Compounds as tyk2 / jak1 pseudokinase domain inhibitors and methods of synthesis and use

Abstract

The present invention provides compounds as TYK2 JAK1 pseudokinase domain inhibitors and methods of synthesis and use. In particular, a compound, or a pharmaceutically acceptable salt thereof, is provided, the compound being of Formula A, the various groups being as defined herein.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a compound as an inhibitor of the TYK2 pseudokinase (JH2) domain, its synthesis method, and its uses. Background Technology

[0002] Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signal transduction and activation of various cytokines. The JAK kinase family is divided into four subtypes: JAK1, 2, 3, and TYK2. Each subtype mediates different types of cytokine signaling pathways. JAK1, 2, and TYK2 are expressed in all tissues and cells of the human body, while JAK3 is mainly expressed in hematopoietic tissue cells.

[0003] TYK2 is the earliest discovered subtype of the JAK family, mediating the function 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 occurrence of immune diseases such as allergies, autoimmune diseases, and inflammation. IL-23 plays a crucial role in the development and progression of psoriasis. Recent research indicates that the pathogenesis of psoriasis involves endogenous unknown antigens activating antigen-presenting cells (APCs) to secrete IL-23. IL-23 then activates Th17 cells to secrete cytokines such as IL-17, inducing keratinocyte differentiation and proliferation and IL-23 secretion, further stimulating inflammation and keratinocyte proliferation to produce psoriasis. TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23. Inhibition of JAK2 can lead to anemia and other blood-related side effects; therefore, inhibiting TYK2 while avoiding inhibition of JAK2 is a good strategy for inhibiting the IL-23 signaling pathway. The first oral tofacitinib is a non-selective JAK inhibitor with significant inhibitory activity against JAK1, 2, 3, and TYK2. It specifically inhibits the catalytic domain (JH1, or "homology 1 domain of JAK protein") that binds to adenosine triphosphate (ATP), preventing phosphorylation of downstream kinases and the resulting pathway signal transduction by blocking ATP. Tofacitinib's inhibition of other subtypes such as JAK1, 2, 3, and TYK2 increases efficacy but also brings more serious side effects, including infection, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. Since JAK2 activity is related to erythroid differentiation and lipid metabolism, some of the aforementioned adverse reactions, such as anemia, are thought to be related to tofacitinib's insufficient selectivity for JAK2, resulting from the drug's non-selective inhibition.

[0004] Given the good efficacy and severe side effects associated with multiple target-related factors of non-selective JAK inhibitors, there is an urgent need in the field for a JAK kinase family inhibitor that can selectively bind to the pseudokinase (JH2) domain (such as the JH2 domains of TYK2 and JAK1) to differentiate itself from the binding catalytic domain (JH1) of previous JAK inhibitors, thereby inhibiting the function of the pseudokinase (JH2) domain and avoiding inhibition of other subtypes such as JAK1, 2, 3, TYK2, or their kinase domains (JH1), thus increasing the pseudokinase (JH2) activity of TYK2 and JAK1. The safety profile of inhibitors suggests their significant clinical potential for use in the treatment of various autoimmune and inflammatory diseases related to the function of the TYK2 and JAK1 pseudokinase (JH2) domains, including psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, dermatitis, lupus nephritis, neuroinflammatory diseases such as multiple sclerosis and Alzheimer's disease, ankylosing spondylitis, hidradenitis suppurativa, 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.

[0005] Therefore, there is an urgent need in this field to develop TYK2 pseudokinase (JH2) domain inhibitors with novel structures, high safety and good efficacy. Summary of the Invention

[0006] The purpose of this invention is to provide a novel type of TYK2 pseudokinase (JH2) domain inhibitor with high safety and excellent efficacy.

[0007] In a first aspect of the invention, a compound or a pharmaceutically acceptable salt thereof is provided, characterized in that the compound is of formula A.

[0008]

[0009] in,

[0010] The ring Ar is a five-membered heteroaromatic ring; and the five-membered heteroaromatic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-4 Alkylene-OC 1-6 Alkyl, substituted or unsubstituted C 1-4 Alkylene-SC 1-6 alkyl;

[0011] Y is either CH or N;

[0012] X is CH or N;

[0013] R3 is selected from the following group: H, halogen, substituted or unsubstituted C. 1-6 Alkyl, hydroxyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkylthio;

[0014] R4 is absent, or represents one or two substituents selected from the group consisting of halogen, substituted or unsubstituted C. 1-3 alkyl;

[0015] W 1a and W 1b Each is independently selected from the following groups: none (single bond), -O-, -S-, -SO. 2- -CO-, -NR5-; and W 1a and W 1b At least one of them is not zero;

[0016] W 2a and W 2b Each is independently selected from the following groups: none (single bond), -O-, -S-, -SO. 2- -CO-, -NR5-; and W 2a and W 2b At least one of them is not zero;

[0017] R5s are independently selected from the following groups: H, substituted or unsubstituted C. 1-4 alkyl;

[0018] Unless otherwise specified, substitution refers to the substitution of one or more (e.g., 1, 2, or 3) hydrogen atoms in a group by a substituent selected from the group consisting of: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups.

[0019] In another preferred embodiment, the five-membered heteroaryl is a five-membered heteroaryl containing one, two, or three heteroatoms selected from O, S, and N; more preferably, the five-membered heteroaryl is a five-membered heteroaryl containing two nitrogen heteroatoms and one or two heteroatoms selected from O, S, and N.

[0020] In another preferred embodiment, the five-membered heteroaryl group is selected from the group consisting of:

[0021]

[0022] In another preferred embodiment, ring A is R1 is selected from the following group: H, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted -C 1-4 Alkylene-OC 1-6 Alkyl, substituted or unsubstituted -C1-4 Alkylene-SC 1-6 alkyl;

[0023] Z is selected from the following group: O, S, N;

[0024] When Z is O or S, R2 does not exist; when Z is N, R2 is selected from the following group: H, substituted or unsubstituted C. 1-6 alkyl.

[0025] In another preferred embodiment, R3 is substituted or unsubstituted C. 1-6 Alkyl group; preferably, R3 is C 1-6 Alkyl group; preferably, R3 is methoxy group.

[0026] In another preferred embodiment, R4 does not exist.

[0027] In another preferred embodiment, W 1a and W 1b Each is independently selected from the following groups: -O-, -S-, -SO 2- -CO-, -NR5-.

[0028] In another preferred embodiment, W 1a and W 1b At most one of them is -O-, that is, -W 1a -W 1b -Not for-OO-.

[0029] In another preferred example, -W 1a -W 1b - is -NR5-CO-; preferably, it is -NH-CO-.

[0030] In another preferred embodiment, W 2a and W 2b Each is independently selected from the following groups: -O-, -S-, -SO 2- -CO-, -NR5-.

[0031] In another preferred embodiment, W 2a and W 2b At most one of them is -O-, that is, -W 2a -W 2b -Not for-OO-.

[0032] In another preferred example, -W 2a -W 2b - is -NR5-CO-; preferably, it is -NH-CO-.

[0033] In another preferred embodiment, the compound is as shown in formula Aa or formula Ab.

[0034]

[0035] In another preferred embodiment, the compound is shown in Formula I.

[0036]

[0037] in,

[0038] R1 is selected from the following group: H, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-4 Alkylene-OC 1-6 Alkyl, substituted or unsubstituted C 1-4 Alkylene-SC 1-6 alkyl;

[0039] Z is selected from the following group: O, S, N;

[0040] When Z is O or S, R2 is not present; when Z is N, R2 is selected from the following group: H, substituted or unsubstituted C1-6 alkyl groups;

[0041] Y is either CH or N;

[0042] X is CH or N;

[0043] Unless otherwise specified, substitution refers to the substitution of one or more (e.g., 1, 2, or 3) hydrogen atoms in a group by a substituent selected from the group consisting of: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups.

[0044] In another preferred example, Z is selected from the group consisting of O and N.

[0045] In another preferred embodiment, when Z is O or S, R2 is absent; when Z is N, R2 is a substituted or unsubstituted C1-6 alkyl group (preferably methyl).

[0046] In another preferred embodiment, R1 is substituted or unsubstituted C. 1-4 Alkylene-OC 1-6 Alkyl group; preferably, R1 is -CH2OCH3.

[0047] In another preferred embodiment, R1 is H; Z is N; and R2 is selected from the group consisting of: H, substituted or unsubstituted C1-6 alkyl groups (preferably, R2 is C1-6 alkyl). 1-6 Alkyl; more preferably, R2-methyl).

[0048] In another preferred embodiment, R1 is selected from the group consisting of: substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 hydroxyalkyl, substituted or unsubstituted C1-6 alkyl, and C1-6 hydroxyalkyl. 1-4 Alkylene-OC 1-6Alkyl, substituted or unsubstituted C 1-4 Alkylene-SC 1-6 Alkyl (preferably, R1 is a substituted or unsubstituted C) 1-4 Alkylene-OC 1-6 Alkyl group; more preferably, R1 is -CH2OCH3); Z is selected from the group consisting of O and S (preferably, Z is O); R2 is absent.

[0049] In another preferred embodiment, Y is CH or N.

[0050] In another preferred embodiment, X is CH or N.

[0051] In another preferred embodiment, the compound is as shown in formula Ia or formula Ib.

[0052]

[0053] In another preferred embodiment, the compound is selected from the compounds in Table A:

[0054] Table A

[0055]

[0056]

[0057] In a second aspect of the invention, a pharmaceutical composition is provided, comprising:

[0058] (i) the compound as described in the first aspect or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.

[0059] In a third aspect of the invention, there is provided the use of a compound as described in the first aspect or a pharmaceutical composition as described in the second aspect in the preparation of (i) a medicament for treating or preventing TYK2 and / or JAK1-mediated diseases and / or (ii) a TYK2 and / or JAK1 inhibitor.

[0060] In another preferred embodiment, TYK2 and / or JAK1 refers to TYK2 or JAK1 or a combination of both.

[0061] In another preferred embodiment, the disease mediated by TYK2 and / or JAK1 is a disease mediated by TYK2, a disease mediated by JAK1, or a disease mediated by both TYK2 and JAK1.

[0062] In another preferred embodiment, TYK2 and / or JAK1 inhibitors refer to TYK2 inhibitors or JAK1 inhibitors or TYK2 and JAK1 inhibitors.

[0063] In another preferred embodiment, the TYK2 and / or JAK1-mediated disease is a disease associated with IL-23, IL-12 and / or IFNα.

[0064] In another preferred embodiment, the compound treats or prevents TYK2 and / or JAK1-mediated diseases by selectively inhibiting TYK2-JH2 and / or JAK-JH2.

[0065] In another preferred embodiment, the TYK2 and / or JAK1-mediated diseases include: inflammation, autoimmune diseases, or combinations thereof.

[0066] In another preferred embodiment, the TYK2 and / or JAK1-mediated diseases include: psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, dermatitis, lupus nephritis, neuroinflammatory diseases such as multiple sclerosis and Alzheimer's disease, ankylosing spondylitis, hidradenitis suppurativa, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, cancer, or combinations thereof.

[0067] In another preferred embodiment, the TYK2 and / or JAK1 inhibitor is a selective TYK2-JH2 and / or JAK1-JH2 inhibitor.

[0068] In a fourth aspect of the invention, a method for selectively inhibiting TYK2 and / or JAK1 is provided, the method comprising:

[0069] Contact the object with the compound as described in the first aspect, thereby inhibiting the activity of TYK2 and / or JAK1 in the object by means of TYK2-JH2 and / or JAK1-JH2.

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

[0071] In another preferred embodiment, the object is TYK2 kinase and / or JAK1 kinase.

[0072] In another preferred embodiment, the inhibition is a selective inhibition of TYK2-JH2 and / or JAK1-JH2.

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

[0074] In a fifth aspect of the invention, a method for treating or preventing TYK2 and / or JAK1-mediated diseases is provided, comprising the steps of:

[0075] Administering a safe and effective amount of the compound as described in the first aspect or the pharmaceutical composition as described in the second aspect to a person in need, thereby treating or preventing TYK2 and / or JAK1-mediated diseases.

[0076] In another preferred embodiment, the TYK2 and / or JAK1-mediated disease is a disease associated with IL-23, IL-12 and / or IFNα.

[0077] In another preferred embodiment, the compound treats or prevents TYK2 and / or JAK1-mediated diseases by selectively inhibiting TYK2-JH2 and / or JAK1-JH2.

[0078] In another preferred embodiment, the TYK2 and / or JAK1-mediated diseases include: inflammation, autoimmune diseases, or combinations thereof.

[0079] In another preferred embodiment, the TYK2 and / or JAK1-mediated diseases include: psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, dermatitis, lupus nephritis, neuroinflammatory diseases such as multiple sclerosis and Alzheimer's disease, ankylosing spondylitis, hidradenitis suppurativa, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, cancer, viral inflammation, or combinations thereof.

[0080] In a sixth aspect of the invention, a method for preparing a compound is provided, the compound being as described in the first aspect and represented by Formula I, the method comprising the steps of:

[0081] Make the intermediate as shown in Formula II and The reaction yields the compound;

[0082]

[0083] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0084] Through extensive and in-depth research, the inventors unexpectedly discovered a class of compounds with a specific novel structure, namely, those possessing a five-membered heteroaryl group (cyclic Ar) and... The compound possesses excellent selective inhibitory activity against the TYK2 pseudokinase (JH2) and JAK1 pseudokinase (JH2) domains. Based on this, the inventors completed the present invention.

[0085] the term

[0086] As described herein, the term "halogen" refers to F, Cl, Br, or I. Correspondingly, "halogenation" refers to the substitution of a hydrogen atom in a group by F, Cl, Br, or I.

[0087] Unless otherwise stated, the term "alkyl" on its own or as part of another substituent refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C64 ... 1-6 (Indicates 1-6 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0088] The term "cycloalkyl" refers to a ring with a specified number of ring atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-6 Cycloalkyl refers to a hydrocarbon ring with 3-6 ring atoms and is fully saturated. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc.

[0089] The term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkane, such as -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, or -CH2CH2CH2-. Alkyl (or alkylene) groups typically have 1-4 carbon atoms. Similarly, "alkenyl" or "ynyneyl" refers to an unsaturated form of "alkylene" having a double or triple bond, respectively.

[0090] Unless otherwise specified, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si) in this document.

[0091] For the compounds presented herein, the bond from the substituent (usually an R group) to the center of the ring (e.g., an aromatic ring, such as benzene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the ring.

[0092] As used herein, the terms “containing,” “comprising,” or “including” indicate that various ingredients may be used together in mixtures or compositions of the present invention. Therefore, the terms “consistent with…” and “composed of…” are included in the term “containing.”

[0093] As used herein, the term "pharmaceuticalally acceptable" means a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., a reasonable benefit / risk ratio.

[0094] Unless otherwise specified, all compounds mentioned in this invention are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0095] Some compounds of this invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) should all be included within the scope of this invention. When the compounds provided herein have a defined stereochemistry (denoted as R or S, or indicated by dashed or wedge-shaped bonds), it will be understood by those skilled in the art that those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and at most 100% free of other isomers).

[0096] The compounds of the present invention may also contain non-natural proportions of atomic isotopes at one or more isotopic atoms constituting such compounds. A non-natural proportion of an isotope can be defined as ranging from the amount of the atom in question that is naturally found to 100% of that atom. For example, the compounds may be doped with radioactive isotopes, such as tritium (…). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium (C). 2 H) or carbon-13 ( 13 C). In addition to the uses described in this application, such isotopic variants may provide additional uses. For example, isotopic variants of the compounds of the present invention may have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, thereby contributing to increased safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, regardless of radioactivity, should be included within the scope of this invention.

[0097] Active ingredients

[0098] As used herein, the term "compound of the invention" refers to a compound of formula (A) or (I). The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of compounds of formula (A) or (I).

[0099] The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Acids suitable for forming salts 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. Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0100] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0101] Furthermore, the compounds of the present invention also include prodrugs of compounds represented by formula (A) or (I). The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, when taken by an appropriate method, are metabolized or chemically reacted in the human body to form compounds of formula (A) or (I), or salts or solutions of compounds of formula (A) or (I). The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0102] Preparation method

[0103] The other parts of this document describe in more detail the methods for preparing compounds of formula (A) or formula (I) of the present invention, but these specific methods do not constitute any limitation on the invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, such combinations being readily performed by those skilled in the art.

[0104] Pharmaceutical Compositions and Administration

[0105] Because the compounds of this invention exhibit excellent selective inhibitory activity against the pseudokinase domains (JH2) of TYK2 and JAK1, the compounds of this invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient can be used to treat, prevent, and alleviate diseases mediated by TYK2 kinase or JAK1 kinase or both (i.e., TYK2 and / or JAK1-mediated diseases). According to the prior art, the compounds of this invention can be used to treat the following diseases: psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, dermatitis, lupus nephritis, neuroinflammatory diseases such as multiple sclerosis and Alzheimer's disease, ankylosing spondylitis, hidradenitis suppurativa, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, and various autoimmune and inflammatory diseases, including some cancers.

[0106] In this paper, the term "selectivity" refers to an activity or potency (e.g., inhibitory activity) against a specified target (e.g., TYK2(JH2), JAK1(JH2)) that is higher than that against other targets (e.g., JAK1, 2, 3(JH1), and / or TYK2(JH1)); for example, the activity or potency (e.g., inhibitory activity) against a specified target (e.g., TYK2(JH2)) is at least 50 times higher than that against other targets (e.g., JAK1, 2, 3(JH1), and / or TYK2(JH1)). For example, when quantifying inhibitory activity using the IC50 value, IC50... 其他 / IC50 TYK2 / JAK1-JH2 >50, of which IC50 TYK2 / JAK1-JH2 This refers to the IC50 (nM) of the compound's inhibitory activity against TYK2-JH2 (the pseudokinase domain of TYK2) or JAK1-JH2 (the pseudokinase domain of JAK1). 其他 The IC50 (nM) of the compound refers to the inhibitory activity of the compound against one or more of the following kinases: TYK2-JH1 (kinase domain of TYK2), JAK1-JH1 (kinase domain of JAK1), JAK2-JH1 (kinase domain of JAK2), and JAK3-JH1 (kinase domain of JAK3).

[0107] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-200 mg of the compound of the present invention per dose, more preferably, 1-50 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0108] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0109] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0110] 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 the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl 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. Buffers may also be included in the dosage forms of capsules, tablets, and pills.

[0111] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound 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 compound may also be formed into microcapsules with one or more of the excipients described above.

[0112] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., 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.

[0113] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0114] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0115] Compositions for parenteral injection may comprise 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.

[0116] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0117] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0118] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–200 mg, preferably 1–50 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0119] The main advantages of this invention include:

[0120] 1. The compounds of the present invention exhibit excellent selectivity. Compared to non-selective JAK inhibitors, the compounds of the present invention possess superior inhibitory activity against the pseudokinase domains (JH2) of TYK2 and JAK1, while not inhibiting the JH1 region which has kinase activity. Therefore, the TYK2 / JAK1 pseudokinase domain (JH2) selective inhibitors of the present invention have superior safety.

[0121] 2. The compounds of the present invention exhibit excellent selectivity and excellent inhibitory activity.

[0122] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0123] Preparation Examples

[0124] Example 1:

[0125]

[0126] Step A

[0127]

[0128] Compound 1a (1.3 g, 6.4 mmol) was dissolved in dioxane (35 mL), followed by the addition of pinacol diborate (2.44 g, 9.6 mmol), potassium acetate (1.26 g, 12.8 mmol), and [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.53 g, 0.64 mmol). The mixture was stirred at 90 °C for 5 hours under nitrogen protection. After LC-MS monitoring, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was then separated by rapid preparative chromatography under medium pressure (eluent: petroleum ether / ethyl acetate, 2 / 1, v / v) to give a yellow solid, compound 1b (680 mg, 43.4%). 1HNMR (400MHz, DMSO-d6): δppm 6.79-6.75. (m, 3H), 4.80 (s, 2H), 3.63 (s, 3H), 1.28 (s, 12H). MS: 249.9 [M+H]+.

[0129] Step B

[0130]

[0131] Compound 1b (330 mg, 1.32 mmol) was dissolved in dioxane (16 mL) and water (4 mL). Compound 1c (233 mg, 1.45 mmol), tetrakis(triphenylphosphine)palladium (150 mg, 0.13 mmol), and cesium carbonate (863 mg, 2.65 mmol) were added sequentially. The mixture was stirred at 90 °C for 6 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL × 2). The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by medium-pressure rapid preparative chromatography (eluent: petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 1d (230 mg, 84.5%) as a yellow solid. 1H NMR (400MHz, DMSO-d6): δppm 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). MS: 205.2[M+H]+.

[0132] Step C

[0133]

[0134] Compound 1d (210 mg, 1.03 mmol) and compound 1e (258 mg, 1.23 mmol) were dissolved in dry tetrahydrofuran (20 mL). Bistrimethylsilylaminolithium (1 M in THF, 3.1 mL, 3.1 mmol) was added dropwise at 0 °C under nitrogen protection and stirred at room temperature for 16 hours. The reaction was monitored by LC-MS. After completion, the mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 2), and the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by rapid preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid, compound 1f (340 mg, 87.8%). MS: 377.2 [M + H]+.

[0135] Step D

[0136]

[0137] Compound 1f (310 mg, 0.82 mmol) and compound 1g (183 mg, 1.64 mmol) were dissolved in dioxane (30 mL), followed by the addition of XantPhos (142 mg, 0.24 mmol), cesium carbonate (536 mg, 1.64 mmol), and XPhosPdG2 (65 mg, 0.08 mmol). The mixture was stirred at 110 °C for 16 hours under nitrogen protection. After LCMS monitoring, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the extracts were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure preparative chromatography (dichloromethane / methanol, 10 / 1–5 / 1, v / v) to obtain 105 mg of crude product. The crude product was separated by SFC (Thar prep 80, column: CHIRALPAK AD-H 250 mm x 20 mm x 5 μm, modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, total flow rate: 40 g / min, temperature: 40 °C) to give two isomers: compound 1S (40 mg, Rt: 8.85 min, OR: 203.4, 24.5 °C) and compound 1R (44 mg, Rt: 13.81 min, OR: -237.6, 24.5 °C). Overall yield: 22.6%.

[0138] Compound 1S:¹H NMR (400 MHz, CD₃OD): δppm 11.10 (s, ¹H), 10.96 (s, ¹H), 9.10 (s, ¹H), 8.53 (s, ¹H), 8.14 (s, ¹H), 7.64–7.61 (m, ¹H), 7.50–7.48 (m, ¹H), 7.28–7.24 (m, ¹H), 3.91 (s, ³H), 3.69 (s, ³H), 2.49–2.38 (m, ¹H), 1.36–1.29 (m, ²H), 0.87–0.69 (m, ⁴H). MS: 452.2 [M+H]⁺.

[0139] Compound 1R: ¹H NMR (400 MHz, CD3OD): δppm 11.10 (s, ¹H), 10.96 (s, ¹H), 9.10 (s, ¹H), 8.53 (s, ¹H), 8.14 (s, ¹H), 7.64–7.61 (m, ¹H), 7.50–7.48 (m, ¹H), 7.28–7.24 (m, ¹H), 3.91 (s, ³H), 3.69 (s, ³H), 2.49–2.38 (m, ¹H), 1.36–1.29 (m, ²H), 0.87–0.69 (m, ⁴H). MS: 452.2 [M+H]+.

[0140] Example 2

[0141]

[0142] Step A

[0143]

[0144] Compound 2a (10 g, 57.82 mmol) was added to a three-necked flask containing 200 mL of concentrated sulfuric acid at 0 °C. 90% fuming concentrated nitric acid (6 g, 86.21 mmol) was added with stirring at 0 °C, and the mixture was stirred for 20 h at room temperature. LC-MS monitoring was performed. After the reaction was complete, the reaction solution was poured into 300 mL of ice water, diluted with ethyl acetate (500 mL), washed with water (200 mL x 2) and saturated sodium chloride aqueous solution (200 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a yellow solid, compound 2b (7.8 g, 61.9%). ¹H NMR (400 MHz, CD₃OD): δppm: 7.99–7.98 (m, 1H), 7.93–7.92 (m, 1H). MS: 219.0, 221.0 [M+H]⁺

[0145] Step B

[0146]

[0147] Compound 2b (7.8 g, 35.79 mmol) and potassium carbonate (9.8 g, 71.24 mmol) were added sequentially to a 250 mL round-bottom flask containing 100 mL of N,N-dimethylformamide. The mixture was stirred at room temperature for 10 minutes, then iodomethane (10.1 g, 71.24 mmol) was added, and the mixture was stirred at 30 °C for 20 h. The reaction was monitored by LCMS. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure. 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The extracts were combined, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and separated by column chromatography (eluent: petroleum ether / ethyl acetate, 20 / 1, v / v) to give a white solid, compound 2c (4 g, 48.2%). 1H NMR (400MHz, CDCL3): δppm: 8.09 (d, J=5.2Hz, 1H), 7.78 (d, J=5.2Hz, 1H), 4.04 (s, 3H). MS: 233.0, 235.0[M+H]+

[0148] Step C

[0149]

[0150] Compound 2c (4 g, 17.2 mmol) and iron powder (4.8 g, 86 mmol) were added sequentially to a 100 mL round-bottom flask containing 20 mL ethanol / 20 mL acetic acid / 10 mL water and stirred at room temperature for 2 h. The reaction was monitored by LCMS. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure. 50 mL of water was added, and the pH was adjusted to 10 with 2N sodium hydroxide solution. The mixture was extracted with dichloromethane (50 mL × 3 times), and the extracts were combined, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and separated by column chromatography (dichloromethane / methanol, 20 / 1, v / v) to give a yellow solid compound 2d (3 g, 86.0%). 1H NMR (400MHz, CDCL3): δppm: 7.60 (d, J=5.2Hz, 1H), 6.82 (d, J=5.6Hz, 1H), 4.99 (s, 2H), 3.85 (s, 3H). MS: 203.0, 205.1[M+H]+

[0151] Step D

[0152]

[0153] Compound 2d (2 g, 9.9 mmol), zinc cyanide (1.28 g, 10.8 mmol), 1,1′-bis(diphenylphosphine)ferrocene (1.05 g, 1.9 mmol), and zinc powder (58.5 mg, 0.9 mmol) were added to a 100 mL round-bottom flask containing N,N-dimethylformamide (40 mL). Then, tris(dibenzylacetone)dipalladium (0.91 g, 0.9 mmol) was added. Under nitrogen protection, the mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (300 mL), filtered, and the filtrate was extracted with ethyl acetate (300 mL × 2). The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure preparative chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give a yellow solid compound 2e (0.98 g, 65.9%). 1H NMR (400MHz, CD3OD): δppm 7.71. (d, J=2.8Hz, 1H), 6.70. (d, J=2.8Hz, 1H), 4.01 (s, 3H). MS: 150.0 [M+H]+.

[0154] Step E

[0155]

[0156] Compound 2e (0.5 g, 3.35 mmol), compound 2f (745 mg, 10.05 mmol), and potassium tert-butoxide (1.5 g, 13.4 mmol) were added to xylene (20 mL) in one step under nitrogen protection and stirred at 140 °C for 3 hours. The reaction was monitored by LC-MS. After completion, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was then separated by rapid preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1, v / v) to give 2 g (60 mg, 8.7%) of a yellow solid. MS: 205.9 [M+H]+.

[0157] Step F

[0158]

[0159] Compound 2 g (60 mg, 0.29 mmol) and compound 1e (73 mg, 0.35 mmol) were dissolved in dry tetrahydrofuran (20 mL). Bistrimethylsilylaminolithium (1 M in THF, 0.88 mL, 0.88 mmol) was added dropwise at -78 °C under nitrogen protection and stirred at room temperature for 16 hours. The reaction was monitored by LC-MS. After completion, the mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 2), and the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid compound 2 h (44 mg, 40.1%). MS: 378.2 [M+H]+.

[0160] Step G

[0161]

[0162] Compound 2h (44 mg, 0.11 mmol) and compound 1g (38.8 mg, 0.35 mmol) were dissolved in dioxane (10 mL), followed by the addition of XantPhos (13.5 mg, 0.023 mmol), cesium carbonate (75 mg, 0.23 mmol), and XPhos PdG2 (18.1 mg, 0.023 mmol). The mixture was stirred at 120 °C for 16 hours under nitrogen protection. After LCMS monitoring, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the extracts were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure preparative chromatography (dichloromethane / methanol, 10 / 1–5 / 1, v / v) to obtain 65 mg of crude product. The crude product was separated by SFC (Thar prep 80, column: CHIRALPAK AD-H 250 mm x 20 mm x 5 μm, modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, total flow rate: 40 g / min, temperature: 40 °C) to give two isomers: compound 2S (5.2 mg, Rt: 8.85 min, OR: 235.9, 27.1 °C) and compound 2R (5.6 mg, Rt: 12.64 min, OR: -237.6, 27.1 °C). Overall yield: 21.7%.

[0163] Compound 2S:¹H NMR (400 MHz, CD₃OD): δppm 12.44 (s, ¹H), 11.15 (s, ¹H), 9.89 (s, ¹H), 9.24 (s, ¹H), 8.67 (s, ¹H), 8.17–8.16 (m, ¹H), 7.51–7.50 (m, ¹H), 4.00 (s, ³H), 3.90 (s, ³H), 2.49–2.47 (m, ¹H), 1.47–1.38 (m, 2H), 0.92–0.80 (m, 4H). LCMS: 453.3 [M+H]⁺.

[0164] Compound 2R: 1H NMR (400 MHz, CD3OD): δppm 12.44 (s, 1H), 11.15 (s, 1H), 9.89 (s, 1H), 9.24 (s, 1H), 8.67 (s, 1H), 8.17–8.16 (m, 1H), 7.51–7.50 (m, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 2.49–2.47 (m, 1H), 1.47–1.38 (m, 2H), 0.92–0.80 (m, 4H). LCMS: 453.2 [M+H]+.

[0165] Example 3

[0166]

[0167] Step A

[0168]

[0169] Compound 3a (1 g, 3.1 mmol) was added to ethanol (20 mL), followed by an aqueous solution of hydroxylamine (0.82 g, 50%, 12.4 mmol). The mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the solution was concentrated under reduced pressure and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid, compound 3b (0.61 g, 55.7%). MS: 353.7 [M+H]+.

[0170] Step B

[0171]

[0172] Compound 3b (300 mg, 0.85 mmol) and triethylamine (257 mg, 2.55 mmol) were added to dichloromethane (10 mL), followed by dropwise addition of methoxyacetyl chloride (184 mg, 1.7 mmol). The mixture was stirred at room temperature for 3 hours under nitrogen protection. Subsequently, a solution of 1N tetrabutylammonium fluoride in tetrahydrofuran (3.4 mL, 3.4 mmol) was added. The reaction was monitored by LC-MS. After completion, the mixture was quenched with water (20 mL), extracted with dichloromethane (30 mL × 2), and the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then separated by preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid, compound 3c (260 mg, 75.1%). MS: 408.1 [M + H]+.

[0173] Step C

[0174]

[0175] Compound 3c (260 mg, 0.64 mmol) and 2,4-dimethoxybenzamine (213 mg, 1.28 mmol) were dissolved in dimethyl sulfoxide (10 mL), and potassium fluoride (110 mg, 19 mmol) was added. The mixture was stirred at 110 °C for 4 hours under nitrogen protection. The reaction was monitored by LC-MS. After completion, the mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 2), and the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid compound 3d (220 mg, 64.1%). MS: 539.2 [M + H]+.

[0176] Step D

[0177]

[0178] Compound 3d (220 mg, 0.41 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 4 hours under nitrogen protection. After the reaction was complete, the solution was concentrated under reduced pressure, the pH was adjusted to 8 with 1 N sodium hydroxide solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by rapid preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid compound 3e (140 mg, 88.0%). MS: 388.7 [M+H]+.

[0179] Step E

[0180]

[0181] Compound 3e (110 mg, 0.28 mmol) and pyridine (67 mg, 0.85 mmol) were dissolved in 1,2-dichloroethane (10 mL), and then compound 3f (111 mg, 0.85 mmol) was added dropwise. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction was monitored by LCMS. After completion, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the extracts were combined. The extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure preparative chromatography (eluent: dichloromethane / methanol, 10 / 1–5 / 1, v / v) to obtain 50 mg of crude product. The crude product was separated by SFC (Thar prep 80, column: CHIRALPAK AD-H2 50mm x 20mm x 5μm, modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, total flow rate: 40 g / min, temperature: 40℃) to give two isomers: compound 3S (12 mg, Rt: 2.60 min, OR: 143.4, 25.0℃) and compound 3R (11 mg, Rt: 3.03 min, OR: -139.1, 25.0℃). Overall yield: 17.0%.

[0182] Compound 3S: ¹H NMR (400 MHz, DMSO-d6): δppm 11.13 (s, ¹H), 11.04 (s, ¹H), 9.13 (s, ¹H), 8.15 (s, ¹H), 7.71–7.66 (m, 2H), 7.40–7.36 (m, 1H), 4.82 (s, 2H), 3.72 (s, 3H), 3.42 (s, 3H), 2.41–2.39 (m, 1H), 1.36–1.30 (m, 2H), 0.84–0.69 (m, 4H). LCMS: 483.2 [M+H]+.

[0183] Compound 3R: ¹H NMR (400 MHz, DMSO-d6): δppm 11.18 (s, ¹H), 11.08 (s, ¹H), 9.18 (s, ¹H), 8.19 (s, ¹H), 7.73–7.70 (m, 2H), 7.44–7.40 (m, 1H), 4.86 (s, 2H), 3.75 (s, 3H), 3.45 (s, 3H), 2.45–2.43 (m, 1H), 1.38–1.34 (m, 2H), 0.90–0.73 (m, 4H). LCMS: 483.2 [M+H]+.

[0184] Example 4

[0185]

[0186] Step A

[0187]

[0188] Compound 1d (500 mg, 2.45 mmol) was dissolved in dry tetrahydrofuran (20 mL), and bis(trimethylsilylaminolithium) (1 M in THF, 7.4 mL, 7.4 mmol) was added dropwise at -78 °C under nitrogen protection and stirred at -78 °C for 1 hour. Then, compound 4a (561 mg, 2.71 mmol) was added, and the mixture was stirred at room temperature for 16 hours under LCMS monitoring. After the reaction was complete, the mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 2), and the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid compound 4b (710 mg, 77.2%). 1HNMR (400MHz, CDCL3): δppm 10.63 (s, 1H), 8.71 (s, 1H), 8.14 (s, 1H), 7.88 (dd, J=7.6, 1.6Hz, 1H), 7.46 (s, 1H), 7.38 (dd, J=7. 8, 1.6Hz, 1H), 7.27-7.25 (m, 1H), 6.90 (s, 1H), 4.02 (s, 3H), 3.81 (s, 3H). MS: 375.7, 377.7[M+H]+.

[0189] Step B

[0190]

[0191] Compound 4b (370 mg, 0.99 mmol), 2,4-dimethoxybenzylamine (329 mg, 1.97 mmol), and potassium fluoride (286 mg, 4.93 mmol) were added sequentially to a round-bottom flask containing 10 mL of dimethyl sulfoxide. The mixture was stirred at 120 °C for 48 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (40 mL), washed with water (20 mL x 2) and saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure preparative chromatography (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid, compound 4c (290 mg, 58.2%). MS: 506.6 [M+H]+.

[0192] Step C

[0193]

[0194] Compound 4c (270 mg, 0.53 mmol) was added to a round-bottom flask containing 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 2 h. LC-MS was used to monitor the reaction. After completion, the pH was adjusted to 8 with 2N sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane (30 mL × 3). The extracts were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure preparative chromatography (dichloromethane / methanol, 10 / 1, v / v) to give a yellow oily compound 4d (170 mg, 89.5%). MS: 356.8 [M+H]+.

[0195] Step D

[0196]

[0197] Compound 4d (50 mg, 0.14 mmol) was dissolved in dry tetrahydrofuran (10 mL), and bis(trimethylsilylaminolithium) (1 M in THF, 0.6 mL, 0.6 mmol) was added dropwise at 0 °C under nitrogen protection and stirred at room temperature (0 °C) for 1 hour. Then, compound 3f (37 mg, 0.28 mmol) was added, and the mixture was stirred at room temperature for 16 hours under LCMS monitoring. After the reaction was complete, the mixture was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 2), and the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 10 / 1, v / v) to give 20 mg of crude product. The crude product was separated by SFC (Thar prep80, column: CHIRALPAK AD-H 250 mm x 20 mm x 5 μm, modifier: 40% methanol (NH4OH 0.2%) / 60% CO2, total flow rate: 40 g / min, temperature: 40 °C) to give two isomers: compound 4S (4.4 mg, Rt: 5.59 min, OR: 228.0, 24.5 °C) and compound 4R (4.2 mg, Rt: 7.07 min, OR: -139.4, 24.5 °C), with an overall yield of 13.6%.

[0198] Compound 4S:¹H NMR (400 MHz, CDCl₃): δppm 10.73 (s, ¹H), 9.06 (s, ¹H), 8.47 (s, ¹H), 8.11 (s, ¹H), 8.04 (s, ¹H). 1H), 7.77-7.75(m, 1H), 7.55-7.52(m, 1H), 7.28-7.26(m, 1H), 7.06(s, 1H), 4.01(s, 3H), 3.81(s, 3H), 2.04-2. 01 (m, 1H), 1.58 (t, J=4.0Hz, 1H), 1.47-1.44 (m, 1H), 1.06-1.02 (m, 1H), 0.97-0.90 (m, 3H). LCMS: 451.2 [M+H]+.

[0199] Compound 4R: ¹H NMR (400 MHz, CDCl₃): δppm 10.74 (s, ¹H), 9.06 (s, ¹H), 8.47 (s, ¹H), 8.12 (s, ¹H), 8.05 (s, ¹H). 1H), 7.77-7.75(m, 1H), 7.54-7.53(m, 1H), 7.28-7.26(m, 1H), 7.06(s, 1H), 4.01(s, 3H), 3.81(s, 3H), 2.05-2. 01 (m, 1H), 1.58 (t, J=4.2Hz, 1H), 1.47-1.44 (m, 1H), 1.06-1.02 (m, 1H), 0.97-0.90 (m, 3H). LCMS: 451.2[M+H]+.

[0200] Example 5

[0201]

[0202] Step A

[0203]

[0204] Compound 2e (300 mg, 2 mmol) was added to ethanol (10 mL), followed by 50% hydroxylamine aqueous solution (528 mg, 8 mmol). The mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the solution was concentrated under reduced pressure and separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid, compound 5a (310 mg, 85.0%). ¹H NMR (400 MHz, DMSO-d6): δppm 9.68 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 5.95 (s, 2H), 5.76 (s, 2H), 3.66 (s, 3H). LCMS: 182.9 [M+H]+.

[0205] Step B

[0206]

[0207] Compound 5a (220 mg, 1.2 mmol) and pyridine (202 mg, 2.55 mmol) were added to dichloromethane (10 mL), followed by dropwise addition of methoxyacetyl chloride (259 mg, 2.4 mmol). The mixture was stirred at room temperature for 3 hours under nitrogen protection. Then, tetrabutylammonium fluoride 1N tetrahydrofuran solution (3 mL, 3 mmol) was added, and the mixture was stirred at room temperature for 2 hours under LC-MS monitoring. After the reaction was complete, the mixture was quenched with water (20 mL), extracted with dichloromethane (30 mL × 2), and the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by medium-pressure rapid preparative chromatography (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid compound 5b (140 mg, 49.2%). LC-MS: 237.2 [M + H]+.

[0208] Step C

[0209]

[0210] Compound 5b (140 mg, 0.59 mmol) and compound 1e (160 mg, 0.77 mmol) were dissolved in dry tetrahydrofuran (10 mL). Sodium hydride (60%, 92 mg, 2.4 mmol) was added at 0 °C under nitrogen protection and stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After completion, the mixture was quenched with water (20 mL), concentrated under reduced pressure to obtain a crude product, and filtered to give a yellow solid compound 5c (150 mg, 61.0%). 1H NMR (400MHz, DMSO-d6): δppm 12.67 (s, 1H), 9.50 (s, 1H), 9.19 (s, 1H), 8.33 (d, J=2.4Hz, 1H), 7.53 (d, J =2.4Hz, 1H), 4.86 (s, 2H), 3.90 (s, 3H), 3.43 (s, 3H). LCMS: 409.1[M+H]+.

[0211] Step D

[0212]

[0213] Compound 5c (150 mg, 0.36 mmol) and 2,4-dimethoxybenzamine (180 mg, 1.08 mmol) were dissolved in dimethyl sulfoxide (10 mL), and potassium fluoride (84 mg, 1.44 mmol) was added. The mixture was stirred at 110 °C for 4 hours under nitrogen protection. LC-MS monitoring was performed. After the reaction was complete, the mixture was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 2), and the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid compound 5d (90 mg, 44.1%). LC-MS: 539.6 [M + H]+.

[0214] Step E

[0215]

[0216] Compound 5d (90 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 4 hours under nitrogen protection. After the reaction was complete, the solution was concentrated under reduced pressure, the pH was adjusted to 8 with 1 N sodium hydroxide solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then separated by rapid preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1, v / v) to give a yellow solid compound 5e (60 mg, 92.7%). LCMS: 390.1 [M + H]+.

[0217] Step F

[0218]

[0219] Compound 5e (50 mg, 0.13 mmol) and pyridine (32 mg, 0.4 mmol) were dissolved in 1,2-dichloroethane (10 mL), and then compound 3f (52 mg, 0.4 mmol) was added dropwise. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction was monitored by LCMS. After completion, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the extracts were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure preparative chromatography (dichloromethane / methanol, 10 / 1–5 / 1, v / v) to give compound 5 (a mixture of isomers, 5 mg, 7.9%). 1H NMR (400MHz, DMSO-d6): δppm 12.56 (s, 1H), 11.20 (s, 1H), 9.90 (s, 1H), 9.29 (s, 1H), 8.30 (d, J = 2.4Hz, 1H), 7.49 (d, J = 2.4Hz, 1H), 4.90 (s, 2H), 3.92(s, 3H), 3.46(s, 3H), 2.00-1.99(m, 1H), 1.49-1.47(m, 2H), 0.92-0.80(m, 4H). LCMS: 483.6[M+H]+.

[0220] Example 6

[0221]

[0222] Compound 1f (310 mg, 0.82 mmol) and compound 6a (prepared from (S)-spiro[2,2]pentane-1-carboxylic acid, CAS#249563-58-4) (183 mg, 1.64 mmol) were dissolved in dioxane (30 mL). XantPhos (142 mg, 0.24 mmol), cesium carbonate (536 mg, 1.64 mmol), and XPhosPdG2 (65 mg, 0.08 mmol) were added sequentially. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was monitored by LCMS, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the extracts were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1–5 / 1, v / v) to give compound 1S (105 mg).

[0223] Compound 1S:¹H NMR (400 MHz, CD₃OD): δppm 11.10 (s, ¹H), 10.96 (s, ¹H), 9.10 (s, ¹H), 8.53 (s, ¹H), 8.14 (s, ¹H), 7.64–7.61 (m, ¹H), 7.50–7.48 (m, ¹H), 7.28–7.24 (m, ¹H), 3.91 (s, ³H), 3.69 (s, ³H), 2.49–2.38 (m, ¹H), 1.36–1.29 (m, ²H), 0.87–0.69 (m, ⁴H). MS: 452.2 [M+H]⁺.

[0224] Example 7

[0225]

[0226] Compound 1f (310 mg, 0.82 mmol) and compound 7a (prepared from (R)-spiro[2,2]pentane-1-carboxylic acid, CAS#249563-53-9) (183 mg, 1.64 mmol) were dissolved in dioxane (30 mL). XantPhos (142 mg, 0.24 mmol), cesium carbonate (536 mg, 1.64 mmol), and XPhosPdG2 (65 mg, 0.08 mmol) were added sequentially. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was monitored by LCMS, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the extracts were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by preparative chromatography under medium pressure (dichloromethane / methanol, 10 / 1–5 / 1, v / v) to obtain compound 1R (100 mg). 1H NMR (400MHz, CD3OD): δppm 11.10 (s, 1H), 10.96 (s, 1H), 9.10 (s, 1H), 8.53 (s, 1H), 8.14 (s, 1H), 7.64-7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.28-7 .24(m, 1H), 3.91(s, 3H), 3.69(s, 3H), 2.49-2.38(m, 1H), 1.36-1.29(m, 2H), 0.87-0.69(m, 4H).MS: 452.2[M+H]+.

[0227] Test Implementation Examples

[0228] Test Example 1: FACS detection of the inhibitory effect of compounds on pSTAT5 expression in CD3+ cells

[0229] 1. Experimental Materials and Instruments

[0230] 1.1 Experimental Reagents

[0231] • DMSO, Sigma, Cat#D2650-100mL, store at room temperature.

[0232] • Perm buffer III, BD Biosciences, Cat#558050, stored at 4°C.

[0233] • Lysis / fixation buffer, BD Biosciences, Cat#558049, store at room temperature.

[0234] • EDTA, Invitrogen, Cat#15575-038, store at room temperature.

[0235] • PBS, Hyclone, Cat#SH30256.01, store at 4℃.

[0236] • PE mouse anti-human CD3, BD Bioscience, Cat#555333, store at 4℃.

[0237] • Mouse anti-human phosphorylated STAT5 (pY694) (Alexa) 647 Conjugate), BD Best, Cat#562076, store at 4°C.

[0238] · IFN-α, Biolegend, Cat#592702.

[0239] 1.2 Experimental Consumables

[0240] Microplate, 96 Well, PP, V-bottom, Greiner, Cat#GN651201-100EA.

[0241] • 5mL polystyrene round-bottom tube, FALCON, Cat#04318011.

[0242] • 96 square hole reservoir plate, Thermo, Cat#AB-0661.

[0243] • 96-well plate, Corning, Cat#3599.

[0244] 1.3 Instruments

[0245] • CO2 cell incubator: MCO-15AC (Thermo).

[0246] • Pipettes: 0.2-10μL, 20-200μL, 200-1000μL (Thermo).

[0247] • Multichannel pipettes: 0.2-10μL, 5-50μL, 20-300μL (Raining).

[0248] • Centrifuges: Thermo Centrifuge ST 40R; Thermo Legend Micro 21R.

[0249] • Water system: Millipore Milli-Q reference system.

[0250] • Freezer: Haier ultra-low temperature freezer.

[0251] Haier 4-degree refrigerator.

[0252] Haier -20 degree freezer.

[0253] • Vortex: Earth Required.

[0254] • Plate-making machine: QI LIN BEI ER; MH-2.

[0255] • Flow cytometer: BD FACSVerse™ flow cytometer.

[0256] 2 Experimental Methods

[0257] 2.1 Compound Dilution

[0258] 1) On the day of the experiment, the compound was prepared into a 10 mM solution in DMSO, diluted to 1.5 mM in DMSO, and then diluted 3 times to obtain 8 gradient concentrations.

[0259] 2) Transfer 5 μL of the diluted compound to 120 μL of DPBS solution containing 0.1% BSA.

[0260] 3) Set up positive and negative control groups, and add 0.2% DMSO to both positive and negative control groups.

[0261] 2.2 Experimental Procedure

[0262] 1) Add 0.5 million human PBMC cells with a volume of 67.5 μL to each well of a 96-well cell culture plate.

[0263] 2) Add 3.5 μL of the diluted compound and mix well.

[0264] 3) Incubate at 37°C for 60 minutes.

[0265] 4) Dilute IFN-alpha to 600 ng / mL in DPBS containing 0.1% BSA, and dilute PE-anti-hCD3 antibody to 3-fold in DPBS containing 0.1% BSA. After the above 60-minute incubation, add 5 μL of the diluted PE-anti-hCD3 antibody and 4 μL of the diluted IFN-alpha to each well, so that the final concentration of IFN-alpha in each well is 30 ng / mL.

[0266] 5) Incubate at 37°C for 30 minutes.

[0267] 6) Transfer all cells to a 96-well deep plate and add 1 mL of lysis / fixation buffer preheated to 37°C.

[0268] 7) Incubate at 37℃ in the dark for 10 minutes.

[0269] 8) After centrifuging at 600g for 5 minutes, discard the supernatant, add 1mL of PBS to wash twice and centrifuge again.

[0270] 9) Add 1 mL of Perm buffer III to the cell pellet.

[0271] 10) Incubate at 4℃ in the dark for 30 minutes.

[0272] 11) After centrifuging at 600g for 5 minutes, discard the supernatant, add 1mL of PBS to wash twice and centrifuge again.

[0273] 12) Dilute the APC anti-human pSTAT5 antibody 200-fold in staining buffer, add 100 μL to each well, and mix well.

[0274] 13) Incubate at room temperature for 40 minutes.

[0275] 14) Wash twice with staining buffer, 1 mL per well, and centrifuge at 600g for 5 minutes.

[0276] 15) After discarding the supernatant, the cell pellet was resuspended in 300 μL of staining buffer.

[0277] 16) Load the sample into a flow cytometer for analysis. Obtain the IC50 of the sample, as shown in Table 1.

[0278] Table 1

[0279] Compound numbering IFN-α / pSTAT5 IC50(nM) 1S 4.2 1R 6.3 2S 3.9 2R 5.7 3S 22.8 3R 6.9 4S 4.1 4R 5.3 5 13

[0280] Test Example 2:

[0281] Selective Comparison of the JAK Family

[0282] 1. Experimental Methods

[0283] 1.1. The experimental procedure for the pseudokinase (JH2) is as follows:

[0284] 1.1.1. Dissolve the compound in DMSO to a storage concentration of 10 mM.

[0285] 1.1.2. Prepare compound concentrations 200 times higher than the final concentration in the compound dilution plate, and dilute from the highest concentration point to four concentration points using the 27-fold serial dilution method, and then transfer them to the Echo plate.

[0286] 1.1.3. The compound was pulsed from the Echo plate to the 384-well experimental plate using an Echo instrument, so that the compound was converted into a 3-fold serial dilution matrix of 11 concentration points.

[0287] 1.1.4. Add 5 μL of 3X TYK2-JH2 or JAK1-JH2 pseudokinase to a 384-well experimental plate.

[0288] 1.1.5. Add 5 μL of 3X Tb to the 384-well experimental plate.

[0289] 1.1.6. Add 5 μL of 3X Tracer to the 384-well experimental plate.

[0290] 1.1.7. Centrifuge for 30 seconds and incubate at room temperature for 60 minutes.

[0291] 1.1.8. Read signal values ​​using the Envision microplate reader (PerkinElmer).

[0292] 1.2. The experimental procedure for kinase (JH1) is as follows:

[0293] 1.2.1. Dissolve the compound in DMSO to a storage concentration of 10 mM.

[0294] 1.2.2. Prepare compound concentrations 100 times the final concentration in the compound dilution plate, and dilute from the highest concentration point to a total of 4 concentration points using the 27-fold serial dilution method, and transfer them to Echo plates.

[0295] 1.2.3. Use an Echo instrument to pulse the compound from the Echo plate to the 384 experimental plate, so that the compound becomes a 3-fold serial dilution matrix with 11 concentration points.

[0296] 1.2.4. Prepare 2X kinase working solution and add 5 μL per well to a 384-well experimental plate. Incubate the compound and kinase at room temperature for 15 minutes.

[0297] 1.2.5. Add 5 μL of 2X substrate (containing ATP) to a 384-well plate.

[0298] 1.2.6. Incubate at room temperature for 45 minutes.

[0299] 1.2.7. Add the test reagent mixture to a 384-well plate, centrifuge for 30 seconds, and incubate at room temperature for 60 minutes.

[0300] 1.2.8. Read signal values ​​using the Envision microplate reader (PerkinElmer).

[0301] 1.3. Data Analysis

[0302] 1.3.1. Data analysis was performed using XL-Fit software to obtain the IC50 of the compound, and the results are shown in Table 2.

[0303] Table 2

[0304] Compound numbering TYK2(JH1)(nM) TYK2(JH2)(nM) JAK1(JH1)(nM) JAK1(JH2)(nM) JAK2(JH1)(nM) JAK3(JH1)(nM) 1S ＞9950 0.13 ＞9950 0.7 ＞9950 8671 1R ＞9950 0.1 1411.9 0.9 ＞9950 ＞9950 2S ＞9950 0.13 1472.9 0.67 2188 5402.2 2R ＞9950 0.2 698 1.7 ＞9950 3682 4S ＞9950 0.12 ＞9950 1.66 ＞9950 ＞9950 4R ＞9950 0.1 5372 3 ＞9950 ＞9950

[0305] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from the following compounds: 。 2. A pharmaceutical composition comprising: (i) the compound of claim 1 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.

3. Use of a compound as claimed in claim 1 or a pharmaceutical composition as claimed in claim 2 in the preparation of (i) a medicament for treating or preventing TYK2 or JAK1-mediated diseases or (ii) a TYK2 / JAK1 inhibitor.

4. The use as described in claim 3, characterized in that, The TYK2 or JAK1-mediated diseases include: inflammation, autoimmune diseases, or combinations thereof.

5. The use as described in claim 3, characterized in that, The TYK2 or JAK1-mediated diseases include: psoriasis, lupus erythematosus, inflammatory bowel disease, arthritis, dermatitis, lupus nephritis, neuroinflammatory diseases, ankylosing spondylitis, hidradenitis suppurativa, respiratory diseases, diabetes, inflammatory eye diseases, hepatitis, cardiovascular diseases, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, viral inflammation, cancer, or combinations thereof.

6. The use as described in claim 5, characterized in that, The arthritis mentioned is psoriatic arthritis.

7. The use as described in claim 5, characterized in that, The neuroinflammatory condition was selected from multiple sclerosis and Alzheimer's disease.

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