Heterocyclic compounds as TYK2 inhibitors and their synthesis and applications

Abstract

The present invention provides heterocyclic compounds as TYK2 inhibitors, and their synthesis and application. Specifically, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is as shown in formula (A), and each group is as defined herein. [Formula 1] TIFF2025534771000074.tif61170

Description

[Technical Field]

[0001] The present invention relates to the fields of medicine and medical cosmetology, in particular to heterocyclic compounds as TYK2 inhibitors and their synthesis and application. [Background technology]

[0002] Janus kinases (JAKs) are intracellular non-receptor tyrosine kinases that mediate the signal transduction and activation of various cytokines. The JAK kinase family is classified into four subtypes: JAK1, JAK2, JAK3, and TYK2. Each subtype mediates a different type of cytokine signaling pathway. JAK1, JAK2, and TYK2 are expressed in cells of various tissues in the human body, while JAK3 is primarily expressed in cells of various hematopoietic tissues. A common feature of cytokine receptors is that the receptors themselves lack kinase activity, but the intracellular segments of the receptors contain binding sites for the tyrosine kinase JAK. After a cytokine receptor binds to its ligand, the receptor-coupled JAK is activated, thereby phosphorylating the receptor. The phosphorylated tyrosine site can bind to SH2 domain-containing STAT proteins, so that STATs are recruited to the receptor and phosphorylated by JAK. Then, the phosphotyrosine mediates STAT dimerization. The activated STAT dimer translocates into the cell nucleus and activates the transcription of its target point genes, thereby controlling various functions of various cells, such as growth, activation, and differentiation.

[0003] TYK2 is the earliest discovered subtype of the JAK family and mediates the functions of cytokines such as IFN-α, IL-6, IL-10, IL-12, and IL-23. Studies have shown that TYK2 deletion mutations can effectively inhibit the development of immune-mediated diseases such as allergies, autoimmunity, and inflammation. IL-23 plays an important role in the development and progression of psoriasis. Recent studies have shown that the pathogenic mechanism of psoriasis involves endogenous antigens activating antigen-presenting cells (APCs) to secrete IL-23, which then activates Th17 cells to secrete cytokines such as IL-17, which in turn stimulates keratinocyte differentiation and division and the secretion of IL-23, further stimulating inflammation and keratinocyte proliferation, leading to psoriasis. TYK2 and JAK2 cooperate to mediate the downstream signaling pathway of IL-23. Because inhibition of JAK2 can cause anemia and other blood-related side effects, targeting TYK2 is an effective strategy for inhibiting the IL-23 signaling pathway.

[0004] Early TYK2 inhibitors, such as tofacitinib, are all non-selective JAK inhibitors. They are the first oral JAK inhibitors and exhibit significant inhibitory activity against JAK1, 2, and 3 subtypes. Inhibiting the activity of other subtypes, such as JAK1, JAK2, and JAK3, increases the therapeutic efficacy of tofacitinib but also causes more serious side effects, including infection, tuberculosis, tumors, anemia, liver damage, and elevated cholesterol. Because JAK2 activity is involved in erythrocyte differentiation and lipid metabolism, some of the aforementioned side effects, such as anemia, are thought to be related to tofacitinib's insufficient selectivity for JAK2, which is caused by the drug's non-selective inhibition. Currently, there are no selective TYK2 inhibitors on the market, and early JAK inhibitors generally suffer from low selectivity because they function primarily by competing with the kinase domain for ATP binding.

[0005] TYK2 is also associated with some cancers; for example, abnormal cell survival in acute lymphoblastic leukemia (T-ALL) cells is associated with TYK2 activation. Gene knockout experiments demonstrated that 88% of T-ALL cell lines and 63% of patient-derived T-ALL cells are dependent on TYK2, suggesting that TYK2 is an oncogene in T-ALL. The TYK2-selective inhibitor NDI-031301 can induce apoptosis and inhibit the growth of human T-ALL cell lines. It also showed good safety and therapeutic efficacy in a mouse model bearing KOPT-K1 T-ALL tumor cells, demonstrating the potential of TYK2-selective inhibitors in the treatment of T-ALL.

[0006] Among the favorable therapeutic effects and severe side effects associated with multiple target points of non-selective JAK inhibitors, psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, neuroinflammation, various types of multiple sclerosis (including optic neuritis and neuromyelitis optica), chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, Lu Gehrig's disease, myasthenia gravis, neurological disorders, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, and neuropsychiatric wolf disease are listed. The development of safer, selective TYK2 inhibitors for the treatment of various TYK2-related autoimmune and inflammation-related diseases, including inflammatory bowel disease, diabetic encephalopathy, sepsis-related encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndromes, pain, itch, depression, hypersomnia, hydrocephalus, ankylosing spondylitis, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, and some cancers, holds great potential for clinical application.

[0007] Therefore, there is an urgent need in the art to develop brain-transmitting TYK2 inhibitors that have novel structures, high selectivity, and superior efficacy, particularly brain-transmitting TYK2 inhibitors that are suitable for central nervous system diseases. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a brain-transmitting TYK2 inhibitor that has a novel structure, high safety, and excellent efficacy. [Means for solving the problem]

[0009] A first aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein said compound is as shown in formula (A1):

[0010] [ka]

[0011] where: X is N or CR8, where R8 is H, optionally substituted C 1-4 alkyl groups, Y, R1, R2, R3, R4, R5, R6, R7, R9 and "optionally substituted" are as defined in formula (A).

[0012] In another preferred embodiment, a compound or a pharmaceutically acceptable salt thereof is provided, wherein the compound is as shown in formula (A):

[0013] [ka]

[0014] Y is N or CR9; R1 is H, optionally substituted C 1-4 alkyl groups, R2 is H, optionally substituted C 1-4 alkyl groups, R3 and R4 are each independently H, halogen, or optionally substituted C 1-4 alkyl groups, R5 is H, optionally substituted C 1-6 alkyl groups, R6 is H, optionally substituted C 1-4 alkyl groups, R7 is H, optionally substituted C 1-4 alkyl groups, R9 is H, optionally substituted C 1-4 alkyl groups, The term "optionally substituted" means that the group is unsubstituted or optionally substituted with deuterium, halogen, C 1-4 Alkyl group, C 1-4 It refers to being substituted by one or more substituents selected from the group consisting of haloalkyl groups.

[0015] In another preferred example, R4 is selected from the group consisting of H, a methyl group, and an ethyl group.

[0016] In another preferred example, R4 is H.

[0017] In another preferred embodiment, R5 is C 1-6 It is an alkyl group.

[0018] In another preferred example, R5 is selected from the group consisting of a methyl group, an ethyl group, an n-propyl group, and an n-butyl group.

[0019] In another preferred example, R5 is an ethyl group.

[0020] In another preferred example, R6 is selected from the group consisting of H, a methyl group, and an ethyl group.

[0021] In another preferred example, R6 is H.

[0022] In another preferred example, R6 is selected from the group consisting of H, a methyl group, and an ethyl group.

[0023] In another preferred example, R6 is H.

[0024] In another preferred example, R7 is selected from the group consisting of H, a methyl group, and an ethyl group.

[0025] In another preferred example, R7 is H.

[0026] In another preferred embodiment, the compound is as shown in formula (A1-S) or formula (A1-R).

[0027] [ka]

[0028] [ka]

[0029] In another preferred embodiment, the compound is as shown in formula (AS) or formula (AR).

[0030] [ka]

[0031] [ka]

[0032] In another preferred embodiment, the compound is as shown in formula (AS) (ie, S configuration).

[0033] In another preferred embodiment, the compound is as shown in formula (I1).

[0034] [ka]

[0035] In another preferred embodiment, the compound is as shown in formula (I).

[0036] [ka]

[0037] In another preferred example, R8 and R9 are each independently selected from the group consisting of H, a methyl group, and an ethyl group.

[0038] In another preferred example, R8 is H.

[0039] In another preferred example, R9 is H.

[0040] In another preferred example, X is N or CH.

[0041] In another preferred example, X is CR8.

[0042] In another preferred example, X is CH.

[0043] In another preferred example, Y is N or CH.

[0044] In another preferred embodiment, Y is N.

[0045] In another preferred embodiment, R1 is C 1-4 Alkyl groups, deuterated C 1-4 The alkyl group is selected from the group consisting of:

[0046] In another preferred example, R1 is selected from the group consisting of a methyl group, an ethyl group, a deuterated methyl group, and a deuterated ethyl group.

[0047] In another preferred example, R1 is selected from the group consisting of -CH3 and -CD3.

[0048] In another preferred embodiment, R2 is C 1-4 Alkyl groups, deuterated C 1-4 The alkyl group is selected from the group consisting of:

[0049] In another preferred example, R2 is selected from the group consisting of a methyl group, an ethyl group, a deuterated methyl group, and a deuterated ethyl group.

[0050] In another preferred example, R2 is selected from the group consisting of -CH3 and -CD3.

[0051] In another preferred embodiment, R3 is H, C 1-4 The alkyl group is selected from the group consisting of:

[0052] In another preferred example, R3 is selected from the group consisting of H, a methyl group, and an ethyl group.

[0053] In another preferred embodiment, the compound is as shown in formula (I1-S) or formula (I1-R).

[0054] [ka]

[0055] [ka]

[0056] In another preferred embodiment, the compound is as shown in formula (IS) or formula (IR).

[0057] [ka]

[0058] [ka]

[0059] In another preferred example, the compound is as shown in formula (IS) (ie, S configuration).

[0060] In another preferred example, X, Y, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently a group corresponding to a specific compound shown in the Examples, Table A or Table B.

[0061] In another preferred embodiment, the compound is a compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof.

[0062] [Table 1]

[0063] [Table 2]

[0064] In another preferred embodiment, the compound is compound 1S, 2S, 3S, 4S, 5S, or 6S in Table B.

[0065] In another preferred embodiment, the compound is compound 4S in Table B.

[0066] A second aspect of the present invention is There is provided a pharmaceutical composition comprising (i) a compound according to the first aspect or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.

[0067] A third aspect of the present invention provides the use of a compound according to the first aspect or a pharmaceutical composition according to the second aspect in the preparation of (i) a medicament for treating or preventing a TYK2-mediated disease and / or (ii) a TYK2 inhibitor.

[0068] In another preferred example, the TYK2-mediated disease comprises psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, neuroinflammation, multiple sclerosis (including optic neuritis and neuromyelitis optica), chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, Lu Gehrig's disease, myasthenia gravis, neurological diseases, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-associated encephalopathy, central nervous system tumor, Huntington's disease, postoperative neurological syndrome, pain, itch, depression, hypersomnia, hydrocephalus, ankylosing spondylitis, respiratory disease, diabetes, inflammatory eye disease, hepatitis, cardiovascular disease, systemic sclerosis, organ transplant, alopecia areata, acne, eczema, vitiligo, Sjogren's syndrome, viral inflammation, cancer, or a combination thereof.

[0069] A fourth aspect of the present invention provides a method of inhibiting TYK2, said method comprising: The method comprises contacting a subject with a compound according to the first aspect, thereby inhibiting TYK2 activity in the subject.

[0070] In another preferred embodiment, the subject is a cell.

[0071] In another preferred embodiment, the method is in vitro and non-therapeutic.

[0072] A fifth aspect of the invention provides a method of inhibiting pSTAT5 expression in a cell, said method comprising: The method comprises contacting a subject with a compound according to the first aspect, thereby inhibiting pSTAT5 expression in the cell.

[0073] In another preferred embodiment, the method is in vitro and non-therapeutic.

[0074] A sixth aspect of the present invention is There is provided a method for treating or preventing a TYK2-mediated disease, comprising administering to a person in need thereof a safe and effective amount of a compound according to the first aspect or a pharmaceutical composition according to the second aspect, thereby treating or preventing the TYK2-mediated disease.

[0075] In another preferred example, the TYK2-mediated disease comprises psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, neuroinflammation, multiple sclerosis (including optic neuritis and neuromyelitis optica), chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, Lu Gehrig's disease, myasthenia gravis, neurological diseases, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-associated encephalopathy, central nervous system tumor, Huntington's disease, postoperative neurological syndrome, pain, itch, depression, hypersomnia, hydrocephalus, ankylosing spondylitis, respiratory disease, diabetes, inflammatory eye disease, hepatitis, cardiovascular disease, systemic sclerosis, organ transplant, alopecia areata, acne, eczema, vitiligo, Sjogren's syndrome, viral inflammation, cancer, or a combination thereof.

[0076] A seventh aspect of the present invention provides a method for preparing a compound, wherein said compound is as shown in formula (IS):

[0077] [ka]

[0078] The preparation method further comprises: reacting an intermediate of formula (II-S) with an intermediate of formula (III) to obtain a compound as shown in formula (IS),

[0079] [ka]

[0080] [ka]

[0081] In each formula, Y, R1, R2 and R3 are as defined in formula (I).

[0082] An eighth aspect of the present invention provides an intermediate of formula (II-S):

[0083] [ka] [Effects of the Invention]

[0084] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief explanation of the drawings]

[0085] [Figure 1A] 1 shows the results of the body weight and clinical scores of the animals in Test Example 3. [Figure 1B] 1 shows the results of the body weight and clinical scores of the animals in Test Example 3. [Figure 2A] 1 shows the results of serum TNF-α and IFN-γ levels in Test Example 3. [Figure 2B] 1 shows the results of serum TNF-α and IFN-γ levels in Test Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0086] As a result of extensive and detailed studies, the present inventors have found that, in particular, certain novel structures (e.g., TIFF2025534771000020.tif12170). The present inventors have overcome the challenges of chiral synthesis of compounds containing the TIFF2025534771000021.tif12170 structure, thereby avoiding the use of chiral chromatography and providing compounds with excellent TYK2 inhibitory activity and lower toxicity that are more readily available industrially. Based on this, the present inventors have completed the present invention.

[0087] term As used herein, the term "halogen" refers to F, Cl, Br, or I. Correspondingly, "halo" refers to a hydrogen atom within a group being replaced by F, Cl, Br, or I.

[0088] Unless otherwise stated, the term "alkyl group," by itself or as part of another substituent, refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (i.e., C 1-6 represents 1 to 6 carbon atoms). Preferably, the alkyl group has 1 to 4 carbon atoms, i.e., C 1-4 Alkyl groups, more preferably having 1 to 3 carbons, i.e., C 1-3 Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group, an isobutyl group, an s-butyl group, an n-pentyl group, an n-hexyl group, and the like.

[0089] As used herein, the terms "comprise," "include," or "comprise" refer to various components that can be used together in the mixtures or compositions of the present invention. Thus, the terms "consisting essentially of" and "consisting of" are included in the term "comprising."

[0090] As used herein, the term "deuterated" refers to one or more hydrogens in a group being replaced with deuterium. Preferably, all hydrogens in a group are replaced with deuterium.

[0091] As used herein, the term "pharmaceutically acceptable" refers to a substance suitable for human and / or animal use without undue adverse side effects (e.g., toxicity, irritation, and allergic response), i.e., with a reasonable benefit / risk ratio.

[0092] Unless otherwise specified, all compounds appearing in this invention are intended to include all possible optical isomers, including single chiral compounds or mixtures of various different chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom can optionally be in the R or S configuration, or a mixture of the R and S configurations.

[0093] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., isolated enantiomers) are all intended to be encompassed within the scope of the present invention. When compounds provided herein have a defined stereochemistry (designated as R or S, or with dashed or wedge bonds), it will be understood by those of skill in the art that these compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and up to 100% free of other isomers).

[0094] The compounds of the present invention may also have unnatural proportions of atomic isotopes at one or more of the isotopic atoms that constitute such compounds. An unnatural proportion of an isotope can be defined as the amount of the atom discussed up to 100% of that atom from the amount found in nature. For example, a compound may contain thorium (3H), iodine-125 (125I), or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13Non-radioactive isotopes such as CI, ...

[0095] Active ingredient As used herein, the term "compound of the invention" or "compound of the invention" refers to a compound of Formula (A) or Formula (I). The term further includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of the compound of Formula (A) or Formula (I).

[0096] Herein, the term "pharmaceutically acceptable salt" refers to a medicament-compatible salt formed between the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salt formed between the compound of the present invention and an acid. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Other preferred salts are salts formed between the compounds of the present invention and bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, t-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0097] The term "solvate" refers to a complex formed when a compound of the present invention is coordinated with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed when a compound of the present invention is coordinated with water.

[0098] Furthermore, the compounds of the present invention further include prodrugs of the compounds represented by Formula (A) or Formula (I). The term "prodrug" includes compounds that may be biologically active or inactive themselves and that, after being administered in an appropriate manner, are converted into the compounds of Formula (A) or Formula (I) or salts or solutions of the compounds of Formula (A) or Formula (I) through metabolism or chemical reactions in the human body. The prodrugs include, but are not limited to, carboxylates, carbonates, phosphates, nitrates, sulfates, sulfonates, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and other forms of the compounds.

[0099] Preparation method Other sections of this specification will describe in more detail methods for preparing the compounds of formula (A) or (I) of the present invention, but these specific methods are not intended to limit the present invention in any way. The compounds of the present invention can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily carried out by those skilled in the art.

[0100] Pharmaceutical compositions and methods of administration Since the compounds of the present invention have excellent inhibitory activity (selective inhibitory activity) against TYK2, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as active ingredients, can be used to treat, prevent and alleviate diseases mediated by TYK2 (i.e., TYK2-mediated diseases). According to the prior art, the compounds of the present invention can be used to treat diseases such as psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, neuroinflammation, various types of multiple sclerosis (including optic neuritis and neuromyelitis optica), chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, Lu Gehrig's disease, myasthenia gravis, neurological diseases, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-related encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndrome, pain, itch, depression, hypersomnia, hydrocephalus, ankylosing spondylitis, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjogren's syndrome, viral inflammation, some cancers, etc.

[0101] The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 500 mg of the compound / agent of the present invention, more preferably 1 to 200 mg of the compound / agent of the present invention. Preferably, the "single agent" is one capsule or tablet.

[0102] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to blend with each other without significantly reducing the efficacy of the compounds of the present invention and with each other. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0103] The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with a mixture of at least one of the following: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarders, such as paraffin; (f) absorption enhancers, such as quaternary amine compounds; (g) cetyl alcohol and glyceryl monostearate. monostearate), (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage forms can also include buffering agents.

[0105] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a specific part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0106] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form can contain an inert diluent conventionally used in the art, such as water or other solvents, and 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 germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0107] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0108] In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0109] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0110] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required. 1

[0111] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0112] When a pharmaceutical composition is used, a safe and prevalent amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage at the time of administration is a considered effective dose, and for a person weighing 60 kg, the daily dose is usually 1 to 500 mg, preferably 1 to 200 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0113] The main advantages of the present invention are: 1. The compounds of the present invention (particularly the compounds of the present invention in the S configuration) have excellent inhibitory activity against TYK2. 2. The compounds of the present invention have excellent inhibitory effects on pSTAT5 expression. 3. The compound of the present invention has excellent brain permeability (ability to penetrate the blood-brain barrier).

[0114] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are generally in accordance with conventional conditions or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight percentages and parts by weight.

[0115] Preparation Examples Example 1

[0116] [ka]

[0117] [ka]

[0118] Step A

[0119] [ka]

[0120] Ethyl magnesium bromide (24 mL, 71.6 mmol) was added to a three-neck flask containing 200 mL of tetrahydrofuran at 0 °C. A solution of compound 1a (6 g, 34.1 mmol) in tetrahydrofuran was slowly added dropwise at 0 °C under nitrogen gas protection, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction was monitored by LCMS. The reaction was quenched with saturated ammonium chloride solution (100 mL), diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. The yellow liquid compound 1b (3.55 g, 50.57%) was separated by column chromatography (petroleum ether / ethyl acetate = 4 / 1). LCMS: 206.0, 208.0 [M+H].

[0121] Step B

[0122] [ka]

[0123] Compound 1b (3.55 g, 17.2 mmol) and Dess-Martin oxidant (14.59 g, 34.4 mmol) were sequentially added to a 250 mL round-bottom flask containing 100 mL of anhydrous dichloromethane and stirred at room temperature for 16 h. After completion of the reaction, the pH was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (100 mL x 3), the combined extracts were washed with saturated brine (100 mL), the organic phase was collected, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate, 4 / 1) to give compound 1c (3.2 g, 91.16%) as a yellow solid. LCMS: 204.0, 206.0 [M+H]+.

[0124] Step C

[0125] [ka]

[0126] Compound 1c (300 mg, 1.47 mmol) and compound 1d (245.1 mg, 2.21 mmol) were dissolved in dioxane (10 mL), and Pd(dba) (238.35 mg, 0.29 mmol), cesium carbonate (1.44 g, 4.41 mmol), and 1,1'-bis(dicyclohexylphosphino)ferrocene (dcpf, 335.5 mg, 0.59 mmol) were added sequentially. The mixture was stirred at 80 °C for 3 h under nitrogen gas protection. After completion of the reaction, the mixture was monitored by LCMS. The mixture was concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate, 3 / 1) to give compound 1e (289 mg, 70.56%) as a yellow solid. 1H NMR(400MHz,CD3OD)δ 8.59(s,1H),8.33(s,1H),3.04(q,J=7.2Hz,2H),2.27(dd,J=7.4,4.2Hz,1H),1.58(t,J=3.9Hz ,1H),1.47(dd,J=7.4,3.6Hz,1H),1.19(t,J=7.2Hz,3H),1.04-0.94(m,3H),0.92-0.87(m,1H). LCMS:279.1,281.1[M+H]+.

[0127] Step D

[0128] [ka]

[0129] Compound 1f (800 mg, 3.94 mmol) and compound 1g (500 mg, 3.94 mmol) were dissolved in a dioxane / water mixture (20 mL / 4 mL), and Pd(dppf)Cl-CHCl (160 mg, 0.20 mmol) and potassium carbonate (1.09 g, 7.88 mmol) were added sequentially. The mixture was stirred at 110 °C for 16 h under nitrogen gas protection. The reaction was monitored by LCMS. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 15 / 1) to give compound 1h (550 mg, 68.06%) as an off-white solid. 1H NMR (400MHz, DMSO-d6): δ ppm: 8.16 (s, 1H), 7.73 (d, J = 5.2 Hz, 1 H), 6.96 (d, J = 5.6 Hz, 1 H), 6.07 (s, 2 H), 4.23 (s, 3 H), 3.64 (s, 3 H). LCMS:205.9[M+H]+.

[0130] Step E

[0131] [ka]

[0132] Compound 1e (75 mg, 0.27 mmol) and compound 1h (55.2 mg, 0.27 mmol) were dissolved in dioxane (5 mL), and XantPhos (62.28 mg, 0.11 mmol), cesium carbonate (263 mg, 0.81 mmol), and Pd2(dba)3 (49.2 mg, 0.054 mmol) were added sequentially. The mixture was stirred under nitrogen gas protection in a microwave oven at 115 °C for 2 h. After completion of the reaction, the mixture was monitored by LCMS. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 20 / 1) to give 200 mg of crude product. The crude product was separated by preparative HPLC (acetonitrile / water = 55:45, Gemini 5u C18 150 × 21.2 mm) to give 25 mg of product, which was then separated by SFC (Thar Preparation Type 80, Column: CHIRALPAK IC 250 mm × 20 mm × 5 μm, Modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, Total flow rate: 40 g / min, Temperature: 40 °C) to give two isomers: white solid Compound 1R (6.1 mg, Rt: 3.65 min) and white solid Compound 1S (7.4 mg, Rt: 7.82 min), total yield: 11.26%.

[0133] Compound 1R:1H NMR(400MHz,DMSO)δ 12.33(s,1H),10.74(s,1H),9.69(s,1H),8.95(s,1H),8.33(s,1H),8.17(d, J=5.2Hz,1H),7.47(d,J=5.2Hz,1H),4.28(s,3H),3.81(s,3H),3.17(q,J=7. 3Hz,2H),2.42(dd,J=7.4,4.4Hz,1H),1.44(t,J=3.8Hz,1H),1.35(dd,J=7.4 ,3.2Hz,1H),1.14(t,J=7.2Hz,3H),0.95-0.82(m,3H),0.78(d,J=5.4Hz,1H). LCMS: 448.2 [M+H]+.

[0134] Compound 1S: 1H NMR (400 MHz, DMSO) δ 12.33(s,1H),10.74(s,1H),9.69(s,1H),8.95(s,1H),8.33(s,1H),8.17(d, J=5.2Hz,1H),7.47(d,J=5.2Hz,1H),4.28(s,3H),3.81(s,3H),3.17(q,J=7. 3Hz,2H),2.42(dd,J=7.4,4.4Hz,1H),1.44(t,J=3.8Hz,1H),1.35(dd,J=7.4 ,3.2Hz,1H),1.14(t,J=7.2Hz,3H),0.95-0.82(m,3H),0.78(d,J=5.4Hz,1H). LCMS: 448.2 [M+H] +.

[0135] Example 2

[0136]

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[0137]

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[0138] ステップA

[0139]

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[0140] Compound 2a (1.3 g, 6.4 mmol) was dissolved in dioxane (35 mL), and pinacol diborate (4.08 g, 16.08 mmol), potassium carbonate (0.63 g, 4.56 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (0.47 g, 0.64 mmol) were added sequentially. The mixture was stirred at 90 °C for 5 h under nitrogen gas protection. After completion of the reaction monitored by LCMS, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product, which was separated by medium-pressure fast preparative chromatography (petroleum ether / ethyl acetate, 2 / 1) to give yellow solid compound 2b (1 g, 43.4%). 1H NMR (400MHz, DMSO) δ 6.82-6.77 (m, 2H), 6.75 (d, J=4.4Hz, 1H), 4.82 (s, 2H), 3.63 (s, 3H), 1.28 (s, 12H). LCMS:250.1[M+H]+.

[0141] Step B

[0142] [ka]

[0143] Compound 2b (1.04 g, 4.17 mmol) was dissolved in dioxane (16 mL) and water (4 mL), and compound 2c (450 mg, 2.78 mmol), tetrakis(triphenylphosphine)palladium (160.51 mg, 0.139 mmol), and cesium carbonate (1.82 g, 5.56 mmol) were added sequentially. The mixture was stirred at 90 °C for 6 h under nitrogen gas protection. After completion of the reaction, monitored by LCMS, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was separated by medium-pressure rapid preparative chromatography (petroleum ether / ethyl acetate, 5 / 1) to give compound 2d (0.55 g, 63.9%) as a yellow solid. 1H NMR (400MHz, DMSO-d6): δ ppm 8.47(s,1H),6.96-6.94(m,1H),6.86(t,J=8.0Hz,1H),6.75-6.73(m,1H),4.98(s,2H),3.91(s,3H),3.66(s,3H). LCMS:205.1[M+H]+.

[0144] Step C

[0145] [ka]

[0146] Compound 2e (1 g, 5.2 mmol) was added to a one-neck flask containing 15 mL of N,N-dimethylformamide at room temperature, and compound 2f (0.61 g, 6.24 mmol), N,N-diisopropylethylamine (2.01 g, 15.6 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.96 g, 7.8 mmol) were added while stirring at room temperature. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, monitor by LCMS. Pour the reaction mixture into 50 mL of ice water, extract with ethyl acetate (50 mL x 3), wash the ethyl acetate phase with saturated aqueous sodium chloride solution (20 mL x 3), dry with anhydrous Na2SO4, filter, collect the filtrate and concentrate under reduced pressure to obtain crude yellow liquid, which is separated by column chromatography (ethyl acetate / petroleum ether, 1 / 5) to obtain product yellow solid compound 2g (1.1 g, 80.77%). LCMS: 235.0, 237.0 [M+H]+.

[0147] Step D

[0148] [ka]

[0149] Compound 2g (460 mg, 1.96 mmol) and compound 2d (400 mg, 1.96 mmol) were dissolved in dry N,N-dimethylformamide (10 mL), added with sodium hydride (234 mg, 5.88 mmol, 60%) at 0 °C, and stirred at room temperature for 16 hours under nitrogen gas protection. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (50 mL × 2). The combined extracts were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was separated by medium-pressure rapid preparative chromatography (petroleum ether / ethyl acetate, 3 / 1) to give compound 2h (500 mg, 66.5%) as a yellow solid. LCMS: 403.0 [M+H]+.

[0150] Step E

[0151] [ka]

[0152] Ethyl magnesium bromide (0.7 mL, 2 mmol) was added to 200 mL of tetrahydrofuran in a three-neck flask at 0 °C, and a solution of compound 2h (500 mg, 1.2 mmol) in tetrahydrofuran was slowly added dropwise at 0 °C under nitrogen gas protection. The mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction was monitored by LCMS. The reaction was quenched with saturated ammonium chloride solution (100 mL), diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. The yellow liquid compound 2i (400 mg, 86.2%) was obtained by column chromatography (petroleum ether / ethyl acetate, 4 / 1).

[0153] Step F

[0154] [ka]

[0155] Compound 2i (50 mg, 0.2 mmol) and compound 1d (22.4 mg, 0.2 mmol) were dissolved in dry dioxane (3 mL), and 4,5-bisdiphenylphosphino-9,9-dimethoxyheteroanthracene (15.6 mg, 0.0269 mmol), cesium carbonate (88.2 mg, 0.269 mmol), and tris(dibenzylideneacetone)dipalladium (10.9 mg, 0.0135 mmol) were added sequentially. The mixture was stirred in a microwave oven at 115 °C under nitrogen gas protection for 1 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with water (30 mL) and saturated brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 10 / 1 to 5 / 1) to give 40 mg of crude product. The crude product was separated by preparative HPLC (acetonitrile / water, 55 / 45, Gemini 5u C18 150 x 21.2 mm) to give 20 mg of product, which was then separated by SFC (Tar Preparation Type 80, CHIRALPAK AD-H 250 mm x 20 mm x 5 μm column, Modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, Total flow rate: 40 g / min, Temperature: 40 °C) to give two isomers: Compound 2R (3.6 mg, Rt: 2.71 min) and Compound 2S (3.9 mg, Rt: 3.51 min), Total yield: 12.3%.

[0156] Compound 2R:1H NMR(400MHz,DMSO)δ 11.09(s,1H),10.74(s,1H),8.88(s,1H),8.13(s,1H),8.05(s,1H),7.7 2-7.68(m,1H),7.49(d,J=7.9Hz,1H),7.31(t,J=7.9Hz,1H),4.24(s,3H) ,3.64(s,3H),3.13(q,J=7.1Hz,2H),2.36(dd,J=7.4,4.2Hz,1H),1.36-1 .29(m,2H),1.12(t,J=7.2Hz,3H),0.88-0.79(m,3H),0.74-0.68(m,1H). LCMS: 446.9 [M+H]+.

[0157] Compound 2S: 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 10.74 (s, 1H), 8.88 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.72-7.68 (m, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 4.24 (s, 3H), 3.64 (s, 3H), 3.13 (q, J = 7.1 Hz, 2H), 2.36 (dd, J = 7.4, 4.2 Hz, 1H), 1.36-1.29 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H), 0.88 -0.79 (m, 3H), 0.74-0.68 (m, 1H). LCMS: 446.9 [M+H] +.

[0158] Example 3

[0159]

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[0160]

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[0161] ステップA

[0162]

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[0163] Compound 1f (780 mg, 3.84 mmol) and compound 3a (500 mg, 3.85 mmol) were dissolved in a dioxane / water mixture (20 mL / 4 mL), and Pd(dppf)Cl-CHCl (157 mg, 0.19 mmol) and potassium carbonate (1.06 g, 7.68 mmol) were added sequentially. The mixture was stirred at 110 °C for 16 h under nitrogen gas protection. The reaction was monitored by LCMS. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 15 / 1) to give compound 3b (300 mg, 37.44%) as an off-white solid. 1H NMR (400MHz, DMSO-d6): δ ppm: 8.15 (s, 1H), 7.73 (d, J = 5.2 Hz, 1H), 6.96 (d, J = 5.6 Hz, 1H), 6.06 (s, 2H), 3.63 (s, 3H). LCMS:209.0[M+H]+.

[0164] Step B

[0165] [ka]

[0166] Compound 1e (65 mg, 0.23 mmol) and compound 3b (48.5 mg, 0.23 mmol) were dissolved in dioxane (5 mL), and XantPhos (53.9 mg, 0.093 mmol), cesium carbonate (227.9 mg, 0.70 mmol), and Pd2(dba)3 (42.7 mg, 0.047 mmol) were added sequentially. The mixture was stirred in a microwave oven at 115 °C for 2 h under nitrogen gas protection. After completion of the reaction, the mixture was monitored by LCMS. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 20 / 1) to give 120 mg of crude product. The crude product was separated by preparative HPLC (acetonitrile / water = 55:45, Gemini 5u C18 150 × 21.2 mm) to give 30 mg of a white solid, which was then separated by SFC (Tar Preparation Type 80, Column: CHIRALPAK IC 250 mm × 20 mm × 5 μm, Modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, Total flow rate: 40 g / min, Temperature: 40 °C) to give two isomers: Compound 3R (11.5 mg, Rt: 3.58 min) and Compound 3S (12.6 mg, Rt: 7.23 min), Total yield: 22.93%.

[0167] Compound 3R:1H NMR(400MHz,DMSO)δ 12.32(s,1H),10.72(s,1H),9.68(s,1H),8.95(s,1H),8.32(s,1H),8.17 (d,J=5.2Hz,1H),7.47(d,J=5.2Hz,1H),3.81(s,3H),3.16(q,J=7.2Hz,2H ),2.42(dd,J=7.2,4.3Hz,1H),1.44(t,J=3.6Hz,1H),1.35(dd,J=7.3,3.1Hz,1H),1.14(t,J=7.1Hz,3H),0.97-0.82(m,3H),0.78(d,J=5.6Hz,1H). LCMS: 451.1 [M+H]+.

[0168] Compound 3S: 1H NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 10.72 (s, 1H), 9.68 (s, 1H), 8.95 (s, 1H), 8.32 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 3.81 (s, 3H), 3.16 (q, J = 7.2 Hz, 2H), 2.42 (dd, J = 7.2, 4.3 Hz, 1H), 1.44 (t, J = 3.6 Hz, 1H), 1.35 (dd, J = 7.3, 3.1 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H), 0.97-0.82 (m, 3H), 0.78 (d, J = 5.6 Hz, 1H). LCMS: 451.2 [M+H] +.

[0169] Example 4

[0170]

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[0171]

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[0172] ステップA

[0173]

change

[0174] Compound 4a (10 g, 45.66 mmol) and potassium carbonate (12.62 g, 91.33 mmol) were sequentially added to a 250 mL round-bottom flask containing 100 mL of N,N-dimethylformamide and stirred at room temperature for 10 min. (2H3)methyl iodide (12.96 g, 91.33 mmol) was added and stirred at 30 °C for 20 h. The reaction was monitored by LCMS. After completion of the reaction, the mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure. 300 mL of water was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 15 / 1) to give compound 4b (5 g, 46.97%) as a yellow solid. LCMS: 236.0, 238.0 [M+H]+.

[0175] Step B

[0176] [ka]

[0177] Compound 4b (5 g, 22.0 mmol), iron powder (4.92 g, 88.1 mmol), and ammonium chloride (4.71 g, 88.1 mmol) were sequentially added to a 500 mL round-bottom flask containing 90 mL of ethanol and 30 mL of water, and the mixture was stirred at 70 °C for 3 h. After completion of the reaction, monitored by LCMS, the mixture was filtered and the filtrate was concentrated under reduced pressure. The mixture was diluted with 50 mL of water and extracted with ethyl acetate (200 mL × 3). The combined extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate, 1 / 1) to give compound 4c (3.3 g, 72.7%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm: 7.60 (d, J = 5.3 Hz, 1H), 6.81 (d, J = 5.2 Hz, 1H), 4.82 (s, 2H). LCMS: 206.0, 208.0 [M+H]+.

[0178] Step C

[0179] [ka]

[0180] Compound 4c (1.0 g, 4.85 mmol) and compound 1g (650 mg, 5.34 mmol) were dissolved in a mixture of dioxane (20 mL) and water (4 mL). Potassium carbonate (2.02 g, 14.55 mmol) and Pd(dppf)Cl-CHCl (400.1 mg, 0.49 mmol) were added sequentially, and the mixture was stirred at 110 °C for 16 h under nitrogen gas protection. After completion of the reaction, the mixture was monitored by LCMS. The mixture was filtered and the filtrate was concentrated under reduced pressure. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (petroleum ether / ethyl acetate, 1 / 2) to give compound 4d (300 mg, 29.7%) as a yellow solid.

[0181] 1H NMR (400MHz, CDCl3): δ ppm 8.10(s,1H),7.87(d,J=5.2Hz,1H),7.18(d,J=5.2Hz,1H),4.84(s,2H),4.28(s,3H). LCMS:209.2[M+H]+.

[0182] Step D

[0183] [ka]

[0184] Compound 1e (65 mg, 0.23 mmol) and compound 4d (48.5 mg, 0.23 mmol) were dissolved in dioxane (5 mL), and XantPhos (53.9 mg, 0.093 mmol), cesium carbonate (227.9 mg, 0.70 mmol), and Pd2(dba)3 (42.7 mg, 0.047 mmol) were added sequentially. The mixture was stirred in a microwave oven at 115 °C for 2 h under nitrogen gas protection. After completion of the reaction, the mixture was monitored by LCMS. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 20 / 1) to give 200 mg of crude product. The crude product was separated by preparative HPLC (acetonitrile / water = 55:45, Gemini 5u C18 150 × 21.2 mm) to give 30 mg of product, which was then separated by SFC (Tar Preparation Type 80, Column: CHIRALPAK IC 250 mm × 20 mm × 5 μm, Modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, Total flow rate: 40 g / min, Temperature: 40 °C) to give two isomers: Compound 4R (10.3 mg, Rt: 3.54 min) and Compound 4S (9.2 mg, Rt: 7.07 min), Total yield: 18.53%.

[0185] Compound 4R:1H NMR(400MHz,DMSO)δ 12.33(s,1H),10.73(s,1H),9.69(s,1H),8.95(s,1H),8.33(s,1H),8.18(d,J=5.2Hz,1H),7.47(d,J=5.2Hz,1H),4.28(s,3H),3. 17(q,J=7.1Hz,2H),2.42(dd,J=7.2,4.4Hz,1H),1.44(t,J=3.7Hz,1H),1.36(dd,J=7.4,3.3Hz,1H),1.14(t,J=7.1Hz,3H),0.95- 0.82(m,3H),0.78(d,J=5.5Hz,1H). LCMS: 451.1 [M+H]+.

[0186] Compound 4S: 1H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 10.73 (s, 1H), 9.69 (s, 1H), 8.95 (s, 1H), 8.33 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 4.28 (s, 3H), 3.17 (q, J = 7.1 Hz, 2H), 2.42 (dd, J = 7.2, 4.4 Hz, 1H), 1.44 (t, J = 3.7 Hz, 1H), 1.36 (dd, J = 7.4, 3.3 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H), 0.95-0.82 (m, 3H), 0.78 (d, J = 5.5 Hz, 1H). LCMS: 451.1 [M+H] +.

[0187] Example 5

[0188]

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[0189]

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[0190] ステップA

[0191]

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[0192] Compound 4c (793.3 mg, 3.85 mmol) and compound 3a (500 mg, 3.85 mmol) were dissolved in a mixture of dioxane (20 mL) and water (4 mL). Potassium carbonate (1.6 g, 11.55 mmol) and Pd(dppf)Cl-CHCl (318.5 mg, 0.39 mmol) were added sequentially, and the mixture was stirred at 90 °C for 16 h under nitrogen gas protection. After monitoring by LCMS, the reaction was completed. The mixture was filtered and the filtrate was concentrated under reduced pressure. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (petroleum ether / ethyl acetate, 1 / 2) to give compound 5a (400 mg, 49.1%) as a yellow solid.

[0193] 1H NMR (400MHz, CDCl3): δ ppm 8.11 (s, 1H), 7.86 (s, 1H), 7.18 (d, J = 5.2Hz, 1H), 4.86 (s, 2H). LCMS:212.3[M+H]+.

[0194] Step B

[0195] [ka]

[0196] Compound 1e (65 mg, 0.23 mmol) and compound 5a (48.5 mg, 0.23 mmol) were dissolved in dioxane (5 mL), and XantPhos (53.9 mg, 0.093 mmol), cesium carbonate (227.9 mg, 0.70 mmol), and Pd2(dba)3 (42.7 mg, 0.047 mmol) were added sequentially. The mixture was stirred in a microwave oven at 115 °C for 2 h under nitrogen gas protection. After completion of the reaction, the mixture was monitored by LCMS. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 20 / 1) to give 200 mg of crude product. The crude product was separated by preparative HPLC (acetonitrile / water = 55:45, Gemini 5u C18 150 × 21.2 mm) to give 25 mg of product, which was then separated by SFC (Tar Preparation Type 80, Column: CHIRALPAK IC 250 mm × 20 mm × 5 μm, Modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, Total flow rate: 40 g / min, Temperature: 40 °C) to give two isomers: Compound 5R (4.3 mg, Rt: 3.78 min) and Compound 5S (6.4 mg, Rt: 7.67 min), Total yield: 10.14%.

[0197] Compound 5R:1H NMR(400MHz,DMSO)δ 12.33(s,1H),10.74(s,1H),9.69(s,1H),8.95(s,1H),8.33(s,1H),8.17(d,J=5.2Hz,1H),7.47(d,J=5.2Hz,1H),3.17(q,J= 1H) LCMS:454.2[M+H]+.

[0198] Compound 5S: 1H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 10.74 (s, 1H), 9.69 (s, 1H), 8.95 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 3.17 (q, J = 7.1 Hz, 2H), 2.42 (dd, J = 7.2, 4.5 Hz, 1H), 1.44 (t, J = 3.7 Hz, 1H), 1.39-1.33 (m, 1H), 1.14 (t, J = 7.1 Hz, 3H), 0.97-0.82 (m, 3H), 0.78 (d, J = 5.4 Hz, 1H). LCMS: 454.0 [M+H].

[0199] Example 6

[0200]

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[0201]

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[0202] ステップA

[0203]

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[0204] Compound 6a (300 mg, 1.59 mmol) was dissolved in concentrated sulfuric acid (4 mL) at 0 °C, and fuming nitric acid (2 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was added to ice water (10 mL) and stirred for 5 min. The mixture was then extracted with ethyl acetate (50 mL × 2). The combined extracts were washed with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL), respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 20 / 1) to give compound 6b (140 mg, 28.24%) as a yellow solid. H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 7.98 (s, 1H), 2.41 (s, 3H). LCMS: Rt = 1.14 min, MS 233.1 [M+H] + .

[0205] Step B

[0206] [ka]

[0207] Compound 6b (140 mg, 0.60 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (166.0 mg, 1.20 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. Under nitrogen gas protection, iodomethane (170.5 mg, 1.20 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS. Upon completion, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (ethyl acetate / petroleum ether, 1 / 10) to give compound 6c (144 mg, 97.02%) as an off-white solid. LCMS: 247.0 [M+H]+.

[0208] Step C

[0209] [ka]

[0210] Compound 6c (144 mg, 0.58 mmol) was dissolved in a mixed solvent containing ethanol:acetic acid:water (5 mL:5 mL:2.5 mL), iron powder (180.8 mg, 3.23 mmol) was added at room temperature, and the mixture was stirred at room temperature under nitrogen gas protection for 2 hours. The reaction was monitored by LCMS. After completion of the reaction, the mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure. 30 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 20 / 1) to give compound 6d (120 mg, 94.81%) as a yellow solid. LCMS: MS 217.1 [M+H]+

[0211] Step D

[0212] [ka]

[0213] Compound 6d (120 mg, 0.5527 mmol) and compound 1g (122.79 mg, 0.96 mmol) were dissolved in a mixture of dioxane (10 mL) and water (1 mL), and potassium carbonate (267.44 mg, 1.93 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (52.67 mg, 0.06 mmol) were added sequentially. The mixture was stirred at 110 °C for 16 hours under nitrogen gas protection. After completion of the reaction, the mixture was monitored by LCMS, filtered, and the filtrate was concentrated under reduced pressure. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 2). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure fast preparative chromatography (dichloromethane / methanol, 20 / 1) to give compound 6e (110 mg, 90.79%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 6.83 (s, 1H), 5.98 (s, 2H), 4.22 (s, 3H), 3.60 (s, 3H), 2.24 (s, 3H). LCMS: MS 220.2 [M+H] +

[0214] Step E

[0215] [ka]

[0216] Compound 1e (33 mg, 0.12 mmol) and compound 6e (25.9 mg, 0.12 mmol) were dissolved in dioxane (5 mL), and XantPhos (27.4 mg, 0.047 mmol), cesium carbonate (115.7 mg, 0.36 mmol), and Pd2(dba)3 (21.6 mg, 0.024 mmol) were added sequentially. The mixture was stirred under nitrogen gas protection in a microwave oven at 115 °C for 2 h. After completion of the reaction, monitored by LCMS, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 20 / 1) to give 50 mg of crude product. The crude product was separated by preparative HPLC (acetonitrile / water, 55 / 45; Gemini 5u C18 150×21.2 mm) to give 20 mg of racemic product, which was then separated by SFC (Tar Preparation Type 80, Column: CHIRALPAK IC 250 mm×20 mm×5 μm, Modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, Total flow rate: 40 g / min, Temperature: 40 °C) to give two isomers: Compound 6R (3.7 mg, Rt: 3.65 min) and Compound 6S (2.5 mg, Rt: 7.82 min), Total yield: 11.2%.

[0217] Compound 6R:1H NMR(400MHz,DMSO)δ 12.25(s,1H),10.70(s,1H),9.92(s,1H),8.94(s,1H),8.29(s,1H),7.33( s,1H),4.27(s,3H),3.78(s,3H),3.16(q,J=7.2Hz,2H),2.51(s,3H),2.42 (dd,J=7.3,4.4Hz,1H),1.43(t,J=3.8Hz,1H),1.35(dd,J=7.4,3.3Hz,1H) ,1.13(t,J=7.2Hz,3H),0.88(dt,J=8.4,4.8Hz,3H),0.77(d,J=5.5Hz,1H). LCMS: 462.0 [M+H]+.

[0218] Compound 6S: 1H NMR(400MHz, DMSO)δ 12.25(s,1H),10.70(s,1H),9.92(s,1H),8.94(s,1H),8.29(s,1H),7.33( s,1H),4.27(s,3H),3.78(s,3H),3.16(q,J=7.2Hz,2H),2.51(s,3H),2.42 (dd,J=7.3,4.4Hz,1H),1.43(t,J=3.8Hz,1H),1.35(dd,J=7.4,3.3Hz,1H) ,1.13(t,J=7.2Hz,3H),0.88(dt,J=8.4,4.8Hz,3H),0.77(d,J=5.5Hz,1H). LCMS: 462.0 [M+H] +.

[0219] Example 7

[0220]

change

[0221] ステップA

[0222]

change

[0223] Compound 1c (450 mg, 2.22 mmol) and compound 7a (370 mg, 3.33 mmol) were dissolved in dioxane (15 mL), and Pd(dba) (360 mg, 0.44 mmol), cesium carbonate (1.44 g, 4.41 mmol), and 1,1'-bis(dicyclohexylphosphino)ferrocene (dcpf, 335.5 mg, 0.59 mmol) were added sequentially. The mixture was stirred at 80 °C for 3 h under nitrogen gas protection. After completion of the reaction, the mixture was monitored by LCMS. The mixture was concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate, 3 / 1) to give compound 7b (521 mg, 84.4%) as a yellow solid. 1H NMR(400MHz,CD3OD)δ 8.59(s,1H),8.33(s,1H),3.04(q,J=7.2Hz,2H),2.27(dd,J=7.4,4.2Hz,1H),1.58(t,J=3.9Hz ,1H),1.47(dd,J=7.4,3.6Hz,1H),1.19(t,J=7.2Hz,3H),1.04-0.94(m,3H),0.92-0.87(m,1H). LCMS:279.1,281.1[M+H]+.

[0224] Step B

[0225] [ka]

[0226] Compound 7b (65 mg, 0.23 mmol) and compound 4d (48.54 mg, 0.23 mmol) were dissolved in dioxane (5 mL), and XantPhos (54 mg, 0.093 mmol), cesium carbonate (228 mg, 0.70 mmol), and Pd2(dba)3 (42.7 mg, 0.047 mmol) were added sequentially. The mixture was stirred in a microwave oven at 115 °C for 2 h under nitrogen gas protection. After completion of the reaction, monitored by LCMS, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 20 / 1) to give 150 mg of crude product. The crude product is separated by preparative HPLC (acetonitrile / water, 55 / 45; Gemini 5u C18 150×21.2 mm) to give a white solid compound 4S (30 mg, 29%) (OR: 110, 23.2° C.). 1H NMR(400MHz,DMSO)δ 12.33(s,1H),10.73(s,1H),9.69(s,1H),8.95(s,1H),8.33(s,1H),8.17( d,J=5.2Hz,1H),7.47(d,J=5.2Hz,1H),4.28(s,3H),3.17(q,J=7.2Hz,2H), 2.43(dd,J=7.4,4.3Hz,1H),1.44(t,J=3.8Hz,1H),1.36(dd,J=7.4,3.3Hz, 1H),1.14(t,J=7.2Hz,3H),0.98-0.83(m,3H),0.78(dd,J=8.2,2.7Hz,1H). LCMS: 451.1 [M+H]+.

[0227] Test Example Test Example 1: FACS detection of the inhibitory effect of compounds on pSTAT5 expression in CD3+ cells 1. Experimental materials and equipment 1.1. Experimental Reagents DMSO, Sigma, Cat# D2650-100ml, store at room temperature. Perm Buffer III, BD Biosciences, Cat# 558050, store at 4°C. Lysis / Fixation Buffer, BD Biosciences, Cat# 558049, store at room temperature. EDTA, Invitrogen, Cat# 15575-038, store at room temperature. · PBS, Hyclone, Cat# SH30256.01, store at 4°C. PE Mouse Anti-Human CD3, BD Biosciences, Cat# 555333, store at 4°C. Mouse anti-human STAT5 (pY694) (Alexa Fluor® 647 conjugate), BD Biosciences, Cat# 562076, store at 4°C. IFN-α, Biolegend, Cat#592702.

[0228] 1.2.Experimental Consumables Microplate, 96 wells, PP, V-bottom, Greiner, Cat# GN651201-100EA. 5mL Polystyrene Round Bottom Tube, FALCON, Cat# 04318011. 96-hole storage plate, Thermo, Cat# AB-0661. 96-well plate, Corning, Cat# 3599.

[0229] 1.3.Equipment CO2 cell incubator: MCO-15AC (Thermo). Pipettes: 0.2-10μL, 20-200μL, 200-1000μL (thermo). Multichannel pipettes: 0.2-10μL, 5-50μL, 20-300μL (Raining). Centrifuge: Thermo Centrifuge ST 40R, Thermo LEGEND Micro 21R. Water system: Millipore Milli-Q Reference System. Freezer: Haier ultra-low temperature freezer. Haier 4°C refrigerator. Haier -20°C freezer. Eddie: EARTH REQUIRED. ·Plate making machine: QI LIN BEI ER, MH-2. ·Flow cytometer: BD FACSVerse™ flow cytometer.

[0230] 2. Experimental Method 2.1. Compound Dilution 1) On the day of the experiment, compounds are prepared in DMSO to a 10 mM solution, diluted to 1.5 mM in DMSO, and then diluted 3-fold to eight gradient concentrations. 2) 5 μL of diluted compound is transferred to 120 μL of 0.1% BSA in DPBS solution. 3) A positive control group and a negative control group are set up, and 0.2% DMSO is added to the positive control group and the negative control group.

[0231] 2.2. Experimental Process 1) Add 0.5 million human PBMC cells in a volume of 67.5 uL to each well of a 96-well cell culture plate. 2) Add 3.5 ul of diluted compound and mix evenly. 3) Incubate in a 37°C incubator for 60 minutes. 4) Dilute IFN-α to 600ng / mL with DPBS containing 0.1% BSA, and dilute PE-anti-hCD3 antibody 3-fold with DPBS containing 0.1% BSA. After the 60-minute incubation, add 5uL of diluted PE-anti-hCD3 antibody to each well and 4uL of diluted IFN-αα to each well, so that the final concentration of IFN-α in each well is 30ng / mL. 5) Incubate in a 37°C incubator for 30 minutes. 6) Transfer all cells to a 96-well deep-well plate and add 1 mL of lysis / fixation buffer preheated to 37°C. 7) Incubate in the dark at 37°C for 10 minutes. 8) After centrifugation at 600 g for 5 minutes, discard the supernatant, add 1 mL of PBS to wash twice, and then centrifuge. 9) Add 1 mL of Perm Buffer III to the cell pellet. 10) Incubate in the dark at 4°C for 30 minutes. 11) After centrifugation at 600 g for 5 minutes, discard the supernatant, add 1 mL of PBS to wash twice, and then centrifuge. 12) Dilute the APC anti-human pSTAT5 antibody 200-fold with staining buffer, add 100 μL per well to the cell wells, and mix evenly. 13) Incubate at room temperature for 40 minutes. 14) Wash twice by adding staining buffer, 1 mL per well, and centrifuge at 600 g for 5 minutes. 15) After discarding the supernatant, resuspend the cell pellet in 300 uL of staining buffer. 16) Load the samples into the flow cytometer and analyze them. Obtain the IC50 of the test sample (Table 1).

[0232] [Table 3]

[0233] A<50nM, B>50nM.

[0234] Test Example 2: Comparison of selectivity of JAK family 1. Experimental Method 1.1. Pseudokinase Experimental Procedure:

[0235] 1.1.1. Compounds are dissolved in DMSO to a stock concentration of 10 mM.

[0236] 1.1.2. Prepare compound concentrations 200 times the final concentration in the compound dilution plate, and dilute them according to the 27-fold dilution method from the highest concentration point to a total of four concentration points, and transfer them to the Echo plate.

[0237] 1.1.3. Using the Echo instrument, pulse the compounds from the Echo plate into a 384-well experimental plate so that the compounds are in a 3-fold dilution matrix with 11 concentration points.

[0238] 1.1.4. Add 5ul of 3X TYK2 (JH2) or JAK1 (JH2) kinase to a 384-well experimental plate.

[0239] 1.1.5. Add 5ul of 3X Tb to a 384-well experimental plate.

[0240] 1.1.6. Add 5ul of 3X Tracer to a 384-well experimental plate.

[0241] 1.1.7.Centrifuge for 30 seconds and incubate at room temperature for 60 minutes.

[0242] 1.1.8. Read the signal value on an Envision microplate reader (PerkinElmer).

[0243] 1.2. The procedure for the kinase experiment is as follows.

[0244] 1.2.1. Compounds are dissolved in DMSO to a stock concentration of 10 mM.

[0245] 1.2.2. Prepare compound concentrations 100 times the final concentration in a compound dilution plate, and dilute from the highest concentration point to a total of four concentration points according to a 27-fold dilution method, and transfer to an Echo plate.

[0246] 1.2.3. Using the Echo instrument, pulse the compounds from the Echo plate into the 384 experimental plate so that the compounds are in a 3-fold dilution matrix with 11 concentration points.

[0247] 1.2.4. Prepare 2X kinase working solution and add 5ul per well to a 384 well experimental plate and incubate compound and kinase for 15 minutes at room temperature.

[0248] 1.2.5. Add 5ul of 2X substrate (containing ATP) to a 384-well plate.

[0249] 1.2.6. Incubate at room temperature for 45 minutes.

[0250] 1.2.7. Add the detection reagent mixture to the 384-well plate, centrifuge for 30 seconds, and incubate at room temperature for 60 minutes.

[0251] 1.2.8. Read the signal value on an Envision microplate reader (PerkinElmer).

[0252] Data Analysis 1.3.1. Analyze the data using XL-Fit software to obtain compound IC50s (Table 2).

[0253] [Table 4]

[0254] Test Example 3: Multiple sclerosis animal model study Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system and a common animal model of multiple sclerosis. This experiment aimed to investigate the efficacy of compound 4S on the clinical symptoms and histopathology of myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice.

[0255] Sixty specific pathogen-free (SPF) female C57BL / 6 mice were randomly divided into six groups based on body weight: normal control group, model (vehicle) group, low-dose Compound 4S (10 mg / kg, QD) group, medium-dose Compound 4S (30 mg / kg, QD) group, medium-dose Compound 4S (30 mg / kg, BID) group, and high-dose Compound 4S (90 mg / kg, QD) group, with 10 animals per group. Except for the normal group, mice in each group were subcutaneously injected with 200 μL of MOG 35-55 emulsion to induce EAE. At 0 and 48 hours after MOG immunization, each mouse was intraperitoneally injected with 250 μL of pertussis toxin (PTX, 1 μg / mL) for boosting immunity. Except for the normal group, mice in each group were administered vehicle (ethanol: vitamin E polyethylene glycol succinate: polyethylene glycol 300 = 5:5:90) or compound 4S daily for a total of 14 days from day 15 (day 15) to day 28 after immunization. The animals' health was closely monitored throughout the experiment, and their weights and clinical scores were recorded daily (Figures 1A and 1B). On day 28, the mice were euthanized with carbon dioxide. Blood samples were collected, and serum TNF-α and IFN-γ levels were measured by ELISA (Figures 2A and 2B).

[0256] Test Example 4: Drug concentration analysis of plasma samples and brain tissue samples The purpose of this study was to evaluate the drug concentrations in plasma and brain tissue samples from female C57BL / 6 mice after 15 consecutive oral doses of 10 mg / kg, 30 mg / kg, and 90 mg / kg of compound 4S. The drug concentrations in plasma and brain tissue homogenate samples were detected using a liquid mass spectrometer in the positive ion (ESI) multiple reaction ion monitoring (MRM) scan mode, with a linear detection range of 1 to 10,000 ng / mL.

[0257] For plasma samples from 10 mice orally administered compound 4S, including the standard curve, quality control, single blank, and unknown samples, the sampling volume was all 10 µL. Add 200 µL of 1:1 methanol:acetonitrile (v / v) precipitant (containing 5 ng / mL terfenadine). For double blank samples, add 200 µL of 1:1 methanol:acetonitrile (v / v) precipitant. Vortex the samples for 1 min and centrifuge them for 15 min (4000 rpm, 4 °C) to obtain the supernatant solution. Dilute the supernatant 10-fold with 1:1 methanol:water (v / v, containing 0.1% FA) for LC-MS / MS analysis.

[0258] Brain tissue homogenate samples from 10 mice orally administered compound 4S were collected in a 50 μL volume for the standard curve, quality control, single blank, and unknown samples. 200 μL of methanol:acetonitrile (1:1, v / v) precipitant (containing 5 ng / mL terfenadine) was added to each sample. For double blank samples, 50 μL of blank brain tissue homogenate was collected and 200 μL of methanol:acetonitrile (1:1, v / v) precipitant was added. The samples were vortexed for 1 minute and centrifuged for 15 minutes at 4000 rpm and 4°C to obtain the supernatant. The supernatant was diluted 10-fold with 1:1 methanol:water (v / v, containing 0.1% FA) for LC-MS / MS analysis. Drug exposure in plasma and brain tissue samples was compared at different doses and at different administration frequencies for the same dose (Table 3).

[0259] [Table 5]

[0260] Two hours after the final administration, comparison of plasma and brain tissue samples at different doses revealed that drug concentrations showed a significant increase with increasing dose, demonstrating a relatively clear dose-dependence. Comparison of the same dose at different dosing frequencies revealed that plasma and brain tissue samples did not significantly increase with increasing dosing frequency. Furthermore, the concentration ratios between brain tissue and plasma samples ranged from 0.788 to 1.32, indicating moderate brain penetration. Comparison of plasma concentration dose differences revealed that the ratio between plasma concentrations was slightly lower with increasing dose, while the ratio between brain sample concentrations was slightly higher with increasing dose.

[0261] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound of formula (A) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 where: Y is N or CR ９ and R １ is H and optionally substituted C １－４ alkyl groups, R ２ is H and optionally substituted C １－４ alkyl groups, R ３ and R ４ are each independently H, halogen, and optionally substituted C １－４ alkyl groups, R ５ is H and optionally substituted C １－６ alkyl groups, R ６ is H and optionally substituted C １－４ alkyl groups, R ７ is H and optionally substituted C １－４ alkyl groups, R ９ is H and optionally substituted C １－４ alkyl groups, The term "optionally substituted" means that the group is unsubstituted or optionally substituted with deuterium, halogen, C １－４ Alkyl groups, and C １－４ A compound or a pharmaceutically acceptable salt thereof, which refers to a compound substituted with one or more substituents selected from the group consisting of haloalkyl groups.

2. Y is N or CH; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ is C １－４ Alkyl groups and deuterated C １－４ alkyl groups, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. R ２ is C １－４ Alkyl groups and deuterated C １－４ alkyl groups, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. R ３ is H, and C １－４ alkyl groups, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. The compound has the formula (I):

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 【Chemistry 2】

7. The compound is represented by formula (IS) or formula (IR):

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 【Chemistry 3】 【Chemistry 4】

8. The compound is a compound selected from Table A or Table B, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 【Table 1】 【Table 2】

9. The compound is compound 1S, 2S, 3S, 4S, 5S, or 6S in Table B.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof.

10. The compound is compound 4S.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof.

11. 1. A pharmaceutical composition comprising:

10. A pharmaceutical composition comprising: (i) a compound of claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or excipient.

12. 10. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 5 in the preparation of (i) a medicament for treating or preventing a TYK2-mediated disease and / or (ii) a TYK2 inhibitor.

13. The TYK2 mediated disease comprises psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, vasculitis, fibrosis, dermatitis, skin aging, encephalitis, lupus nephritis, neuroinflammation, multiple sclerosis (including optic neuritis and neuromyelitis optica), chronic inflammatory demyelinating polyneuropathy, Parkinson's disease, dementia, Lu Gehrig's disease, myasthenia gravis, neurological diseases, schizophrenia, epilepsy, spinal cord injury, sleep disorders, brain injury, stroke, neuropsychiatric lupus, diabetic encephalopathy, sepsis-related encephalopathy, central nervous system tumors, Huntington's disease, postoperative neurological syndrome, pain, itch, depression, hypersomnia, hydrocephalus, ankylosing spondylitis, respiratory disease, diabetes, inflammatory eye disease, hepatitis, cardiovascular disease, systemic sclerosis, organ transplant, alopecia areata, acne, eczema, vitiligo, Sjogren's syndrome, viral inflammation, cancer, or a combination thereof.

13. The use according to claim 12.

14. A process for preparing a compound of formula (IS), comprising the steps of: 【Chemistry 5】 The preparation method comprises reacting an intermediate of formula (II-S) with an intermediate of formula (III) to obtain a compound as shown in formula (IS), 【Chemistry 6】 【Chemistry 7】 In each formula, Y, R １ , R ２ and R ３ A process for preparing the compound defined by formula (I).

15. Intermediates of formula (II-S). 【Chemistry 8】

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