Macrocyclic compounds, pharmaceutical compositions, and their use

Abstract

This invention relates to a macrocyclic compound, a pharmaceutical composition, and its uses. The compound has the structural formula shown in formula I. The macrocyclic compound is an allosteric inhibitor of TYK2 with potent blood-brain barrier penetration ability and high selectivity, and can be used to modulate TYK2-mediated diseases. JPEG2026512838000061.jpg78140

Description

[Technical Field]

[0001] This application provides a macrocyclic compound, a pharmaceutical composition, and its use. The macrocyclic compound is an allosteric inhibitor of TYK2, possessing potent blood-brain barrier crossing ability and high selectivity, and is used to modulate TYK2-mediated diseases. [Background technology]

[0002] The JAK family includes JAK1, JAK2, JAK3, and TYK2, which are crucial for mediating the signaling of numerous inflammatory cytokines. TYK2 and JAK1 / 2 / 3 typically function in pairs or as "dimers," transmitting extracellular cytokine signals to the cell nucleus. TYK2 is selectively involved in the signaling of inflammatory cytokines such as IL-23, IL-12, and type I IFNs. Therefore, TYK2 inhibitors can be used as an effective therapeutic tool for a variety of serious inflammatory and autoimmune diseases.

[0003] The JAK family, consisting of JAK1, JAK2, JAK3, and TYK2, all possess a JAK homology domain (JH). The JH1 domain is also called the kinase domain, and the JH2 domain is also called the pseudokinase domain. The earliest TYK2 inhibitors (such as Pfizer's Brepocitinib) all act directly on the JH1 kinase catalytic domain, i.e., the ATP binding pocket. Due to the high homology of the JH1 catalytic domain, these TYK2 inhibitors have limited selectivity for other members of the JAK family, making it difficult to avoid cardiovascular events or venous thromboembolism, which are commonly seen with JAK inhibitors.

[0004] Duclavacitinib, an allosteric inhibitor of BMS's TYK2, acts specifically on the pocket of the TYK2 JH2 pseudokinase domain, exhibiting allosteric properties and high selectivity for other JAK family members and the entire kinase family, thereby reducing the risk of adverse events such as cardiovascular events or venous thromboembolism. Therefore, duclavacitinib is the first oral JAK inhibitor to be marketed without a black box warning. [Overview of the project] [Problems that the invention aims to solve]

[0005] However, duklavacitinib also exerts some effect on the JH2 domain of JAK1, and there is a risk of adverse events occurring due to JAK1 inhibition. The development of allosteric inhibitors of TYK2 with higher selectivity for JAK1 is expected to further reduce the side effects caused by JAK1 inhibition and lead to safer treatment options for autoimmune diseases. At the same time, when many autoimmune diseases progress to the terminal stage, they invade the brain and cause symptoms such as multifocal or diffuse brain injury. However, currently, no TYK2 molecule with high selectivity to penetrate the brain has been reported, and the development of such clinical drugs is urgently needed. Furthermore, TYK2 is a STAT channel activator that targets a range of inflammatory cytokines, and inhibition of TYK2 may play an important role in reducing inflammation in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Therefore, there is a clinical urgency to develop allosteric inhibitors of TYK2 with better selectivity and stronger blood-brain barrier crossing ability in order to provide drugs for neurodegenerative diseases. [Means for solving the problem]

[0006] One aspect of the present invention provides a compound represented by formula I, its isotopic isomers, or a pharmaceutically acceptable salt thereof: JPEG2026512838000002.jpg78140 This compound is an allosteric inhibitor of TYK2 with potent blood-brain barrier penetration ability and high selectivity, and can be used to modulate TYK2-mediated diseases.

[0007] The present invention also relates to pharmaceutical compositions comprising the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.

[0008] The present invention also relates to the use of the compounds disclosed herein or their pharmaceutically acceptable salts, hydrates, solvates, active metabolites, crystalline polymorphs, isotope-labeled compounds, isomers or prodrugs, and pharmaceutical compositions in the preparation of agents for treating tyrosine kinase-mediated diseases.

[0009] The present invention relates to a method for treating tyrosine kinase-mediated diseases, comprising administering to a patient in need of administration a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof, or a pharmaceutical composition thereof.

[0010] In one embodiment, the tyrosine kinase is selected from TYK2 kinase. In one embodiment, diseases mediated by the tyrosine kinase include inflammatory autoimmune diseases, tumors, and neurodegenerative diseases. For example, inflammatory autoimmune diseases are selected from the group consisting of atopic dermatitis, hidradenitis suppurativa, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, scleroderma, autoimmune encephalopathy, etc.; tumors are selected from the group consisting of cancers such as leukemia, lymphoma, myeloma, and brain tumors; and neurodegenerative diseases are selected from the group consisting of cerebral atrophy, dementia, Parkinson's syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, etc. [Modes for carrying out the invention]

[0011] The present invention will be described in more detail below through embodiments. Through these descriptions, the features and advantages of the present invention will be more clearly defined.

[0012] As used herein, the term “exemplary” means “useful as an example, embodiment, or for illustrative purposes.” Embodiments described herein as “exemplary” should not be construed as superior to, or having any connotation of being superior to, other embodiments.

[0013] Furthermore, the technical features of the different embodiments of the present invention described below can be combined with each other, provided they do not contradict each other.

[0014] definition Unless otherwise defined, all technical terms herein have the same meaning as those generally understood by those skilled in the art in the field to which the subject matter of the claims pertains. Unless otherwise noted, all patents, patent applications, and disclosure materials cited herein are incorporated herein by reference in their entirety. Where trade names are mentioned herein, they are intended to refer to the product or its active ingredient.

[0015] Please understand that the brief description above and the subsequent detailed description are illustrative and for illustrative purposes only, and do not limit the subject matter of the present invention in any way. It is important to note that the singular forms used in the specification and claims of the present invention include the plural forms of those mentioned unless explicitly stated otherwise. Also note that unless otherwise specified, the terms “or” and “or” are used to mean “and / or.” Furthermore, the use of the term “including,” such as “comprising,” “containing,” and “having,” is not limited to these.

[0016] The standard definitions of chemical terms are found in Carey and Sundberg's "Advanced Organic Chemistry 4". thReferences can be made to literature such as "Ed, Vol A (2000) and B (2001), Plenum Press, New York." Unless otherwise specified, conventional methods within the scope of the art, including mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacological methods, are used. Unless otherwise specified, nomenclature, laboratory operations, and techniques related to chemistry in analytical chemistry, organic synthesis, and medical and pharmaceutical chemistry are known to those skilled in the art. Standard techniques can be used for chemical synthesis, chemical analysis, preparation of pharmaceuticals, formulation, drug delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transfection). As an example, reaction and purification techniques can be carried out using kits with instructions provided by the manufacturer, or according to methods known in the art, or according to methods described herein. In general, the techniques and steps can be carried out by conventional methods well known in the art and described in various ordinary or more specific literature. Such literature is cited and discussed herein.

[0017] When substituents are represented in a conventional chemical formula written from left to right, the substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2.

[0018] The term "substitution" means that one or more hydrogen atoms on a given atom are substituted by a substituent, provided that the valence of the given atom is normal and the substituted compound is stable. If the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are substituted, and substitution of oxo groups does not occur in aromatic groups.

[0019] In the composition and structure of a compound, if any variable (e.g., R) appears multiple times, its definition in each appearance is independent. Therefore, for example, if a group is substituted with 0 to 2 Rs, that group can be substituted with up to 2 Rs, and each appearance of R is an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in a stable compound.

[0020] C used in this specification m~n This means that the part has m to n carbon atoms. For example, the above "C 1~8 A "C" group has 1 to 8 carbon atoms in that part; that is, this group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms... up to 8 carbon atoms. Therefore, for example, "C 1~8 "Alkyl" means an alkyl group containing 1 to 8 carbon atoms. That is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl...octyl, etc. Numerical ranges in this specification, for example "1 to 8", mean each integer within a given range, and for example "1 to 8 carbon atoms" means that the group may 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.

[0021] The term "member" refers to the number of atoms that make up the ring's framework. For example, pyridine is a 6-membered ring, while pyrrole is a 5-membered ring.

[0022] In this invention, the definitions of each group are as follows: Hydrogen is represented by -H or can be substituted with isotopes such as deuterium or tritium.

[0023] "Halogens" include fluorine, chlorine, bromine, and iodine.

[0024] C 1~8The alkyl group includes 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, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, hexyl, heptyl, octyl, and the like.

[0025] Deuterated C 1~8 Alkyl, tritiated C 1~8 Alkyl is the said C 1~8 In some cases, it may indicate that one or more, or all, of the hydrogen atoms of the alkyl are substituted with isotopes such as deuterium and tritium.

[0026] C 1~8 Alkoxy is -OC 1~8 represented by alkyl, where C 1~8 alkyl is as defined above; for example, C 1~8 Alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0027] C 1~8 Haloalkyl is C 1~8 a group in which any number of hydrogen atoms in alkyl are substituted with halogen, and C 1~8 alkyl and halogen are as defined above; for example, C 1~8 Haloalkyl includes -CF3 and the like.

[0028] C 3~8 Cycloalkyl represents a non-aromatic saturated carbon ring, including monocyclic carbon rings (having one ring) and bicyclic carbon rings (having two rings), for example, C3~8 Cycloalkyls include, JPEG2026512838000003.jpg18156

[0029] C 3~8 Cycloalkyl C 1~8 Alkyl is C 3~8 C having a cycloalkyl group 1~8 This represents alkyl, where C 3~8 Cycloalkyl and C 1~8 The definition of alkyl is as described above, for example C 3~8 Cycloalkyl C 1~8 Alkyl compounds include cyclopropylmethyl, cyclobutylmethyl, and cyclohexylethyl.

[0030] C 3~8 Heterocyclines are C 3~8 This represents a group obtained by substituting any number of ring atoms in a cycloalkyl group with heteroatoms such as O, S, N, P, Si, where C 3~8 The groups included in cycloalkyls are as defined above. For example, C 3~8 Examples of heterocyclyls include oxyranil, thioethanethiol, azilidinil, azetidinil, oxetanil, thietanil, tetrahydrofuranil, pyrrolidinil, oxazolidinil, tetrahydropyrazolidinil, pyrrolinil, dihydrofuranil, dihydrothienyl, piperidinil, tetrahydropyranil, tetrahydrothiopyranil, morpholinil, piperazinil, dihydropyridyl, tetrahydropyridyl, dihydropyranil, tetrahydropyranil, dihydrothiopyranil, azepanil, oxetanil, thiepanil, oxazabicyclo[2.2.1]heptyl, and azapiro[3.3]heptyl.

[0031] C 6~20 Aryls include monocyclic, bicyclic, or polycyclic aryls, such as phenyl, biphenyl, naphthyl, phenanthryl, anthracenyl, and azlenyl.

[0032] C 5~20Heteroaryl groups are unsaturated groups that contain any number of heteroatoms such as O, S, N, P, and Si as ring atoms. For example, C 5~20 Heteroaryls include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolylyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophenyl, indolyl, and isoindolyl.

[0033] Hydroxyl is represented as -OH.

[0034] Sulfhydryls are represented by -SH.

[0035] Carboxylate is represented as -COOH.

[0036] Esters are represented by -COOR', where R' is C 1~8 It is alkyl, for example C 1~8 Alkyl-substituted ester groups are -COOC 1~8 Represented by alkyl, C 1~8 The groups included in alkyl are as defined above.

[0037] The acyl is represented by -COR', and R' is C 1~8 It is alkyl, for example C 1~8 Alkyl-substituted acyls are -COC 1~8 Represented by alkyl, C 1~8 The groups included in alkyl are as defined above.

[0038] Amino is represented as -NH2, -NHR', or -N(R')2, where R' is C 1~8 It is alkyl, for example C 1~8 Alkyl-substituted aminos are -NHC 1~8 Alkyl or -N(C) 1~8 Represented as alkyl)2, C 1~8 The groups included in alkyl are as defined above.

[0039] Amides are represented as -COamino, and aminos are defined as previously defined.

[0040] Sulfonyl is represented as -S(O)2R', where R' is C 1~8 It is alkyl, for example C 1~8 Alkyl-substituted sulfonyls are -S(O)2C 1~8 Represented by alkyl, C 1~8 The groups included in alkyl are as defined above.

[0041] Cyano is represented by -CN.

[0042] Oxo is represented by (=O).

[0043] In the above definition, if the number of carbon atoms changes, only the number of carbon atoms changes in the above definition, and it does not affect the definition of the type of group. For example, "C 1~5 "Alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentanyl, iso-pentanyl, neopentyl, etc., as mentioned above in "C 1~8 This includes groups where all carbon atoms satisfy the definition of "alkyl," with a total number of carbon atoms ranging from 1 to 5.

[0044] The term "pharmaceutically acceptable" means that a compound, material, composition, and / or dosage form is within the bounds of sound medical judgment, suitable for use in contact with human and animal tissues, does not cause excessive toxicity, irritation, allergic reactions, or other problems or complications, and is commensurate with a reasonable benefit-to-risk ratio.

[0045] The term "pharmaceutically acceptable salt" means a salt that retains the biological potency of the free acid and free base of a particular compound and does not have any biologically or otherwise undesirable effects. Unless otherwise specified, salts in this disclosure refer to metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids. Non-limiting examples of metal salts include, but are not limited to, salts of alkali metals, such as sodium salts and potassium salts; salts of alkaline earth metals, such as calcium salts, magnesium salts and barium salts; and aluminum salts. Non-limiting examples of salts formed with organic bases include, but are not limited to, salts formed with trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, and dicyclohexyleneamine. 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, and phosphoric acid. 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, benzenesulfinic acid, and p-toluenesulfonic acid. Non-limiting examples of salts formed with alkaline amino acids include, but are not limited to, salts formed with arginine, lysine, and ornithine. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid and glutamic acid.

[0046] pharmaceutically acceptable salts can be synthesized by conventional chemical methods from parent compounds containing acidic or basic groups. Generally, such salts are prepared by reacting these compounds in the form of free acids or free bases with stoichiometrically appropriate bases or acids in water, an organic solvent, or a mixture of both. Non-aqueous media such as ether, ethyl acetate, ethanol, isopyropanol, or acetonitrile are generally preferred.

[0047] In this disclosure, the term "solvate" refers to a physical aggregate formed by a compound with one or more solvent molecules, which may contain varying degrees of ionic and covalent bonds (e.g., hydrogen bonds). These solvates have been shown to be isolated, for example, when one or more solvent molecules are present in the crystal lattice of a crystal. "Solvates" include both the solvent phase and the separable solvent compound. Many examples of corresponding solvates exist, such as ethanol solvate and methanol solvate. "Hydrate" refers to a solvate using water (H2O) as the solvent. One or more of the compounds in this disclosure can be optionally prepared as solvates. 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, i.e., a preparation using ethyl acetate and water. Similar preparation methods for solvates and hydrates are also described in EC van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and ALBingham et al, Chem.Commun., 603-604 (2001). A typical example of an unrestricted preparation step is to dissolve the compound of the present invention in a desired amount of a preferred solvent (organic solvent, water, or a mixture thereof) at a temperature above room temperature, cool and allow to stand to precipitate crystals, and then isolate and extract the crystals by a standard method. The presence of the solvent (water) that forms the solvate (hydrate) in the crystals can be verified by IR spectroscopy.

[0048] The term "active metabolite" refers to an active derivative of a compound that is produced when the compound is metabolized.

[0049] The term "crystalline polymorph" refers to the compound of this invention that exists in different crystalline structures.

[0050] The term "isotope-labeled compound" refers to a compound of this disclosure that is labeled with an isotope. For example, the isotopes in the compounds of this invention include various isotopes of elements such as H, C, N, O, P, F, and S. 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 is included.

[0051] The term “pharmaceutically acceptable prodrug” or “prodrug” refers to a pharmaceutically acceptable salt, ester, ester salt, or other derivative of the compound of the present invention that, after administration to a subject, can directly or indirectly provide the compound of the present invention or its pharmaceutically active metabolite or residue. Particularly preferred derivatives or prodrugs are those that, when administered to a patient, can improve the bioavailability of the compound of the present invention (e.g., enable easier absorption of the orally administered compound into the bloodstream) or contribute to 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 degradation into the parent compound by conventional procedures or in vivo. Various forms of prodrugs are well known in the art. See Pro-drugs as Novel Delivery Systems (1987), Vol. 14 of the ACS Symposium Series, by T. Higuchi and V. Stella. There is also information on prodrugs in Bioreversible Carriers in Drug Design (1987), edited by Edward B. Roche, 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. 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 are incorporated herein by reference.

[0052] The term "stereoisomer" refers to an isomer arising from differences in the spatial arrangement of atoms within a molecule. The compounds of the present invention include structures such as asymmetric or chiral centers and double bonds. Therefore, the compounds of the present invention include various isomers such as optical isomers, geometric isomers, tautomers, and blocking isomers. These isomers, their single isomers, and racemates are also included in the scope of the present invention. For example, optical isomers can be prepared by chiral resolution, chiral synthesis, chiral reagents, or other prior arts to produce optically active (R)- and (S)-isomers, as well as D and L isomers. For example, they can be separated and converted to the corresponding single isomers (e.g., by hydrolysis) by reacting them with a suitable optically active substance (e.g., chiral alcohol, Mosher's acid chloride) to convert them into diastereoisomers. Furthermore, they can also be separated by chromatography, for example.

[0053] The term "pharmaceutical composition" refers to a biologically active compound that is a mixture of at least one pharmaceutically acceptable chemical component or reagent. These pharmaceutically acceptable chemical components or reagents are "carriers" that facilitate the introduction of compounds into cells or tissues. Examples include, but are not limited to, stabilizers, diluents, suspending agents, thickeners, and / or excipients.

[0054] The “pharmaceutical compositions” as used herein can be prepared by methods well known in the pharmaceutical field and can be administered by various routes. This depends on whether topical or systemic treatment is required and the site being treated. The “pharmaceutical compositions” as used herein can be administered topically (e.g., transdermally, through the skin, eyes, and mucous membranes including intranasal, intravaginal, and rectal), pulmonaryly (e.g., by inhalation or blowing of powders or aerosols, including administration via a nebulizer; intratracheal, intranasal), orally, or parenterally. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, for example, subarachnoid or intraventricular administration. Administration can be parenterally in the form of a single large dose, or, for example, by a continuous infusion pump. Pharmaceutical compositions as used herein include, but are not limited to, the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (dissolved in solid or liquid solvents); for example, ointments, soft or hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders containing up to 10% by weight of the active compound.

[0055] The pharmaceutical compositions described herein can be formulated into unit dosage forms, each containing approximately 0.1 to 1000 mg of the active ingredient, typically about 5 to 1000 mg, and more commonly about 100 to 500 mg. The term "unit dosage form" means a physically separated single-dose unit suitable for use in human patients and other mammals, each unit containing a predetermined amount of the active substance calculated to produce a desired therapeutic effect, mixed with a suitable pharmaceutical carrier.

[0056] The term "individual" refers to an individual, including both mammals and non-mammals, that is suffering from a disease, illness, or disease progression. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees, other monkeys and apes); domesticated animals, such as cattle, horses, sheep, goats, and pigs; domesticated animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs.

[0057] The term “treatment” and other similar synonyms include relieving, reducing or improving symptoms of a disease or condition, preventing other symptoms, improving or preventing potential metabolic causes of symptoms, suppressing a disease or condition, for example, stopping the progression of a disease or condition, relieving a disease or condition, improving a disease or condition, relieving symptoms caused by a disease or condition, or stopping symptoms of a disease or condition. Furthermore, the term may also include preventive purposes. The term also includes obtaining therapeutic and / or preventive effects. The therapeutic effect refers to curing or improving the underlying disease being treated. Furthermore, the curing or improvement of one or more physiological symptoms associated with an underlying disease is also a therapeutic effect, for example, when an improvement in the patient's condition is observed even though the patient is still affected by the underlying disease. With respect to preventive effects, the composition or compound may be administered to a patient at risk of developing a particular disease, or to a patient who is exhibiting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0058] The term “the amount required to obtain the desired therapeutic effect” or “effective dose” refers to the amount of at least one drug or compound that, after administration, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result may be a reduction and / or remission of signs, symptoms or etiology, or other desirable changes in the biological system. Techniques such as dose escalation studies can be used to determine the effective dose appropriate for any individual case. The actual dose of a compound, pharmaceutical composition, or drug is usually determined by a physician based on relevant circumstances such as the condition being treated, the chosen route of administration, the compound actually administered, the patient’s age, weight, and response, and the severity of the patient’s symptoms.

[0059] The proportion or concentration of the compound of the present invention in a pharmaceutical composition does not have to be fixed and depends on various factors such as dosage, chemical properties (e.g., hydrophobicity), and route of administration. The compound of the present invention can be provided, for example, as a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. A typical dosage range is about 1 μg / kg (body weight) / day to about 1 g / kg (body weight) / day. In some embodiments, the dosage range is about 0.01 mg / kg (body weight) / day to about 100 mg / kg (body weight) / day. The dosage is likely to depend on factors such as the type and progression of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation and its route of administration.

[0060] The term "administration" refers to a method that enables the delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral, duodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), topical, and rectal administration. Those skilled in the art will be familiar with the administration techniques available for the compounds and methods described herein. Examples include the administration techniques described in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; *Pergamon*; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa.

[0061] The term “IC 50 " is an indicator of the inhibitory effect that a compound has on a process, and it refers to the concentration of the compound required to inhibit the maximum effect by 50%.

[0062] To further clarify the object, technical configuration, and advantages of the present invention, the technical configuration of an exemplary embodiment of the present invention will be described below.

[0063] compound The present invention provides compounds represented by formula I or pharmaceutically acceptable salts, hydrates, solvates, active metabolites, crystalline polymorphs, isotope-labeled compounds, isomers, or prodrugs thereof. JPEG2026512838000004.jpg78138 Here, X and Y are selected from the group consisting of N and C, where one of X and Y is N and the other is C; W is selected from the group consisting of N and C; Z1 is independently selected from the group consisting of O and S; Z2 is selected from the group consisting of O, S, and NR, and R is hydrogen or C 1-6 It is alkyl; JPEG2026512838000005.jpg14167R 1 , R2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, oxo, C 1-6 alkyl and C 1-6 alkoxy; or, R 2 and R 3 together with the ring atom to which they are attached form a 5- to 6-member heteroaryl ring substituted with 0 to 2 R 23 ; R 4 is selected from the group consisting of NR 41 R 42 alkyl and C 1-6 alkoxy; 1-6 R 5 is selected from hydrogen and NR 51 R 52 ; L is each independently selected from -CR L1 R L2 -; R L1 and R L2 in each L are each independently selected from the group consisting of hydrogen and C 1-6 alkyl, or two R L2 in two adjacent Ls together with the carbon atom in the L to which they are attached form a C 23 cycloalkyl ring substituted with 0 to 2 R 3-6 ; R 23 is each independently selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy; R 41 and R 42 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; R 51 and R 52 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; n is an integer from 2 to 5.

[0064] ​JPEG2026512838000006.jpg7170 However, depending on the selection of X and Y, the single or double bond in the five-membered ring will make the five-membered ring structure a heteroaromatic ring structure. Depending on the selection of X and Y, the compound will have the structure of formula IIa or formula IIb. JPEG2026512838000007.jpg58170 Here, R 1 , R 2 , R 3 , R 4 , R 5 The definitions of W, L, and n are as described above.

[0065] In the above formulas I, IIa and IIb, when W is a C atom, then W and R 3 A double bond is formed between the W atom and the connected C atom. In other words, the six-membered ring containing the W atom forms a benzene ring structure.

[0066] In one embodiment, Z1 is O or S.

[0067] In one embodiment, R 4 is NR 41 R 42 And here, R 41 is hydrogen, R 42 is C 1-3 It is alkyl. In one embodiment, R 4 is NR 41 R 42 And here, R 41 is hydrogen, R 42 It is methyl, that is, R 4 It becomes methylamino.

[0068] In one embodiment, R 5 It is hydrogen or -NH2.

[0069] In one embodiment, n is 2 or 3; L is independently -CR L1 R L2 - is selected from; here, R in each L L1 is hydrogen, and R in each L L2Each is independently selected from hydrogen and methyl. Preferably, in (L)n formed by n Ls, R is methyl. L2 There is one.

[0070] In one embodiment, n is 2 or 3; L is independently -CR L1 R L2 -Selected from, where R in each L L1 is hydrogen, and the two R in the two adjacent L L2 These, along with the carbon atoms of L to which they are linked, include C such as a cyclobutyl ring or a cyclopentyl ring. 3-6 It forms a cycloalkyl ring.

[0071] In one aspect, (L)n formed by n Ls is *-CH2CH2-**, *-CH2CH2CH2-**, *-CH(CH3)CH2-**, *-CH2CH(CH3)-**, *-CH(CH3)CH2CH2-**, JPEG2026512838000008.jpg32129 Here, * represents the binding site with the Z1 atom, and ** represents the binding site with the O atom.

[0072] In one embodiment, W is N. In the embodiment where W is N, R 1 is hydrogen, R 2 is hydrogen or C 1-3 Alkyl, R 3 It is preferable that it be oxo.

[0073] In one embodiment, W is C. In this embodiment where W is C, R 1 is hydrogen or halogen, R 2 is hydrogen or halogen, R 3 is C 1-3 It is preferable that it be an alkoxy. In one embodiment, W is C and R 1 is hydrogen, R 2 is fluorine, and R 3 is methoxy. In one embodiment, W is C and R 1 is fluorine, and R 2is hydrogen, R 3 is methoxy. In one embodiment, W is C and R 1 is hydrogen, R 2 is hydrogen, R 3 is methoxy. In the above embodiment, W and R 3 The bond between the W atom and the connected C atom is a double bond. In other words, the six-membered ring containing the W atom has a benzene ring structure.

[0074] In one embodiment, W is C and R 2 and R 3 These, along with the ring atoms to which they are linked, have 0 to 2 R 23 The substituted member forms a heteroaryl ring, such as a triazole ring.

[0075] In one embodiment, in the structure of formulas I, IIa, and IIb JPEG2026512838000009.jpg50148 Here, R 23 is hydrogen and C 1-3 Selected from the group consisting of alkyl groups, * indicates a connection site with CH2, and ** indicates a connection site with NH.

[0076] As a result, the compound of the present invention has one of the following general formulas: The definitions of each element in formula JPEG2026512838000010.jpg230155 are as described above.

[0077] In the above formula I-1, it is preferable that Z2 is O.

[0078] In addition, in the above formulas I-1, IIa-1, and IIb-1, R on the triazole ring 23 Depending on the substitution position of the group, the position of the double bond in the benzotriazole structure may change, but this is acceptable as long as the double bond in the benzotriazole ring structure is in the form of a conjugated double bond.

[0079] For example, R 23 Depending on the substitution position on the triazole ring of the group, JPEG2026512838000011.jpg64145

[0080] In the formula, R 23 is hydrogen and C 1-3 Selected from alkyl groups, * indicates a connection site with CH2, and ** indicates a connection site with NH.

[0081] In one aspect, JPEG2026512838000012.jpg52168

[0082] R 23 It is methyl; * indicates a connection site with CH2, and ** indicates a connection site with NH.

[0083] In one embodiment, the compound is selected from the group consisting of the following compounds: JPEG2026512838000013.jpg250152

[0084] In the present invention, the compounds described herein can be prepared by the following methods. The following methods and examples are for illustrative purposes only. These processes and examples should not be construed as limiting the present invention in any way. The compounds described herein can be synthesized by standard synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and the methods described herein.

[0085] The chemical reactions in the examples herein are carried out in a suitable solvent, which must be suitable for the chemical changes described herein and the reagents and materials required therefor. To obtain the compounds of the present invention, it may be necessary for those skilled in the art to modify or select synthesis steps or reaction processes based on existing embodiments.

[0086] A key consideration in the experimental design of any synthetic route in this field is the selection of appropriate protecting groups for reactive functional groups (e.g., aminos in this disclosure). For trained operators, Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991) is the authority in this field. All references cited herein are incorporated herein in their entirety.

[0087] The reactions described herein can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be monitored by optical methods such as infrared spectroscopy, spectrophotometric methods (e.g., UV-visible light), mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin-layer chromatography.

[0088] The compound of general formula I of the present invention can be prepared by those skilled in the field of organic synthesis using standard methods in the art by the following process: JPEG2026512838000014.jpg105162 Compound 1 undergoes a condensation reaction with compound 2 to produce compound 3, compound 3 undergoes a reduction reaction to produce compound 4, and compound 4 undergoes an intramolecular conjugate reaction to obtain the compound of formula I of the present invention.

[0089] Pharmaceutical composition and use The present invention relates to a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer or prodrug thereof, and a pharmaceutically acceptable carrier.

[0090] As demonstrated herein, the compounds of the present invention possess excellent TYK2 inhibitory activity, particularly acting on the TYK2 JH2 pseudokinase domain, and are allosteric inhibitors of TYK2 with potent blood-brain barrier penetration ability and high selectivity, and can be used to modulate TYK2-mediated diseases. Furthermore, the present invention relates to the use of the compounds or their pharmaceutically acceptable salts, hydrates, solvates, active metabolites, crystalline polymorphs, isotope-labeled compounds, isomers or prodrugs in the preparation of pharmaceutical compositions for the treatment of tyrosine kinase-mediated diseases.

[0091] In one embodiment, the tyrosine kinase is selected from TYK2 kinase. In one embodiment, diseases mediated by the tyrosine kinase include inflammatory autoimmune diseases, tumors, and neurodegenerative diseases. Here, inflammatory autoimmune diseases mainly include atopic dermatitis, hidradenitis suppurativa, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, and autoimmune diseases of the brain such as the central nervous system; tumors mainly include cancers such as leukemia, lymphoma, myeloma, and brain tumors; and neurodegenerative diseases mainly include cerebral atrophy, dementia, parkinsonist syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

[0092] The disclosure also relates to a method for treating a disease mediated by tyrosine kinase, the method comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer or prodrug thereof, or a pharmaceutical composition, to a patient in need of administration.

[0093] The present invention will be described in more detail by specific embodiments. The following examples are provided for illustrative purposes only and do not limit the present invention in any way. Those skilled in the art should readily recognize that various non-essential parameters can be changed or modified to obtain substantially the same results. According to one or more assays described herein, the compounds of the following examples were found to be allosteric inhibitors of TYK2.

[0094] Example 1: (7R,E)-3 6 -Methoxy-7-methyl-1 8 -(methylamino)-5,8-dioxa-2-aza-1(6,3)-imidazo[1,2-b]pyridazine-3(1,3)-benzeneheterocyclononan-9-one JPEG2026512838000015.jpg71118 Synthesis path: JPEG2026512838000016.jpg94164 Step A: 4-(bromomethyl)-1-methoxy-2-nitrobenzene JPEG2026512838000017.jpg4213310 g (59.8 mmol, 1.0 eq) of 1-methoxy-4-methyl-2-nitrobenzene was added to 150 mL of carbon tetrachloride, and the atmosphere was changed to a nitrogen atmosphere. Then, 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 the addition was complete, the reaction system was set to 80°C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, the residue was diluted with water, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA = 10:1 to 4:1) to obtain the product (13 g, yield = 88%).

[0095] Step B: (R)-1-((4-Methoxy-3-nitrobenzyl)oxy)prope-2-ol JPEG2026512838000018.jpg421345 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-propanediol. After replacing the atmosphere with nitrogen, the reaction system was cooled to 0°C, and 0.73 g (30.5 mmol, 1.5 eq) of 60% sodium hydride was added in several portions. After the addition was complete, the reaction system was allowed to react at room temperature for 2 hours. After the reaction was complete, water was added in an ice bath to quench the mixture, the pH was adjusted to 6-7 with 3 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA = 5:1 to 4:1) to obtain the product (1.28 g, yield = 27%).

[0096] LC-MS:(M+H) + ;m / z=242.1 Step C: 8-Bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate ethyl ester JPEG2026512838000019.jpg6813920 g (96.0 mmol, 1.0 eq) of 4-bromo-6-chloropyridazine-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. The reaction was then carried out overnight at 80°C after replacing the atmosphere with nitrogen. After the reaction was complete, the solvent was removed by reduced pressure until dry, and the residue was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA = 6:1~5:1) to obtain the product (21 g, yield = 72%).

[0097] LC-MS:(M+H) + ;m / z=303.9 Step D: 6-Chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate ethyl 6-chloro JPEG2026512838000020.jpg7614810 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 addition was complete, the reaction system was purged with nitrogen gas and the reaction was carried out overnight at 90°C. After the reaction was complete, the mixture was cooled to room temperature, concentrated, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (12 g, yield = 97%).

[0098] LC-MS:(M+H) + m / z = 375.1.

[0099] Step E: 6-Chloro-8-((4-Methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid JPEG2026512838000021.jpg62168 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, followed by 1.28 g (53.4 mmol, 4.0 eq) of lithium hydroxide (dissolved in 25 mL of water), and the mixture was stirred overnight at room temperature. The pH was adjusted to 4 using a 1 M HCl solution, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with water, dried over anhydrous sodium sulfate, and the mixture was distilled off under reduced pressure to obtain the crude product, which was used directly in the next step.

[0100] LC-MS:(M+H) + ;m / z=347.1 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-methanoate JPEG2026512838000022.jpg51122600 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)prope-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 overnight at room temperature. The solvent was removed under reduced pressure to a dry state, and the residue was extracted with dichloromethane. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (PE:EA = 5:1 to 4:1) to obtain the product (1.1 g, yield = 89%).

[0101] LC-MS:(M+H) + ;m / z=570.2 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-methanoate JPEG2026512838000023.jpg 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-methanoate 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, and the mixture was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure to a dry state, and the residue was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was used directly in the next step.

[0102] LC-MS:(M+H) + ;m / z=540.2 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]pyridazine-3(1,3)-benzeneheterocyclononan-9-one JPEG2026512838000024.jpg72158 At room temperature, the starting material (R)-1-((3-amino-4-methoxybenzyl)oxy)propan-2-yl 6-chloro-8-((4-methoxyphenyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-methanoate (900 mg, crude product) was added to a 10 mL reaction bottle, and 5 mL of 1,4-dioxane was added, followed by 869 mg (2.7 mmol, 2.0 eq) of cesium carbonate and 106 mg (0.1 mmol, 0.1 Ditert-butyl[2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine and palladium 2'-amino-[1,1'-biphenyl]-2-yl]methanesulfonic acid were added, the mixture was immediately purged with nitrogen gas, and the reaction bottle was stirred overnight at 90°C. After cooling, the reaction mixture was concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined and concentrated, and the residue was separated and purified by column chromatography to obtain the product (170 mg, 25%).

[0103] LC-MS:(M+H) + ;m / z=504.2 Step I: (7R,E)-3 6 -Methoxy-7-methyl-1 8 -(methylamino)-5,8-dioxa-2-aza-1(6,3)-imidazo[1,2-b]pyridazine-3(1,3)-benzeneheterocyclononan-9-one JPEG2026512838000025.jpg 68157160 mg (0.3 mmol, 1.0 eq) of (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]pyridazine-3(1,3)-benzeneheterocyclononan-9-one was dissolved in 3 mL of dichloromethane, and 1 mL of hydrochloric acid (4 M in 1,4-dioxane) solution was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was separated and purified by preparative liquid chromatography to obtain the product (8.8 mg).

[0104] LC-MS:(M+H) + ;m / z=384.2 1 H-NMR(400 MHz,DMSO-d6)δ9.05(s,1H),8.21(s,1H),8.00(s,1H),7.26(d,J=5.2 Hz,1H),6.95(d,J=8.0 Hz,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=4.8 Hz,3H),1.32(d,J=6.4 Hz,3H).

[0105] 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]pyrimidine-3(1,3)-benzeneheterocyclononan-9-one JPEG2026512838000026.jpg69160

[0106] Synthesis pathway: JPEG2026512838000027.jpg104169

[0107] Step A: 5,7-Dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate ethyl carboxylate JPEG2026512838000028.jpg68145 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, followed by 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. The reaction mixture was raised to 80°C and stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the solvent, and diluted with water, resulting in a precipitate. The precipitated solid was filtered, and the filtered cake was dried to obtain the product (21.0 g, 73%).

[0108] LC-MS:(M+H) + ;m / z=224.1 Step B: 5,7-Dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate JPEG2026512838000029.jpg68137

[0109] 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, followed by 22.2 g (281.3 mmol, 3.0 eq) of pyridinium and 73 g (469.1 mmol, 5.0 eq) of phosphorus oxychloride. The reaction mixture was stirred overnight at 100°C. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the phosphorus oxychloride. The mixture was diluted with water in an ice bath, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the product was extracted with dichloromethane. The mixture was concentrated under reduced pressure to obtain the product (17.0 g, 70%).

[0110] LC-MS:(M+H) + ;m / z=260.0 Step C: 5-Chloro-7-((4-methoxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate ethyl JPEG2026512838000030.jpg74154

[0111] 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 system was purged with nitrogen gas and allowed to react overnight at 90°C. After the reaction was complete, the mixture was cooled to room temperature, concentrated, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and the residue was separated and purified by column chromatography to obtain the product (2.1 g, 30%).

[0112] LC-MS:(M+H) + ;m / z=375.1 Step D: 5-Chloro-7-[(4-methoxyphenyl)methyl](methyl)amino}pyrazolo[1,5-a]pyrimidine-3-carboxylic acid JPEG2026512838000031.jpg621262.0 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 allowed to react overnight at 100°C. After the reaction was complete, the mixture was cooled to room temperature, concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and the residue was purified by reverse-phase C18 column separation to obtain the product (1.0 g, 54%).

[0113] LC-MS:(M+H) + ;m / z=347.1 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 JPEG2026512838000032.jpg83150

[0114] 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. Then, 1.39 g (5.8 mmol, 2.0 eq) of (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 in sequence, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water, extracted with dichloromethane, the organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain a pale yellow oily product (1.5 g, 73%).

[0115] LC-MS:(M+H) + ;m / z=570.2 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 JPEG2026512838000033.jpg79153

[0116] 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, followed by the addition of 2 mL of acetic acid and 1.28 g (19.7 mmol, 10 eq) of zinc powder. The reaction mixture was left at room temperature and stirred overnight. After the reaction was complete, the zinc powder was filtered, the filtrate was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain the product (1.4 g, crude product).

[0117] LC-MS:(M+H) + ;m / z=540.2 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]pyrimidine-3(1,3)-benzeneheterocyclononan-9-one JPEG2026512838000034.jpg73164

[0118] At room temperature, 1.3 g (crude) of (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. Then, 1.18 g (3.6 mmol, 2.0 eq) of cesium carbonate, 140 mg (0.2 mmol, 0.1 eq) of ditert-butyl[2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine, and palladium 2'-amino-[1,1'-biphenyl]-2-yl}methanesulfonic acid were added in sequence, the mixture was purged with nitrogen gas, and the reaction was stirred at 90°C for 6 hours. The solution was cooled, concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, combined with the organic phase, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain a pale yellow solid product (750 mg, 74%).

[0119] LC-MS:(M+H) + ;m / z=504.2 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]pyrimidine-3(1,3)-benzeneheterocyclononan-9-one JPEG2026512838000035.jpg 47119650 mg (1.3 mmol, 1.0 eq) of (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]pyrimidine-3(1,3)-benzeneheterocyclononan-9-one was dissolved in 10 mL of dichloromethane, and 3 mL of hydrochloric acid (4 M in 1,4-dioxane) solution was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was prepared by high-pressure liquid chromatography, separated, and purified to obtain the product (96.8 mg, 20%).

[0120] LC-MS:(M+H) + ;m / z=384.2 1 H-NMR(400 MHz,DMSO-d6)δ9.37(s,1H),8.71(s,1H),8.23(s,1H),7.70(d,J=4.8 Hz,1H),6.95(d,J=8.4 Hz,1H),6.75(d,J=8.0 Hz,1H),6.06(s,1H),4.87(t,J=5.2 Hz,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=4.8 Hz,3H),1.32(d,J=6.4 Hz,3H).

[0121] The following examples were prepared with reference to the experimental pathway and method of Example 1 or Example 2: JPEG2026512838000036.jpg249170JPEG2026512838000037.jpg242170JPEG2026512838000038.jpg230170JPEG2026512838000039.jpg171170

[0122] Biological activity and pharmacokinetic experiments 1. Enzymatic activity of the compound against TYK2-JH2 and JAK1-JH2 (IC) 50 Experiment to detect ) 1.2 μL each of control compound A, duklavacitinib, and the test compound (compound from the example) were taken and added to 58.8 μL of DMSO to dilute from a 10 mmol / L stock solution to 0.2 mmol / L. Then, the solutions were diluted fourfold to obtain 10 different concentrations. Using an Echo, 50 nL of the test material was transferred to a 384-well reaction plate, with each compound plated in two overlapping wells. The solutions were centrifuged at 1000 rpm for 1 minute, and the final DMSO concentration for all solutions was adjusted to 0.5%. 5 μL of TYK2 (or JAK1) was added to the 384-well reaction plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. 5 μL of JH2 probe 1 was added to the 384-well reaction plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. The FP 520 / 48 signal was read using a BMG high-throughput drug screening multifunction microplate reader.

[0123] The experimental data for YK2-JH2 were analyzed using GraphPad Prism 8 software. The negative control (well with 0.5% DMSO) reading was set to 0% inhibition, and the positive control (well with the highest concentration of the control compound) reading was set to 100% inhibition. After calculating the inhibition rates, the IC50 ratio of the control and test compounds was calculated using the software's nonlinear approximation formula. 50 The value (median inhibitory concentration) was obtained.

[0124] JPEG2026512838000040.jpg46150Specific IC 50 The detection results are shown in Table 1 below:

[0125] Table 1 Compound IC of the example 50 Detection results JPEG2026512838000041.jpg103159

[0126] As is clear from Table 1, all of the compounds in the examples of the present invention showed excellent enzymatic inhibitory activity against TYK2-JH2, and some of these compounds showed IC25 activity.50 The concentration was less than 5 nM. The compounds of the examples of the present invention showed low inhibitory activity against JAK1-JH2 and IC2. 50 The concentration was >5000 nM. Based on these results, the compound of the present invention was confirmed to be a potent and highly selective TYK2 (tyrosine kinase 2) allosteric inhibitor.

[0127] 2. Affinity of compounds for JAK1-JH2 and TYK2-JH2 (K d )analysis 1) Buffer preparation: An appropriate running buffer was prepared according to the situation.

[0128] 2) Pre-enrichment: The ligand was conjugated to a CM5 chip, and the conjugation conditions for TYK2 / JAK1 were explored.

[0129] 3) Ligand conversion: An appropriate amount of TYK2 / JAK1 was immobilized on the tip.

[0130] 4) Kinetic assay: An appropriate kinetic method (usually single-cycle or multi-cycle kinetics) was selected, and contact time, dissociation time, and flow rate were set according to the actual conditions. The concentration gradient of the analyte was set based on the possible KD value, and the molecular interaction status was monitored in real time by the instrument.

[0131] 5) Data Analysis: TYK2 experimental data were analyzed using Biacore Insight evaluation software, and the software evaluated the K of TYK2-JH2 and JAK1-JH2 coupling. d The value was automatically estimated.

[0132] The test results showed that the compound in the example had high affinity for TYK2-JH2 and low affinity for JAK1-JH2, indicating high selectivity.

[0133] 3. Pharmacokinetic studies Male SD rats were divided into groups of three, and each group received either the compound from Example 2 (2 mg / kg) intravenously or a single oral dose of the compound from Example 2 (10 mg / kg) or the control compound (10 mg / kg) into the stomach. The animals were fasted overnight before the experiment, from 10 hours before administration to 4 hours after administration. Blood samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration in animals administered intravenously, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration in animals administered orally. After anesthetizing the animals with isoflurane, 0.3 mL of whole blood was collected from the retinal venous plexus and placed in a heparin sodium collection tube. The samples were centrifuged at 4°C and 4000 rpm for 5 minutes, the plasma was transferred to a centrifuge tube, and the samples were stored at -80°C until analysis. Plasma samples were extracted by protein precipitation, and the extracts were analyzed by LC / MS / MS. The results of the pharmacokinetic studies are shown in Tables 2 and 3 below:

[0134] Table 2 Pharmacokinetic parameters of the compound in Example 2 in rat plasma after intravenous administration JPEG2026512838000042.jpg79149

[0135] Table 3 Pharmacokinetic parameters of the compound in Example 2 in rat plasma after oral administration As shown in Table 3 (JPEG2026512838000043.jpg66170), the compound of Example 2 of the present invention exhibited good bioavailability after oral administration, at 57.1%, and its oral drug exposure was confirmed to be far superior to that of control compounds A and B.

[0136] 4. Experiments on the distribution of the blood-brain barrier Male SD rats were divided into groups of three and administered either a single oral intragastric (PO) dose of the drug compound (10 mg / kg) or a single intravenous (IV) dose of the drug compound (2 mg / kg). The animals were fasted overnight before the experiment, with fasting periods ranging from 10 hours to 4 hours after administration. Each rat was euthanized 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 4000 rpm for 5 minutes, the plasma was transferred to a centrifuge tube, and stored at -80°C until analysis. The samples in the plasma were extracted by protein precipitation, and the extracts were analyzed by LC / MS / MS. The obtained data revealed that the compounds in the examples of the present invention possessed a blood-brain barrier crossing ability that exceeded expectations.

[0137] As shown in Table 4, the brain / blood drug concentration ratio of the compound in Example 2 reached 5.08 at 0.5 hours after oral administration, indicating that its brain penetration capacity exceeded expectations. On the other hand, the brain penetration rates of duclavacitinib and control compound A were found to be extremely low.

[0138] Table 4 Ratio of drug concentration in the blood brain of rats 0.5 h after oral administration in Example 2 JPEG2026512838000044.jpg38161 Similar tests were conducted, and the compounds in the other examples also showed extremely high brain / blood drug concentration ratios that exceeded expectations.

[0139] Table 5 Ratio of blood cerebral drug concentrations after administration in different examples The compound of the present invention is the first class of allosteric inhibitors of TYK2 that possess brain-penetrating properties and high selectivity, and is also the structural type with the strongest brain-penetrating ability among the reported molecular structures.

[0140] The characteristics of duklavacitinib, control compound A, and control compound B, which are used for comparison in this specification, are as follows: Duclavacitinib has the following structure: JPEG2026512838000046.jpg95161

[0141] Control compound A has the following structure and can be prepared according to the preparation method of Example 1 in the document WO2022060973A1: JPEG2026512838000047.jpg72150

[0142] Control compound B has the following structure and can be prepared according to the preparation method of Example 25 in the document WO2020185755A1: JPEG2026512838000048.jpg49120

[0143] This specification describes the above-mentioned preferred embodiments, which are merely illustrative and for illustrative purposes only. Based thereon, various substitutions and improvements to the present invention are possible, all of which fall within the scope of protection of the present invention.

Claims

1. The compound represented by formula I, or its pharmaceutically acceptable salts, hydrates, solvates, active metabolites, crystalline polymorphs, isotope-labeled compounds, isomers, or prodrugs. (In the above formula I, X and Y are selected from the group consisting of N and C, where one of X and Y is N and the other is C; W is selected from the group consisting of N and C; Z １ They are independently selected from the group consisting of O and S; Z ２ R is selected from the group consisting of O, S, and NR, where R is hydrogen or C １－６ It is alkyl; R １ 、 R ２ and R ３ each independently is selected from the group consisting of hydrogen, halogen, oxo, C １－６ alkyl and C １－６ alkoxy; or, R ２ and R ３ together with the ring atom to which they are attached form a 5- to 6-membered heteroaryl ring substituted with 0 to 2 R ２３ ; R ４ NR ４１ R ４２ , C １－６ Alkyl and C １－６ Selected from the group consisting of alkoxys; R ５ is hydrogen and NR ５１ R ５２ Selected from; L is independently -CR Ｌ１ R Ｌ２ - Selected from; R in each L Ｌ１ and R Ｌ２ These are hydrogen and C, respectively, independently. １－６ Selected from the group consisting of alkyl groups, or two R in two adjacent Ls. Ｌ２ These are linked together with 0 to 2 R atoms in the L atom. ２３ C replaced by ３－６ Forming a cycloalkyl ring; R ２３ These are halogen and C, respectively, independently. １－６ Alkyl and C １－６ Selected from the group consisting of alkoxys; R ４１ and R ４２ These are hydrogen and C, respectively, independently. １－６ Selected from the group consisting of alkyl groups; R ５１ and R ５２ These are hydrogen and C, respectively, independently. １－６ Selected from the group consisting of alkyl groups; n is an integer between 2 and 5.

2. The compound is represented by formula IIa or formula IIb, In the formula, R １ , R ２ , R ３ , R ４ , R ５ The definitions of W, L, and n are the same as those in claim 1. The compound described in claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

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

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

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

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

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

8. In (L)n, which is formed by n Ls, the R is methyl. Ｌ２ There is one. The compound described in claim 7, or a pharmaceutically acceptable salt, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

9. n is either 2 or 3; L is independently -CR Ｌ１ R Ｌ２ - Selected from, and here, R in each L Ｌ１ It is hydrogen, and two R in two adjacent L Ｌ２ These are linked together with the carbon atoms in L, and C ３－６ Forming a cycloalkyl ring, The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

10. The (L)n formed by n Ls is *-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 -**, Here, * is Z １ This represents the bonding site with an atom, and ** represents the bonding site with an oxygen atom. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

11. The (L)n formed by n Ls is *-CH(CH ３ )CH ２ -** is; Here, * is Z １ This represents the bonding site with an atom, and ** represents the bonding site with an oxygen atom. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

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

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

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

17. Here, R ２３ is selected from hydrogen and C １－３ alkyl, * is CH ２ This represents the linked site with NH, and ** represents the linked site with NH. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

18. Here, R ２３ is hydrogen and C １－３ Selected from alkyl groups, * is CH ２ This represents the linked site with NH, and ** represents the linked site with NH. The compound described in claim 17, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

19. Here, R ２３ is methyl; * represents a linking site with CH ２ and ** represents a linking site with NH. The compound described in claim 17, or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, crystalline polymorph, isotope-labeled compound, isomer, or prodrug thereof.

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

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

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

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

24. The use according to claim 22, wherein the disease mediated by the tyrosine kinase includes inflammatory autoimmune diseases, tumors, or neurodegenerative diseases.

25. The use according to claim 22, wherein inflammatory autoimmune diseases are selected from the group consisting of atopic dermatitis, hidradenitis suppurativa, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, scleroderma, and autoimmune encephalopathy; tumors are selected from the group consisting of leukemia, lymphoma, myeloma, and brain tumors; and neurodegenerative diseases are selected from the group consisting of cerebral atrophy, dementia, parkinsonist syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

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

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