Triazolopyrazine compounds and their uses

Abstract

The present invention provides a triazolopyrazine compound, characterized in that it is a compound represented by the following formula, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt or prodrug thereof: wherein W is selected from substituted or unsubstituted aryl or heteroaryl, X is C or N, and R is H or any substituent. When the triazolopyrazine compounds provided by the present invention are used as Tyk2-specific inhibitors, they provide more targeted drugs for autoimmune inflammatory diseases driven by the IL-23 / Th17 axis, and can more safely and effectively treat rheumatoid arthritis, psoriasis, ankylosing spondylitis, Sjögren's syndrome, lupus erythematosus, inflammatory bowel disease, Behçet's disease, Covid-19 severe pneumonia, and other diseases. TIFF2023543908000011.tif2881

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to a patent application filed on December 7, 2020, bearing application number "CN202011432143.1" and entitled "Triazolopyrazine Compounds and Uses Thereof," the entire contents of which are incorporated herein by reference.

[0002] [Technical field] The present invention relates to the field of small molecule compounds, and in particular to triazolopyrazine compounds and their uses, which can be used to prevent or treat autoimmune diseases such as rheumatoid arthritis inflammation, inflammatory bowel disease, systemic lupus erythematosus, Sjogren's syndrome and severe Covid-19 pneumonia, or related inflammatory skin diseases such as psoriasis, lichen planus, vitiligo, hidradenitis suppurativa, cutaneous lupus erythematosus, lichen sclerosus, etc. [Background technology]

[0003] JAK (Janus Kinase) is a family of intracellular non-receptor tyrosine protein kinases, including four members: JAK1, JAK2, JAK3, and Tyk2. The JAK-STAT (Signal Transducer and Activator of Transcription protein) signaling pathway is the primary intracellular signaling pathway stimulated by the combination of inflammatory cytokines and receptors. It primarily mediates various innate and adaptive immune responses to counter attacks by various internal and external pathogens, including viruses, mycobacteria, and other microorganisms, thereby maintaining homeostasis and immune balance. However, for unknown reasons, the immune response stimulated by these pathogens may persist or intensify even after their elimination, leading to chronic inflammatory diseases. A growing body of evidence indicates that excessive activation of the JAK-STAT signaling pathway plays an essential driving role in the pathogenesis of many diseases, particularly autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, argyria, alopecia areata, and vitiligo, as well as allergic diseases such as asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, and eczema. Tyk2 specifically mediates the signal transduction of autoimmune-related cytokines, such as IL-12, IL-23, and IFN-α and IFN-β, and therefore plays an essential driving role in the pathogenesis of autoimmune diseases. Therefore, efficient small molecule inhibition of Tyk2 kinase activity can block cytokine-mediated signaling pathways involved in inflammatory responses, thereby controlling inflammation and effectively treating autoimmune-related diseases.

[0004] During the development of various inflammatory diseases, T cells differentiate in different directions with the help of antigen-presenting cells (e.g., monocytes) in response to different inflammatory triggers, such as viral or bacterial infections, autoantigens, and allergens, generating T cell subsets such as Th1, Th2, and Th17. These T cells, monocytes, and tissue cells produce various cytokines in response to different stimuli. Th1 cytokines associated with acute inflammation caused by viral infection include IFN, IL-2, and IL-12; Th2 cytokines associated with allergies include IL-4, IL-5, and IL-13; and Th17 cytokines associated with autoimmunity include IL-17, IL-12, IL-21, IL-22, and IL-23. These cytokines bind to cell surface receptors and transmit inflammatory signals via intracellular JAKs, promoting the pathological process of the disease.

[0005] Cytokine-mediated immune responses are necessary for the normal response of the human immune system to various pathogens in the environment and the body. However, if these immune responses persist even after the pathogens are eliminated, they can lead to chronic inflammatory diseases. Therefore, inhibiting cytokines and their signaling pathways has become a hot topic for developing new therapies for inflammatory diseases. A growing body of research has shown that selectively blocking the activity of JAK subtypes is beneficial for achieving both high efficacy and safety. Regarding autoimmune diseases, Tyk2 is responsible for signaling the IL-23 / Th17 axis. The presence of Th17 cells and Th17-related cytokines is central to autoimmunity. Among these, IL-23 is required for the differentiation and induction of Th17 cells, while IL-12 and IFN-α and IFN-β are also involved in the pathogenesis of autoimmunity, and the signaling of these important cytokines depends on Tyk2. Therefore, inhibiting Tyk2 without involving other JAK subtypes may provide greater benefits for autoimmune-related diseases and be advantageous for achieving efficient and safe treatment of such autoimmune inflammatory diseases. Summary of the Invention

[0006] The objective of the present invention is to obtain a highly efficient Tyk2-specific inhibitor and provide a more appropriate treatment for autoimmune inflammatory diseases driven by the IL-23 / Th17 axis. Tyk2-specific inhibitors may be more suitable for the treatment of rheumatoid arthritis, psoriasis, ankylosing spondylitis, Sjögren's syndrome, lupus erythematosus, Behçet's disease, and severe COVID-19 pneumonia. Highly selective Tyk2-specific inhibitors can simultaneously overcome hematopoietic inhibition and coagulation abnormalities caused by JAK2 inhibition, as well as viral infections caused by reduced interferon response due to JAK1 inhibition. Furthermore, because Tyk2 mediates innate immune functions against viruses and bacteria, selecting a Tyk2 inhibitor suitable for external administration can avoid the risks of systemic treatment, such as infections. Therefore, Tyk2-specific inhibitors are highly important for the treatment of autoimmune inflammatory skin diseases, which are often mild to moderate in severity.

[0007] On the other hand, the active centers (JH1 domains) of the ATP-binding moieties of the four members of the JAK kinase family share a high degree of homology conservation. For a long time, various pharmaceutical development companies have hoped to discover highly selective and specific small molecule inhibitors, especially those specific to the active center of Tyk2 kinase, but no significant breakthroughs have been achieved. The discovery of an ATP-competitive specific inhibitor of Tyk2 kinase in the present invention is the first discovery with very high inhibitory specificity for Tyk2, which is of great importance for the development of Tyk2 inhibitors for the treatment of various autoimmune diseases and inflammatory skin diseases.

[0008] To achieve the above object, in one aspect, the present invention provides a triazolopyrazine compound, which is a compound represented by the following formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt or prodrug thereof: [ka] where: W is selected from substituted or unsubstituted aryl or heteroaryl; X is C or N, and R is H or any substituent.

[0009] In one embodiment, W is a substituted or unsubstituted C5-C6 monocyclic group or a C8-C10 fused ring group.

[0010] In one embodiment, W is selected from any one of the following groups: [ka]

[0011] In another embodiment, R is selected from H, halogen, cyano, amino, (C1-C5) alkyl, (C1-C5) alkoxy, cyanoalkyl, haloalkyl, hydroxyalkyl, benzene-substituted (C1-C5) alkyl, (C3-C6) cycloalkyl, halogenated (C3-C8) cycloalkyl, (C3-C6) heterocycloalkyl, spirocycloalkyl, formyl, (C5-C10) aryl, (C5-C10) heteroaryl, heteroalicyclic, amido, or sulfamido group.

[0012] In another embodiment, when X=C, said R is selected from halogen, C1-C5 alkyl, halogenated C1-C5 alkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, amido, or sulfonamido.

[0013] In another embodiment, when X=N, said R is selected from C1-C5 alkyl, halogenated C1-C5 alkyl, cyano, amino, C3-C6 cycloalkyl, amido, or sulfonamido.

[0014] In another embodiment, the halogen is F, Cl or Br, the alkyl group is a methyl, ethyl, propyl or isopropyl group, and / or the cycloalkyl group is cyclopropyl, cyclobutyl or cyclopropylmethyl.

[0015] In another aspect, the present invention further provides a use of the triazolopyrazine compound in the preparation of a medicament for the prevention or treatment of autoimmune diseases and related inflammatory skin diseases, the pathogenesis of which is related to the dysregulation of JAK kinase pathway signaling. Preferably, the medicament is administered by oral administration, topical application, or aerosol administration, but is not limited to these.

[0016] In one embodiment, the autoimmune disease is selected from at least one of rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis, ankylosing spondylitis, multiple sclerosis, Behcet's disease, Covid-19 severe pneumonia, Reiter's syndrome, and uveitis.

[0017] In another embodiment, the associated inflammatory skin disease is selected from at least one of psoriasis, autoimmune-associated vasculitis, scleroderma, dermatomyositis, acrodermatitis enteropathica, hidradenitis suppurativa, lichen planus, vitiligo, cutaneous lupus erythematosus, and lichen sclerosus.

[0018] The functions and effects of the present invention are as follows.

[0019] When used as a Tyk2-specific inhibitor, the triazolopyrazine compounds provided by the present invention can provide more targeted treatment for autoimmune inflammatory diseases driven by the IL-23 / Th17 axis, making them more suitable for the treatment of rheumatoid arthritis, psoriasis, ankylosing spondylitis, Sjögren's syndrome, lupus erythematosus, Behçet's disease, etc., and can simultaneously overcome hematopoietic inhibition and coagulation abnormalities caused by JAK2 inhibition and viral infections that are prone to occur due to reduced interferon response caused by JAK1 inhibition. Furthermore, the Tyk2 inhibitors provided by the present invention are useful for avoiding the risks of systemic treatment, making them extremely important for autoimmune inflammatory skin diseases, which are often mild to moderate in severity. DETAILED DESCRIPTION OF THE INVENTION

[0020] Specific embodiments of the present invention will be described in detail below. It should be understood that the specific embodiments described herein are for the purpose of explanation and interpretation of the present invention, and are not intended to limit the present invention.

[0021] It should be understood that the endpoints of any ranges and any values ​​disclosed herein are not limited to that exact range or value, and that these ranges or values ​​include values ​​approaching these ranges or values. In the case of numerical ranges, values ​​between the endpoints of the ranges, between the endpoints of the ranges and the individual point values, and between the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed herein.

[0022] Before describing the present invention in detail, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which will be limited only by the appended claims. In order to provide a more complete understanding of the invention described herein, the following terms are used and their definitions are set forth below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0023] In one aspect, the present invention provides a triazolopyrazine compound, which is a compound represented by Formula I below, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt or prodrug thereof:

[0024] [ka] where: W is selected from substituted or unsubstituted aryl or heteroaryl; X is C or N, and R is H or any substituent.

[0025] In the present invention, the substituted or unsubstituted aryl or heteroaryl groups each independently contain 1 to 2 single or fused rings and may have 5 to 10 (i.e., C5-C10, for example, 5, 6, 7, 8, 9, or 10) ring atoms. In a preferred embodiment, the W may be a substituted or unsubstituted C5-C6 monocyclic group or a C8-C10 fused ring group. In a more preferred embodiment, the W may be, but is not limited to, a benzene ring, a pyridine ring, or a pyrrole ring. Furthermore, for heteroaryl groups, the heteroatom therein may be, as known to those skilled in the art, a heteroatom such as N, O, or S, preferably an N atom, and the number thereof may be, for example, 1, 2, or 3.

[0026] Furthermore, in one embodiment of the present invention, W may be selected from any one of the following groups: [ka]

[0027] As used herein, the term "substituted" or "substituted" means that any one or more hydrogens on the designated atom or group are replaced with a moiety selected from the designated group. In a preferred embodiment, the substitution may be with a halogen, alkyl, cyano, amino, amido, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In yet another preferred embodiment, the substitution may be with a halogen, alkyl, cyano, amino, amido, or cycloalkyl. In yet another preferred embodiment, the halogen is F, Cl, or Br, the alkyl is methyl, ethyl, propyl, or isopropyl, and / or the cycloalkyl is cyclopropyl, cyclobutyl, or cyclopropylmethyl. It should be understood that methods for making routine substitutions to the molecular structure according to the present invention without affecting the overall properties of the molecule are well known to those skilled in the art.

[0028] On the other hand, for the triazolopyrazine compounds according to the present invention, the R group at the right side thereof is not particularly limited and may be a common substituent in the art. In another embodiment, the R may be selected from H, halogen, cyano, amino, alkyl, alkoxy, cyanoalkyl, haloalkyl, hydroxyalkyl, benzene-substituted alkyl, cycloalkyl, halogenated cycloalkyl, heterocycloalkyl, spirocycloalkyl, formyl, aryl, heteroaryl, heteroalicyclic, amido, or sulfonamido. More preferably, when X=C, the R may be selected from halogen, C1-C5 alkyl, halogenated C1-C5 alkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, amido, or sulfonamido. And, when X=N, the R may be selected from C1-C5 alkyl, halogenated C1-C5 alkyl, cyano, amino, C3-C6 cycloalkyl, amido, or sulfonamido.

[0029] As used herein, the term "pharmaceutically acceptable" refers to a substance that does not affect the biological activity or properties of a compound of the present invention and is relatively non-toxic. That is, the substance can be administered to an individual without causing adverse biological reactions or interacting undesirably with any of the components contained in the composition. In the present invention, "pharmaceutically acceptable salts" include inorganic salts and organic salts, including, but not limited to, ammonium, lithium, sodium, potassium, cesium, calcium, magnesium, copper, aluminum, zinc, barium, or quaternary ammonium salts, and inorganic salts including, but not limited to, arginine, tert-butylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, imidazole, lysine, methylamine, pyridine, formic acid picolyl ester, piperazine, triethylamine, triethanolamine, trimethylamine, or urea salts.

[0030] In another aspect, the present invention provides the use of the above triazolopyrazine compounds for inhibiting JAK kinases, particularly as Tyk2-specific inhibitors.

[0031] In another aspect, the present invention further provides the use of the triazolopyrazine compounds in the preparation of a medicament for preventing or treating autoimmune diseases and related inflammatory skin diseases, the pathogenesis of which has been shown to be related to the deregulation of JAK kinase pathway signaling.

[0032] As used herein, the term "treatment" means that the treatment regimen achieves a desired effect, i.e., partial or complete alleviation, amelioration, mitigation, inhibition, delay, reduction in severity, and / or reduction in incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition, upon any administration of a therapeutic agent according to the treatment regimen. In some embodiments, the administration of a therapeutic agent according to the treatment regimen is associated with achieving a desired effect. Such treatment may be directed to subjects who do not exhibit the relevant disease, disorder, and / or condition and / or subjects who exhibit only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be directed to subjects who exhibit one or more identified signs of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who have been diagnosed with the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who have one or more predisposing factors statistically associated with an increased risk of developing the relevant disease, disorder, and / or condition.

[0033] According to the present invention, the pharmaceutical preparation prepared for the above uses may contain an effective amount of the triazolopyrazine compound according to the present invention and a pharmaceutically acceptable excipient, carrier or diluent.

[0034] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of a therapeutic agent that confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio appropriate for any drug treatment. Such therapeutic effect may be objective (i.e., measurable by some test or indicator) or subjective (i.e., the effect as reported or felt by the subject). In some embodiments, a "therapeutically effective amount" refers to an amount of a therapeutic agent or composition that effectively treats, ameliorates, or prevents (e.g., delays the onset of) the relevant disease or condition, and / or exhibits a detectable therapeutic or prophylactic effect, such as by ameliorating symptoms associated with the disease, preventing or delaying the onset of the disease, and / or reducing the severity or frequency of symptoms of the disease.

[0035] Those skilled in the art will recognize that the therapeutically effective amount of the triazolopyrazine compound administered will vary depending on the subject and the nature and severity of the disease, the subject's physical condition, the treatment regimen (e.g., whether or not a second therapeutic agent is used), and the selected route of administration. The appropriate dosage can be easily determined by those skilled in the art. Meanwhile, the optimal frequency and interval of individual administrations of the drug will depend on the nature and severity of the condition being treated, the form, route, and site of administration, and the age and condition of the specific subject being treated, and the appropriate dosage will ultimately be determined by a physician. This dosage may be repeated multiple times as necessary, and if side effects occur, the amount and / or frequency of administration may be changed or reduced in accordance with standard clinical practice.

[0036] In the present invention, "pharmaceutically acceptable excipient, carrier or diluent" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier, etc., approved by the relevant governmental authority as acceptable for use in humans or veterinary animals.

[0037] Furthermore, according to the present invention, the pharmaceutical preparation prepared for the above-mentioned use may contain, in addition to the triazolopyrazine compound of the present invention as an active ingredient, a drug usable for the prevention or treatment of autoimmune diseases and immune-related inflammatory skin diseases as another active ingredient. Examples of such drugs include, but are not limited to, vitamin D derivatives, vitamin A derivatives, glucocorticoids, calcineurin inhibitors, nonsteroidal anti-inflammatory drugs, etc. When the pharmaceutical preparation contains multiple active ingredients, the active ingredients may be administered simultaneously, sequentially, or separately, according to the physician's discretion.

[0038] Meanwhile, the triazolopyrazine compounds according to the present invention can be administered to patients by various routes, such as oral, transdermal, subcutaneous, intranasal, intravenous, intramuscular, intrathecal, regional, or local (e.g., mucosal) administration. The optimal administration route in any given case depends on the subject, the nature and severity of the disease, and the subject's physical condition. In one embodiment, the triazolopyrazine compounds according to the present invention can be administered intravenously. In another embodiment, the triazolopyrazine compounds according to the present invention can be administered orally. Therefore, depending on the different administration route, the pharmaceutical preparations according to the present invention can be prepared in different dosage forms. For example, in one embodiment, the pharmaceutical preparations can be prepared as tablets, capsules, pills, granules, nebulizers, sprays, or injections.

[0039] Through research, the inventors have discovered that the triazolopyrazine compounds according to the present invention or pharmaceutical preparations prepared therefrom are effective in preventing or treating JAK-related autoimmune diseases and related inflammatory skin diseases, specifically, the autoimmune diseases selected from rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, ankylosing spondylitis, multiple sclerosis, Behçet's disease, severe COVID-19 pneumonia, Reiter's syndrome, uveitis, etc., and the related inflammatory skin diseases selected from psoriasis, autoimmune-related vasculitis, scleroderma, dermatomyositis, acrodermatitis enteropathica, hidradenitis suppurativa, lichen planus, vitiligo, cutaneous lupus erythematosus, lichen sclerosus, etc.

[0040] The effects of specific compounds of the present invention will be described in detail below with reference to examples. [Example]

[0041] <Example 1. General synthesis method of compound 1 (TDM-181020)> [ka]

[0042] Step 1: Preparation of compound 1c (6-chloro-8-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)-[1,2,4]triazolo[1,5-a]pyrazine) Compound 1a (500 mg, 2.65 mmol), compound 1b (924 mg, 2.65 mmol), tetrakis(triphenylphosphine)palladium (214 mg, 0.19 mmol), potassium carbonate (732.5 mg, 5.3 mmol), dioxane (30 mL), and water (30 mL) were added to a three-neck flask. After purging with nitrogen several times, the mixture was heated to 80 °C and stirred for 60 min. Completion of the reaction was monitored by LCMS. Workup: The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: ethyl acetate / petroleum ether = 0-50%] to afford the target compounds (compound 1c, 252.5 mg, compound 1d, 95.7 mg) as yellow solids. LCMS[M+1] + =220,376.

[0043] Step 2: Preparation of compound 1d (6-chloro-8-(1H-pyrrol-3-yl)-[1,2,4]triazolo[1,5-a]pyrazine) To a solution of compound 1c (252.5 mg, 0.67 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (2 mL, 2.01 mmol). The reaction mixture was stirred at room temperature for 30 minutes and monitored for completion by LCMS. Workup: The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: ethyl acetate / petroleum ether = 0-50%] to afford the target compound (compound 1d, 123 mg, 83.3% yield) as a yellow solid. LCMS[M+1] + =220.

[0044] Step 3: Preparation of compound 1f ((1r,3r)-3-(3-(6-chloro-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-1H-pyrrol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile) To a solution of compound 1d (198.7 mg, 0.91 mmol) in acetonitrile (20 mL), compound 1e (161 mg, 1.36 mmol) and DBU (94 mg, 0.62 mmol) were added, and the reaction mixture was heated to 70 °C and stirred for 2 h. The reaction was monitored by LCMS and completed. Workup: The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: ethyl acetate / petroleum ether = 0-50%] to obtain the target compound (compound 1f, 95.2 mg, 62.3% yield). LCMS[M+1] + =338. 1H NMR (400 MHz, DMSO)δ9.17 (s, 1H), 8.77 (s, 1H), 8.37 - 8.18 (m, 1H), 7.22 (dd, J = 3.0, 2.4 Hz, 1H), 7.14 (dd, J = 3.1, 1.6 Hz, 1H), 3.56 - 3.45 (m, 1H), 3.43 (s, 2H), 3.16 - 3.08 (m, 2H), 2.94 - 2.86 (m, 2H).

[0045] Step 4: Preparation of compound 1 ((1r,3r)-3-(cyanomethyl)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-1H-pyrrol-1-yl)cyclobutane-1-carbonitrile) Compound 1f (95.2 mg, 0.28 mmol), compound 1g (58.6 mg, 0.28 mmol), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (22 mg, 0.03 mmol), cesium carbonate (184 mg, 0.56 mmol), dioxane (12 mL), and water (2 mL) were added to a three-neck flask. The reaction mixture was purged with argon several times, then heated to 100 °C and stirred for 2 h. Completion of the reaction was monitored by LCMS. Workup: The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel chromatography [eluent: (D / M = 10:1) / DCM = 0-40%]. The obtained crude product was purified by preparative methods to give the target compound (Compound 1, 31.6 mg, yield 29.22%) as a yellow solid. LCMS[M+1] + =384. 1H NMR (400 MHz, DMSO)δ9.16 (s, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 8.35 - 8.29 (m, 1H), 8.16 (d, J = 0.6 Hz, 1H), 7.27 (dd, J = 3.0, 1.6 Hz, 1H), 7.23 - 7.18 (m, 1H), 3.93 (s, 3H), 3.57 - 3.47 (m, 1H), 3.43 (s, 2H), 3.19 - 3.10 (m, 2H), 2.94 - 2.85 (m, 2H).

[0046] <Example 2. General synthesis method of compound 2 (TDM-181021)> [ka] Step 1: Preparation of compound 2 ((1s,3s)-3-(cyanomethyl)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-1H-pyrrol-1-yl)cyclobutane-1-carbonitrile) Compound 2 (white solid, 38.4 mg, yield 26.7%) was obtained by the same method as in Example 1. 1 H NMR (400 MHz, DMSO) δ9.16 (s, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 8.27 - 8.21 (m, 1H), 8.16 (s, 1H), 7.25 (dd, J = 3.0, 1.6 Hz, 1H), 7.16 - 7.09 (m, 1H), 3.93 (s, 3H), 3.62 (p, J = 8.8 Hz, 1H), 3.45 (s, 2H), 3.05 - 2.85 ( m, 4H). LCMS [M+1] + = 384.2.

[0047] Test Example 1. Enzyme activity inhibition assay of small molecule inhibitors of JAK kinases Experimental Program 1. Reagent Preparation Kinase reaction buffer: Prepare kinase reaction buffer, the components are as follows: 50 mM HEPES, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween20. 1X Assay Buffer: Prepare assay buffer by diluting 10X assay buffer to 1X with deionized water 9:1. 4X Kinase Solution: Dilute JAK kinases to a final concentration of 4X (JAK1: 80 nM, JAK2 / JAK3 / Tyk2: 4 nM) in kinase reaction buffer. 4X Substrate Solution: Dilute ULight™-JAK (Tyr1023) substrate to 200 nM (final concentration: 50 nM) in kinase reaction buffer. 4X ATP solution: Dilute ATP in kinase reaction buffer to a final concentration of 4X (JAK1: 160 μM, JAK2 / JAK3 / Tyk2: 40 μM). 4X test compound solution: Dissolve test compounds in DMSO at 10 mM stock solution and dilute 3-fold to the required concentration. Ten concentration points were set for each compound, with the final test compound concentration range being 10 μM-0.5 nM. 4X enzyme reaction stop solution: Dissolve EDTA to 40 mM (final EDTA concentration: 10 mM) in 1X assay buffer. 4X assay antibody solution: Dilute Eu-labeled assay antibody (anti-phosphotyrosine (PT66)) to 8 nM (final concentration of antibody: 2 nM) in 1X assay buffer.

[0048] 2. Experimental Process 2.5 μL of 4X kinase solution and 2.5 μL of diluted 4X test compound solutions at different concentrations were added sequentially to a 384-well plate, with two replicate wells for each concentration, as well as a blank control group and a negative control group (DMSO) for the enzyme solution. The 384-well plate was shaken to mix the enzyme and compound, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes. 2.5 μL of 4X substrate solution was added to the 384-well plate and centrifuged at 1000 rpm for 1 minute. 2.5 μL of 4X ATP solution was added to the 384-well plate and centrifuged at 1000 rpm for 1 minute to initiate the enzyme reaction. JAK1 was incubated at room temperature for 2 hours, and JAK2 / JAK3 / Tyk2 for 1 hour. The final concentrations of JAK1 reaction components were 20 nM for JAK1, 50 nM for substrate, and 40 μM for ATP, with the final concentration range of test compounds being 10 μM–0.5 nM. The final concentrations of JAK2 / JAK3 / Tyk2 reaction components were 1 nM for JAK2, 50 nM for substrate, and 10 μM for ATP, with the final concentration range of test compounds being 10 μM–0.5 nM. After the enzyme reaction was complete, 5 μL of 4X enzyme reaction stop solution was added to each well of a 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 5 minutes. 5 μL of 4X assay antibody solution was added to each well of a 384-well plate (final assay antibody concentration: 2 nM), centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 1 hour. After antibody incubation, the signal value of each well was measured using an Envision plate reader.

[0049] 3. Data Analysis The inhibition rate for each concentration was calculated by setting the blank control group of the enzyme solution as 100% inhibition rate and the negative control group (DMSO group) as 0% inhibition rate. GraphPad Prism software performed nonlinear regression analysis on the logarithm of the concentration of the assay compound and the corresponding percent inhibition rate to obtain the half inhibitory concentration (IC50) of the assay compound. 50 The experimental results obtained with the compounds of Examples 1 to 10 are shown in Table 1 below.

[0050] [Table 1]

[0051] As can be seen from the results in Table 1 above, the compounds according to the present application have excellent enzyme activity data, and the half-maximal inhibitory concentrations measured for the specific compounds are low, especially for Tyk2. Therefore, the above experiments demonstrate that the small molecule compounds according to the present application have strong targeting properties for the JAK family and excellent enzyme activity, and can be used as Tyk2-specific inhibitors in particular.

[0052] Although the preferred embodiments of the present invention have been described in detail above, the present invention is not limited to the specific contents of the above embodiments, and various simple modifications can be made to the technical solutions of the present invention within the technical concept of the present invention, and all of these simple modifications fall within the protection scope of the present invention.

[0053] Furthermore, the various specific technical features described in the above specific embodiments may be combined in any appropriate manner unless they are inconsistent, and in order to avoid unnecessary duplication, the present invention does not separately describe the various possible combination forms.

[0054] Furthermore, any combination between various different embodiments according to the present invention is possible, and unless it is contrary to the spirit of the present invention, it should also be considered as the disclosure of the present invention.

Claims

1. A triazolopyrazine compound characterized by being a compound represented by the following formula I, a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 where: W is selected from a C5-C6 monocyclic or C8-C10 fused ring group that is an aryl or heteroaryl, unsubstituted or substituted by halogen, alkyl, cyano, amino, amido, or cycloalkyl or cyclopropylmethyl; Or, the W is 【change】 is selected from X is CH or N, and When X=CH, R is selected from halogen, C1-C5 alkyl, halogenated C1-C5 alkyl, cyano, amino, C3-C6 cycloalkyl, cyclopropylmethyl, C3-C6 heterocycloalkyl, C5-C10 aryl, C5-C10 heteroaryl, amido, or sulfonamido; When X=N, said R is selected from C1-C5 alkyl, halogenated C1-C5 alkyl, cyano, amino, C3-C6 cycloalkyl, cyclopropylmethyl, amido, or sulfonamido.

2. the halogen is F, Cl or Br; the alkyl group is a methyl, ethyl, propyl or isopropyl group, and / or The triazolopyrazine compound according to claim 1, wherein the cycloalkyl group is cyclopropyl or cyclobutyl.

3. A drug for the prevention or treatment of autoimmune diseases and related inflammatory skin diseases, the etiology of which is characterized by being related to dysregulation of JAK kinase pathway signaling, comprising the triazolopyrazine compound of claim 1 or 2.

4. The drug according to claim 3, characterized in that the autoimmune disease is selected from at least one of rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis, ankylosing spondylitis, multiple sclerosis, Behcet's disease, COVID-19 severe pneumonia, Reiter's syndrome, and uveitis.

5. 4. The method of claim 3, wherein the associated inflammatory skin disease is selected from at least one of psoriasis, autoimmune-associated vasculitis, scleroderma, dermatomyositis, acrodermatitis enteropathica, hidradenitis suppurativa, lichen planus, vitiligo, cutaneous lupus erythematosus, and lichen sclerosus.

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