Novel aromatic ring derivatives having amide substitution and uses thereof

Abstract

The present invention belongs to the field of medicine, and in particular relates to novel aromatic ring derivatives having amide substitutions or pharmaceutically acceptable salts thereof. Diseases include, but are not limited to, inflammatory or autoimmune diseases such as psoriasis, psoriatic arthritis, dermatitis, lupus erythematosus, inflammatory bowel disease, hidradenitis suppurativa, rheumatoid arthritis, and uveitis. The structure of the compound of Formula I is as set forth in the claims and the specification. The aromatic ring derivatives having amide substitutions provided by the present invention can be used as novel TYK2 inhibitors, and have good TYK2 inhibitory activity, good therapeutic effects in in vivo animal models of psoriasis and asthma, and excellent drug discoverability, high stability, and good safety.

Description

[Technical Field]

[0001] The present invention belongs to the technical field of medicinal chemistry and particularly relates to novel aromatic ring derivatives having amide substitutions and their use for the manufacture of medicaments for the treatment of diseases including, but not limited to, inflammatory or autoimmune diseases such as psoriasis, psoriatic arthritis, dermatitis, lupus erythematosus, inflammatory bowel disease, hidradenitis suppurativa, rheumatoid arthritis, and nephritis. [Background technology]

[0002] Janus kinases (JAKs) belong to a family of intracellular non-receptor tyrosine kinases that mediate the signal transduction of most cytokines within cells, including interleukins (ILs), interferons (IFNs), erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF). Because JAK family members mediate various cytokine signaling pathways, currently approved JAK inhibitors (targeting JAK1–3) inevitably cause adverse effects. Therefore, most FDA-approved JAK inhibitors carry a black box warning on their labels, significantly limiting their clinical application. While early JAK inhibitors, such as tofacitinib, have demonstrated favorable therapeutic effects, they all exhibit high inhibitory activity against JAK1, JAK2, and JAK3, resulting in significant adverse effects. The FDA requires tofacitinib to include a black box warning about the risk of thrombosis and death in its labeling. Meanwhile, other JAK inhibitors, such as upadacitinib and baricitinib, are associated with the risk of "serious infections, malignancies, and thrombosis." TYK2, a member of the JAK family, plays a key role in regulating signaling cascades downstream of IL-12, IL-23, and type I interferon receptors. IL-12 and IL-23 are currently considered important cytokines that influence psoriasis disease progression. Furthermore, TYK2-mediated signaling is also associated with various inflammatory and autoimmune diseases, including arthritis, dermatitis, lupus erythematosus, and inflammatory bowel disease. Therefore, there is a strong need for novel TYK2 inhibitors with improved efficacy and safety. Summary of the Invention

[0003] The present invention provides the following technical solutions: In a first aspect, embodiment 1: a novel aromatic ring derivative having an amide substitution, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula I: [ka] In the compounds of formula I, X and P are selected independently of each other, and: X is selected from CH, N; P is selected from C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 6-membered heteroaryl, and the substituents are selected from one or more of the following: C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, -CN; When X is N, P is as defined above; or When X is CH, P is as defined above. or a pharmaceutically acceptable salt thereof.

[0004] Embodiment 2: In a compound of Formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is selected from C1-C4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered heteroaryl containing 2-3 N, substituted or unsubstituted 6-membered heteroaryl containing 1-2 N, and the substituents are selected from one or two of the following: C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, -CN; When X is N, P is as defined above; or When X is CH, P is as defined above. 2. A compound of formula I according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0005] Embodiment 3: In a compound of Formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is tert-butyl, substituted or unsubstituted phenyl, [ka] a substituted or unsubstituted 5-membered heteroaryl selected from [ka] wherein the substituents are selected from one or two of the following: methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, cyano, fluoro, and trifluoromethyl; When X is N, P is as defined above; or When X is CH, P is as defined above. 2. A compound of formula I according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0006] Embodiment 4: In a compound of Formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is tert-butyl, substituted or unsubstituted phenyl, [ka] a substituted or unsubstituted 5-membered heteroaryl selected from [ka] and wherein the substituted or unsubstituted 6-membered heteroaryl is selected from In the case of said phenyl, the substituents are selected from one or two of the following: methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, cyano, fluoro, and trifluoromethyl; In the case of said 5-membered heteroaryl, the substituent is methyl; For said 6-membered heteroaryl, the substituents are selected from methyl or fluoro; When X is N, P is as defined above; or When X is CH, P is as defined above. 2. A compound of formula I according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0007] Embodiment 5: In a compound of Formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is tert-butyl, [ka] Selected from; When X is N, P is as defined above; or When X is CH, P is as defined above. 2. A compound of formula I according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0008] Embodiment 6: In a compound of Formula I, X and P are selected independently from each other, and: X is selected from CH or N; P is a substituted or unsubstituted phenyl, a substituted or unsubstituted 5-membered heteroaryl [ka] , Substituted or unsubstituted 6-membered heteroaryl [ka] , is selected from In the case of said phenyl, the substituents are selected from one or two of the following: methyl, fluoro; In the case of said 5-membered heteroaryl, the substituent is methyl; In the case of the six-membered heteroaryl mentioned above, the substituent is methyl; Preferably, P is [ka] Selected from; When X is N, P is as defined above; or When X is CH, P is as defined above. 2. A compound of formula I according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0009] Embodiment 7: The novel aromatic ring derivative having an amide substitution according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula I is selected from compounds 1 to 106.

[0010] Embodiment 8: The novel aromatic ring derivative with amide substitution according to embodiment 7, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from Compound 2, Compound 3, Compound 4, Compound 5, Compound 34, Compound 38, Compound 54, Compound 55, Compound 57, Compound 62, Compound 86, and Compound 91.

[0011] In a second aspect, there is provided, embodiment 9: a pharmaceutical composition, comprising a novel aromatic ring derivative having an amide substitution according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers, diluents, excipients, or adjuvants.

[0012] In a third aspect, there is provided embodiment 10: use of a novel aromatic ring derivative having an amide substitution according to any one of embodiments 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 9, in the manufacture of a medicament for the treatment of a TYK2-mediated related disease; Preferably, the disease is selected from an inflammatory disease or an autoimmune disease; More preferably, the disease is selected from psoriasis, psoriatic arthritis, dermatitis, lupus erythematosus, inflammatory bowel disease, hidradenitis suppurativa, rheumatoid arthritis, or uveitis.

[0013] Embodiment 11: A method for treating a TYK2-mediated related disease, comprising administering to a subject in need thereof the novel aromatic ring derivative having an amide substitution described in any one of Embodiments 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in Embodiment 9; Preferably, the disease is selected from an inflammatory disease or an autoimmune disease; More preferably, the disease is selected from psoriasis, psoriatic arthritis, dermatitis, lupus erythematosus, inflammatory bowel disease, hidradenitis suppurativa, rheumatoid arthritis, or uveitis.

[0014] Embodiment 12: A novel aromatic ring derivative having amide substitution according to any one of embodiments 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 9, for use in treating a TYK2-mediated related disease; Preferably, the disease is selected from an inflammatory disease or an autoimmune disease; More preferably, the disease is selected from psoriasis, psoriatic arthritis, dermatitis, lupus erythematosus, inflammatory bowel disease, hidradenitis suppurativa, rheumatoid arthritis, or uveitis.

[0015] The present invention also relates to the following embodiments. Embodiment 1A: The present invention provides novel aromatic ring derivatives having amide substitutions, or pharmaceutically acceptable salts thereof, which compounds are represented by Formula I: [ka] In the compounds of formula I, X and P are selected independently of each other, and: X is selected from CH, N; P is selected from tert-butyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 6-membered heteroaryl, and the substituents are selected from C1-6 alkyl or C3-6 cycloalkyl, halogen, —OCH3, —CF3, and —CN.

[0016] Embodiment 2A: In the compound of Formula I described in embodiment 1A, X and P are selected independently from each other, and: X is selected from CH, N; P is selected from tert-butyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered heteroaryl containing 2-3 N, and substituted or unsubstituted 6-membered heteroaryl containing 1-2 N, and the substituents are selected from C1-4 alkyl or C3-6 cycloalkyl, -F, -OCH3, -CF3, and -CN.

[0017] Embodiment 3A: A compound of Formula I according to embodiment 1A or 2A selected from compounds 1-106 below: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0018] The compounds and intermediates of the present invention may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the invention. The term "tautomers" refers to structural isomers of different energies that are interconvertible via a low energy barrier.

[0019] The pharmaceutically acceptable salts of the compounds of this invention refer to the conventional non-toxic salts formed, from pharmaceutically acceptable inorganic or organic acids.

[0020] The present invention also includes isotopically labeled compounds of the present invention similar to those described herein, except that one or more atoms have been replaced with an atom having a different atomic mass or mass number than that generally found in nature. Examples of isotopes that may be incorporated into compounds of the present invention include hydrogen ( 2 H, 3 H), carbon ( 11 C. 13 C. 14 C), nitrogen ( 13 N, 15 N), oxygen ( 15 O. 17 O. 18 O), phosphorus ( 31 P, 32 P), sulfur ( 35 S), fluorine ( 18 F), iodine ( 123 I, 125 I), and chlorine ( 36 Cl).

[0021] Additionally, deuterium (i.e. 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from increased metabolic stability and may be preferred in certain circumstances. Deuterium substitution may be partial or complete, with partial deuterium substitution meaning the replacement of at least one hydrogen with at least one deuterium, and all such forms of the compounds are encompassed within the scope of the present invention.

[0022] Embodiment 4A: The present invention further provides a pharmaceutical composition comprising a novel aromatic ring derivative having an amide substitution according to any one of Embodiments 1A to 3A, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers, diluents, excipients, or adjuvants.

[0023] Embodiment 5A: The present invention provides use of a pharmaceutical composition comprising a novel aromatic ring derivative having amide substitution as described in any one of Embodiments 1A to 3A or a pharmaceutically acceptable salt thereof, or a novel aromatic ring derivative having amide substitution as described in Embodiment 4A or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a TYK2-mediated related disease.

[0024] Embodiment 6A: The use of embodiment 5A, wherein the disease is selected from an inflammatory disease or an autoimmune disease.

[0025] Embodiment 7A: The use of embodiment 5A or 6A, wherein the disease is psoriasis, psoriatic arthritis, dermatitis, lupus erythematosus, inflammatory bowel disease, hidradenitis suppurativa, rheumatoid arthritis, or uveitis; preferably, including but not limited to psoriasis, psoriatic arthritis, atopic dermatitis, dermatomyositis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, hidradenitis suppurativa, Crohn's disease, ulcerative colitis, rheumatoid arthritis, or uveitis.

[0026] Compared with the prior art, the present invention has the following advantageous effects: As a novel TYK2 inhibitor, the aromatic ring derivative having amide substitution provided by the present invention has good TYK2 inhibitory activity, good therapeutic effects in in vivo animal models of psoriasis and asthma, and also has excellent drug discoverability, high stability, and good safety. DETAILED DESCRIPTION OF THE INVENTION

[0027] In the present invention, unless otherwise specified, the phrase "selected independently from each other..." used throughout this document may mean that specific options expressed between the same or different symbols do not affect each other in different groups, or that specific options expressed between the same or different symbols do not affect each other in the same group.

[0028] The substituents of the compounds of the present invention are disclosed according to group types or ranges. Specifically, the present invention includes each independent subcombination of each member of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, which are each independently disclosed.

[0029] Unless otherwise indicated, the above groups and substituents have their conventional meanings within the art of medicinal chemistry.

[0030] The term "C1-C6 alkyl" refers to any straight or branched chain group containing 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, etc. Similarly, "C1-C4 alkyl" refers to any straight or branched chain group containing 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0031] The terms "alkoxy" and "alkyloxy" refer to any of the above alkyl groups (e.g., C1-C6 alkyl, C1-C4 alkyl, etc.) attached to the remainder of the molecule via an oxygen atom -O-, and are exemplified by C1-C6 alkoxy, C1-C4 alkoxy, and specifically methoxy, ethoxy, etc.

[0032] The term "haloalkyl" refers to any of the above alkyl groups (e.g., C1-C6 alkyl, C1-C4 alkyl, etc.) substituted with one or more (e.g., 2 to 13 or 2 to 9) halogen atoms (e.g., fluorine, chlorine, bromine, iodine), such as trifluoromethyl, difluoromethyl, dichloromethyl, trichloromethyl, iodomethyl, bromoethyl, 1,2-dichloroethyl, etc.

[0033] The term "C3-C6 cycloalkyl" refers to a saturated hydrocarbon monovalent ring containing from 3 to 6 ring carbon atoms, and the cycloalkyl may be in the form of a single ring, fused rings, bridged rings, etc. Exemplary cycloalkyls include: [ka] Examples of the term "C3-C6 cycloalkyl" include, but are not limited to: [ka] There is.

[0034] Halogen refers to fluorine, chlorine, bromine, or iodine.

[0035] The term "6- to 10-membered aryl" refers to an aromatic 6- to 10-membered monocyclic or bicyclic group. Examples include phenyl and naphthyl, preferably phenyl.

[0036] The term "5 / 6-membered heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups having at least one heteroatom (N, O, S, or P) in at least one ring, and the heteroatom-containing ring optionally further has 1, 2, or 3 heteroatoms selected from N, O, S, or P.

[0037] Exemplary "5-membered / 6-membered heteroaryl" groups include, but are not limited to, pyrrolyl / ring, pyrazolyl / ring, imidazolyl / ring, oxazolyl / ring, isoxazolyl / ring, thiazolyl / ring, thiadiazolyl / ring, isothiazolyl / ring, furyl / ring, thienyl / ring, oxadiazolyl / ring, pyridyl / ring, pyrazinyl / ring, pyrimidinyl / ring, pyridazinyl / ring, triazinyl / ring, triazolyl / ring, pyridazinyl / ring, 2-pyridone, and the like.

[0038] The term "substituted" means optionally substituted with one or more (e.g., 2 to 9, e.g., 2, 3, 4, 5, 6, 7, 8, 9) halogen atoms, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, etc.

[0039] As used herein, "treatment" generally means obtaining a desired pharmacological and / or physiological effect. The effect may be preventative, in that a disease or its symptoms are completely or partially prevented, and / or therapeutic, in that the disease and / or its side effects are partially or completely stabilized or cured. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) preventing a disease or condition from occurring in a patient who is susceptible to the disease or condition but has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease, i.e., preventing its development, or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or condition.

[0040] In the present invention, "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the necessary dosage and for the necessary time. The "therapeutically effective amount" of a substance / molecule of the present invention may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the substance / molecule to elicit a desired response in an individual. A therapeutically effective amount also encompasses an amount effective to achieve a therapeutically beneficial effect of the substance / molecule that exceeds toxic or harmful consequences. A "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic effect at the necessary dosage and for the necessary time. Because a prophylactic dose is administered to a subject before the onset of disease or at an early stage of disease, a prophylactically effective amount is generally, although not necessarily, less than a therapeutically effective amount. In the case of cancer, a therapeutically effective amount of a drug may reduce the number of cancer cells; reduce tumor volume; inhibit (i.e., slow to some extent, and preferably stop) cancer cell invasion into peripheral organs; inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more symptoms associated with cancer.

[0041] In the present invention, a "subject" refers to a vertebrate. In some embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cows), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, a mammal refers to a human.

[0042] The pharmaceutical composition of the present invention can be prepared in various forms for various administration routes. For example, the pharmaceutical composition can be administered orally, by aerosol inhalation, rectally, nasally, intravaginally, topically, parenterally, for example, by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or via an implanted reservoir. Among these, topical administration is preferred.

[0043] The compounds described in the present invention can optionally be used in combination with one or more other active ingredients, the amounts and ratios of each of which can be adjusted by those skilled in the art according to the particular disease, the condition of the patient, and the clinical needs.

[0044] As used herein, the term "pharmaceutically acceptable salts" refers to (i) salts formed between an acidic functional group present in a compound provided by the present invention and a suitable inorganic or organic cation (base), including, but not limited to, alkali metal salts such as sodium, potassium, lithium, and the like; alkaline earth metal salts such as calcium, magnesium, and the like; other metal salts such as aluminum, iron, zinc, copper, nickel, and cobalt salts; inorganic base salts such as ammonium salts; and organic base salts such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, and tris(hydroxymethyl)aminomethane salts. and (ii) salts formed by alkaline functional groups present in the compounds provided by the present invention with suitable inorganic or organic anions (acids), including, but not limited to, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.; arylsulfonates such as benzenesulfonate, parabenzenesulfonate, etc.; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.; and amino acid salts such as glycinate, trimethylglycinate, arginate, ornithine, glutamate, aspartate, etc.

[0045] The embodiments of the present invention will be described in detail with reference to examples. However, it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention. Unless specific conditions are specified, the examples are carried out under conventional conditions. All reagents and equipment used without a specified manufacturer are commercially available conventional products.

[0046] The structures of the compounds of the present invention were determined by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). LC-MS determination was performed using an AB Sciex TripleTOF 4600 mass spectrometer and a Shimadzu LC-20AD XR high-performance liquid chromatograph, with an Agela Venusil MP C18 (2.1x50, 3µm) chromatography column. NMR measurements were performed using a BRUKER AVANCE NEO 400MHz nuclear magnetic resonance spectrometer.

[0047] Unless otherwise specified, all reactions of this invention were carried out under dry nitrogen or argon and continuous magnetic stirring, solvents were pre-dried solvents, and reaction temperatures are in degrees Celsius.

[0048] Example 1 6-(Cyclopropanamido)-4-(2-methoxy-3-(benzoylanilino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] Step 1 [ka] 2-Methoxy-3-nitrobenzoic acid (1.0 g, 5.1 mmol) was added to thionyl chloride (15.0 g) and heated under reflux with stirring until completion was detected by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 5 mL of acetone and added dropwise to a solution of aniline (0.4 g, 4.6 mmol) and triethylamine (1.0 g, 10.2 mmol) in 10 mL of acetone, controlling the temperature below 10 °C. After the addition was complete, the resulting solution was reacted at room temperature until completion was detected by TLC. 50 mL of water was added, filtered, and dried at room temperature for 24 hours to give 2-methoxy-3-nitro-N-benzoylaniline (1.1 g, 71.9%). MS m / z (ESI): 273.08 [M + H] + .

[0049] Step 2 [ka] 2-Methoxy-3-nitro-N-benzoylaniline (1.0 g, 3.7 mmol) and 10% Pd / C (0.15 g) were added to 30 mL of methanol, and hydrogen was charged. The resulting solution was reacted under a hydrogen atmosphere at 25° C. until completion was detected by TLC. The reaction solution was filtered, and the filtrate was evaporated to dryness to give 3-amino-2-methoxy-N-benzoylaniline (0.81 g, 91.0%). MS m / z(ESI):243.11[M+H] + .

[0050] Step 3 [ka] To a solution of 3-amino-2-methoxy-N-benzoylaniline (0.8 g, 3.3 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (0.68 g, 3.3 mmol) in tetrahydrofuran (THF) (5 mL) at room temperature, a solution of bis(trimethylsilyl)aminolithium (1 M, 9.9 mL, 9.9 mmol) in THF was added dropwise. The resulting solution was reacted at room temperature until completion was detected by TLC. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 6-chloro-4-((2-methoxy-3-(benzoylanilino)-N-(methyl-d3)pyridazine-3-carboxamide) (0.89 g, 55%). MS m / z(ESI):415.81[M+H] + .

[0051] Step 4 [ka] 6-chloro-4-((2-methoxy-3-(benzoylanilino)-N-(methyl-d3)pyridazine-3-carboxamide (0.8 g, 1.9 mmol), cyclopropanecarboxamide (0.16 g, 1.9 mmol), tri(dibenzylideneacetone)dipalladium (0.1 g, 0.1 mmol), 4,5-diphenylphosphine-9,9-dimethyloxaanthracene (0.12 g, 0.2 mmol), and cesium carbonate (1.27 g, 3.9 mmol) were dissolved in 1 mL of 10 ... The mixture was added to 4-dioxane (10 mL) and heated under reflux until completion was detected by TLC. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 6-(cyclopropanamido)-4-(2-methoxy-3-(benzoylanilino)-N-(methyl-d3)pyridazine-3-carboxamide (0.43 g, 48%). MS m / z(ESI):464.20[M+H] + . 1 H-NMR(DMSO-d6)б:11.34(1H,s), 10.34(1H,s), 9.14(1H,s), 8.16(1H,s), 7.73-7.71(2H,m), 7.58-7 .56(1H,m), 7.35-7.26(5H,m), 7.11-7.07(1H,m), 3.74(3H,s), 2.08-2.06(1H,m), 0.83-0.81(4H,m).

[0052] Example 2 [ka] Compound 2 was obtained by using the synthesis method of Example 1 as a reference, but using 4-methylaniline instead of aniline in Step 1. MS m / z(ESI):478.22[M+H] + . 1 H-NMR(DMSO-d6)б:11.34(1H,s), 10.97(1H,s), 10.25(1H,s), 9.14(1H,s), 8.16(1H,s), 7.55-7.62(3H,m ), 7.25-7.34(2H,m), 7.13-7.15(2H,m), 3.76(3H,s), 2.26(3H,m), 2.07-2.09(1H,m), 0.81-0.83(4H,m).

[0053] Example 3 [ka] Compound 3 was obtained by using the synthesis method of Example 1 as a reference, but using 3-methylaniline instead of aniline in Step 1. MS m / z(ESI):478.22[M+H] + . 1H-NMR(DMSO-d6)б:11.34(1H,s), 10.97(1H,s), 10.25(1H,s), 9.14(1H,s), 8.16(1H,s), 7.55-7.62(3H,m ), 7.25-7.34(2H,m), 7.13-7.15(2H,m), 3.74(3H,s), 2.26(3H,m), 2.07-2.09(1H,m), 0.81-0.83(4H,m).

[0054] Example 4 [ka] Compound 4 was obtained by using the synthesis method of Example 1 as a reference, but using 3,4-dimethylaniline instead of aniline in Step 1. MS m / z(ESI):492.21[M+H] + . 1 H-NMR(DMSO-d6)б:11.34(1H,s), 10.97(1H,s), 10.17(1H,s), 9.14(1H,s), 8.16(1H,s), 7.55-7.57(1H,m), 7.50-7.51(1H,m), 7.41-7.44(1H,m), 7.25-7.34(2H,m), 7.07-7.09(1H,m), 3.75(3H,s), 2.17-2.20(6H,m), 2.06-2.09(1H,m), 0.81-0.83(4H,m).

[0055] Example 5 [ka] Compound 5 was obtained by using the synthesis method of Example 1 as a reference, but using 4-fluoroaniline instead of aniline in Step 1. MS m / z(ESI):482.20[M+H] + . 1H-NMR(DMSO-d6)б:11.34(1H,s), 10.98(1H,s), 10.41(1H,s), 9.14(1H,s), 8.16(1H,s), 7.77-7 .73(2H,m), 7.65-7.56(1H,m), 7.53-7.04(4H,m), 3.74(3H,s), 2.08-2.06(1H,m), 0.83(4H,d).

[0056] (Examples 6 to 32) By referring to the synthesis method of Example 1, the aniline in Step 1 was substituted accordingly to obtain the compounds having the structures shown in the table below. [Table 1] JPEG2026501357000030.jpg199170JPEG2026501357000031.jpg219170JPEG2026501357000032.jpg112170

[0057] Example 33 6-(Cyclopropanecarboxamido)-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. [ka] Step 1 [ka] 2-Methoxy-3-nitrobenzoic acid (1.0 g, 5.1 mmol) was added to thionyl chloride (15.0 g) and heated under reflux with stirring until completion was detected by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 5 mL of acetone and added dropwise to a solution of 1-methyl-1H-pyrazol-3-amine (0.4 g, 4.1 mmol) and triethylamine (1.0 g, 10.2 mmol) in 10 mL of acetone, controlling the temperature below 10 °C. After the addition was complete, the resulting solution was reacted at room temperature until completion was detected by TLC. 50 mL of water was added, filtered, and dried at room temperature for 24 hours to give 2-methoxy-N-(1-methyl-1H-pyrazol-3-yl)-3-nitrobenzamide (1.0 g, 71.4%). MS m / z(ESI):277.09[M+H] + .

[0058] Step 2 [ka] 2-Methoxy-N-(1-methyl-1H-pyrazol-3-yl)-3-nitrobenzamide (0.9 g, 3.2 mmol) and 10% Pd / C (0.15 g) were added to 30 mL of methanol, and the resulting solution was reacted under a hydrogen atmosphere at 25° C. until completion was detected by TLC. The reaction was filtered, and the filtrate was evaporated to dryness to give 3-amino-2-methoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.71 g, 88.8%). MS m / z(ESI):247.10[M+H] + .

[0059] Step 3 [ka] To a solution of 3-amino-2-methoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.7 g, 2.8 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (0.58 g, 2.8 mmol) in THF (5 mL) was added dropwise a solution of bis(trimethylsilyl)aminolithium (1 M, 8.4 mL, 8.4 mmol) in THF at room temperature. The resulting solution was reacted at room temperature until completion was detected by TLC. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 6-chloro-4-((2-methoxy-3-((1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)amino)-N-(methyl-d3)pyridazine (0.59 g, 49.6%). MS m / z(ESI):419.14[M+H] + .

[0060] Step 4 [ka] 6-Chloro-4-((2-methoxy-3-((1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.5 g, 1.2 mmol), cyclopropanecarboxamide (0.10 g, 1.2 mmol), tri(dibenzylideneacetone)dipalladium (0.1 g, 0.1 mmol), 4,5-diphenylphosphine-9,9-dimethyloxaanthracene (0.12 g, 0.2 mmol), and cesium carbonate (1.27 g, 3.9 mmol) were added to 1,4-dioxane (10 mL) and heated under reflux until completion was detected by TLC. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 6-(cyclopropanecarboxamido)-4-(2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.33 g, 59.1%). MS m / z(ESI):468.22[M+H] + . 1 H-NMR(DMSO-d6)б:11.3(1H,s), 10.93(1H,s), 10.57(1H,s), 9.14(1H,s), 8.13(1H,s), 7.60-7.54(2H,m), 7.3 8-7.35(1H,m), 7.28-7.24(1H,m), 6.57-6.56(1H,m), 3,75-3.72(6H,m), 2.07-2.05(1H,m), 0.82-0.80(4H,m).

[0061] Example 34 [ka] Compound 34 was obtained by using the synthesis method of Example 33 as a reference, except that 1-methyl-1H-pyrazol-4-amine was used instead of 1-methyl-1H-pyrazol-3-amine in Step 1. MS m / z(ESI):468.22[M+H] + . 1 H-NMR(DMSO-d6)δ:11.34(1H,s), 10.98(1H,s), 10.35(1H,s), 9.14(1H,s), 8.15(1H,s), 8.00(1H,s), 7.55-7.57(1H,m ), 7.50(1H,s), 7.31-7.33(1H,m), 7.24-7.28(1H,m), 3.80(3H,s), 3.71(3H,s), 2.06-2.08(1H,m), 0.80-0.83(4H,m).

[0062] (Examples 35 to 36) Referring to the synthesis method of Example 33, 1-methyl-1H-pyrazol-3-amine in Step 1 was substituted accordingly to give the compounds with the structures shown in the table below. [Table 2]

[0063] Example 37 6-(Cyclopropanecarboxamido)-4-(2-methoxy-3-(4-methylpyridin-2-yl)carbamoyl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. [ka] Step 1 [ka] 2-Methoxy-3-nitrobenzoic acid (1.0 g, 5.1 mmol) was added to thionyl chloride (15.0 g) and heated under reflux with stirring until completion was detected by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 5 mL of acetone and added dropwise to a solution of 4-methylpyridin-2-amine (0.5 g, 4.6 mmol) and triethylamine (1.0 g, 10.2 mmol) in 10 mL of acetone, controlling the temperature below 10 °C. After the addition was complete, the resulting solution was reacted at room temperature until completion was detected by TLC. 50 mL of water was added, filtered, and dried at room temperature for 24 hours to give 2-methoxy-N-(4-methylpyridin-2-yl)-3-nitrobenzamide (1.2 g, 82.3%). MS m / z(ESI):288.12[M+H] + .

[0064] Step 2 [ka] 2-Methoxy-N-(4-methylpyridin-2-yl)-3-nitrobenzamide (1.1 g, 3.8 mmol) and 10% Pd / C (0.15 g) were added to 30 mL of methanol, and the resulting solution was reacted under a hydrogen atmosphere at 25° C. until completion was detected by TLC. The reaction was filtered, and the filtrate was evaporated to dryness to give 3-amino-2-methoxy-N-(4-methylpyridin-2-yl)benzamide (0.92 g, 93.4%). MS m / z(ESI):258.13[M+H] + .

[0065] Step 3 [ka] To a solution of 3-amino-2-methoxy-N-(4-methylpyridin-2-yl)benzamide (0.9 g, 3.5 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (0.72 g, 3.5 mmol) in THF (5 mL) was added dropwise a solution of bis(trimethylsilyl)aminolithium (1 M, 10.5 mL, 10.5 mmol) in THF at room temperature. The resulting solution was allowed to react at room temperature until completion was detected by TLC. The reaction solution was diluted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 6-chloro-4-((2-methoxy-3-((4-methylpyridin-2-yl)carbamoyl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.88 g, 58%). MS m / z(ESI):430.03[M+H] + .

[0066] Step 4 [ka] 6-Chloro-4-((2-methoxy-3-((4-methylpyridin-2-yl)carbamoyl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.8 g, 1.8 mmol), cyclopropanecarboxamide (0.15 g, 1.8 mmol), tri(dibenzylideneacetone)dipalladium (0.1 g, 0.1 mmol), 4,5-diphenylphosphine-9,9-dimethyloxaanthracene (0.12 g, 0.2 mmol), and cesium carbonate (1.27 g, 3.9 mmol) were added to 1,4-dioxane (10 mL) and heated under reflux until completion was detected by TLC. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 6-(cyclopropanecarboxamido)-4-(2-methoxy-3-(4-methylpyridin-2-yl)carbamoyl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.42 g, 47%). MS m / z(ESI):479.24[M+H] + . 1 H-NMR(DMSO-d6)б:11.34(1H,s), 10.96(1H,s), 10.58(1H,s), 9.15(1H,s), 8.20-8.08(3H,m), 7.62-7.59(1 H,m), 7.50-7.48(2H,m), 7.32-7.29(1H,m), 3,75(3H,s), 2.30(3H,s), 2.07-2.05(1H,m), 0.81-0.79(4H,m).

[0067] Example 38 [ka] Compound 38 was obtained by using the synthesis method of Example 37 as a reference, except that 5-methylpyridin-3-amine was used instead of 4-methylpyridin-2-amine in Step 1. MS m / z(ESI):479.24[M+H] + . 1H-NMR(DMSO-d6)δ:11.35(1H,s), 10.99(1H,s), 10.51(1H,s), 9.15(1H,s), 8.65(1H,s), 8.15-8.16(2H,m), 8.0 3(1H,s), 7.58-7.61(1H,m), 7.28-7.37(2H,m), 3.75(3H,s), 2.30(3H,s), 2.07-2.08(1H,m), 0.81-0.83(4H,m).

[0068] (Examples 39 to 52, 105) Referring to the synthesis method of Example 37, 4-methylpyridin-2-amine in Step 1 was substituted accordingly to give the compounds with the structures shown in the table below.

[0069] [Table 3] JPEG2026501357000047.jpg199170JPEG2026501357000048.jpg148170

[0070] Example 57 6-(cyclopropanecarboxamido)-4-((3-((4-fluorophenyl)carbamoyl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide [ka] Step 1 [ka] 2-Methoxy-3-nitrobenzoic acid (1.0 g, 5.1 mmol) was added to thionyl chloride (15.0 g) and heated under reflux with stirring until completion was detected by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 5 mL of acetone and added dropwise to a solution of 4-fluoroaniline (0.5 g, 4.5 mmol) and triethylamine (1.0 g, 10.2 mmol) in 10 mL of acetone, controlling the temperature below 10 °C. After the addition was complete, the resulting solution was reacted at room temperature until completion was detected by TLC. 50 mL of water was added, filtered, and dried at room temperature for 24 hours to give N-(4-fluorophenyl)-2-methoxy-3-nitrobenzamide (1.1 g, 74.8%). MS m / z(ESI):291.38[M+H] + .

[0071] Step 2 [ka] N-(4-fluorophenyl)-2-methoxy-3-nitrobenzamide (1.0 g, 3.4 mmol) and 10% Pd / C (0.15 g) were added to 30 mL of methanol, and the resulting solution was reacted under a hydrogen atmosphere at 25° C. until completion was detected by TLC. The reaction was filtered, and the filtrate was evaporated to dryness to give 3-amino-N-(4-fluorophenyl)-2-methoxybenzamide (0.82 g, 91.4%). MS m / z (ESI): 261.02 [M + H] + .

[0072] Step 3 [ka] To a solution of 3-amino-N-(4-fluorophenyl)-2-methoxybenzamide (0.8 g, 3.1 mmol) and 4,6-dichloro-N-(methyl-d3)pyridine-3-carboxamide (0.64 g, 3.1 mmol) in THF (5 mL) was added dropwise a solution of bis(trimethylsilyl)aminolithium (1 M, 9.3 mL, 9.3 mmol) in THF at room temperature. The resulting solution was allowed to react at room temperature until completion was detected by TLC. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 6-chloro-4-((3-((4-fluorophenyl)carbamoyl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide (0.92 g, 69.3%). MS m / z(ESI):432.06[M+H] + .

[0073] Step 4 [ka] 6-Chloro-4-((3-((4-fluorophenyl)carbamoyl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide (0.9 g, 2.0 mmol), cyclopropanecarboxamide (0.17 g, 2.0 mmol), tri(dibenzylideneacetone)dipalladium (0.1 g, 0.1 mmol), 4,5-diphenylphosphine-9,9-dimethyloxaanthracene (0.12 g, 0.2 mmol), and cesium carbonate (1.27 g, 3.9 mmol) were added to 1,4-dioxane (10 mL) and heated under reflux until completion was detected by TLC. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated by column chromatography to give 6-(cyclopropanecarboxamido)-4-((3-((4-fluorophenyl)carbamoyl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide (0.42 g, 42%). MS m / z(ESI):481.16[M+H] + . 1 H-NMR(DMSO-d6)б:10.78(1H,s), 10.69(1H,s), 10.39(1H,s), 8.59(1H,s), 8.52(1H,s), 8.05(1H,s), 7.77-7.73(2H,m), 7.56-7.53(1H,m), 7.27-7.16(4H,m), 3.73(3H,s), 2.00-1.94(1H,m), 0.77(4H,m).

[0074] Using the synthesis method of Example 57 as a reference, 4-fluoroaniline in Step 1 was substituted accordingly to give compounds with the structures shown in the table below.

[0075] [Table 4] JPEG2026501357000055.jpg199170JPEG2026501357000056.jpg204170JPEG2026501357000057.jpg199170JPEG2026501357 000058.jpg209170JPEG2026501357000059.jpg209170JPEG2026501357000060.jpg204170JPEG2026501357000061.jpg56170

[0076] BMS-986165 was prepared according to Chinese Patent Application Publication No. 201380069692.9 and has the following specific structure: [ka]

[0077] Biological assays The present invention will now be further described and explained with reference to the following test examples, which should not be construed as limiting the scope of the invention.

[0078] Test Example 1: In vitro cell inhibition assay The inhibitory effect of the compounds of formula (I) according to the present invention on the intracellular TYK2 signaling pathway was evaluated using the following method. Equipment used: SpectraMax Paradigm reader. Methods: In this experiment, the cell growth inhibitory activity of compounds was evaluated by measuring their effects on cell activity in vitro using the TYK2-expressing Ba / F3 cell line. Procedure: CellTiter-Glo buffer was thawed and allowed to warm to room temperature. CellTiter-Glo substrate was allowed to warm to room temperature and dissolved in buffer to prepare CellTiter-Glo standard solution. 98 μL of cell culture medium and 2 μL of gradient diluted compound solution were added to a 96-well flat-bottom clear drug plate. After allowing the drug plate to stand for 10 minutes, 50 μL of CellTiter-Glo standard solution was added. The drug plate was then shaken on an orbital shaker for 2 minutes and allowed to stand at room temperature for an additional 10 minutes. Finally, the luminescence signal was measured using a SpectraMax Paradigm reader. Data analysis: Cell growth inhibition rate data was processed using the following formula: Inhibition rate (Inh%) = 100 - (RLUDrug - RLUMin) / (RLUMax - RLUMin) × 100%. The inhibition rates of various concentrations of compounds were calculated using EXCEL, and the inhibition rate curves were plotted using GraphPad Prism software to calculate the maximum and minimum cell inhibition rates, IC 50 The relevant parameters such as the value were calculated. The inhibitory activities of the compounds obtained by the above method were as follows:

[0079] [Table 5] TIFF2026501357000064.tif72170Note: A is 1nM <IC 50 <5nM, B is 5nM <IC 50 <10 nM.

[0080] Conclusion: The compounds according to the present invention have significant inhibitory effects on the TYK2 signaling pathway in cells.

[0081] Test Example 2: hERG potassium channel inhibition assay Equipment used: HEKA EPC10 patch clamp amplifier. Methods: In this experiment, the blocking effect of compounds on the current of HEK-293 cell lines stably expressing the hERG channel was measured using the manual patch clamp technique, and the risk of compounds to inhibit the cardiac hERG potassium channel was assessed by fitting concentration-effect relationships.

[0082] Equipment used: SpectraMax Paradigm reader. Methods: In this study, the cardiotoxicity of compounds was evaluated by measuring their inhibitory effects on cellular activity in vitro using expressing cell lines. Procedure: For patch clamp recording, a glass capillary tube was first pulled into the recording electrode using a microelectrode puller. The electrode, filled with intracellular solution, was then attached to the microelectrode holder. Using a microelectrode manipulator under an inverted microscope, the electrode was immersed in the extracellular solution and the electrode resistance (Rpip) was recorded. The electrode was then slowly brought into contact with the cell surface and suctioned by applying negative pressure, forming a GΩ seal. At this point, fast capacitance compensation was performed, and continuous negative pressure was applied to suction and rupture the cell membrane, forming a whole-cell recording mode. Finally, slow capacitance compensation was performed, and experimental parameters, including series resistance (Rs), were recorded. No leak compensation was performed. Drug administration began once the hERG current recorded from the whole cell stabilized. Each drug concentration was allowed to act for approximately 5 minutes (or until the current stabilized) before recording the next concentration. The coverslip with attached cells was placed in a recording chamber under an inverted microscope. A blank control extracellular solution and standard solutions of the test compounds were perfused into the recording chamber using gravity perfusion, with solutions exchanged using a peristaltic pump during recording. Currents measured in each cell in compound-free extracellular solution served as the respective control group. Each concentration was evaluated independently twice. All electrophysiological experiments were performed at room temperature. Data analysis: First, tail current after each drug concentration

number

number

number

[0083] Test Example 3: Kinase selectivity profiling 3.1 In vitro JAK1-3 / TYK2 JH1 enzyme binding assay Equipment used: Envision microplate reader (PerkinElmer), ECHO550 (LABCYTE). Methods: In this experiment, the inhibitory effects of compounds on JAK1-3 / TYK2 JH1 kinase were tested using time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Procedure: Compounds were prepared in DMSO to a 10 mM stock solution, which was then further diluted with DMSO to form compound dilutions with various concentrations. The 100x compound dilutions were then transferred to a 384-well assay plate using the Echo instrument. For this experiment, the assay buffer, SEB, TK-Substrate biotin, and detection reagents were all included in the TK kit (Cisbio, catalog number: 62TK0PEC). Three 1x assay standard solutions were prepared: 1. JAK1 JH1 assay standard solution: 1x assay buffer, 5mM MgCl2, 0.625mM EGTA, 60nM SEB, 0.01% Brij-35, and 1mM DTT. 2. JAK2-3 JH1 assay standard solution: 1x assay buffer, 5mM MgCl2, and 1mM DTT. 3. TYK2 JH1 assay standard solution: 1x assay buffer, 5mM MgCl2, 1mM MnCl2, 12.5nM SEB, and 1mM DTT. 2x JAK1-3 / TYK2 JH1 kinase and 2x TK-Substrate biotin substrates were prepared using their respective 1x standard solutions. Five microliters of JAK1-3 / TYK2 JH1 kinase was added to a 384-well assay plate, centrifuged at 1000 rpm for 30 seconds, and then incubated at room temperature for 15 minutes. Five microliters of TK-Substrate biotin substrate was added to the 384-well assay plate, centrifuged at 1000 rpm for 30 seconds, and then incubated at room temperature for 45 minutes for JAK1-2 JH1 and 60 minutes for JAK3 / TYK2 JH1. Ten microliters of the prepared 2x detection reagent was added to the 384-well assay plate, centrifuged at 1000 rpm for 30 seconds, and then incubated at room temperature for 60 minutes for JAK1-2 JH1 and 120 minutes for JAK3 / TYK2 JH1, followed by overnight incubation at 4°C. Finally, the 665 nm / 615 nm fluorescence signal ratio was measured using an Envision microplate reader (PerkinElmer). Data analysis: XLfit, a software developed by IDBS and integrated into the Microsoft Excel environment, was used to process and analyze the test data. First, the average response signals of the high-signal control wells and the low-signal control wells were calculated separately. Then, the reaction inhibition rate of each compound well was calculated according to the formula: "Single-well inhibition rate % = 100% - (mean value of high-signal control group - single-well signal value) / (mean value of high-signal control group - mean value of low-signal control group) × 100%." ​​The concentration and corresponding inhibition rate data were then imported into XLfit software, and the Dose Response One Site 205 model in the software was used to fit the inhibition rate-concentration curve with a four-parameter method to obtain the IC value of the compound. 50 The value was calculated.

[0084] 3.2 In vitro JAK1 JH2 enzyme binding assay Equipment used: Envision microplate reader (PerkinElmer), Echo (LABCYTE). Methods: In this experiment, the inhibitory effects of compounds on JAK1 JH2 pseudokinase were tested using time-resolved fluorescence resonance energy transfer (TR-FRET) techniques. Procedure: Compounds were prepared in DMSO to a 10 mM stock solution, which was then further diluted with DMSO to form compound dilutions with various concentrations. The compound dilutions were transferred to a 384-well assay plate using the Echo instrument to a final concentration of 200x. The following 1x assay standard solutions were prepared: 20 mM HEPES pH 7.5, 10 mM MgCl2, 0.015% Brij-35, 2 mM DTT, and 50 μg / mL BSA. The JAK1 JH2 pseudokinase, Tb antibody, and tracer were each prepared at a final concentration of 3x using the 1x standard solutions. 5 μL of JAK1 JH2 pseudokinase was added to a 384-well assay plate and centrifuged at 1000 rpm for 30 seconds. 5 μL of Tb antibody was added to a 384-well assay plate and centrifuged at 1000 rpm for 30 seconds. Five microliters of tracer was added to a 384-well assay plate and centrifuged at 1000 rpm for 30 seconds. Incubation was carried out at room temperature for 60 minutes, followed by overnight at 4°C. Finally, the fluorescence signal ratio at 495 nm / 520 nm was measured using an Envision microplate reader (PerkinElmer). Data analysis: XLfit, a software developed by IDBS and integrated into the Microsoft Excel environment, was used to process and analyze the test data. First, the average response signals of the high-signal control wells and the low-signal control wells were calculated separately. Then, the reaction inhibition rate of each compound well was calculated according to the formula: "Single-well inhibition rate % = 100% - (mean value of high-signal control group - single-well signal value) / (mean value of high-signal control group - mean value of low-signal control group) × 100%." ​​The concentration and corresponding inhibition rate data were then imported into XLfit software, and the Dose Response One Site 205 model in the software was used to fit the inhibition rate-concentration curve with a four-parameter method to obtain the IC value of the compound. 50 The value was calculated.

[0085] 3.3 In vitro TYK2 JH2 enzyme binding assay Equipment used: Envision microplate reader (PerkinElmer), ECHO550 (LABCYTE). Methods: The inhibitory effects of compounds on TYK2 JH2 pseudokinase were tested using time-resolved fluorescence resonance energy transfer (TR-FRET) method. Procedure: Compounds were prepared at 10 mM stock solutions in DMSO, which were then further diluted with DMSO to create compound dilutions (200x) with varying concentrations. The compound dilutions (200x) were then transferred to a 384-well assay plate using the Echo instrument. A dilution buffer (20 mM HEPES pH 7.5, 10 mM MgCl2, 0.015% Brij-35, 2 mM DTT, and 50 μg / mL BSA) was prepared. TYK2 JH2 pseudokinase, Tb antibody, and tracer standard solutions were prepared using the dilution buffer. 5 μL of the TYK2 JH2 pseudokinase standard solution (final concentration 0.5 nM) was added to a 384-well assay plate and centrifuged at 1000 rpm for 30 seconds. 5 μL of the Tb antibody (final concentration 1x) was added to a 384-well assay plate and centrifuged at 1000 rpm for 30 seconds. Five microliters of tracer (final concentration 0.5 nM) was added to a 384-well assay plate and centrifuged at 1000 rpm for 30 seconds. Incubation was carried out at room temperature for 60 minutes, followed by overnight at 4°C. Finally, the fluorescence signal ratio at 495 nm / 520 nm was measured using an Envision microplate reader (PerkinElmer). Data analysis: XLfit, a software developed by IDBS and integrated into the Microsoft Excel environment, was used to process and analyze the test data. First, the mean reaction signals of the high-signal control group and the low-signal control group were calculated separately. Then, the reaction inhibition rate of each compound well was calculated according to the formula: "Single-well inhibition rate % = 100% - (mean value of high-signal control group - single-well signal value) / (mean value of high-signal control group - mean value of low-signal control group) × 100%." ​​The concentration and corresponding inhibition rate data were then imported into XLfit software, and the Dose Response One Site 205 model in the software was used to fit the inhibition rate-concentration curve with a four-parameter method to obtain the IC value of the compound. 50 The value was calculated.

[0086] [Table 6]

[0087] Conclusion: The selectivity level of the compounds according to the present invention against the JH1 target of JAK1-3 / TYK2 is comparable to that of BMS-986165, and neither exhibits inhibitory activity. Furthermore, their inhibitory activity against JAK1 JH2 is significantly reduced compared to BMS-986165. The compounds according to the present invention have good selectivity against TYK2 JH2 and low off-target effects.

[0088] Test Example 4: In vivo efficacy: imiquimod-induced psoriasis-like mouse model The efficacy of compounds according to the invention in an imiquimod-induced mouse psoriasis-like model can be evaluated using the following method. Sample preparation: Based on the preparation of commercially available Benvitimod cream, the compound (the compound of Example 3), oil phase (hexadecanol, petrolatum, liquid paraffin, glyceryl mono- and distearate), water phase (propylene glycol, Tween 80, and water), and appropriate additives (ethylparaben) were mixed and subjected to a vacuum emulsifier to prepare a 1% cream sample. The test site on the back of the mouse was shaved and cut into a 2 x 3 cm 2 An area of ​​1000 mm was exposed. Imiquimod ointment was applied to the dorsal skin of mice for six consecutive days to establish a mouse psoriasis model. From day 1 to day 6, it was administered to different groups of mice according to the experimental protocol. The experimental design of the imiquimod-induced mouse psoriasis-like model is shown in the table below.

[0089] [Table 7]

[0090] On the 7th day, the severity of dermatitis was evaluated and scored on a 5-point scale (0-4) (PASI score). Skin thickness: 0: The skin was smooth and wrinkle-free; 1: There were slight wrinkles on the skin at the edge of the drug application site; 2: There were slight wrinkles all over the skin at the drug application site; 3: The degree of wrinkles at the drug application site was more severe; 4: In addition to a score of 3, the mouse's condition included weight loss or poor condition. Crust: 0: The skin was smooth and free of scale; 1: There was slight scaling on the skin at the application site; 2: The skin at the application site was completely covered with scale; 3: The degree of scaling at the application site was more severe; 4: In addition to a score of 3, the condition of the mouse was observed, such as weight loss or poor condition. Erythema: 0: The skin was smooth; 1: There was slight redness of the skin at the drug application site; 2: The skin at the drug application site was completely red; 3: The redness at the drug application site was more severe; 4: In addition to a score of 3, the mouse's condition included weight loss or poor condition.

[0091] A comparison of the PASI scores of various compounds in the imiquimod-induced mouse psoriasis-like model is shown in the table below.

[0092] [Table 8] Note: Compared with the model group, *** P<0.001, **P<0.01, data represent the mean PASI score within the group.

[0093] Conclusion: The compound of Example 3 effectively improved psoriasis symptoms in an imiquimod-induced mouse psoriasis-like model with a significant difference (P<0.001) compared to the model group, and showed superior efficacy compared to Benvitimod cream and BMS-986165. Compounds such as Examples 2, 4, 5, 34, 38, 54, 55, 57, 62, 86, and 91 showed similar pharmacological effects to the compound of Example 3, and therefore are not described in detail here for brevity.

[0094] In an imiquimod-induced mouse psoriasis-like model, compounds such as Examples 2, 3, 4, 5, 34, 38, 54, 55, 57, 62, 86, and 91 can effectively improve psoriasis symptoms by oral administration (gavage oral administration, 10 mg / kg, 25 mg / kg, 50 mg / kg, twice daily) with significant differences compared to the model group. Pharmacodynamic studies have shown that there are some differences in the antipsoriatic efficacy of the same compound when administered orally versus topically.

[0095] Test Example 5: In vivo mouse asthma model The efficacy of compounds according to the invention in an OVA-induced mouse asthma model can be assessed using the following method.

[0096] 5.1 Preparation of test samples Test sample: The compound of Example 3 was accurately weighed and dissolved in DMSO to prepare a solution with a concentration of 2 mg / mL.

[0097] 5.2 Model Preparation Thirty female BALB / c mice were bred for the adaptive control group. After one week, 10 mice were randomly selected as blank controls, and 20 mice were used as asthma models. The model mice were intraperitoneally injected with 0.2 mL of a sensitizing solution on days 0, 7, and 14 for sensitization. The sensitizing solution contained 50 μg of OVA and 2 mg of Al(OH)3. The blank control group received the same volume of saline. From the 21st to the 23rd day after sensitization, mice in the model group and the treatment group were stimulated by spraying 5% OVA for 30 minutes, and mice in the blank control group were stimulated by spraying saline for the same period.

[0098] 5.3 Group Assignment and Dosing 30 minutes before stimulation of the mice every day, 50 μL of saline was administered intratracheally to the mice in the blank control group and model group, and 50 μL of the corresponding drug was administered intratracheally to the mice in the Example 3 compound group once a day for three consecutive days. The animal groups and dosages are as shown in the table below.

[0099] [Table 9]

[0100] 5.4 Airway hyperresponsiveness (AHR) measurement After the final challenge, airway hyperresponsiveness was measured in each mouse group. Mice were placed in a whole-body plethysmograph. After recording baseline enhanced pause (Ph) values, mice were challenged with methacholine nebulization. Methacholine concentrations ranged from low to high: 0, 6.25, and 12.5 mg / mL. Each nebulization was 100 μL for 60 seconds. After each nebulization, mice were observed for signs of hypoxia, such as difficulty breathing, head scratching, or restlessness. Penh values ​​were recorded for 3 minutes, and the average values ​​were used to compare AHRs between each mouse group.

[0101] 5.5 Detection of inflammatory cells in bronchoalveolar lavage fluid After measuring airway hyperresponsiveness, mice were euthanized by cervical dislocation and fixed on a dissection tray. The mouse's abdomen and thoracic cavity were opened, and the neck skin and excess tissue were removed to expose the mouse trachea. A small incision was made in the transverse axis of the trachea with small scissors, and a 1 mL syringe needle was inserted and secured with surgical suture. 0.5 mL of pre-cooled phosphate buffer solution (PBS) was aspirated with a 1 mL syringe and slowly injected into the mouse lungs, then slowly withdrawn. Each mouse was lavaged once, and a total of approximately 0.4 mL of lavage fluid was collected. The number of inflammatory cells in the bronchoalveolar lavage fluid was measured using a cell counter.

[0102] 5.6 Statistical analysis Statistical analysis was performed using SPSS software, and the measurement data were expressed as mean ± standard deviation. One-way analysis of variance was used for comparison between groups, the LSD test for homogeneous variances, and the Dunnett t-test for heterogeneous variances. Differences were considered statistically significant at P < 0.05.

[0103] 5.7 Results 5.7.1 Effect on Mouse Enhanced Pose (Penh) Value The results are as follows:

[0104] [Table 10] NOTE: Compared to the blank control group, # P<0.05, ### P<0.001 compared with the model group * P<0.05.

[0105] Mice were sensitized with OVA + Al(OH)3 for 3 weeks, then challenged with 5% OVA for 3 consecutive days. Subsequently, the Penh values ​​significantly increased (P<0.001 or P<0.05) compared with the blank control group. This demonstrated that the mouse asthma model was successfully established. Compared with the model group, administration of the compound of Example 3 to mice before stimulation could significantly reduce the enhanced pause (Penh) value (P<0.05).

[0106] 5.7.2 Effects on inflammatory cells in bronchoalveolar lavage fluid of mice The results are as follows:

[0107] [Table 11] NOTE: Compared to the blank control group, ## P<0.01, ### P<0.001 compared with the model group * P<0.05.

[0108] Mice were sensitized with OVA + Al(OH)3 for 3 weeks, and then challenged with 5% OVA for 3 consecutive days. A significant increase in the number of inflammatory cells in bronchoalveolar lavage fluid was observed (P<0.001 or P<0.01). Pre-administration of the compound described in Example 3 before challenge significantly reduced the number of inflammatory cells (leukocytes, lymphocytes) compared to the model group.

[0109] Test Example 6: 4-week repeated dose toxicity test using rats 6.1 Materials Animals: SD rats, SPF grade, equal numbers of males and females, weighing 200±20g. Test sample: Example 3 formulation cream (2%) based on the preparation of commercially available Benvitimod cream. Positive control: BMS-986165. Reagents: urethane, hematology analyzer reagents, automated clinical chemistry analyzer reagents, automated coagulation analyzer reagents, and electrolyte analyzer reagents. Equipment: electronic balance, hematology analyzer, fully automatic biochemistry analyzer, fully automatic coagulation analyzer, and electrolyte analyzer.

[0110] 6.2 Group Assignment and Dosing Regimen Grouping: The animals were randomly divided into three groups based on body weight: a blank control group, an Example 3 compound group, and a BMS-986165 group, with 10 animals in each group, with an equal number of males and females. Dosing regimen: The Example 3 compound group was topically applied to the skin twice daily, and the BMS-986165 group was administered orally twice daily by force. The administration period was 4 consecutive weeks (28 days). The specific administration regimen is shown in the table below.

[0111] [Table 12]

[0112] 6.3 Observed parameters Daily clinical observations and weight measurements. After the final administration, the rats were fasted for over 16 hours, and the next day they were anesthetized and blood was collected from the abdominal aorta. Blood tests (EDTA-2K anticoagulant), blood biochemistry tests (serum), and coagulation function tests (separated plasma using sodium citrate anticoagulant) were performed. After the rats were euthanized, the tissues and organs were dissected and observed grossly, and the organ weights and indices (heart, liver, spleen, kidney, and thymus) were measured. Skin and lung tissues from the administration site were collected and stained with HE to observe changes in epidermal thickness, inflammatory cells in the skin, and lung lesions.

[0113] 6.4 Results [Table 13] Note: Compared to the blank control: * P<0.05, ** P<0.01. WBC: white blood cells, Lymph: lymphocytes, Mono: monocytes, Gran: granulocytes, PLT: platelets, APTT: activated partial thromboplastin time, TB: total bilirubin.

[0114] The results of blood tests showed that BMS-986165 could significantly reduce the white blood cell count (P<0.01) and platelet count (P<0.05) in rats, while the compound of Example 3 had no significant effect on the white blood cell count (P>0.05). The results of the coagulation function test showed that BMS-986165 could significantly prolong the APTT (P<0.01), while the compound of Example 3 had no significant effect on the APTT (P>0.05). The results of blood biochemistry tests showed that BMS-986165 could significantly increase the total bilirubin (TB) level in serum (P<0.05), while the compound of Example 3 had no significant effect on total bilirubin (P>0.05). Furthermore, the compound of Example 3 showed no significant effects on general condition, body weight, organ index, skin and lung pathology, other hematological, coagulation, and blood biochemistry indices, indicating low toxicity potential. Furthermore, the compounds of the present invention have shown low toxicity potential in skin irritation tests, skin sensitization tests, and oral acute toxicity tests.

[0115] Finally, it should be noted that the above examples are only used to explain the technical solutions of the present invention, and do not limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments can still be modified or equivalently replaced with part or all of the technical features. These modifications or replacements do not cause the essence of the corresponding technical solutions to depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A novel aromatic ring derivative having an amide substitution or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula I: 【Chemistry 1】 In said compounds of formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is selected from C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 6-membered heteroaryl, wherein the substituents are one or more selected from C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, and —CN; When X is N, P is as defined above; or When X is CH, P is as defined above. A novel aromatic ring derivative having an amide substitution, or a pharmaceutically acceptable salt thereof, characterized in that:

2. In said compounds of formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is selected from C1-C4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-membered heteroaryl containing 2-3 N, substituted or unsubstituted 6-membered heteroaryl containing 1-2 N, wherein the substituents are one or two selected from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, and -CN; When X is N, P is as defined above; or When X is CH, P is as defined above.

2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

3. In said compounds of formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is tert-butyl, substituted or unsubstituted phenyl, 【Chemistry 2】 a substituted or unsubstituted 5-membered heteroaryl selected from 【Transformation 3】 wherein the substituents are one or two selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, cyano, fluoro, and trifluoromethyl; When X is N, P is as defined above; or When X is CH, P is as defined above.

2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

4. In said compounds of formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is tert-butyl, substituted or unsubstituted phenyl, 【Chemistry 4】 a substituted or unsubstituted 5-membered heteroaryl selected from 【Transformation 5】 and wherein the substituted or unsubstituted 6-membered heteroaryl is selected from In the case of said phenyl, the substituents are one or two selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, cyano, fluoro, and trifluoromethyl; In the case of said 5-membered heteroaryl, the substituent is methyl; For said 6-membered heteroaryl, the substituents are selected from methyl or fluoro; When X is N, P is as defined above; or When X is CH, P is as defined above.

2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

5. In said compounds of formula I, X and P are selected independently from each other, and: X is selected from CH, N; P is tert-butyl, 【Transformation 6】 Selected from: When X is N, P is as defined above; or When X is CH, P is as defined above.

2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

6. In said compounds of formula I, X and P are selected independently from each other, and: X is selected from CH or N; P is a substituted or unsubstituted phenyl, a substituted or unsubstituted 5-membered heteroaryl. 【Transformation 7】 、 Substituted or unsubstituted 6-membered heteroaryl 【Transformation 8】 is selected from In the case of phenyl, the substituents are one or two selected from methyl, fluoro; In the case of said 5-membered heteroaryl, the substituent is methyl; In the case of said 6-membered heteroaryl, the substituent is methyl; Preferably, P is 【Chemistry 9】 Selected from: When X is N, P is as defined above; or When X is CH, P is as defined above.

2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

7. wherein said compound of formula I is 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 6. The novel aromatic ring derivative having an amide substitution according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the aromatic ring derivative is selected from the following:

8. 8. The novel aromatic ring derivative having an amide substitution according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula I is selected from Compound 2, Compound 3, Compound 4, Compound 5, Compound 34, Compound 38, Compound 54, Compound 55, Compound 57, Compound 62, Compound 86, and Compound 91.

9. A pharmaceutical composition comprising the novel aromatic ring derivative having an amide substitution according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers, diluents, excipients, or adjuvants.

10. Use of the novel aromatic ring derivative having an amide substitution according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the manufacture of a medicament for treating a TYK2-mediated related disease.

11. 11. The use according to claim 10, characterized in that the disease is selected from inflammatory diseases or autoimmune diseases.

12. 12. Use according to claim 10 or 11, characterized in that the disease is selected from psoriasis, psoriatic arthritis, dermatitis, lupus erythematosus, inflammatory bowel disease, hidradenitis suppurativa, rheumatoid arthritis or uveitis.

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