WO2024088282A1 - 一种哒嗪酰胺类化合物、其药物组合物及其作为tyk2抑制剂的用途 - Google Patents

一种哒嗪酰胺类化合物、其药物组合物及其作为tyk2抑制剂的用途 Download PDF

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WO2024088282A1
WO2024088282A1 PCT/CN2023/126345 CN2023126345W WO2024088282A1 WO 2024088282 A1 WO2024088282 A1 WO 2024088282A1 CN 2023126345 W CN2023126345 W CN 2023126345W WO 2024088282 A1 WO2024088282 A1 WO 2024088282A1
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compound
alkyl
pharmaceutically acceptable
acceptable salt
cycloalkyl
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PCT/CN2023/126345
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English (en)
French (fr)
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许忻
周晓波
***
张小娟
郭凤英
陈嘉
江湘梅
李鲜妮
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浙江华海药业股份有限公司
上海华汇拓医药科技有限公司
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Publication of WO2024088282A1 publication Critical patent/WO2024088282A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine and relates to a pyridazine compound, a preparation method and use thereof.
  • Psoriasis is an autoimmune disease, a chronic, recurrent, inflammatory skin disease mediated by the immune system. Its pathogenesis is complex and currently cannot be completely cured.
  • Traditional treatments for psoriasis mainly include topical treatments such as hydrotherapy, phototherapy, Chinese medicine, salicylic acid, as well as glucocorticoids, immunosuppressants, and retinoic acid drugs. Due to the significant efficacy of biological agents (mainly TNF inhibitors and IL inhibitors) and PDE4 small molecule inhibitors in recent years, they have now become the main treatment for psoriasis.
  • Tyrosine Kinase 2 is a non-receptor tyrosine kinase belonging to the Janus kinase (JAK) family and plays an important role in the pathogenesis of psoriasis.
  • JNK Janus kinase
  • the activation of the TH17 pathway mediated by the cytokine IL-23 is considered to be the most important pathway, and the IL-23 signal mainly mediates related effects in cells through the TYK2-JAK2 and STAT3 pathways.
  • the new tyrosine kinase 2 (TYK2) inhibitor can block the activation of TYK2 stimulated by receptors, thereby inhibiting the phosphorylation of STAT1 and STAT3 caused by TYK2, thereby inhibiting the pathogenesis of psoriasis.
  • the present invention provides a pyridazine compound, a pharmaceutically acceptable salt thereof and an isotope derivative thereof, a preparation method thereof, a pharmaceutical composition thereof and use thereof in a drug for preventing and treating diseases related to a TYK2 signaling pathway.
  • the present invention provides a compound represented by general formula (II) or a pharmaceutically acceptable salt or isotopic derivative thereof,
  • R 1 is -C 1-3 alkylamino, wherein the alkyl in the -C 1-3 alkylamino is optionally further selected from deuterium atoms, -substituted by one or more substituents selected from C 1-3 alkyl and halogen;
  • R 5 is H or -C 1-3 alkyl, wherein the -C 1-3 alkyl is optionally further substituted by one or more substituents selected from hydrogen atom, deuterium atom, -C 1-3 alkyl and halogen;
  • R 6 is -C(O)R 2 or a 4-6 membered heterocyclic group; wherein the -4-6 membered heterocyclic group is optionally further substituted by one or more substituents selected from hydrogen atoms, deuterium atoms, -C 1-3 alkyl groups and halogens, and R 2 is -C 3-6 cycloalkyl;
  • R 7 is -OR 3 or -NR 8 R 9 , wherein R 8 R 9 is optionally H, -C 1-3 alkyl or, R 8 R 9 are each independently selected from -(CH 2 ) n- or -SO 2 - and together with the N to which they are attached form a 5-6 membered heterocyclic ring, wherein n is any integer from 1 to 4;
  • R 3 is -C 1-3 alkyl or -C 3-6 cycloalkyl, wherein the -C 1-3 alkyl or -C 3-6 cycloalkyl is optionally further substituted by one or more substituents selected from hydrogen atoms, deuterium atoms, -C 1-3 alkyl and halogen;
  • R 4 is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted by Ra ;
  • Ra is -H, -CN, -halogen, -CF3 , -C1-3 alkyl, -C3-6 cycloalkyl or 4-6 membered heterocyclic group, wherein the -C1-3 alkyl or -C3-6 cycloalkyl is optionally further substituted by one or more substituents selected from hydrogen, -C1-3 alkyl and halogen.
  • R 5 is H or -methyl.
  • R 1 is -NH-CHF 2 , -NH-CH 2 F, -NH-CH 2 CH 2 F, -NH-CH 2 CHF 2 , -NH-CH 3 , or -NH-CH 2 CH 3 .
  • R6 is
  • R 7 is -OCH 3 , -OCF 3 , -OCH 2 CF 3 , -OCHF 2 , -OCH 2 CHF 2 , -OCH(CH 3 ) 2 or
  • the present invention provides a compound represented by the structure of Formula II-1 or Formula II-2 or a pharmaceutically acceptable salt or isotopic derivative thereof,
  • R 1 is -C 1-3 alkylamino, wherein the alkyl in the -C 1-3 alkylamino is optionally further selected from deuterium atoms, -substituted by one or more substituents selected from C 1-3 alkyl and halogen;
  • R2 is -C3-6 cycloalkyl
  • R 3 is -C 1-3 alkyl or -C 3-6 cycloalkyl, wherein the -C 1-3 alkyl or -C 3-6 cycloalkyl is optionally further substituted by one or more substituents selected from hydrogen atoms, deuterium atoms, -C 1-3 alkyl and halogen;
  • R 4 is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally substituted by Ra ;
  • Ra is -H, -CN, -CF3 , -C1-3 alkyl, -C3-6 cycloalkyl or 4-6 membered heterocyclic group, wherein the -C1-3 alkyl or -C3-6 cycloalkyl is optionally further substituted by one or more substituents selected from hydrogen, -C1-3 alkyl and halogen.
  • R1 is selected from -NH- CHF2 , -NH- CH2F , -NH- CH2CH2F , -NH-CH2CHF2 , -NH- CH3 , or -NH- CH2CH3 .
  • R 1 is -NH-CH 3 or -NH-CH 2 CH 3 ;
  • R2 is cyclopropane
  • R 3 is -CH 3 , -CF 3 , -CH 2 CF 3 , -CHF 2 , -CH 2 CHF 2 or -CH(CH 3 ) 2 .
  • R4 is
  • Ra is -H, -CN, -CHF2 , methyl, ethyl, trifluoromethyl, or -CH( CH3 ) 2 .
  • the compound of the present invention or its pharmaceutically acceptable salt or isotopic derivative is selected from the following compounds or its pharmaceutically acceptable salt or isotopic derivative:
  • the present invention also provides a method for preparing the compound represented by general formula II, which can be Scheme 1 or Scheme 2.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula II and one or more pharmaceutically acceptable carriers and/or diluents.
  • the present invention also provides the use of the compound represented by formula II or the pharmaceutical composition in the preparation of a drug for preventing and/or treating a TYK2-mediated disease; preferably, the TYK2-mediated disease is an inflammatory disease or an autoimmune disease; more preferably, the inflammatory disease is psoriasis or inflammatory bowel disease; and the autoimmune disease is lupus erythematosus.
  • the present invention also provides a method for treating TYK2-mediated diseases, comprising administering a therapeutically effective amount of a compound represented by Formula II or a pharmaceutically acceptable salt or isotope derivative thereof to a patient in need of such treatment.
  • substituted means that any one or more hydrogens on the designated atom or group are replaced by the selection of the designated group, provided that the normal valence of the designated atom is not exceeded.
  • 2 hydrogens on the atom are replaced.
  • “optional” or “optionally” means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation.
  • “Optionally substituted” refers to a group with 0, 1, 2 or more substituents. It will be understood by those skilled in the art that for any group containing one or more substituents, these groups will not introduce any sterically impractical, synthetically infeasible and/or inherently unstable substitution or substitution pattern.
  • “optionally substituted aryl” means that the aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.
  • the compounds herein encompass within their scope the compounds, their pharmaceutically acceptable salts, and their isotopic derivatives, and the compounds of the present invention also encompass within their scope their stereoisomers, polymorphs, solvates, and prodrugs.
  • stereoisomers herein are intended to encompass within their scope tautomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof.
  • isotopic derivative refers to a derivative in which one or more atoms in a compound are replaced by an isotope thereof (an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature).
  • isotopes include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H), isotopes of carbon (e.g., 11 C, 13 C, and 14 C), isotopes of fluorine (e.g., 18 F), isotopes of nitrogen (e.g., 13 N and 15 N), and isotopes of oxygen (e.g., 15 O, 17 O, and 18 O).
  • alkyl refers to a branched and straight chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms.
  • C1 - C10 alkyl refers to C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 and C10 alkyl.
  • C 1 -C 6 alkyl means an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by another chemical group.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl, isohexyl), and the like.
  • C 1-3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms, specifically methyl, ethyl, n-propyl, and isopropyl.
  • deuterated alkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by deuterium.
  • C 1-3 deuterated alkyl refers to methyl, ethyl, n-propyl and isopropyl groups in which one or more hydrogen atoms are replaced by deuterium.
  • deuterated methyl groups include CD 3 , CHD 2 , and CH 2 D.
  • halo or halogen refers to chlorine, bromine, fluorine and iodine.
  • haloalkyl refers to a substituted alkyl group having one or more halogen substituents.
  • fluoromethyl includes CF3 , CHF2 , CH2F .
  • alkyloxy refers to a substituent formed by linking an alkyl group as defined herein and an oxygen atom.
  • C1-3 alkoxy refers to an alkoxy group containing 1 to 3 carbon atoms, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • haloalkoxy and “halogen-substituted alkoxy” have the same meaning and refer to an alkoxy group having one or more halogen substituents.
  • fluoromethoxy includes OCF3 , OCHF2 , OCH2F
  • fluoroethoxy includes OCH2CF3 , OCH2CHF2 , OCH2CH2F , OCF2CF3 , OCF2CHF2 , OCF2CH2F , OCHFCF3, OCHFCHF2 , OCHFCH2F .
  • cycloalkyl refers to a cyclized alkyl group, including a monocyclic, bicyclic or polycyclic ring system, wherein the ring of the monocyclic, bicyclic or polycyclic ring system does not contain an aromatic ring.
  • the cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.
  • C3-6 cycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms.
  • heterocycle or “heterocyclyl” has the same meaning and refers to any ring structure (saturated, unsaturated or aromatic) containing at least one ring heteroatom (e.g., nitrogen atom, oxygen atom or sulfur atom).
  • Heterocycle includes "aliphatic heterocycle” and "aromatic heterocycle”.
  • the heterocyclic group is a 4-6 membered heterocyclic group, examples of which include, but are not limited to, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoquinolinyl, thiazolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, oxazolidinyl, oxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 5(oxadiazolyl).
  • alicyclic or "alicyclic group” has the same meaning and refers to a heterocyclic compound without aromatic characteristics, for example, oxetane, azetidine, pyrrolidinyl, 2H-pyrrolyl, tetrahydrofuranyl.
  • aromatic heterocycle refers to heterocyclic compounds with aromatic characteristics, including single heterocyclic aromatic groups and fused heterocyclic aromatic groups.
  • the monocyclic heteroaryl group may be a 5-6 membered heteroaryl group that may contain 1-4 heteroatoms, such as pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine, etc.
  • 1-4 heteroatoms such as pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine, etc.
  • Typical 5-6 membered heteroaryl groups include, but are not limited to, 2- or 3-thienyl; 2- or 3-furanyl; 2- or 3-pyrrolyl; 2-, 4- or 5-imidazolyl; 3-, 4- or 5-pyrazolyl; 2-, 4- or 5-thiazolyl; 3-, 4- or 5-isothiazolyl; 2-, 4- or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; 3- or 5-1,2,4-triazolyl; 4- or 5-1,2,3-triazolyl; tetrazolyl; 2-, 3- or 4-pyridyl; 3- or 4-pyridazinyl; 3-, 4- or 5-pyrazinyl; 2-pyrazinyl; 2-, 4- or 5-pyrimidinyl.
  • the aromatic ring of the "heteroaryl” group may be substituted at one or more ring positions with substituents as described above, for example, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, hydroxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, cyano, amino (including alkylamino, dialkylamino,
  • the invention also includes a moiety comprising a cyclopentyl group, ...
  • pharmaceutically acceptable salts and “pharmaceutically acceptable salts” are interchangeable and include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include hydrochlorides, hydrobromides, etc.; organic acid salts include formate, acetate, etc.
  • the compound of the present invention contains at least one nitrogen atom capable of forming a salt, it can be converted into a corresponding salt by reacting with a corresponding organic acid or inorganic acid in an organic solvent such as acetonitrile or tetrahydrofuran.
  • organic acids include formic acid and acetic acid
  • typical inorganic acids include hydrochloric acid and hydrobromic acid.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound as described above and optionally one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical composition provided by the present invention can be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained-release preparations of active ingredients, wherein examples of capsules include hard or soft gelatin capsules, and granules and powders can be non-effervescent or effervescent forms.
  • the pharmaceutical composition of the present invention may further include one or more pharmaceutically or physiologically acceptable carriers, which are appropriately formulated for administration.
  • the pharmaceutically or physiologically acceptable carrier may be one or more of saline, autoclaved water, Ringer's solution, buffered saline, glucose, alcohol, honey, mannitol, sorbitol, dextrin, lactose, caramel, gelatin, calcium sulfate, magnesium stearate, talc, kaolin, glycerol, tween, agar, calcium carbonate, calcium bicarbonate, surfactants, cyclodextrin and its derivatives, phospholipids, phosphates, starch and its derivatives, silicon derivatives, cellulose and its derivatives, pyrrolidones, polyethylene glycols, acrylic resins, phthalates, acrylic acid copolymers, trimellitic acid esters.
  • the pharmaceutical composition of the present invention may further include pharmaceutically or physiologically acceptable additives, such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, dispersants, surfactants, solvents, coating agents, foaming agents, or aromatics.
  • pharmaceutically or physiologically acceptable additives such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, dispersants, surfactants, solvents, coating agents, foaming agents, or aromatics.
  • Examples of diluents that can be used include, but are not limited to, lactose, sucrose, starch, salt, mannitol, and dicalcium phosphate;
  • examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodiola, and stearic acid;
  • examples of binders include, but are not limited to, microcrystalline cellulose, tragacanth gum, glucose solution, acacia gum, gelatin solution, sucrose, and starch paste;
  • examples of glidants include, but are not limited to, colloidal silicon dioxide;
  • examples of disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, and cellulose acetate.
  • sweeteners include, but are not limited to, sucrose, lactose, mannitol and artificial sweeteners such as sodium cyclamate and saccharin, and any number of spray-dried flavoring agents
  • flavoring agents include, but are not limited to, natural flavoring agents extracted from plants, such as fruits, and tastier compounds such as, but not limited to, mint and methyl salicylate
  • wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • composition of the present invention can be administered by various routes according to conventional methods, including oral, intravenous, intraarterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular and subcutaneous administration.
  • TYK2 inflammatory diseases or autoimmune diseases through TYK2, such as psoriasis, inflammatory bowel disease or lupus erythematosus.
  • the general dosage range of the compounds provided by the present invention is about 0.05 mg/kg to 1000 mg/kg per day, preferably about 1 mg/kg to 100 mg/kg, and more preferably about 1 to 50 mg/kg.
  • the dosage range of the pharmaceutical composition is calculated based on the amount of the above-mentioned compound contained therein.
  • Step 4 Synthesis of tert-butyl 2-(6-(cyclopropanecarboxamido)-4-((2-(methoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)-1-ethylhydrazine-1-carboxylate (1 g)
  • Step 7 Synthesis of tert-butyl 2-(6-(cyclopropanecarboxamido)-4-(2-(difluoromethoxy)-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)-1-ethylhydrazine-1-carboxylic acid (2i)
  • reaction solution of compound 3c was dissolved in 1,4-dioxane/H 2 O (20ml/10ml), and 3-bromo-1-methyl-1,2,4-thiazole (1.3g, 7.8mmol), Pd(dppf)Cl 2 (570mg, 0.78mmol) and K 2 CO 3 (3.2g, 23.4mmol) were added.
  • the reaction solution was reacted at 90°C for 4 hours under nitrogen protection.
  • Step 6 Synthesis of tert-butyl 2-(6-(cyclopropanecarboxamido)-4-((2-(2,2-difluoroethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)-1-ethylhydrazine-1-carboxylate (3 g)
  • the IC 50 of the compounds of the present invention (Compound 1 to Compound 32) and the positive control drug BMS-986165 were all less than 5 nM.
  • the compounds of the present invention have significant inhibitory activity against TYK2 JH2 pseudokinase.
  • the drug concentrations in the plasma of rats at different times after oral and intravenous administration of compound 1 and compound 3 were determined by liquid chromatography-tandem mass spectrometry (LS/MS/MS) and the relevant pharmacokinetic parameters were calculated to evaluate the pharmacokinetic properties of the example compounds of the present invention in rats.
  • LS/MS/MS liquid chromatography-tandem mass spectrometry
  • Example compound 1 Example compound 3.
  • Blood was collected through the eye socket before administration and 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. 0.2 milliliters (mL) of blood was collected each time, placed in an anticoagulant tube, mixed, and stored in a -20°C refrigerator for later use.
  • Liquid chromatography-tandem mass spectrometry was used to determine the content of the compounds in rat whole blood.
  • the pharmacokinetic parameters of the compounds of the present invention after administration are shown in the following Table 3. As shown in Table 3, the compounds of the present invention have good metabolic characteristics and bioavailability.
  • mice 8-week-old female BALB/c mice were purchased, with an average weight of 20g.
  • the experiment began after the mice adapted for 3 days.
  • the experiment was divided into five groups, normal control group, model group, example compound group and positive drug group (BMS-986165), with 5-8 mice in each group.
  • the mice in the model group, example compound group and positive drug group were anesthetized by intraperitoneal injection of sodium pentobarbital (80mg/kg), and 62.5mg of 5% imiquimod cream was evenly applied to the back after hair removal, once a day, and the normal control group was applied with an equal amount of vaseline.
  • the example compound group (10mg/kg) was administered by gavage at 10mL/kg, once a day; the normal control group was gavaged with an equal amount of pure water, and the model group was gavaged with an equal amount of solvent for 7 consecutive days.
  • the specific design is shown in Table 4.
  • the specific administration is carried out according to the administration plan.
  • mice were observed every day, and digital photography was used to score the erythema, scaling, and infiltration degree of the skin lesions of mice according to the psoriasis area and severity index (PASI) scoring standard (0: none; 1: mild; 2: moderate; 3: severe; 4: extremely severe), and the changes in skin lesions of mice in each group were observed.
  • PASI psoriasis area and severity index
  • mice in the model control group After 5 days of external application of imiquimod to the back skin of mice, the back skin lesions of mice in the model control group were thickened and infiltrated significantly, a large number of plaque-like scales appeared, and the skin turned red. The erythema and scales of the skin lesions of mice in Example Compound 1 were significantly reduced, and the infiltration was alleviated.
  • the PASI scores of mice in the model control group continued to increase with the number of days, and the PASI scores of the Example Compound 1 group began to decrease significantly after the third day, and the effect was better than that of the positive drug group.
  • mice in the model group After oral gavage of 2.5% dextran sulfate sodium (DSS) to induce IBD in mice, the mice in the model group showed symptoms such as weight loss, mental depression, lethargy, bloody stools, diarrhea, etc., and their disease activity index (DAI) was significantly higher than that of the control group.
  • DAI disease activity index
  • the Example Compound 1 group was able to significantly reduce the DAI score of mice on the third day of administration, inhibit the weight loss and colon shortening caused by DSS, and significantly reduce the intestinal damage of DSS to mice. Pathological examination found that the Example Compound group was able to effectively inhibit inflammatory infiltration in the colon.
  • mice Female MRL/lpr mice were selected as experimental animals for the lupus erythematosus model. The lymph node enlargement and skin damage of the mice were evaluated weekly, and the related urine albumin and creatinine indicators were tested. In vivo efficacy experiments found that the example compound 1 could significantly reduce the pristane-induced lupus mouse autoantibodies (anti-ds DNA, anti-SLE) and urine protein concentrations, reduce glomerular swelling, and pathological tissue examination found that it could effectively reduce inflammatory cell infiltration.
  • anti-ds DNA, anti-SLE pristane-induced lupus mouse autoantibodies
  • urine protein concentrations reduce glomerular swelling
  • pathological tissue examination found that it could effectively reduce inflammatory cell infiltration.
  • the purpose of this experiment is to test the acute toxicity of the example compounds on mice.
  • ICR mice SPF grade, 6-8 weeks old, half male and half female, were purchased from Shanghai Xipu-Bikai Experimental Animal Co., Ltd., license number SCXK (Shanghai) 2018-0006, animal certificate number: 20180006010983.
  • ICR mice were given a single dose of different doses of the compound and observed for 14 consecutive days, and the animal deaths, poisoning reactions, weight changes, diet, appearance, behavior, etc. were recorded. At the end point, the animals were dissected, organs were removed, and histopathological examinations and related hematological examinations were performed.
  • the no-toxicity event dose (NOAEL) of Example Compound 1 is greater than 1000 mg/kg. Compared with the mice in the control group, the mice in the drug administration group showed no abnormalities in body weight and behavior within 14 days from the date of administration, and no obvious abnormalities were found in related hematology. No toxic effects of the relevant Example compounds were found in pathological examinations, indicating that Example Compound 1 of the present invention has good safety and can be safely tolerated by animals.
  • the purpose of this experiment is to test the long-term toxic effects of the example compounds on mice.
  • ICR mice SPF grade, 6-8 weeks old, half male and half female, were purchased from Shanghai Xipu-Bikai Experimental Animal Co., Ltd., license number SCXK (Shanghai) 2018-0006, animal certificate number: 20180006010983.
  • ICR mice were given different doses of the compound and observed for 14 consecutive days, and the animal deaths, poisoning reactions, weight changes, diet, appearance, behavior, etc. were recorded. At the end point, the animals were dissected, organs were removed, and histopathological examinations and related hematological examinations were performed.
  • Example Compound 1 The no-toxicity event level (NOAEL) of Example Compound 1 was greater than 500 mg/kg. Compared with the mice in the control group, the mice in the drug administration group showed no abnormalities in body weight and behavior within 14 days from the date of administration, and no obvious abnormalities were found in related hematology. No toxic effects of the related Example compounds were found in pathological examinations, indicating that Example Compound 1 of the present invention has good safety and can be safely tolerated by animals.
  • NOAEL no-toxicity event level

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Abstract

本发明提供了式（Ⅱ）所示的哒嗪类化合物、其制备方法和用途。本发明还公开了本发明化合物或其药物组合物在制备用于预防和/或治疗TYK2介导的疾病的药物中的用途。

Description

一种哒嗪酰胺类化合物、其药物组合物及其作为TYK2抑制剂的用途 技术领域
本发明属于医药领域，涉及一种哒嗪类化合物、其制备方法和用途。
背景技术
银屑病属于自身免疫***疾病，是由免疫介导的慢性、复发性、炎症性皮肤病，其发病机制复杂，目前无法彻底治愈。银屑病的传统疗法主要包括水疗、光疗、中药、水杨酸类等外用治疗方法，以及糖皮质激素、免疫抑制剂和维A酸类药物。由于生物制剂(主要为TNF剂抑制剂和IL抑制剂)和PDE4小分子抑制剂近年来的疗效显著，现已成为银屑病的主要治疗用药。
酪氨酸激酶2(Tyrosine Kinase 2,TYK2)是一种非受体酪氨酸激酶，属于Janus激酶(JAK)家族，在银屑病发病机制上起到重要作用。现有研究认为，部分适应性免疫***的过度激活是银屑病发病的核心，在银屑病的发病过程中，多种免疫细胞和细胞因子共同导致下游角质细胞增殖，增加血管生成、促进内皮黏附分子的表达，同时激活的免疫细胞浸润到病变皮肤，最终形成银屑病。细胞因子IL-23介导的TH17途径的激活被认为是最主要的途径，而IL-23信号主要通过TYK2-JAK2和STAT3通路在细胞内介导相关效应。新型酪氨酸激酶2(Tyrosine Kinase 2,TYK2)抑制剂可以阻断受体刺激的TYK2的激活，从而抑制TYK2引起的STAT1和STAT3的磷酸化，从而抑制银屑病的发病过程。
本发明提供一类哒嗪化合物、其可药用盐及其同位素衍生物，其制备方法、药物组合物和其在预防和治疗与TYK2信号通路有关疾病药物中的用途。
发明内容
本发明提供一种通式(Ⅱ)所示的化合物或其可药用盐或同位素衍生物，
其中R1为-C1-3烷基氨基，其中所述的-C1-3烷基氨基中的烷基任选地进一步被选自氘原子、 -C1-3烷基和卤素中的一个或多个取代基所取代；
R5为H或-C1-3烷基，其中所述的-C1-3烷基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
R6为-C(O)R2或4-6元杂环基；其中所述的-4-6元杂环基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代，R2为-C3-6环烷基；
R7为-OR3或-NR8R9，其中R8R9任选地为H、-C1-3烷基或，R8R9各自独立地选自-(CH2)n-或-SO2-且和与其相连的N一同形成一个5-6元的杂环，其中n为1～4中的任一整数；
R3为-C1-3烷基或-C3-6环烷基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
Ra为-H、-CN、-卤素、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
在本发明的一些实施方式中，R5为H或-甲基。
在本发明的一些实施方式中，R1为-NH-CHF2、-NH-CH2F、-NH-CH2CH2F、-NH-CH2CHF2、-NH-CH3或-NH-CH2CH3。
在本发明的一些实施方式中，R6为
在本发明的一些实施方式中，R7为-OCH3、-OCF3、-OCH2CF3、-OCHF2、-OCH2CHF2、-OCH(CH3)2或
在本发明的一些实施方式中，本发明提供一种式Ⅱ-1或式Ⅱ-2结构所示的化合物或其可药用盐或同位素衍生物，
其中R1为-C1-3烷基氨基，其中所述的-C1-3烷基氨基中的烷基任选地进一步被选自氘原子、 -C1-3烷基和卤素中的一个或多个取代基所取代；
R2为-C3-6环烷基；
R3为-C1-3烷基或-C3-6环烷基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
Ra为-H、-CN、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
在本发明的一些实施方式中，R1选自-NH-CHF2、-NH-CH2F、-NH-CH2CH2F、-NH-CH2CHF2、-NH-CH3或-NH-CH2CH3。
在本发明的一些实施方式中，
R1为-NH-CH3或-NH-CH2CH3；
R2为环丙烷基；
R3为-CH3、-CF3、-CH2CF3、-CHF2、-CH2CHF2或-CH(CH3)2。
在本发明的一些实施方式中，R4为
在本发明的一些实施方式中，Ra为-H、-CN、-CHF2、甲基、乙基、三氟甲基或-CH(CH3)2。
在本发明的一些实施方式中，本发明的化合物或其可药用盐或同位素衍生物，选自如下化合物或其可药用盐或同位素衍生物：

本发明还提供了通式II所示的化合物的制备方法，可以是方案一或方案二，
方案一：
方案二：
化合物IIa硼酸化后和R4X反应得到化合物IId，或化合物IIa和R4H直接反应得到化合物IId；
化合物IId和化合物IIe反应得到化合物IIf；
化合物IIf和R2C(O)NH2反应得到化合物II；
其中X为Br或I，R1、R2、R3和R4如前所述。
本发明还提供一种药物组合物，包括治疗有效量的式II所示化合物以及一种或多种药学上可接受的载剂和/或稀释剂。
本发明还提供所述的式II所示化合物或者所述的药物组合物在制备用于预防和/或治疗TYK2介导的疾病的药物中的用途；优选地，所述TYK2介导的疾病为炎性疾病或自身免疫性疾病；更优选地，所述炎性疾病为银屑病、炎症性肠病；所述自身免疫疾病为红斑狼疮。
本发明还提供治疗TYK2介导的疾病的方法，包括给需要这种治疗的患者施用治疗有效量的式II所示化合物或其可药用盐或同位素衍生物。
定义和说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。
术语“被取代的”是指所指定原子或基团上的任一或多个氢被指定基团的选择替代，条件为不超过所指定原子的正常价态。当取代基是氧代或酮基(即＝O)时，则所述原子上的2个氢被替代。
取代基和/或变量的组合仅在这些组合产生稳定化合物或可用的合成的中间体时才允许。稳定化合物或稳定结构是指足够稳定以经受自反应混合物以有用的纯度分离出并随后配制成有效治疗药物的化合物。
在本发明中，“任选”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。“任选被取代”是指具有0个、1个、2个或更多个取代基的基团。本领域技术人员应理解，对于含有一或多个取代基的任何基团而言，这些基团不会引入任何立体上不合实际、合成上不可行和/或固有地不稳定的取代或取代模式。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
除非具体指明，否则本文中化合物在其范围内涵盖化合物、其可药用盐及其同位素衍生物，本发明化合物在其范围内还涵盖其立体异构体、多晶型物、溶剂合物和前药。
除非具体指明，否则本文中立体异构体在其范围内涵盖互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、及其混合物形式。
术语“同位素衍生物”指化合物中一个或多个原子被其同位素(具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子)替代的衍生物。同位素的实例包括但不限于，氢的同位素(例如2H、3H)、碳的同位素(例如11C、13C及14C)、氟的同位素(例如18F)、氮的同位素(例如13N及15N)、氧的同位素(例如15O、17O及18O)。
术语“烷基”或”亚烷基”是指包括具有指定碳原子数的支链和直链饱和脂肪族烃基。例如，“C1-C10烷基”(或亚烷基)是指包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外， 例如，“C1-C6烷基”表示具有1至6个碳原子的烷基。烷基可以是未被取代的或被取代的，从而使它的一或多个氢被另一化学基团替代。烷基的实例包括但不限于，甲基(Me)、乙基(Et)、丙基(例如，正丙基和异丙基)、丁基(例如，正丁基、异丁基、叔丁基)、戊基(例如，正戊基、异戊基、新戊基)、己基(例如，正己基、异己基)等。术语“C1-3烷基”是指包含1至3个碳原子的烷基，具体指甲基、乙基、正丙基及异丙基。
术语“氘代烷基”是指烷基中的一或多个氢被氘替代，C1-3氘代烷基指一或多个氢被氘替代的甲基、乙基、正丙基及异丙基，例如氘代甲基包括CD3，CHD2，CH2D。
术语“卤素(halo或halogen)”是指氯、溴、氟和碘。
术语“卤代烷基”是指具有一或多个卤素取代基的被取代的烷基。例如，“氟代甲基”包括CF3、CHF2、CH2F。
术语“烷氧基”(alkyloxy)是指本文所定义的烷基和氧原子连接形成的取代基。C1-3烷氧基指包含1至3个碳原子的烷氧基，例如，甲氧基、乙氧基、丙氧基和异丙氧基。
术语“卤代烷氧基”和“卤素取代的烷氧基”具有相同含义，是指具有一或多个卤素取代基的烷氧基。例如，“氟代甲氧基”包括OCF3、OCHF2、OCH2F，“氟代乙氧基”包括OCH2CF3、OCH2CHF2、OCH2CH2F、OCF2CF3、OCF2CHF2、OCF2CH2F、OCHFCF3、OCHFCHF2、OCHFCH2F。
术语“环烷基”是指环化的烷基，包括单环、二环或多环体系，其中单环、二环或多环体系的环不包含芳香环。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
C3-6环烷基是指包含3至6个碳原子的环烷基。例如，环丙基、环丁基、环戊基、环己基等。术语“杂环”或“杂环基”具有相同的含义，是指包含至少一个环杂原子(例如，氮原子、氧原子或硫原子)的任何环结构(饱和的、不饱和的或芳族的)。杂环包括“脂杂环”和“芳杂环”。
在本发明的一些实施例中，杂环基为4-6元杂环基，其实例包括但不限于，呋喃基、咪唑烷基、咪唑啉基、咪唑基、异喹啉基、噻唑基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、恶唑烷基、恶唑基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、1,2,4-恶二唑5(4H)-酮基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、四氢呋喃基、四唑基、噻吩基、四氢噻吩、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基、氧杂环丁烷、氮杂环丁烷。术语“脂杂环”或“脂杂环基”具有相同的含义，是指没有芳香特征的杂环化合物，例如，氧杂环丁烷、氮杂环丁烷、吡咯烷基、2H-吡咯基、四氢呋喃基。
术语“芳杂环”、“芳杂环基”、“杂芳环”或“杂芳环基”具有相同的含义，是指有芳香特征的杂环化合物，包括单杂环芳基和稠杂环芳基。所述杂原子独立地选自氮、氧和硫，氮原子可以被取代或不被取代，氮和硫杂原子可任选被氧化(即，N→O和S(O)p，其中p＝1或2)，芳杂环中硫和氧原子的总数不超过1。
在本发明的一些实施方式中，单杂环芳基可以是5-6元杂芳基可以包含1-4个杂原子，例如吡咯、呋喃、噻吩、噻唑、异噻唑、咪唑、***、四唑、吡唑、噁唑、异噁唑、吡啶、吡嗪、哒嗪和嘧啶等。
典型的5-6元杂芳基包括但不限于，2-或3-噻吩基；2-或3-呋喃基；2-或3-吡咯基；2-、4-或5-咪唑基；3-、4-或5-吡唑基；2-、4-或5-噻唑基；3-、4-或5-异噻唑基；2-、4-或5-唑基；3-、4-或5-异唑基；3-或5-1，2，4-***基；4-或5-1，2，3-***基；四唑基；2-、3-或4-吡啶基；3-或4-哒嗪基；3-、4-或5-吡嗪基；2-吡嗪基；2-、4-或5-嘧啶基。
“杂芳基”的芳环可以在一个或多个环位置上被上文所述的取代基取代，例如卤素、羟基、烷氧基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳基氧基羰基氧基、羟基羰基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、烯基氨基羰基、烷基羰基、芳基羰基、芳基烷基羰基、烯基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、磷酸酯、膦酸酯、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、羟基硫代羰基、硫酸酯、烷基亚磺酰基、磺酸酯基、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳族基团或杂芳族基团，其中芳基基团也可以与非芳族的脂环或杂环稠合或桥连，以形成多环(例如四氢萘)。
术语“药用盐”和“药用可接受的盐”、“药学上可接受的盐”可互换，其包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐例如盐酸盐、氢溴酸盐等；有机酸盐例如甲酸盐、乙酸盐等。
在本发明的化合物分子中包含至少一个可成盐的氮原子时，可以通过在有机溶剂如乙腈、四氢呋喃中与相应的有机酸或无机酸反应，从而转化为相应的盐。典型的有机酸有甲酸、乙酸，典型的无机酸有盐酸、氢溴酸。
本发明还提供了一种药物组合物，其包含上述至少一个化合物以及任选一种或多种药学上可接受的载剂和/或稀释剂。
本发明所提供的药物组合物可以制备为任何形式，例如颗粒、粉末、片剂、包衣片剂、胶囊、药丸、糖浆、滴剂、溶液、混悬剂和乳剂，或者活性成分的缓释制剂，其中胶囊剂的实例包括硬或软明胶胶囊剂，颗粒剂和粉剂可以是非泡腾或泡腾形式。
本发明的药物组合物可进一步包括一种或多种医药或生理上可接受的载体,这些载体将适当配制以便于给药。例如，医药或生理上可接受的载体可以是盐水、热压水、林格氏液、缓冲盐水、葡萄糖、醇、蜂蜜、甘露醇、山梨醇、糊精、乳糖、焦糖、明胶、硫酸钙、硬脂酸镁、滑石粉、高岭土、甘油、吐温、琼脂、碳酸钙、碳酸氢钙、表面活性剂、环糊精及其衍生物、磷脂类、磷酸盐类、淀粉类及其衍生物、硅衍生物、纤维素类及其衍生物、吡咯烷酮类、聚乙二醇类、丙烯酸树脂类、酞酸酯类、丙烯酸共聚物、苯三酸酯类中的一种或几种。
本发明的药物组合物还可以包括医药或生理上可接受的添加剂，例如稀释剂、润滑剂、粘合剂、助流剂、崩解剂、甜味剂、矫味剂、湿润剂、分散剂、表面活性剂、溶剂、涂层剂、发泡剂、或芳香剂。
可以使用的稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、盐、甘露糖醇和磷酸二钙；润滑剂的实例包括但不限于滑石、淀粉、镁或钙的硬脂酸盐、石松子和硬脂酸；粘合剂的实例包括但不限于微晶纤维素、黄蓍胶、葡萄糖溶液、***胶浆、明胶溶液、蔗糖和淀粉糊；助流剂的实例包括但不限于胶体二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、膨润土、甲基纤维素、琼脂和羧甲基纤维素；甜味剂的实例包括但不限于蔗糖、乳糖、甘露糖醇和人工甜味剂，例如环磺酸钠和糖精，和任意数量的喷雾干燥矫味剂；矫味剂的实例包括但不限于从植物提取的天然矫味剂,例如果实，和味道较好的化合物，例如但不限于薄荷和水杨酸甲酯；湿润剂的实例包括但不限于丙二醇一硬脂酸酯、脱水山梨醇一油酸酯、二甘醇一月桂酸酯和聚氧乙烯月桂基醚。
本发明的药物组合物可以根据传统方法来通过各种途径给药，包括口服、静脉内、动脉内、腹腔内、胸腔内、透皮、鼻腔、吸入、直肠、眼部和皮下导入。
经药理实验验证，本发明所提供的化合物或者药物组合物可通过TYK2治疗炎性疾病或自身免疫性疾病，所述炎性疾病和自身免疫疾病例如银屑病、炎症性肠病或红斑狼疮。
本发明所提供的化合物一般的剂量范围为约每天0.05mg/kg至1000mg/kg，优选为约1mg/kg至100mg/kg，更优选为约1至50mg/kg，药物组合物的剂量范围为以其含有的上述化合物的量来计算。
具体实施方式
通过以下实施例进一步举例描述本发明，这些方案是说明性的，并不以任何方式限制本发明。对本发明所作的本领域普通技术人员容易实现的任何改动或改变都将落入本发明的范围内。
本发明实施例中所用的原料或试剂除特别说明之外，均市售可得。
本发明中使用的缩写具有本领域常规含义，例如以下缩写的含义如下：

化合物的制备方法
实施例1
N-(5-(2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(1)的合成
第一步 6-氯-4-[2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯胺基]哒嗪-3-羧酸甲酯(1c)的合成
将化合物1a(1g，4.83mmol)溶于乙腈(10mL)中，依次加入DIEA(1.25g,9.66mmol)和化合物1b(0.99g,4.83mmol)，反应液微波加热110℃反应5小时。LCMS显示部分原料剩余，反应液降至室温，减压旋干，残余物柱层析(EA/PE＝0-70％)得化合物1c(0.71g,)。
LCMS(ESI-MS)m/z:375.2(M+H+).
第二步 6-(环丙烷甲酰胺基)-4-[2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯胺基]哒嗪-3-羧酸甲酯(1d)合成
将化合物1c(710mg，1.89mmol)、环丙酰胺(321mg，3.78mmol)、dppf(209mg，0.378mmol)、K3PO4(1.2g，5.67mmol)和1,4-dioxane(10mL)加入反应瓶，抽空换氮后，再加入Pd2(dba)3(173mg，0.189mmol)，再次抽空换氮后，放入90℃油浴，反应7小时。LCMS显示反应完全。反应液降至室温，加水(50mL)，EA(30mL*2)萃取。合并有机相，饱和食盐水(30mL)洗涤，无水Na2SO4干燥，过滤，浓缩，得到褐色油状化合物1d粗品(130mg)，水相直接冻干得化合物1d粗品(150mg)
LCMS(ESI-MS)m/z:424.2(M+H+).
第三步 6-(环丙烷甲酰胺基)-4-[2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯胺基]哒嗪-3-羧酸(1e)的合成
将化合物1d(130mg，0.31mmol)溶于甲醇/水(5/1.5mL)中，加入碳酸钾(85mg,0.62mmol)，反应液室温反应3h。LCMS显示原料反应完全，减压旋干得化合物1e粗品(90mg)。
LCMS(ESI-MS)m/z:410.2(M+H+).
第四步 2-(6-(环丙烷甲酰胺基)-4-((2-(甲氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-羰基)-1-乙肼-1-羧酸叔丁酯(1g)的合成
将化合物1e(210mg，0.51mmol)溶于DMF(5mL)，加入1-乙基肼甲酸叔丁酯1f(99mg,0.62mmol),DIEA(197mg,1.53mmol)和HATU(293mg,0.77mmol),反应液于室温反应3小时。LCMS显示反应完全，反应液加水(30mL)，EA(30mL*2)萃取,合并有机相，有机相依次用水(20mL),饱和食盐水(20mL)洗涤，无水Na2SO4干燥，过滤，残余物用Prep-HPLC纯化得化合物1g(26mg)
LCMS(ESI-MS)m/z:552.4(M+H+).
第五步 N-(5-(2-(甲氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(1)的合成
将化合物1g(23mg，0.042mmol)溶于4MHCl/EtOAc(4ml)和MeOH(1mL)中,反应液于室温反应6h。LCMS显示反应完全。反应液加水(20mL)，用饱和碳酸氢钠溶液调PH＝7-8,用DCM(30mL*2)萃取。合并有机相，用水(15mL)洗涤，浓缩冻干，得化合物1(16mg)。
LCMS(ESI-MS)m/z:452.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.70(s,1H),10.48(d,J＝6.1Hz,1H),8.54(s,1H),8.14(s,1H),7.63(dd,J＝7.8,1.6Hz,1H),7.49(dd,J＝8.0,1.6Hz,1H),7.25(t,J＝7.9Hz,1H),5.15(d,J＝7.0Hz,1H),3.93(s,3H),3.70(s,3H),2.87(m,2H),2.05(m,1H),1.04(t,J＝7.1Hz,3H),0.84–0.77(m,4H).
实施例2
N-(5-(2-(二氟甲氧基)-4-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(2)的合成
第一步 2-(4,6-二氯吡嗪-3-羰基)-1-乙基肼-1-羧酸叔丁酯(2b)的合成
将化合物1-乙基肼-1-羧酸叔丁酯1f(1g,6.24mmol)和DIPEA(1.61g,12.47mmol)溶解在二氯甲烷(30mL)中,将混合液冷却到0℃，向反应液中缓慢滴加4,6-二氯哒嗪-3-羰基氯2a(1.65g,7.8mmol)的二氯甲烷(10mL)溶液，滴加完毕后升至室温反应1小时，反应结束后过flash柱得到化合物2b(1.3g,3.9mmol)。
LCMS(ESI-MS)m/z:335.1(M+H+).
第二步 4-溴-2-(二氟甲氧基)-1-硝基苯(2d)的合成
将化合物2c(16g,73.4mmol)溶解在乙腈(240mL)中，加入KOH(61.6g,1.1mol)的水溶液(240mL)，混液冷却到-25℃，将溴代二氟甲基膦酸二乙酯(19.6g,73.4mmol)缓慢滴加到反应液中，然后慢慢升温到室温搅拌4小时，反应完全后用乙酸乙酯萃取，有机相用食盐水洗涤，干燥旋干得到粗品，经过硅胶柱层析纯化后得到化合物2d(18g,67mmol)。
LCMS(ESI-MS)m/z:269.1(M+H+).
第三步 4-硝基-3-(二氟甲氧基)苯硼酸频那醇酯(2e)的合成
将化合物2d(4g,14.9mmol)，频那醇硼酸酯(4.93g,19.4mmol)，Pd(dppf)Cl2(1.09g,1.49mmol)和醋酸钾(2.92g,29.8mmol)混合在1,4-二氧六环(60mL)中，反应液通过氮气置换3次后在100℃下反应2小时，反应完成后，旋干溶剂，加入水(60ml),用乙酸乙酯(100mL*2)萃取，有机相干燥旋干得到粗品，经过硅胶柱层析纯化后得到化合物2e(3.3g,14mmol)。
LCMS(ESI-MS)m/z:316.2(M+H+).
第四步 3-[3-(二氟甲氧基)-4-硝基苯基]-1-甲基-1H-1,2,4-***(2f)的合成
将化合物2e(3g,14mmol)，3-溴-1-甲基-1H-1,2,4-***(2.95g,18.2mmol)，Pd(PPh3)4(820mg,0.71mmol)和碳酸钾(3.86g,28.4mmol)混合在dioxane(60ml)和水(15ml)中，氮气置换3次。反应液升温至100℃搅拌3小时。反应完成后，旋去1,4-二氧六环，向反应液中加入乙酸乙酯和水，有机相干燥浓缩，粗品过柱纯化得到化合物2f(2g,7.4mmol)。
LCMS(ESI-MS)m/z:271.1(M+H+).
第五步 2-(二氟甲氧基)-4-(1-甲基-1H-1,2,4-***-3-基)苯胺(2g)的合成
将化合物2f(2g,7.4mmol)溶解在甲醇(40ml)中，加入Pd/C(200mg)，反应液在常温下搅拌2小时，反应完全后过滤旋干得到化合物2g(1.2g,5mmol)。
LCMS(ESI-MS)m/z:241.1(M+H+).
第六步 叔丁基2-(6-氯-4-((2-(二氟甲氧基)-4-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-羰基)-1-乙肼-1-羧酸(2h)的合成
将化合物2g(400mg，1.67mmol)，化合物2b(520mg,2.5mmol)溶解在无水THF(30ml)中，冷却到0℃，向反应液中加入NaH(400mg，60％in mineral oil，10mmol)。反应液升至室温搅拌2小时。反应完成后，向反应液中滴加饱和氯化铵溶液，然后加入水，用乙酸乙酯萃取，有机相干燥浓缩，粗品过柱纯化得到化合物2h(430mg,0.8mmol)。
LCMS(ESI-MS)m/z:539.9(M+H+).
第七步 叔丁基2-(6-(环丙烷甲酰胺基)-4-(2-(二氟甲氧基)-4-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-羰基)-1-乙基肼-1-羧酸(2i)的合成
将化合物2h(330mg,0.61mmol)，环丙酰胺(104mg,1.22mmol)，Pd2(dba)3(55mg,0.06mmol)，dppf(66.48mg，0.12mmol)和磷酸钾(388mg,1.83mmol)混合在1,4-二氧六环(12mL)中，反应液通过氮气置换3次，在微波反应器上升温至100℃反应2小时，冷却后过滤，用二氯甲烷和甲醇的混合液洗涤固体滤渣，有机相过柱纯化后得到化合物2i(150mg,0.255mmol)。
LCMS(ESI-MS)m/z:588.5(M+H+).
第八步 N-(5-(2-(二氟甲氧基)-4-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(2)的合成
将化合物2i(130mg,0.22mmol)加入到4M HCl/EtOAc(10mL)中,反应液在常温下搅拌2小时，反应完全后用饱和碳酸氢钠中和至弱碱性，然后用二氯甲烷萃取，有机相干燥旋干得到化合物2(150mg,0.255mmol)。
LCMS(ESI-MS)m/z:488.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.65(s,1H),10.51(s,1H),8.55(s,1H),8.11(s,1H),7.87(dd,J＝10.0,1.7Hz,2H),7.63(d,J＝8.3Hz,1H),7.33(t,J＝73.3Hz,1H),5.15(s,1H),3.92(s,3H),2.87(m,2H),2.06(m,1H),1.04(t,J＝7.2Hz,3H),0.89–0.70(m,4H).
实施例3
N-(5-(2-(2,2-二氟乙氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(3)的合成
第一步 1-溴-2-(2,2-二氟乙氧基)-3-硝基苯(3b)的合成
将化合物3a(10.0g，45.9mmol)溶于DMF(150mL)中，依次加入Cs2CO3(44.7g,137.7mmol)和1,1-二氟-2-碘代乙烷(10.6g,55mmol)，反应液N2保护下于110℃反应7小时。LCMS显示部分原料剩余。反应倒入冰水(300mL),用EA(150mL*2)萃取。合并有机相，饱和食盐水(150mL)洗涤，无水Na2SO4干燥，过滤，浓缩得化合物3b(4.8g)。
LCMS(ESI-MS)m/z:282.0(M+H+).
第二步 2-(2,2-二氟乙氧基)-3-硝基-苯基硼酸频哪醇酯的(3c)合成
将化合物3b(2.2g，7.8mmol)溶于1,4-dioxane(30mL)中，联硼酸频那醇酯(2.38g,9.4mmol),Pd(dppf)Cl2(570mg,0.78mmol)和KOAc(2.3g,23.4mmol)。反应液在氮气保护下90℃反应7小时。LCMS显示发现目标产物。反应液降至室温，直接用于下一步反应。
LCMS(ESI-MS)m/z:330.2(M+H+).
第三步 3-[2-(2,2-二氟乙氧基)-3-硝基苯基]-1-甲基-1H-1,2,4-***(3d)的合成
将化合物3c的反应液溶于1,4-dioxane/H2O(20ml/10ml)中，加入3-溴-1-甲基-1,2,4-噻唑(1.3g,7.8mmol)，Pd(dppf)Cl2(570mg,0.78mmol)和K2CO3(3.2g,23.4mmol)。反应液于氮气保护下90℃反应4小时。LCMS检测原料反应完全，反应液降至室温，加水(100mL)，EA(80mL*2)萃取。合并有机相，饱和食盐水(50mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(EA/PE＝0-70％)得化合物3d(0.46g)。
LCMS(ESI-MS)m/z:285.1(M+H+).
第四步 2-(2,2-二氟乙氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯胺(3e)的合成
将化合物3d(0.46g，1.62mmol)溶于THF(10mL)中，加入Pd/C(230mg)。H2保护下室温反应过夜。LCMS显示反应完全。反应液用Celite过滤，THF(20mL)淋洗。滤液减压浓缩，得褐色固体化合物3e(0.4g)，直接用于下一步反应。
LCMS(ESI-MS)m/z:255.1(M+H+).
第五步 2-(6-氯-4-((2-(2,2-二氟乙氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-羰基)-1-乙肼-1-羧酸叔丁酯(3f)的合成
将化合物3e(0.2g，0.78mmol)和化合物2b(0.34g，1mmol)溶于THF(10mL)中，室温下加入LiHMDS(2.4mL,2.4mmol)。室温反应1.5h。LCMS显示反应完全。加水(60mL)，EA(50mL*2)萃取。合并有机相，饱和食盐水(50mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物柱层析(EA/PE＝0-80％)得化合物3f(0.19g)。
LCMS(ESI-MS)m/z:553.3(M+H+).
第六步 2-(6-(环丙烷甲酰胺基)-4-((2-(2,2-二氟乙氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-羰基)-1-乙肼-1-羧酸叔丁酯(3g)的合成
将化合物3f(190mg，0.34mmol)、环丙酰胺(58mg，0.68mmol)、dppf(38mg，0.068mmol)、K3PO4(216mg，1.02mmol)和1,4-dioxane(10mL)加入反应瓶，抽空换氮后，再加入Pd2(dba)3(31mg，0.034mmol)，再次抽空换氮后，放入90℃油浴，反应7小时。LCMS显示反应少量原料剩余。反应液降至室温，加水(80mL)，EA(60mL*2)萃取。合并有机相，饱和食盐水(30mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物用Prep-HPLC制备得化合物3g(30mg)。
LCMS(ESI-MS)m/z:602.4(M+H+).
第七步 N-(5-(2-(二氟乙氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(3)的合成
将化合物3g(30mg，0.05mmol)溶于4M HCl/EtOAc(3mL),反应液于室温反应4h。LCMS显示反应完全。反应液加水(20mL)，用饱和碳酸氢钠溶液调PH＝7-8,EA(30mL*2)萃取。合并有机相，用水(15mL)洗涤，浓缩冻干，得化合物3(12mg)。
LCMS(ESI-MS)m/z:502.3(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.59(s,1H),10.47(s,1H),8.57(s,1H),8.02(s,1H),7.72(dd,J＝7.9,1.6Hz,1H),7.51(dd,J＝8.0,1.6Hz,1H),7.31(t,J＝7.9Hz,1H),6.30(t,J＝4.0Hz,1H),5.14(s,1H),4.16(m，2H),3.93(s,3H),2.87(q,J＝7.2Hz,2H),2.09–2.02(m,1H),1.03(t,J＝7.1Hz,3H),0.84–0.74(m,4H).
实施例4
N-(6-(2-乙基肼-1-羰基)-5-((2-异丙氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺
化合物4的制备参照实施例3。
LCMS(ESI-MS)m/z:480(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.63(s,1H),10.44(s,1H),8.54(s,1H),8.21(s,1H),7.60–7.58(d,1H),7.50–7.47(d,1H),7.24–7.20(t,1H),5.34(s,1H),4.07–4.04(m,1H),3.92(s,3H),2.90–2.84(m,2H),2.11–2.05(m,1H),1.09–1.02(m,9H),0.81–0.80(m,4H).
实施例52-[3-({6-[(环丙基羰基)氨基]-3-[(2-甲基二氮酰基)羰基]-1,2-二嗪-4-基}氨基)-2-[(二氟甲基)氧基]苯基]-5-甲基咪唑-5-酰亚胺
化合物5的制备参照实施例3。
LCMS(ESI-MS)m/z:474(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.66(s,1H),10.51(s,1H),8.60(s,1H),8.03(s,1H),7.85(dd,J＝7.7,1.6Hz,1H),7.63–7.57(m,1H),7.46(t,J＝7.9Hz,1H),7.04(t,J＝75.6Hz,1H),5.23(s,1H),3.93(s,3H),2.56(s,3H),2.05(d,J＝5.6Hz,1H),0.79(t,J＝5.8Hz,4H).
实施例6
N-(5-((3-(1-乙基-1H-吡唑-4-基)-2-甲氧基苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙甲酰胺

第一步 1-乙基-4-(2-甲氧基-3-硝基苯基)-1H-吡唑(6c)的合成
在6a(2.5g,10.8mmol)的1,4-二氧六环溶液(24mL)中，加入水(5mL)，6b(2.88g,12.98mmol)，Pd(dppf)Cl2(362mg，0.495mmol)，碳酸钾(1.36g，9.9mmol)，氮气置换，100℃搅拌4小时。冷却至室温，硅藻土过滤，滤液浓缩，残余物用硅胶柱层析纯化(0-50％EA/PE)得目标化合物6c(3.0g)。
LCMS(ESI-MS)m/z:248.1(M+H+).
第二步 3-(1-乙基-1H-吡唑-4-基)-2-甲氧基苯胺(6d)的合成
将6c(3.0g，12.1mmol)溶于乙醇/水(24mL/20mL)中，加入铁粉(3.4g，60.7mmol)、氯化铵(6.41g，121mmol)。80℃搅拌1小时。LCMS显示反应完全。趁热过滤，滤液浓缩，残余物用硅胶柱层析纯化得产物6d(2.3g)。
LCMS(ESI-MS)m/z:218.2(M+H+).
第三步 2-(6-氯-4-((3-(1-乙基-1H-吡唑-4-基)-2-甲氧基苯基)氨基)哒嗪-3-羰基)-1-乙基肼-1-羧酸叔丁酯(6e)的合成
将6d(217mg，1.0mmol)和化合物2b(500mg，1.49mmol)溶于THF(9.0mL)中，在冰浴下缓慢滴加LiHMDS(3mL，3mmol,)，恢复室温反应1小时。LCMS显示反应完全。加NH4Cl水溶液(20mL)淬灭，EA(20mL×3)萃取。合并有机相，饱和食盐水(20mL)洗涤，无水Na2SO4干燥，过滤，浓缩。残余物用硅胶柱层析纯化(0-40％(25％EtOH/EA)/PE)得化合物6e(450mg)。
LCMS(ESI-MS)m/z:515.9(M+H+).
第四步 2-(6-(环丙烷甲酰胺)-4-((3-(1-乙基-1H-吡唑-4-基)-2-甲氧基苯基)氨基)哒嗪-3-羰基)-1-乙基肼-1-羧酸叔丁酯(6f)的合成
于封管中，加入6e(300mg，0.59mmol)，环丙酰胺(101mg,1.196mmol)，Pd(AcO)2(5mg,0.022mmol)，xantphos(25mg,0.044mmol)，Cs2CO3(143mg,0.44mmol)和dioxane(2mL)。封管，N2保护下115℃反应3小时。LCMS显示反应完全。过滤，DCM/MeOH(10/1,10mL×3)洗涤。浓缩滤液。残余物用硅胶柱层析纯化(0-40％(25％EtOH/EA)/PE,0-9％MeOH/DCM)得化合物6f(200mg)。
LCMS(ESI-MS)m/z:565.3(M+H+).
第五步 N-(5-((3-(1-乙基-1H-吡唑-4-基)-2-甲氧基苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙甲酰胺(6)合成
于封管中，加入6f(200mg，0.35mmol)，溶于甲醇1ml,加入HCl/EA(2ml)室温搅拌4小时，LCMS显示反应完全，浓缩滤液。残余物用硅胶柱层析纯化(0-40％(25％EtOH/EA)/PE,0-9％MeOH/DCM)得化合物6(72mg)。
LCMS(ESI-MS)m/z:465.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.72(s,1H),10.50(s,1H),8.19(s,1H),8.15(s,1H),7.91(s,1H),7.42(dd,J＝7.8,1.5Hz,1H),7.27(dd,J＝8.0,1.5Hz,1H),7.17(t,J＝7.9Hz,1H),5.15(s,1H),4.17(q,J＝7.3Hz,2H),3.57(s,3H),2.87(d,J＝7.4Hz,2H),2.10–2.02(m,1H),1.39(t,J＝7.3Hz,3H),1.04(t,J＝7.1Hz,3H),0.87–0.77(m,4H).
实施例7
2-[3-({6-[(环丙基羰基)氨基]-3-[(2-乙基二氮酰基)羰基]-1,2-二嗪-4-基}氨基)-2-[(二氟甲基)氧基]苯基]-5-甲基咪唑-5-酰亚胺(7)
化合物7的制备参照实施例3。
LCMS(ESI-MS)m/z:488(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.63(s,1H),10.46(s,1H),8.60(s,1H),8.02(s,1H),7.85(d,J＝7.8Hz,1H),7.60(d,J＝7.9Hz,1H),7.46(t,J＝7.9Hz,1H),7.04(t,J＝75.6Hz,1H),5.15(s,1H),3.92(s,3H),2.86(s,2H),2.05(s,1H),1.04(t,J＝7.2Hz,3H),0.79(t,J＝6.0Hz,4H).
实施例8
N-(5-((2-(2,2-二氟乙氧基)-4-(1-乙基-1H-吡唑-4-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙甲酰胺(8)
化合物8的制备参照实施例2。
LCMS(ESI-MS)m/z:515(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.44–10.42(m,1H),10.37(s,1H),8.28(s,1H),7.96(m,1H),7.92(m,1H),7.44(m,1H),7.36–7.34(m,1H),7.29–7.27(m,1H),6.43–6.16(m,1H),5.12–5.10(m,1H),4.48–4.40(m,2H),4.18–4.13(m,2H),2.91–2.84(m,2H),2.08–2.05(m,1H),1.43–1.40(m,3H),1.07–1.03(m,3H),0.82–0.77(m,4H).
实施例9
N-{6-[(2-乙基乙氮基)羰基]-5-{[4-(1-乙基吡唑-4-基)-2-甲氧基苯基]氨基}-1,2-二氮杂环己熳-3-基}环丙甲酰胺(9)
化合物9的制备参照实施例2。
LCMS(ESI-MS)m/z:465(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.42(s,1H),10.38(s,1H),8.25(s,1H),7.98(s,1H),7.92(d,1H),7.33–7.31(d,2H),7.20–7.18(d,1H),5.13(s,1H),4.16–4.11(m,2H),3.86(s,3H),2.88–2.85(m,2H),2.08–2.02(m,1H),1.41–1.38(m,3H),1.05–1.02(m,3H),0.8–0.78(m,4H).
实施例10
N-(6-(2-乙基肼-1-羰基)-5-((2-异丙氧基-4-(1-异丙基-1H-吡唑-4-基)苯基)氨基)哒嗪-3-基)环丙烷甲酰胺(10)
化合物10的制备参照实施例2。
LCMS(ESI-MS)m/z:507(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.40(s,1H),10.38(d,J＝6.1Hz,1H),8.27(s,1H),8.04(s,1H),7.89(s,1H),7.36–7.29(m,2H),7.20(dd,J＝8.2,1.8Hz,1H),5.15–5.07(m,1H),4.70(p,J＝6.0Hz,1H),4.47(p,J＝6.7Hz,1H),2.91–2.82(m,2H),2.09–2.01(m,1H),1.43(d,J＝6.7Hz,6H),1.24(d,J＝6.0Hz,6H),1.04(t,J＝7.1Hz,3H),0.83–0.75(m,4H).
实施例11
N-(5-(2-(甲氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)-[(2S)-2-氟环丙烷]-1-甲酰胺(11)
化合物11的制备参照实施例1。
LCMS(ESI-MS)m/z:470(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.73(s,1H),10.50(s,1H),8.54(s,1H),8.13(s,1H),7.64(dd,J＝7.9,1.6Hz,1H),7.51(dd,J＝8.1,1.7Hz,1H),7.27(t,J＝7.9Hz,1H),5.00(td,J＝6.2,3.7Hz,1H),4.84(td,J＝6.2,3.8Hz,1H),3.93(s,3H),3.71(s,3H),2.87(q,J＝7.1Hz,2H),2.30–2.22(m,1H),1.60(dtd,J＝23.3,6.9,3.6Hz,1H),1.16(ddd,J＝12.6,6.2,2.8Hz,1H),1.04(t,J＝7.1Hz,3H).
实施例12
N-(5-((2-(二氟甲氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2,2-二甲基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(12)
化合物12的制备参照实施例1。
LCMS(ESI-MS)m/z:488(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),10.69(s,1H),9.99(s,1H),8.60(s,1H),8.02(s,1H),7.85(dd,J＝7.9,1.6Hz,1H),7.59(dd,J＝8.2,1.6Hz,1H),7.46(t,J＝7.9Hz,1H),7.04(t,J＝76Hz,1H),3.93(s,3H),2.60(s,6H),2.10–2.01(m,1H),0.83–0.72(m,4H).
实施例13
N-{6-[(2-乙基二氮烷基)羰基]-5-{[3-(5-氯嘧啶-2-基)-2-甲氧苯基]氨基}-1,2-二嗪-3-基}环丙甲酰胺(13)
化合物13的制备参照实施例3。
LCMS(ESI-MS)m/z:483(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.72(s,1H),10.53(s,1H),9.08(s,2H),8.17(d,J＝1.4Hz,1H),7.62(dd,J＝8.0,1.6Hz,1H),7.55(dd,J＝7.8,1.6Hz,1H),7.33(dd,J＝8.5,7.3Hz,1H),5.17(s,1H),3.69(s,3H),2.89(d,J＝7.6Hz,2H),2.15–2.04(m,1H),1.06(t,J＝7.1Hz,3H),0.88–0.78(m,4H).
实施例14
N-{6-[(2-乙基二氮烷基)羰基]-5-{[3-(5-氰基嘧啶-2-基)-2-甲氧苯基]氨基}-1,2-二嗪-3-基}环丙甲酰胺(14)
化合物14的制备参照实施例3。
LCMS(ESI-MS)m/z:474.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.71(s,1H),10.52(s,1H),9.42(d,J＝1.0Hz,2H),8.14(s,1H),7.64(td,J＝8.5,7.8,1.6Hz,2H),7.34(t,J＝7.9Hz,1H),5.18(s,1H),3.70(s,3H),2.87(q,J＝7.2Hz,2H),2.06(t,J＝5.9Hz,1H),1.04(t,J＝7.2Hz,3H),0.80(dd,J＝6.3,3.0Hz,4H).
实施例15
N-(6-(2-乙基肼-1-羰基)-5-((2-甲氧基-3-(5-甲基吡嗪-2-基)苯基)氨基)哒嗪-3-基)环丙烷甲酰胺(15)
化合物15的制备参照实施例3。
LCMS(ESI-MS)m/z:463.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.77(s,1H),10.54–10.53(m,1H),8.95–8.94(m,1H),8.68–8.67(m,1H),8.19(m,1H),7.57–7.53(m,2H),7.36–7.32(m,1H),5.18–5.16(m,1H),3.51(s,3H),2.91–2.87(m,2H),2.56(s,3H),2.11–2.07(m,1H),1.08–1.04(m,3H),0.85–0.82(m,4H).
实施例16
N-(5-{[3-(5-氰基吡啶-2-基)-2-甲氧基苯基]氨基}-6-[(2-乙基乙氮基)羰基]-1,2-二氮杂环己熳-3-基)环丙烷甲酰胺(16)
化合物16的制备参照实施例3。
LCMS(ESI-MS)m/z:473.0(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.76(s,1H),10.54(d,J＝6.9Hz,1H),9.15(s,1H),8.40(d,J＝10.5Hz,1H),8.17(s,1H),8.11–8.04(m,1H),7.59(d,J＝7.9Hz,2H),7.40-7.30(m,1H),5.15(s,1H),3.50(s,3H),2.89(d,J＝6.5Hz,2H),2.13–2.03(m,1H),1.12-0.93(m 3H),0.93-0.7(m,4H).
实施例17
N-(6-(1,2-二甲基肼-1-羰基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-基)环丙烷甲酰胺(17)
化合物17的制备参照实施例1。
LCMS(ESI-MS)m/z:452(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.54(s,1H),8.42(s,1H),8.07(d,J＝19.0Hz,1H),7.72–7.60(m,1H),7.33(dd,J＝8.0,1.8Hz,1H),7.24(dd,J＝8.9,6.7Hz,1H),5.20(d,J＝5.7Hz,1H),3.92(s,3H),3.66(d,J＝26.8Hz,3H),3.25(s,3H),2.44(d,J＝5.4Hz,3H),2.01–1.94(m,1H),0.77(dt,J＝11.4,6.1Hz,4H).
实施例18
N-(6-(2,2-二甲基肼-1-羰基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-基)环丙烷甲酰胺(18)
化合物18的制备参照实施例1。
LCMS(ESI-MS)m/z:452(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.63(s,1H),8.56(s,1H),8.15(s,1H),7.65(dd,J＝7.8,1.6Hz,1H),7.50(dd,J＝8.0,1.6Hz,1H),7.26(t,J＝7.9Hz,1H),3.93(s,3H),3.72(s,3H),2.73(s,6H),2.16–1.95(m,1H),0.89–0.70(m,4H).
实施例19
N-(6-(2-乙基肼-1-羰基)-5-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)哒嗪-3-基)环丙烷甲酰胺(19)
化合物19的制备参照实施例3。
LCMS(ESI-MS)m/z:467(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.88(s,1H),10.55(s,1H),8.96(d,J＝4.9Hz,2H),8.25(s,1H),7.59–7.48(m,2H),7.37–7.26(m,1H),5.17(s,1H),3.68(s,3H),2.87(d,J＝7.7Hz,2H),2.09(d,J＝9.2Hz,1H),1.03(t,J＝7.2Hz,3H),0.84(d,J＝6.1Hz,4H).
实施例20
N-{6-[(2-乙基乙氮基)羰基]-5-{[2-甲氧基-3-(5-甲基嘧啶-2-基)苯基]氨基}-1,2-二氮杂环己熳-3-基}环丙烷甲酰胺(20)
化合物20的制备参照实施例3。
LCMS(ESI-MS)m/z:463(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.68(s,1H),10.49(s,1H),8.77(d,J＝0.9Hz,2H),8.15(s,1H),7.51(ddd,J＝28.2,7.9,1.6Hz,2H),7.27(t,J＝7.9Hz,1H),5.16(s,1H),3.65(s,3H),2.87(q,J＝7.1Hz,2H),2.32(s,3H),2.14–1.97(m,1H),1.04(t,J＝7.1Hz,3H), 0.93–0.69(m,4H).
实施例21
N-{6-[(2-乙基二氮烷基)羰基]-5-{[3-(5-氟嘧啶-2-基)-2-甲氧苯基]氨基}-1,2-二嗪-3-基}环丙甲酰胺(21)
化合物21的制备参照实施例3。
LCMS(ESI-MS)m/z:467(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.72(s,1H),10.53(s,1H),9.05(d,J＝0.9Hz,2H),8.17(s,1H),7.60(dd,J＝7.9,1.6Hz,1H),7.52(dd,J＝7.8,1.6Hz,1H),7.32(t,J＝7.9Hz,1H),5.18(s,1H),3.68(s,3H),2.89(q,J＝7.1Hz,2H),2.17–2.02(m,1H),1.06(t,J＝7.1Hz,3H),0.88–0.78(m,4H).
实施例22
N-(5-(5-氟-2-(甲氧基)-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(22)
化合物22的制备参照实施例3。
LCMS(ESI-MS)m/z:470(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.91(s,1H),10.54(s,1H),8.59(s,1H),8.25(s,1H),7.40(ddd,J＝12.8,9.5,3.1Hz,2H),5.17(s,1H),3.94(s,3H),3.73(s,3H),2.87(q,J＝7.2Hz,2H),2.09(p,J＝6.2Hz,1H),1.04(t,J＝7.1Hz,3H),0.83(d,J＝6.1Hz,4H).
实施例23
N-(5-((4-(5-氰基吡啶-2-基)-2-(1,1-二氧化异噻唑啉-2-基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(23)
化合物23的制备参照实施例3。
LCMS(ESI-MS)m/z:562(M+H+)
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),11.12(s,1H),10.53(s,1H),9.09(dd,J＝2.1,0.9Hz,1H),8.43–8.33(m,3H),8.27(dd,J＝8.5,2.9Hz,2H),7.71(d,J＝8.6Hz,1H),5.17(s,1H),3.68(t,J＝6.8Hz,2H),3.50(t,J＝7.5Hz,2H),2.88(d,J＝7.5Hz,2H),2.13–2.05(m,1H),1.23(d,J＝9.9Hz,2H),1.05(t,J＝7.1Hz,3H),0.88–0.78(m,4H).
实施例24
N-(5-((4-(1-环丙基-1H-吡唑-4-基)-2-(2,2,2-三氟乙氧基)苯基)氨基)-6-(2-乙基肼-1-羰基)哒嗪-3-基)环丙烷甲酰胺(24)
化合物24的制备参照实施例2。
LCMS(ESI-MS)m/z:545(M+H+)
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.38(d,J＝28.4Hz,2H),8.31(d,J＝0.8Hz,1H),7.95(d,J＝0.8Hz,1H),7.89(s,1H),7.50(d,J＝1.7Hz,1H),7.41–7.28(m,2H),5.10(s,1H),4.85(q,J＝8.8Hz,2H),3.75(tt,J＝7.4,3.9Hz,1H),2.93–2.83(m,2H),2.07(tt,J＝7.6,4.8Hz,1H),1.4–0.94(m,7H),0.86–0.72(m,4H).
实施例25
6-((2,6-二甲基嘧啶-4-基)氨基)-N’-乙基-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-碳酰肼(25)
化合物25的制备参照实施例3。
LCMS(ESI-MS)m/z:490(M+H+)
1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),10.47(s,2H),8.55(s,1H),8.37(d,J＝11.1Hz,2H),7.74–7.56(m,2H),7.29(t,J＝7.9Hz,1H),7.14(s,1H),3.93(s,3H),3.74(s,3H),2.88(q,J＝7.1Hz,2H),2.37(s,3H),2.29(s,3H),1.05(t,J＝7.1Hz,3H).
实施例26
N-(4-((4-(5-氰基吡啶-2-基)-2-(1,1-二氧化异噻唑啉-2-基)苯基)氨基)-5-(2-乙基肼-1-羰基)吡啶-2-基)环丙甲酰胺(26)
化合物26的制备参照实施例2。
LCMS(ESI-MS)m/z:561(M+H+)
1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.74(s,1H),10.18(m,1H),9.08(m,1H),8.49(s,1H),8.39–8.36(m,2H),8.28–8.23(m,3H),7.71–7.69(m,1H),5.18(s,1H),3.67–3.64(m,2H),3.56–3.52(m,2H),2.86–2.83(m,2H),2.55–2.52(m,2H),2.02–1.99(m,1H),1.08–1.04(m,3H),0.81–0.79(m,4H).
实施例27
N-{6-[(2-乙基二氮烷基)羰基]-5-{[4-(1-乙基吡唑-4-基)-2-[(2,2,2-三氟乙基)氧代]苯基]氨基}-1,2-二嗪-3-基}环丙甲酰胺(27)
化合物27的制备参照实施例2。
LCMS(ESI-MS)m/z:533.1(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.43(s,1H),10.35(s,1H),8.27(d,J＝0.8Hz,1H),7.96(d,J＝0.8Hz,1H),7.90(s,1H),7.50(d,J＝1.7Hz,1H),7.41–7.30(m,2H),5.11(s,1H),4.86(q,J＝8.8Hz,2H),4.16(q,J＝7.3Hz,2H),2.88(q,J＝7.1Hz,2H),2.07(ddd,J＝9.6,7.7,4.8Hz,1H),1.42(t,J＝7.3Hz,3H),1.05(t,J＝7.2Hz,3H),0.85–0.75(m,4H).
实施例28
N-(6-(2-乙基肼-1-羰基)-5-((3-(1-异丙基-1H-1,2,4-***-3-基)-2-甲氧基苯基)氨基)哒嗪-3-基)环丙烷甲酰胺(28)
化合物28的制备参照实施例3。
LCMS(ESI-MS)m/z:480(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),11.44(s,1H),10.27(s,1H),8.66(s,1H),8.20(s,1H),7.72–7.70(m,1H),7.55–7.53(m,1H),7.32–7.28(m,2H),4.76–4.70(m,1H),3.74(s,3H),3.29–3.24(m,2H),2.32–2.13(m,1H),1.52–1.50(d,6H),1.24–1.20(m,3H),0.85–0.82(m,4H).
实施例29
N-(4-{[3-(5-氟嘧啶-2-基)-2-甲氧苯基]氨基}-5-[(2-乙基二氮烷基)羰基]吡啶-2-基)环丙甲酰胺(29)
化合物29的制备参照实施例3。
LCMS(ESI-MS)m/z:466(M+H+).
1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),10.38(s,1H),10.14(s,1H),9.03(d,J＝0.9Hz,2H),8.49(s,1H),8.09(s,1H),7.57(dd,J＝8.0,1.7Hz,1H),7.43(dd,J＝7.8,1.6Hz,1H),7.27(t,J＝7.9Hz,1H),5.34(d,J＝62.2Hz,1H),3.68(s,3H),2.84(q,J＝7.1Hz,2H),1.99(tt,J＝7.2,5.4Hz,1H),1.05(t,J＝7.2Hz,3H),0.81–0.76(m,4H).
实施例30
N-(6-(2-(2-氟乙基)肼-1-羰基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-基)环丙烷甲酰胺(30)
化合物30的制备参照实施例3。
LCMS(ESI-MS)m/z:470(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.69(s,1H),10.61(s,1H),8.56(s,1H),8.16(s,1H),7.66(dd,J＝7.9,1.6Hz,1H),7.52(dd,J＝8.0,1.6Hz,1H),7.27(t,J＝7.9Hz,1H),5.49(s,1H),4.62(t,J＝4.9Hz,1H),4.51(t,J＝4.9Hz,1H),3.95(s,3H),3.73(s,3H),3.21(s,1H),3.14(s,1H),2.08(td,J＝5.4,4.6,2.8Hz,1H),0.85–0.79(m,4H).
实施例31
N-(5-(2-乙基肼-1-羰基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)吡啶-2-基)环丙烷甲酰胺(31)
化合物31的制备参照实施例3。
LCMS(ESI-MS)m/z:448(M+H+).
1H NMR(600MHz,DMSO-d6)δ10.78(s,1H),10.37(s,1H),10.14(s,1H),9.00–8.92(m,2H),8.49(s,1H),8.09(s,1H),7.56(dd,J＝8.0,1.6Hz,1H),7.51(td,J＝4.9,3.0Hz,1H),7.43(dd,J＝7.7,1.6Hz,1H),7.27(t,J＝7.9Hz,1H),5.18(s,1H),3.69(s,3H),2.83(q,J＝7.2Hz,2H),1.99(tt,J＝7.4,5.2Hz,1H),1.05(t,J＝7.2Hz,3H),0.78(m,4H).
实施例32
N-(6-(2-(2,2-二氟乙基)肼-1-羰基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-***-3-基)苯基)氨基)哒嗪-3-基)环丙烷甲酰胺(32)
化合物32的制备参照实施例3。
LCMS(ESI-MS)m/z:488(M+H+).
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.66(s,1H),10.59(d,J＝6.2Hz,1H),8.56(s,1H),8.17(s,1H),7.66(dd,J＝7.8,1.6Hz,1H),7.52(dd,J＝8.0,1.6Hz,1H),7.28(t,J＝7.9Hz,1H),6.19–6.12(m,1H),5.69(q,J＝5.4Hz,1H),3.95(s,3H),3.73(s,3H),3.31–3.19(m,2H),2.12–2.05(m,1H),0.86–0.78(m,4H).
生物活性试验
实验一、本发明TYK2抑制剂小分子化合物的体外活性测定
1.实验目的
本实验通过荧光共振能量转移(TR-FRET)法测试本发明化合物(化合物1-化合物32)对TYK2 JH2假激酶的抑制作用，根据半抑制浓度(IC50)评价化合物的体外活性。
2.实验方法
2.1准备1×实验工作液
实验工作液配制
2.2实验流程
(1)用DMSO溶解化合物到10mM的存储浓度。
(2)在化合物稀释板子中配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。
(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。
(4)加5uL 3X TYK2JH2激酶到384实验板中。
(5)加5uL 3X Tb到384实验板中。
(6)加5uL 3X Tracer到384孔实验板中。
(7)离心30秒，室温孵育60分钟。
(8)Envision酶标仪(PerkinElmer)495/520荧光信号值。
(9)使用XL-Fit软件进行数据分析，得出化合物IC50。
2.3实验结果
在TYK2 JH2假激酶体外活性实验中，本发明化合物(化合物1-化合物32)及阳性对照药BMS-986165的IC50均小于5nM。
结论：本发明化合物对TYK2 JH2假激酶具有明显的抑制活性。
实验二、本发明化合物在大鼠中药物代谢动力学实验
1.实验目的：
以SD大鼠为例，以液相色谱-串联质谱(LS/MS/MS)法测定了大鼠分别灌胃和静脉给予化合物1、化合物3后不同时刻血浆中药物浓度并计算相关药代参数，评价本发明实施例化合物在大鼠体内的药代动力学特性。
2.试验方案
2.1试验药物
实施例化合物1、实施例化合物3。
2.2试验动物
健康成年的SD大鼠，SPF级，雄性，购自上海西普尔-必凯实验动物有限公司，许可证号SCXK(沪)2018-0006，动物合格证编号：20180006006321。
2.3药物配置
称取一定量的化合物，溶于5％乙醇(ethanol)涡旋超声，加入5％水溶性天然维生素E(TPGS，配置前需加热)混匀，加入90％纯水混匀配置成1mg/mL的均一口服溶液。称取一定量的化合物，溶于80％聚乙二醇400(PEG400)涡旋超声，再加入20％纯水配置成0.4mg/mL澄清透明静脉给药溶液。
2.4给药
具体给药按照试验方案进行，详情见表2。
表2大鼠药代动力学试验方案
2.5采血时间及样品处理
给药前及给药后5分钟、15分钟、0.5小时、1小时、2小时、4小时、6小时、8小时及24小时分别通过眼眶采血，每次采血0.2毫升(mL)，置于抗凝管中，混匀，保存于-20℃冰箱中备用。
3.样品测试及数据分析
采用液相色谱-串联质谱(LS/MS/MS)方法测定大鼠全血中化合物的含量。
利用WinNonLin5.3软件的非房室模型计算给药后化合物的药代动力学参数。
4.试验结果
本发明化合物给药后药代动力学参数见以下表3。由表3所示，本发明的化合物具有较好的代谢特征及生物利用度。
表3本发明的化合物的药代动力学参数
实验三、本发明化合物的小鼠体内药效实验
一、银屑病模型
1.造模及给药
购买8周龄雌性BALB/c小鼠，平均体重20g。小鼠适应3天后开始实验，实验分为五组，正常对照组、模型组、实施例化合物组及阳性药组(BMS-986165)，每组5-8只。模型组、实施例化合物组及阳性药组小鼠用戊巴比妥钠腹腔注射麻醉(80mg/kg),背部去毛后均匀涂抹5％咪喹莫特乳膏62.5mg，每日一次，正常对照组涂抹等量凡士林。实施例化合物组(10mg/kg)按10mL/kg灌胃给药，每日一次；正常对照组灌胃等量纯水，模型组灌胃等量溶媒，连续7d。具体设计见表4。
表4化合物体内药效实验方案

NA表示空白项。
2.实验动物
雌性BALB/c小鼠37只，8周龄。小鼠均购自北京维通利华实验动物技术有限公司，许可证号SCXK(沪)2017-0011，动物合格证编号：20170011003865。
3.实验药物
实施例化合物1。
4.药物的配置
称取适量化合物，溶于5％乙醇(ethanol)涡旋超声，加入5％水溶性天然维生素E(TPGS，配置前需加热)混匀，加入90％纯水混匀配置成1mg/mL的均一溶液。
5.给药
具体给药按照给药方案进行。
6.检测指标和方法
每天观察小鼠皮损情况，并采用数码照相，依据小鼠银屑病样皮损面积和疾病严重程度(psoriasis area and severity index,PASI)评分标准，给予小鼠皮损处红斑、鳞屑及浸润程度(0:无；1:轻度；2:中度；3:重度；4:极重度)打分，观察各组小鼠皮损的变化情况。
7.实验结果及结论
咪喹莫特外涂与小鼠背部皮肤5d后，模型对照组小鼠背部皮损增厚、浸润显著，大量斑块状鳞屑出现，皮肤变红。实施例化合物1小鼠皮损红斑和鳞屑明显减少，浸润减轻。模型对照组小鼠PASI评分随天数持续增高，实施例化合物1组第3天后PASI评分开始明显降低，作用效果优于阳性药组。
二、炎症性肠病模型
口服灌胃2.5％葡聚糖硫酸钠(DSS)诱导小鼠IBD造模后，模型组小鼠出现体重减轻、精神萎靡、嗜睡、血便、腹泻等症状，其疾病活动指数(DAI)明显高于对照组。实施例化合物1组在给药第三天能够显著降低小鼠的DAI评分，抑制DSS带来的体重下降和结肠缩短，显著减轻DSS对小鼠的肠道损伤，病理学检查发现实施例化合物组能够有效抑制结肠中的炎症浸润。
三、红斑狼疮模型
选择雌性MRL/lpr小鼠作为红斑狼疮模型的实验动物，每周评估小鼠***肿大及皮肤损伤，及相关尿白蛋白及肌酐的指标测试，体内药效试验发现实施例化合物1能显著降低Pristane诱导的狼疮小鼠自身抗体(anti-ds DNA,anti-SLE)和尿蛋白浓度，降低肾小球肿胀度，病理学组织检查中发现能够有效减少炎症细胞浸润。
实验四、本发明化合物的小鼠急毒实验
1.实验目的
本实验目的是为了测试实施例化合物在小鼠上的急性毒性作用。
2.实验动物
ICR小鼠，SPF级，6-8周龄，雌雄各半，购自上海西普尔-必凯实验动物有限公司，许可证号SCXK(沪)2018-0006，动物合格证编号：20180006010983。
3.试验药物
实施例化合物1。
4.实验方法
ICR小鼠单次给予不同剂量的化合物，连续观察14天，记录动物死亡情况，中毒反应，体重变化，饮食，外观，行为等。终点解剖动物，取脏器，进行组织病理学检查及相关血液学检查。
5.实验结果及结论
实施例化合物1的无毒性反应剂量(NOAEL)大于1000毫克每公斤(mg/kg)，与对照组小鼠比较，给药组小鼠自给药日起14天内均未见体重及行为异常，且相关血液学未见明显异常，病理学检查未见相关实施例化合物毒性作用，说明本发明实施例化合物1安全性良好，动物能够安全耐受。
实验五、本发明化合物的小鼠长毒实验
1.实验目的
本实验目的是为了测试实施例化合物在小鼠上的长期毒性作用。
2.实验动物
ICR小鼠，SPF级，6-8周龄，雌雄各半，购自上海西普尔-必凯实验动物有限公司，许可证号SCXK(沪)2018-0006，动物合格证编号：20180006010983。
3.试验药物
实施例化合物1。
4.实验方法
ICR小鼠给予不同剂量的化合物，连续给药观察14天，记录动物死亡情况，中毒反应，体重变化，饮食，外观，行为等。终点解剖动物，取脏器，进行组织病理学检查及相关血液学检查。
5.实验结果及结论
实施例化合物1的无毒性反应剂量(NOAEL)均大于500毫克每公斤(mg/kg)，与对照组小鼠比较，给药组小鼠自给药日起14天内均未见体重及行为异常，且相关血液学未见明显 异常，病理学检查未见相关实施例化合物毒性作用，说明本发明实施例化合物1安全性良好，动物能够安全耐受。

Claims (16)

  1. 一种通式Ⅱ所示的化合物或其可药用盐或同位素衍生物，
    其中R1为-C1-3烷基氨基，其中所述的-C1-3烷基氨基中的烷基任选地进一步被选自氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R5为H或-C1-3烷基，其中所述的-C1-3烷基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R6为-C(O)R2或4-6元杂环基；其中所述的-4-6元杂环基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代，R2为-C3-6环烷基；
    R7为-OR3或-NR8R9，其中R8R9任选地为H、-C1-3烷基或，R8R9各自独立地选自-(CH2)n-或-SO2-且和与其相连的N一同形成一个5-6元的杂环，其中n为1～4中的任一整数；
    R3为-C1-3烷基或-C3-6环烷基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
    Ra为-H、-CN、-卤素、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
  2. 根据权利要求1所述的化合物或其可药用盐或同位素衍生物，其特征在于，
    R5为H或-甲基。
  3. 根据权利要求1或2所述的化合物或其可药用盐或同位素衍生物，其特征在于，R1为-NH-CHF2、-NH-CH2F、-NH-CH2CH2F、-NH-CH2CHF2、-NH-CH3或-NH-CH2CH3。
  4. 根据权利要求1～3任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，R6为
  5. 根据权利要求1～4任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，
    R7为-OCH3、-OCF3、-OCH2CF3、-OCHF2、-OCH2CHF2、-OCH(CH3)2或
  6. 根据权利要求1～5任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，R4为
  7. 据权利要求1～6任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，Ra为-H、-F、-Cl、-CN、-CHF2、甲基、乙基、三氟甲基或-CH(CH3)2。
  8. 根据权利要求1所述所示的化合物或其可药用盐或同位素衍生物，其具式Ⅱ-1或式Ⅱ-2结构：
    其中R1为-C1-3烷基氨基，其中所述的-C1-3烷基氨基中的烷基任选地进一步被选自氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R2为-C3-6环烷基；
    R3为-C1-3烷基或-C3-6环烷基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、氘原子、-C1-3烷基和卤素中的一个或多个取代基所取代；
    R4为5-6元杂芳基，其中所述的5-6元杂芳基任选地被Ra取代；
    Ra为-H、-CN、-CF3、-C1-3烷基、-C3-6环烷基或4-6元杂环基，其中所述的-C1-3烷基或-C3-6环烷基任选地进一步被选自氢原子、-C1-3烷基和卤素中的一个或多个取代基所取代。
  9. [根据细则26改正 03.11.2023]
    根据权利要求8所述的化合物或其可药用盐或同位素衍生物，其特征在于，R1选自-NH-CHF2、-NH-CH2F、-NH-CH2CH2F、-NH-CH2CHF2、-NH-CH3或-NH-CH2CH3。
  10. [根据细则26改正 03.11.2023]
    根据权利要求8或9所述的化合物或其可药用盐或同位素衍生物，其特征在于，R1为-NH-CH3或-NH-CH2CH3；
    R2为环丙烷基；
    R3为-CH3、-CF3、-CH2CF3、-CHF2、-CH2CHF2或-CH(CH3)2。
  11. 根据权利要求8～10任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，
    R4为
  12. 据权利要求8～11任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，Ra为-H、-CN、-CHF2、甲基、乙基、三氟甲基或-CH(CH3)2。
  13. 根据权利要求1～12任一项所述的化合物或其可药用盐或同位素衍生物，其特征在于，所述化合物选自如下化合物或其可药用盐或同位素衍生物：

  14. 一种药物组合物，其特征在于，包括治疗有效量的权利要求1-13中任一项的式II所示化合物或其可药用盐或同位素衍生物，以及任选一种或多种药学上可接受的载剂和/或稀释剂。
  15. 根据权利要求1-13任一项所述的式II所示化合物或其可药用盐或同位素衍生物，或者根据权利要求14所述的药物组合物在制备用于预防和/或治疗TYK2介导的疾病的药物中的用途；优选地，所述TYK2介导的疾病为炎性疾病或自身免疫性疾病；更优选地，所述炎性疾病为银屑病、炎症性肠病；所述自身免疫疾病为红斑狼疮。
  16. 治疗TYK2介导的疾病的方法，包括给需要这种治疗的患者施用治疗有效量的权利要求1～13中任一项所述的式II所示化合物或其可药用盐或同位素衍生物。
PCT/CN2023/126345 2022-10-28 2023-10-25 一种哒嗪酰胺类化合物、其药物组合物及其作为tyk2抑制剂的用途 WO2024088282A1 (zh)

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CN110475774A (zh) * 2017-03-30 2019-11-19 百时美施贵宝公司 用于制备6-(环丙烷酰氨基)-4-((2-甲氧基-3-(1-甲基-1h-1,2,4-***-3-基)苯基)氨基)-n-(甲基-d3)哒嗪-3-甲酰胺的方法
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CN113968846A (zh) * 2020-07-24 2022-01-25 上海翰森生物医药科技有限公司 一种哒嗪类衍生物的盐、晶型及其制备方法和应用

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CN110475774A (zh) * 2017-03-30 2019-11-19 百时美施贵宝公司 用于制备6-(环丙烷酰氨基)-4-((2-甲氧基-3-(1-甲基-1h-1,2,4-***-3-基)苯基)氨基)-n-(甲基-d3)哒嗪-3-甲酰胺的方法
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