brain ratio of drug concentration after IV administration of the compound in SD rats for 0.5 h in the examples

[0075] Blood-brain distribution assays showed that, 0.5 hours after a single intravenous injection in male SD rats, the compounds in the examples exhibited significant concentrations in brain tissue. LC / MS / MS measurements and calculations of the brain-to-plasma drug concentration ratio (brain-to-blood ratio) revealed that most of the compounds in the examples had a brain-to-blood ratio greater than 100%, indicating their efficient ability to cross the blood-brain barrier and excellent central nervous system penetration.

[0076] 3. Manual patch-clamp technique to detect the effect of compounds on stably overexpressed hERG channels. Using the HEK293 cell line stably expressing hERG channels, potassium currents were recorded using whole-cell patch-clamp techniques. hERG currents were activated by step depolarization to +20 or +40 mV, followed by hyperpolarization to -50 mV to remove inactivation, and tail current amplitudes were recorded. The inhibition rate of tail currents by different concentrations of compounds was determined using a cumulative dosing method, and concentration-response curves were fitted to obtain the IC50. 50 The data shows that the compounds in the embodiments of this application have little effect on hERG channel current and a low inhibition rate, indicating low cardiotoxicity and high safety.

[0077] Table 3: Effects of Compounds from Examples on hERG

[0078] 4. Whole blood stability in rats The compound was preheated in a water bath at 37°C and then prepared into a 10 mM stock solution using DMSO for later use.

[0079] 20 μL of a 10 mM compound stock solution was mixed with 180 μL of 50% methanol to obtain a 1 mM working solution. The 10 μL of the 1 mM working solution was diluted with 990 μL of plasma to a final 10 μM working solution. The 10 μM whole blood working solution was incubated in a 37°C water bath. Three replicates were prepared, with 50 μL added to each well. Protein precipitation was performed at 0 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h using 500 μL of acetonitrile containing the internal standard to terminate the reaction. Centrifuge at 4000 rpm for 20 minutes in a 4°C centrifuge, collect the supernatant, and add formic acid solution to reduce acetonitrile volatilization (supernatant: formic acid solution = 1:1); inject the sample into LCMS / MS, obtain the peak area of ​​the target compound and the internal standard peak area in Analyst software, and calculate the ratio of target peak area to internal standard peak area; normalize the ratio at time 0 to 100%, and calculate the remaining percentage at other time points = (ratio of each time point) / (ratio at time 0) × 100%, with the remaining 50% of time points being T. 1 / 2 Data shows that the compounds in the embodiments of this application have good stability in rat whole blood.

[0080] Table 4: Stability of Compounds in Rat Whole Blood (Examples)

[0081] 5. Stability of rat brain tissue The compound was preheated in a water bath at 37°C and then prepared into a 10 mM stock solution using DMSO for later use.

[0082] The experimental animals were euthanized, and brain tissue was quickly removed on ice. The tissue was washed with pre-chilled PBS, dried with filter paper, and weighed. Pre-chilled PBS buffer was added at a ratio of 1:9 (w / v), and the tissue was thoroughly homogenized using a homogenizer or ultrasonic homogenizer. The test compound was added to the prepared brain homogenate in a pre-chilled centrifuge tube and vortexed to mix. 20 μL of a 10 mM stock solution of the compound was mixed with 180 μL of 50% methanol to obtain a 1 mM working solution. The 10 μL of the 1 mM working solution was diluted to 10 μM with 990 μL of brain homogenate. The 10 μM brain homogenate working solution was incubated in a 37°C water bath. Three replicates were performed, with 50 μL added to each well. Protein precipitation was performed at 0 h, 0.5 h, 1 h, 2 h, 4 h, and 6 h using 500 μL of acetonitrile containing the internal standard to terminate the reaction. Centrifuge at 4000 rpm for 20 minutes at 4°C, collect the supernatant, and add formic acid solution to reduce acetonitrile volatilization (supernatant: formic acid solution = 1:1). Inject the sample into LCMS / MS, obtain the peak area of ​​the target compound and the internal standard peak area in Analyst software, and calculate the ratio of target peak area to internal standard peak area. After normalization, set the ratio at time 0 to 100%, and calculate the remaining percentage at other time points = (ratio of each time point) / (ratio at time 0) × 100%. The remaining 50% of time points is T1 / 2. Data shows that the compound in the embodiments of this application has good stability in rat brain tissue.

[0083] Table 5: Stability of Compounds in Rat Brain Tissue from Examples

[0084] In summary, the compound in this application is a potent TYK2 (tyrosine kinase 2) allosteric inhibitor with efficient blood-brain barrier crossing ability; it has little effect on hERG channel current, a low inhibition rate, high cardiac safety, and good stability in rat whole blood and brain tissue.

[0085] The present application has been described above with reference to preferred embodiments; however, these embodiments are merely exemplary and illustrative. Various substitutions and modifications can be made to the present application based on these embodiments, all of which fall within the protection scope of the present application.

Claims

1. A compound as shown in formula (II) or a pharmaceutically acceptable salt thereof, （Ⅱ） R1 is selected from -NR a R b R a R b Each is independently hydrogen or C 1-3 alkyl; R2 is selected from C 1-3 Alkyl or C 3-6 cycloalkyl; R3 and R4 are each independently hydrogen or C. 1-6 Alkyl group; or R3, R4, and the attached carbon atom together form a C12 group. 3-6 cycloalkyl; X, Y, and Z are each independently selected from C or N; " " indicates a single or double bond.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 is -NHCH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2 is -CH3 or cyclopropyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R3 and R4 are each independently hydrogen or C. 1-3 Alkyl group; or R3, R4, and the attached carbon atom together form a C12 group. 4-5 Cycloalkyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following compounds: 。 6. A pharmaceutical composition comprising the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, in the preparation of a medicament for treating tyrosine kinase-mediated diseases.

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