WO2022206705A1 - 作为tyk2假激酶结构域抑制剂的杂环化合物及合成方法和用途 - Google Patents

作为tyk2假激酶结构域抑制剂的杂环化合物及合成方法和用途 Download PDF

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WO2022206705A1
WO2022206705A1 PCT/CN2022/083480 CN2022083480W WO2022206705A1 WO 2022206705 A1 WO2022206705 A1 WO 2022206705A1 CN 2022083480 W CN2022083480 W CN 2022083480W WO 2022206705 A1 WO2022206705 A1 WO 2022206705A1
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compound
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heterocyclic compound
tyk2
substituted
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French (fr)
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王能辉
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浙江文达医药科技有限公司
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Priority to CN202280022420.2A priority Critical patent/CN117177960A/zh
Publication of WO2022206705A1 publication Critical patent/WO2022206705A1/zh

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    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a heterocyclic compound as a TYK2 pseudokinase (Pseudokinase, JH2) domain inhibitor, a synthesis method and application thereof
  • Janus kinase is an intracellular non-receptor tyrosine kinase that mediates the signaling 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 various human tissue cells.
  • JAK3 is mainly expressed in in each hematopoietic tissue.
  • TYK2 is the first subtype discovered in the JAK family, which mediates the functions of cytokines such as IFN- ⁇ , IL-6, IL-10, IL-12 and IL-23. Studies have shown that TYK2 deletion mutations can effectively inhibit allergy and autoimmunity. and immune diseases such as inflammation. IL-23 plays a crucial role in the occurrence and development of psoriasis. The latest research shows that the pathogenesis of psoriasis is that endogenous unknown antigen activates the secretion of antigen-presenting cells (APC).
  • APC antigen-presenting cells
  • IL-23 activates Thi7 cells to secrete cytokines such as IL-17, induces the differentiation and division of keratinocytes and secretes IL-23, which further stimulates inflammation and keratinocyte proliferation to produce psoriasis.
  • TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23, and inhibition of JAK2 can lead to anemia and other blood-related side effects, so inhibiting TYK2 while avoiding inhibition of JAK2 is a good strategy to inhibit IL-23 signaling.
  • the first oral tofacitinib is a non-selective JAK inhibitor, which has significant inhibitory activity against JAK1, 2, 3, and TYK2.
  • the homology 1 domain prevents phosphorylation of the catalytic activity of downstream kinases by blocking ATP, and the resulting pathway signal transduction.
  • the activity inhibition of tofacitinib on other subtypes such as JAK1, 2, 3 and TYK2 increases the efficacy, but also brings more serious side effects, including infection, tuberculosis, tumor, anemia, liver damage and cholesterol increase. Since JAK2 activity is related to erythroid cell differentiation and lipid metabolism, some of the above-mentioned adverse reactions such as anemia are thought to be related to the insufficient selectivity of Tofacitinib for JAK2, which is caused by the non-selective inhibition of the drug.
  • TYK2 inhibitor that can bind the function of the catalytic domain (JH1) of previous JAK inhibitors Distinguished, selectively binds to the TYK2 pseudokinase (JH2) domain, inhibits the function of the pseudokinase (JH2) domain, avoids the inhibition of other isoforms such as JAK1, 2, 3, TYK2 (JH1), increases Safety of TYK2 pseudokinase (JH2) inhibitors for psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, dermatitis, lupus nephritis, neuroinflammation such as multiple sclerosis and Alzheimer's disease, ankylosing spondylitis, hidradenitis suppurativa, respiratory disease, diabetes, inflammatory eye disease,
  • JH2 TYK2 pseudokinase
  • the object of the present invention is to provide a TYK2 pseudokinase (JH2) domain inhibitor with novel structure with high safety and excellent efficacy.
  • X and Y are each independently CR 5 or N;
  • Z is CR 6 or N
  • W 1 and W 2 are each independently a divalent group selected from the group consisting of O, S, SO 2 , CO, NR 7 CO, CONR 7 ;
  • W 3 is a divalent group selected from the group consisting of CO, NR 7 , NR 7 CO, CONR 7 ;
  • R 3 is substituted or unsubstituted C 3-6 cycloalkyl
  • R 4 is selected from the group consisting of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-6 cycloalkyl; and R 4 is also optionally substituted with R 1 and R 2 ;
  • R 1 and R 2 are each independently selected from the group consisting of H, substituted or unsubstituted C1-6 alkyl; alternatively, R 1 and R 2 and the carbon atom to which they are attached together form a substituted or unsubstituted C 3-6 cycloalkyl;
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of H, substituted or unsubstituted C 1-4 alkyl;
  • n 1 or 2;
  • substitution refers to the substitution of one or more hydrogens in a group with a substituent selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl.
  • R 3 is substituted or unsubstituted cyclopropyl.
  • R 3 is cyclopropyl
  • X, Y, Z, W 1 , W 2 , W 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are the specific compounds in the examples (Compounds shown in Table A, more preferably compounds 2-5) corresponding groups.
  • heterocyclic compound is shown in formula IA;
  • heterocyclic compound is shown in formula IB;
  • heterocyclic compound is shown in formula IC;
  • heterocyclic compound is shown in formula II,
  • X and Y are each independently CR 5 or N;
  • Z is CR 6 or N
  • R 1 and R 2 are each independently selected from the group consisting of H, substituted or unsubstituted C1-6 alkyl; alternatively, R 1 and R 2 and the carbon atom to which they are attached together form a substituted or unsubstituted C 3-6 cycloalkyl;
  • R 5 and R 6 are each independently selected from the group consisting of H, substituted or unsubstituted C 1-4 alkyl;
  • substitution refers to the substitution of one or more hydrogens in a group with a substituent selected from the group consisting of halogen, C1-4 alkyl, C1-4 haloalkyl.
  • both R 5 and R 6 are H.
  • X, Y and Z are each independently CH or N.
  • X is N.
  • Y is CR 5 ; preferably, Y is CH.
  • Z is N.
  • X and Z are N.
  • X is N
  • Y is CR 5 (preferably, X is N and Y is CH).
  • X is N
  • Y is CR 5 (preferably, Y is CH)
  • Z is N
  • R 1 and R 2 are H.
  • R 1 and R 2 are H, or R 1 and R 2 and the carbon atoms connected to them together form a cyclopropyl group.
  • X, Y, Z, R 1 and R 2 are the corresponding groups in the specific compounds in the examples (such as the compounds shown in Table A, more preferably compounds 2-5).
  • the compound is a compound selected from Table A:
  • R X is halogen
  • X, Y, Z, W 1 , W 2 , W 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined in the first aspect .
  • R X is Cl
  • a method for preparing a heterocyclic compound according to the first aspect wherein the heterocyclic compound is shown in formula I, and wherein W 3 is NR 7 CO; the The method includes the steps:
  • R4 and R7 are as defined in the first aspect.
  • R 1 and R 2 are as defined in the first aspect.
  • a pharmaceutical composition comprising:
  • the TYK2-mediated disease is a disease associated with IL-23, IL-12 and/or IFN ⁇ .
  • the heterocyclic compound treats or prevents TYK2-JH2-mediated diseases by selectively inhibiting TYK2-JH2.
  • the TYK2-JH2-mediated diseases include: inflammation, autoimmune diseases, or a combination thereof.
  • the TYK2-JH2-mediated diseases include: psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, dermatitis, lupus nephritis, neuroinflammation such as multiple sclerosis and Alzheimer's disease, ankylosing spondylitis, hidradenitis suppurativa, respiratory disease, diabetes, inflammatory eye disease, hepatitis, cardiovascular disease, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, cancer or its combination.
  • the TYK2-JH2 inhibitor is a selective TYK2-JH2 inhibitor.
  • a method for selectively inhibiting TYK2 comprising:
  • a subject is contacted with a heterocyclic compound as described in the first aspect, thereby inhibiting TYK2-JH2 activity in the subject.
  • the subject is a cell or TYK2 kinase.
  • the inhibition is selective inhibition of TYK2-JH2.
  • the method is non-therapeutic in vitro.
  • a seventh aspect of the present invention there is provided a method for treating or preventing TYK2-mediated diseases, comprising the steps of:
  • the TYK2-mediated disease is a disease associated with IL-23, IL-12 and/or IFN ⁇ .
  • the heterocyclic compound treats or prevents TYK2-JH2-mediated diseases by selectively inhibiting TYK2-JH2.
  • the TYK2-JH2-mediated diseases include: inflammation, autoimmune diseases, or a combination thereof.
  • the TYK2-JH2-mediated diseases include: psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, dermatitis, lupus nephritis, neuroinflammation such as multiple sclerosis and Alzheimer's disease, ankylosing spondylitis, hidradenitis suppurativa, respiratory disease, diabetes, inflammatory eye disease, hepatitis, cardiovascular disease, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjögren's syndrome, cancer, or a combination thereof.
  • the inventor found that the compound with novel structure of the present invention has excellent selective inhibition of TYK2 (JH2), and then the present invention provides a compound that can effectively inhibit the desired target without affecting other non-target targets. compounds with higher safety profile. Based on this, the inventors have completed the present invention.
  • JH2 TYK2
  • halogen refers to F, Cl, Br or I.
  • halo means that the hydrogen atoms in the group are replaced with F, Cl, Br or I.
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (ie, C1-6 represents 1-6 carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • alkenyl refers to an unsaturated alkyl group having one or more double bonds.
  • the alkenyl group includes 1 to 4 carbons, ie C1-4 alkenyl.
  • alkynyl refers to an unsaturated alkyl group having one or more triple bonds (preferably having one triple bond).
  • the alkenyl group includes 1 to 4 carbons. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, ethynyl, 1- and 3-propynyl, 3-butynyl, and the like.
  • cycloalkyl refers to a fully saturated hydrocarbon ring having the specified number of ring atoms (eg, C3-6 cycloalkyl has 3-6 ring atoms).
  • Cycloalkyl also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.
  • alkylene by itself or as part of another substituent refers to a divalent group derived from an alkane , such as -CH2- or -CH2CH2CH2- .
  • Alkyl groups typically have 1-4 carbon atoms.
  • alkenylene or “alkynylene” refer to unsaturated forms of “alkylene” having double or triple bonds, respectively.
  • R', R" and R"' each independently represent hydrogen, unsubstituted C 1-8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted by 1-3 halogens, unsubstituted C 1-8 alkyl, C 1-8 alkoxy or C 1-8 thioalkoxy, or unsubstituted aryl-C 1-4 alkyl.
  • R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 3-,4- , 5-, 6- or 7-membered rings.
  • -NR'R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • acyl used alone or as part of another group, refers to where the point of attachment is closest to the group
  • substituent O (eg -C(O) CH3 , -C (O) CH2CH2OR ', etc.).
  • heteroatom is intended to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si); preferably, heteroatoms include oxygen (O), nitrogen (N), sulfur ( S).
  • a bond from a substituent (usually an R group) to the center of an aromatic ring will be understood to mean a bond that provides a link at any available vertex of the aromatic ring.
  • the description also includes linkages on rings fused to aromatic rings.
  • a bond drawn to the center of the indole benzene moiety would represent a bond to any available vertex of the six- or five-membered ring moiety of the indole.
  • the terms "containing”, “comprising” or “including” mean that the various ingredients can be used together in the mixture or composition of the present invention.
  • the terms “consisting essentially of” and “consisting of” are encompassed by the term “comprising”.
  • the term "pharmaceutically acceptable” ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (eg, toxicity, irritation, and allergy), ie, with a reasonable benefit/risk ratio.
  • each chiral carbon atom can optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (eg, isolated enantiomers) body) shall be included within the scope of the present invention.
  • compounds provided herein have a defined stereochemistry (denoted as R or S, or indicated with a dashed line or a wedge bond)
  • those compounds will be understood by those of skill in the art to be substantially free of other isomers (eg, at least 80% , 90%, 95%, 98%, 99% and up to 100% free of other isomers).
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the isotopic atoms that constitute such compounds.
  • the unnatural proportion of a certain isotope can be defined as the amount from the naturally found amount of the atom in question to 100% of that atom.
  • compounds can incorporate radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C) ).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C) ).
  • isotopic variants may provide additional uses beyond those described herein.
  • 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. Additionally, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic profiles, thereby contributing to increased safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the term "compound of the present invention” or “heterocyclic compound of the present invention” refers to a compound of formula (I) or formula (II).
  • the term also includes the various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I) or formula (II).
  • pharmaceutically acceptable salts refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicaments.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the present invention with acids.
  • Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric; formic, acetic, trifluoroacetic, propionic, oxalic, malonic, succinic, Organic acids such as 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 acid, phenylalanine, aspartic acid, glutamic acid and other amino acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric
  • formic acetic, trifluoroacetic, propionic,
  • salts are those of the compounds of the invention with bases, such as alkali metal salts (eg, sodium or potassium), alkaline earth metal salts (eg, magnesium or calcium), ammonium salts (eg, lower alkanolammonium salts) salts and other pharmaceutically acceptable amine salts) such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • bases such as alkali metal salts (eg, sodium or potassium), alkaline earth metal salts (eg, magnesium or calcium), ammonium salts (eg, lower alkanolammonium salts) salts and other pharmaceutically acceptable amine salt
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.
  • Hydrophilate refers to a complex formed by the coordination of a compound of the present invention with water.
  • the compounds of the present invention also include prodrugs of the heterocyclic compounds represented by formula (I) or formula (II).
  • prodrug includes a class of compounds of formula (I) which may be biologically active or inactive by themselves and undergo a metabolic or chemical reaction in the human body when administered in an appropriate manner, or A salt or solution of a compound of formula (I).
  • the prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compounds, carbamates, azo compounds of the compounds , phosphoramide, glucoside, ether, acetal and other forms.
  • compositions and methods of administration are provided.
  • the compound of the present invention Since the compound of the present invention has excellent selective inhibitory activity against the TYK2 pseudokinase domain (JH2), the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, And the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used for the treatment, prevention and alleviation of diseases mediated by TYK2 kinase.
  • JH2 pseudokinase domain JH2 pseudokinase domain
  • the compounds of the present invention are useful in the treatment of the following diseases: psoriasis, lupus erythematosus, inflammatory bowel disease, psoriatic arthritis, arthritis, dermatitis, lupus nephritis, neuroinflammation such as multiple sclerosis and senile dementia , Ankylosing spondylitis, hidradenitis suppurativa, respiratory disease, diabetes, inflammatory eye disease, hepatitis, cardiovascular disease, systemic sclerosis, organ transplantation, alopecia areata, acne, eczema, vitiligo, Sjogren's syndrome, some cancers, etc. of various autoimmune and inflammation-related diseases.
  • diseases such as multiple sclerosis and senile dementia , Ankylosing spondylitis, hidradenitis suppurativa, respiratory disease, diabetes, inflammatory eye disease, hepatitis, cardiovascular disease, systemic sclerosis, organ transplantation,
  • the term "selective” refers to higher activity or potency (eg, inhibitory activity) against a given target (eg, TYK2 (JH2)) than against other targets (eg, JAK1, 2, 3 (JH1 and JH2), and/or or TYK2(JH1)) activity or potency (inhibitory activity); for example, activity or potency (e.g. inhibitory activity) against a given target (eg, TYK2(JH2)) is a JH2), and/or TYK2 (JH1)) activity or potency (eg, inhibitory activity) at least 50-fold, etc.
  • IC50 other refers to the inhibitory activity IC50 (nM) of the heterocyclic compounds on one or more of the following kinases: TYK2-JH1 (kinase domain of TYK2), JAK1-JH1 (kinase structure of JAK1) domain), JAK1-JH2 (pseudokinase domain of JAK1), JAK2-JH1 (kinase domain of JAK2), JAK3-JH1 (kinase domain of JAK3).
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • 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.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • 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 .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • 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.
  • Dosage forms for topical administration of the compounds of this invention 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 if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 200 mg, preferably 1 to 50 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the compounds of the present invention have excellent selectivity. Compared with JH1 and JH2 of JAK1, 2, 3 and JH1 of TYK2, the compound of the present invention has more excellent inhibitory activity on JH2 of TYK2. Therefore, the compound of the present invention is less likely to act on other similar kinases and has more excellent safety.
  • the compounds of the present invention have excellent inhibitory activity while having excellent selectivity.
  • ⁇ Multi-channel pipette 0.2-10 ⁇ l, 5-50 ⁇ l, 20-300 ⁇ l (Raining)
  • the cell pellet was resuspended in 300ul staining buffer.
  • 1.1.2 Prepare compound concentration of 200 times the final concentration in the compound dilution plate. According to the 27-fold dilution method, dilute from the highest concentration point, a total of 4 concentration points, and transfer to the Echo plate.
  • Envision microplate reader (PerkinElmer) reads the ratio of fluorescence at 520nm and 495nm.
  • the compound dilution plate is equipped with a compound concentration of 100 times the final concentration. According to the 27-fold dilution method, dilute from the highest concentration point, a total of 4 concentration points, and transfer to the Echo plate.
  • Envision microplate reader (PerkinElmer) reads the ratio of fluorescence at 665nm and 615nm.

Abstract

本发明提供了作为TYK2假激酶(Pseudokinase,JH2)结构域抑制剂的杂环化合物及合成方法和用途。具体地，本发明提供了如式I所示的杂环化合物或其药学上可接受的盐，其中，各基团如文本中定义。本发明的杂环化合物具有优异的TYK2(JH2)选择抑制活性。

Description

作为TYK2假激酶结构域抑制剂的杂环化合物及合成方法和用途 技术领域
本发明属于医药领域，具体涉及一种作为TYK2假激酶(Pseudokinase,JH2)结构域抑制剂的杂环化合物及合成方法和用途
背景技术
Janus激酶(JAK)是一种细胞内非受体酪氨酸激酶，介导各种细胞因子的信号传导和激活。JAK激酶家族分为JAK1、2、3、TYK2四个亚型，各亚型分别介导不同类型的细胞因子信号通路，JAK1、2、TYK2在人体各组织细胞中均有表达，JAK3主要表达于各造血组织细胞中。
TYK2是JAK家族最早发现的一个亚型，介导IFN-α、IL-6、IL-10、IL-12和IL-23等细胞因子的功能，研究表明TYK2缺失突变能有效抑制过敏、自身免疫和炎症等免疫性疾病的发生。IL-23在银屑病的发生发展过程中起着至关重要的作用，最新研究表明，银屑病的发病机理是内源性未知抗原激活抗原递呈细胞(antigen-presenting cells,APC)分泌IL-23，IL-23激活Thi7细胞而分泌IL-17等细胞因子，诱发角质细胞分化分裂和分泌IL-23，进一步刺激炎症和角质细胞增殖产生银屑病。TYK2和JAK2共同介导IL-23的下游信号通路，抑制JAK2会导致贫血和其它血液相关副作用，因此抑制TYK2同时避免抑制JAK2是抑制IL-23信号通路的良好策略。首个口服Tofacitinib属于非选择性JAK抑制剂，对JAK1、2、3、TYK2均有显著的抑制活性,可以定点抑制与腺苷三磷酸腺苷(ATP)位点结合的催化结构域(JH1或“JAK蛋白的同源性1域”)，可防止通过阻断ATP，下游的激酶的催化活性磷酸化，以及由此产生的通路信号转导。Tofacitinib对其它亚型如JAK1、2、3、TYK2的活性抑制增加了疗效，但同时也带来了较为严重的副作用，不良反应包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。由于JAK2活性与红系细胞分化以及脂代谢过程相关，上述贫血等部分不良反应被认为可能与Tofacitinib对JAK2选择性不足相关，是该药物的非选择性抑制引起的。
鉴于JAK非选择性抑制剂的良好疗效和多种靶点相关性严重副作用，本领域迫切需要一种TYK2抑制剂，该抑制剂能够和以前的JAK抑制剂的结合催化结构域(JH1)的功能区別开来，选择性地结合到TYK2假激酶(JH2)结构域上，抑制假激酶(JH2)结构域的功能，避免对其它亚型如JAK1、2、3、TYK2(JH1)的抑制，增加TYK2假激酶(JH2)抑制剂的安全性，从而能够用于银屑病、红斑狼疮、炎性肠病、银屑病关节炎、关节炎、皮炎、狼疮肾炎、神经性炎症如多发性硬化和老年痴呆、强直性脊柱炎、化脓性汗腺炎、呼吸道疾病、糖尿病、炎症眼疾、肝炎、心血管疾病、系统性硬化症、器官移植、斑秃、痤疮、湿疹、白癜风、干燥综合症、一些癌症等在内的和TYK2假激酶(JH2)结构域功能相关的多种自身免疫及炎症相关疾病的治疗中具有巨大临床应用潜力。
因此，本领域迫切需要开发结构新颖的高安全性和优药效的TYK2假激酶(JH2)结构域抑制剂。
发明内容
本发明的目的就是提供结构新颖的高安全性和优药效的TYK2假激酶(JH2)结构域 抑制剂。
在本发明的第一方面中，提供了一种杂环化合物或其药学上可接受的盐，所述的化合物如式I所示
Figure PCTCN2022083480-appb-000001
其中，
X和Y各自独立地为CR 5或N；
Z为CR 6或N；
W 1和W 2各自独立地为选自下组的二价基团：O、S、SO 2、CO、NR 7CO、CONR 7；
W 3选自下组的二价基团：CO、NR 7、NR 7CO、CONR 7；
R 3为取代或未取代的C 3-6环烷基；
R 4选自下组：取代或未取代的C 1-6烷基、取代或未取代的C 3-6环烷基；并且R 4还任选地被R 1和R 2取代；
R 1和R 2各自独立地选自下组：H、取代或未取代的C1-6烷基；或者，R 1和R 2以及与其相连的碳原子共同形成取代或未取代的C 3-6环烷基；
R 5、R 6和R 7各自独立地选自下组：H、取代或未取代的C 1-4烷基；
n＝1或2；
除非特别说明，所述取代是指基团中一个或多个氢被选自下组的取代基所述取代：卤素、C1-4烷基、C1-4卤代烷基。
在另一优选例中，R 3为取代或未取代的环丙基。
在另一优选例中，R 3为环丙基。
在另一优选例中，X、Y、Z、W 1、W 2、W 3、R 1、R 2、R 3、R 4、R 5、R 6、R 7和n为实施例中具体化合物(如表A中所示的化合物，更佳地为化合物2-5)中对应的基团。
在另一优选例中，所述杂环化合物如式IA所示；
Figure PCTCN2022083480-appb-000002
其中，各基团如前定义。
在另一优选例中，所述杂环化合物如式IB所示；
Figure PCTCN2022083480-appb-000003
其中，各基团如前定义。
在另一优选例中，所述杂环化合物如式IC所示；
Figure PCTCN2022083480-appb-000004
其中，各基团如前定义。
在另一优选例中，所述杂环化合物如式II所示，
Figure PCTCN2022083480-appb-000005
其中，
X和Y各自独立地为CR 5或N；
Z为CR 6或N；
R 1和R 2各自独立地选自下组：H、取代或未取代的C1-6烷基；或者，R 1和R 2以及与其相连的碳原子共同形成取代或未取代的C 3-6环烷基；
R 5和R 6各自独立地选自下组：H、取代或未取代的C 1-4烷基；
除非特别说明，所述取代是指基团中一个或多个氢被选自下组的取代基所述取代：卤素、C1-4烷基、C1-4卤代烷基。
在另一优选例中，R 5和R 6均为H。
在另一优选例中，X、Y和Z各自独立地为CH或N。
在另一优选例中，X为N。
在另一优选例中，Y为CR 5；较佳地，Y为CH。
在另一优选例中，Z为N。
在另一优选例中，X和Z为N。
在另一优选例中，X为N，Y为CR 5(较佳地，X为N且Y为CH)。
在另一优选例中，X为N，Y为CR 5(较佳地，Y为CH)，且Z为N。
在另一优选例中，R 1和R 2为H。
在另一优选例中，R 1和R 2以及与其相连的碳原子共同形成取代或未取代的C 3-6环烷基。
在另一优选例中，R 1和R 2为H，或者R 1和R 2以及与其相连的碳原子共同形成环丙基。
在另一优选例中，X、Y、Z、R 1和R 2为实施例中具体化合物(如表A中所示的化合物，更佳地为化合物2-5)中对应的基团。
在另一优选例中，所述化合物为选自表A的化合物：
表A
Figure PCTCN2022083480-appb-000006
在本发明的第二方面中，提供了一种用于制备如第一方面所述杂环化合物的中间体，所述中间体如式III、式IIIA、式IIIB、式IIIC或式IV所示：
Figure PCTCN2022083480-appb-000007
Figure PCTCN2022083480-appb-000008
其中，R X为卤素；X、Y、Z、W 1、W 2、W 3、R 1、R 2、R 3、R 4、R 5、R 6、R 7和n如第一方面中定义。
在另一优选例中，R X为Cl。
在本发明的第三方面中，提供了一种如第一方面所述的杂环化合物的制备方法，其中，所述杂环化合物如式I所示，并且其中W 3为NR 7CO；所述方法包括步骤：
使如式III所示的中间体与如V所示的化合物反应，从而得到式I化合物；
Figure PCTCN2022083480-appb-000009
其中，R4和R7如第一方面中定义。
在另一优选例中，使如式IV所示的中间体与如VI所示的化合物反应，从而得到式II化合物
Figure PCTCN2022083480-appb-000010
其中，R 1和R 2如第一方面中定义。
在本发明的第四方面中，提供了一种药物组合物，包括：
(i)如第一方面所述的杂环化合物或其药学上可接受的盐，和(ii)药学上可接受的载体或赋形剂。
在本发明的第五方面中，提供了一种如第一方面所述的杂环化合物在制备(i)用于治疗或预防TYK2介导的疾病的药物和/或(ii)TYK2抑制剂中的用途。
在另一优选例中，所述TYK2介导的疾病为与IL-23、IL-12和/或IFNα关联的疾病。
在另一优选例中，所述杂环化合物通过选择性抑制TYK2-JH2来治疗或预防TYK2-JH2介导的疾病。
在另一优选例中，所述TYK2-JH2介导的疾病包括：炎症、自身免疫性疾病，或其组合。
在另一优选例中，所述TYK2-JH2介导疾病包括：银屑病、红斑狼疮、炎性肠病、银屑病关节炎、关节炎、皮炎、狼疮肾炎、神经性炎症如多发性硬化和老年痴呆、强直性脊柱炎、化脓性汗腺炎、呼吸道疾病、糖尿病、炎症眼疾、肝炎、心血管疾病、系统性硬化症、器官移植、斑秃、痤疮、湿疹、白癜风、干燥综合症、癌症或其组合。
在另一优选例中，所述TYK2-JH2抑制剂为选择性TYK2-JH2抑制剂。
在本发明的第六方面中，提供了一种选择性抑制TYK2的方法，所述方法包括：
使对象与如第一方面所述的杂环化合物接触，从而抑制对象中TYK2-JH2活性。
在另一优选例中，所述对象为细胞或TYK2激酶。
在另一优选例中，所述抑制是对TYK2-JH2的选择性抑制。
在另一优选例中，所述的方法是体外非治疗性的。
在本发明的第七方面中，提供了一种治疗或预防TYK2介导的疾病的方法，包括步骤：
向有需要的人施用安全有效量的如第一方面的杂环化合物或如第三方面所述的药物组合物，从而抑制或
在另一优选例中，所述TYK2介导的疾病为与IL-23、IL-12和/或IFNα关联的疾病。
在另一优选例中，所述杂环化合物通过选择性抑制TYK2-JH2来治疗或预防TYK2-JH2介导的疾病。
在另一优选例中，所述TYK2-JH2介导的疾病包括：炎症、自身免疫性疾病，或其组合。
在另一优选例中，所述TYK2-JH2介导疾病包括：银屑病、红斑狼疮、炎性肠病、银屑病关节炎、关节炎、皮炎、狼疮肾炎、神经性炎症如多发性硬化和老年痴呆、强直性脊柱炎、化脓性汗腺炎、呼吸道疾病、糖尿病、炎症眼疾、肝炎、心血管疾病、系统性硬化症、器官移植、斑秃、痤疮、湿疹、白癜风、干燥综合症、癌症，或其组合。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
发明人经过广泛而深入地研究，发现本发明的具有新颖结构的化合物具有优异的对TYK2(JH2)的选择抑制，进而本发明提供了一种能够在有效抑制所需靶标不影响其他非目标靶标的具有更高安全性的化合物。基于此，发明人完成了本发明。
术语
如本文所述，术语“卤素”是指F、Cl、Br或I。相应地，“卤代”是指基团中的氢原子被F、Cl、Br或I取代。
除非另有表述，术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烃基(即，C 1-6表示1-6个碳)。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基等。
术语“烯基”指具有一个或多个双键的不饱和烷基。优选地，烯基包括1至4个碳，即C1-4烯基。类似地，术语“炔基”指具有一个或多个三键的不饱和烷基(优选具有一个三键)。优选地，烯基包括1至4个碳。这些不饱和烷基的实例包括乙烯基、2-丙烯基、乙炔基、1-和3-丙炔基、3-丁炔基等。
术语“环烷基”是指具有指定环原子数(例如，C 3-6环烷基具有3-6个环原子)并且完全饱和的烃环。“环烷基”也指双环和多环烃环，例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团，例如-CH 2-或-CH 2CH 2CH 2-。烷基(或亚烷基)通常具有1-4个碳原子。类似地，“亚烯基”或“亚炔基”分别指具有双键或三键的不饱和形式的“亚烷基”。
烷基(包括通常称为亚烷基，烯基，炔基和环烷基的那些基团)的取代基可以是选自下组的各种基团：-卤素、-OR'、-NR'R"、-SR'、-OC(O)R'、-C(O)R'、-CO 2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R"'、-NR"C(O) 2R'、-NH-C(NH 2)＝NH、-NR'C(NH 2)＝NH、-NH-C(NH 2)＝NR'、-S(O)R'、-S(O) 2R'、-S(O) 2NR'R"、-NR'S(O) 2R"、-CN和-NO 2，数量从零到(2m'+1)，其中m'是这种基团中的碳原子总数。R'、R"和R"'各自独立地表示氢，未取代的C 1-8烷基，未取代的杂烷基，未取代的芳基，被1-3个卤素取代的芳基，未取代的C 1-8烷基，C 1-8烷氧基或C 1-8硫代烷氧基，或未取代的芳基-C 1-4烷基。当R'和R”连接到相同的氮原子时，它们可以与氮原子结合形成3-，4-，5-，6-或7-元环。例如，-NR'R”是指包括1-吡咯烷基和4-吗啉基。术语“酰基”，单独或作为另一基团的一部分使用，是指其中在最接近该基团的连接点的碳上两个取代基的被取代基＝O取代(例如-C(O)CH 3,-C(O)CH 2CH 2OR'等)。
如本文所用，术语“杂原子”意在包括氧(O)、氮(N)、硫(S)和硅(Si)；优选地，杂原子包括氧(O)、氮(N)、硫(S)。
对于本文提供的化合物，从取代基(通常为R基团)到芳香环(例如苯，吡啶等)的中心的键将被理解为是指在芳香环的任何可用顶点提供连接的键。在一些实施例中，该描述也包括稠合在芳环上的环上的连接。例如，绘制到吲哚苯部分的中心的键将表示与吲哚的六元或五元环部分的任何可用顶点连接的键。
如本文所用，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
如本文所用，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
本发明的某些化合物拥有不对称碳原子(光学中心)或双键；消旋体、非对映体、几何异构体、区域异构体和单独的异构体(例如，分离的对映体)均应包括在本发明范围内。当本文提供的化合物具有确定的立体化学(表示为R或S，或具有虚线或楔形键指明)时，被本领域技术人员将理解那些化合物为基本上不含其他异构体(例如至少80％，90％，95％，98％，99％和至多100％不含其他异构体)。
本发明化合物还可在构成此类化合物的一个或多个同位素原子处含有非天然比例的原子同位素。某同位素的非天然比例可以定义为从所讨论原子的天然发现的量到100％该原子的量。例如，化合物可以掺入放射性同位素，例如氚( 3H)、碘-125( 125I)或碳-14( 14C)，或非放射性同位素，例如氘( 2H)或碳-13( 13C)。除了本申请所述的那些用途，此类同位素变体可提供额外的用途。例如，本发明化合物的同位素变体可以有额外的用途，包括但不限于作为诊断的和/或成像试剂，或作为细胞毒性/放射毒性治疗剂。另外，本发明化合物的同位素变体可具有改变的药代动力学和药效学特征，从而有助于增加治疗期间的安全性、耐受性或疗效。无论是否有放射性，本发明化合物的所有同位素变体 均应包括在本发明范围内。
活性成分
如本文所用，术语“本发明化合物”或“本发明杂环化合物”指式(I)或式(II)所示的化合物。该术语还包括及式(I)或式(II)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
其中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外，本发明化合物还包括式(I)或式(II)所示的杂环化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
下面更具体地描述本发明式(I)或式(II)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
药物组合物和施用方法
由于本发明化合物具有优异的对TYK2假激酶结构域(JH2)的选择抑制活性，因此，本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由TYK2激酶介导的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：银屑病、红斑狼疮、炎性肠病、银屑病关节炎、关节炎、皮炎、狼疮肾炎、神经性炎症如多发性硬化和老年痴呆、强直性脊柱炎、化脓性汗腺炎、呼吸道疾病、糖尿病、炎症眼疾、肝炎、心血管疾病、系統性硬化症、器官移植、斑秃、痤疮、湿疹、白癜风、干燥综合症、一些癌症等在内的多种自身免疫及炎症相关疾病。
在本文中，术语“选择性”是指对指定靶标(如TYK2(JH2))的活性或效力(如抑制活性)高于对其他靶标(如JAK1、2、3(JH1和JH2)，和/或TYK2(JH1))的活 性或效力(抑制活性)；例如，对指定靶标(如TYK2(JH2))的活性或效力(如抑制活性)是对其他靶标(如JAK1、2、3(JH1和JH2)，和/或TYK2(JH1))的活性或效力(如抑制活性)至少50倍等。例如，以IC50值来定量抑制活性时，IC50 其他/IC50 TYK2-JH2>50，其中，IC50 TYK2-JH2是指所述的杂环化合物对TYK2-JH2(TYK2的假激酶结构域)抑制活性IC50(nM)，IC50 其他是指所述的杂环化合物对下述一种或多种激酶的抑制活性IC50(nM)：TYK2-JH1(TYK2的激酶结构域)、JAK1-JH1(JAK1的激酶结构域)、JAK1-JH2(JAK1的假激酶结构域)、JAK2-JH1(JAK2的激酶结构域)、JAK3-JH1(JAK3的激酶结构域)。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-200mg本发明化合物/剂，更佳地，含有1-50mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022083480-appb-000011
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或 这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～200mg，优选1～50mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.本发明的化合物具有优异的选择性。相比于JAK1、2、3的JH1和JH2以及TYK2的JH1，本发明的化合物具有更优异的对TYK2的JH2的抑制活性。因此，本发明的化合物不易对其他类似激酶产生作用而具有更优异的安全性。
2.本发明的化合物在具有优异的选择性的同时具有优异的抑制活性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
制备实施例
实施例1：化合物1的合成
Figure PCTCN2022083480-appb-000012
步骤A：
Figure PCTCN2022083480-appb-000013
250ml三口瓶中加入化合物1a(6.4g,0.045mol，1.0eq)，二甲亚砜(100ml)，环丙基亚磺酸钠(6.4g,0.06mol，1.2eq)，氮气保护，在100℃加热搅拌反应1hr，TLC检测直到反应完全,降温，将反应液倒入冰水中(600ml)，用甲基叔丁基醚萃取3次，合并的有机相用饱和食盐水洗2次，用Na2SO4干燥，浓缩，石油醚打浆，得白色粉末状固体化合物1b(7.8g,0.034mol,产率76％)。1H NMR(300MHz,CDCl3):8.05(m,1H),7.7-7.9(m,3H),3.2-3.3(m,1H),1.3-1.5(m,2H),1.0-1.2(m,2H).
步骤B：
Figure PCTCN2022083480-appb-000014
250ml单口瓶中加入化合物1b(3.2g,0.014mol，1.0eq)，乙醇(100ml),Pd/C(10％,1.0g)，室温，氢气袋氢化反应3hrs，TLC原料反应完全，过滤，浓缩，拌样柱层析，得白色固体化合物1c(2.6g,0.013mol,产率94％)。1H NMR(300MHz,CDCl3):7.65(m,1H),7.2-7.4(m,1H),6.7-6.9(m,2H),2.6-2.8(m,1H),1.3-1.4(m,2H),0.9-1.0(m,2H).
步骤C：
Figure PCTCN2022083480-appb-000015
100ml三口瓶中加入化合物1c(0.8g,4mmol，1.0eq)，化合物1d(0.91g,4.4mmol，1.1eq)，THF(40ml)，氮气保护，0-5℃滴加NaHMDS(2M,3ml,6mmol)，加毕，室温反应1hr，TLC原料反应完全，将反应液倒入冷的饱和氯化铵水溶液中(200ml)，用乙酸乙脂萃取2次，合并的有机相用饱和食盐水洗2次，用Na2SO4干燥，浓缩，拌样柱层析，得浅黄色固体化合物1f(0.4g,1mmol,产率94％))。MS-ESI:[M+1]+＝370.9。1H NMR(300MHz,CDCl3):11.4(s,1H),8.2(s,1H),8.0(m,1H),7.7(m,1H),7.4-7.6(m,2H),7.1(s,1H),2.5-2.7(m,1H),1.2-1.4(m,2H),0.97-1.04(m,2H).
步骤D：
Figure PCTCN2022083480-appb-000016
100ml单口瓶中加入化合物1f(0.4g,1.0mmol，1.0eq)，1,4-二氧六环(30ml)，环丙基甲酰胺(0.14g,1.63mol，1.5eq)，Pd 2(dba) 3(0.1g),DPPF(0.01g)，2M K3PO4水溶液(1.6ml,3.24mol，3.0eq)，氮气保护，110℃反应过夜，TLC原料未能反应完全，浓缩，柱层析，得黄色粉末化合物1(90mg,0.22mmol,产率22％)。
MS-ESI:[M+1]+＝419.5。1H NMR(300MHz,d6-DMSO):11.35(s,1H),11.06(s,1H),9.09(s,1H),8.04(s,1H),7.89(m,1H),7.7-7.73(m,2H),7.42(m,1H),2.75(m,1H),2.03(m,1H),0.75-1.02(m,8H).
实施例2:化合物2的合成
Figure PCTCN2022083480-appb-000017
步骤A
Figure PCTCN2022083480-appb-000018
250ml三口瓶中加入化合物2a(10g，0.0575mol，1.0eq)，二甲亚砜(100ml)，环丙基亚磺酸钠(11g，0.086mol，1.5eq),L-脯氨酸(1.32g,0.2eq)，碘化亚铜(1.1g,0.1eq)，氢氧化钠(0.46g,0.2eq)，氮气保护，150℃反应48hrs，TLC原料反应完全，降温，倒入冰水中(2L)，用乙酸乙脂萃取2次，合并的有机相用饱和食盐水洗2次，干燥，浓缩，柱层析，得白色粉末状化合物2b(6.6g,0.0331mol,产率57.6％)。MS-ESI:[M+1]+＝200.2。1H NMR(300MHz,CDCl3):8.24(d,1H),8.01(d,1H),2.8-2.9(m,1H),1.4-1.5(m,2H),1.05-1.15(m,2H).
步骤B
Figure PCTCN2022083480-appb-000019
100ml三口瓶中加入化合物2b(0.4g,2mmol，1.0eq),THF(20ml)，氮气保护，0-5℃滴加NaHMDS(2M,1.5ml,3mmol)，室温搅拌30mins，再加入化合物1d(0.42g,2mmol，1.0eq)，TLC检测原料未能反应完全。即使是延时,反应无变化，倒入冰水中，乙酸乙脂萃取，饱和食盐水洗，干燥浓缩，柱层析，白色粉末状化合物2c(0.53g,1.42mmol,产率71％)。MS-ESI:[M+1]+＝372.8。
步骤C:
Figure PCTCN2022083480-appb-000020
100ml单口瓶中加入化合物2c(0.25g,0.67mmol，1.0eq)，二氧六环(20ml)，环丙基甲酰胺(85mg,1mmol，1.5eq)，Pd2(dba)3(50mg)，DPPF(60mg)，氮气置换3次，搅拌5mins，再加入K3PO4水溶液(1ml,2M,3.0eq)，氮气置换3次，112℃反应过夜，TLC原料未反应完全，浓缩，柱层析后再用甲基叔丁基醚打浆，得黄色粉末化合物2(80mg,0.19mmol,产率28.5％)。MS-ESI:[M+1]+＝421.5。1H NMR(300MHz,d6-DMSO):12.3(s,1H),11.5(s,1H),9.44(s,1H),9.18(s,1H),8.67(d,1H),8.44(d,1H),3.16(m,1H),2.13(m,1H),1.10-1.22(m,4H),0.86-0.88(m,4H).
实施例3:化合物3的合成
Figure PCTCN2022083480-appb-000021
步骤A
Figure PCTCN2022083480-appb-000022
500ml三口瓶中加入化合物3a(25g，0.144mol，1.0eq)，二甲亚砜(300ml)，环丙基亚磺酸钠(28g，0.218mol，1.5eq),L-脯氨酸(3.3g,0.2eq)，碘化亚铜(2.74g,0.1eq)，氢氧化钠(1.2g,0.2eq)，氮气保护，150℃反应48hrs，TLC原料反应完全，降温，倒入冰水中(2L)，乙酸乙脂萃取2次，合并的有机相用饱和食盐水洗2次，用Na2SO4干燥，浓缩,用石油醚-甲基叔丁基醚打浆，得米黄色粉末化合物3b(16g,0.081mol,产率56.1％)。MS-ESI:[M+1]+＝199.2。1H NMR(300MHz,CDCl3):8.25-8.27(d,1H),7.87-7.90(m,1H),6.73-6.78(m,1H),2.60-2.70(m,1H),1.29-1.35(m,2H),0.97-1.05(m,2H).
步骤B
Figure PCTCN2022083480-appb-000023
500ml三口瓶中加入化合物3b(5.5g,0.028mol，1.0eq),THF(200ml)，氮气保护，0-5℃滴加NaHMDS(2M,21ml,0.042mol,1.5eq)，室温搅拌30mins，冰浴下再加入化合物1d(6.3g,0.03mol，1.1eq)，室温搅拌1hr，TLC原料反应完全，倒入冷的饱和氯化铵水溶液中(100ml)，加入甲基叔丁基醚(100ml)，搅拌10mins，有固体析出，过滤，水洗，乙酸乙脂洗，烘干，得白色粉末化合物3c(3.1g,8.3mmol,产率30％)。MS-ESI:[M+1]+＝371.9。1H NMR(300MHz,d6-DMSO):12.3(s,1H),9.40(s,1H),8.88(s,1H),8.70(d,1H),8.25-8.28(m,1H),8.37-8.41(m,1H),3.12(m,1H),1.18(m,2H),1.09(m,2H).
步骤C
Figure PCTCN2022083480-appb-000024
250ml单口瓶中加入化合物3c(3.1g,8.3mmol，1.0eq)，二氧六环(150ml)，环丙基甲酰胺(1.1g,13.0mmol，1.6eq)，Pd2(dba)3(0.5g)，DPPF(0.6g)，氮气置换3次，搅拌5mins，再加入K3PO4水溶液(12.5ml,2M,3.0eq)，氮气置换3次，112℃反应过夜，TLC原料未反应完全，浓缩，柱层析，得白色粉末化合物3(1.25g,3mmol,产率36％)。MS-ESI:[M+1]+＝420.5。1H NMR(300MHz,CDCl3):12.4(s,1H),9.66(s,1H),9.23(s,1H),8.62(m,1H),8.16-8.23(m,2H),7.12-7.16(m,1H),2.82-2.90(m,1H),1.64-1.82(m,1H),1.40(m,2H),1.20(m,2H),0.98-1.11(m,4H).
实施例4:化合物4的合成
Figure PCTCN2022083480-appb-000025
步骤如下：
Figure PCTCN2022083480-appb-000026
100ml单口瓶中加入化合物3c(0.21g,0.56mmol，1.0eq)，二氧六环(20ml)，化合物4a(94mg,0.85mmol，1.5eq)，Pd2(dba)3(0.05g)，DPPF(0.06g)，氮气置换3次，搅拌5mins，再加入K3PO4水溶液(1ml,2M,3.6eq)，氮气置换3次，112℃反应过夜，TLC原料未反应完全，浓缩，柱层析，得粉色粉末化合物4(异构体混合物)(0.07g,3mmol,产率28％)。MS-ESI:[M+1]+＝446.5。1H NMR(300MHz,CDCl3):12.4(s,1H),9.64(s,1H),8.86(s,1H),8.61-8.64(m,1H),8.14-8.23(m,2H),7.12-7.17(m,1H),2.86-2.92(m,1H),2.18-2.22(m,1H)，1.66(m,1H),1.55(m,1H),1.40(m,2H)，1.0-1.13(m,6H).
实施例5:化合物5的合成
Figure PCTCN2022083480-appb-000027
100ml单口瓶中加入化合物2c(0.25g,0.67mmol，1.0eq)，二氧六环(20ml)，化合物 4a(111mg,1mmol，1.5eq)，Pd2(dba)3(0.05g)，DPPF(0.06g)，氮气置换3次，搅拌5mins，再加入K3PO4水溶液(1ml,2M,3.0eq)，氮气置换3次，112℃反应过夜，TLC原料未反应完全，浓缩，柱层析，甲基叔丁基醚打浆，得黄色粉末状化合物5(异构体混合物)(0.05g,0.112mml,产率16.7％)。MS-ESI:[M+1]+＝447.4。1H NMR(300MHz,CDCl3):12.6(s,1H),9.68(s,1H),8.84(s,1H),8.60(d,1H),8.29(d,1H),8.16(s,1H),3.03-3.09(m,1H),2.17-2.21(m,1H)，1.5-1.7(m,4H),1.0-1.3(m,6H).
实施例6:化合物6的合成
Figure PCTCN2022083480-appb-000028
步骤A
Figure PCTCN2022083480-appb-000029
200ml三口瓶中加入化合物3b(532mg,2.68mmol，1.0eq),DMF(20ml)，氮气保护，0-5℃加NaH(539mg,13.4mmol,60％)，室温搅拌30mins，冰浴下再加入化合物6a(700mg,3.38mol，1.2eq)，室温搅拌1hr，50℃反应3h,倒入冷的饱和氯化铵水溶液中(100ml)，乙酸乙脂萃取2次，合并的有机相用饱和食盐水洗2次，用Na2SO4干燥，浓缩，柱层析，得白色粉末化合物6b(220mg,0.6mmol,产率22％)。MS-ESI:[M+1]+＝370.1。1H NMR(400MHz,CDCl3):11.7(s,1H),8.64(s,1H),8.60(s,1H),8.56(m,1H),8.20(m,1H),7.16(m,1H),6.88(m,1H),2.83-2.9(m,1H),1.41-1.43(m,2H),1.05-1.1(m,2H).
步骤B
Figure PCTCN2022083480-appb-000030
100ml单口瓶中加入化合物6b(200mg,0.51mmol，1.0eq)，二氧六环(150ml)，环丙基甲酰胺(230mg,2.7mmol)，Pd2(dba)3(43mg)，DPPF(94mg)，氮气置换3次，搅拌5mins，再加入Cs2CO3(355mg,1.08mmol)，氮气置换3次，130℃反应过夜， TLC原料未反应完全，浓缩，柱层析，得白色粉末化合物6(55mg,0.13mmol,产率25.5％)。MS-ESI:[M+1]+＝419.2。1H NMR(400MHz,d6-DMSO):11.42(s,1H),10.86(s,1H),8.93(s,1H),8.5-8.54(m,2H),8.17-8.2(m,1H),7.22-7.26(m,1H),3.0(m,1H),2.0(m,1H),1.2(m,2H),1.0(m,2H),0.8(m,4H).
测试例1
FACS检测化合物对CD3+细胞中pSTAT5表达的抑制作用
1实验材料和仪器
1.1实验试剂
·DMSO,西格玛(Sigma),Cat#D2650-100ml,室温保存。
·Perm缓冲液III,BD百赛(BD Biosciences),Cat#558050,4℃保存。
·裂解/固定缓冲液,BD百赛,Cat#558049,室温保存。
·EDTA,英杰(Invitrogen),Cat#15575-038,室温保存。
·PBS,Hyclone,Cat#SH30256.01,4℃保存。
·PE鼠抗人CD3,BD百赛,Cat#555333,4℃保存。
·鼠抗人磷酸化STAT5(pY694)(Alexa
Figure PCTCN2022083480-appb-000031
647偶联物),BD百赛,Cat#562076,4℃保存。
·IFN-α,Biolegend,Cat#592702
1.2实验耗材
·微孔板(Microplate),96孔,PP,v形底,Greiner,Cat#GN651201-100EA。
·5ml聚苯乙烯圆底管,FALCON,Cat#04318011。
·96方孔储板,Thermo,Cat#AB-0661。
·96孔板,Corning,Cat#3599。
1.3仪器
·CO 2细胞孵育仪:MCO-15AC(Thermo)
·移液管:0.2-10μl,20-200μl,200-1000μl(Thermo)
·多通道移液管:0.2-10μl,5-50μl,20-300μl(Raining)
·离心机:赛默(Thermo)离心ST 40R；赛默LEGEND Micro 21R
·水系统:Millipore Milli-Q Reference system
·冰柜：海尔超低温冰柜
·海尔4度冰箱
·海尔-20度冰柜
·涡流：EARTH REQUIRED
·制版机：其林贝尔(QI LIN BEI ER)；MH-2
·流式细胞仪：BD FACSVerseTM流式细胞仪
2实验方法
2.1化合物稀释
1)实验当天，化合物用DMSO配制10mM溶液，在DMSO中稀释至1.5mM,再3倍稀释8个梯度浓度。
2)转移5μl稀释好的化合物到120ul含0.1％BSA的DPBS溶液中。
3)设置阳性和阴性对照组，阳性对照和阴性对照组加0.5％DMSO。
2.2实验过程
1)在96孔细胞培养板中加入67.5ul新鲜的人的全血。
2)加入3.5ul稀释好的化合物，混匀。
3)在37℃培养箱中孵育60分钟。
4)将IFN-α在含0.1％BSA的DPBS中稀释成400ng/ml,将PE-抗hCD3抗体在含0.1％BSA的DPBS中稀释成5倍。上述60分钟孵育完成后，加入5ul每孔稀释好的PE-抗hCD3抗体，加入4ul每孔稀释好的IFN-α，即每孔IFN-α终浓度为20ng/ml。
5)在37℃培养箱中孵育15分钟。
6)将所有细胞转移到96孔深孔板中，加入1ml 37℃预热的裂解/固定缓冲液。
7)37℃避光孵育10分钟。
8)600g离心5分钟后弃上清，加入1ml PBS洗两遍并离心。
9)细胞沉淀中加入1ml Perm缓冲液III。
10)4℃避光孵育30分钟。
11)600g离心5分钟后弃上清，加入1ml PBS洗两遍并离心。
12)将APC抗人pSTAT5抗体在染色缓冲液中稀释，100ul每孔加入细胞孔中，混匀。
13)室温孵育40分钟。
14)加入染色缓冲液洗两遍，1ml每孔，600g离心5分钟。
15)弃上清后细胞沉淀在300ul染色缓冲液中重悬。
16)在流式细胞仪中上样分析。从计算获得待测样品的IC50,结果见表1。
表1
化合物编号 IFN-α/pSTAT5 IC50(nM)
1 2800
2 867
3 64
4 168
5 2111
6 128
测试例2
JAK家族选择性比较
1.实验方法
1.1.假激酶(JH2)实验操作如下：
1.1.1.用DMSO溶解化合物到10mM的存储浓度。
1.1.2.在化合物稀释板中配备200倍于终浓度的化合物浓度，按照27倍倍比稀释法，从最高浓度点稀释，共4个浓度点，并转移到Echo板中。
1.1.3.用Echo仪器将化合物从Echo板脉冲到384孔实验板，使得化合物变成3倍倍比稀释矩阵11个浓度点。
1.1.4.加5ul 3倍于终浓度的TYK2-JH2或JAK1-JH2假激酶到384孔实验板中。
1.1.5.加5ul 3倍于终浓度的Tb到384孔实验板中。
1.1.6.加5ul 3倍于终浓度的Tracer到384孔实验板中。
1.1.7.离心30秒，室温孵育60分钟。
1.1.8.Envision酶标仪(PerkinElmer)读取520nm处与495nm处荧光比值。
1.2.激酶(JH1)实验操作如下：
1.2.1.用DMSO溶解化合物到10mM的存储浓度。
1.2.2.在化合物稀释板子中配备100倍于终浓度的化合物浓度，按照27倍倍比稀释法，从最高浓度点稀释，共4个浓度点，并转移到Echo板中。
1.2.3.用Echo仪器将化合物从Echo板脉冲到384实验板，使得化合物变成3倍倍比稀释矩阵11个浓度点。
1.2.4.配备2倍于终浓度的激酶工作液，并加5ul每孔到384孔实验板中，化合物和激酶室温孵育15分钟。
1.2.5.加入5ul 2倍于终浓度的底物(含有ATP)到384孔板中。
1.2.6.室温孵育45分钟。
1.2.7.加入检测试剂混合液到384孔板，离心30秒，室温孵育60分钟。
1.2.8.Envision酶标仪(PerkinElmer)读取665nm处与615nm处荧光比值。
1.3.数据分析
1.3.1.使用XL-Fit软件进行数据分析，计算得出化合物IC50，见表2.
表2
化合物编号 TYK2(JH1) TYK2(JH2) JAK1(JH1) JAK1(JH2) JAK2(JH1) JAK3(JH1)
3 4313.5nM 0.32nM 3185.5nM 53.1nM 2812.9nM 2378.3nM
IC50 其他/IC50 TYK2-JH2 13480 1 9955 166 8790 7432
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种杂环化合物或其药学上可接受的盐，其特征在于，所述的化合物如式I所示
    Figure PCTCN2022083480-appb-100001
    其中，
    X和Y各自独立地为CR 5或N；
    Z为CR 6或N；
    W 1和W 2各自独立地为选自下组的二价基团：O、S、SO 2、CO、NR 7CO、CONR 7；
    W 3选自下组的二价基团：CO、NR 7、NR 7CO、CONR 7；
    R 3为取代或未取代的C 3-6环烷基；
    R 4选自下组：取代或未取代的C 1-6烷基、取代或未取代的C 3-6环烷基；并且R 4还任选地被R 1和R 2取代；
    R 1和R 2各自独立地选自下组：H、取代或未取代的C1-6烷基；或者，R 1和R 2以及与其相连的碳原子共同形成取代或未取代的C 3-6环烷基；
    R 5、R 6和R 7各自独立地选自下组：H、取代或未取代的C 1-4烷基；
    n＝1或2；
    除非特别说明，所述取代是指基团中一个或多个氢被选自下组的取代基所述取代：卤素、C 1-4烷基、C 1-4卤代烷基。
  2. 如权利要求1所述的杂环化合物，其特征在于，所述杂环化合物如式IA所示；
    Figure PCTCN2022083480-appb-100002
    其中，X、Y、Z、W 1、W 2、W 3、R 4、R 5和n如权利要求1中定义。
  3. 如权利要求1所述的杂环化合物，其特征在于，所述杂环化合物如式II所示，
    Figure PCTCN2022083480-appb-100003
    其中，
    X和Y各自独立地为CR 5或N；
    Z为CR 6或N；
    R 1和R 2各自独立地选自下组：H、取代或未取代的C 1-6烷基、；或者，R 1和R 2以及与其相连的碳原子共同形成取代或未取代的C 3-6环烷基；
    R 5和R 6各自独立地选自下组：H、取代或未取代的C 1-4烷基；
    除非特别说明，所述取代是指基团中一个或多个氢被选自下组的取代基所述取代：卤素、C1-4烷基、C1-4卤代烷基。
  4. 如权利要求1所述的杂环化合物，其特征在于，X为N，Y为CR 5，且Z为N。
  5. 如权利要求1所述的杂环化合物，其特征在于，所述化合物为选自表A的化合物：
    表A
    Figure PCTCN2022083480-appb-100004
  6. 一种用于制备如权利要求1所述的杂环化合物的中间体，其特征在于，所述中间体如式III、式IIIA、式IIIB、式IIIC或式IV所示：
    Figure PCTCN2022083480-appb-100005
    其中，R X为卤素；X、Y、Z、W 1、W 2、W 3、R 1、R 2、R 3、R 4、R 5、R 6、R 7和n如权利要求1中定义。
  7. 一种药物组合物，其特征在于，包括：
    (i)如权利要求1所述的杂环化合物或其药学上可接受的盐，和(ii)药学上可接受的载体或赋形剂。
  8. 一种如权利要求1所述的杂环化合物在制备(i)用于治疗或预防TYK2介导的疾病的药物和/或(ii)TYK2抑制剂中的用途。
  9. 如权利要求8所述的用途，其特征在于，所述TYK2-JH2介导的疾病包括：炎症、自身免疫性疾病，或其组合。
  10. 一种选择性抑制TYK2的方法，其特征在于，所述方法包括：
    使对象与如权利要求1所述的杂环化合物接触，从而抑制对象中TYK2-JH2活性。
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