Sulfoxide imine compound and application thereof in medicine

Abstract

The invention provides a sulfoximine compound with a structure as shown in a formula (I) or pharmaceutically acceptable salts, isotope derivatives and solvates of the sulfoximine compound, or stereoisomers, geometric isomers and tautomers of the sulfoximine compound, or prodrug molecules and metabolites of the sulfoximine compound, as well as a medicinal composition and application of the sulfoximine compound. The compound provided by the invention can efficiently inhibit the activity of TYK2, and can be used for preparing drugs for preventing and treating proliferative diseases, metabolic diseases, allergic diseases, inflammatory diseases and autoimmune diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a sulfoximine compound binding to the pseudokinase domain (JH2) of non-receptor tyrosine-protein kinase 2 (TYK2), a preparation method thereof and a medical use thereof, in particular to a compound shown in formula (I) or a pharmaceutically acceptable salt, isotope derivative, solvate, stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, and a medical use thereof. BACKGROUND

[0002] The Janus kinase (JAK) family is a class of intracellular non-receptor tyrosine kinases, including four subtypes of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). The JAK family is involved in hematopoiesis, lymphocyte differentiation and function, mucus secretion, bone resorption and inflammatory response, and plays a key role in the signal transduction of cytokines and growth factors.

[0003] TYK2 is the first subtype discovered in the JAK family, which is mainly involved in the regulation of IL-23, IL-12 and type I interferon (IFNα) signaling. The signal pathways mediated by these cytokines are closely related to autoimmune diseases and inflammatory diseases such as psoriasis and inflammatory bowel disease. In addition, TYK2 may also be a potential therapeutic target for some cancers, such as the abnormal survival of T-ALL cells is related to the activation of TYK2.

[0004] The JAK family members are all composed of four JAK homology regions (JH), including a catalytically active kinase domain (JH1), a catalytically inactive pseudokinase domain (JH2), a SH2-like domain (JH3) and four FERM domains (JH4-7). Early JAK inhibitors mainly compete with the binding of ATP to the kinase domain JH1, but due to the high homology of the JH1 domain between different subtypes, JH1 inhibitors often have insufficient selectivity in the same JAK family, resulting in more serious side effects such as infection, tuberculosis, tumor, anemia, liver damage and increased cholesterol. Therefore, the development of a TYK2 selective inhibitor with higher safety has great potential for clinical application.

[0005] Although the TYK2 JH2 domain is highly similar in overall folding and conformation to JAK1 and JAK2, residues in the selective JH2 binding site are not highly conserved among JAK family members. This provides an opportunity for selective TYK2 inhibitors by targeting the TYK2 JH2 domain. Deucravacitinib (BMS-986165) developed by Bristol-Myers Squibb is the first selective inhibitor acting on TYK2 JH2, which inhibits TYK2 kinase function through an allosteric effect without binding to the JH1 region of JAKs. The drug has been approved by the National Medical Products Administration (NMPA) of China on October 18, 2023 for the treatment of plaque psoriasis.

[0006] In summary, the inhibitors targeting the TYK2 JH2 domain can better balance the safety and effectiveness of the drug with its new binding mode, and have become a promising disease treatment strategy. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a structurally novel sulfoximine compound which can be used as a TYK2 inhibitor for preparing a drug for treating TYK2-mediated diseases or disorders and related diseases or disorders. To solve the above technical problem, the technical solution provided by the present application is as follows:

[0008] In one aspect, the present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof:

[0009]

[0010] wherein,

[0011] A is a 5-6 membered heteroaryl, which is optionally further substituted with one or more substituents selected from a deuterium atom, C 1-3 alkyl or halogen,

[0012] L is selected from a bond or

[0013] Alternatively, A and L form

[0014] R1 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14aryl or 5-14 membered heteroaryl, each optionally substituted with one or more substituents selected from a deuterium atom, cyano, nitro, or halogen; 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, each optionally substituted with one or more substituents selected from a deuterium atom, cyano, nitro, or halogen;

[0015] R2is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, each optionally substituted with one or more substituents selected from a deuterium atom, cyano, nitro, or halogen; 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, each optionally substituted with one or more substituents selected from a deuterium atom, cyano, nitro, or halogen;

[0016] R3is selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl containing 1 to 4 heteroatoms, wherein the heteroatoms are selected from O, N or S, each optionally substituted with one or more substituents selected from a deuterium atom or halogen; 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclyl containing 1 to 4 heteroatoms, each optionally substituted with one or more substituents selected from a deuterium atom or halogen;

[0017] X is selected from CR7or N;

[0018] Y is selected from CH or N;

[0019] Ring B is 5-6 membered heteroaryl;

[0020] R4is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C1-6 alkoxy C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl or 5-6 membered heteroaryl, said C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkynyl or 5-6 membered heteroaryl can be optionally substituted with one or more R’ selected from halogen, cyano, nitro, deuterium atom, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl or C 3-6 cycloalkyl, when R’ is selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl or C 3-6 cycloalkyl, said R’ can be further substituted with one or more substituents selected from deuterium atom, cyano, nitro or halogen;

[0021] R5is selected from C 1-6 alkyl, C 1-6 deuteroalkyl or C 1-6 haloalkyl;

[0022] R6, R7are each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl.

[0023] In some embodiments, in the compounds of general formula (I), or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolic product thereof, said R5is selected from C 1-6 alkyl or C 1-6 haloalkyl.

[0024] In further embodiments, said R5is selected from -CH3or -CF3.

[0025] In some embodiments, the compound represented by formula (I), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has a structure represented by formula (II), (III), (IV) or (V) as follows:

[0026]

[0027] The definitions of A, L, R1, R2, R3, ring B, R4, R6, and R7 are as described in general formula (I).

[0028] In some embodiments, the compound represented by formula (I), (II), (III), (IV) or (V), or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, wherein ring B is a 5-6 member nitrogen-containing heteroaryl group;

[0029] R4 is selected from halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl, C 3-6 The alkynyl or 5-6 heteroaryl group, wherein the 5-6 heteroaryl group is optionally substituted with one or more substituents selected from halogens.

[0030] In some embodiments, the compound represented by formula (I), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, has a structure represented by formula (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb):

[0031]

[0032] The definitions of A, L, R1, R2, R3, R6, and R7 are as described in general formula (I);

[0033] The R 42a R 43a R 44a R 45a Each is independently selected from halogens or 5-6 nitrogen-containing heteroaryl groups, wherein the 5-6 nitrogen-containing heteroaryl groups are optionally further substituted by one or more halogens;

[0034] The R 42b R 43b R 44b R 45b Each was independently selected from C1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl or C 3-6 alkynyl group;

[0035] The R 42c R 42d Each was independently selected from C 1-6 alkyl.

[0036] In a further implementation, the R 42a R 43a R 44a Each is independently selected from -F or The R 45a For -F, the R 42b Selected from -CH3, -CD3, The R 43b R 44b R 45b R 42c R 42d It is -CH3.

[0037] In some embodiments, in the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecule or metabolite, A is a 6-membered nitrogen-containing heteroaryl group, and L is selected from bonds or Or A and L form

[0038] In a further embodiment, A and L form the following structure:

[0039] In some embodiments, in the compounds represented by the above general formulas, or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecule or metabolite thereof, R1 is selected from C 1-6 alkyl.

[0040] In some embodiments, in the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecule or metabolite, R2 is selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0041] In some embodiments, in the compounds represented by the above general formulas, or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecule or metabolite thereof, R3 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy or C 1-6 Alkylamine group.

[0042] In some embodiments, R6 is selected from hydrogen in the compounds represented by the above general formulas, or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules or metabolites thereof.

[0043] In some embodiments, R7 is selected from hydrogen in the compounds represented by the above general formulas, or pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules or metabolites thereof.

[0044] In some embodiments, the compounds represented by the above general formulas, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or their stereoisomers, geometric isomers, tautomers, or their prodrug molecules or metabolites are selected from the following structural compounds:

[0045]

[0046]

[0047]

[0048] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb) or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof.

[0049] In another aspect, the present invention provides the use of compounds of formulas (I), (II), (III), (IV), (V), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb) as described above, or their pharmaceutically acceptable salts, isotope derivatives, solvates, or stereoisomers, geometric isomers, tautomers, or prodrug molecules, metabolites, or pharmaceutical compositions described above, in the preparation of medicaments for treating TYK2-mediated diseases or conditions and related diseases or conditions.

[0050] The present invention also provides a method for treating and / or preventing disease, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb) as described above, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or a pharmaceutical composition described above.

[0051] In some implementations, the diseases to be treated and / or prevented are TYK2-mediated diseases or conditions and related diseases or conditions, including proliferative diseases, metabolic diseases, allergic diseases, inflammatory diseases, infectious diseases, neurodegenerative diseases and autoimmune diseases.

[0052] Furthermore, the TYK2-mediated diseases or conditions and related diseases or conditions are selected from psoriasis, systemic lupus erythematosus, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, dermatitis, inflammatory bowel disease, diabetes, sepsis, septic shock, Shigella disease, Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis (RMS and / or progressive MS, including CIS, optic neuritis, neuromyelitis optica), cerebral ischemia or neurodegenerative diseases or cancer caused by traumatic injury.

[0053] Preferably, the inflammatory disease or autoimmune disease is selected from arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, inflammatory bowel disease, psoriasis, psoriatic arthritis, intestinal diseases, Crohn's disease, Sjögren's syndrome, systemic scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult-onset Still's disease, juvenile idiopathic arthritis, gout, gouty arthritis, sepsis, septic shock, Shigella infection, pancreatitis, glomerulonephritis, spontaneous nephritis, and autoimmune hemolytic disease. Anemia, autoimmune neutropenia, thrombocytopenia, vitiligo, atopic dermatitis, myasthenia gravis, ankylosing spondylitis, pemphigus vulgaris, pulmonary hemorrhage-nephritis syndrome, antiphospholipid syndrome, idiopathic thrombocytopenic purpura, ANCA-associated small vessel vasculitis, pemphigus, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, polymyositis, uveitis, Guillain-Barré syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, chronic demyelinating polyneuropathy, alopecia areata, and hidradenitis suppurativa.

[0054] Preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer, lung cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumors, peritoneal tumors, melanoma, glioma, neuroblastoma, head and neck cancer, leukemia, lymphoma, and myeloma.

[0055] The "compounds represented by the above general formulas" in this invention refers to compounds selected from any one or more of the general formulas (I), (II), (III), (IV), (V), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb).

[0056] In some embodiments, the present invention provides an intermediate compound M2, chemically named 5-(isopropylthio)pyrimidine-2-amine, with the following structural formula:

[0057]

[0058] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0059] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0060] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6 "" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0061] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0062] The term "alkylamino" refers to an open-chain alkyl group containing a nitrogen atom, such as C1-C6 alkylamino groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0063] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom has been replaced by a hydroxyl group, such as hydroxymethyl, hydroxyethyl, hydroxymethyl-ethyl, hydroxypropyl, hydroxymethylpropyl, and dihydroxypropyl.

[0064] The term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by deuterium atoms.

[0065] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C 3-12 Cycloalkyl, more preferably C 3-6 Yuan, of which "C" 3-12 The term "cycloalkyl" refers to the fact that a cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic atoms. The cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclic, or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0066] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0067] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, 1-propynyl, 3-propynyl, etc.

[0068] The term "aryl" refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising a carbon ring atom. C is preferred. 6-12 Aryl, more preferably aryl, is C 6-10Aromatic ring groups, either monocyclic or bicyclic. Preferably phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring; non-limiting examples include, but are not limited to, benzocyclopentyl.

[0069] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl, and even more preferably, it is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0070] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, wherein the heteroatom is selected from N, O, and / or S. The heterocyclic group can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-6 membered heterocyclic group, and even more preferably, a 5-6 membered heterocyclic group; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, aza-butyl, pyrrolidinyl, piperidinyl, piperazinyl, oxoperazinyl, oxoperridinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. Spiroheterocycles can be 6- to 12-membered spiroheterocycles, including, but not limited to, 4-azaspiro[2,4]heptane and 4-azaspiro[2,4]heptane. The heterocyclic group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0071] The term "cyano" refers to the -CN group.

[0072] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0073] The "compound" described in this invention includes, but is not limited to, compounds in the following forms: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0074] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0075] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0076] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or acid addition salt.

[0077] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in water or an organic solvent, or a mixture thereof, with a stoichiometric amount of a suitable base or acid in the form of a free acid or base.

[0078] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereo isomers, enantiomers, optical isomers, diastereomers and tautomers.

[0079] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0080] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0081] When the compounds provided by this invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0082] When the compound provided by this invention is a base, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0083] The drug prodrugs of the compounds of this invention are included within the scope of protection of this invention. Generally, a drug prodrug refers to a functional derivative that is readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of this application, which, upon administration to a receptor, can directly or indirectly provide the compound of this application or its pharmaceutically active metabolites or residues.

[0084] The so-called metabolites produced by the breakdown of the compounds of the present invention in the body are also included within the scope of the claims of this application. The "metabolites" of the compounds disclosed in this invention are derivatives formed during the metabolism of the compounds. The metabolites of the compounds disclosed in this invention may optionally be identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds.

[0085] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0086] Unless otherwise stated, this invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof, when the compounds represented by formulas (I), (II), (III), (IV), (V), (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb) are present.

[0087] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0088] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their pharmaceutical salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0089] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0090] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0091] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0092] Typical routes of administration for the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0093] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0094] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0095] The term "TYK2" refers to tyrosine protein kinase 2.

[0096] Based on the target of TYK2 inhibitors, this invention developed a series of novel sulfoxide imine compounds and conducted related biological experiments. The results showed that the series of compounds significantly inhibited TYK2 activity, had good stability in liver microsomal metabolism, and exhibited superior active transport and passive diffusion-mediated permeation properties. They also showed good pharmacokinetic properties in mice and have great potential for clinical application. Detailed Implementation

[0097] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0098] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0099] This invention uses the following abbreviations:

[0100] ACN: Acetonitrile; DCM: Dichloromethane; DMF: N,N-Dimethylformamide; DMF-DMA: N,N-Dimethylformamide dimethyl acetal; DIPEA: N,N-Diisopropylethylamine; AcOK: Potassium acetate; PE: Petroleum ether; EA: Ethyl acetate; LC-MS: Liquid chromatography-mass spectrometry; Pd2(dba)3: Tris(dibenzylacetone)dipalladium; XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene; PhI(AcO)2: Iodophenyldiacetic acid; AcNH4: Ammonium acetate; MeOH: Methanol; Pd(PPh3)4: Tetra(triphenylphosphino)palladium; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; TBS-Cl: tert-butyldimethylchlorosilane; Ph3P: triphenylphosphine; Et3N: triethylamine; MeOTf: methyl trifluoromethanesulfonate; Et2O: diethyl ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran; PBS: phosphate buffer; DMSO: dimethyl sulfoxide; HBSS: Hanks balanced salt solution; HEPES: hydroxyethylpiperazine ethanesulfonic acid; tris: tris(hydroxymethyl)aminomethane; HPMC: hydroxypropyl methylcellulose; PEG: polyethylene glycol; Tween: Tween; Saline: sodium chloride.

[0101] Synthesis of intermediate M1 in Preparation Example 1

[0102]

[0103] Step 1: Synthesis of 4,6-dichloropyridazine-3-formyl chloride (M1-2)

[0104] 4,6-Dihydroxypyridazine-3-carboxylic acid (M1-1, 15.00 g, 96.09 mmol) was dissolved in triethylamine (9.72 g, 96.09 mmol), and phosphorus oxychloride (150 mL) was slowly added dropwise under an ice-water bath and nitrogen protection. After the addition was complete, the reaction mixture was transferred to 110 °C and refluxed for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the crude product was directly used for the next reaction.

[0105] Step 2: Synthesis of 4,6-dichloro-N-methylpyridazine-3-carboxamide (M1)

[0106] Under nitrogen protection, the crude product obtained in step 1 was dissolved in ultra-dry tetrahydrofuran (200 mL), and methylamine hydrochloride (9.73 g, 144.10 mmol) was added. N,N-diisopropylethylamine (24.84 g, 192.20 mmol) was slowly added dropwise in an ice-water bath. After the addition was complete, the ice-water bath was removed. The reaction was allowed to proceed at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1 to 1:1) to give 4,6-dichloro-N-methylpyridazine-3-carboxamide (10.20 g), in 51.5% yield.

[0107] LC-MS (m / z): 205.9 [M+H] + .

[0108] Preparation Example 2: Synthesis of Intermediate M2

[0109]

[0110] Step 1: Synthesis of 5-(isopropylthio)pyrimidine-2-amine (M2)

[0111] 2-Amino-5-fluoropyrimidine (M2-1, 5.00 g, 44.25 mmol) and sodium 2-propanethiolate (8.69 g, 88.55 mmol) were dissolved in N,N-dimethylformamide (50 mL) and stirred at 40 °C for 12 h. After the reaction was complete, the reaction mixture was diluted with water (150 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 5-(isopropylthio)pyrimidine-2-amine (3.30 g), yield 45.4%.

[0112] LC-MS (m / z): 170.0 [M+H] + .

[0113] Synthesis of intermediate M3 in Preparation Example 3

[0114]

[0115] Step 1: Synthesis of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (M3-3)

[0116] Under nitrogen protection, 3-bromo-2-methoxyaniline (M3-1, 25.00 g, 123.73 mmol) and pinocynal diboronate (M3-2, 47.13 g, 185.60 mmol) were dissolved in ultra-dry 1,4-dioxane (375 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (9.05 g, 12.37 mmol) and potassium acetate (36.43 g, 371.20 mmol) were added. The reaction was carried out at 130 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate (375 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 50:1 to 15:1) to give 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (28.11 g), with a yield of 91.2%.

[0117] LC-MS: m / z = 249.8 [M+H] + .

[0118] Step 2: Synthesis of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (M3-4)

[0119] Under nitrogen protection, 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (M3-3, 10.00 g, 40.80 mmol), 3-bromo-1-methyl-1,2,4-triazole (8.10 g, 49.80 mmol), and water (20 mL) were dissolved in 1,4-dioxane (100 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (300 mg, 0.41 mmol) and potassium carbonate (16.90 g, 122.28 mmol) were added. The reaction was carried out at 110 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate (80 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 2:1 to 1:2) to give 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (4.40 g), with a yield of 52.6%.

[0120] LC-MS: m / z = 205.0 [M+H] + .

[0121] Step 3: Synthesis of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (M3)

[0122] 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (M3-4, 1.90 g, 9.26 mmol), 4,6-dichloro-N-methylpyridazin-3-carboxamide (M1, 1.91 g, 9.26 mmol), and N,N-diisopropylethylamine (2.39 g, 18.53 mmol) were dissolved in acetonitrile (20 mL). The reaction was carried out under microwave conditions at 120 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with acetonitrile (20 mL), and filtered. The filter cake was slurried with ethyl acetate (50 mL) and filtered to give 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazin-3-carboxamide (1.78 g), yield 51.5%.

[0123] LC-MS: m / z = 374.1 [M+H] + .

[0124] Preparation Example 4: Synthesis of Intermediate M4

[0125]

[0126] Step 1: Synthesis of tert-butyl 3-(6-aminopyridin-3-yl)azacyclobutane-1-carboxylate (M4)

[0127] Under nitrogen protection, (6-aminopyridin-3-yl)boronic acid (M4-1, 2.44 g, 17.66 mmol) and tert-butyl 3-iodoazacyclobutane-1-carboxylate (5.0 g, 17.66 mmol) were dissolved in a mixed solvent of DMF (50 mL) and water (10 mL), and tetrakis(triphenylphosphine)palladium (2.0 g, 1.766 mmol) and potassium carbonate (7.32 g, 52.98 mmol) were added. The reaction was carried out at 60 °C for 8 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to give tert-butyl 3-(6-aminopyridin-3-yl)azacyclobutane-1-carboxylate (2.7 g), with a yield of 61.4%.

[0128] LC-MS: m / z = 250.0 [M+H] + .

[0129] Synthesis of intermediate M5 in Preparation Example 5

[0130]

[0131] Step 1: Synthesis of N-(tert-butyldimethylsilyl)methanesulfonamide (M5-3)

[0132] Methanesulfonamide (M5-1, 5.0 g, 52.5 mmol), triethylamine (15.8 g, 157.0 mmol), and DCM (60 mL) were added to a reaction flask and stirred at 0 °C. Tert-butyldimethylchlorosilane (M5-2, 8.69 g, 57.7 mmol) was dissolved in DCM (40 mL) and slowly added dropwise to the flask. After the addition was complete, the reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with DCM (50 mL × 3), and the combined organic phases were washed with saturated NaCl (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with PE (50 mL) for 3 hours. After slurrying, the mixture was filtered, and the filter cake was dried to give N-(tert-butyldimethylsilyl)methanesulfonamide (8.52 g), yield 77.5%.

[0133] 1 H NMR (600MHz, DMSO-d6) δ7.03(s,1H),2.91(s,3H),0.90(s,9H),0.17(s,6H).

[0134] Step 2: Synthesis of N-(tert-butyldimethylsilyl)methanesulfonylimide chloride (M5-4)

[0135] Triphenylphosphine (4.3 g, 16.5 mmol), hexachloroethane (3.9 g, 16.5 mmol), and chloroform (15 mL) were added to a reaction flask and refluxed at 70 °C for 6 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, and triethylamine (2.27 g, 22.5 mmol) was added. The mixture was reacted at room temperature for 10 minutes. After the reaction was complete, the mixture was cooled to 0 °C, and a chloroform (12 mL) solution of N-(tert-butyldimethylsilyl)methanesulfonamide (M5-3, 3.14 g, 15.0 mmol) was slowly added to the system. The mixture was reacted for 30 minutes. The system was used directly for the next reaction without further treatment.

[0136] Step 3: Synthesis of 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimide)-1H-imidazolium (M5-5)

[0137] 1H-imidazole (1.12 g, 16.5 mmol), triethylamine (1.67 g, 16.5 mmol), and tetrahydrofuran (6 mL) were added to the system from step 2. The mixture was stirred at 0 °C for half an hour, and then reacted at room temperature for 16 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, diluted with water (30 mL), and extracted with PE (30 mL × 3). The combined organic phases were washed with saturated NaCl (40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-1H-imidazole (1.9 g), with a two-step yield of 48.8%.

[0138] 1 H NMR (600MHz, DMSO-d6) δ7.98(s,1H),7.49(s,1H),7.07(t,J=1.2Hz,1H),3.45(s,3H),0.87(s,9H),0.00(d,J=2.6Hz,6H).

[0139] Step 4: Synthesis of 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-3-methyl-1H-imidazol-3-onium (M5)

[0140] 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-1H-imidazolium (M5-5, 1.9 g, 7.32 mmol) and diethyl ether (30 mL) were added to a three-necked flask, purged with nitrogen, and stirred at 0 °C. Methyl trifluoromethanesulfonate (1.22 g, 7.47 mmol) was dissolved in diethyl ether (30 mL) and slowly added to the three-necked flask. After the addition was complete, the reaction was carried out at 0 °C for 1 hour. After the reaction was completed, the mixture was filtered, and the filter cake was dried to give 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-3-methyl-1H-imidazol-3-onium (2.35 g), with a yield of 75.8%.

[0141] 1 H NMR(600MHz,Chloroform-d)δ8.99–8.64(m,1H),7.38(d,J=41.4Hz,1H),7.28(s,0H),7.11(d,J=20.0Hz,1H),3 .90(d,J=58.0Hz,5H),3.44(s,2H),2.88(s,2H),0.79(d,J=18.7Hz,15H),0.15(s,5H),-0.01(d,J=17.4Hz,4H).

[0142] Synthesis of intermediate M6 in Preparation Example 6

[0143]

[0144] Step 1: Synthesis of 5-(methylthio)pyrimidine-2-amine (M6)

[0145] 2-Amino-5-fluoropyrimidine (M6-1, 5.27 g, 46.6 mmol) and sodium methanethiol (4.9 g, 69.9 mmol) were dissolved in N,N-dimethylformamide (60 mL) and stirred at 40 °C for 12 h. After the reaction was complete, the reaction mixture was diluted with water (150 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to give 5-(methylthio)pyrimidine-2-amine (4.10 g), yield 62.2%.

[0146] LC-MS (m / z): 141.8 [M+H] + .

[0147] Synthesis of intermediate M7 in Preparation Example 7

[0148]

[0149] Step 1: Synthesis of 5-(isopropylthio)-2-nitropyridine (M7-2)

[0150] 2-Nitro-5-fluoropyridine (M7-1, 1.0 g, 7.04 mmol) and sodium isopropylthiolate (1.38 g, 14.08 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 40 °C for 12 h. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 50:1) to give 5-(isopropylthio)-2-nitropyridine (0.91 g), yield 65.2%.

[0151] LC-MS (m / z): 199.1 [M+H] + .

[0152] Step 2: Synthesis of 5-(isopropylthio)-2-aminopyridine (M7)

[0153] 5-(isopropylthio)-2-nitropyridine (M7-2, 0.3 g, 1.5 mmol) and Raney Ni (0.1 g, 10% wt) were dissolved in ethyl acetate (10 mL) and stirred at room temperature for 6 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 0.168 g of 5-(isopropylthio)-2-aminopyridine, with a yield of 66.7%.

[0154] LC-MS (m / z): 169.2 [M+H] + .

[0155] Synthesis of intermediate M8 in Preparation Example 8

[0156]

[0157] Referring to steps 2 to 3 in Preparation Example 3, 3-bromo-1-methyl-1H-1,2,4-triazole was replaced with 2-chloro-5-fluoropyrimidine to obtain the intermediate 6-chloro-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide.

[0158] LC-MS (m / z): 389.0 [M+H] + .

[0159] Synthesis of intermediate M9 in Preparation Example 9

[0160]

[0161] 2-Chloropyrimidine-4-amine (M9-1, 1.0 g, 7.72 mmol) and sodium isopropylthiolate (1.38 g, 15.44 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 40 °C for 12 h. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 50:1) to give 2-(isopropylthio)pyrimidine-4-amine (1.3 g), yield 99%.

[0162] LC-MS (m / z): 170.0 [M+H] + .

[0163] Synthesis of intermediate M10 in Preparation Example 10

[0164]

[0165] Step 1: Synthesis of methyl 2-methoxy-3-nitrobenzene (M10-2)

[0166] 3-Nitrosalicylic acid (M10-1, 25 g, 135.5 mmol), cesium carbonate (178 g, 546 mmol), and DMF (500 mL) were added to a 3000 mL three-necked flask. Iodomethane (97 g, 683 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 hours. At the end of the reaction, water (1000 mL) was added to the reaction system, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was extracted with ethyl acetate (1000 mL). The filter cake was dissolved in ethyl acetate (1000 mL). The organic phases were combined, and the reaction solution was concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1–3:1) to give methyl 2-methoxy-3-nitrobenzoate (18 g), with a yield of 62.5%.

[0167] LC-MS (m / z): 212.2 [M+H] + .

[0168] Step 2: Synthesis of 2-methoxy-3-nitrobenzamide (M10-3)

[0169] Methyl 2-methoxy-3-nitrobenzene (M10-2, 23.3 g, 110.3 mmol), ammonia-methanol solution (76 mL, 7.0 M in MeOH), and ammonia water (93 mL) were sequentially added to a 500 mL autoclave. The autoclave was sealed, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction system was concentrated to remove methanol. Then, water (500 mL) was added, and the mixture was extracted with dichloromethane (300 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-methoxy-3-nitrobenzeneamide (15.8 g), with a yield of 94.5%.

[0170] LC-MS (m / z): 197.0 [M+H] + .

[0171] Step 3: Synthesis of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (M10-4)

[0172] 2-Methoxy-3-nitrobenzamide (M10-3, 5 g, 25.5 mmol) and DMF-DMA (34.2 mL) were added to a 500 mL single-necked flask and heated to 95 °C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting yellow oil was azeotropically reacted twice with 1,2-dichloroethane (8 mL) to remove residual DMF-DMA. The resulting yellow oil was dissolved in ethanol (20 mL) for use in the next step.

[0173] In a separate 500 mL single-necked flask, 100 mL of ethanol and 25.7 mL of acetic acid were added. The mixture was cooled in an ice-water bath, and 12.65 mL of hydrazine hydrate (80% wt) was added dropwise. The resulting yellow oily substance, soluble in ethanol, was then added dropwise to the reaction mixture. After the addition was complete, the mixture was brought to room temperature and stirred overnight. Upon completion of the reaction, the mixture was concentrated to remove most of the ethanol, diluted with water (a solid precipitated during the process), filtered, and the filter cake was washed with water and dried in a 45 °C oven to give 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (3.7 g), in 66% yield.

[0174] LC-MS (m / z): 221.0 [M+H] + .

[0175] Step 4: Synthesis of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (M10-5)

[0176] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (M10-4, 6.9 g, 31.4 mmol), cyclopropylboronic acid (5.39 g, 62.8 mmol), copper acetate (5.68 g, 31.4 mmol), sodium carbonate (6.66 g, 62.8 mmol), 2,2-bipyridine (4.9 g, 31.4 mmol), and 1,4-dioxane (150 mL) were added to a 500 mL round-bottom flask. The mixture was purged with oxygen three times, and the temperature was raised to 85 °C for 3 hours. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1 to 1:1) to give 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (5.2 g), with a yield of 63.7%.

[0177] LC-MS (m / z): 261.1 [M+H] + .

[0178] Step 5: Synthesis of 1-cyclopropyl-3-(2-methoxy-3-aminophenyl)-1H-1,2,4-triazole (M10-6)

[0179] 1-Cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (M10-5, 5.2 g, 20 mmol) and Raney Ni (0.52 g, 10% wt) were dissolved in ethyl acetate (60 mL) and stirred at room temperature for 6 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 1-cyclopropyl-3-(2-methoxy-3-aminophenyl)-1H-1,2,4-triazole (3.5 g), in 76% yield.

[0180] LC-MS (m / z): 231.1 [M+H] + .

[0181] Step 6: Synthesis of 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (M10)

[0182] 1-Cyclopropyl-3-(2-methoxy-3-aminophenyl)-1H-1,2,4-triazole (M10-6, 0.80 g, 3.47 mmol), 4,6-dichloro-N-methylpyridazin-3-carboxamide (M1, 0.86 g, 4.16 mmol), and N,N-diisopropylethylamine (0.9 g, 6.94 mmol) were dissolved in acetonitrile (10 mL). The reaction was carried out under microwave conditions at 120 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with acetonitrile (20 mL), and filtered. The filter cake was slurried with ethyl acetate and filtered to give 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methylpyridazin-3-carboxamide (0.74 g), yield 53.4%.

[0183] LC-MS: m / z = 400.1 [M+H] + .

[0184] Synthesis of intermediate M11 in Preparation Example 11

[0185]

[0186] Step 1 is the same as step 1 in Preparation Example 1.

[0187] Step 2: Synthesis of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (M11-1)

[0188] Under nitrogen protection, the crude product obtained in step 1 was dissolved in ultra-dry tetrahydrofuran (200 mL), and deuterated methylamine hydrochloride (10.16 g, 144.10 mmol) was added. N,N-diisopropylethylamine (24.84 g, 192.20 mmol) was slowly added dropwise in an ice-water bath. After the addition was complete, the ice-water bath was removed. The reaction was allowed to proceed at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1 to 1:1) to give 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (10.45 g), in 52% yield.

[0189] LC-MS (m / z): 209.0 [M+H] + .

[0190] Step 3: Synthesis of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (M11)

[0191] For the preparation of compound M3-4, refer to steps 1-2 of Preparation Example 3.

[0192] 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (M3-4, 1.90 g, 9.26 mmol), 4,6-dichloro-N-(methyl-d3)pyridazin-3-carboxamide (M11-1, 1.94 g, 9.26 mmol), and N,N-diisopropylethylamine (2.39 g, 18.53 mmol) were dissolved in acetonitrile (20 mL). The reaction was carried out under microwave conditions at 120 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with acetonitrile (20 mL), and filtered. The filter cake was slurried with ethyl acetate and filtered to give 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazin-3-carboxamide (1.80 g), yield 51.6%.

[0193] LC-MS: m / z = 377.1 [M+H] + .

[0194] Synthesis of intermediate M12 in Preparation Example 12

[0195]

[0196] Referring to steps 1-3 in Preparation Example 11, intermediate M3-4 was replaced with M8-1 to obtain the target compound 6-chloro-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0197] LC-MS: m / z = 392.1 [M+H] + .

[0198] Synthesis of intermediate M13 in Preparation Example 13

[0199]

[0200] Referring to step 6 in Preparation Example 10, intermediate M1 was replaced with M11-1 to obtain the target compound 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0201] LC-MS: m / z = 403.2 [M+H] + .

[0202] Synthesis of intermediate M14 in Preparation Example 14

[0203]

[0204] Referring to Preparation Example 9, intermediate M9-1 was replaced with M14-1 to obtain the target compound 2-(isopropylthio)-6-methylpyrimidine-4-amine.

[0205] LC-MS: m / z = 184.1 [M+H] + .

[0206] Synthesis of intermediate M15 in Preparation Example 15

[0207]

[0208] Referring to steps 1 and 2 in Preparation Example 7, sodium isopropanethiolate was replaced with sodium methanethiol to obtain the target compound 5-(methylthio)pyridine-2-amine.

[0209] LC-MS: m / z = 141.0 [M+H] + .

[0210] Example 1 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (Compound 1)

[0211]

[0212] Step 1: Synthesis of 6-((5-(isopropylthio)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (1-1)

[0213] Under nitrogen protection, 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazin-3-carboxamide (M3, 548 mg, 1.47 mmol) and 5-(isopropylthio)pyrimidine-2-amine (M2, 370 mg, 2.19 mmol) were dissolved in ultradry 1,4-dioxane (30 mL), and tris(dibenzylacetone)dipalladium (134 mg, 0.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (169 mg, 0.29 mmol), and cesium carbonate (950 mg, 2.91 mmol) were added. The reaction was carried out at 130 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 100:1 to 20:1) to give 6-((5-(isopropylthio)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (570 mg), yield 76.7%.

[0214] LC-MS: m / z = 507.3 [M+H] + .

[0215] Step 2: Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (Compound 1)

[0216] 6-((5-(isopropylthio)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (1-1,570 mg, 1.13 mmol) was dissolved in a mixed solvent of methanol (15 mL) and dichloromethane (12 mL), and ammonium acetate (347 mg, 4.50 mmol) and iodophenyldiacetic acid (1.09 g, 3.38 mmol) were added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 100:1 to 20:1) to give 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (132 mg), yield 24.2%.

[0217] LC-MS: m / z = 538.2 [M+H] + .

[0218] 1 H NMR (600MHz, DMSO-d6) δ11.28(s,1H),11.07(s,1H),9.19(d,J=5.0Hz,1H),8.76(s,2H),8.42(s,1H),8.13(s,1H),7.67(dd, J=48.7,7.9Hz,2H),7.38(t,J=7.9Hz,1H),4.47(s,1H),4.24(s,3H),3.68(s,3H),3.32(s,3H),1.18(dd,J=9.0,6.8Hz,6H).

[0219] Example 2 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(1-(S-methylsulfonylimino)azacyclobutane-3-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 2)

[0220]

[0221] Step 1: Synthesis of tert-butyl 3-(6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)pyridin-3-yl)azacyclobutane-1-carboxylate (2-1)

[0222] 6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazin-3-carboxamide (M3, 580 mg, 1.55 mmol) and tert-butyl 3-(6-aminopyridin-3-yl)azacyclobutane-1-carboxylate (M4, 463.4 mg, 1.86 mmol) were dissolved in ultradry 1,4-dioxane (20 mL), and tris(dibenzylacetone)dipalladium (142.01 mg, 0.156 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (179.6 mg, 0.31 mmol), and cesium carbonate (1.01 g, 3.10 mmol) were added. The reaction mixture was reacted at 130 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 10:1) to give tert-butyl 3-(6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)pyridin-3-yl)azacyclobutane-1-carboxylate (650 mg), yield 71.48%.

[0223] LC-MS: m / z = 587.2 [M+H] + .

[0224] Step 2: Synthesis of 6-((5-(azacyclobutane-3-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (2-2)

[0225] 3-(6-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)amino)pyridin-3-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (2-1, 650 mg, 1.11 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and trifluoroacetic acid (2.0 mL) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was allowed to rise to room temperature and react for 2 hours. After the reaction was completed, saturated sodium carbonate was added to adjust the pH to 7-8, and the reaction solution was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (water:acetonitrile = 10:1-1:10) to give 6-((5-(azacyclobutane-3-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (335 mg), yield 62.01%.

[0226] LC-MS: m / z = 487.2 [M+H] + .

[0227] Step 3: Synthesis of 6-((5-(1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)azacyclobutane-3-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (2-3)

[0228] 6-((5-(azacyclobutan-3-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazin-3-carboxamide (2-2, 335 mg, 0.69 mmol) and DIPEA (535 mg, 4.16 mmol) were dissolved in DMF (5 mL), and then 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-3-methyl-1H-imidazol-3-onyl ( 585 mg (1.37 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the product was purified by reversed-phase column chromatography (water:acetonitrile = 1:1) to give 6-((5-(1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)azacyclobutane-3-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (130 mg), yield 27.8%.

[0229] LC-MS: m / z = 678.2 [M+H] + .

[0230] Step 4: Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(1-(S-methylsulfonylimino)azacyclobutane-3-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 2)

[0231] 6-((5-(1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)azacyclobutane-3-yl)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (2-3, 130 mg, 0.19 mmol) was dissolved in 1,4-dioxane hydrochloride solution (8 mL) and reacted at 0 °C for 1 h. After completion, saturated sodium bicarbonate solution was added to adjust the pH to 7-8, the reaction solution was evaporated to dryness, and purified by reversed-phase column chromatography (water:acetonitrile = 1:1) to give 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(1-(S-methylsulfonylimino)azacyclobutane-3-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide (6.45 mg), yield 6.03%.

[0232] LC-MS: m / z = 564.2 [M+H] + .

[0233] 1 H NMR(600MHz,DMSO-d6)δ10.99(s,1H),10.19(s,1H),9.12(d,J=4.9Hz,1H),8 .57(s,1H),8.22–8.14(m,2H),7.81(dd,J=8.6,2.4Hz,1H),7.64(dd,J=12.6 ,8.1Hz,3H),7.33(t,J=7.9Hz,1H),4.08–4.03(m,2H),3.96(s,3H),3.82(q, J=7.1Hz,2H),3.75(s,4H),3.67(s,1H),2.93(s,3H),2.86(d,J=4.8Hz,3H).

[0234] Example 3 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-(1-(S-methylsulfonylimino)azacyclobutane-3-carbamate)pyridazine-3-carboxamide (compound 3)

[0235]

[0236] Step 1: Synthesis of tert-butyl 3-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazine-3-yl)carbamoyl)azacyclobutane-1-carboxylate (3-1)

[0237] Under nitrogen protection, 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (M3, 50 mg, 0.13 mmol), N-BOC-azacyclobutane-3-carboxamide (32 mg, 0.16 mmol), tris(dibenzylacetone)dipalladium (12 mg, 0.013 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (15 mg, 0.026 mmol), cesium carbonate (86 mg, 0.26 mmol), and ultra-dry 1,4-dioxane (10 mL) were added to a 25 mL sealed tube. The reaction was carried out at 130 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with methanol (30 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 100:1 to 20:1) to give tert-butyl 3-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)carbamoyl)azacyclobutane-1-carboxylate (44 mg), yield 61.8%.

[0238] LC-MS (m / z): 538.2 [M+H] + .

[0239] Step 2: Synthesis of 6-(azacyclobutane-3-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (3-2)

[0240] 3-((5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(methylcarbamoyl)pyridazin-3-yl)carbamoyl)azacyclobutane-1-carboxylic acid tert-butyl ester (3-1, 730 mg, 1.36 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the ice-water bath was removed. The reaction mixture was allowed to react at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 1:1 to 1:2) to give 6-(azacyclobutane-3-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (10.20 g), yield 51.5%.

[0241] LC-MS (m / z): 438.2 [M+H] + .

[0242] Step 3: Synthesis of 6-(1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)azacyclobutane-3-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (3-3)

[0243] 6-(azacyclobutane-3-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazin-3-carboxamide (3-2, 485 g, 1.11 mmol) and N,N-diisopropylethylamine (860 mg, 6.65 mmol) were dissolved in N,N-dimethylformamide (10 mL). Under ice-water bath conditions, 1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-3-methyl-1H-imidazolium-3-trifluoromethanesulfonate (M5, 939 mg, 2.22 mmol) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography to give 6-(1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)azacyclobutane-3-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (81 mg), yield 11.6%.

[0244] LC-MS (m / z): 629.2 [M+H] + .

[0245] Step 4: Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-(1-(S-methylsulfonylimino)azacyclobutane-3-carboxamido)pyridazine-3-carboxamide (compound 3)

[0246] 6-(1-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)azacyclobutane-3-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (3-3, 81 mg) was dissolved in 1,4-dioxane (5 mL, 1.0 mol / L) of hydrogen chloride and stirred at room temperature for 20 min. After the reaction was complete, the mixture was transferred to an ice-water bath, and water (5 mL) was added to dissolve the solid. Then, a saturated sodium carbonate solution was added until the pH reached 7-8. The reaction compound was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-(1-(S-methylsulfonylimino)azacyclobutane-3-carboxamido)pyridazine-3-carboxamide (15 mg), with a yield of 22.6%.

[0247] LC-MS: m / z = 515.1 [M+H] + .

[0248] 1 H NMR (600MHz, DMSO-d6) δ11.16(s,1H),10.99(s,1H),9.18(d,J=5.6Hz,1H),8.57(d ,J=1.6Hz,1H),8.18(s,1H),7.68(dd,J=7.8,1.7Hz,1H),7.55(dd,J=7.9,1.7Hz,1H ),7.31(dd,J=8.7,7.1Hz,1H),3.95(d,J=1.6Hz,3H),3.91–3.82(m,4H),3.73(d,J =1.6Hz,3H),3.63–3.56(m,2H),2.86(dd,J=4.8,1.5Hz,3H),2.84(t,J=1.5Hz,3H).

[0249] Example 4 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((4-(N-methylpropyl-2-ylsulfonylamino)phenyl)amino)pyridazine-3-carboxamide (compound 4)

[0250]

[0251] Step 1: Synthesis of (2-aminopyrimidin-5-yl)(imino)(isopropyl)-16-thionone (4-1)

[0252] 5-(isopropylthio)pyrimidine-2-amine (M2, 4.70 g, 27.77 mmol) was dissolved in a mixed solvent of methanol (100 mL) and dichloromethane (80 mL), and ammonium acetate (8.56 g, 111.05 mmol) and iodophenyldiacetic acid (26.83 g, 83.30 mmol) were added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 100:1–20:1) to give (2-aminopyrimidine-5-yl)(imino)(isopropyl)-16-thione (1.06 g), in 19.1% yield.

[0253] LC-MS: m / z = 200.9 [M+H] + .

[0254] Step 2: Synthesis of (2-aminopyrimidin-5-yl)(isopropyl)(methylamino)-16-thionone (4-2)

[0255] (2-Aminopyrimidin-5-yl)(imino)(isopropyl)-16-thione (4-1, 150 mg, 0.75 mmol) was dissolved in ultradry 1,4-dioxane (5 mL), and copper acetate (408 mg, 2.25 mmol) and pyridine (143 mg, 1.81 mmol) were added. The mixture was stirred at room temperature for 10 min, and methylboric acid (44 mg, 0.74 mmol) was added. The mixture was refluxed at 110 °C with stirring for 4 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with methanol (20 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA) to give (2-aminopyrimidin-5-yl)(isopropyl)(methylamino)-16-thione (17 mg), in 10.6% yield.

[0256] LC-MS: m / z = 215.0 [M+H] + .

[0257] Step 3: Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((4-(N-methylpropyl-2-ylsulfonylamino)phenyl)amino)pyridazine-3-carboxamide (compound 4)

[0258] (2-aminopyrimidin-5-yl)(isopropyl)(methylamino)-16-thione (4-2, 37 mg, 0.17 mmol) and 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (M3, 40 mg, 0.11 mmol) were dissolved in ultradry 1,4-dioxane (10 mL), and tris(dibenzylacetone)dipalladium (10 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (13 mg, 0.02 mmol), and cesium carbonate (70 mg, 0.21 mmol) were added. The reaction mixture was reacted at 130 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((4-(N-methylpropyl-2-ylsulfonylamino)phenyl)amino)pyridazine-3-carboxamide (15 mg), yield 24.8%.

[0259] LC-MS: m / z = 552.1 [M+H] + .

[0260] 1 H NMR(600MHz,DMSO-d6)δ11.27(s,1H),11.02(s,1H),9.16(d,J=4.9Hz,1H) ,8.68(s,2H),8.57(s,1H),8.40(s,1H),7.66(ddd,J=14.4,7.9,1.6Hz,2H) ,7.36(dd,J=9.1,6.6Hz,1H),3.96(s,3H),3.74(s,3H),3.41(p,J=6.9Hz,1 H),2.88(d,J=4.8Hz,3H),2.54(s,3H),1.24(s,3H),1.15(d,J=6.8Hz,3H).

[0261] Example 5 Synthesis of 6-((4-(N-ethylpropyl-2-ylsulfonylimino)phenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (compound 5)

[0262]

[0263] Referring to steps 1 to 3 in Example 4, methylboric acid was replaced with ethylboric acid to obtain the target compound 6-((4-(N-ethylpropyl-2-ylsulfonylimino)phenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide.

[0264] LC-MS: m / z = 566.3 [M+H] + .

[0265] 1 H NMR (600MHz, DMSO-d6) δ11.29 (s, 1H), 11.02 (s, 1H), 9.16 (d, J = 5.0Hz, 1H), 8.70 (d ,J=1.2Hz,2H),8.58(s,1H),8.45–8.32(m,1H),7.74–7.63(m,2H),7.45–7.31(m,1H ),3.96(d,J=1.2Hz,3H),3.74(s,3H),3.40(p,J=6.9Hz,1H),2.96–2.86(m,4H),2. 86–2.75(m,1H),1.28–1.23(m,3H),1.18–1.13(m,3H),1.07(td,J=7.1,1.2Hz,3H).

[0266] Example 6 Synthesis of 6-((5-(N-cyclopropylpropyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (compound 6)

[0267]

[0268] Referring to steps 1 to 3 in Example 4, methylboronic acid was replaced with cyclopropylboronic acid to obtain the target compound 6-((5-(N-cyclopropylpropyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide.

[0269] LC-MS: m / z = 578.2 [M+H] + .

[0270] 1H NMR(600MHz,DMSO-d6)δ11.32(s,1H),11.03(s,1H),9.17(q,J=4.9Hz,1H),8.75(s,2H),8.57 (s,1H),8.40(s,1H),7.67(ddd,J=14.2,7.9,1.6Hz,2H),7.36(t,J=7.9Hz,1H),3.96(s,3H),3 .74(s,3H),3.42(p,J=6.8Hz,1H),2.89(d,J=4.8Hz,3H),2.34(tt,J=7.1,3.8Hz,1H),1.22(d, J=6.9Hz,3H),1.13(d,J=6.8Hz,3H),0.45–0.41(m,2H),0.38–0.33(m,1H),0.28–0.24(m,1H).

[0271] Example 7 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(S-methylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (compound 7)

[0272]

[0273] Referring to steps 1 to 2 in Example 1, 5-(isopropylthio)pyrimidine-2-amine (M2) was replaced with 5-(methylthio)pyrimidine-2-amine (M6) to obtain the target compound 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(S-methylsulfonylimino)pyrimidine-2-yl)amino)pyridazine-3-carboxamide.

[0274] LC-MS: m / z = 510.2 [M+H] + .

[0275] 1 H NMR (600MHz, DMSO-d6) δ11.25(s,1H),11.02(s,1H),9.17(q,J=4.9Hz,1H),8.89(s,2H),8.60(s,1H),8.43(s,1H),7. 66(t,J=9.1Hz,2H),7.37(t,J=7.9Hz,1H),4.53(s,1H),3.96(s,3H),3.74(s,3H),3.17(s,3H),2.88(d,J=4.8Hz,3H).

[0276] Example 8 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(N-methylpropyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 8)

[0277]

[0278] Referring to steps 1 to 3 in Example 4, 5-(isopropylthio)pyrimidine-2-amine (M2) was replaced with 5-(isopropylthio)-2-aminopyridine (M7) to obtain the target compound 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(N-methylpropyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide).

[0279] LC-MS: m / z = 551.2 [M+H] + .

[0280] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),10.69(s,1H),9.16(q,J=4.8Hz,1H),8.56(s,1H),8 .41(d,J=2.4Hz,1H),8.10(s,1H),7.95(dd,J=8.8,2.5Hz,1H),7.84(d,J=8.8Hz,1H),7.65 (ddd,J=11.4,7.8,1.5Hz,2H),7.33(t,J=7.9Hz,1H),3.96(s,3H),3.75(s,3H),3.30–3.2 7(m,1H),2.88(d,J=4.8Hz,3H),2.52(s,3H),1.22(d,J=6.8Hz,3H),1.12(d,J=6.8Hz,3H).

[0281] Example 9 Synthesis of 6-((5-(N,S-dimethylsulfonylimino)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (compound 9)

[0282]

[0283] Referring to steps 1 to 3 in Example 4, 5-(isopropylthio)pyrimidine-2-amine (M2) was replaced with 5-(methylthio)pyrimidine-2-amine (M6) to obtain the target compound 6-((5-(N,S-dimethylsulfonylimino)pyrimidine-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide.

[0284] LC-MS: m / z = 524.2 [M+H] + .

[0285] 1 H NMR (600MHz, DMSO-d6) δ11.26(s,1H),11.03(s,1H),9.17(d,J=4.9Hz,1H),8.80(s,2H),8.58(s,1H),8.43(s,1H),7.66( dd,J=11.6,7.9Hz,2H),7.37(t,J=7.9Hz,1H),3.96(s,3H),3.74(s,3H),3.22(s,3H),2.88(d,J=4.8Hz,3H),2.51(s,3H).

[0286] Example 10 Synthesis of 6-((5-(N-ethyl-S-methylsulfonylimino)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (Compound 10)

[0287]

[0288] Referring to steps 1 to 3 in Example 9, methylboric acid was replaced with ethylboric acid to obtain the target compound 6-((5-(N-ethyl-S-methylsulfonylimino)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide.

[0289] LC-MS: m / z = 538.2 [M+H] + .

[0290] 1H NMR (600MHz, DMSO-d6) δ11.28(s,1H),11.02(s,1H),9.16(d,J=4.9Hz,1H),8.79(s,2H),8.58(s,1H),8.40(s,1H),7.66(ddd,J=14.1,7.9,1.6 Hz,2H),7.36(t,J=7.9Hz,1H),3.96(s,3H),3.75(s,3H),3.21(s,3H),2.96–2.84(m,4H),2.78(dq,J=12.3,7.2Hz,1H),1.06(t,J=7.2Hz,3H).

[0291] Example 11 Synthesis of 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(N-methyl-propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (compound 11)

[0292]

[0293] Referring to steps 1 to 3 in Example 4, intermediate M3 is replaced with intermediate M8 to obtain the target compound 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(N-methyl-propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide.

[0294] LC-MS: m / z = 567.2 [M+H] + .

[0295] 1 H NMR(600MHz,DMSO-d6)δ11.29(s,1H),10.98(s,1H),9.17(q,J=4.8Hz,1H),9 .05(s,2H),8.69(s,2H),8.38(s,1H),7.73(dd,J=8.0,1.6Hz,1H),7.52(dd,J =7.7,1.5Hz,1H),7.40(t,J=7.8Hz,1H),3.68(s,3H),3.44–3.40(m,1H),2.8 8(d,J=4.8Hz,3H),2.54(s,3H),1.24(d,J=7.0Hz,3H),1.15(d,J=6.8Hz,3H).

[0296] Example 12 Synthesis of 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(N-ethyl-propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (compound 12)

[0297]

[0298] Referring to steps 1 to 3 in Example 11, methylboric acid was replaced with ethylboric acid to obtain the target compound 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(N-ethyl-propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide.

[0299] LC-MS: m / z = 581.2 [M+H] + .

[0300] 1 H NMR (600MHz, DMSO-d6) δ11.31(s,1H),10.98(s,1H),9.17(q,J=4.8Hz,1H),9.05(s,2H),8.70( s,2H),8.39(s,1H),7.73(dd,J=8.0,1.6Hz,1H),7.52(dd,J=7.8,1.6Hz,1H),7.39(t,J=7.9Hz, 1H),3.67(s,3H),3.40(p,J=6.7Hz,1H),2.92(dt,J=12.4,7.1Hz,1H),2.88(d,J=4.8Hz,3H),2. 82(dq,J=12.4,7.1Hz,1H),1.24(d,J=6.8Hz,3H),1.14(d,J=6.7Hz,3H),1.07(t,J=7.1Hz,3H).

[0301] Example 13 Synthesis of 6-((5-(N-cyclopropyl-S-methylsulfonylimino)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (compound 13)

[0302]

[0303] Referring to steps 1 to 3 in Example 9, methylboronic acid was replaced with cyclopropylboronic acid to obtain the target compound 6-((5-(N-cyclopropyl-S-methylsulfonylimino)pyrimidin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide.

[0304] LC-MS: m / z = 550.2 [M+H] + .

[0305] 1 H NMR(600MHz,DMSO-d6)δ11.06(s,1H),10.80(s,1H),8.94(q,J=4.8Hz,1H),8.62(s,2H),8.34 (s,1H),8.18(s,1H),7.44(dd,J=11.5,7.9Hz,2H),7.14(t,J=7.9Hz,1H),3.73(s,3H),3.52( s,3H),2.99(s,3H),2.66(d,J=4.8Hz,3H),2.09(tt,J=7.1,3.8Hz,1H),0.19(dddd,J=14.2,1 0.4,7.1,3.1Hz,2H),0.12(dtd,J=10.4,6.5,4.3Hz,1H),0.01(ddt,J=10.4,7.4,4.0Hz,1H).

[0306] Example 14 Synthesis of 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (compound 14)

[0307]

[0308] Referring to steps 1 to 2 in Example 1, intermediate M3 was replaced with intermediate M8 to obtain the target compound 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide.

[0309] LC-MS: m / z = 553.2 [M+H] + .

[0310] 1H NMR (600MHz, DMSO-d6) δ11.27(s,1H),10.97(s,1H),9.17(q,J=4.8Hz,1H),9.05(s,2H),8.79(s,2H),8.39(s,1H),7.72(dd,J=8.0,1.7Hz,1H),7. 52(dd,J=7.8,1.7Hz,1H),7.39(t,J=7.9Hz,1H),4.51(s,1H),3.67(s,3H ),3.32–3.29(m,1H),2.88(d,J=4.7Hz,3H),1.18(dd,J=8.5,6.8Hz,6H).

[0311] Example 15 Synthesis of 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((2-(propyl-2-ylsulfonylimino)pyrimidin-4-yl)amino)pyridazine-3-carboxamide (compound 15)

[0312]

[0313] Referring to steps 1 to 2 in Example 14, intermediate M2 is replaced with intermediate M9 to obtain the target compound 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((2-(propyl-2-ylsulfonylimino)pyrimidin-4-yl)amino)pyridazine-3-carboxamide.

[0314] LC-MS: m / z = 553.2 [M+H] + .

[0315] 1 H NMR (600MHz, DMSO-d6) δ11.17(s,1H),11.10(s,1H),9.27(s,1H),9.05(s,2H),8.64(d,J=5.9Hz,1H),7.86–7.77(m,3H),7.52( d,J=7.7Hz,1H),7.36(t,J=8.1Hz,1H),4.18(s,1H),3.70(s,3H),3.65(s,1H),2.90–2.81(m,3H),1.17(dd,J=19.9,6.7Hz,6H).

[0316] Example 16 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((2-(propyl-2-ylsulfonylimino)pyrimidin-4-yl)amino)pyridazine-3-carboxamide (compound 16)

[0317]

[0318] Referring to steps 1 to 2 in Example 1, intermediate M2 is replaced with intermediate M9 to obtain the target compound 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((2-(propyl-2-ylsulfonylimino)pyrimidin-4-yl)amino)pyridazine-3-carboxamide.

[0319] LC-MS: m / z = 538.2 [M+H] + .

[0320] 1 H NMR(600MHz,DMSO-d6)δ11.19(s,1H),11.10(s,1H),9.26(d,J=4.9Hz,1H),8.64 (d,J=5.9Hz,1H),8.58(s,1H),7.87(s,1H),7.82(s,1H),7.72–7.68(m,1H),7.65 (dd,J=7.9,1.6Hz,1H),7.32(t,J=7.9Hz,1H),4.16(s,1H),3.96(s,3H),3.76(s ,3H),3.63(p,J=6.9Hz,1H),2.87(d,J=4.8Hz,3H),1.16(dd,J=19.9,6.8Hz,6H).

[0321] Example 17 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 17)

[0322]

[0323] Referring to steps 1 to 2 in Example 1, intermediate M2 is replaced with intermediate M7 to obtain the target compound 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide.

[0324] LC-MS: m / z = 537.1 [M+H] + .

[0325] 1H NMR (600MHz, DMSO-d6) δ11.04(s,1H),10.82(s,1H),9.21(q,J=4.8Hz,1H),8.58–8.57(m,2H),8.12–8.09(m,2H),7.84(d,J=8.9Hz,1H),7.66(ddd ,J=12.3,7.9,1.6Hz,2H),7.33(t,J=7.9Hz,1H),3.96(s,3H),3.75(s,3H ),3.45–3.41(m,2H),2.87(d,J=4.8Hz,3H),1.19(dd,J=6.8,2.1Hz,6H).

[0326] Example 18 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(S-methylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 18)

[0327]

[0328] Referring to steps 1 to 2 in Example 17, intermediate M7 is replaced with intermediate M15 to obtain the target compound 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((5-(S-methylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide.

[0329] LC-MS: m / z = 509.2 [M+H] + .

[0330] 1 H NMR (600MHz, DMSO-d6) δ11.02(s,1H),10.72(s,1H),9.20(q,J=4.8Hz,1H),8.63(d,J=2.5Hz,1H),8.58(s,1H),8.16–8.14(m,2H),7.80 (d,J=8.8Hz,1H),7.67–7.64(m,2H),7.34(t,J=7.9Hz,1H),4.29(s,1H),3.96(s,3H),3.75(s,3H),3.09(s,3H),2.87(d,J=4.7Hz,3H).

[0331] Example 23 Synthesis of 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (compound 23)

[0332]

[0333] Referring to steps 1-2 in Example 1, intermediate M3 is replaced with intermediate M10 to obtain the target compound 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide.

[0334] LC-MS: m / z = 564.2 [M+H] + .

[0335] 1 H NMR(600MHz,DMSO-d6)δ11.29(s,1H),11.06(s,1H),9.18(q,J=4.9Hz,1H),8 .79(s,2H),8.69(s,1H),8.44(s,1H),7.67(ddd,J=16.9,7.9,1.6Hz,2H),7.3 6(t,J=7.9Hz,1H),4.49(s,1H),3.88(tt,J=7.5,3.8Hz,1H),3.74(s,3H),3. 33–3.30(m,1H),2.88(d,J=4.8Hz,3H),1.19–1.16(m,8H),1.09–1.06(m,2H).

[0336] Example 24 Synthesis of 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 24)

[0337]

[0338] Referring to steps 1-2 in Example 17, intermediate M3 is replaced with intermediate M10 to obtain the target compound 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide.

[0339] LC-MS: m / z = 563.2 [M+H] + .

[0340] 1 H NMR (600MHz, DMSO-d6) δ11.03(s,1H),10.70(s,1H),9.20(q,J=4.8Hz,1H),8.70(s,1H),8.53( d,J=2.5Hz,1H),8.11(s,1H),8.07(dd,J=8.8,2.5Hz,1H),7.83(d,J=8.8Hz,1H),7.66(ddd,J=8 .1,6.2,1.6Hz,2H),7.32(t,J=7.9Hz,1H),4.23(s,1H),3.88(tt,J=7.4,3.8Hz,1H),3.75(s,3H ),3.23(p,J=6.8Hz,1H),2.87(d,J=4.8Hz,3H),1.19–1.14(m,8H),1.08(dt,J=7.4,3.6Hz,2H).

[0341] Example 25 Synthesis of 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methyl-6-((2-(propyl-2-ylsulfonylimino)pyrimidin-4-yl)amino)pyridazine-3-carboxamide (compound 25)

[0342]

[0343] Referring to steps 1-2 in Example 16, intermediate M3 is replaced with intermediate M10 to obtain the target compound 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-methyl-6-((2-(propyl-2-ylsulfonylimino)pyrimidin-4-yl)amino)pyridazine-3-carboxamide.

[0344] LC-MS: m / z = 564.1 [M+H] + .

[0345] 1H NMR(600MHz,DMSO-d6)δ11.20(s,1H),11.06(s,1H),9.26(q,J=4.8Hz,1H),8.70(s,1H),8.6 4(d,J=5.8Hz,1H),7.85–7.81(m,2H),7.70–7.68(m,1H),7.65(dd,J=7.9,1.5Hz,1H),7.32(t ,J=7.9Hz,1H),4.16(s,1H),3.88(tt,J=7.4,3.9Hz,1H),3.75(s,3H),3.64(p,J=6.8Hz,1H), 2.87(d,J=4.8Hz,3H),1.18–1.17(m,5H),1.14(d,J=6.7Hz,3H),1.08(td,J=7.4,5.1Hz,2H).

[0346] Example 26 Synthesis of 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 26)

[0347]

[0348] Referring to steps 1-2 in Example 1, intermediate M3 is replaced with intermediate M8, and intermediate M2 is replaced with intermediate M7, thus obtaining the target compound 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methyl-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide.

[0349] LC-MS: m / z = 552.1 [M+H] + .

[0350] 1 H NMR (600MHz, DMSO-d6) δ11.00 (s, 1H), 10.88 (s, 1H), 9.21 (d, J = 5.0Hz, 1H), 9.05 (s, 2H),8.59(d,J=2.5Hz,1H),8.13(dd,J=8.9,2.6Hz,1H),8.05(s,1H),7.83(d,J=8.9H z,1H),7.70(d,J=8.0Hz,1H),7.54(d,J=7.7Hz,1H),7.37(t,J=7.8Hz,1H),4.04(s,1 H), 3.69 (s, 3H), 3.54 (p, J = 7.1Hz, 1H), 2.87 (d, J = 4.8Hz, 3H), 1.21 (t, J = 7.5Hz, 6H).

[0351] Example 57 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide (compound 57)

[0352]

[0353] Referring to steps 1-2 in Example 1, intermediate M3 is replaced with intermediate M11 to obtain the target compound 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(propyl-2-ylsulfonylimino)pyrimidin-2-yl)amino)pyridazine-3-carboxamide.

[0354] LC-MS: m / z = 541.2 [M+H] + .

[0355] 1 H NMR (600MHz, DMSO-d6) δ11.28(s,1H),11.03(s,1H),9.14(s,1H),8.78(s,2H),8.57(s,1H),8.40(s,1H),7.66(ddd,J=12.7,7 .9,1.6Hz,2H),7.36(t,J=7.9Hz,1H),4.48(s,1H),3.96(s,3H),3.75(s,3H),3.32–3.30(m,1H),1.18(dd,J=8.7,6.7Hz,6H).

[0356] Example 65 Synthesis of 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)6-((5-(N-cyclopropyl-S-methylsulfonylimino)pyrimidin-2-yl)amino)-N-methylpyridazine-3-carboxamide (compound 65)

[0357]

[0358] Referring to steps 1-3 in Example 13, intermediate M3 is replaced with intermediate M10 to obtain the target compound 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)6-((5-(N-cyclopropyl-S-methylsulfonylimino)pyrimidin-2-yl)amino)-N-methylpyridazine-3-carboxamide.

[0359] LC-MS: m / z = 576.1 [M+H]+ .

[0360] 1 H NMR (600MHz, DMSO-d6) δ11.31(s,1H),11.05(s,1H),9.17(q,J=4.9Hz,1H),8.84(s,2H),8.70(s,1H),8.42 (s,1H),7.67(dd,J=16.8,7.9Hz,2H),7.37(t,J=7.9Hz,1H),3.88(tt,J=7.3,3.8Hz,1H),3.75(s,3H),3.2 3(s,3H),2.88(d,J=4.8Hz,3H),2.32(tt,J=7.1,3.8Hz,1H),1.18(p,J=4.8Hz,2H),1.08(h,J=5.2Hz,2H), 0.42(ddp,J=14.2,10.3,4.9,4.3Hz,2H), 0.35(ddt,J=13.5,10.2,5.4Hz,1H), 0.23(dq,J=9.7,4.3Hz,1H).

[0361] Example 66 Synthesis of 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-((5-(N-cyclopropylpropyl-2-ylsulfonylimino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (compound 66)

[0362]

[0363] Referring to steps 1 to 3 in Example 8, methylboronic acid was replaced with cyclopropylboronic acid, and intermediate M3 was replaced with intermediate M10, thus obtaining the target compound 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-((5-(N-cyclopropylpropyl-2-ylsulfonylimino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide.

[0364] LC-MS: m / z = 603.3 [M+H] + .

[0365] 1H NMR (600MHz, DMSO-d6) δ11.03(s,1H),10.74(s,1H),9.21(q,J=4.7Hz,1H),8.70(s,1H),8.47(d,J=2.5Hz,1H ),8.12(s,1H),8.02(dd,J=8.8,2.5Hz,1H),7.85(d,J=8.8Hz,1H),7.66(dq,J=5.5,1.5Hz,2H),7.33(t,J=7. 9Hz,1H),3.88(tt,J=7.4,3.8Hz,1H),3.75(s,3H),3.32–3.31(m,1H),2.87(d,J=4.8Hz,3H),2.29(tq,J=8.1 ,4.1Hz,1H),1.20–1.16(m,5H),1.09–1.06(m,5H),0.42–0.37(m,2H),0.35–0.31(m,1H),0.27–0.23(m,1H).

[0366] Example 67 Synthesis of 6-((5-(N-cyclopropylpropyl-2-ylsulfonylimino)pyridin-2-yl)amino)-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide (compound 67)

[0367]

[0368] Referring to steps 1 to 3 in Example 8, methylboronic acid was replaced with cyclopropylboronic acid, and intermediate M3 was replaced with intermediate M8, thus obtaining the target compound 6-((5-(N-cyclopropylpropyl-2-ylsulfonylimino)pyridin-2-yl)amino)-4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide.

[0369] LC-MS: m / z = 592.2 [M+H] + .

[0370] 1H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.74(s,1H),9.20(q,J=4.8Hz,1H),9.05(s,2H),8.48(d,J=2.4Hz,1H),8 .12(s,1H),8.02(dd,J=8.9,2.5Hz,1H),7.81(d,J=8.8Hz,1H),7.71(dd,J=8.0,1.6Hz,1H),7.54(dd,J=7.8,1.6 Hz,1H),7.37(t,J=7.9Hz,1H),3.69(s,3H),3.32–3.31(m,1H).,2.87(d,J=4.8Hz,3H),2.29(ddd,J=9.3,6.9,4. 0Hz,1H),1.20(d,J=6.7Hz,3H),1.09(d,J=6.8Hz,3H),0.42–0.38(m,2H),0.35–0.31(m,1H),0.27–0.23(m,1H).

[0371] Example 68 Synthesis of 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 68)

[0372]

[0373] Referring to steps 1 to 2 in Example 1, intermediate M3 is replaced with intermediate M12, and intermediate M2 is replaced with intermediate M7, thus obtaining the target compound 4-((3-(5-fluoropyrimidin-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide.

[0374] LC-MS: m / z = 555.2 [M+H] + .

[0375] 1H NMR(600MHz,DMSO-d6)δ10.97(s,1H),10.71(s,1H),9.18(s,1H),9.05(s,2H ),8.53(d,J=2.5Hz,1H),8.11(s,1H),8.06(dd,J=8.9,2.5Hz,1H),7.78(d,J =8.9Hz,1H),7.71(d,J=7.9Hz,1H),7.53(d,J=7.7Hz,1H),7.37(t,J=7.8Hz, 1H), 4.23 (s, 1H), 3.68 (s, 3H), 3.23 (p, J = 6.8Hz, 1H), 1.15 (t, J = 7.0Hz, 6H).

[0376] Example 69 Synthesis of 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 69)

[0377]

[0378] Referring to steps 1 to 2 in Example 17, intermediate M3 is replaced with intermediate M13 to obtain the target compound 4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide.

[0379] LC-MS: m / z = 566.1 [M+H] + .

[0380] 1 H NMR (600MHz, DMSO-d6) δ11.05(s,1H),10.83(s,1H),9.18(s,1H),8.70(s,1H),8.58(d,J= 2.5Hz,1H),8.13(dd,J=8.9,2.6Hz,1H),8.04(s,1H),7.86(d,J=8.9Hz,1H),7.65(ddd,J= 15.0,7.9,1.6Hz,2H),7.33(t,J=7.9Hz,1H),3.88(tt,J=7.3,3.8Hz,1H),3.74(s,3H),3. 49(d,J=3.8Hz,2H),1.20(t,J=6.1Hz,6H),1.18–1.16(m,2H),1.08(td,J=7.4,5.1Hz,2H).

[0381] Example 70 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide (compound 70)

[0382]

[0383] Referring to steps 1 to 2 in Example 17, intermediate M3 is replaced with intermediate M11 to obtain the target compound 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((5-(propyl-2-ylsulfonylimino)pyridin-2-yl)amino)pyridazine-3-carboxamide.

[0384] LC-MS: m / z = 540.2 [M+H] + .

[0385] 1 H NMR(600MHz,DMSO-d6)δ11.02(s,1H),10.70(s,1H),9.17(s,1H),8.57(s,1 H),8.53(d,J=2.5Hz,1H),8.11(s,1H),8.06(dd,J=8.8,2.5Hz,1H),7.81(d ,J=8.8Hz,1H),7.65(td,J=8.2,1.6Hz,2H),7.33(t,J=7.9Hz,1H),4.22(s, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 3.24 (h, J = 6.8Hz, 1H), 1.15 (t, J = 7.1Hz, 6H).

[0386] Example 71 Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((6-methyl-2-(propyl-2-ylsulfonylimino)pyrimidin-4-yl)amino)pyridazine-3-carboxamide (compound 71)

[0387]

[0388] Referring to steps 1 to 2 in Example 16, intermediate M9 was replaced with intermediate M14 to obtain the target compound 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-6-((6-methyl-2-(propyl-2-ylsulfonylimino)pyrimidin-4-yl)amino)pyridazine-3-carboxamide.

[0389] LC-MS: m / z = 552.2 [M+H] + .

[0390] 1 H NMR (600MHz, DMSO-d6) δ11.15(s,1H),10.95(s,1H),9.27(q,J=4.8Hz,1H),8.57(s,1H),7.77–7.64(m,4H),7.31(t,J=7.9Hz,1H) ,4.10(s,1H),3.96(s,3H),3.76(s,3H),3.64(p,J=6.9Hz,1H),2.87(d,J=4.8Hz,3H),2.46(s,3H),1.16(dd,J=21.3,6.8Hz,6H).

[0391] Example 72 Synthesis of 6-((5-(N-cyclopropyl-S-methylsulfonylimino)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (compound 72)

[0392]

[0393] Referring to steps 1 to 3 in Example 13, intermediate M6 is replaced with intermediate M15 to obtain the target compound 6-((5-(N-cyclopropyl-S-methylsulfonylimino)pyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide.

[0394] LC-MS: m / z = 549.2 [M+H] + .

[0395] 1H NMR (600MHz, DMSO-d6) δ11.02 (s, 1H), 10.72 (s, 1H), 9.20 (d, J = 4.9Hz, 1H), 8.59–8. 58(m,2H),8.13–8.10(m,2H),7.83(d,J=8.9Hz,1H),7.66(td,J=7.6,1.6Hz,2H),7. 34(t,J=7.9Hz,1H),3.96(s,3H),3.75(s,3H),3.15(s,3H),2.87(d,J=4.7Hz,3H),2 .28(tt,J=7.0,3.9Hz,1H),0.43–0.37(m,2H),0.34–0.29(m,1H),0.24–0.20(m,1H).

[0396] Bioactivity test

[0397] Test Example 1: Inhibitory activity of compound against TYK2 signaling pathway in NK-92 cells

[0398] The purpose of this experiment was to detect the inhibitory effect of the compound on the cytokine-activated JAK-STAT signaling pathway in NK-92 cells.

[0399] 1. Main Reagents and Instruments

[0400] 1.1 Cells: NK-92 (Supplier: Wuhan Pronosai Life Science Technology Co., Ltd., Catalog No.: CL-0530)

[0401] 1.2 Reagents

[0402] Name Supplier Catalog No. NK-92 Cell Special Medium Wuhan Pinnos Life Science Co., Ltd. CM-0530 Recombinant Human IL-12 Cytokine Peprotech 200-12H Human pSTAT4 Antibody BD Biosciences 562074 PBS Cytiva SH30256.01 Human Serum Immunoglobulin G (IgG) Sigma-Aldrich I4506-10MG Methanol Shanghai Generay Biotech Co., Ltd. A601617 4% Paraformaldehyde Fixative Shanghai Generay Biotech Co., Ltd. E672002

[0403] 1.3 Instruments

[0404] Flow cytometer: Brand: Thermofisher; Model: Attune Nxt

[0405] 2 Experimental Procedure

[0406] 2.1 Collect the cultured NK-92 cells and centrifuge at 1000 rpm for 3 min;

[0407] 2.2 After resuspending the cells in culture medium without IL-2, count them and adjust the cell concentration to 2*105 cells / well with culture medium. Seed the cells into 96-well round-bottom plates and incubate at 37°C and 5% CO2 for 3 hours.

[0408] 2.3 Add different concentrations of the test compound (starting at 1000 nM, serially diluted 5 times, for a total of 8 concentrations), with 3 replicates per group. Also set up a DMSO control group and a blank control group. Incubate at 37℃ and 5% CO2 for 20 min.

[0409] 2.4 Recombinant human IL-12 cytokine (final concentration 50 ng / mL) was added to both the IL-12 stimulation control group and the drug treatment group. The same volume of culture medium was added to the DMSO control group and the blank control group. The mixture was incubated at 37℃ and 5% CO2 for 60 min.

[0410] 2.5 Centrifuge cells at 200g for 5 min, and wash each well once with 200μL PBS;

[0411] 2.6 Fix cells with 4% paraformaldehyde fixative for 15 min, wash twice with PBS; rupture the membrane with methanol for 10 min, wash twice with PBS;

[0412] 2.7 Add blocking agent human serum immunoglobulin G to each well and block for 10 min, then wash once with PBS;

[0413] 2.8 Add 100 μL of staining solution containing human pSTAT4 antibody to each well, stain at 4 degrees Celsius for 30 min, and wash twice with PBS;

[0414] 2.9 The fluorescence intensity of pSTAT4 in NK-92 cells was detected by flow cytometry;

[0415] 3 Data Analysis

[0416] The MFI value was obtained through data analysis using the built-in software of the Thermofisher Attune Nxt instrument. Then, the IC50 of the compound was calculated using the formula: Inhibition Percentage = (MFI value of IL-12 stimulation group - MFI value of test compound group) / (MFI value of IL-12 stimulation group - MFI value of DMSO group). 50 The results are shown in Table 1:

[0417] Table 1. Inhibitory activity of the compounds of this invention on the TYK2 signaling pathway in NK-92 cells.

[0418]

[0419] in,

[0420] "A" indicates IC with a value less than 100 nm. 50 ;

[0421] "B" indicates ICs ranging from 100nM to less than 500nM. 50 ;

[0422] "C" indicates an IC of 500nM or larger. 50 ;

[0423] Test Example 2: Determination of Hepatic Microsomal Metabolic Stability

[0424] The metabolic stability of the compounds of this invention in liver microsomes was determined by the following experimental method.

[0425] 1. Main test materials

[0426] 1.1 Sources of liver microsomes: Human (mixed) liver microsomes (batch number: OUP, BIOIVT, USA); SD rat (mixed) liver microsomes (batch number: YYMG, Rede Liver Disease Research (Shanghai) Co., Ltd.); CD mouse (mixed) liver microsomes (batch number: TZZL, Rede Liver Disease Research (Shanghai) Co., Ltd.)

[0427] 1.2 NADPH (Batch No.: A2305348, Shanghai Aladdin Biochemical Technology Co., Ltd.)

[0428] 1.3 Testosterone (Batch No.: G1217507, Dr Ehrenstorfer GmbH)

[0429] 2. Experimental Procedure

[0430] 2.1 Preparation of phosphate buffer

[0431] Weigh out a certain amount of NaH2PO4 and dissolve it in deionized water to prepare a 0.1M (12.0 g / L) solution A; weigh out a certain amount of Na2HPO4 and dissolve it in deionized water to prepare a 0.1M (14.2 g / L) solution B; mix solutions A and B in a ratio of 19:81 (v:v), and adjust the pH to 7.4 ± 0.3 using H3PO4 or NaOH to obtain a 100 mM PB buffer solution (concentration is expressed as phosphate ion concentration).

[0432] 2.2 Preparation of magnesium chloride aqueous solution

[0433] Weigh a certain amount of MgCl2 powder and dissolve it in deionized water to prepare a 60mM MgCl2 solution.

[0434] 2.3 Configuration of the reaction system

[0435] Configure the reaction system according to the table below.

[0436]

[0437] 2.4 Liver microsomes taken from a -70℃ freezer were thawed in an ice bath. Liver microsomes and test solution or probe substrate solution (PC) were added to the reaction tube, followed by NADPH or blank buffer (NC) to start the reaction. The reaction was incubated for 0, 15, and 60 min. Pre-cooled stop solution containing internal standard was added to precipitate the protein. The supernatant was collected by centrifugation, and the remaining amount of test solution or probe substrate was detected by LC-MS / MS.

[0438] 3. Experimental Results and Analysis

[0439] All data were calculated using Microsoft Excel software. Peak areas were detected by extracting ion spectra. The in vitro half-life (T0) of the parent drug was determined by linearly fitting the natural logarithm of the elimination percentage of the parent drug to time. 1 / 2 ).

[0440] In vitro half-life (T 1 / 2 Calculate using the following formula:

[0441] T 1 / 2 =0.693 / K, where K is the elimination rate constant;

[0442] Plotting the logarithm of the remaining maternal percentage (Ln%) against incubation time (Time), the slope of the resulting line is Slope, K = -Slope. In vitro intrinsic clearance rate (CL) int (μL / min / mg protein) is calculated using the following formula:

[0443] CL int = 0.693 × incubation volume (μL) / incubated protein (mg) / T 1 / 2 .

[0444] T calculated using the above formula 1 / 2 and CL int The values ​​are shown in Table 2.

[0445] Table 2. Half-life and intrinsic clearance values ​​of the compounds of the present invention in liver microsomes.

[0446]

[0447] Test Example 3: Permeability Measurement in MDCK Cells

[0448] The permeability of the compounds of this invention in MDCK cells was determined using the following experimental method.

[0449] 1. Main test materials

[0450] MDCK-MDR1 cells (catalog number: T9646), passage 14, purchased from Applied Biological Materials Inc.

[0451] 2 Experimental Procedure

[0452] 2.1 MDR1-MDCK cell culture:

[0453] MDR1-MDCK cells were cultured in MEM (Minimum Essential Media) medium at 37.0°C, 5.0% CO2, and saturated humidity. The cells were then seeded into Transwell-24-well cell culture plates and incubated in a CO2 incubator for 3-5 days before being used for transport experiments, with the medium changed every other day during this period.

[0454] 2.2 Preparation of the drug solution:

[0455] Accurately weigh an appropriate amount of reference standard, dissolve it in DMSO, and dilute it with HBSS to prepare a 2 μM drug solution;

[0456] 2.3 Preparation of receiving solution and transfer buffer:

[0457] HBSS solution (30 mM HEPES / Tris, pH 7.4 ± 0.05).

[0458] 2.4 Translocation Permeation Test:

[0459] Pre-incubate the drug solution, receiver solution, and transport buffer in a 37.0°C water bath for 30 minutes. Rinse the cell layer twice with transport buffer. Add the drug solution and receiver solution to the corresponding wells of the cell plate (200 μL and 700 μL to each top and base well, respectively). After adding samples, incubate the cell plate in a 37.0°C, 5.0% CO2, and saturated humidity incubator for 120 minutes. Collect the initial drug solution as the T0 sample. After 120 minutes of incubation, collect samples from each well and label them as AB receiver end, BA receiver end, AB cell lysis end, BA cell lysis end, AB drug delivery end, and BA drug delivery end, respectively. Add an appropriate amount of methanol containing internal standard to all samples, vortex centrifuge, and analyze the supernatant using LC-MS / MS.

[0460] 3. Experimental Results and Analysis

[0461] The apparent permeability coefficient and efflux rate of the compounds of this invention were calculated using the following formulas, and the specific data are shown in Table 3.

[0462] Calculation of apparent permeability coefficient Papp (cm / s) for drugs:

[0463] Papp=(dCr / dt)×Vr / (A×C0)

[0464] Where dCr / dt: the concentration of the compound in the receiving cell as a function of time; Vr: the solution volume in the receiving cell (top-side volume 0.2 mL, bottom-side volume 0.7 mL); A: the area of ​​the transfer membrane (cm²). 2 C0: Initial concentration (μM) of the compound supplied to the pool.

[0465] Formula for calculating the discharge rate:

[0466] Efflux Ratio = Papp(B→A) / Papp(A→B)

[0467] Table 3. Average apparent permeability and efflux rate of the compounds of this invention.

[0468]

Claims

1. A sulfoxide imine compound having the structure shown in formula (I), or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite: in, A is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally further selected from deuterium atoms, C atoms, and C atoms. 1-3 Replaced by one or more substituents in the alkyl or halogen group. L is selected from key or Alternatively, A and L form R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Each of the aryl or 5-14 heteroaryl groups is optionally substituted by one or more substituents selected from deuterium, cyano, nitro or halogen; R2 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Each of the aryl or 5-14 heteroaryl groups is optionally substituted by one or more substituents selected from deuterium, cyano, nitro or halogen; R3 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups containing 1 to 4 heteroatoms, wherein the heteroatoms are selected from O, N, or S, and the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylamine group, C 3-6 The cycloalkyl group or the 3-6 membered heterocyclic group containing 1 to 4 heteroatoms is optionally replaced by one or more substituents selected from deuterium or halogens; X is selected from CR7 or N; Y is selected from CH or N; Ring B is a 5-6 membered heteroaryl group; R4 is selected from H, halogen, cyano, C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkyne or 5-6 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 The alkynyl or 5-6 heteroaryl group may optionally be substituted by one or more R's, wherein the R's are selected from halogens, cyano groups, nitro groups, deuterium atoms, and C atoms. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or C 3-6 cycloalkyl, where R' is selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or C 3-6 In the case of cycloalkyl groups, R' may be further substituted with one or more substituents selected from deuterium, cyano, nitro, or halogen; R5 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl groups; R6 and R7 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, The compound has a structure as shown in formula (IIa), (IIb), (IIc), (IId), (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb): The definitions of A, L, R1, R2, R3, R6, and R7 are as described in claim 1; The R 42a R 43a R 44a R 45a Each is independently selected from halogens or 5-6 nitrogen-containing heteroaryl groups, wherein the 5-6 nitrogen-containing heteroaryl groups are optionally further substituted by one or more halogens; The R 42b R 43b R 44b R 45b Each is independently selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-6 cycloalkyl or C 3-6 alkynyl group; The R 42c R 42d Each is independently selected from C 1-6 alkyl.

3. The compound as described in claim 1 or 2, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, A and L form the following structure:

4. The compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt, isotope derivative, solvate, or its stereoisomer, geometric isomer, tautomer, or its prodrug molecule or metabolite, characterized in that, R1 is selected from C 1-6 Alkyl group; R2 is selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, R3 is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy or C 1-6 Alkylamine group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, R6 is selected from hydrogen; R7 is selected from hydrogen.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof, characterized in that, The compound is selected from the following structural compounds:

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of any one of the compounds of claims 1-7 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof.

9. Use of any compound of claims 1 to 7 or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or pharmaceutical composition of claim 8 in the preparation of a medicament for treating TYK2-mediated diseases or conditions and related diseases or conditions.

10. The use according to claim 9, characterized in that, The TYK2-mediated diseases or conditions and related diseases or conditions include proliferative diseases, metabolic diseases, allergic diseases, inflammatory diseases, infectious diseases, neurodegenerative diseases, autoimmune diseases, and cancer.

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