Macrocyclic compound, pharmaceutical composition and application thereof

Abstract

The invention relates to a macrocyclic compound, a pharmaceutical composition and application of the macrocyclic compound. The macrocyclic compound has a structural formula as shown in a formula I. The macrocyclic compound is a TYK2 allosteric inhibitor with high blood brain barrier passing ability and high selectivity, and can be used for regulating TYK2 mediated diseases.

Description

Macrocyclic compound, pharmaceutical composition and use thereof Technical Field

[0001] 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. Background Art

[0002] The JAK family, which includes JAK1, JAK2, JAK3, and TYK2, is crucial in mediating the signaling of numerous cytokines that cause inflammation. TYK2 and JAK1 / 2 / 3 typically work in pairs, or "dimers," to transmit extracellular cytokine signals to the cell nucleus. TYK2 selectively participates in the signaling of proinflammatory cytokines such as IL-23, IL-12, and type I interferon (IFN). Therefore, TYK2 inhibitors could be effective treatments for a variety of severe inflammatory and autoimmune diseases.

[0003] JAK1, JAK2, JAK3, and TYK2 in the JAK family all share a JAK homology domain (JH). The JH1 domain is also known as the kinase domain, while JH2 is a pseudokinase domain. Early TYK2 inhibitors, such as Pfizer's Brepocitinib, target the JH1 kinase catalytic domain, directly acting on the ATP-binding pocket. However, due to the high homology of the JH1 catalytic domain, selectivity against other JAK family members is limited, making it difficult to avoid adverse events such as cardiovascular events and venous thromboembolism, which are common with JAK inhibitors.

[0004] BMS's TYK2 allosteric inhibitor 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.

[0005] However, deucravacitinib also has a certain effect on the JH2 domain of JAK1, which carries the risk of adverse events associated with JAK1 inhibition. Developing a TYK2 allosteric inhibitor with greater selectivity for JAK1 could further reduce the adverse reactions associated with JAK1 inhibition, providing a safer treatment for autoimmune diseases. Furthermore, many autoimmune diseases progress to the late stages and invade the brain, presenting symptoms such as multifocal or diffuse brain damage. Currently, highly selective TYK2 molecules that can penetrate the brain have not been reported, and clinical drugs are urgently needed. Furthermore, TYK2 is a STAT pathway activator targeting a range 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, developing a TYK2 allosteric inhibitor with improved selectivity and the ability to cross the blood-brain barrier to address neurodegenerative diseases is an urgent clinical need.

[0006] Summary of the Invention

[0007] In one aspect, the present disclosure provides a compound as shown in Formula I, an isotope isomer thereof, or a pharmaceutically acceptable salt thereof:

[0008] This 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.

[0009] The present disclosure also relates to a pharmaceutical composition comprising a 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.

[0010] The present disclosure also relates to the use of the compounds disclosed herein or pharmaceutically acceptable salts, hydrates, solvates, active metabolites, polymorphs, isotope-labeled substances, isomers or prodrugs thereof, and pharmaceutical compositions for the preparation of drugs for treating tyrosine kinase-mediated diseases.

[0011] The present disclosure relates to a method for treating tyrosine kinase-mediated diseases, comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled compound, isomer or prodrug thereof, or a pharmaceutical composition thereof, to a patient in need of administration.

[0012] In one embodiment, the tyrosine kinase is selected from TYK2 kinase. In one embodiment, the tyrosine kinase-mediated disease includes inflammatory autoimmune diseases, tumors, and neurodegenerative diseases. For example, the inflammatory autoimmune disease is selected from atopic dermatitis, hidradenitis suppurativa, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, lupus erythematosus, scleroderma, and autoimmune encephalopathy; the tumor is selected from leukemia, lymphoma, myeloma, brain tumor, and other cancers; and the neurodegenerative disease is selected from brain atrophy, Alzheimer's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis. DETAILED DESCRIPTION

[0013] The present disclosure is further described in detail below through examples, through which the features and advantages of the present disclosure will become more clear and distinct.

[0014] The word “exemplary” is used exclusively herein to mean “serving as an example, example, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0015] In addition, the technical features involved in different embodiments of the present disclosure described below can be combined with each other as long as they do not conflict with each other.

[0016] definition

[0017] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. When trade names appear in this document, they are intended to refer to the corresponding commercial products or their active ingredients.

[0018] It should be understood that the foregoing brief description and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the present invention in any way. In this disclosure, it must be noted that, unless otherwise clearly indicated, the singular forms used in this specification and claims include the plural forms of the referents. It should also be noted that, unless otherwise indicated, the use of "or" and "or" means "and / or". In addition, the use of the term "include" and other forms, such as "comprises", "includes" and "comprising" are not limiting.

[0019] Definitions of standard chemical terms can be found in the literature, including Advanced Organic Chemistry by Carey and Sundberg. thEd, Vol A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacological methods, are employed. Unless specifically defined, nomenclature and laboratory procedures and techniques in analytical chemistry, organic synthetic chemistry, and medicinal and pharmaceutical chemistry are known to those skilled in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, drug delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid filtration). For example, reactions and purification techniques can be performed using kits with manufacturer's instructions, or according to methods known in the art, or as described in this disclosure. In general, the aforementioned techniques and steps 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.

[0020] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2.

[0021] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0022] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0023] The C m～n It means that there are m to n carbon atoms in the part. For example, the “C 1～8 " group means that the part has 1-8 carbon atoms, that is, the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms...8 carbon atoms. Therefore, for example, "C 1～8"Alkyl" refers to an alkyl group containing 1 to 8 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl...octyl, etc. The numerical ranges herein, such as "1-8", refer to each integer in the given range, for example, "1-8 carbon atoms" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms or 8 carbon atoms.

[0024] The term "membered" refers to the number of atoms that make up the ring. For example, pyridine is a six-membered ring, and pyrrole is a five-membered ring.

[0025] In the present disclosure, each group may have the following definitions:

[0026] Hydrogen can be represented as -H, or it can be replaced by isotopes such as deuterium and tritium.

[0027] Halogen may include fluorine, chlorine, bromine, and iodine.

[0028] C 1～8 The alkyl group may include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-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 like.

[0029] Deuterated C 1～8 Alkyl, tritiated C 1～8 Alkyl can represent the C 1～8 One or more or even all hydrogen atoms on the alkyl group are replaced by isotopes such as deuterium and tritium.

[0030] C 1～8 Alkoxy can be represented by -OC 1～8 Alkyl, where C 1～8 Alkyl groups include those defined above; for example, C 1～8 Alkoxy groups may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0031] C 1～8 Halogenated alkyl can be represented by C 1～8 A group in which any number of hydrogen atoms in an alkyl group are replaced by halogens, wherein C 1～8 The groups included in alkyl and halogen are as defined above; for example, C1～8 The haloalkyl group may include -CF3 and the like.

[0032] C 3～8 Cycloalkyl can be represented by a non-aromatic saturated carbocyclic ring, including monocarbocyclic rings (having one ring) and bicarbocyclic rings (having two rings), for example, C 3～8 Cycloalkyl groups may include wait.

[0033] C 3～8 Cycloalkyl C 1～8 Alkyl groups can be represented by C 3～8 Cycloalkyl C 1～8 Alkyl, where C 3～8 Cycloalkyl and C 1～8 The definition of alkyl is as above, for example, C 3～8 Cycloalkyl C 1～8 The alkyl group may include cyclopropylmethyl, cyclobutylmethyl, cyclohexylethyl, and the like.

[0034] C 3～8 Heterocyclic groups can be represented by C 3～8 A group obtained by replacing any number of ring atoms in a cycloalkyl group with heteroatoms such as O, S, N, P, or Si, wherein C 3～8 The groups included in the cycloalkyl group are as defined above. For example, C 3～8 Heterocyclyl groups can include oxiranyl, thioranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepanyl, oxetanyl, thiepanyl, oxazabicyclo[2.2.1]heptyl, azaspiro[3.3]heptyl, and the like.

[0035] C 6～20 The aryl group may include a monocyclic aryl group, a bicyclic aryl group, or a polycyclic aryl group, and may include, for example, phenyl, biphenyl, naphthyl, phenanthrenyl, anthracenyl, azulenyl, and the like.

[0036] C 5～20 Heteroaryl can represent an unsaturated group containing any number of heteroatoms such as O, S, N, P, Si as ring atoms. 5～20 Heteroaryl groups can include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0037] The hydroxyl group can be represented as -OH.

[0038] A mercapto group can be represented as -SH.

[0039] The carboxyl group can be represented as -COOH.

[0040] The ester group can be represented by -COOR', where R' can be C 1～8 Alkyl groups, such as C 1～8 Alkyl substituted ester groups can be represented as -COOC 1～8 Alkyl, where C 1～8 Alkyl groups include groups as defined above.

[0041] Acyl can be represented by -COR', R' can be C 1～8 Alkyl groups, such as C 1～8 Alkyl substituted acyl can be represented as -COC 1～8 Alkyl, where C 1～8 Alkyl groups include groups as defined above.

[0042] Amino groups can be represented by -NH2, -NHR' or -N(R')2, where R' can be C 1～8 Alkyl groups, such as C 1～8 Alkyl-substituted amino groups can be represented by -NHC 1～8 Alkyl or -N(C 1～8 Alkyl)2, wherein C 1～8 Alkyl groups include groups as defined above.

[0043] The amide group may be represented by -COamino, wherein the amino group is as defined above.

[0044] Sulfonyl can be represented by -S(O)2R', where R' can be C 1～8 Alkyl groups, such as C 1～8 Alkyl substituted sulfonyl can be represented by -S(O)2C 1～8 Alkyl, where C 1～8 Alkyl groups include groups as defined above.

[0045] A cyano group can be represented as -CN.

[0046] Oxo can be represented as (=O).

[0047] In the above definition, when the number of carbon atoms changes, the above definition changes only according to the change in the number of carbon atoms and does not affect the definition of the group type; for example, "C 1～5 The "alkyl" may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, etc. 1～8 The term "alkyl" is defined as any group having 1 to 5 carbon atoms.

[0048] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are 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.

[0049] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy of the free acid and free base of the specified compound and has no adverse biological or other effects. Unless otherwise indicated, the 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. Non-limiting examples of 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.

[0050] Pharmaceutically acceptable salts can be synthesized from parent compounds containing acid or basic groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0051] The term "solvate" refers to a physical aggregate formed by a compound of the present disclosure and one or more solvent molecules, which includes varying degrees of ionic and covalent bonds, such as hydrogen bonds. It has been shown that such solvates can be isolated, for example, when one or more solvent molecules are mixed in the crystal lattice. A "solvate" includes two parts: a solvent phase and a separable solvate. There are many examples of corresponding solvates, including ethanol solvates, methanol solvates, etc. A "hydrate" is a solvate with water (H2O) molecules as the solvent. One or more compounds of the present disclosure can be prepared as a solvate at will. The preparation of solvates is well known. For example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of a solvate of the antifungal drug fluconazole, which was prepared using ethyl acetate and water. Similar preparation methods for solvates and hydrates are also described in EC van Tonder et al, AAPS Pharm Sci Tech., 5(1), article 12 (2004); and AL Bingham et al, Chem. Commun., 603-604 (2001). 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 mixture thereof) at a temperature above room temperature, cool the solution, allow the solution to crystallize, and then separate and select the crystals using standard methods. IR spectroscopy can be used to confirm the presence of the solvent (water) that forms the solvate (hydrate) in the crystals.

[0052] The term "active metabolite" refers to an active derivative of a compound that is formed when the compound is metabolized.

[0053] The term "polymorph" refers to compounds of the present disclosure that exist in different crystal lattice forms.

[0054] The term "isotope-labeled compound" refers to a compound of the present disclosure that is isotopically labeled. For example, the isotopes in the compounds of the present disclosure may include various isotopes of elements such as H, C, N, O, P, F, and 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.

[0055] The term "pharmaceutically acceptable prodrug" or "prodrug" refers to any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present disclosure that, upon administration to a recipient, 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 that increase the bioavailability of a compound of the present disclosure when administered to a patient (e.g., by making an orally administered compound more readily absorbed into the blood), or that promote the delivery of the parent compound to biological organs or sites of action (e.g., the brain or lymphatic system). Prodrugs can be prepared by modifying functional groups present in a compound, either by conventional manipulation or in vivo, in a manner that allows for decomposition to the parent compound. 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 ACSSymposium Series, Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and in Pergamon Press. Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and 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, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, the above documents are incorporated herein by reference.

[0056] The term "stereoisomer" refers to an isomer produced by the different spatial arrangement of atoms in a molecule. The disclosed compounds contain structures such as asymmetric or chiral centers, double bonds, etc. Therefore, the disclosed compounds may include multiple isomeric forms such as optical isomers, geometric isomers, tautomers, atropisomers, and these isomers and their single isomers, racemates, etc. are all included in the scope of the present disclosure. For example, for optical isomers, optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral resolution, chiral synthesis or chiral reagents or other conventional techniques. For example, diastereomers can be converted into diastereomers by reacting with appropriate optically active substances (such as chiral alcohols or Mosher's acyl chlorides), which are separated and converted (such as hydrolyzed) into corresponding single isomers. For another example, separation can also be carried out by chromatographic column.

[0057] The term "pharmaceutical composition" refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component or agent, namely a "carrier", which facilitates the introduction of the compound into cells or tissues, including but not limited to stabilizers, diluents, suspending agents, thickening agents and / or excipients.

[0058] The "pharmaceutical compositions" 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. Administration can be topical (e.g., transdermal, skin, eye and mucous membranes 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. Parenteral administration can be in the form of a single bolus, or can be administered, for example, by a continuous infusion pump. The pharmaceutical 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.

[0059] The pharmaceutical compositions herein can be formulated in unit dosage form, each dose containing about 0.1 to 1000 mg, usually about 5 to 1000 mg, more usually about 100 to 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as single dosage units for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in admixture with a suitable pharmaceutical carrier.

[0060] The term "subject" refers to an individual suffering from a disease, disorder, condition, etc., including mammals and non-mammals. Examples of 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.

[0061] The term "treat" and other similar synonyms include alleviating, reducing or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, such as preventing the development of the disease or condition, alleviating the disease or condition, making the disease or condition better, alleviating the symptoms caused by the disease or condition, or stopping the symptoms of the disease or condition. 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. In addition, 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. In terms of prophylactic effect, the composition or compound can be administered to a patient at risk for a particular disease, or even if a diagnosis of the disease 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.

[0062] The term "amount to achieve the necessary therapeutic effect" or "therapeutically effective amount" refers to the amount of at least one pharmaceutical agent or compound that, after administration, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case. The actual amount of compound, pharmaceutical composition, or medicament administered is generally determined by the physician based on relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered; the age, weight, and response of the individual patient; the severity of the patient's symptoms, etc.

[0063] The ratio or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), route of administration, etc. For example, the disclosed compounds can 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 μg / kg to about 1 g / kg body weight / day. In certain embodiments, 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.

[0064] The term "administering" refers to a method for delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Those skilled in the art are familiar with 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, currented.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0065] The term "IC 50 ” refers to a 50% inhibition of the maximal effect in the assay measuring such effect.

[0066] In order to make the purpose, technical solutions and advantages of the present disclosure more clear, the technical solutions of exemplary embodiments of the present disclosure will be further described below.

[0067] Compound

[0068] 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,

[0069] wherein X and Y are selected from N or C, and one of X and Y is N and the other is C;

[0070] W is selected from N or C;

[0071] Z1 is independently selected from O or S;

[0072] Z2 is selected from O, S or NR, R is hydrogen or C 1-6 alkyl;

[0073] is a single bond or a double bond;

[0074] R 1 、R 2 and R 3 are 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, they form 0-2 R 23 A 5-6 membered heteroaryl ring;

[0075] R 4 Selected from NR 41 R 42 、C 1-6 Alkyl and C 1-6 alkoxy;

[0076] R 5 Selected from hydrogen or NR 51 R 52 ;

[0077] L is each independently selected from -CR L1 R L2 -;

[0078] R on each L L1 and R L2 are each independently selected from hydrogen and C 1-6 Alkyl, or two R on two adjacent L L2 Together with the carbon atom on L to which they are attached, they form a substituted 0-2 R 23 C 3-6 cycloalkyl ring;

[0079] R 23 are each independently selected from halogen, C 1-6 Alkyl and C 1-6 alkoxy;

[0080] R 41 and R 42 are each independently selected from hydrogen and C 1-6 alkyl;

[0081] R 51 and R 52 are each independently selected from hydrogen and C 1-6 alkyl;

[0082] n is an integer from 2 to 5.

[0083] In the five-membered ring structure comprising X and Y, It can be a single bond or a double bond, but depending on the selection of X and Y, the single bond or double bond in the five-membered ring needs to make the five-membered ring structure a heteroaromatic ring structure. Depending on the selection of X and Y, the compound can have the structural formula of formula IIa or formula IIb

[0084] Among them, R 1 、R 2 、R 3 、R 4 、R 5 , W, L and n are defined as above.

[0085] In the above formulas I, IIa and IIb, when W is a C atom, between W and R 3 There is a double bond between the connected C atoms, that is, the six-membered ring containing the W atom is a benzene ring structure.

[0086] In one embodiment, Z1 is O or S.

[0087] In one embodiment, R 4 NR 41 R 42 , where R 41 is hydrogen, R 42 C 1-3 In one embodiment, R 4 NR 41 R 42 , where R 41 is hydrogen, R 42 is a methyl group, i.e. R 4 It is methylamino.

[0088] In one embodiment, R 5 It is hydrogen or -NH2.

[0089] In one embodiment, n is 2 or 3; each L is independently selected from -CR L1 R L2 -; Among them, R on each L L1 is hydrogen, and R on each L L2 Each is independently selected from hydrogen and methyl. Preferably, there is only one R in (L)n formed by n L. L2 It is a methyl group.

[0090] In one embodiment, n is 2 or 3; each L is independently selected from -CR L1 R L2 -, where R on each L L1 is hydrogen, and the two R on two adjacent L L2 Together with the carbon atoms on L to which they are attached, they form C3-6 Examples of the cycloalkyl ring include a cyclobutyl ring and a cyclopentyl ring.

[0091] In one embodiment, (L)n formed by n L is selected from *-CH2CH2-**, *-CH2CH2CH2-**, *-CH(CH3)CH2-**, *-CH2CH(CH3)-**, *-CH(CH3)CH2CH2-**, or

[0092] Wherein, * indicates the site of connection to the Z1 atom, and ** indicates the site of connection to the O atom.

[0093] In one embodiment, W is N. Preferably, in the embodiment where W is a N atom, R 1 is hydrogen, R 2 is hydrogen or C 1-3 Alkyl, R 3 For oxygen.

[0094] In one embodiment, W is C. Preferably, in the embodiment where W is a C atom, R 1 is hydrogen or halogen, R 2 is hydrogen or halogen, R 3 C 1-3 In one embodiment, W is C, R 1 is hydrogen, R 2 is fluorine, R 3 In one embodiment, W is C, R 1 is fluorine, R 2 is hydrogen, R 3 In one embodiment, W is C, R 1 is hydrogen, R 2 is hydrogen, R 3 In the above embodiment, W and R 3 The connected C atoms is a double bond, that is, the six-membered ring containing the W atom is a benzene ring structure.

[0095] In one embodiment, W is C, and R 2 and R 3 Together with the ring atoms to which they are attached, they form 0-2 R 23 A 5-6 membered heteroaryl ring such as a triazole ring and the like.

[0096] In one embodiment, the structures of Formula I, IIa and IIb

[0097] Part of

[0098] where R 23 Selected from hydrogen or C 1-3 alkyl,

[0099] * indicates the site of attachment to CH2, and ** indicates the site of attachment to NH.

[0100] Thus, the disclosed compounds may have one of the following general formulas:

[0101] wherein each group is as defined above.

[0102] In the above formula I-1, preferably, Z2 is O.

[0103] It should be noted that in the above formulas I-1, IIa-1 and IIb-1, R 23 Different substitution positions of the groups on the triazole ring will change the position of the double bond in the benzotriazole structure, as long as the double bond in the benzotriazole ring structure is in the form of a conjugated double bond.

[0104] For example, According to R 23 The different substitution positions of the group on the triazole ring can be or where R 23 Selected from hydrogen or C 1-3 alkyl,

[0105] * indicates the site of attachment to CH2, and ** indicates the site of attachment to NH.

[0106] In one embodiment, for Among them, R 23 is methyl;

[0107] * indicates the site of attachment to CH2, and ** indicates the site of attachment to NH.

[0108] In one embodiment, the compound is selected from the group consisting of:

[0109] The present disclosure can prepare the compounds described herein by the following methods. The following methods and examples are intended to illustrate these methods. These schemes 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.

[0110] The chemical reactions of the disclosed embodiments are performed in suitable solvents that are compatible with the chemical transformations disclosed herein and the reagents and materials required. To obtain the compounds disclosed herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing implementations.

[0111] An important consideration in planning any synthetic route in this area is the selection of an appropriate protecting group for a reactive functional group, such as the amino group in the present disclosure. For the trained practitioner, Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991) is an authority in this regard. All references cited in this disclosure are incorporated herein in their entirety.

[0112] The reactions described herein can be monitored by any suitable method known in the art. For example, the reactions can be monitored by broad spectrum methods such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg, UV-visible), mass spectrometry, or the like, or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography, to monitor product formation.

[0113] The compounds of the general formula I disclosed herein can be prepared by those skilled in the art of organic synthesis using the following process using standard methods in the art:

[0114] Compound 1 and compound 2 undergo a condensation reaction to generate compound 3, compound 3 undergoes a reduction reaction to generate compound 4, and compound 4 undergoes an intramolecular coupling reaction to obtain the compound of formula I of the present disclosure.

[0115] Pharmaceutical compositions and applications

[0116] The present disclosure relates to a pharmaceutical composition comprising 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.

[0117] As demonstrated in this disclosure, the compounds of this disclosure exhibit excellent TYK2 inhibitory activity, particularly targeting the TYK2 JH2 pseudokinase domain. They are highly selective TYK2 allosteric inhibitors with strong blood-brain barrier crossability and can be used to modulate TYK2-mediated diseases. Therefore, this disclosure also relates to the use of the aforementioned compounds, or pharmaceutically acceptable salts, hydrates, solvates, active metabolites, polymorphs, isotope-labeled forms, isomers, or prodrugs thereof, as well as pharmaceutical compositions, for the preparation of pharmaceutical compositions for the treatment of tyrosine kinase-mediated diseases.

[0118] In one embodiment, the tyrosine kinase is selected from TYK2 kinase. In one embodiment, the tyrosine kinase-mediated diseases include inflammatory autoimmune diseases, tumors, and neurodegenerative diseases. Inflammatory autoimmune diseases primarily include atopic dermatitis, hidradenitis suppurativa, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, lupus erythematosus, and autoimmune brain diseases such as the central nervous system; tumors primarily include leukemia, lymphoma, myeloma, brain tumors, and other cancers; and neurodegenerative diseases primarily include cerebral atrophy, Alzheimer's disease, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

[0119] 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 a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope label, isomer or prodrug thereof, or a pharmaceutical composition thereof, to a patient in need of administration.

[0120] The present disclosure is further illustrated by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present disclosure in any way. One skilled in the art will readily recognize that various noncritical parameters can be varied or modified to achieve substantially the same results. The following example compounds were found to be allosteric inhibitors of TYK2 according to one or more of the assays described herein.

[0121] Example 1: (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)-benzheterocyclononan-9-one

[0122] Synthesis route:

[0123] Step A: 4-(Bromomethyl)-1-methoxy-2-nitrobenzene

[0124] 10 g (59.8 mmol, 1.0 eq) of 1-methoxy-4-methyl-2-nitrobenzene was added to 150 mL of carbon tetrachloride. After replacing the atmosphere with nitrogen, 10.7 g (60.4 mmol, 1.01 eq) of N-bromosuccinimide and 1.96 g (12.0 mmol, 0.2 eq) of azobisisobutyronitrile were added. After complete addition, the reaction system was moved to 80°C and allowed to react overnight. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and the residue diluted with water. The mixture was extracted with dichloromethane. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 10:1 to 4:1) to obtain the product (13 g, yield = 88%).

[0125] Step B: (R)-1-((4-methoxy-3-nitrobenzyl)oxy)propan-2-ol

[0126] 5 g (20.3 mmol, 1.0 eq) of 4-bromomethyl-1-methoxy-2-nitrobenzene was added to 50 mL of N,N-dimethylformamide, followed by 1.55 g (20.3 mmol, 1.0 eq) of (R)-1,2-propylene glycol. After nitrogen was replaced, the reaction system was cooled to 0°C and 0.73 g (30.5 mmol, 1.5 eq) of 60% sodium hydride was added portionwise. After complete addition, the reaction system was brought to room temperature and allowed to react for two hours. After completion of the reaction, the mixture was quenched with water in an ice-water bath, the pH was adjusted to 6-7 with 3 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1-4:1) to obtain the product (1.28 g, yield = 27%).

[0127] LC-MS: (M+H) + ; m / z = 242.1

[0128] Step C: 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester

[0129] 20 g (96.0 mmol, 1.0 eq) of 4-bromo-6-chloropyridazin-3-amine was added to 200 mL of ethanol, followed by 23.1 g (153.5 mmol, 1.6 eq) of ethyl 2-chloro-3-oxopropionate. After nitrogen was replaced, the reaction system was moved to 80°C and allowed to react overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 6:1 to 5:1) to obtain the product (21 g, yield = 72%).

[0130] LC-MS: (M+H) +; m / z = 303.9

[0131] Step D: Ethyl 6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate

[0132] 10 g (32.8 mmol, 1.0 eq) of ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate was added to 100 mL of 1,4-dioxane, followed by 5.46 g (36.1 mmol, 1.1 eq) of [(4-methoxyphenyl)methyl](methyl)amine and 6.65 g (65.7 mmol, 2.0 eq) of triethylamine. After the additions were complete, the atmosphere was replaced with nitrogen and the reaction system was moved to 90°C to react overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, diluted with water, and extracted with dichloromethane. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (12 g, yield = 97%).

[0133] LC-MS: (M+H) + ; m / z = 375.1.

[0134] Step E: 6-Chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid

[0135] At room temperature, 5 g (13.3 mmol, 1.0 eq) of ethyl 6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate was added to 150 mL of tetrahydrofuran. Then, 1.28 g (53.4 mmol, 4.0 eq) of lithium hydroxide (dissolved in 25 mL of water) was added and stirred at room temperature overnight. The pH was adjusted to 4 using 1 M HCl solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain the crude product, which was used directly in the next step.

[0136] LC-MS: (M+H) + ; m / z = 347.1

[0137] 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

[0138] 600 mg (1.7 mmol, 1.0 eq) of 6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid was added to 6 mL of dichloromethane, followed by 835 mg (3.5 mmol, 2.0 eq) of (R)-1-((4-methoxy-3-nitrobenzyl)oxy)propan-2-ol, 428 mg (2.1 mmol, 1.2 eq) of dicyclohexylcarbodiimide, and 21 mg (0.2 mmol, 0.1 eq) of N,N-4-dimethylaminopyridine. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was extracted with dichloromethane. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1 to 4:1) to obtain the product (1.1 g, yield = 89%).

[0139] LC-MS: (M+H) + ; m / z = 570.2

[0140] 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

[0141] 100 mg (0.2 mmol, 1.0 eq) of (R)-1-((4-methoxy-3-nitrobenzyl)oxy)propan-2-yl 6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate was added to 1 mL of tetrahydrofuran, followed by 0.1 mL of acetic acid and 115 mg (1.8 mmol, 10 eq) of zinc powder. The mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product that was used directly in the next step.

[0142] LC-MS: (M+H) + ; m / z = 540.2

[0143] 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)-benzheterocyclononan-9-one

[0144] At room temperature, a 10 ml reaction flask was charged with the raw material (R)-1-((3-amino-4-methoxybenzyl)oxy)propan-2-yl 6-chloro-8-((4-methoxyphenyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate (900 mg, crude product), 5 mL of 1,4-dioxane, 869 mg (2.7 mmol, 2.0 eq) of cesium carbonate, and 106 mg (0.1 mmol, 0.1 eq) of di-tert-butyl[2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine; 2'-amino-[1,1'-biphenyl]-2-yl} palladium methanesulfonate. The atmosphere was immediately purged with nitrogen, and the reaction flask was stirred at 90°C overnight. After cooling, the reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic phases were combined and concentrated, and the residue was purified by column chromatography to give the product (170 mg, 25%).

[0145] LC-MS: (M+H) + ; m / z = 504.2

[0146] 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)-benzheterocyclononan-9-one

[0147] 160 mg (0.3 mmol, 1.0 eq) (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 was dissolved in 3 mL of dichloromethane, 1 mL of hydrochloric acid (4 M in 1,4-dioxane) solution was added, and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated, and the residue was purified by high pressure preparative liquid separation to obtain the product (8.8 mg).

[0148] LC-MS: (M+H) + m / z = 384.2

[0149] 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).

[0150] Example 2: (R, 1 3 E,1 4 E)-3 6 -methoxy-7-methyl-1 7 -(Methylamino)-5,8-dioxa-2-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(1,3)-benzheterocyclononan-9-one

[0151] Synthesis route:

[0152] Step A: Ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate

[0153] At room temperature, 20.0 g (129.0 mmol, 1.0 eq) of ethyl 5-amino-1H-pyrazole-4-carboxylate was dissolved in 200 mL of ethanol. 21.3 g (387.1 mmol, 3.0 eq) of sodium methoxide and 31.0 g (194.1 mmol, 1.5 eq) of dimethyl malonate were added sequentially. The reaction solution was stirred at 80°C overnight. After the reaction was complete, the solvent was removed by evaporation under reduced pressure, and the mixture was diluted with water. A solid precipitated, which was filtered and the filter cake dried to yield the product (21.0 g, 73%).

[0154] LC-MS: (M+H) + m / z = 224.1

[0155] Step B: Ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate

[0156] At room temperature, 21.0 g (93.8 mmol, 1.0 eq) of ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate was dissolved in 200 mL of acetonitrile. 22.2 g (281.3 mmol, 3.0 eq) of pyridine and 73 g (469.1 mmol, 5.0 eq) of phosphorus oxychloride were added sequentially. The reaction solution was stirred at 100°C overnight. After completion of the reaction, the phosphorus oxychloride was removed by vacuum concentration. The solution was diluted with water under ice-water bath, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the product (17.0 g, 70%) was obtained by extraction with dichloromethane. The product was then concentrated under reduced pressure to obtain the product (17.0 g, 70%).

[0157] LC-MS: (M+H) + ; m / z = 260.0

[0158] Step C: Ethyl 5-chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0159] 5 g (19.2 mmol, 1.0 eq) of ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate was added to 100 mL of 1,4-dioxane, followed by 5.19 g (21.1 mmol, 1.1 eq) of [(4-methoxyphenyl)methyl](methyl)amine and 3.89 g (38.4 mmol, 2.0 eq) of triethylamine. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction system was moved to 90°C to react overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, diluted with water, and extracted with dichloromethane. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and the residue was purified by column chromatography to obtain the product (2.1 g, 30%).

[0160] LC-MS: (M+H) + ; m / z = 375.1

[0161] Step D: 5-Chloro-7-[(4-methoxyphenyl)methyl](methyl)amino}pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0162] 2.0 g (5.3 mmol, 1.0 eq) of ethyl 5-chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate was added to 20 mL of toluene, followed by 4.7 g (8.0 mmol, 1.5 eq) of tributyltin oxide. The reaction mixture was left to react at 100°C overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with water and dried over anhydrous sodium sulfate. The residue was purified by reverse-phase C18 column to obtain the product (1.0 g, 54%).

[0163] LC-MS: (M+H) + ; m / z = 347.1

[0164] 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

[0165] At room temperature, 1 g (2.9 mmol, 1.0 eq) of 5-chloro-7-[(4-methoxyphenyl)methyl](methyl)amino}pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was dissolved in 20 mL of dichloromethane. 1.39 g (5.8 mmol, 2.0 eq) (2R)-1-[(4-methoxy-3-nitrophenyl)methoxy]propanol, 0.71 g (3.5 mmol, 1.2 eq) of N,N'-dicyclohexylcarbodiimide, and 40 mg (0.3 mmol, 0.1 eq) of 4-dimethylaminopyridine were added sequentially. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, it was diluted with water and extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the product as a pale yellow oil (1.5 g, 73%).

[0166] LC-MS: (M+H) + ; m / z = 570.2

[0167] 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

[0168] At room temperature, 1.4 g (2.0 mmol, 1.0 eq) of (R)-1-((4-methoxy-3-nitrobenzyl)oxy)propan-2-yl 5-chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate was dissolved in 20 mL of tetrahydrofuran. 2 mL of acetic acid and 1.28 g (19.7 mmol, 10 eq) of zinc powder were added sequentially. The reaction solution was stirred at room temperature overnight. After the reaction was complete, the zinc powder was filtered, the filtrate was diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain the product (1.4 g, crude product).

[0169] LC-MS: (M+H) + ; m / z = 540.2

[0170] Step G: (R,1 3 E,1 4 E)-3 6-Methoxy-1 7 -((4-methoxybenzyl)(methyl)amino)-7-methyl-5,8-dioxa-2-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(1,3)-benzheterocyclononan-9-one

[0171] At room temperature, 1.3 g (crude) (R)-1-((3-amino-4-methoxybenzyl)oxy)propan-2-yl 5-chloro-7-((4-methoxyphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate was dissolved in 15 mL of 1,4-dioxane, and 1.18 g (3.6 mmol, 2.0 eq) of cesium carbonate, 140 mg (0.2 mmol, 0.1 eq) of di-tert-butyl[2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine, and 2'-amino-[1,1'-biphenyl]-2-yl}palladium methanesulfonate were added in sequence. The atmosphere was replaced with nitrogen, and the reaction solution was stirred at 90°C for 6 hours. The mixture was cooled and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to give a light yellow solid product (750 mg, 74%).

[0172] LC-MS: (M+H) + ; m / z = 504.2

[0173] Step H: (R,1 3 E,1 4 E)-3 6 -methoxy-7-methyl-1 7 -(Methylamino)-5,8-dioxa-2-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(1,3)-benzheterocyclononan-9-one

[0174] 650 mg (1.3 mmol, 1.0 eq) (R, 1 3 E,1 4 E)-3 6 -Methoxy-1 7 7-((4-Methoxybenzyl)(methyl)amino)-7-methyl-5,8-dioxa-2-aza-1(5,3)-pyrazolo[1,5-a]pyrimidin-3(1,3)-benzheterocyclononan-9-one was dissolved in 10 mL of dichloromethane, 3 mL of hydrochloric acid (4 M in 1,4-dioxane) was added, and the mixture was stirred at room temperature for two hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by preparative high-pressure liquid chromatography to obtain the product (96.8 mg, 20%).

[0175] LC-MS: (M+H)+ m / z = 384.2

[0176] 1 H-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).

[0177] The following examples were prepared with reference to the experimental routes and methods in Example 1 or Example 2:

[0178] Biological activity and pharmacokinetic experiments

[0179] 1. Enzymatic activity of compounds TYK2-JH2 and JAK1-JH2 (IC 50 ) Detection experiment

[0180] The 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 μL of the compound was added to 58.8 μL of DMSO, and then 4 times

[0181] Dilute to 10 concentrations; use an Echo to transfer 50 nL of test compound to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and use a final DMSO concentration of 0.5%. Add 5 μL of TYK2 (or JAK1) to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes. Add 5 μL of JH2 probe 1 to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes. Read the FP 520 / 48 signal using a BMG High-Throughput Drug Screening Multi-Purpose Microplate Reader.

[0182] TYK2-JH2 experimental data were analyzed using GraphPad Prism 8 software. The reading of the negative control (0.5% DMSO well) was set to 0% inhibition, and the reading of the positive control (the well with the highest concentration of the control compound) was set to 100% inhibition. After calculating the inhibition rate, the IC values ​​of the control compound and the test compound were obtained using the software's nonlinear fitting formula. 50 value (half maximal inhibitory concentration);

[0183] Average of the values ​​of the positive control wells

[0184] Average of the negative control well values

[0185] Specific IC 50 The test results are shown in Table 1 below:

[0186] Table 1 IC of Example compounds 50 Test results

[0187] From the data in the table, it can be seen that the compounds of the present disclosure have good enzymatic inhibitory activity against TYK2-JH2, and some of the compounds IC 50 Even <5nM, the inhibitory activity against JAK1-JH2 is weak, IC 50 >5000 nM. Therefore, the disclosed compound is a potent and more selective TYK2 (tyrosine kinase 2) allosteric inhibitor.

[0188] 2. Affinity of compounds for JAK1-JH2 and TYK2-JH2 (K d )test

[0189] 1) Buffer preparation: Prepare appropriate running buffer according to the situation.

[0190] 2) Pre-enrichment: Use CM5 chip to couple ligands and explore the coupling conditions of TYK2 / JAK1.

[0191] 3) Ligand coupling: Immobilize an appropriate amount of TYK2 / JAK1 on the chip.

[0192] 4) Kinetics: Select an 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 based on the possible KD value. The instrument monitors the molecular interactions in real time.

[0193] 5) Data analysis: TYK2 experimental data were analyzed using Biacore Insight Evaluation Software, which automatically fitted the K values ​​for the binding of TYK2-JH2 to JAK1-JH2. d value.

[0194] The test results show that the example compounds have high affinity for TYK2-JH2 and low affinity for JAK1-JH2, and are highly selective for the latter.

[0195] 3. Pharmacokinetic studies

[0196] Male SD rats were divided into groups of 3 per group and received intravenous injection of the compound of Example 2 (2 mg / kg) and oral single gavage of the compound of Example 2 and the control compound (10 mg / kg). 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 anticoagulant tube. The sample was centrifuged at 4°C and 4000 rpm for 5 minutes. The plasma was transferred to a centrifuge tube and stored at -80°C until sample analysis. The sample in the plasma was extracted using protein precipitation method, and the extract was analyzed by LC / MS / MS. The pharmacokinetic results are shown in Tables 2 and 3 below:

[0197] Table 2 Pharmacokinetic parameters of Example 2 compound in rat plasma after intravenous administration

[0198] Table 3 Pharmacokinetic parameters of the compound of Example 2 in rat plasma after oral administration

[0199] It can be seen from the data in the table that the compound of 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.

[0200] 4. Blood-brain distribution experiment

[0201] Male SD rats were divided into groups of 3 in each group and were administered the drug compound (10 mg / kg) orally by a single gavage (PO) or by a single intravenous injection (IV) of the drug compound (2 mg / kg). The animals were fasted overnight before the experiment and fasted from 10 hours before administration to 4 hours after administration. Each rat was killed 0.5 hours after PO administration (5 minutes after IV administration) and blood and brain tissue were collected. The samples were centrifuged at 4°C and 4000rpm for 5 minutes, and the plasma was transferred to a centrifuge tube and stored at -80°C until sample analysis. The samples in the plasma were extracted using protein precipitation, and the extract was analyzed by LC / MS / MS. The data show that the compounds of the embodiments of the present disclosure have an unexpected ability to pass through the blood-brain barrier.

[0202] As shown in Table 4, 0.5 h after oral administration, the brain / blood ratio of the drug concentration of the compound of Example 2 reached 5.08, and its brain penetration ability was unexpected, while the brain penetration rates of Deucravacitinib and the control compound A were extremely low.

[0203] Table 4 Blood-brain ratio of drug concentration in rats after oral administration for 0.5 h

[0204] Similar tests were performed and the other example compounds also had unexpectedly high drug concentration brain / blood ratios.

[0205] Table 5 Blood-brain ratio of drug concentration after administration in different embodiments

[0206] The disclosed compounds are the first known class of highly selective TYK2 allosteric inhibitors with brain penetrability, and are also the structural type with the strongest brain penetrability among reported molecular structures.

[0207] In the present disclosure, the properties of Deucravacitinib, reference compound A, and reference compound B used for comparison are as follows:

[0208] Deucravacitinib has the following structural formula

[0209] The control compound A has the following structural formula and can be prepared according to the preparation method of Example 1 in document WO2022060973A1:

[0210] The control compound B has the following structural formula and can be prepared according to the preparation method of Example 25 in the document WO2020185755A1:

[0211] The present disclosure has been described above in conjunction with preferred embodiments, but these embodiments are merely exemplary and serve only as an illustration. On this basis, various replacements and improvements can be made to the present disclosure, all of which fall within the scope of protection of the present disclosure.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, 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 Independently selected from O or S; Z 2 is selected from O, S or NR, R is hydrogen or C 1-6 alkyl; is a single bond or a double bond; R 1 , R 2 and R 3 are 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, they form a substitution with 0-2 R 23 A 5-6 membered heteroaryl ring; R 4 Selected from NR 41 R 42 , C 1-6 Alkyl and C 1-6 Alkoxy; R 5 Selected from hydrogen or NR 51 R 52 ; L is each independently selected from -CR L1 R L2 -; R on each L L1 and R L2 are each independently selected from hydrogen and C 1-6 Alkyl, or two R on two adjacent L L2 Together with the carbon atom on L to which they are attached, they form a substitution with 0-2 R 23 C 3-6 Cycloalkyl ring; 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.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, The compound has a structural formula of formula IIa or formula IIb Among them, R 1 , R 2 , R 3 , R 4 , R 5 , W, L and n are defined as in claim 1.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, Z 1 It is O or S.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, R 4 NR 41 R 42 , where R 41 is hydrogen, R 42 C 1-3 alkyl.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, R 4 NR 41 R 42 , where R 41 is hydrogen, R 42 It is methyl.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, R 5 is hydrogen or -NH 2 .

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, n is 2 or 3; L is each independently selected from -CR L1 R L2 -; where R on each L L1 is hydrogen, and the R on each L L2 are each independently selected from hydrogen and methyl.

8. The compound according to claim 7 or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, There is only one R in (L)n formed by n Ls L2 It is methyl.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, n is 2 or 3; L is each independently selected from -CR L1 R L2 -, where R on each L L1 is hydrogen, and the two R on two adjacent L L2 Together with the carbon atom on L to which they are attached, they form C 3-6 Cycloalkyl ring.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, The (L)n formed by n Ls is 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 Among them, * indicates that Z 1 The site where the atom is connected, ** indicates the site where it is connected to the O atom.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, n L forms (L)n*-CH(CH 3 )CH 2 -**; Or, (L)n formed by n L is Among them, * indicates that Z 1 The site where the atom is connected, ** indicates the site where it is connected to the O atom.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, W is N, R 1 is hydrogen, R 2 is hydrogen or C 1-3 Alkyl, R 3 For oxygen.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, W is C, R 1 is hydrogen or halogen, R 2 is hydrogen or halogen, R 3 C 1-3 Alkoxy.

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, W is C, between W and R 3 The connected C atoms is a double bond, R 1 is hydrogen, R 2 is fluorine, R 3 It is a methoxy group.

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, W is C, between W and R 3 The connected C atoms is a double bond, R 1 is fluorine, R 2 is hydrogen, R 3 It is a methoxy group.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, W is C, between W and R 3 The connected C atoms is a double bond, R 1 is hydrogen, R 2 is hydrogen, R 3 It is a methoxy group.

17. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, In formula I, formula IIa or formula IIb Part of Where R 23 Selected from hydrogen or C 1-3 Alkyl, * indicates CH 2 The connection site, ** indicates the site of connection with NH.

18. The compound according to claim 17, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, for or Where R 23 Selected from hydrogen or C 1-3 alkyl, * indicates CH 2 The connection site, ** indicates the site of connection with NH.

19. The compound according to claim 17 or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, for Among them, R 23 is methyl; * indicates CH 2 The connection site, ** indicates the site of connection with NH.

20. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, in, The compound is selected from the following compounds:

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.

22. Use of the compound according to any one of claims 1 to 20 or its pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug, and the pharmaceutical composition according to claim 18 in the preparation of a drug for treating a tyrosine kinase-mediated disease.

23. The use according to claim 22, in, The tyrosine kinase is selected from TYK2 kinase.

24. The use according to claim 22, in, The tyrosine kinase-mediated diseases include inflammatory autoimmune diseases, tumors, and neurodegenerative diseases.

25. The use according to claim 22, in, Inflammatory autoimmune diseases are selected from atopic dermatitis, hidradenitis suppurativa, 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.

26. A method for treating a tyrosine kinase-mediated disease, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotope-labeled substance, isomer or prodrug thereof, or a pharmaceutical composition according to claim 21, to a patient in need of administration.

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