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WO2024199479A1 - 一种大环化合物、药物组合物及其用途 - Google Patents

一种大环化合物、药物组合物及其用途 Download PDF

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Publication number
WO2024199479A1
WO2024199479A1 PCT/CN2024/084966 CN2024084966W WO2024199479A1 WO 2024199479 A1 WO2024199479 A1 WO 2024199479A1 CN 2024084966 W CN2024084966 W CN 2024084966W WO 2024199479 A1 WO2024199479 A1 WO 2024199479A1
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Prior art keywords
pharmaceutically acceptable
hydrogen
solvate
prodrug
isomer
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PCT/CN2024/084966
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English (en)
French (fr)
Inventor
胡伟
祝力
戴丽光
朱冰
杜云龙
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北京普祺医药科技股份有限公司
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Publication of WO2024199479A1 publication Critical patent/WO2024199479A1/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
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present disclosure provides a macrocyclic compound, a pharmaceutical composition and uses.
  • the macrocyclic compound is a TYK2 allosteric inhibitor with strong ability to pass through the blood-brain barrier and high selectivity, and can be used to regulate TYK2-mediated diseases.
  • the JAK family is critical in mediating the signaling of numerous cytokines that cause inflammation, and includes JAK1, JAK2, JAK3, and TYK2.
  • TYK2 and JAK1/2/3 usually work in pairs, or "dimers,” to transmit signals from extracellular cytokines to the cell nucleus.
  • TYK2 selectively participates in the transmission of proinflammatory cytokines such as IL-23, IL-12, and type I IFN signals. Therefore, TYK2 inhibitors could be an effective treatment for a variety of severe inflammatory and autoimmune diseases.
  • JAK1, JAK2, JAK3 and TYK2 in the JAK family all have JAK homology domains (JAK homology domain, JH), of which the JH1 domain is also called the kinase domain, and JH2 is a pseudokinase domain.
  • JH JAK homology domain
  • Deucravacitinib acts on a specific pocket in the TYK2 JH2 pseudokinase domain, achieving high selectivity for other JAK family members and the entire kinase family through allosteric inhibition, reducing the risk of adverse events such as cardiovascular events or venous thromboembolism. Deucravacitinib has thus become the first oral JAK inhibitor to be marketed without a black box warning.
  • Deucravacitinib also has a certain effect on the JH2 domain of JAK1, and there is a risk of adverse events caused by inhibiting JAK1.
  • Developing a TYK2 allosteric inhibitor with higher selectivity for JAK1 can further reduce the adverse reactions caused by JAK1 inhibition and provide a safer treatment for autoimmune diseases.
  • many autoimmune diseases will invade the brain in the later stages and show symptoms such as multifocal or diffuse brain damage.
  • TYK2 is a STAT pathway activator for a series of proinflammatory cytokines.
  • Inhibiting TYK2 may play an important role in reducing inflammation in neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. Therefore, it is an urgent clinical need to develop a TYK2 allosteric inhibitor with better selectivity and strong ability to pass through the blood-brain barrier to solve neurodegenerative diseases.
  • the present disclosure provides a compound as shown in Formula I, an isotope isomer thereof, or a pharmaceutically acceptable salt thereof:
  • the compound is a TYK2 allosteric inhibitor with strong ability to cross the blood-brain barrier and high selectivity, and can be used to regulate TYK2-mediated diseases.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure also relates to the use of the compounds disclosed herein or their pharmaceutically acceptable salts, hydrates, solvates, active metabolites, polymorphs, isotope labels, isomers or prodrugs, and pharmaceutical compositions in the preparation of drugs for treating tyrosine kinase-mediated diseases.
  • the tyrosine kinase is selected from TYK2 kinase.
  • the tyrosine kinase-mediated diseases include inflammatory autoimmune diseases, tumors, and neurodegenerative diseases, for example, inflammatory autoimmune diseases are selected from atopic dermatitis, suppurative hidradenitis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, lupus erythematosus, scleroderma, autoimmune encephalopathy, etc.; tumors are selected from leukemia, lymphoma, myeloma, brain tumor and other cancers; neurodegenerative diseases are selected from brain atrophy, Alzheimer's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, etc.
  • Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid infection).
  • the reactions and purification techniques can be performed using kits with instructions provided by the manufacturer, or according to methods known in the art, or according to the methods described in this disclosure.
  • the aforementioned techniques and procedures can be performed by conventional methods well known in the art and described in various general or more specific literature, which are cited and discussed in this disclosure.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2 .
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • Cm ⁇ n means that there are m to n carbon atoms in the moiety.
  • the "C1 ⁇ 8 " group means that there are 1-8 carbon atoms in the moiety, that is, the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms...8 carbon atoms. Therefore, for example, " C1 ⁇ 8 alkyl” refers to an alkyl group containing 1-8 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl...octyl, etc.
  • pyridine is a six-membered ring
  • pyrrole is a five-membered ring.
  • each group may have the following definitions:
  • Hydrogen can be represented by -H, and can also be replaced by isotopes such as deuterium and tritium.
  • Halogen may include fluorine, chlorine, bromine, iodine.
  • the C1-8 alkyl group may include methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, and the
  • Deuterated C 1-8 alkyl and tritiated C 1-8 alkyl may mean that one or more or even all hydrogen atoms on the C 1-8 alkyl are replaced by isotopes such as deuterium and tritium.
  • the C 1-8 alkoxy group may be represented by -OC 1-8 alkyl, wherein the C 1-8 alkyl group includes groups as defined above; for example, the C 1-8 alkoxy group may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • C1-8 haloalkyl can be represented by a group in which any number of hydrogen atoms in a C1-8 alkyl group are replaced by halogen, wherein the C1-8 alkyl group and the halogen group include the same groups as defined above; for example, the C1-8 haloalkyl group may include -CF3, etc.
  • the C 3-8 cycloalkyl group may be represented by a non-aromatic saturated carbocyclic ring, including a monocarbocyclic ring (having one ring) and a dicarbocyclic ring (having two rings).
  • the C 3-8 cycloalkyl group may include wait.
  • C3-8 cycloalkylC1-8 alkyl can be represented by a C1-8 alkyl group with a C3-8 cycloalkyl group, wherein the definitions of C3-8 cycloalkyl and C1-8 alkyl are as described above.
  • C3-8 cycloalkylC1-8 alkyl may include cyclopropylmethyl, cyclobutylmethyl, cyclohexylethyl and the like.
  • the C 3-8 heterocyclic group can be represented by a group obtained by replacing any number of ring atoms in a C 3-8 cycloalkyl group with heteroatoms such as O, S, N, P, Si, etc., wherein the C 3-8 cycloalkyl group includes groups as defined above.
  • the C 3-8 heterocyclic group may include an oxirane group, an oxirane group, an oxadiazine group, an azetidinyl group, an oxetanyl group, a thiazole group, a tetrahydrofuranyl group, a pyrrolidinyl group, an oxazolidinyl group, a tetrahydropyrazolyl group, a pyrrolinyl group, a dihydrofuranyl group, a dihydrothiophenyl group, a piperidinyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a morpholinyl group, a piperazinyl group, a dihydropyridinyl group, a tetrahydropyridinyl group, a dihydropyranyl group, a tetrahydropyranyl group, a dihydropyr
  • the C 6-20 aryl group may include a monocyclic aryl group, a bicyclic aryl group or more cyclic aryl groups, for example, may include phenyl, biphenyl, naphthyl, phenanthrenyl, anthracenyl, azulenyl and the like.
  • the C 5-20 heteroaryl group may represent an unsaturated group containing any number of heteroatoms such as O, S, N, P, Si as ring atoms.
  • the C 5-20 heteroaryl group may include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.
  • the hydroxyl group can be represented as -OH.
  • a mercapto group can be represented as -SH.
  • the carboxyl group can be represented as -COOH.
  • the ester group can be represented by -COOR', R' can be a C 1-8 alkyl group, for example, the ester group substituted by a C 1-8 alkyl group can be represented by -COOC 1-8 alkyl, wherein the C 1-8 alkyl group includes the groups defined above.
  • the acyl group may be represented by -COR', and R' may be a C 1-8 alkyl group.
  • R' may be a C 1-8 alkyl group.
  • the acyl group substituted by a C 1-8 alkyl group may be represented by -COC 1-8 alkyl, wherein the C 1-8 alkyl group includes the groups defined above.
  • the amino group can be represented by -NH2 , -NHR' or -N(R') 2 , R' can be C1-8 alkyl, for example, the amino group substituted by C1-8 alkyl can be represented by -NHC1-8 alkyl or -N( C1-8 alkyl) 2 , wherein the C1-8 alkyl group includes the groups as defined above.
  • the amide group may be represented by -COamino, wherein the amino group is as defined above.
  • the sulfonyl group can be represented by -S(O) 2 R', where R' can be a C 1-8 alkyl group.
  • R' can be a C 1-8 alkyl group.
  • a sulfonyl group substituted with a C 1-8 alkyl group can be represented by -S(O) 2 C 1-8 alkyl group, wherein the C 1-8 alkyl group includes groups as defined above.
  • the cyano group can be represented as -CN.
  • C 1-5 alkyl may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and all other groups that meet the definition of "C 1-8 alkyl" with a carbon number of 1-5.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts in the present disclosure may refer to metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.
  • metal salts include, but are not limited to, salts of alkali metals, such as sodium salts, potassium salts, and the like; salts of alkaline earth metals, such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts, and the like.
  • Non-limiting examples of salts formed with organic bases include, but are not limited to, salts formed with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and the like.
  • Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, etc.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, etc.
  • salts can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods.
  • such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • solvate refers to a physical combination of a compound of the present disclosure and one or more solvent molecules. Collectively, this physical aggregate includes varying degrees of ionic and covalent bonds, such as hydrogen bonds. It has been shown that this solvate can be separated, for example, when one or more solvent molecules are mixed in the crystal lattice.
  • Solvate includes two parts: a solvent phase and a separable solvate. There are many examples of corresponding solvates, including ethanol solvates, methanol solvates, etc.
  • “Hydrate” is a solvate with water ( H2O ) molecules as solvent.
  • One or more compounds in the present disclosure can be prepared into solvates at will. The preparation of solvates is well known.
  • a typical, non-limiting preparation process is to dissolve the compound of the invention in a desired amount of an ideal solvent (organic solvent or water or a mixed solvent thereof) at a temperature higher than room temperature, cool it, place it for crystallization, and then separate and pick out the crystals using a standard method.
  • an ideal solvent organic solvent or water or a mixed solvent thereof
  • the presence of the solvent (water) that forms the solvate (hydrate) in the crystals can be confirmed by IR spectroscopy analysis technology.
  • active metabolite refers to an active derivative of a compound that is formed when the compound is metabolized.
  • polymorph refers to compounds of the present disclosure that exist in different crystal lattice forms.
  • isotope-labeled compound refers to a compound of the present disclosure that is labeled with an isotope.
  • the isotopes in the compounds of the present disclosure may include various isotopes of elements such as H, C, N, O, P, F, S, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 S.
  • pharmaceutically acceptable prodrug refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present disclosure, which, upon administration to a receptor, is capable of providing, directly or indirectly, a compound of the present disclosure or a pharmaceutically active metabolite or residue thereof.
  • Particularly preferred derivatives or prodrugs are those compounds that, when administered to a patient, can increase the bioavailability of the compound of the present disclosure (e.g., can make an orally administered compound more easily absorbed into the blood), or those compounds that promote the delivery of the parent compound to a biological organ or site of action (e.g., the brain or lymphatic system).
  • Prodrugs can be prepared by modifying functional groups present in the compound in a manner that allows for decomposition into the parent compound, either by conventional manipulation or in vivo.
  • Various prodrug forms are well known in the art. See, for a discussion of prodrugs, T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Vol. 14 of the A.C.S. Symposium Series, Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association, and Pergamon Press. Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p.
  • stereoisomer refers to isomers produced by different spatial arrangements of atoms in a molecule.
  • the compounds disclosed herein contain structures such as asymmetric or chiral centers, double bonds, etc. Therefore, the compounds disclosed herein may include multiple isomer forms such as optical isomers, geometric isomers, tautomers, atropisomers, etc. These isomers and their single isomers, racemates, etc. are all included in the scope of the present disclosure.
  • optical isomers it can be Optically active (R)- and (S)-isomers and D and L isomers are prepared by chiral resolution, chiral synthesis or chiral reagents or other conventional techniques.
  • diastereomers can be converted by reaction with appropriate optically active substances (e.g., chiral alcohols or Mosher's acyl chloride), which are separated and converted (e.g., hydrolyzed) to the corresponding single isomers.
  • optically active substances e.g., chiral alcohols or Mosher's acyl chloride
  • separation can also be performed by chromatographic columns.
  • composition refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component or agent, namely a “carrier” that facilitates the introduction of the compound into cells or tissues, including but not limited to stabilizers, diluents, suspending agents, thickening agents and/or excipients.
  • the "pharmaceutical composition” herein can be prepared in a manner well known in the pharmaceutical art, and can be administered or applied by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. It can be administered topically (e.g., transdermal, skin, eye and mucous membrane including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration.
  • compositions herein include, but are not limited to, the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle); ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders, etc.
  • each dose can contain about 0.1 to 1000 mg, usually about 5 to 1000 mg of active ingredient, more usually about 100 to 500 mg of active ingredient.
  • unit dosage form refers to physically discrete single dosage units suitable for use in human patients and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in admixture with a suitable pharmaceutical carrier.
  • subject refers to an individual suffering from a disease, disorder, condition, etc., including mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.
  • treat and other similar synonyms include relieving, alleviating or ameliorating symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, making a disease or condition better, alleviating symptoms caused by a disease or condition, or stopping symptoms of a disease or condition, and in addition, the term may also include the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a prophylactic effect.
  • the therapeutic effect refers to curing or improving the underlying disease being treated.
  • the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, the patient's condition is observed to improve.
  • the composition or compound can be administered to a patient at risk for a particular disease, or even if a disease diagnosis has not yet been made, the composition or compound can be administered to a patient who has one or more physiological symptoms of the disease.
  • amount necessary to achieve the therapeutic effect refers to that amount of at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated.
  • the result can be the reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired change in a biological system.
  • the technique of dose escalation testing determines the effective amount suitable for any individual case.
  • the actual amount of compound, pharmaceutical composition or medicament administered is usually determined by the physician based on relevant circumstances, including the condition being treated, the route of administration selected, the actual compound administered; the age, weight and response of the individual patient; the severity of the patient's symptoms, etc.
  • the ratio or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), route of administration, and the like.
  • the disclosed compounds may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound for parenteral administration.
  • Some typical dosage ranges are from about 1 ⁇ g/kg to about 1 g/kg body weight/day.
  • the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration.
  • administration refers to a method capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
  • IC50 refers to a 50% inhibition of the maximal effect in an assay measuring such effect.
  • the present disclosure provides a compound as shown in Formula I or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof,
  • X and Y are selected from N or C, and one of X and Y is N and the other is C;
  • W is selected from N or C
  • Z 1 is independently selected from O or S
  • Z 2 is selected from O, S or NR, R is hydrogen or C 1-6 alkyl;
  • R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, oxo, C 1-6 alkyl and C 1-6 alkoxy; or, R 2 and R 3 together with the ring atoms to which they are attached form a 5-6 membered heteroaryl ring substituted with 0-2 R 23 ;
  • R 4 is selected from NR 41 R 42 , C 1-6 alkyl and C 1-6 alkoxy;
  • R 5 is selected from hydrogen or NR 51 R 52 ;
  • L is each independently selected from -CR L1 R L2 -;
  • RL1 and RL2 on each L are independently selected from hydrogen and C1-6 alkyl, or two RL2 on two adjacent Ls together with the carbon atom on the L to which they are attached form a C3-6 cycloalkyl ring substituted with 0-2 R23;
  • R 23 are each independently selected from halogen, C 1-6 alkyl and C 1-6 alkoxy;
  • R 41 and R 42 are each independently selected from hydrogen and C 1-6 alkyl
  • R 51 and R 52 are each independently selected from hydrogen and C 1-6 alkyl
  • n is an integer from 2 to 5.
  • the compound can have a structural formula of formula IIa or formula IIb
  • R 1 , R 2 , R 3 , R 4 , R 5 , W, L and n are as defined above.
  • Z 1 is O or S.
  • R 4 is NR 41 R 42 , wherein R 41 is hydrogen and R 42 is C 1-3 alkyl. In one embodiment, R 4 is NR 41 R 42 , wherein R 41 is hydrogen and R 42 is methyl, that is, R 4 is methylamino.
  • R 5 is hydrogen or -NH 2 .
  • n is 2 or 3; each L is independently selected from -CR L1 RL2 -; wherein RL1 on each L is hydrogen, and RL2 on each L is independently selected from hydrogen and methyl.
  • RL1 on each L is hydrogen
  • RL2 on each L is independently selected from hydrogen and methyl.
  • only one RL2 in (L)n formed by n Ls is methyl.
  • n is 2 or 3;
  • L is independently selected from -CR L1 RL2 -, wherein RL1 on each L is hydrogen, and the two RL2 on two adjacent Ls together with the carbon atoms on the L to which they are connected form a C 3-6 cycloalkyl ring such as a cyclobutyl ring, a cyclopentyl ring, and the like.
  • n L forms (L)n selected from *-CH 2 CH 2 -**, *-CH 2 CH 2 CH 2 -**, *-CH(CH 3 )CH 2 -**, *-CH 2 CH(CH 3 )-**, *-CH(CH 3 )CH 2 CH 2 -**, or
  • * indicates the site of connection with the Z1 atom
  • ** indicates the site of connection with the O atom
  • W is N.
  • R 1 is hydrogen
  • R 2 is hydrogen or C 1-3 alkyl
  • R 3 is oxo.
  • W is C.
  • R 1 is hydrogen or halogen
  • R 2 is hydrogen or halogen
  • R 3 is a C 1-3 alkoxy group.
  • W is C, R 1 is hydrogen, R 2 is fluorine, and R 3 is methoxy.
  • W is C, R 1 is fluorine, R 2 is hydrogen, and R 3 is methoxy.
  • W is C, R 1 is hydrogen, R 2 is hydrogen, and R 3 is methoxy.
  • the C atom to which W and R 3 are attached is is a double bond, that is, the six-membered ring including the W atom is a benzene ring structure.
  • W is C
  • R 2 and R 3 together with the ring atoms to which they are attached form a 5-6 membered heteroaryl ring substituted with 0-2 R 23, such as a triazole ring, etc.
  • R 23 is selected from hydrogen or C 1-3 alkyl
  • * indicates the site of attachment to CH2
  • ** indicates the site of attachment to NH.
  • the disclosed compounds may have one of the following general formulas:
  • Z 2 is O.
  • R23 group on the triazole ring it can be or wherein R 23 is selected from hydrogen or C 1-3 alkyl,
  • * indicates the site of attachment to CH2
  • ** indicates the site of attachment to NH.
  • R 23 is methyl
  • * indicates the site of attachment to CH2
  • ** indicates the site of attachment to NH.
  • the compound is selected from the following compounds:
  • the present disclosure can prepare the compounds described in the present disclosure by the following methods.
  • the following methods and examples are intended to illustrate these methods. These processes and examples should not be construed as limiting the present disclosure in any way.
  • the compounds described herein can also be synthesized using standard synthetic techniques known to those skilled in the art, or a combination of methods known in the art and the methods described herein can be used.
  • Reactions described herein can be monitored by any suitable method known in the art.
  • product formation can be monitored by broad spectrum methods such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectroscopy, etc., or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • broad spectrum methods such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectroscopy, etc.
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • the present disclosure relates to a pharmaceutical composition, which comprises the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the compounds of the present disclosure have good TYK2 inhibitory activity, and in particular can act on the TYK2 JH2 pseudokinase domain, and are a TYK2 allosteric inhibitor with strong ability to pass through the blood-brain barrier and high selectivity, and can be used to regulate TYK2-mediated diseases. Therefore, the present disclosure also relates to the use of the above-mentioned compounds or their pharmaceutically acceptable salts, hydrates, solvates, active metabolites, polymorphs, isotope labels, isomers or prodrugs, and pharmaceutical compositions in the preparation of drugs for treating tyrosine kinase-mediated diseases.
  • the tyrosine kinase is selected from TYK2 kinase.
  • the tyrosine kinase-mediated diseases include inflammatory autoimmune diseases, tumors, neurodegenerative diseases, etc.
  • inflammatory autoimmune diseases mainly include atopic dermatitis, suppurative hidradenitis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, lupus erythematosus, central nervous system and other brain autoimmune diseases, etc.
  • tumors mainly include leukemia, lymphoma, myeloma, brain tumor and other cancers
  • neurodegenerative diseases mainly include brain atrophy, Alzheimer's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, etc.
  • the present disclosure also relates to a method for treating tyrosine kinase-mediated diseases, comprising administering a therapeutically effective amount of the above-mentioned compound of the present disclosure or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug, or pharmaceutical composition to a patient in need of administration.
  • Step B (R)-1-((4-methoxy-3-nitrobenzyl)oxy)propan-2-ol
  • Step C 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester
  • Step D Ethyl 6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate
  • Step E 6-Chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid
  • Step F (R)-1-((4-methoxy-3-nitrobenzyl)oxy)propan-2-yl 6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate
  • Step G (R)-1-((3-amino-4-methoxybenzyl)oxy)propan-2-yl 6-chloro-8-((4-methoxyphenyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate
  • Step H (7R,E)-3 6 -methoxy-1 8 -((4-methoxybenzyl)(methyl)amino)-7-methyl-5,8-dioxa-2-aza-1(6,3)-imidazo[1,2-b]pyridazin-3(1,3)-benzheterocyclononane-9-one
  • Step I (7R,E)-3 6 -methoxy-7-methyl-1 8 -(methylamino)-5,8-dioxa-2-aza-1(6,3)-imidazo[1,2-b]pyridazin-3(1,3)-benzheterocyclononane-9-one
  • Step A Ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step B Ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate
  • the phosphorus oxychloride was removed by vacuum concentration, and water was added to dilute it under an ice-water bath, and the pH was adjusted to neutral with a saturated sodium bicarbonate solution, and the product (17.0g, 70%) was obtained by extraction with dichloromethane and vacuum concentration.
  • Step C Ethyl 5-chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • reaction solution was cooled to room temperature, concentrated, diluted with water, extracted with dichloromethane, the combined organic phases were washed with water, dried over anhydrous sodium sulfate, and the residue was separated and purified by column chromatography to obtain the product (2.1g, 30%).
  • Step D 5-Chloro-7-[(4-methoxyphenyl)methyl](methyl)amino ⁇ pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
  • reaction solution was cooled to room temperature, concentrated, diluted with water, extracted with ethyl acetate, the combined organic phases were washed with water, dried over anhydrous sodium sulfate, and the residue was separated and purified by reverse phase C18 column to obtain the product (1.0g, 54%).
  • Step E (R)-1-((4-methoxy-3-nitrobenzyl)oxy)propan-2-yl 5-chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step F (R)-1-((3-amino-4-methoxybenzyl)oxy)propan-2-yl 5-chloro-7-((4-methoxyphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate
  • Step G (R, 13E , 14E ) -36 -methoxy- 17 -((4-methoxybenzyl)(methyl)amino)-7-methyl-5,8-dioxa-2-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(1,3)-benzanilidenonane-9-one
  • Step H (R, 13E , 14E ) -36 -methoxy-7-methyl- 17- (methylamino)-5,8-dioxa-2-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(1,3)-benzheterocyclononane-9-one
  • Example 1 The following examples were prepared by referring to the experimental routes and methods in Example 1 or Example 2:
  • control compound A Deucravacitinib and the test compound were diluted from 10 mmol/L stock solution to 0.2 mmol/L, i.e., 1.2 ⁇ L of the compound was added to 58.8 ⁇ L of DMSO, and then 4 times
  • the TYK2-JH2 experimental data were analyzed using GraphPad Prism 8 software, with the reading of the negative control (0.5% DMSO well) set as 0% inhibition rate, and the reading of the positive control (the well with the highest concentration of the control compound) set as 100% inhibition rate. After calculating the inhibition rate, the IC 50 values (half-maximal inhibition concentration) of the control compound and the test compound were obtained using the software's nonlinear fitting formula;
  • the compounds of the examples disclosed in the present invention have good enzymatic inhibitory activity against TYK2-JH2, and some of the compounds have an IC 50 of even ⁇ 5 nM, and have weaker inhibitory activity against JAK1-JH2, with an IC 50 of >5000 nM. Therefore, the compounds disclosed in the present invention are potent and more selective TYK2 (tyrosine kinase 2) allosteric inhibitors.
  • Buffer preparation Prepare an appropriate running buffer according to the situation.
  • Kinetic detection Choose the appropriate kinetic method, usually single-cycle kinetics or multi-cycle kinetics, set the Contact time, Dissociation time, and Flow rate according to the actual situation, set the concentration gradient of the analyte according to the possible KD value, and the instrument monitors the molecular interaction in real time.
  • test results show that the example compounds have high affinity for TYK2-JH2 and low affinity for JAK1-JH2, and have extremely high selectivity for the latter.
  • Example 2 Male SD rats were divided into groups, 3 in each group, and the compound of Example 2 (2 mg/kg) was intravenously injected and the compound of Example 2 and the control compound (10 mg/kg) were orally gavaged once. The animals were fasted overnight before the experiment, and fasted from 10 hours before administration to 4 hours after administration. Blood was collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after oral administration. After the animals were anesthetized with isoflurane, 0.3 mL of whole blood was collected through the fundus venous plexus and placed in a heparin anticoagulation tube.
  • the sample was centrifuged at 4°C and 4000 rpm for 5 minutes, and the plasma was transferred to a centrifuge tube and stored at -80°C until the sample was analyzed.
  • the sample in the plasma was extracted using a protein precipitation method, and the extract was analyzed by LC/MS/MS.
  • the pharmacokinetic results are shown in Tables 2 and 3 below:
  • Example 2 of the present disclosure has good bioavailability after oral administration, with a bioavailability of 57.1%, and its oral drug exposure is much better than that of the control compounds A and B.
  • the disclosed compounds are the first known class of highly selective TYK2 allosteric inhibitors with brain penetrating properties, and are also the structural type with the strongest brain penetrating ability among the reported molecular structures.
  • Deucravacitinib has the following structural formula
  • the reference compound A has the following structural formula and can be prepared according to the preparation method of Example 1 in document WO2022060973A1:
  • the reference compound B has the following structural formula and can be prepared according to the preparation method of Example 25 in document WO2020185755A1:

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Abstract

本公开涉及一种大环化合物、药物组合物及其用途，该化合物具有式I所示的结构式。该大环化合物是一种通过血脑屏障能力强且高选择性的TYK2变构抑制剂，可用于调节TYK2介导的疾病。

Description

一种大环化合物、药物组合物及其用途 技术领域
本公开申请提供一种大环化合物、药物组合物和用途，该大环化合物是一种通过血脑屏障能力强且高选择性的TYK2变构抑制剂，可用于调节TYK2介导的疾病。
背景技术
JAK家族在介导引起炎症的众多细胞因子的信号传导方面至关重要，其包括JAK1、JAK2、JAK3和TYK2。TYK2和JAK1/2/3通常成对工作，或称为“二聚体”，将细胞外细胞因子的信号传递到细胞核。TYK2选择性地参与促炎细胞因子如IL-23、IL-12和I型IFN信号的传递。因此，TYK2抑制剂可以成为各种严重炎症和自身免疫疾病的有效治疗手段。
JAK家族中的JAK1、JAK2、JAK3以及TYK2都有JAK同源结构域(JAK homology domain,JH)，其中JH1结构域也称为激酶域，JH2为假激酶域。最早出现的TYK2抑制剂如辉瑞的Brepocitinib等，均作用于JH1激酶催化结构域，即直接作用于ATP的结合口袋，由于JH1催化结构域高度的同源性，其对JAK家族其它成员的选择性有限，因而也难以避免JAK类抑制剂常见的心血管事件或静脉血栓栓塞等不良事件。
BMS的TYK2变构抑制剂Deucravacitinib，作用于TYK2 JH2假激酶域中的特异性口袋，以变构抑制的方式实现了对其他JAK家族成员以及整个激酶家族的高度选择性，降低了心血管事件或静脉血栓栓塞等不良事件的发生风险，Deucravacitinib也因此成为了首个上市不带黑框警告的口服JAK抑制剂。
然而，Deucravacitinib对JAK1的JH2结构域也有一定作用，存在因抑制JAK1所带来的不良事件的风险。开发一款对JAK1选择性更高的TYK2变构抑制剂，能进一步降低JAK1抑制带来的不良反应，为自身免疫性疾病带来更安全的治疗手段；同时，很多自身免疫性疾病进展到后期，会侵袭大脑，出现多灶或弥漫性脑损害等症状，目前能透脑的高选择性TYK2分子尚未见报道，临床药物急缺；此外，TYK2是针对一系列促炎细胞因子的STAT通路激活剂，抑制TYK2可能在减少包括帕金森氏病、阿尔茨海默氏病、肌萎缩性侧索硬化症和多发性硬化症等疾病在内的神经退行性疾病中的炎症方面发挥重要作用，因此开发一种选择性更好且通过血脑屏障能力较强的TYK2变构抑制剂来解决神经退行性疾病的药物是临床的迫切需求。
发明内容
本公开一方面提供如式I所示的化合物、其同位素异构体、或其药学上可接受的盐：
该化合物是一种通过血脑屏障能力强且高选择性的TYK2变构抑制剂，可用于调节TYK2介导的疾病。
本公开还涉及一种药物组合物，其包含本公开的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，以及药学可接受的载体。
本公开还涉及本公开公开的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，以及药物组合物在制备用于治疗酪氨酸激酶介导的疾病的用途。
本公开涉及一种治疗酪氨酸激酶介导的疾病的方法，包括将治疗有效量的本公开公开的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，或药物组合物，给药于需要给药的患者。
在一种实施方式中，所述酪氨酸激酶选自TYK2激酶。在一种实施方式中，所述酪氨酸激酶介导的疾病包括炎性自身免疫性疾病、肿瘤、神经退行性疾病，例如，炎性自身免疫性疾病选自特应性皮炎、化脓性汗腺炎、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎、红斑狼疮、硬皮病、自身免疫性脑病等；肿瘤选自白血病、淋巴瘤、骨髓瘤、脑瘤等癌症；神经退行性疾病选自脑萎缩、老年痴呆症、帕金森综合征、阿尔茨海默病、肌肉萎缩侧索硬化、多发性硬化症等。
具体实施方式
下面通过实施例对本公开进一步详细说明。通过这些说明，本公开的特点和优点将变得更为清楚明确。
在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
此外，下面所描述的本公开不同实施方式中涉及的技术特征只要彼此之间未构成冲突就可以相互结合。
定义
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人 员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本文发明主题做任何限制。在本公开中，必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其他形式，例如“包含”、“含”和“含有”并非限制性。
标准化学术语的定义可以在文献著作中找到，包括Carey和Sundberg的“Advanced Organic Chemistry 4th Ed,Vol A(2000)and B(2001),Plenum Press,New York。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、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及医学和药物化学等化学上的相关的命名和实验室操作和技术，是本领域技术人员已知的。标准技术可以用于化学合成，化学分析，药物制备，制剂，递药和患者的治疗。标准技术可以用于重组DNA，寡核苷酸合成，以及组织培养和转化(例如电穿孔、脂质传染法)。举例来说，可以使用附有生厂商提供的说明书的试剂盒，或者按照本领域公知的方法，或者按照本公开表述的方法，来实施反应和纯化技术。一般而言，前述技术和步骤可以通过本领域众所周知的和在各种一般文献或更具体文献中描述的常规方法来实施，这些文献在本公开中被引用和讨论。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。
术语“取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的即可。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本文所用Cm～n指该部分中具有m～n个碳原子。举例而言，所述“C1～8”基团是指该部分中具有1-8个碳原子，即基团包含1个碳原子，2个碳原子、3个碳原子……8个碳原子。因此，举例而言“C1～8烷基”是指含有1-8个碳原子的烷基，即所述烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基……辛基等。本文中的数字范围，例如“1-8”是指给定范围中的各个整数，例如“1-8个碳原子”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子或8个碳原子。
术语“元”是指构成环的骨架原子的个数。例如吡啶是六元环，吡咯是五元环。
在本公开中，各基团可以具有如下的定义：
氢可表示为-H，也可以替换为氘、氚等同位素。
卤素可包括氟、氯、溴、碘。
C1～8烷基可包括甲基、乙基、正丙基、异丙基、2-甲基-l-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-l-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-l-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-l-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、己基、庚基、辛基等。
氘代C1～8烷基、氚代C1～8烷基可以表示该C1～8烷基上的一个或多个甚至全部的氢原子替换为氘、氚等同位素。
C1～8烷氧基可表示为-OC1～8烷基，其中的C1～8烷基包括的基团如前定义；例如，C1～8烷氧基可包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。
C1～8卤代烷基可表示为C1～8烷基中的任意个数的氢原子被卤素取代后的基团，其中的C1～8烷基、卤素包括的基团如前定义；例如，C1～8卤代烷基可包括-CF3等。
C3～8环烷基可表示为非芳香的饱和碳环，包括单碳环(具有一个环)及双碳环(具有两个环)，例如，C3～8环烷基可包括等。
C3～8环烷基C1～8烷基可表示为带有C3～8环烷基的C1～8烷基，其中C3～8环烷基以及C1～8烷基的定义如上所述，例如C3～8环烷基C1～8烷基可包括环丙基甲基、环丁基甲基、环己基乙基等。
C3～8杂环基可表示为C3～8环烷基中的任意个数的环原子被O、S、N、P、Si等杂原子取代后所得的基团，其中的C3～8环烷基包括的基团如前定义。例如，C3～8杂环基可包括环氧乙烷基、环硫乙烷基、环氮乙烷基、吖丁啶基、噁丁环基、噻丁环基、四氢呋喃基、吡咯烷基、噁唑烷基、四氢吡唑基、吡咯啉基、二氢呋喃基、二氢噻吩基、哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、二氢吡啶基、四氢吡啶基、二氢吡喃基、四氢吡喃基、二氢噻喃基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧杂氮杂双环[2.2.1]庚基、氮杂螺[3.3]庚基等。
C6～20芳基可包括单环芳基、双环芳基或更多环芳基，例如，可包括苯基、联苯基、萘基、菲基、蒽基、薁基等。
C5～20杂芳基可表示含有任意个数的O、S、N、P、Si等杂原子作为环原子所得的不饱和基团。例如，C5～20杂芳基可包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。
羟基可表示为-OH。
巯基可表示为-SH。
羧基可表示为-COOH。
酯基可表示为-COOR’，R’可为C1～8烷基，例如C1～8烷基取代的酯基可表示为-COOC1～8烷基，其中的C1～8烷基包括的基团如前定义。
酰基可表示为-COR’，R’可为C1～8烷基，例如C1～8烷基取代的酰基可表示为-COC1～8烷基，其中的C1～8烷基包括的基团如前定义。
氨基可表示为-NH2、-NHR’或-N(R’)2，R’可为C1～8烷基，例如C1～8烷基取代的氨基可表示为-NHC1～8烷基或-N(C1～8烷基)2，其中的C1～8烷基包括的基团如前定义。
酰胺基可表示为-CO氨基，其中的氨基如前定义。
磺酰基可表示为-S(O)2R’，R’可为C1～8烷基，例如C1～8烷基取代的磺酰基可表示为-S(O)2C1～8烷基，其中的C1～8烷基包括的基团如前定义。
氰基可表示为-CN。
氧代可表示为(＝O)。
前述定义中，当碳原子数变化时，上述定义仅根据碳原子数变化而变化，不影响基团种类的定义；例如，“C1～5烷基”可包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基等前述“C1～8烷基”定义中符合碳原子数为1-5的所有基团。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。除特别指示外，本公开中的盐可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。金属盐的非限制性实例包括但不限于碱金属的盐，例如钠盐、钾盐等；碱土金属的盐，例如钙盐、镁盐、钡盐等；铝盐等。与有机碱形成的盐的非限制性实例包括但不限于与三甲胺、三乙胺、吡啶、甲基吡啶、2,6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己基胺等形成的盐。与无机酸形成的盐的非限制性实例包括但不限于与盐酸、氢溴酸、硝酸、硫酸、磷酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、乙酸、三氟乙酸、富马酸、草酸、苹果酸、马来酸、酒石酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲基苯磺酸等形成的盐。与碱性氨基酸形成的盐的非限制性实例包括但不限于与精氨酸、赖氨酸、鸟氨酸等形成的盐。与酸性氨基酸形成的盐的非限制性实例包括但不限于与天冬氨酸、谷氨酸等形成的盐。
药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“溶剂化物”是指本公开中的一个化合物与一个或多个溶剂分子形成的物理聚 集体，这个物理聚集体包括离子的不同程度和共价键，例如氢键。已证实这个溶剂化物可以被分离，例如，当晶体的晶格中混有一个或多个溶剂分子时。“溶剂化物”包括溶剂相和可分离的溶剂化物两部分。相应的溶剂化物例子有很多，包括乙醇溶剂化物、甲醇溶剂化物等。“水合物”是一种以水(H2O)分子为溶剂的溶剂化物。本公开中的一个或多个化合物都可以随意的制备成溶剂化物。溶剂化物的制备众所周知。例如M.Caira et al,J.Pharmaceutical Sci.,93(3),601-611(2004)中描述了抗真菌药氟康唑的溶剂化物的制备，即用乙酸乙酯和水制备。E.C.van Tonder et al,AAPS PharmSciTech.,5(1),article 12(2004)；和A.L.Bingham et al,Chem.Commun.,603-604(2001)中也描述了溶剂化物、水合物的类似制备方法。一种典型的、非限制性的制备过程是在高于常温的温度时将发明的化合物溶解于所需要量的理想溶剂中(有机溶剂或水或它们的混合溶剂)，降温，放置析晶，然后用标准的方法分离挑出晶体。用I.R.光谱学分析技术可以证实结晶中形成溶剂化物(水合物)的溶剂(水)的存在。
术语“活性代谢物”是指在化合物代谢时形成的该化合物的具有活性的衍生物。
术语“多晶型物”是指以不同的晶格形式存在的本公开化合物。
术语“同位素标记物”是指有同位素标记的本公开化合物。例如本公开的化合物中的同位素可包括H,C,N,O,P,F,S等元素的各种同位素,如2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F和36S。
术语“药学上可接受的前药”或“前药”是指本公开化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本公开的化合物或其具有药学活性的代谢物或残基。特别优选的衍生物或前药是在施用于患者时可以提高本公开化合物生物利用度的那些化合物(例如，可以使口服的化合物更易于被吸收到血液中)，或者促进母体化合物向生物器官或作用位点(例如脑部或淋巴系统)递送的那些化合物。可通过常规操作或在体内，按可分解为母体化合物的修饰方式，修饰存在于化合物中的官能团，制备前药。各种前药形式是本领域熟知的。参见，在T.Higuchi和V.Stella所著的Pro-drugs as Novel Delivery Systems(1987)Vol.14of the A.C.S.Symposium Series,Bioreversible Carriers in Drug Design,(1987)Edward B.Roche,ed.,American Pharmaceutical Association和在Pergamon Press中提供了有关前药的讨论。Design of Prodrugs,Bundgaard,A.Ed.,Elseview,1985and Method in Enzymology,Widder,K.et al.,Ed.；Academic,1985,vol.42,p.309-396；Bundgaard,H."Design and Application of Prodrugs"in A Textbook of Drug Design and Development,Krosgaard-Larsen and H.Bundgaard,Ed.,1991,第五章，113-191页；以及Bundgaard,H.,Advanced Drug Delivery Review,1992,8,1-38，以上文献通过引用并入本文。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。本公开化合物含有不对称或手性中心、双键等结构，因此，本公开的化合物可能包括光学异构体、几何异构体、互变异构体、阻转异构体等多种异构体形式，这些异构体及其单一异构体、外消旋体等等都包括在本公开的范围之内。例如，对于光学异构体而言，可以 通过手性拆分、手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。例如，可通过与适当的光学活性物质(例如手性醇或Mosher`s莫氏酰氯)反应转换为非对映异构体，将其分离并转化(如水解)为相对应的单一的异构体。再例如，还可通过色谱柱进行分离。
术语“药物组合物”是指任选的混合有至少一种药学上可接受的化学成分或试剂的生物活性化合物，所述药学上可接受的化学成分或试剂即为“载体”，其有助于将化合物引入到细胞或组织中，包括但不限于稳定剂、稀释剂、悬浮剂、增稠剂和/或赋形剂。
本文的“药物组合物”可按药剂领域中熟知的方式制备，并可通过多种途径给予或施用它们，这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如，透皮、皮肤、眼和粘膜包括鼻内、阴道和直肠递药)、肺(例如，通过吸入或吹入粉末或气雾剂，包括通过喷雾器；气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药，或可通过例如连续灌注泵给药。本文的药物组合物包括但不限于以下形式：片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒)；含例如高达10％重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末等。
本文的药物组合物可按单位剂型配制，每一剂量可含约0.1～1000mg，通常约5～1000mg活性成分，更通常约100～500mg活性成分。术语“单位剂型”是指物理上分离的适宜作为用于人患者和其它哺乳动物的单一剂量单位，各单位含有与适宜的药物载体混合的经计算可产生所需疗效的预定量的活性物质。
术语“个体”是指患有疾病、病症或病况等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实施例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。
术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状，预防其它症状，改善或预防导致症状的潜在代谢原因，抑制疾病或病症，例如阻止疾病或病症的发展，缓解疾病或病症，使疾病或病症好转，缓解由疾病或病症导致的症状，或者中止疾病或病症的症状，此外，该术语还可包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外，对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果，例如尽管患者可能仍然受到潜在疾病的影响，但观察到患者情况改善。就预防效果而言，可向具有患特定疾病风险的患者施用所述组合物或化合物，或者即便尚未做出疾病诊断，但向出现该疾病的一个或多个生理症状的患者施用所述组合物或化合物。
术语“获得必要的治疗效果的计量”或“治疗有效量”是指施用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。可使用诸如剂 量递增试验的技术测定适合于任意个体病例中的有效量。实际给予的化合物、药物组合物或药剂的量通常由医师根据相关情况决定，包括所治疗的病症、所选择的给药途径、所给予的实际化合物；患者个体的年龄、重量和反应；患者症状的严重程度等。
本公开化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)、给药途径等。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本公开化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。
术语“施用”是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,currented.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。
术语“IC50”是指在测量这样的效应的分析中获得最大效应的50％抑制。
为使本公开的目的、技术方案和优点更加清楚，下面将进一步描述本公开的示例性实施例的技术方案。
化合物
本公开提供一种如式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，
其中，X和Y选自N或C，且X和Y中之一为N，另一个为C；
W选自N或C；
Z1独立地选自O或S；
Z2选自O、S或NR，R为氢或C1-6烷基；
为单键或双键；
R1、R2和R3各自独立地选自氢、卤素、氧代、C1-6烷基和C1-6烷氧基；或者，R2 和R3与它们所连接的环原子一起形成取代有0-2个R23的5-6元杂芳基环；
R4选自NR41R42、C1-6烷基和C1-6烷氧基；
R5选自氢或NR51R52；
L各自独立地选自-CRL1RL2-；
各个L上的RL1和RL2各自独立地选自氢和C1-6烷基，或者相邻两个L上的两个RL2与它们所连接的L上的碳原子一起形成取代有0-2个R23的C3-6环烷基环；
R23各自独立地选自卤素、C1-6烷基和C1-6烷氧基；
R41和R42各自独立地选自氢和C1-6烷基；
R51和R52各自独立地选自氢和C1-6烷基；
n为2-5的整数。
在包含X和Y的五元环结构中，可以为单键或双键，不过根据X和Y的选择，该五元环中单键或双键需要使得该五元环结构为杂芳环结构。根据X和Y的选择，所述化合物可以具有式IIa或者式IIb的结构式
其中，R1、R2、R3、R4、R5、W、L和n的定义如前。
在以上式I、IIa和IIb中，当W为C原子，在W和R3所连接的C原子之间存在双键，即包含该W原子的六元环为苯环结构。
在一种实施方式中，Z1为O或者S。
在一种实施方式中，R4为NR41R42，其中，R41为氢，R42为C1-3烷基。在一种实施方式中，R4为NR41R42，其中，R41为氢，R42为甲基，即R4为甲氨基。
在一种实施方式中，R5为氢或者-NH2。
在一种实施方式中，n为2或3；L各自独立地选自-CRL1RL2-；其中，各个L上的RL1为氢，各个L上的RL2各自独立地选自氢和甲基。优选地，n个L形成的(L)n中有且仅有一个RL2为甲基。
在一种实施方式中，n为2或3；L各自独立地选自-CRL1RL2-，其中，各个L上的RL1为氢，相邻两个L上的两个RL2与它们所连接的L上的碳原子一起形成C3-6环烷基环例如环丁基环、环戊基环等。
在一种实施方式中，n个L形成的(L)n选自*-CH2CH2-**、*-CH2CH2CH2-**、 *-CH(CH3)CH2-**、*-CH2CH(CH3)-**、*-CH(CH3)CH2CH2-**、或者
其中，*表示与Z1原子连接的位点，**表示与O原子连接的位点。
在一种实施方式中，W为N。优选地，在W为N原子的实施方式中，R1为氢，R2为氢或C1-3烷基，R3为氧代。
在一种实施方式中，W为C。优选地，在W为C原子的实施方式中，R1为氢或卤素，R2为氢或卤素，R3为C1-3烷氧基。在一种实施方式中，W为C，R1为氢，R2为氟，R3为甲氧基。在一种实施方式中，W为C，R1为氟，R2为氢，R3为甲氧基。在一种实施方式中，W为C，R1为氢，R2为氢，R3为甲氧基。在以上实施方式中，在W和R3所连接的C原子之间的为双键，即包含该W原子的六元环为苯环结构。
在一种实施方式中，W为C，且R2和R3与它们所连接的环原子一起形成取代有0-2个R23的5-6元杂芳基环例如三唑环等。
在一种实施方式中，式I、IIa以及IIb结构中的
部分为
其中R23选自氢或者C1-3烷基，
*表示与CH2连接的位点，**表示与NH连接的位点。
由此，本公开化合物可以具有以下的通式之一：
其中各基团定义如上。
在以上式I-1中，优选地，Z2为O。
需要说明的是，在以上式I-1、IIa-1以及IIb-1中，R23基团在三唑环上的不同取代位置会使得苯并三唑结构中双键的位置会发生变化，只要苯并三唑环结构中的双键呈共轭双键的形式即可。
例如，根据R23基团在三唑环上的不同取代位置可以为 或者其中R23选自氢或C1-3烷基，
*表示与CH2连接的位点，**表示与NH连接的位点。
在一种实施方式中，为其中，R23为甲基；
*表示与CH2连接的位点，**表示与NH连接的位点。
在一种实施方式中，所述化合物选自以下的化合物：

本公开可以通过下述方法制备本公开所述的化合物。以下方法和实施例是为了说明这些方法。这些流程和实施例不应以任何方式被解释为对本公开的限制。也可使用本领域技术人员已知的标准合成技术合成本文所述的化合物，或者组合使用本领域已知方法和本文所述方法。
本公开实施例的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本公开的化学变化及其所需的试剂和物料。为了获得本公开的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本公开中的氨基)选择合适的保护基。对于经过训练的从业者来说，Greene and Wuts的(Protective Groups In Organic Synthesis,Wiley and Sons,1991)是这方面的权威。本公开引用的所有参考文献整体上并入本公开。
可按照本领域中已知的任何合适的方法监测本文中所述的反应。例如，可通过广谱方法例如核磁共振波谱(例如1H或13C)、红外光谱、分光光度测定(例如UV-可见光)、质谱等，或通过色谱例如高效液相色谱(HPLC)或薄层层析监测产物形成。
本公开通式I的化合物可以由有机合成领域技术人员通过以下流程用本领域的标准方法来制备：
化合物1与化合物2通过缩合反应生成化合物3，化合物3经过还原反应生成化合物4，化合物4发生分子内偶联反应得到本公开式I化合物。
药物组合物与应用
本公开涉及一种药物组合物，其包含本公开上述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，以及药学可接受的载体。
如本公开所证实的，本公开的化合物具有良好的TYK2抑制活性，特别是可以作用于TYK2 JH2假激酶域，是一种通过血脑屏障能力强且高选择性的TYK2变构抑制剂，可以用于调节TYK2介导的疾病。因此，本公开还涉及上述化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，以及药物组合物在制备用于治疗酪氨酸激酶介导的疾病的用途。
在一种实施方式中，所述酪氨酸激酶选自TYK2激酶。在一种实施方式中，所述酪氨酸激酶介导的疾病包括炎性自身免疫性疾病、肿瘤、神经退行性疾病等。其中炎性自身免疫性疾病主要有特应性皮炎、化脓性汗腺炎、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎、红斑狼疮、中枢神经系统等脑部自身免疫性疾病等；肿瘤主要有白血病、淋巴瘤、骨髓瘤、脑瘤等癌症；神经退行性疾病主要有脑萎缩、老年痴呆症、帕金森综合征、阿尔茨海默病、肌肉萎缩侧索硬化、多发性硬化症等。
本公开还涉及一种治疗酪氨酸激酶介导的疾病的方法，包括将治疗有效量的本公开上述化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，或药物组合物，给药于需要给药的患者。
通过具体的实施例更详细地说明本公开。为说明目的提供以下实施例，它们不应以任何方式限制本公开。本领域技术人员应容易认识到，可改变或修改多种非关键性参数，得到基本上相同的结果。按照一种或多种本文中所述的测定，发现以下实施例化合物是TYK2变构抑制剂。
实施例1：(7R,E)-36-甲氧基-7-甲基-18-(甲氨基)-5,8-二氧杂-2-氮杂-1(6,3)-咪唑并[1,2-b]哒嗪杂-3(1,3)-苯杂环壬烷-9-酮
合成路线：
步骤A：4-(溴甲基)-1-甲氧基-2-硝基苯
将10g(59.8mmol,1.0eq)1-甲氧基-4-甲基-2-硝基苯加入到150mL的四氯化碳中，置换氮气后加入10.7g(60.4mmol,1.01eq)N-溴代丁二酰亚胺和1.96g(12.0mmol,0.2eq)偶氮二异丁腈，加完后将反应体系移至80℃反应过夜。反应完全，冷却至室温，反应液浓缩，残余物加水稀释，混合液用二氯甲烷萃取。合并有机相用水洗，无水硫酸钠干燥， 减压浓缩。残余物用硅胶柱层析(PE:EA＝10:1～4:1)得到产物(13g,产率＝88％)。
步骤B：(R)-1-((4-甲氧基-3-硝基苄基)氧基)丙-2-醇
将5g(20.3mmol,1.0eq)4-溴甲基-1-甲氧基-2-硝基苯加入到50mL N,N-二甲基甲酰胺中，然后加入1.55g(20.3mmol,1.0eq)(R)-1,2-丙二醇，置换氮气后将反应体系降温至0℃后分批次加入0.73g(30.5mmol,1.5eq)60％氢化钠，加完后将反应体系移至室温反应两小时。反应完全，冰水浴下加水淬灭，用3M的盐酸溶液调pH至6～7，混合液用乙酸乙酯萃取。合并有机相用水洗，无水硫酸钠干燥，减压浓缩。残余物用硅胶柱层析(PE:EA＝5:1～4:1)得到产物(1.28g，产率＝27％)。
LC-MS：(M+H)+；m/z＝242.1
步骤C:8-溴-6-氯咪唑并[1,2-b]哒嗪-3-羧酸乙酯
将20g(96.0mmol,1.0eq)4-溴-6-氯哒嗪-3-胺加入到200mL乙醇中，然后加入23.1g(153.5mmol,1.6eq)2-氯-3-氧代丙酸乙酯，置换氮气后将反应体系移至80℃反应过夜。反应完全，减压蒸干溶剂，残余物用乙酸乙酯萃取。合并有机相用水洗，无水硫酸钠干燥，减压浓缩。残余物用硅胶柱层析(PE:EA＝6:1～5:1)得到产物(21g，产率＝72％)。
LC-MS：(M+H)+；m/z＝303.9
步骤D：6-氯-8-((4-甲氧基苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸乙酯
将10g(32.8mmol,1.0eq)8-溴-6-氯咪唑并[1,2-b]哒嗪-3-羧酸乙酯加入到100mL的1,4-二氧六环中，然后加入5.46g(36.1mmol,1.1eq)[(4-甲氧基苯基)甲基](甲基)胺和6.65g(65.7mmol,2.0eq)三乙胺，加完后置换氮气将反应体系移至90℃反应过夜。反应完全，冷却至室温，反应液浓缩，加水稀释，二氯甲烷萃取，合并有机相用水洗，无水硫酸钠干燥，减压浓缩得产物(12g,产率＝97％)。
LC-MS：(M+H)+；m/z＝375.1。
步骤E：6-氯-8-((4-甲氧基苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸
室温下，将5g(13.3mmol,1.0eq)6-氯-8-((4-甲氧基苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸乙酯加入到150mL四氢呋喃中，然后加入1.28g(53.4mmol,4.0eq)氢氧化锂(溶解于25mL水)，室温下搅拌过夜。使用1M的HCl溶液调节PH＝4，使用乙酸乙酯萃取水相，将合并的有机相用水洗,无水硫酸钠干燥，减压蒸干得到粗产物直接用于下一步。
LC-MS：(M+H)+；m/z＝347.1
步骤F：(R)-1-((4-甲氧基-3-硝基苄基)氧基)丙-2-基6-氯-8-((4-甲氧基苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-甲酸酯
将600mg(1.7mmol,1.0eq)6-氯-8-((4-甲氧基苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸加入到6mL二氯甲烷中，然后加入835mg(3.5mmol,2.0eq)(R)-1-((4-甲氧基-3-硝基苄基)氧基)丙-2-醇,428mg(2.1mmol,1.2eq)二环己基碳二亚胺和21mg(0.2mmol,0.1eq)N,N-4-二甲氨基吡啶，室温下搅拌过夜。减压蒸干溶剂，残余物用二氯甲烷萃取。合并有机相用水洗，无水硫酸钠干燥，减压浓缩。残余物用硅胶柱层析(PE:EA＝5:1～4:1)得到产物(1.1g，产率＝89％)。
LC-MS：(M+H)+；m/z＝570.2
步骤G:(R)-1-((3-氨基-4-甲氧基苄基)氧基)丙-2-基6-氯-8-((4-甲氧基苯基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-甲酸酯
将100mg(0.2mmol,1.0eq)(R)-1-((4-甲氧基-3-硝基苄基)氧基)丙-2-基6-氯-8-((4-甲氧基苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-甲酸酯加入到1mL四氢呋喃中的，然后加入0.1mL醋酸和115mg(1.8mmol,10eq)锌粉，室温下搅拌过夜。反应完全，减压蒸干溶剂，残余物用乙酸乙酯萃取。合并有机相用水洗，无水硫酸钠干燥，减压浓缩，得到粗 产物直接用于下一步。
LC-MS：(M+H)+；m/z＝540.2
步骤H：(7R,E)-36-甲氧基-18-((4-甲氧基苄基)(甲基)氨基)-7-甲基-5,8-二氧杂-2-氮杂-1(6,3)-咪唑并[1,2-b]哒嗪杂-3(1,3)-苯杂环壬烷-9-酮
在室温下，向10毫升反应瓶内加入原料(R)-1-((3-氨基-4-甲氧基苄基)氧基)丙-2-基6-氯-8-((4-甲氧基苯基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-甲酸酯(900mg,粗品)加入5mL1,4-二氧六环，再加入869mg(2.7mmol,2.0eq)碳酸铯和106mg(0.1mmol,0.1eq)二叔丁基[2,4,6-三(丙基-2-基)-[1,1'-联苯]-2-基]膦；2'-氨基-[1,1'-联苯]-2-基}甲磺酸钯酯立刻进行氮气置换，将反应瓶放在90℃下搅拌过夜。冷却，将反应混合物浓缩，加水稀释，用乙酸乙酯萃取，有机相合并，浓缩，残余物通过柱色谱分离纯化得到产物(170mg,25％)。
LC-MS：(M+H)+；m/z＝504.2
步骤I：(7R,E)-36-甲氧基-7-甲基-18-(甲氨基)-5,8-二氧杂-2-氮杂-1(6,3)-咪唑并[1,2-b]哒嗪杂-3(1,3)-苯杂环壬烷-9-酮
将160mg(0.3mmol,1.0eq)(7R,E)-36-甲氧基-18-((4-甲氧基苄基)(甲基)氨基)-7-甲基-5,8-二氧杂-2-氮杂-1(6,3)-咪唑并[1,2-b]哒嗪杂-3(1,3)-苯杂环壬烷-9-酮溶于3mL二氯甲烷溶，加入1mL盐酸(4M in 1,4-二氧六环)溶液，置于室温搅拌两小时.反应液浓缩，残余物通过高压制备液相分离纯化得到产物(8.8mg)。
LC-MS：(M+H)+；m/z＝384.2
1H-NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.21(s,1H),8.00(s,1H),7.26(d,J＝5.2Hz,1H),6.95(d,J＝8.0Hz,1H),6.70(d,J＝8.0,1H),6.33(s,1H),5.07-5.06(m,1H),4.63-4.51(m,2H),388(s,3H),3.68-3.60(m,2H),3.32(s,1H),2.87(d,J＝4.8Hz,3H),1.32(d,J＝6.4Hz,3H)。
实施例2：(R,13E,14E)-36-甲氧基-7-甲基-17-(甲氨基)-5,8-二氧杂-2-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶杂-3(1,3)-苯杂环壬烷-9-酮
合成路线：
步骤A：5,7-二羟基吡唑并[1,5-a]嘧啶-3-羧酸乙酯
室温下，将20.0g(129.0mmol,1.0eq)5-氨基-1H-吡唑-4-羧酸乙酯溶于200mL乙醇中，依次加入21.3g(387.1mmol,3.0eq)甲醇钠和31.0g(194.1mmol,1.5eq)丙二酸二甲酯,将反应液置于80℃下搅拌过夜。反应完全后，减压浓缩出去溶剂，加水稀释，有固体析出，过滤，滤饼烘干得产品(21.0g,73％)。
LC-MS：(M+H)+；m/z＝224.1
步骤B：5,7-二氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯
室温下，将21.0g(93.8mmol,1.0eq)5,7-二羟基吡唑并[1,5-a]嘧啶-3-羧酸乙酯溶于200mL乙腈中，依次加入22.2g(281.3mmol,3.0eq)吡啶和73g(469.1mmol,5.0eq)三氯氧磷,将反应液置于100℃下搅拌过夜。反应完全后，减压浓缩出去三氯氧磷，冰水浴下加入水稀释，饱和碳酸氢钠溶液调pH至中性，用二氯甲烷萃取，减压浓缩得产品(17.0g,70％)。
LC-MS：(M+H)+；m/z＝260.0
步骤C：5-氯-7-((4-甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯
将5g(19.2mmol,1.0eq)5,7-二氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯加入到100mL的1,4-二氧六环中，然后加入5.19g(21.1mmol,1.1eq)[(4-甲氧基苯基)甲基](甲基)胺和3.89g(38.4mmol,2.0eq)三乙胺，加完后置换氮气将反应体系移至90℃反应过夜。反应完全，冷却至室温，反应液浓缩，加水稀释，二氯甲烷萃取，合并有机相用水洗，无水硫酸钠干燥，残余物通过柱层析色谱分离纯化得到产物(2.1g,30％)。
LC-MS：(M+H)+；m/z＝375.1
步骤D：5-氯-7-[(4-甲氧基苯基)甲基](甲基)氨基}吡唑并[1,5-a]嘧啶-3-羧酸
将2.0g(5.3mmol,1.0eq)5-氯-7-((4-甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯加入到20mL的甲苯中，然后加入4.7g(8.0mmol,1.5eq)三丁基氧化锡，反应液置于100℃反应过夜。反应完全，冷却至室温，反应液浓缩，加水稀释，乙酸乙酯萃取，合并有机相用水洗，无水硫酸钠干燥，残余物通过反相C18柱分离纯化得到产物(1.0g,54％)。
LC-MS：(M+H)+；m/z＝347.1
步骤E：(R)-1-((4-甲氧基-3-硝基苄基)氧基)丙-2-基5-氯-7-((4-甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸酯
室温下，将1g(2.9mmol,1.0eq)5-氯-7-[(4-甲氧基苯基)甲基](甲基)氨基}吡唑并[1,5-a]嘧啶-3-羧酸溶于20mL二氯甲烷中，依次加入1.39g(5.8mmol,2.0eq)(2R)-1-[(4-甲氧基-3-硝基苯基)甲氧基]丙醇，0.71g(3.5mmol,1.2eq)N,N'-二环己基碳二亚胺和40mg(0.3mmol,0.1eq)4-二甲氨基吡啶,将反应液置于室温下搅拌过夜。反应完全后加入水稀释，混合液用二氯甲烷萃取，将有机相合并，硫酸钠干燥，减压浓缩，残余物通过柱层析分离纯化得到淡黄色油状产品(1.5g,73％)。
LC-MS：(M+H)+；m/z＝570.2
步骤F：(R)-1-((3-氨基-4-甲氧基苄基)氧基)丙-2-基5-氯-7-((4-甲氧基苯基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸酯
室温下，将1.4g(2.0mmol,1.0eq)(R)-1-((4-甲氧基-3-硝基苄基)氧基)丙-2-基5-氯-7-((4-甲氧基苄基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸酯溶于20mL四氢呋喃，依次加入2mL醋酸和1.28g(19.7mmol,10eq)锌粉。将反应液置于室温下搅拌过夜。反应完全后，将锌粉过滤，滤液用水稀释，乙酸乙酯萃取，合并有机相用水洗，硫酸钠干燥，减压浓缩得产品(1.4g,粗品)。
LC-MS：(M+H)+；m/z＝540.2
步骤G：(R,13E,14E)-36-甲氧基-17-((4-甲氧基苄基)(甲基)氨基)-7-甲基-5,8-二氧杂-2-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶杂-3(1,3)-苯杂环壬烷-9-酮
室温下，将1.3g(粗品)(R)-1-((3-氨基-4-甲氧基苄基)氧基)丙-2-基5-氯-7-((4-甲氧基苯基)(甲基)氨基)吡唑并[1,5-a]嘧啶-3-羧酸酯溶于15mL 1,4-二氧六环，依次加入1.18g (3.6mmol,2.0eq)碳酸铯，140mg(0.2mmol,0.1eq)二叔丁基[2,4,6-三(丙基-2-基)-[1,1'-联苯]-2-基]膦；2'-氨基-[1,1'-联苯]-2-基}甲磺酸钯酯,置换氮气，将反应液置于90℃下搅拌6小时。冷却，减压浓缩，残余物加水稀释，用乙酸乙酯萃取，合并有机相用水洗，无水硫酸钠干燥，减压浓缩，残余物通过柱层析色谱分离纯化得到淡黄色固体产品(750mg,74％)。
LC-MS：(M+H)+；m/z＝504.2
步骤H：(R,13E,14E)-36-甲氧基-7-甲基-17-(甲氨基)-5,8-二氧杂-2-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶杂-3(1,3)-苯杂环壬烷-9-酮
将650mg(1.3mmol,1.0eq)(R,13E,14E)-36-甲氧基-17-((4-甲氧基苄基)(甲基)氨基)-7-甲基-5,8-二氧杂-2-氮杂-1(5,3)-吡唑并[1,5-a]嘧啶杂-3(1,3)-苯杂环壬烷-9-酮溶于10mL二氯甲烷，加入3mL盐酸(4M in 1,4-二氧六环)溶液，置于室温搅拌两小时。反应完全后减压浓缩，粗产物通过高压液相制备分离纯化得到产品(96.8mg,20％)。
LC-MS：(M+H)+；m/z＝384.2
1H-NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.71(s,1H),8.23(s,1H),7.70(d,J＝4.8Hz,1H),6.95(d,J＝8.4Hz,1H),6.75(d,J＝8.0Hz,1H),6.06(s,1H),4.87(t,J＝5.2Hz,1H),4.60-4.52(m,2H),3.87(s,3H),3.66-3.61(m,2H),3.32(s,2H),2.90(d,J＝4.8Hz,3H),1.32(d,J＝6.4Hz,3H)。
以下实施例参照实施例1或实施例2中实验路线与方法进行制备：




生物活性与药代动力学实验
1、化合物TYK2-JH2和JAK1-JH2酶学活性(IC50)检测实验
将对照化合物A、Deucravacitinib和待测化合物从10mmol/L储液稀释到0.2mmol/L，即取1.2μL的化合物加入58.8μL的DMSO中，然后开始4倍
稀释，10个浓度；使用Echo转移50nL待测物到384反应板中,每个化合物两个复孔，1000rpm，离心1分钟，DMSO终浓度均为0.5％。添加5μL TYK2(或JAK1)到384反应板中，1000rpm离心1分钟，25℃孵育10分钟。添加5μL JH2 probe1到384反应板中，1000rpm离心1分钟，25℃孵育60分钟。用BMG高通量药筛多功能酶标仪读FP 520/48信号。
用GraphPad Prism 8软件对TYK2-JH2实验数据进行分析，将阴性对照(0.5％ DMSO孔)的读值设为0％抑制率，阳性对照(对照化合物最高浓度孔)的读值设为100％抑制率，计算抑制率后，利用软件非线性拟合公式得到对照化合物以及待测化合物的IC50值(半数抑制浓度)；
阳性对照孔数值的平均值
阴性对照孔数值的平均值
具体IC50检测结果如下表1所示：
表1实施例化合物的IC50检测结果
由表中数据可见：本公开的实施例化合物对TYK2-JH2均有很好的酶学抑制活性，其中一部分化合物IC50甚至<5nM，对JAK1-JH2抑制活性较弱，IC50>5000nM。因此本公开化合物为一种强效的更高选择性的TYK2(酪氨酸激酶2)变构抑制剂。
2、化合物对JAK1-JH2以及TYK2-JH2亲和力(Kd)试验
1)Buffer配制：根据情况配制适用的running buffer。
2)预富集：采用CM5芯片偶联配体,对TYK2/JAK1偶联条件摸索。
3)配体偶联：在芯片上固定合适量的TYK2/JAK1。
4)动力学检测：选择合适的动力学方法通常为single-cycle kinetics或multi-cycle kinetics，根据实际情况设定Contact time和Dissociation time，Flow rate，依据可能的KD值设置分析物的浓度梯度，仪器实时监测分子互作情况。
5)数据分析：用Biacore Insight Evaluation Software软件对TYK2实验数据进行分析，软件自动拟合TYK2-JH2与JAK1-JH2结合的Kd值。
试验结果显示，实施例化合物对TYK2-JH2亲和力高，对JAK1-JH2亲和力低，其对后者有极高的选择性。
3、药代动力学试验
将雄性SD大鼠分组，每组3只，分别静脉注射实施例2化合物(2mg/kg)和口服单次灌胃实施例2化合物和对照化合物(10mg/kg)。动物在实验前禁食过夜，禁食前从给药前10小时至给药后4小时。静脉注射给药后0.0833、0.25、0.5、1、2、4、6、8和24小时采血，口服给药后0.25、0.5、1、2、4、6、8和24小时采血。动物经异氟烷麻醉后通过眼底静脉丛采取0.3mL全血，放于肝素抗凝管中，样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直至样品分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC/MS/MS分析。药代动力学结果如下表2和3所示：
表2实施例2化合物在静脉给药后在大鼠血浆中的药物动力学参数
表3实施例2化合物在口服给药后在大鼠血浆中的药物动力学参数

由表中数据可见：本公开实施例2化合物经口服给药后有较好的生物利用度，生物利用度为57.1％，其口服药物暴露量远优于对照化合物A和B。
4、血脑分布实验
将雄性SD大鼠分组，每组3只，分别口服单次灌胃(PO)给予药物化合物(10mg/kg)或者单次静脉注射(IV)给予药物化合物(2mg/kg)。动物在实验前禁食过夜，禁食从给药前10小时至给药后4小时。每只大鼠PO给药后0.5小时处死(IV给药后5分钟处死)并采集血与脑组织，样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直至样品分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC/MS/MS分析。数据显示本公开实施例化合物具有出乎意料的通过血脑屏障能力。
如表4所示，在口服给药0.5h后，实施例2化合物的药物浓度脑/血比达到5.08，其透脑能力出人意料，而Deucravacitinib和对照化合物A透脑率极低。
表4实施例2大鼠口服给药0.5h后药物浓度的血脑比
进行类似的测试，其他实施例化合物也具备出乎意料的极高的药物浓度脑/血比
表5不同实施例给药后药物浓度的血脑比
本公开化合物是目前已知的首类具备透脑性能的高选择性TYK2变构抑制剂，也是见于报道的分子结构中透脑能力最强的结构类型。
在本公开中，用作对比的Deucravacitinib、对照化合物A以及对照化合物B的性质如下：
Deucravacitinib具有如下的结构式
对照化合物A具有如下的结构式，可以根据文献WO2022060973A1中的Example1的制备方法制备：
对照化合物B具有如下的结构式，可以根据文献WO2020185755A1中的Example 25的制备方法制备：
以上结合了优选的实施方式对本公开进行了说明，不过这些实施方式仅是范例性的，仅起到说明性的作用。在此基础上，可以对本公开进行多种替换和改进，这些均落入本公开的保护范围内。

Claims (26)

  1. 一种如式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，
    其中，X和Y选自N或C，且X和Y中之一为N，另一个为C；
    W选自N或C；
    Z1独立地选自O或S；
    Z2选自O、S或NR，R为氢或C1-6烷基；
    为单键或双键；
    R1、R2和R3各自独立地选自氢、卤素、氧代、C1-6烷基和C1-6烷氧基；或者，R2和R3与它们所连接的环原子一起形成取代有0-2个R23的5-6元杂芳基环；
    R4选自NR41R42、C1-6烷基和C1-6烷氧基；
    R5选自氢或NR51R52；
    L各自独立地选自-CRL1RL2-；
    各个L上的RL1和RL2各自独立地选自氢和C1-6烷基，或者相邻两个L上的两个RL2与它们所连接的L上的碳原子一起形成取代有0-2个R23的C3-6环烷基环；
    R23各自独立地选自卤素、C1-6烷基和C1-6烷氧基；
    R41和R42各自独立地选自氢和C1-6烷基；
    R51和R52各自独立地选自氢和C1-6烷基；
    n为2-5的整数。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    所述化合物具有式IIa或者式IIb的结构式
    其中，R1、R2、R3、R4、R5、W、L和n的定义如权利要求1。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    Z1为O或S。
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    R4为NR41R42，其中，R41为氢，R42为C1-3烷基。
  5. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    R4为NR41R42，其中，R41为氢，R42为甲基。
  6. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    R5为氢或者-NH2。
  7. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    n为2或3；
    L各自独立地选自-CRL1RL2-；其中，各个L上的RL1为氢，各个L上的RL2各自独立地选自氢和甲基。
  8. 根据权利要求7所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    n个L形成的(L)n中有且仅有一个RL2为甲基。
  9. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    n为2或3；
    L各自独立地选自-CRL1RL2-，其中，各个L上的RL1为氢，相邻两个L上的两个RL2与它们所连接的L上的碳原子一起形成C3-6环烷基环。
  10. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    n个L形成的(L)n选自*-CH2CH2-**、*-CH2CH2CH2-**、*-CH(CH3)CH2-**、*-CH2CH(CH3)-**、*-CH(CH3)CH2CH2-**、或者
    其中，*表示与Z1原子连接的位点，**表示与O原子连接的位点。
  11. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    n个L形成的(L)n为*-CH(CH3)CH2-**；
    或者，n个L形成的(L)n为
    其中，*表示与Z1原子连接的位点，**表示与O原子连接的位点。
  12. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    W为N，R1为氢，R2为氢或C1-3烷基，R3为氧代。
  13. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    W为C，R1为氢或卤素，R2为氢或卤素，R3为C1-3烷氧基。
  14. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    W为C，在W和R3所连接的C原子之间的为双键，R1为氢，R2为氟，R3为甲氧基。
  15. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    W为C，在W和R3所连接的C原子之间的为双键，R1为氟，R2为氢，R3为甲氧基。
  16. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    W为C，在W和R3所连接的C原子之间的为双键，R1为氢，R2为氢，R3为甲氧基。
  17. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，式I、式IIa或者式IIb中的 部分为其中R23选自氢或C1-3烷基，*表示与CH2连接的位点，**表示与NH连接的位点。
  18. 根据权利要求17所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，为或者
    其中R23选自氢或C1-3烷基，
    *表示与CH2连接的位点，**表示与NH连接的位点。
  19. 根据权利要求17所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    为
    其中，R23为甲基；
    *表示与CH2连接的位点，**表示与NH连接的位点。
  20. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，其中，
    所述化合物选自以下的化合物：
  21. 一种药物组合物，其包含权利要求1-20中任一项所述的化合物或其药学上可接 受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，以及药学可接受的载体。
  22. 权利要求1-20中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，以及权利要求18所述的药物组合物在制备用于治疗酪氨酸激酶介导的疾病的用途。
  23. 根据权利要求22所述的用途，其中，所述酪氨酸激酶选自TYK2激酶。
  24. 根据权利要求22所述的用途，其中，所述酪氨酸激酶介导的疾病包括炎性自身免疫性疾病、肿瘤、神经退行性疾病。
  25. 根据权利要求22所述的用途，其中，炎性自身免疫性疾病选自特应性皮炎、化脓性汗腺炎、银屑病、银屑病关节炎、克罗恩病、溃疡性结肠炎、红斑狼疮、硬皮病、自身免疫性脑病等；肿瘤选自白血病、淋巴瘤、骨髓瘤、脑瘤等癌症；神经退行性疾病选自脑萎缩、老年痴呆症、帕金森综合征、阿尔茨海默病、肌肉萎缩侧索硬化、多发性硬化症等。
  26. 一种治疗酪氨酸激酶介导的疾病的方法，包括将治疗有效量的权利要求1-20任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、活性代谢物、多晶型物、同位素标记物、异构体或前药，或权利要求21所述的药物组合物，给药于需要给药的患者。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019206069A1 (zh) * 2018-04-25 2019-10-31 北京普祺医药科技有限公司 一种二芳基巨环化合物、药物组合物以及其用途
CN113811534A (zh) * 2019-03-11 2021-12-17 埃斯克疗法股份有限公司 Tyk2抑制剂和其用途
CN113874021A (zh) * 2019-03-26 2021-12-31 温缇克斯生物科学公司 Tyk2假激酶配体
WO2022060973A1 (en) * 2020-09-16 2022-03-24 Alumis, Inc. Tyk2 inhibitors and uses thereof
WO2022171139A1 (zh) * 2021-02-10 2022-08-18 北京国鸿生物医药科技有限公司 一种巨环化合物、药物组合物以及其用途
WO2023178235A1 (en) * 2022-03-16 2023-09-21 Alumis Inc. Tyk2 inhibitors and uses thereof
WO2023178234A1 (en) * 2022-03-16 2023-09-21 Alumis Inc. Tyk2 inhibitors and uses thereof
WO2023208244A1 (zh) * 2022-04-29 2023-11-02 南京明德新药研发有限公司 大环类化合物及其应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019206069A1 (zh) * 2018-04-25 2019-10-31 北京普祺医药科技有限公司 一种二芳基巨环化合物、药物组合物以及其用途
CN113811534A (zh) * 2019-03-11 2021-12-17 埃斯克疗法股份有限公司 Tyk2抑制剂和其用途
CN113874021A (zh) * 2019-03-26 2021-12-31 温缇克斯生物科学公司 Tyk2假激酶配体
WO2022060973A1 (en) * 2020-09-16 2022-03-24 Alumis, Inc. Tyk2 inhibitors and uses thereof
WO2022171139A1 (zh) * 2021-02-10 2022-08-18 北京国鸿生物医药科技有限公司 一种巨环化合物、药物组合物以及其用途
WO2023178235A1 (en) * 2022-03-16 2023-09-21 Alumis Inc. Tyk2 inhibitors and uses thereof
WO2023178234A1 (en) * 2022-03-16 2023-09-21 Alumis Inc. Tyk2 inhibitors and uses thereof
WO2023208244A1 (zh) * 2022-04-29 2023-11-02 南京明德新药研发有限公司 大环类化合物及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG, KUOJUN ET AL.: "Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 66, no. 7, 23 March 2023 (2023-03-23), pages 4378 - 4416, XP093093077, DOI: 10.1021/acs.jmedchem.2c01800 *

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