N-disubstituted phenylacrylamide compounds, pharmaceutical compositions and uses thereof

Abstract

The application discloses N-disubstituted phenyl acrylamide compounds, pharmaceutical compositions and purposes thereof, and belongs to the field of chemical medicines, and specifically relates to a compound with a structure shown in a general formula (I) or a salt thereof. The compound can selectively inhibit Janus kinase 3 (JAK3) and has good in-vitro inhibitory activity, so that the compound can be used as a therapeutic agent for treating related diseases such as atopic dermatitis, rheumatoid arthritis and alopecia areata.

Description

Technical Field

[0001] This invention belongs to the field of chemical medicine, specifically relating to N-disubstituted phenylacrylamide compounds, their pharmaceutical compositions, and uses. Background Technology

[0002] Atopic dermatitis (AD), rheumatoid arthritis (RA), and alopecia areata (AA) are three chronic diseases with immunopathological characteristics. These diseases have a high incidence rate worldwide and severely impact patients' quality of life. Drug development for treating these diseases has long been a focus of the medical and pharmaceutical industries.

[0003] Atopic dermatitis: Atopic dermatitis is a common chronic skin disease characterized by dry, itchy, and red skin. The exact cause is not fully understood, but it is associated with a variety of factors, including genetics, environment, and abnormal immune responses. Currently, the main treatments for atopic dermatitis include corticosteroids, antihistamines, immunosuppressants, and biologics. However, these medications may cause side effects during use. For example, long-term use of corticosteroids may lead to complications such as skin atrophy and diabetes; antihistamines may cause drowsiness; and immunosuppressants may increase the risk of infection.

[0004] Rheumatoid arthritis (RA): RA is an immune-mediated chronic inflammatory disease characterized by arthritis, bone destruction, and disability. The etiology is not fully understood, but genetic, environmental, and immune factors are involved. Treatments for RA primarily include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-control antirheumatic drugs (DMARDs), and biologics. However, these medications may cause adverse effects such as gastrointestinal irritation, liver and kidney damage, and immunosuppression.

[0005] Alopecia areata: Alopecia areata is a common autoimmune disease characterized by localized or generalized hair loss. The exact cause is not fully understood, but it is believed to be related to factors such as genetics, environment, psychological stress, and immune abnormalities. Treatments for alopecia areata mainly include corticosteroids, immunosuppressants, biologics, and topical medications. However, these medications may also cause side effects; for example, corticosteroids may lead to complications such as skin atrophy and high blood pressure; immunosuppressants may increase the risk of infection.

[0006] Given the limitations of existing drug treatments for diseases such as atopic dermatitis, rheumatoid arthritis, and alopecia areata, there is an urgent need to develop safer and more effective treatments. The development of novel therapeutics requires a deeper understanding of the pathogenesis of these diseases in order to identify new targets and drug design strategies.

[0007] Janus kinase 3 (JAK)-mediated cytokine pathways play a crucial role in the pathogenesis of diseases such as atopic dermatitis, rheumatoid arthritis, and alopecia areata. Based on these new findings, efforts are being made to design and screen therapeutic agents targeting specific targets. However, drug development targeting these targets still faces many challenges, such as selecting suitable compounds, assessing the bioactivity and safety of drugs, and addressing issues related to drug bioavailability and pharmacokinetics. Summary of the Invention

[0008] The problem the invention aims to solve

[0009] To address the aforementioned technical problems, the inventors have discovered a new class of N-disubstituted phenylacrylamide compounds that, while ensuring pharmacodynamic properties, also exhibit good metabolic stability and superior skin penetration characteristics.

[0010] The present invention also provides a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof.

[0011] Furthermore, the present invention provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof.

[0012] Solution for solving the problem

[0013] This invention provides the following solution:

[0014] The present invention first provides a compound having general formula (I) or a pharmaceutically acceptable salt thereof.

[0015]

[0016] In the formula:

[0017] R1 is selected from H and C1-6 alkyl groups;

[0018] X is CH2 or NH;

[0019] A is a saturated heterocyclic group or an aromatic hybrid group, selected from: substituted or unsubstituted pyridinyl, pyrimidinyl, ... The substituents on the pyridyl or pyrimidinyl groups are selected from halogens, CN, and OR. c NO2, NH2, C1-6 alkyl, C3-8 cycloalkyl;

[0020] R2 is selected from -SO2-R d -COR e ;

[0021] R a R bEach is independently selected from H, C1-6 alkyl, and C3-8 cycloalkyl;

[0022] R c Selected from H, C1-6 alkyl, C3-8 cycloalkyl, acyl-COR c ';R c 'It is a C1-6 alkyl group;

[0023] R d Selected from C1-6 alkyl and C3-8 cycloalkyl groups;

[0024] R e Selected from C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, amino-NR e 'R e ”;R e '、R e "Each is independently selected from H, C1-6 alkyl, and C3-8 cycloalkyl."

[0025] In one embodiment of the present invention, A is further selected from:

[0026]

[0027] Among them, R 3a Selected from C1-6 alkyl and C3-8 cycloalkyl; R 3b Selected from C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, amino-NR 3b 'R 3b ”;R 3b '、R 3b "Each is independently selected from H, C1-6 alkyl, and C3-8 cycloalkyl; R" 3c R 3d R 3e Selected from H, OR4, where R4 is H, C1-6 alkyl, C3-8 cycloalkyl, or acyl-COR4'; R4' is C1-6 alkyl.

[0028] In one embodiment of the present invention, the compound is selected from:

[0029]

[0030] In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt. The inorganic salt includes hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate. The organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

[0031] In one embodiment of the invention, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, succinate, or mesylate.

[0032] The present invention also provides a pharmaceutical composition comprising the compound according to the above description or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient, diluent or carrier.

[0033] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of JAK inhibitors.

[0034] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for treating JAK-mediated diseases, including but not limited to atopic dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, Crohn's disease, vitiligo, psoriasis, lymphoma, solid tumors, etc.

[0035] The effects of the invention

[0036] This invention provides a compound of general formula (I) that exhibits significant pharmacodynamic properties and high metabolic stability in the treatment of atopic dermatitis, rheumatoid arthritis, alopecia areata, and related diseases. Furthermore, the compounds of this invention, or pharmaceutically acceptable salts thereof, are suitable for the preparation of medicaments for treating these diseases. Unexpectedly, these compounds also possess excellent skin permeability, making them particularly suitable for the preparation of medicaments for treating atopic dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, Crohn's disease, vitiligo, psoriasis, lymphoma, solid tumors, etc.

[0037] In certain specific embodiments, the compounds of the present invention are particularly suitable for preparing medicaments for treating atopic dermatitis, rheumatoid arthritis, alopecia areata, and related diseases. This application can improve the efficacy of the drugs and reduce damage to normal tissues, thereby providing patients with better treatment options and quality of life.

[0038] In summary, the compounds of general formula (I) of the present invention have the following advantages:

[0039] 1. It has excellent pharmacodynamic properties and high metabolic stability in the treatment of atopic dermatitis, rheumatoid arthritis, alopecia areata and other related diseases, making it a potential effective treatment option.

[0040] 2. Due to their excellent blood-brain barrier permeability, the compounds of this invention can be widely used in the preparation of drugs for the treatment of atopic dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, Crohn's disease, vitiligo, psoriasis, lymphoma, solid tumors, etc.

[0041] 3. In some embodiments, the compounds of the present invention can be used as drugs for treating atopic dermatitis, rheumatoid arthritis, alopecia areata and other related diseases, improving drug efficacy, reducing damage to normal tissues, and providing patients with better treatment options and quality of life.

[0042] Therefore, this invention provides a novel, effective, and potentially widely applicable therapeutic agent for treating atopic dermatitis, rheumatoid arthritis, alopecia areata, and other related diseases. Detailed Implementation

[0043] The technical solution of the present invention will be described in detail below with reference to the embodiments.

[0044] In this invention, C 1-6 Alkyl refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, tert-butyl, etc.

[0045] C 1-6 Alkoxy groups are saturated hydrocarbon groups with 1 to 6 carbon atoms connected by oxygen bridges, either straight or branched. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0046] C 3-6 Cycloalkyloxy groups refer to monocyclic or polycyclic hydrocarbon groups with 3 to 6 cyclic carbon atoms connected by oxygen bridges.

[0047] This indicates that the substituent is attached from this location.

[0048] As used in this article, “disease” refers to any condition or disorder that impairs or interferes with the normal function of cells, organs, or tissues.

[0049] As used herein, the term "inhibitor" refers to a compound or reagent that has the ability to inhibit the biological function of a target protein or peptide, for example, by inhibiting the activity or expression of the protein or peptide.

[0050] As used in this article, the term "antitumor agent" refers to any agent that is useful in the treatment of cancer conditions.

[0051] As used herein, "pharmaceutically acceptable" means a component that, within reasonable medical limits, is suitable for contact with tissues of humans and other mammals without excessive toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, can directly or indirectly provide the compound or prodrug of the present invention.

[0052] As used herein, the terms "effective amount" or "effective therapeutic amount" mean that the amount of the compound or pharmaceutical composition described herein is sufficient to achieve the intended application, including, but not limited to, the treatment of a disease. The effective therapeutic amount can vary depending on the intended application, such as in vitro or in vivo, the condition and severity of the disease, the age and weight of the subject, or the route of administration. The specific dosage will depend on, for example, the choice of a particular compound, the species of the subject and their age / existing health condition or risk of health condition, the route of administration, the severity of the disease, whether it is administered in combination with other agents, the time of administration, the tissue to which it is administered, and the delivery device, etc.

[0053] In this invention, “administering” or “giving” an individual compound means providing the compound of this invention to an individual in need of treatment.

[0054] The compounds of the present invention may contain one or more asymmetric centers and thus appear as racemic mixtures and racemic mixtures, single enantiomers, single diastereomers, and diastereomer mixtures. All such isomers of these compounds are explicitly included in this invention. The compounds of the present invention may also exist in a variety of tautomer forms; in this case, the present invention explicitly includes all tautomers of the compounds described herein. All such isomers of such compounds are included in this invention. All crystalline forms of the compounds described herein are explicitly included in this invention.

[0055] To overcome the shortcomings of existing drug treatments for diseases such as atopic dermatitis, rheumatoid arthritis, and alopecia areata, this invention proposes a novel therapeutic agent. This agent, acting on specific targets, can effectively regulate the patient's immune and inflammatory responses, thereby alleviating symptoms and slowing disease progression. Simultaneously, this therapeutic agent has low toxicity and side effects, providing patients with a better treatment experience and quality of life.

[0056] In the research process of this invention, various cytokines and signaling pathways were studied in depth. Through rigorous in vitro and in vivo experiments, a novel compound was screened that can effectively improve the symptoms of diseases such as atopic dermatitis, rheumatoid arthritis, and alopecia areata by acting on key targets and regulating the patient's immune and inflammatory responses. At the same time, this compound exhibits low toxicity and side effects during treatment, providing patients with a safer and more effective treatment option.

[0057] To further optimize the drug properties of this compound, its structure was modified, and multiple derivatives were synthesized and their bioactivity and pharmacokinetic properties were evaluated. Ultimately, an optimized therapeutic agent was identified, exhibiting significantly improved bioavailability, stability, and safety.

[0058] In animal models and clinical trials, this therapeutic agent has demonstrated significant efficacy, effectively alleviating symptoms of atopic dermatitis, rheumatoid arthritis, and alopecia areata, slowing disease progression, and exhibiting low toxicity and side effects. Compared to existing treatments, this agent offers higher efficacy and better safety, providing patients with a better treatment experience and quality of life.

[0059] In summary, this invention provides a novel therapeutic agent for treating atopic dermatitis, rheumatoid arthritis, and alopecia areata. This therapeutic agent modulates the patient's immune and inflammatory responses by acting on specific targets, providing a safer and more effective treatment option. In the future, this therapeutic agent is expected to represent a significant breakthrough and a new treatment approach in the treatment of atopic dermatitis, rheumatoid arthritis, and alopecia areata.

[0060]

[0061] This invention provides a novel N-disubstituted phenylacrylamide compound or a pharmaceutically acceptable salt thereof that inhibits JAK3 activity, selected from the following structures:

[0062]

[0063] It should be understood that certain compounds of formula (I) or their pharmaceutically acceptable salts may be in both solvate and nonsolvent forms, such as hydrated forms. It should be understood that this invention covers all such solvate forms possessing JAK3 inhibitory activity.

[0064] The synthesis of compounds of general formula (I) of this invention can be performed by those skilled in synthetic chemistry. All references to the background art mentioned herein are incorporated herein by reference in their entirety. Preparation methods are described in detail in the examples.

[0065] <Pharmaceutical Composition>

[0066] The present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0067] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compound of general formula (I) of the present invention is mixed as the active ingredient with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate. Or it may be mixed with the following components: (1) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silica; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) slowing agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, such as kaolin; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium dodecyl sulfate, etc., or mixtures thereof. Buffers may also be included in capsules, tablets and pills.

[0068] The solid dosage forms, such as tablets, sugar pills, capsules, pellets, and granules, can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They may contain opaque agents, and the release of the active ingredient from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0069] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compound of general formula (I) or its pharmaceutically acceptable salt as the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc., or mixtures thereof. In addition to these inert diluents, the liquid dosage forms of the present invention may also include conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0070] The suspending agent includes, for example, ethoxylated octadecyl alcohol, polyoxyethylene sorbitol, and dehydrated sorbitol, microcrystalline cellulose, agar, or mixtures thereof.

[0071] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, and excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0072] The compounds of this invention or pharmaceutically acceptable salts thereof can be formulated into dosage forms for topical administration, including ointments, powders, suppositories, drops, sprays, and inhalers. The compounds of general formula (I) of this invention or pharmaceutically acceptable salts thereof, as active ingredients, are mixed under sterile conditions with a physiologically acceptable carrier and optionally with preservatives, buffers, and propellants, if necessary.

[0073] The compounds of formula (I) of the present invention, or pharmaceutically acceptable salts thereof, shall be administered to mammals at unit doses ranging from 0.01 to 2000 mg / kg, particularly 2.5 to 1000 mg / kg, particularly 5 to 500 mg / kg, and this should provide an effective dose. However, the daily dose will necessarily vary depending on the host being treated, the specific route of administration, and the severity of the disease being treated. Therefore, the optimal dose may be determined by the practitioner treating any particular patient.

[0074] <Applications>

[0075] This invention provides the use of a compound of formula (I) as defined above and its pharmaceutically acceptable salt in the preparation of treatments for diseases mediated by JAK3 in mammals, particularly humans.

[0076] Types of diseases that may be susceptible to therapeutic effects from the use of compounds of formula (I) or their pharmaceutically acceptable salts include, but are not limited to: atopic dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, Crohn's disease, vitiligo, psoriasis, lymphoma, and solid tumors.

[0077] In the treatment of the disease described in this invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof shall be administered to mammals, more specifically humans.

[0078] The JAK inhibitory activity therapy described in this invention can be used as a standalone therapy or, in combination with other pharmaceutically acceptable therapeutic agents besides the compounds of this invention. This combination therapy can be achieved by administering the therapeutic components simultaneously, sequentially, or separately. The components to be combined can be administered simultaneously or sequentially, in a single formulation or in different formulations. The combination includes not only combinations of one or other active agents of the compounds of this invention, but also combinations of two or more other active agents of the compounds of this invention.

[0079] The following examples are illustrative, not limiting, of the synthesis of compounds of general formula (I). All temperatures are in degrees Celsius. Unless otherwise specified, all evaporations were performed under reduced pressure. Unless otherwise specified, reagents were purchased from commercial suppliers and used without further purification. The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as elemental analysis and spectroscopic characterization, such as MS and NMR. Abbreviations used are conventional abbreviations in the art. Some intermediates were purchased from Yancheng Zhengchi Biotechnology Co., Ltd.

[0080] Intermediate 1: 2-Chloroquinoxaline (2)

[0081] 2-chloroquinoxaline(2)

[0082]

[0083] Procedure: At room temperature, 2-hydroxyquinoxaline (2.0 g, 13.7 mmol) was suspended in 1,2-dichloroethane (20 mL), two drops of DMF were added, followed by SOCl2 (5.0 g, 42.0 mmol), and the mixture was stirred and refluxed for 6 h. The reaction solution was concentrated under reduced pressure, and petroleum ether (20 mL) with thionyl chloride was added three times. The solution was then dissolved in petroleum ether, filtered, and the filtrate was concentrated under vacuum to give 2.0 g of a yellow solid, with a yield of 88.7%. No further purification was required; the solid was used directly in the next reaction. 1 HNMR(400MHz, DMSO-d6)δ:9.02(s,1H),8.15-8.18(m,1H),8.05-8.08(m,1H),7.90-7.97(m,2H).

[0084] Intermediate 2: 3-hydroxymethyl-5-nitrophenylboronic acid (4)

[0085] (3-(hydroxymethyl)-5-nitrophenyl)boronic acid(4)

[0086]

[0087] Procedure: 2.1 g (10.0 mmol) of 3-carboxy-5-nitrophenylboronic acid was dissolved in 40 mL of THF. The solution was cooled to 0 °C, and isobutyl chloroformate (1.50 g, 11.0 mmol) was added dropwise. The mixture was stirred at 0 °C for 1 h, filtered to remove the solid, and 20 mL of water was added to the filtrate. Sodium borohydride (1.1 g, 30.0 mmol) was added in portions at 0 °C, and the mixture was stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to 3-4 with 1 N dilute hydrochloric acid, and extracted with 40 mL of ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.90 g of a yellowish-brown solid (96.5% yield). No further purification was required; the solid was used directly in the next step. ESI-MS (m / z): 198.0 [M+H] + .

[0088] Intermediate 3: (3-nitro-5-(quinoxalo-2-yl)phenyl)methanol (5)

[0089] (3-nitro-5-(quinoxalin-2-yl)phenyl)methanol(5)

[0090]

[0091] Procedure: Under nitrogen protection, 2 (2.2 g, 13.4 mmol), 4 (2.6 g, 13.4 mmol), sodium carbonate (5.7 g, 53.6 mmol), and PdCl2 dppf (196 mg, 0.02 eq) were added to 1,4-dioxane (20 mL) and water (4 mL), and reacted at 80 °C for 3 h. After cooling to room temperature, the reaction solution was poured into water (30 mL), slurried, filtered, washed with water, and dried to obtain 3.4 g of gray solid, with a yield of 90.2%. No further purification was required; it was used directly in the next reaction.

[0092] Intermediate 4: 2-(3-(chloromethyl)-5-nitrophenyl)quinoxaline (6)

[0093] 2-(3-(chloromethyl)-5-nitrophenyl)quinoxaline(6)

[0094]

[0095] Procedure: 5 g (3.2 g, 11.4 mmol) was dispersed in DCE (40 mL), a catalytic amount of DMF was added, followed by thionyl chloride (4.1 g, 34.1 mmol). The reaction mixture was heated under reflux for 4 h. The solvent was removed by concentration under reduced pressure, and petroleum ether (40 mL * 3) was added three times to remove thionyl chloride, yielding 3.0 g of gray solid, with a yield of 87.8%. No further purification was required; it was used directly in the next reaction. 1HNMR(400MHz, DMSO-d6)δ:9.72(s,1H),9.00(s,1H),8.74(s,1H),8.37(s,1H),8.17-8.25(m,2H),7.89-7.97(m,2H),4.78(s,2H).

[0096] Intermediate 5: 2-(3-((4-(methanesulfonyl)piperazin-1-yl)methyl)-5-nitrophenyl)quinoxaline (7)

[0097] 2-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-nitrophenyl)quinoxaline(7)

[0098]

[0099] Procedure: 6 (600 mg, 2.0 mmol), N-methanesulfonylpiperazine (345 mg, 2.1 mmol), and potassium carbonate (332 mg, 2.4 mmol) were suspended in acetonitrile (15 mL). A catalytic amount of potassium iodide was added, and the mixture was heated under reflux overnight. After cooling to room temperature, the reaction solution was poured into water (20 mL), filtered to remove the solid, and dried to obtain 688 mg of a yellow solid, with a yield of 80.5%. No further purification was required; it was used directly in the next reaction.

[0100] Intermediate 6: 3-((4-(methanesulfonyl)piperazin-1-yl)methyl)-5-(quinoxalin-2-yl)aniline (8)

[0101] 3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-(quinoxalin-2-yl)aniline(8)

[0102]

[0103] Procedure: 7 (427 mg, 1.0 mmol), reduced iron powder (279 mg, 5.0 mmol), and ammonium chloride (374 mg, 7.0 eq) were suspended in a mixed solvent of ethanol (12 ml) and water (4 ml). The mixture was heated under reflux for 2 h, filtered while hot, the filter cake was washed with ethanol, the filtrate was concentrated under reduced pressure, the pH was adjusted to 7-8 with sodium hydroxide, and extracted with a mixed solvent of dichloromethane and methanol (10:1 volume ratio, 20 ml). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 350 mg of a yellow solid (88.0% yield). No further purification was required; the solid was used directly in the next reaction.

[0104] Intermediate 7: 3-chloro-N-(3-((4-(methanesulfonyl)piperazin-1-yl)methyl)-5-(quinoxalo-2-yl)phenyl)propionamide (9)

[0105] 3-chloro-N-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-(quinoxalin-2-yl)phenyl)propana mide(9)

[0106]

[0107] Procedure: 8 (298 mg, 0.75 mmol) was suspended in THF (10 mL) and water (1 mL), cooled to 0 °C, and 3-chloropropionyl chloride (114 mg, 0.9 mmol) in THF (2 mL) was slowly added dropwise. The mixture was reacted at room temperature for 1 h, filtered, washed with dichloromethane, and the filter cake was dried to give 301 mg of a yellow solid, yield 82.2%. No further purification was required; it was used directly in the next reaction.

[0108] Example 1: N-(3-((4-(methanesulfonyl)piperazin-1-yl)methyl)-5-(quinoxalo-2-yl)phenyl)acrylamide (10)

[0109] N-(3-((4-(methylsulfonyl)piperazin-1-yl)methyl)-5-(quinoxalin-2-yl)phenyl)acrylamide(10)

[0110]

[0111] Procedure: d1-8 (244 mg, 0.5 mmol) was suspended in acetonitrile (15 mL), and triethylamine (152 mg, 1.5 mmol) was added. The mixture was reacted at 80 °C for 8 h. The reaction solution was concentrated under vacuum to remove acetonitrile. Water (15 mL) and a mixed solvent of dichloromethane and methanol (10:1 volume ratio, 15 mL) were added for extraction. The extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 148 mg of a yellow solid powder, yield 65.6%. ESI-MS (m / z): 452.2 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ:10.50(s,1H),9.51(s,1H),8.53(s,1H),8.14-8.18(m,2H),7.97(s,2H),7.85-7.94(m,2H),6. 52-6.58(q,1H),6.34-6.38(dd,1H),5.82-5.85(dd,1H),3.67(s,2H),3.17-3.20(m,4H),2.92(s,3H),2.56-2.59(m,4H).

[0112] Examples 2-5 were synthesized using a similar procedure to that of Example 1 (see Table 1) to obtain the desired products.

[0113] Table 1

[0114]

[0115] Application examples

[0116] Assay 1: Lance screening assay for JAK3 inhibitory activity

[0117] A europium-labeled time-resolved fluorescence resonance energy transfer (TR-FRET) method was employed, which utilizes a europium-labeled peptide and a europium chelate-labeled antiphosphoprotectant. When the protein substrate is phosphorylated by JAK, the phosphorylation site of the substrate is recognized by the europium-labeled antiphosphoprotectant. When the europium chelate is excited at 320 nm or 340 nm, energy is transferred to the Ulight fluorescent receptor, causing it to emit fluorescence at 665 nm. The fluorescence intensity is proportional to the phosphorylation level of the Ulight peptide. The fluorescence value was read on a microplate reader, and the inhibition rate of the JAK small molecule inhibitor on JAK at this inhibitor concentration was further quantitatively calculated based on the specific fluorescence value and comparisons with the DMSO control group and the enzyme-free control group. 40 μL of test compound solutions diluted to 0.1 mM (JAK1, JAK2, JAK3, and TYK2) and 0.1 mM & 0.03 mM reference compounds (tofacitinib) were transferred to Echo 384-well PP plates. The dilution and transfer of compounds were performed using a Labcyte Echo plate, with 3-fold dilutions and a total of 8 dose points, 100 nL of compound per well. The highest concentration of the test compounds in the kinase reaction solution was 1000 nM. The highest concentration of the reference compounds (tofacitinib) in the kinase reaction solution was 1000 nM. The highest concentration of the reference compounds (tofacitinib) in the kinase reaction solution was 500 nM.

[0118] Assay 2: Enzymatic reaction

[0119] The compound was tested at a concentration of 500 nM, using a single concentration and multiple wells for monitoring.

[0120] (1) Prepare a 50 μM composite DMSO solution for each compound using 100% DMSO.

[0121] (2) Add the kinase to be tested to 1x kinase buffer (50mM HEPES pH 7.5, 10mM MgCl2, 2mM DTT, 0.01% Tween-20, 0.01% 10% BSA) to prepare a kinase solution with a concentration of 1nM. Add 10μL of kinase solution to each well, and add 10μL of kinase buffer to the enzyme-free control well instead.

[0122] (3) Add Ulight substrate and ATP to 1x kinase buffer to prepare 2x substrate solution.

[0123] (4) Add 10 μL of 2x substrate solution to each well of the detection plate to start the kinase reaction and incubate at 25°C for 30 minutes.

[0124] (5) Prepare a 2x test solution of the final concentration in antibody dilution buffer.

[0125] (6) Add 20 μL of detection solution to each well of the detection plate and stop the reaction. Incubate at 25°C for 60 minutes.

[0126] Data Analysis:

[0127] (1) Obtain the Lance signal value from the Envision microplate reader software.

[0128] (2) Calculate the ratio of Lance signal 665nm / Lance signal 615nm, and calculate the percentage suppression rate based on the Lance signal ratio. Calculate the data using the formula.

[0129] (3) Data were displayed in MS Excel, with the concentration log value as the X-axis and the percentage inhibition rate as the Y-axis. The dose-response curve was fitted using the XLFit Excel plugin version 5.4.0.8 to obtain the IC50 value of the compound.

[0130] The experimental results of the embodiments of the present invention, as well as the reference compound (tofacitinib) and the comparative compound, are shown in Table 1.

[0131] The structures of the comparative compounds are shown below:

[0132] Table 1 IC50 values ​​for the activity determination of each compound 50 (nM) data

[0133] Example 1 0.9 Example 2 1.0 Example 3 1.9 Example 4 5.2 Example 5 6.7 Tofacitinib (reference example) 1.2 Comparative compounds 70.9

[0134] As can be seen from the kinase activity data of the compounds in Examples 1-5, the JAK3 inhibitory activity is high for compounds of general formula (I), which makes the present invention a potential therapeutic agent for JAK3-related diseases.

[0135] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined in the claims of this invention.

Claims

1. A compound having the general formula (I) or a pharmaceutically acceptable salt thereof, In the formula: R1 is selected from H; X is CH2; A is , , ; R b Independently selected from H, C1-6 alkyl, and C3-8 cycloalkyl; R 3a Selected from C1-6 alkyl and C3-8 cycloalkyl; R 3b It is selected from C1-6 alkyl, C3-8 cycloalkyl, and C1-6 alkoxy.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from: 、 、 、 、 、 。 3. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, characterized in that, The pharmaceutically acceptable salt is an inorganic or organic salt; wherein the inorganic salt is selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; and the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

4. A pharmaceutical composition comprising the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

5. The pharmaceutical composition according to claim 4, characterized in that, The optionally pharmaceutically acceptable pharmaceutical excipients include excipients.

6. The pharmaceutical composition according to claim 4, characterized in that, The optionally pharmaceutically acceptable pharmaceutical excipients include diluents.

7. The pharmaceutical composition according to claim 4, characterized in that, It also includes pharmaceutical carriers.

8. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a JAK inhibitor.

9. The use according to claim 8, characterized in that, The JAK inhibitors are used to treat dermatitis, rheumatoid arthritis, alopecia areata, ulcerative colitis, Crohn's disease, vitiligo, psoriasis, lymphoma, or solid tumors.

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