Pyridazine-3-carboxamide compounds as TYK2 inhibitors

Abstract

The present invention provides a pyridazine-3-carboxamide compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorphic form, prodrug, or isotope variant thereof. The present invention further provides a pharmaceutical composition comprising the compound, a method for preparing the pharmaceutical composition, and the use of the pharmaceutical composition in treating or preventing a TYK2 kinase-mediated disease. TIFF2025518997000118.tif41128

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically to pyridazine-3-carboxamide compounds, compositions containing pyridazine-3-carboxamide compounds, methods for their preparation, and their use as TYK2 inhibitors.

Background Art

[0002] The Janus kinase (JAK) family is composed of intracellular non-receptor tyrosine kinases that mediate the signal transduction and activation of various cytokines. Gain-of-function expression or mutations of JAK are associated with many autoimmune diseases, inflammatory conditions, and cancers. This family includes JAK1, JAK2, JAK3, and TYK2, among which JAK1, JAK2, and TYK2 are widely present in various tissues and cells of the human body, and JAK3 is mainly present in myeloid cells, thymocytes, NK cells, and activated B and T cells.

[0003] The JAK-mediated signal transduction pathway includes three important parts: cytokine receptors on the cell surface, JAK, and downstream proteins. Cytokines such as various interferons (IFN) and interleukins (IL) bind to cytokine receptors on the cell surface, bringing JAKs that bind to the intracellular domain of the receptor into proximity. Next, the tyrosine residues of JAK are phosphorylated, increasing the activity of the kinase domain. Then, the activated JAK phosphorylates the tyrosine residues of the receptor, creating a binding site for proteins with SH2 domains. STAT (signal transducer and activator of transcription) binds to phosphorylated tyrosine on the receptor through its SH2 domain, is phosphorylated by JAK, generating phosphorylated STAT dimers, which then translocate to the nucleus to induce the transcription of target genes. In addition, other proteins with SH2 domains can also bind to the activated JAK, thereby bridging with other signal transduction pathways such as PI3K / AKT, MAPK / ERK.

[0004] TYK2 is a non-receptor tyrosine kinase that mediates immune signals. TYK2 mainly regulates signal transduction pathways driven by IL-23, IL-12, and type I interferon (IFNα), and is used as an IL-12, IL-23, and / or IFNa regulator by inhibiting TYK2-mediated signal transduction. TYK2 plays an important role in transmitting inflammatory and immune response signals and is involved in the pathophysiological processes of various immune-related diseases such as psoriasis (PS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). TYK2 does not mediate cytokine responses driven by other kinases (such as IL-6, hematopoietic growth factors, and IL-2). Therefore, TYK2 inhibitors can avoid the adverse reactions associated with currently marketed JAK inhibitors by not acting on other subtypes.

[0005] Common small molecule JAK inhibitors are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (JH1) of JAK proteins. Due to the high homology of the ATP sites of JAK family kinases and the similarity to the ATP binding regions of the human kinase group, generally, there is a problem of low selectivity.

[0006] Research has shown that the pseudokinase domain (JH2) in the JAK family, which exhibits significant catalytic activity, can provide an ideal allosteric site for the discovery of TYK2-selective inhibitors. Compound BMS-986165 is a currently known compound that can selectively bind to JH2 of TYK2 and inhibit TYK2 kinase function through an allosteric effect.

[0007] Currently, there is a need for drugs with improved activity in selectively inhibiting TYK2 by binding to JH2 and thereby providing a therapeutic benefit in the treatment of diseases. SUMMARY OF THE INVENTION

[0008] In view of the above, the present invention provides a pyridazine-3-carboxamide compound having excellent activity against the selective inhibition of TYK2 and capable of treating various TYK2-mediated diseases.

[0009] The present invention provides a compound represented by general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof: TIFF2025518997000002.tif41128wherein each substituent is as defined in the present invention.

[0010] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient, preferably further containing other therapeutic agents.

[0011] In one embodiment, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, and a pharmaceutical composition containing the same, in the preparation of a medicament for treating and / or preventing TYK2-mediated diseases.

[0012] In one embodiment, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, or a pharmaceutical composition containing the compound, in the treatment and / or prevention of TYK2 kinase-mediated diseases.

[0013] In one embodiment, the present invention provides a method for treating and / or preventing a TYK2 kinase-mediated disease in a subject by using a compound as defined herein, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0014] The TYK2 kinase-mediated diseases described in the present invention are selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, and polycythemia vera. Further, the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease, the skin disease is psoriasis, rash, or atopic dermatitis, the allergic disease is asthma or rhinitis, the organ transplant rejection is allograft rejection or graft-versus-host disease, and the cancer is kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma, or leukemia.

[0015] In some embodiments, the TYK2 kinase-mediated disease associated with the method is selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

Embodiments for Carrying Out the Invention

[0016] Detailed Description Definitions The compounds of the present invention, methods for their preparation, and their uses are described in more detail below with reference to specific examples. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided for the purpose of providing a thorough and complete understanding of the disclosure of the present invention.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terms used in the description herein are for the purpose of illustrating specific examples only and are not intended to limit the invention. As used herein, the term "and / or" means any one or more of the associated listed items and all combinations of the items.

[0018] The term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Alkyl is preferably, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, and C1-C3 alkyl. When using "C1-C3 alkyl" as an example, this term refers to an alkyl containing 1 to 3 carbon atoms, and each occurrence thereof can independently be C1 alkyl, C2 alkyl, or C3 alkyl. Suitable examples include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2).

[0019] "Alkenyl" is an alkyl as defined herein that contains at least one carbon-carbon double bond. In one example, alkenyl contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkenyl include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, or 4-decenyl. When alkenyl is substituted, preferably there are 1 to 5 substituents, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0020] "Alkynyl" is an alkyl as defined herein that contains at least one carbon-carbon triple bond. In one example, alkynyl contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkynyl include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-heptynyl, or 4-decynyl, etc. When alkynyl is substituted, preferably there are 1 to 5 substituents, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0021] "Carbocyclic" or "cycloalkyl" refers to a saturated or partially unsaturated cyclic carbon-containing group such as a 5- to 6-membered saturated carbocyclic ring and a 5- to 6-membered partially unsaturated carbocyclic ring. In one embodiment, carbocyclic is a 3- to 4-membered monocyclic, 3- to 5-membered monocyclic, 3- to 6-membered monocyclic, 3- to 7-membered monocyclic, 3- to 8-membered monocyclic, 3- to 10-membered monocyclic, 5- to 8-membered monocyclic, 5- to 6-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic ring system. The carbocyclic ring includes a bridged ring or a spiro ring. Non-limiting examples of carbocyclic include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrieneyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl, or spiro[3.3]heptyl, etc. Carbocyclic may be substituted. When carbocyclic is substituted, preferably there are 1 to 5 substituents, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0022] The term "halogen" means -F, -Cl, -Br, or -I. Further, the term "haloalkyl" refers to an alkyl substituted with a halogen group, where the alkyl is as defined above, preferably C 1~6 haloalkyl, C 1~5 haloalkyl, C 1~4 haloalkyl, C 1~3 haloalkyl, and C 1~2 is haloalkyl.

[0023] The term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom, and can be monocyclic aryl, fused-ring aryl, or polycyclic aryl, preferably 6- to 10-membered aryl. For polycyclic ring species, at least one is an aromatic ring system. Phrases containing this term, such as "5- to 6-membered aryl", mean that the aromatic ring system contains 5 to 6 ring atoms. Preferably, aryl is phenyl.

[0024] The term "heteroaryl" refers to aryl containing heteroatoms which can be monocyclic rings or fused rings, the heteroatoms are independently selected from N, O, and S, and heteroaryl is preferably 5- to 12-membered heteroaryl, 5- to 10-membered heteroaryl, preferably 5- to 8-membered heteroaryl, more preferably 5- to 6-membered heteroaryl, and even more preferably 5-membered heteroaryl. Examples of heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, tetrahydropyrrolyl, and thiadiazolyl. In one embodiment, typically, 5- to 6-membered monocyclic heteroaryl containing one or more, preferably 1 to 3, heteroatoms independently selected from N, O, and S is provided. Unless otherwise specified, "5-membered heteroaryl" is as follows: Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.

[0025] "Heterocyclyl" or "heterocyclic ring" refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing heteroatoms selected from N, O, and S. Further, the term "heterocyclyl" refers to a group having a stable 3- to 10-membered saturated heterocyclic system in which one or more atoms constituting the non-aromatic ring are heteroatoms and the rest are carbon. Examples of heteroatoms include, but are not limited to, nitrogen atoms, oxygen atoms, sulfur atoms, etc. Heterocyclyl can be a 3- to 7-membered monocyclic, 5- to 8-membered monocyclic, 5- to 6-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic ring system, preferably a 3- to 10-membered heterocyclyl, and contains at least 1, preferably 1 to 4, heteroatoms selected from N, O, or S. Unless otherwise indicated herein, a heterocycloalkyl group can be a monocyclic system ("monocyclic heterocycloalkyl") or can include a fused (condensed), bridged (bridged ring), or spiro ring system (e.g., a bicyclic system ("bicyclic heterocycloalkyl") that can be a bicyclic system, a tricyclic system, or a polycyclic system having more rings). The ring system of bicyclic heterocycloalkyl can contain one or more heteroatoms in one or both rings and is saturated. Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thiaranyl, or their stereoisomers. Exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, or their isomers and stereoisomers. Exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, or their isomers and stereoisomers. Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thioxanyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or their isomers and stereoisomers.Exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and diazepanyl, or their isomers and stereoisomers. In one embodiment, a typical heterocyclyl is a 5- to 6-membered monocyclic heterocyclyl containing one or more, preferably 1 to 4, more preferably 1 to 3 heteroatoms independently selected from N, O, and S. In one embodiment, "heterocycloalkyl" is a 4- to 6-membered heterocycloalkyl, and the heteroatom is selected from one or more of N, O, and S, and 1, 2, or 3 heteroatoms are provided.

[0026] In various sections of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood as the linking group. For example, when the structure requires a linking group and the definition of the Markush group for its variable element lists "alkyl" or "aryl", "alkyl" or "aryl" should be understood to represent a linking alkylene group or an arylene group, respectively. In some specific structures, when an alkyl group is clearly shown as the linking group, the alkyl group represents a linking alkylene group. For example, the alkyl in the "-C1-C3 haloalkyl" group should be understood as alkylene.

[0027] The term "pharmaceutically acceptable salt" means that the compound can be converted into the corresponding salt by conventional methods, and the salt is chemically or physically compatible with the other components constituting the pharmaceutical dosage form and is physiologically compatible with the receptor. The salts can be acidic and / or basic salts formed from the compound and inorganic and / or organic acids and / or inorganic and / or organic bases, including zwitterionic salts (inner salts), and further including quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. The salts can also be obtained by appropriately mixing the compound of the present invention, or its stereoisomer or solvate, with a specific amount of an acid or a base. These salts can be precipitated from the solution, collected by filtration, or recovered after evaporation of the solvent, or obtained by reacting in an aqueous medium followed by cooling and drying. Specifically, the salts are preferably water-soluble, pharmaceutically acceptable, non-toxic acid addition salts, examples of which are salts formed from amino acids and inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other conventional methods in the art (such as ion exchange methods).Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, diglucosate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactoate, lactate, laurate, laurylsulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, niacin, nitrate, oleate, oxalate, palmitate, dihydroxynaphthaleneate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Additional pharmaceutically acceptable salts can further include salts derived from suitable bases, including, where appropriate, alkali metal salts, alkaline earth metal salts, and ammonium salts. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Additional pharmaceutically acceptable salts can include salts formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates, together with non-toxic ammonium cations, quaternary ammonium cations, and amine cations, where appropriate.

[0028] The term "solvate" may also be referred to as "solvated compound" or "solvate", and refers to a compound containing solvent molecules, which can bind to the compound molecules in ways including coordination bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds, etc. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric and non-stoichiometric solvates. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvates" include solvates in solution and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0029] The term "hydrate" refers to a compound that binds to water. Usually, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is fixed. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form two or more types of hydrates, including, for example, a monohydrate (x is 1), a lower hydrate (x is greater than 0 and less than 1, for example, a hemihydrate (R·0.5H2O)), and a polyhydrate (x is greater than 1, for example, a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0030] The term "prodrug" refers to any compound that, when administered to a living being, results in a drug, i.e., the active ingredient, as a consequence of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. Thus, a prodrug is a covalently modified analog or latent form of a therapeutically active compound. Suitable examples include, but are not limited to, carboxylates, carbonates, phosphates, nitrates, sulfates, sulfones, sulfoxides, amides, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and other forms of compounds.

[0031] The present invention further includes isotopically labeled compounds (isotope variants), which are equivalent to the general formulas or specific compounds described herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include, respectively, 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, preferably 2 isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, such as 3 H and 14 C). Compounds of the present invention containing the aforementioned isotopes and / or other isotopes of other atoms, prodrugs of the compounds, and pharmaceutically acceptable salts of the compounds or prodrugs are all within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as compounds incorporating radioactive isotopes (such as 3 H and 14C) Isotopes are particularly preferred for ease of preparation and detectability. Additionally, substituted compounds can provide therapeutic advantages due to greater metabolic stability, such as an extended in vivo half-life or a reduced required dosage, so substitution with heavier isotopes such as deuterium (i.e., 2 H) may be preferred in some cases. Isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents when carrying out the procedures and / or processes disclosed in the following procedures and / or examples and preparative examples.

[0032] The compounds of the present invention contain one or more asymmetric centers and thus can have multiple stereoisomeric forms, such as enantiomeric and / or diastereomeric forms. For example, the compounds of the present invention can be separate enantiomers, diastereomers, or geometric isomers (e.g., cis- and trans-isomers), or can be in the form of a mixture of enantiomers and a mixture rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, the preferred isomers can be prepared by asymmetric synthesis.

[0033] "Optional" or "optionally" means that the event or circumstance described thereafter may or may not occur, including both the case where the event or circumstance occurs and the case where it does not occur. For example, "aryl may be substituted with alkyl" means that alkyl may or may not be present, and this term includes both the case where aryl is substituted with alkyl and the case where aryl is not substituted with alkyl.

[0034] "Pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or agent such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the term "pharmaceutically acceptable excipient" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like that are compatible with pharmaceutical administration. Each excipient must be "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include (1) sugars such as lactose, glucose, and sucrose, (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrin, (3) celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate, (4) powdered tragacanth gum, (5) malt, (6) gelatin, (7) talc, (8) excipients such as cocoa butter and suppository wax, (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, (10) glycols such as propylene glycol, (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethanol, (20) phosphate buffer, and (21) other non-toxic compatible substances used in pharmaceutical formulations, but are not limited thereto.

[0035] The term "polymorph" refers to the crystalline form of a compound (or its salt, hydrate, or solvate) with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectronic properties, stabilities, and solubilities. One crystalline form may predominate depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the standard meanings in the technical field to which the claimed subject matter belongs. In case of multiple definitions for a term, the definition in this specification shall prevail. It should be understood that the singular forms such as "a" and "an" used in the present invention include plural referents unless otherwise specified.

[0037] In addition, the terms "comprise" and "include" are non-limiting and non-exclusive, that is, they include the content specified in the present invention but do not exclude other aspects.

[0038] Unless otherwise specified, the present invention can use conventional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and for procedures and conditions, reference can be made to the conventional operating procedures and conditions in the technical field.

[0039] Unless otherwise indicated, the present invention uses standard nomenclature in analytical chemistry, synthetic organic chemistry, and optics as well as standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

[0040] In addition, it should be noted that unless otherwise explicitly stated, the description "each independently" used in the present invention should be understood in a broad sense, which means that each entity described is independent of each other and can be in the same specific group or different specific groups independently. More specifically, the description "each independently" may mean that specific options represented by the same symbol do not affect each other among different groups, or may mean that specific options represented by the same symbol do not affect each other within the same group.

[0041] Specifically, the present invention relates to the following technical solutions.

[0042] In one embodiment, the present invention relates to a compound represented by the general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof: TIFF2025518997000003.tif41128 wherein, X is CR' or N, Y is CR', R1 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the group may be substituted with one or more deuteriums until it is fully deuterated, R2 is C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6~10 aryl, or 5- to 10-membered heteroaryl, and the group may be substituted with one or more deuteriums until it is fully deuterated, R3 is -L-C 1~6 alkyl, -L-C 1~6 haloalkyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl, or -L-5- to 10-membered heteroaryl, and the group may be substituted with one or more deuteriums until it is fully deuterated, R4 is H, C 1~6 alkyl, or C 1~6 haloalkyl, and the group may be substituted with one or more deuteriums until it is fully deuterated, Each of the groups R1, R2, R3, and R4 may be substituted with 1, 2, 3, or 4 R's, L is selected from a bond, -C(O)-, or -C(S)-, R is selected from H, D, halogen, CN, C 1~6 alkyl, or C 1~6 haloalkyl, and R’ is selected from H, D, halogen, or CN.

[0043] In a more specific embodiment, the present invention provides a compound represented by the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, wherein, X is CR’ or N, Y is CR’, R1 is selected from C 1~6 alkyl, C 3~7 cycloalkyl, or 3- to 7-membered heterocyclyl, and this group may be substituted with one or more deuteriums until it is fully deuterated, R2 is selected from C 1~6 alkyl, C 1~6 haloalkyl, C 3~7 cycloalkyl, or 3- to 7-membered heterocyclyl, and this group may be substituted with one or more deuteriums until it is fully deuterated, R3 is -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, C 6~10 aryl, or 5- to 6-membered heteroaryl, and this group may be substituted with one or more deuteriums until it is fully deuterated, R4 is H, C 1~6 alkyl, or C 1~6 haloalkyl, and this group may be substituted with one or more deuteriums until it is fully deuterated, each of the groups R1, R2, R3, and R4 may be substituted with 1, 2, 3, or 4 Rs, L is selected from -C(O)- or -C(S)-, R is selected from H, D, halogen, or CN, R’ is selected from H, D, halogen, or CN.

[0044] In a more specific embodiment, the present invention provides a compound represented by the above formula (I) wherein X is CR', preferably CH, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof.

[0045] In a more specific embodiment, the present invention provides a compound represented by the above formula (I) wherein Y is CH or CF, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof.

[0046] In a more specific embodiment, the present invention provides a compound represented by the above formula (I) wherein R1 is selected from C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 cycloalkyl, or 3- to 7-membered heterocyclyl, and this group may be substituted with one or more deuteriums until it is fully deuterated, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof. Preferably, R1 is selected from C 1~6 alkyl or C 3~7 cycloalkyl, and this group may be substituted with one or more deuteriums until it is fully deuterated. Preferably, R1 is C 1~6 alkyl which may be substituted with one or more deuteriums until it is fully deuterated. Preferably, R1 is C 3~7 cycloalkyl.

[0047] In a more specific embodiment, the present invention provides a compound represented by the above formula (I) wherein R2 is C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7A compound represented by the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, which is selected from cycloalkyl or 3- to 7-membered heterocyclyl, and this group may be substituted by one or more deuteriums until it is completely deuterated. Preferably, R2 is C 1~6 alkyl, C 1~6 haloalkyl, or C 3~7 cycloalkyl, which is selected, and this group may be substituted by one or more deuteriums until it is completely deuterated. Preferably, R2 is C 1~6 alkyl which may be substituted by one or more deuteriums until it is completely deuterated.

[0048] In a more specific embodiment, the present invention provides a compound represented by the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, wherein R3 is selected from -C(O)-C 3~7 cycloalkyl or 5- to 6-membered heteroaryl, and this group may be substituted by one or more deuteriums until it is completely deuterated. Preferably, R3 is -C(O)-C 3~7 cycloalkyl.

[0049] In a more specific embodiment, the present invention provides a compound represented by the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, wherein R4 is selected from C 1~6 alkyl or C 1~6 haloalkyl, and this group may be substituted by one or more deuteriums until it is completely deuterated. Preferably, R4 is C 1~6 alkyl which may be substituted by one or more deuteriums until it is completely deuterated.

[0050] In a more specific embodiment, the present invention provides a compound represented by the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, which has the following general formula: TIFF2025518997000004.tif44155, wherein each group is as defined in the present application.

[0051] In a more specific embodiment, the present invention provides a compound represented by the above formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and this compound is selected from TIFF2025518997000005.tif251161TIFF2025518997000006.tif149161.

[0052] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition further contains other therapeutic agents.

[0053] In one embodiment, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, and a pharmaceutical composition containing the same, in the preparation of a medicament for treating and / or preventing a TYK2 kinase-mediated disease.

[0054] In one embodiment, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, or a pharmaceutical composition comprising such a compound, in the treatment and / or prevention of TYK2 kinase-mediated diseases.

[0055] In one embodiment, the present invention provides a method for treating and / or preventing a TYK2 kinase-mediated disease in a subject by using a compound as defined herein, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.

[0056] The TYK2 kinase-mediated diseases described in the present invention are selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, and polycythemia vera. Further, the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease, the skin disease is psoriasis, rash, or atopic dermatitis, the allergic disease is asthma or rhinitis, the organ transplant rejection is allograft rejection or graft-versus-host disease, and the cancer is kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma, or leukemia.

[0057] In some embodiments, the TYK2 kinase-mediated disease associated with the method is selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

[0058] Those skilled in the art will understand that various preferred embodiments of the present invention can be obtained by arbitrarily combining the above various preferred conditions without departing from the common general knowledge in the art.

[0059] Administration The compounds represented by (I) of the present invention can be administered by any means suitable for the condition of the disease to be treated. This means may depend on the need for site-specific treatment or the amount of medicament to be delivered. Although other delivery modes are contemplated, topical administration is generally preferred for skin-related diseases, and systemic treatment is preferred for cancerous or pre-cancerous disease states. For example, the compound can be administered orally, in the form of, for example, tablets, capsules, granules, powders, or liquid preparations (including syrups); topically, in the form of, for example, solutions, suspensions, gels, or ointments; sublingually; buccally; parenterally, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection, or by infusion techniques (for example, in the form of a sterile injectable aqueous or non-aqueous solution or suspension); intranasally, for example, by inhalation of a spray; topically, in the form of, for example, creams or ointments; rectally, in the form of, for example, suppositories; or delivered by liposomes. Unit dosage formulations containing non-toxic pharmaceutically acceptable carriers or diluents can be administered. The compound can be administered in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved using suitable pharmaceutical compositions or, particularly in the case of sustained release, using devices such as subcutaneous implants or osmotic pumps.

[0060] Exemplary compositions for topical administration include topical carriers.

[0061] Exemplary compositions for oral administration include, for example, suspensions that may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a tackifier, and sweeteners or flavoring agents such as those known in the art, and immediate release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose, and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants such as those known in the art. The compounds of the present invention may also be delivered orally by sublingual and / or buccal administration using, for example, molded, compressed, or lyophilized tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. These formulations may also include high molecular weight excipients such as cellulose (AVICEL®) or polyethylene glycol (PEG); excipients for assisting mucoadhesion such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), and / or maleic anhydride copolymer (e.g., GANTREZ®); and agents for controlled release such as polyacrylic acid copolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavoring agents, coloring agents, and stabilizers may also be added to facilitate preparation and use.

[0062] Exemplary compositions for nasal aerosol or inhalation administration include, for example, solutions that may contain benzyl alcohol or other suitable preservatives, absorption enhancers for enhancing absorption and / or bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0063] Exemplary compositions for parenteral administration include, for example, suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or injectable solutions or suspensions that may contain other suitable dispersing or wetting agents and suspending agents, including synthetic monoglycerides or diglycerides containing oleic acid and fatty acids.

[0064] Exemplary compositions for rectal administration include, for example, suppositories that may contain suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycol, which are solid at room temperature but liquefy and / or dissolve in the rectal cavity to release the medicament.

[0065] The therapeutically effective amount of the compounds of the present invention can be determined by those skilled in the art and includes exemplary dosages of the active compound of about 0.05 - 1000 mg / kg, 1 - 1000 mg / kg, 1 - 50 mg / kg, 5 - 250 mg / kg, and 250 - 1000 mg / kg body weight per day for mammals, which can be administered as a single dose or as individual divided doses (e.g., 1 - 4 times per day). The specific dosage level and frequency of administration for any particular subject may vary and depend on a variety of factors including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the species, age, weight, general health status, sex, and diet of the subject, the mode and time of administration, the rate of excretion, drug combinations, and the severity of the particular disease state. Preferred subjects for treatment include animals, most preferably humans, and mammalian species such as domestic animals like dogs, cats, horses, etc. Thus, when the term "patient" is used herein, this term is meant to include all subjects, most preferably mammalian species suffering from a TYK2 kinase-mediated disease.

Examples

[0066] The materials and reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.

[0067] Example 1 6-(Cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 1)

[0068] Synthesis of Intermediate 1C TIFF2025518997000007.tif25128Step 1: 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline TIFF2025518997000008.tif211283-Bromo-2-methoxyaniline (10 g, 49.5 mmol) was dissolved in 1,4-dioxane (150 mL), and then pinacol borate (25.1 g, 98.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (3.62 g, 4.95 mmol), and potassium acetate (9.72 g, 99 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 110 °C for 3 hours. The reaction solution was poured into water (80 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain a crude product. The crude product was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain the title compound (7.8 g, yield: 63.4%, yellow solid). MS(ESI): m / z 249.9 [M+H] + .

[0069] Step 2: 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline TIFF2025518997000009.tif221282-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.4 g, 21.7 mmol) was dissolved in 1,4-dioxane (80 mL), and water (16 mL), 3-bromo-1-methyl-1H-1,2,4-triazole (5.27 g, 32.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.59 g, 2.17 mmol), and potassium carbonate (9.0 g, 65.1 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 110 °C for 16 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain a crude product. The crude product was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (3.1 g, yield: 70.1%, brown solid). MS(ESI): m / z 205.1[M+H] + 。

[0070] Synthesis of Compound 1 TIFF2025518997000010.tif67146

[0071] Step 1: Lithium 4,6-dichloropyridine-3-carboxylate TIFF2025518997000011.tif13128Methyl 4,6-dichloropyridine-3-carboxylate (10 g, 48.31 mmol) was dissolved in water (7.5 mL) and acetonitrile (50 mL), and lithium bromide (12.58 g, 144.93 mmol) and DIEA (18.7 g, 144.93 mmol) were added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was filtered by suction, and the filter cake was washed with acetonitrile to obtain the title compound (6.84 g, yield: 71.3%, white solid). MS(ESI): m / z 192.9[M+H] + 。

[0072] Step 2: 4,6-Dichloro-N-methoxypyridazine-3-carboxamide TIFF2025518997000012.tif13128 Lithium 4,6-dichloropyridine-3-carboxylate (2 g, 10.4 mmol) was dissolved in thionyl chloride (20 mL), DMF (0.5 mL) was added, and the mixture was reacted at 90 °C for 1 h. The reaction solution was spin-dried, DCM (20 mL) was added, the temperature was lowered to 0 °C, and methoxyamine (910.4 mg, 10.5 mmol) and triethylamine (5.26 g, 52.0 mmol) were added at 0 °C. The reaction solution was reacted at room temperature for 1 h and spun in vacuo to remove the solvent, giving a crude product. The crude product was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to give the title compound (613 mg, yield: 27.5%, yellow solid). MS (ESI): m / z 208.9 [M+H] + 。

[0073] Step 3: 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide TIFF2025518997000013.tif331282-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.0 g, 4.90 mmol) was dissolved in THF (40 mL). After replacing with nitrogen three times, the reaction system was cooled to 0 °C, and lithium bis(trimethylsilyl)amide (2.46 g, 14.71 mmol) was slowly added dropwise at 0 °C using a syringe. The reaction solution was reacted at 0 °C for 1 hour. Then, a solution of 4,6-dichloro-N-methoxypyridazine-3-carboxamide (1.08 g, 4.90 mmol) in tetrahydrofuran was injected into the reaction solution at 0 °C using a syringe. After the reaction solution was warmed to room temperature naturally, the mixture was reacted at room temperature for 16 hours. An aqueous saturated ammonium chloride solution (10 mL) was added to the reaction solution to quench it. After quenching, the reaction solution was poured into water (10 mL). The aqueous phase was extracted three times with ethyl acetate (30 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain a crude product. The crude product was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the title compound (880 mg, yield: 46.3%, yellow solid). MS(ESI):m / z 390.1[M+H] + 。

[0074] Step 4: 6-(Cyclopropylcarboxamido)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 1) TIFF2025518997000014.tif 391286 - chloro - N - methoxy - 4 - ((2 - methoxy - 3-(1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide (200 mg, 0.51 mmol) was dissolved in 1,4 - dioxane (8.5 mL), and cyclopropylcarboxamide (434 mg, 5.10 mmol), tris(dibenzylideneacetone)dipalladium (186.8 mg, 0.204 mmol), 4,5 - bis(diphenylphosphino - 9,9 - dimethylxanthene) (235.8 mg, 0.408 mmol), and cesium carbonate (498.5 mg, 1.53 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 110 °C for 16 h. The reaction solution was spun in vacuo to remove the solvent, and then filtered by suction using dichloromethane:methanol = 15:1 to obtain the crude product. The crude product was purified by reverse - phase preparative chromatography to give the title compound (5.9 mg, yield: 2.6%, white solid). MS(ESI): m / z 439.1[M + H] + 。 1 H NMR(400 MHz, CD3OD) δ 8.47(s, 1H), 8.25(s, 1H), 7.67(d, J = 7.5 Hz, 1H), 7.59(d, J = 7.8 Hz, 1H), 7.29(t, J = 7.9 Hz, 1H), 4.01(s, 3H), 3.87(s, 3H), 3.74(s, 3H), 1.29(s, 1H), 0.99 - 0.87(m, 4H).

[0075] Example 2 6 - ((6 - cyanopyridin - 2 - yl)amino) - N - methoxy - 4 - ((2 - methoxy - 3-(1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide (Compound 2) TIFF2025518997000015.tif 411286 - chloro - N - methoxy - 4 - ((2 - methoxy - 3-(1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide (200 mg, 0.51 mmol) was dissolved in 1,4 - dioxane (3 mL), and 6 - aminopyridinecarbonitrile (303.8 mg, 2.55 mmol), tris(dibenzylideneacetone)dipalladium (140.1 mg, 0.153 mmol), 4,5 - bis(diphenylphosphino - 9,9 - dimethylxanthene) (147.4 mg, 0.255 mmol), and cesium carbonate (830.8 mg, 2.55 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 130 °C for 16 h. The reaction solution was spun in vacuo to remove the solvent, then slurried using a mixed solvent of dichloromethane:methanol = 15:1 and filtered by suction to obtain the crude product. The crude product was purified by reverse - phase preparative chromatography to obtain the title compound (9.72 mg, yield: 4.0%, yellow powder). MS(ESI): m / z 473.2[M + H] + 。 1 H NMR(400 MHz, DMSO - d6) δ 8.57(s, 1H), 8.38(s, 2H), 7.92(d, J = 7.6 Hz, 1H), 7.72(s, 2H), 7.62 - 7.59(m, 3H), 7.38(s, 1H), 3.96(s, 3H), 3.77(s, 3H), 3.76(s, 3H).

[0076] Example 3 6 - (Cyclopropylcarboxamido) - N - ethoxy - 4 - ((2 - methoxy - 3-(1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide (Compound 3) TIFF2025518997000016.tif 42146

[0077] Step 1: 6 - chloro - N - ethoxy - 4 - ((2 - methoxy - 3-(1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide TIFF2025518997000017.tif341282-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (420 mg, 2.06 mmol) was dissolved in tetrahydrofuran (10 mL). After replacement with nitrogen, the reaction solution was cooled to 0 °C. Lithium bis(trimethylsilyl)amide (1.03 g, 6.16 mmol) was slowly added dropwise at 0 °C, and the reaction solution was reacted at 0 °C for 1 hour. Then, a solution (2 mL) of 4,6-dichloro-N-ethoxypyridazine-3-carboxamide (484 mg, 2.06 mmol) in tetrahydrofuran was added at 0 °C. The reaction solution was allowed to warm to room temperature naturally and then reacted at room temperature for 16 hours. Methanol (2 mL) was added to the reaction solution to quench it, and the reaction solution was spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the title compound (270 mg, yield: 32.5%, white solid). MS(ESI): m / z 404.4[M+H] + 。

[0078] Step 2: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 3) TIFF2025518997000018.tif351286 - chloro - N - ethoxy - 4 - ((2 - methoxy - 3 - (1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide (140 mg, 0.347 mmol) was dissolved in 1,4 - dioxane (3 mL), and cyclopropylcarboxamide (295 mg, 3.47 mmol), tris(dibenzylideneacetone)dipalladium (127 mg, 0.139 mmol), 4,5 - bis(diphenylphosphino - 9,9 - dimethylxanthene) (166 mg, 0.287 mmol), and cesium carbonate (339 mg, 1.04 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 110 °C for 16 h. The reaction solution was filtered by suction and spun in vacuo to remove the solvent, and a crude product was obtained. The crude product was separated and purified by high - performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to give the title compound (4 mg, yield: 2.55%, white solid). MS(ESI): m / z 453.1[M + H] + 。 1 H NMR(400 MHz, CD3OD) δ 8.47(s, 1H), 8.26(s, 1H), 7.68(d, J = 7.7 Hz, 1H), 7.60(d, J = 8.0 Hz, 1H), 7.30(t, J = 7.8 Hz, 1H), 4.12 - 4.06(m, 2H), 4.02(s, 3H), 3.74(s, 3H), 1.37(brs, 1H), 1.29(brs, 3H), 0.97(d, J = 4.4 Hz, 2H), 0.92(d, J = 8.0 Hz, 2H).

[0079] Example 4 6 - (Cyclopropylcarboxamido) - N - ethoxy - 4 - ((5 - fluoro - 2 - methoxy - 3 - (1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide (Compound 4) TIFF2025518997000019.tif60146

[0080] Step 1: 3 - Bromo - 5 - fluoro - 2 - methoxyaniline TIFF2025518997000020.tif151281 - Bromo - 5 - fluoro - 2 - methoxy - 3 - nitrobenzene (2.539 g, 10.15 mmol) was dissolved in a mixed solution of isopropanol and water (12 ml), ammonium chloride (2.714 g, 50.74 mmol) was added, and then iron powder (2.79 g, 50.74 mmol) was added in several portions. After replacing with nitrogen, the mixture was reacted in an oil bath at 80 °C for 2 hours. The reaction solution was filtered by suction, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the title compound (1.68 g, yield: 75.3%, yellow solid). MS(ESI): m / z 221.9[M + H] + 。

[0081] Step 2: 5 - Fluoro - 2 - methoxy - 3 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)aniline TIFF2025518997000021.tif261283 - Bromo - 5 - fluoro - 2 - methoxyaniline (1.582 g, 7.19 mmol) was dissolved in a 1,4 - dioxane solution (12 mL), and pinacol borate (3.62 g, 14.25 mmol), potassium acetate (1.398 g, 14.25 mmol), and [1,1’ - bis(diphenylphosphino)ferrocene]palladium dichloride (521.7 mg, 0.713 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 110 °C for 2 hours. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the title compound (1.05 g, yield: 54.7%, yellow solid). MS(ESI): m / z 268.0[M + H] + 。

[0082] Step 3: 5-Fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline TIFF2025518997000022.tif251285-Fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.05 g, 3.93 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (8 mL), and 3-bromo-1-methyl-1H-1,2,4-triazole (955 mg, 5.90 mmol), potassium carbonate (1.63 g, 11.8 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (288 mg, 0.394 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 110 °C for 16 h. The reaction was stopped and cooled to room temperature, then water (40 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (600 mg, yield: 68.6%, yellow solid). MS(ESI): m / z 223.1 [M+H] + 。

[0083] Step 4: ((6-Chloro-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000023.tif361285-Fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (410 mg, 1.80 mmol) was dissolved in water (7 mL) and isopropanol (1 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (414.7 mg, 2.16 mmol) and zinc acetate (396.4 mg, 2.16 mmol) were added. After replacing with nitrogen three times, the mixture was reacted in an oil bath at 65 °C for 16 h. The reaction was stopped, and water (10 mL) was added to the reaction solution. The solution was stirred at room temperature for 1 h and then filtered by suction. The filter cake was washed with water (10 mL × 2) and tetrahydrofuran (3 mL) to obtain the title compound (140 mg, yield: 20.1%, yellow solid). MS(ESI): m / z 379.0 [M+H] + 。

[0084] Step 5: ((6-(Cyclopropylcarboxamido)-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (6-Chloro-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (140 mg, 0.371 mmol) was dissolved in toluene (2 mL) and acetonitrile (1 mL), and cyclopropylcarboxamide (78.9 mg, 0.927 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (41.1 mg, 0.074 mmol), 1,8-diazabicycloundec-7-ene (56.5 mg, 0.371 mmol), cesium carbonate (242 mg, 0.742 mmol), and palladium acetate (8.33 mg, 0.0371 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 100 °C for 16 h. After stopping the reaction, the reaction solution was cooled to room temperature. Water (6 mL) and acetic acid (3 mL) were added, and the mixture was washed with petroleum ether (10 mL × 3). The aqueous phase was extracted with dichloromethane (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining the title compound (110 mg, yield: 69.6%, brown solid). MS(ESI): m / z 428.1 [M+H] + 。

[0085] Step 6: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 4) TIFF2025518997000025.tif40128N-methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added to a reaction flask, and then ((6-(cyclopropylcarboxamido)-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (110 mg, 0.258 mmol), O-ethylhydroxylamine hydrochloride 12 (37.7 mg, 0.387 mmol), and N-methylimidazole (63.5 mg, 0.773 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (69.7 mg, 0.516 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (98.9 mg, 0.516 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (10 mL) was added to the reaction solution to quench it. The aqueous phase was extracted with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (6.01 mg, yield: 5.0%, yellow solid). MS(ESI): m / z 471.0 [M+H] + 。 1 H NMR(400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.60 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.45 - 7.39 (m, 2H), 4.02 - 3.98 (m, 2H), 3.96 (s, 3H), 3.74 (s, 3H), 2.11 (dd, J = 12.1, 5.7 Hz, 1H), 1.23 (t, J = 7.0 Hz, 3H), 0.85 (d, J = 5.7 Hz, 4H).

[0086] Example 5 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 5) TIFF2025518997000026.tif59146

[0087] Step 1: Methyl 2-methoxy-3-nitrobenzoate TIFF2025518997000027.tif151282-Hydroxy-3-nitrobenzoic acid (2.5 g, 13.65 mmol) was dissolved in N,N-dimethylacetamide (50 mL), and iodomethane (9.7 g, 68.3 mmol) and cesium carbonate (17.8 g, 54.61 mmol) were added, followed by reaction at room temperature for 16 hours. Water (250 mL) was added to the reaction solution, and the solution was stirred for 1 hour and then filtered by suction. The filter cake was taken out, washed with acetonitrile (10 mL × 3), and spun in vacuo to remove the solvent. The crude product was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 4:1) to obtain the title compound (2.36 g, yield: 82.1%, yellow solid). MS(ESI): m / z 212.1 [M+H] + 。

[0088] Step 2: 2-Methoxy-3-nitrobenzamide TIFF2025518997000028.tif16128Methyl 2-methoxy-3-nitrobenzoate (2.26 g, 10.7 mmol) was dissolved in methanolic ammonia solution (12 mL, 48 mmol), and aqueous ammonia (9 mL) was added. The mixture was sealed and reacted at room temperature for 16 hours. The reaction solution was spun in vacuo to remove the solvent and separated and purified by column chromatography (silica gel, petroleum ether:ethyl = 1:1) to obtain the title compound (1.545 g, yield: 73.7%, yellow solid). MS(ESI): m / z 197.0 [M+H] + 。

[0089] Step 3: 3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025518997000029.tif221282-Methoxy-3-nitrobenzamide (1.62 g, 8.26 mmol) was dissolved in N,N-dimethylformamide dimethylacetal (22 mL), and the mixture was reacted in an oil bath at 95 °C for 1 hour. Subsequently, it was spun in vacuo to remove the solvent, ethanol (6 mL) was added and dissolved to obtain a crude solution. In an ice bath, ethanol (16 mL) and acetic acid (6 mL) were added to the reaction flask, stirred for 5 minutes, then hydrazine hydrate (12 mL) was added dropwise, and stirring was continued for 15 minutes. Then, the ethanol solution of the crude product was added dropwise. The solution was slowly warmed to room temperature and stirred for 4 hours. After the reaction solution was spun in vacuo to remove the solvent, ethyl acetate (200 mL) was added for dilution and washed with saturated aqueous sodium bicarbonate solution (200 mL × 2). The organic phase was separated, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (830 mg, yield: 45.7%, yellow solid). MS(ESI): m / z 221.0 [M+H] + 。

[0090] Step 4: 3-(2-Methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole TIFF2025518997000030.tif251283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1 g, 4.55 mmol) was dissolved in N,N-dimethylacetamide (16 mL), cesium carbonate (2.96 g, 9.1 mmol) was added, and iodomethane-d3 (988.4 mg, 6.82 mmol) was added at 0 °C. The solution was slowly warmed to room temperature and reacted for 2 hours. Saturated ammonium chloride solution (15 mL) was added to the reaction solution to quench it, and extraction was performed using ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 2:3) to obtain the title compound (866 mg, yield: 80.3%, yellow solid). MS(ESI): m / z 238.3 [M+H] + 。

[0091] Step 5: 2-Methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)aniline TIFF2025518997000031.tif261283-(2-Methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole (866 mg, 3.65 mmol) was dissolved in methanol (20 mL), aqueous ammonia (1 mL) and palladium / carbon (155.6 mg) were added. After replacing with hydrogen, the mixture was reacted at room temperature for 2 hours. The reaction solution was filtered by suction, washed with methanol (20 mL × 3), and spun in vacuo to remove the solvent to obtain the title compound (622 mg, yield: 82%, yellow solid). MS(ESI): m / z 208.1 [M+H] + 。

[0092] Step 6: ((6-Chloro-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000032.tif361282 - Methoxy - 3-(1-(methyl - d3)-1H - 1,2,4 - triazol - 3 - yl)aniline (320 mg, 1.55 mmol) and lithium 4,6 - dichloropyridazine - 3 - carboxylate (357.1 mg, 1.86 mmol) were dissolved in a mixed solvent of isopropanol (2 mL) and water (14 mL), zinc acetate (340 mg, 1.86 mmol) was added, and the mixture was reacted in an oil bath at 65 °C for 16 h. After the reaction was stopped, water (15 mL) was added to the reaction solution and stirred at room temperature for 1 h. The reaction solution was filtered by suction, and the filter cake was washed with water (10 mL × 2) and tetrahydrofuran (5 mL × 3), and then spun in vacuo to remove the solvent, obtaining the title compound (420 mg, yield: 74.6%, yellow solid). MS(ESI): m / z 364.0 [M + H] + 。

[0093] Step 7: ((6 - (Cyclopropylcarboxamido)-4 - ((2 - methoxy - 3-(1-(methyl - d3)-1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carbonyl)oxy)zinc (0.5) ((6-Chloro-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (400 mg, 1.02 mmol) was dissolved in toluene (7 mL) and acetonitrile (14 mL), and cyclopropylcarboxamide (216 mg, 2.454 mmol), (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (112.6 mg, 0.203 mmol), diazabicyclo (154.6 mg, 1.02 mmol), cesium carbonate (661 mg, 2.03 mmol), and palladium acetate (45.6 mg, 0.203 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 100 °C for 16 hours. After stopping the reaction, water (20 mL) and acetic acid (10 mL) were added to the reaction solution, stirred at room temperature for 0.5 hour, and then washed with petroleum ether (15 mL × 3). The aqueous phase was extracted with dichloromethane (20 mL × 3), washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining the title compound (400 mg, yield: 88.5%, brown solid). MS(ESI): m / z 413.1[M+H] + 。

[0094] Step 8: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 5) TIFF2025518997000034.tif34128N-methylpyrrolidone (15 mL) and acetonitrile (15 mL) were added to a reaction flask, stirred at room temperature for 10 minutes, and then ((6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (400 mg, 0.9 mmol), O-ethylhydroxylamine hydrochloride (132 mg, 1.35 mmol), and N-methylimidazole (222.3 mg, 2.71 mmol) were added. After replacement with nitrogen, the mixture was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (244 mg, 1.81 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (346.1 mg, 1.81 mmol) were added. After replacement with nitrogen, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (30 mL) was added to the reaction solution to quench it, and extraction was performed using ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent. The crude product was prepared and purified by high performance liquid chromatography (elution system: ammonia, water, and acetonitrile) to obtain the title compound (11.4 mg, yield: 2.8%, white solid). MS(ESI):m / z 456.2[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H),11.31(s,1H),10.55(s,1H),8.56(s,1H),8.15(s,1H),7.66(d,J=6.9Hz,1H),7.51(d,J=5.8Hz,1H),7.28(d,J=6.6Hz,1H),3.99(d,J=5.4Hz,2H),3.73(s,3H),2.09(brs,1H),1.23(brs,3H),0.82(brs,4H).

[0095] Example 6 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 6) TIFF2025518997000035.tif98146

[0096] Step 1: 5-Fluoro-2-methoxybenzamide TIFF2025518997000036.tif151285-Fluoro-2-methoxybenzoic acid (7.2 g, 42.32 mmol) was dissolved in thionyl chloride (20 mL), and N,N-dimethylformamide (0.5 mL) was added. The reaction solution was reacted in an oil bath at 85 °C for 2 hours. The reaction solution was spun in vacuo to remove the solvent, dichloromethane (50 mL × 3) was added little by little, and spinning was performed to remove the residual thionyl chloride to obtain a crude product. For subsequent use, the crude product was dissolved in dichloromethane (20 mL). A 500 mL three-necked flask was taken, and an ammonia 1,4-dioxane solution (0.4 M, 170 mL) was added thereto. The solution was cooled to 0 °C, and the prepared dichloromethane solution was slowly added dropwise. The reaction solution was continuously stirred for 30 minutes. The reaction solution was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (70 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining the title compound (6.25 g, yield: 87.3%, white solid). MS(ESI): m / z 170.1 [M+H] + 。

[0097] Step 2: 3-(5-Fluoro-2-methoxyphenyl)-1H-1,2,4-triazole TIFF2025518997000037.tif211285-Fluoro-2-methoxybenzamide (6.25 g, 36.95 mmol) was dissolved in N,N-dimethylformamide dimethylacetal (50 mL). After replacement with nitrogen, the mixture was reacted in an oil bath at 95 °C for 1 hour. The reaction solution was spun in vacuo to remove the solvent, and the crude DMF-DMA adduct was obtained, which was dissolved in ethanol (30 mL) for later use. In an ice bath, ethanol (80 mL) and acetic acid (30 mL) were added to the reaction flask, and hydrazine hydrate (98 wt%, 15 mL) was added dropwise. The mixture was stirred continuously for 15 minutes, and then a solution of the crude DMF-DMA adduct in ethanol was added dropwise. After the reaction solution was allowed to warm to room temperature naturally, the reaction solution was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, then diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (400 mL × 3). The organic phase was washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining the title compound (5.46 g, yield: 76.5%, white solid). MS(ESI): m / z 194.1[M+H] + 。

[0098] Step 3: 3-(5-Fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025518997000038.tif221283-(5-Fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (5.46 g, 28.26 mmol) was dissolved in concentrated sulfuric acid (50 mL). Nitric acid (68 wt%, 5.24 g, 56.55 mmol) was added dropwise in an ice bath. After the addition was complete, the solution was stirred continuously in the ice bath for 2 hours. The reaction was stopped, and the reaction solution was poured into ice water (50 mL), and aqueous ammonia was added dropwise slowly to adjust the pH to 9.0. The aqueous phase was extracted with ethyl acetate (100 mL × 3), the combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining the title compound (6.4 g, yield: 95.1%, yellow solid). MS(ESI): m / z 239.1 [M+H] + 。

[0099] Step 4: 3-(5-Fluoro-2-methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole TIFF2025518997000039.tif261283-(5-Fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (3.4 g, 14.3 mmol) and cesium carbonate (5.59 g, 17.16 mmol) were added to N,N-dimethylformamide (60 mL). After replacing with nitrogen, the reaction system was cooled to 0 °C, then iodomethane-d3 (3.11 g, 21.5 mmol) was added, and the reaction solution was stirred at room temperature for 4 hours. The reaction was stopped, water (70 mL) was added to the reaction solution to quench it, and extraction was performed 3 times using ethyl acetate (80 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining the title compound (1.831 g, yield: 49%, yellow solid). MS(ESI): m / z 256.1 [M+H] + 。

[0100] Step 5: 5-Fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)aniline TIFF2025518997000040.tif241283-(5-Fluoro-2-methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole (1.831 g, 7.18 mmol) was dissolved in methanol (50 mL), aqueous ammonia (25 wt%, 1 mL) and palladium / carbon (305.39 mg) were added. After replacing with hydrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered by suction, washed with methanol, the filtrates were combined and concentrated under reduced pressure, and then separated and purified by column chromatography (silica gel, dichloromethane:methanol = 92:8) to obtain the title compound (1.493 g, yield: 92.39%, yellow solid). MS(ESI): m / z 226.0 [M+H] + 。

[0101] Step 6: ((6-Chloro-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000041.tif381285-Fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)aniline (300 mg, 1.33 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (318.06 mg, 1.60 mmol), and zinc acetate (293.29 mg, 1.60 mmol) were dissolved in a solvent of 4.8 mL of water:toluene = 7:1. After replacing with nitrogen, the mixture was reacted at 100 °C for 16 hours. The reaction was stopped. 6 mL of water was added to the reaction solution, and the mixture was stirred for 1 hour, followed by filtration by suction and washing with tetrahydrofuran (2 mL). The filter cake was dried to obtain the title compound (276 mg, yield: 50.12%, white solid). MS(ESI): m / z 382.0 [M+H] + 。

[0102] Step 7: ((6-(Cyclopropylcarboxamido)-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000042.tif41128((6-chloro-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (200 mg, 0.48 mmol), cyclopropylcarboxamide (102.92 mg, 1.21 mmol), (R)-(S)-Cy2PF-PtBu2 (554.55 mg, 0.097 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (73.64 mg, 0.48 mmol), cesium carbonate (315.22 mg, 0.97 mmol), and palladium acetate (21.72 mg, 0.097 mmol) were dissolved in 1.8 mL of a solvent of toluene:acetonitrile = 2:1. After replacing with nitrogen, the mixture was reacted at 100 °C for 16 h. The reaction was stopped, 6 mL of a solution of water:acetic acid = 2:1 was added to the reaction solution, and extraction was performed using petroleum ether (8 mL). The lower aqueous phase was extracted 3 times using dichloromethane (10 mL), the combined dichloromethane organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining the title compound (250 mg, purity: 77%, brown solid). MS(ESI): m / z 431.0 [M+H] + 。

[0103] Step 8: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 6) TIFF2025518997000043.tif38128N-Methylpyrrolidone (6.25 mL) and acetonitrile (6.25 mL) were added to a reaction flask, followed by the addition of ((6-(Cyclopropylcarboxamido)-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (250 mg, 0.54 mmol), O-Ethylhydroxylamine hydrochloride (79.16 mg, 0.81 mmol), and N-Methylimidazole (133.25 mg, 1.62 mmol). After replacing with nitrogen, the mixture was reacted in an oil bath at 65 °C for 15 minutes, then 1-Hydroxybenzotriazole (146.20 mg, 1.08 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (207.42 mg, 1.08 mmol) were added. After replacing with nitrogen, the reaction was continued in an oil bath at 65 °C for 16 hours. The reaction was stopped, ethyl acetate (30 mL) was added to the reaction solution, and then it was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by reverse-phase chromatography (elution system: hydrochloric acid, water, and acetonitrile) to obtain the title compound (26.59 mg, yield: 10.38%, white solid). MS(ESI):m / z 474.0[M+H] + 。

[0104] Example 7 6-(Cyclopropylcarboxamido)-4-((3-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 7) TIFF2025518997000044.tif71137

[0105] Step 1: 1-Cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025518997000045.tif291283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (420 mg, 1.909 mmol) was dissolved in 1,4-dioxane (15 mL), and cyclopropylboronic acid (246 mg, 2.864 mmol), sodium carbonate (405 mg, 3.821 mmol), 2,2-bipyridine (298 mg, 1.908 mmol), and copper acetate (347 mg, 1.91 mmol) were added. After replacing with oxygen, the mixture was reacted in an oil bath at 85 °C for 16 h. The reaction was stopped, and the reaction solution was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (270 mg, yield: 62.5%, yellow oil). MS(ESI): m / z 261.0 [M+H] + 。

[0106] Step 2: 3-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline TIFF2025518997000046.tif281281-Cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (270 mg, 1.037 mmol) was dissolved in methanol (10 mL), and palladium / carbon catalyst (27 mg, 0.254 mmol) was added. After replacing with hydrogen three times, the mixture was reacted at room temperature for 16 h. The reaction was stopped, filtered to remove palladium / carbon, and the filtrate was spun in vacuo to remove the solvent, obtaining a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (200 mg, yield: 83.6%, colorless and transparent oil). MS(ESI): m / z 231.1 [M+H] + 。

[0107] Step 3: ((6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000047.tif391283-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (200 mg, 0.869 mmol) was dissolved in water (7 mL) and isopropanol (1 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (200 mg, 1.042 mmol) and zinc acetate (191 mg, 1.041 mmol) were added. After replacing with nitrogen three times, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (5 mL) was added to the reaction solution. The solution was stirred at room temperature for 1 hour and then filtered by suction. The filter cake was washed with water (6 mL × 2) and tetrahydrofuran (1 mL) and dried to obtain the title compound (170 mg, yield: 46.8%, yellow solid). MS(ESI): m / z 387.0 [M+H] + 。

[0108] Step 4: ((6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000048.tif42128((6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)(170 mg, 0.406 mmol) was dissolved in toluene (2 mL) and acetonitrile (1 mL), and then cyclopropylcarboxamide (86.4 mg, 1.015 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (45 mg, 0.0811 mmol), 1,8-diazabicycloundec-7-ene (61.8 mg, 0.406 mmol), cesium carbonate (265 mg, 0.813 mmol), and palladium acetate (9.12 mg, 0.0406 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 100 °C for 16 h. The reaction was stopped and the reaction solution was cooled to room temperature. Water (6 mL) and acetic acid (3 mL) were added, and the mixture was extracted with petroleum ether (10 mL × 3), then the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined dichloromethane organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, giving the title compound (195 mg, brown solid). MS(ESI): m / z 436.2[M + H] + 。

[0109] Step 5: 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 7) TIFF2025518997000049.tifA 4412850 mL reaction flask was taken, and N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added thereto. The mixed solvent was stirred at room temperature for 10 minutes, and then ((6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (195 mg, 0.417 mmol), O-ethylhydroxylamine hydrochloride (61 mg, 0.625 mmol), and N-methylimidazole (103 mg, 1.255 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (113 mg, 0.836 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.836 mmol) were added. The reaction solution was continuously stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (15 mL) was added to the reaction solution to quench it. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (16.03 mg, yield: 8.02%, yellow solid). MS(ESI):m / z 479.2[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.55(s,1H),8.69(s,1H),8.40(s,1H),8.14(s,1H),7.66(d,J=7.6Hz,1H),7.51(d,J=8.0Hz,1H),7.27(t,J=7.9Hz,1H),3.99(q,J=7.0Hz,2H),3.90-3.84(m,1H),3.71(s,3H),2.12-2.05(m,1H),1.23(t,J=7.0Hz,3H),1.17-1.16(m,2H),1.07-1.06(m,2H),0.86-0.80(m,4H).

[0110] Example 8 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 8) TIFF2025518997000050.tif63130

[0111] Step 1: 1-Cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025518997000051.tif271283-(5-Fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (3.1 g, 13.02 mmol) was dissolved in a 1,4-dioxane solution (50 mL), and cyclopropylboronic acid (1.68 g, 19.56 mmol), sodium carbonate (2.76 g, 26.04 mmol), 2,2-bipyridine (2.03 g, 13.0 mmol), and copper(II) acetate (2.36 g, 13.0 mmol) were added. After replacing with oxygen, the mixture was reacted in an oil bath at 85 °C for 16 h. The reaction was stopped, and the reaction solution was poured into water (60 mL). The aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, giving a crude product. The crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate = 3:1) to give the title compound (2.1 g, yield: 58.0%, yellow oil). MS(ESI): m / z 279.0 [M+H] + 。

[0112] Step 2: 3-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline TIFF2025518997000052.tif281281-Cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (2.1 g, 7.55 mmol) was dissolved in methanol (50 mL), and palladium / carbon catalyst (321 mg, 3.02 mmol) and aqueous ammonia (1 mL) were added. After replacing with hydrogen three times, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, filtered to remove palladium / carbon, and the filtrate was spun in vacuo to remove the solvent, obtaining a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give the title compound (1.5 g, yield: 80.2%, colorless and transparent oil). MS(ESI): m / z 249.2[M+H] + 。

[0113] Step 3: ((6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) TIFF2025518997000053.tif391283-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (400 mg, 1.61 mmol) was dissolved in water (7 mL) and isopropanol (1 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (371 mg, 1.93 mmol) and zinc acetate (355 mg, 1.93 mmol) were added. After replacing with nitrogen three times, the mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped, and water (10 mL) was added to the reaction solution. The solution was stirred at room temperature for 1 hour and then filtered by suction. The filter cake was washed with water (10 mL × 2) and tetrahydrofuran (3 mL) and dried to give the title compound (310 mg, yield: 44.1%, yellow solid). MS(ESI): m / z 405.2[M+H] + 。

[0114] Step 4: ((6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000054.tif42128 ((6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (160 mg, 0.367 mmol) was dissolved in toluene (2 mL) and acetonitrile (1 mL), and cyclopropylcarboxamide (78.1 mg, 0.918 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (40.7 mg, 0.073 mmol), 1,8-diazabicycloundec-7-ene (55.9 mg, 0.367 mmol), cesium carbonate (239 mg, 0.736 mmol), and palladium acetate (8.24 mg, 0.0367 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped, the reaction solution was cooled to room temperature, water (6 mL) and acetic acid (3 mL) were added. The mixture was extracted with petroleum ether (10 mL × 3), then the aqueous phase was extracted with dichloromethane (20 mL × 3), the combined dichloromethane organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, giving the title compound (168 mg, yield: 94.5%, brown solid). MS(ESI): m / z 454.3 [M+H] + 。

[0115] Step 5: 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 8) TIFF2025518997000055.tifA 3812850 mL reaction flask was taken, and N-methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added thereto. The mixed solvent was stirred at room temperature for 10 minutes, and then ((6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (130 mg, 0.268 mmol), O-ethylhydroxylamine hydrochloride 12 (39.2 mg, 0.402 mmol), and N-methylimidazole (66 mg, 0.804 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (72.4 mg, 0.536 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.537 mmol) were added. The reaction solution was stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (10 mL) was added to the reaction solution to quench it. The aqueous phase was extracted with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (7.54 mg, yield: 5.7%, yellow solid). MS(ESI):m / z 497.2[M+H] + 。

[0116] Example 9 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 9) TIFF2025518997000056.tif63150

[0117] Step 1: Methyl 2-(methoxy-d3)-3-nitrobenzoate TIFF2025518997000057.tif14128 Methyl 2-hydroxy-3-nitrobenzoate (1.7 g, 8.623 mmol) was dissolved in N,N-dimethylformamide (20 mL), and methyl iodide-d3 (1.87 g, 12.9 mmol) and potassium carbonate (2.38 g, 17.221 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 60 °C for 2 hours. The reaction was stopped, and the reaction solution was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the title compound (1.69 g, yield: 91.5%, yellow oil). MS(ESI): m / z 215.1[M+H] + 。

[0118] Step 2: 2-(Methoxy-d3)-3-nitrobenzamide TIFF2025518997000058.tif18128 Methyl 2-(methoxy-d3)-3-nitrobenzoate (1.69 g, 7.89 mmol) was dissolved in methanolic ammonia solution (30 mL), and aqueous ammonia (15 mL) was added. After replacing with nitrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, and the reaction solution was spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the title compound (1.45 g, yield: 92.2%, yellow solid). MS(ESI): m / z 200.1[M+H] + 。

[0119] Step 3: 3-(2-(Methoxy-d3)-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025518997000059.tif221282 - (Methoxy - d3)-3 - nitrobenzamide (1.45 g, 7.28 mmol) was dissolved in N,N - dimethylformamide dimethylacetal (10 mL). After replacing with nitrogen, the mixture was reacted in an oil bath at 95 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, and for later use, the crude product was dissolved in ethanol (10 mL). A 250 mL single - necked flask was taken, and ethanol (40 mL) and acetic acid (10 mL) were added thereto. This system was cooled to 0 °C, hydrazine hydrate (4 mL) was added dropwise, and stirring was carried out at 0 °C for 1 hour. The crude product ethanol solution was added dropwise to this system, and stirring was continued for 2 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in ethyl acetate (200 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (1.1 g, yield: 67.7%, pale yellow solid). MS(ESI): m / z 224.1[M + H] + 。

[0120] Step 4: 1 - Cyclopropyl - 3-(2-(methoxy - d3)-3 - nitrophenyl)-1H - 1,2,4 - triazole TIFF2025518997000060.tif291283-(2-(Methoxy-d3)-3-nitrophenyl)-1H-1,2,4-triazole (1.1 g, 4.928 mmol) was dissolved in 1,4-dioxane (40 mL), and cyclopropylboronic acid (635 mg, 7.392 mmol), sodium carbonate (1.04 g, 9.812 mmol), 2,2-bipyridine (770 mg, 4.93 mmol), and copper acetate (895 mg, 4.928 mmol) were added. After replacing with oxygen, the mixture was reacted in an oil bath at 85 °C for 16 h. The reaction was stopped, and the reaction solution was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, giving a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title compound (900 mg, yield: 69.2%, yellow oil). MS(ESI): m / z 264.0 [M+H] + 。

[0121] Step 5: 3-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)aniline TIFF2025518997000061.tif281281-Cyclopropyl-3-(2-(methoxy-d3)-3-nitrophenyl)-1H-1,2,4-triazole (900 mg, 3.419 mmol) was dissolved in methanol (25 mL), and palladium / carbon catalyst (90 mg) was added. After replacing with hydrogen three times, the mixture was reacted at room temperature for 16 h. The reaction was stopped, and the reaction solution was filtered. The filtrate was spun in vacuo to remove the solvent, giving a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give the title compound (520 mg, yield: 65.2%, colorless and transparent oil). MS(ESI): m / z 234.2 [M+H] + 。

[0122] Step 6: ((6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000062.tif381283-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)aniline (520 mg, 2.229 mmol) was dissolved in water (14 mL) and isopropanol (2 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (530 mg, 2.677 mmol) and zinc acetate (491 mg, 2.676 mmol) were added. After replacing with nitrogen three times, the mixture was reacted in an oil bath at 65 °C for 16 h. The reaction was stopped, and water (10 mL) was added to the reaction solution. The solution was stirred at room temperature for 1 h and then filtered by suction. The filter cake was washed with water (15 mL × 3) and tetrahydrofuran (4 mL) and then dried to obtain the title compound (680 mg, yield: 72.3%, white solid). MS(ESI): m / z 390.2 [M+H] + 。

[0123] Step 7: ((6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000063.tif42128((6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)(680 mg, 1.613 mmol) was dissolved in toluene (8 mL) and acetonitrile (4 mL), and cyclopropylcarboxamide (343 mg, 4.031 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (179 mg, 0.323 mmol), 1,8-diazabicycloundec-7-ene (246 mg, 1.616 mmol), cesium carbonate (1.05 g, 3.223 mmol), and palladium acetate (72.4 mg, 0.322 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped, the reaction solution was cooled to room temperature, water (20 mL) and acetic acid (10 mL) were added. The mixture was extracted with petroleum ether (30 mL × 3), then the aqueous phase was extracted with dichloromethane (50 mL × 3), the combined dichloromethane organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, giving the title compound (720 mg, yield: 94.9%, brown solid). MS(ESI): m / z 439.3 [M+H] + 。

[0124] Step 8: 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 9) A 4212850 mL reaction flask was taken, and N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added thereto. The mixed solvent was stirred at room temperature for 10 minutes, and then ((6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (370 mg, 0.787 mmol), O-ethylhydroxylamine hydrochloride (153.5 mg, 1.574 mmol), and N-methylimidazole (193.8 mg, 2.361 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (212.7 mg, 1.574 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (301.7 mg, 1.574 mmol) were added. The reaction solution was continuously stirred and reacted in an oil bath at 65 °C for 3 hours. The reaction was stopped, and water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (40 mL × 3), the combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent to obtain a crude product. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (88.36 mg, yield: 23.3%, pink solid). MS(ESI): m / z 482.1[M+H] + 。 1 H NMR(400MHz, DMSO-d6) δ 11.32(s, 1H), 10.55(s, 1H), 8.69(s, 1H), 8.38(s, 1H), 8.14(s, 1H), 7.66(d, J = 7.8Hz, 1H), 7.51(d, J = 7.9Hz, 1H), 7.27(t, J = 7.9Hz, 1H), 4.02 - 3.96(m, 2H), 3.89 - 3.85(m, 1H), 2.11 - 2.07(m, 1H), 1.23(t, J = 7.0Hz, 3H), 1.17 - 1.15(m, 2H), 1.09 - 1.05(m, 2H), 0.84 - 0.80(m, 4H).

[0125] Example 10 6-(Cyclopropylcarboxamido)-N-(2-fluoroethoxy)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 10) TIFF2025518997000065.tif31160

[0126] Synthesis of Intermediate 10C TIFF2025518997000066.tif25128Step 1: 2-(2-Fluoroethoxy)isoindoline-1,3-dione TIFF2025518997000067.tif151282-Fluoroethanol (5.0 g, 78.052 mmol) was dissolved in an over-dried tetrahydrofuran solution (50 mL), and 2-hydroxyisoindoline-1,3-dione (12733 mg, 78.052 mmol) and triphenylphosphine (26.614 g, 101.468 mmol) were added. After replacing with nitrogen, diethyl azodicarboxylate (17.671 g, 101.468 mmol) was added dropwise at 0 °C. After the addition was completed, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, and then spin-dried. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (8.4 g, yield: 51.4%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.83 (m, 4H), 4.78 - 4.74 (m, 1H), 4.66 - 4.62 (m, 1H), 4.46 - 4.41 (m, 1H), 4.38 - 4.34 (m, 1H).

[0127] Step 2: O-(2-Fluoroethyl)hydroxylamine hydrochloride TIFF2025518997000068.tif61282-(2-Fluoroethoxy)isoindoline-1,3-dione (8.4 g, 40.157 mmol) was dissolved in dichloromethane solution (50 mL), and hydrazine hydrate (4.016 g, 80.314 mmol) was added dropwise. After replacing with nitrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, the filtrate was washed with water (20 mL × 2), and the aqueous phase was collected. The aqueous phase was extracted with a mixed solution of chloroform and isopropanol (3:1) (30 mL × 6). The organic phases were combined, and then a solution of hydrogen chloride in dioxane (30 mL) was added. The resulting solution was stirred at room temperature for 30 minutes and then spin-dried to obtain the title compound (1.7 g, yield: 36.6%, white solid).

[0128] Synthesis of Compound 10 Step 1: ((6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000069.tif351282-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (500 mg, 2.448 mmol) was dissolved in water (35 mL) and isopropanol (5 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (974 mg, 4.896 mmol) and zinc acetate (898 mg, 4.896 mmol) were added. After replacing with nitrogen three times, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (15 mL) was added to the reaction solution. The solution was stirred at room temperature for 1 hour and then filtered by suction. The filter cake was rinsed with water (10 mL × 2) and tetrahydrofuran (1 mL) to obtain the title compound (530 mg, yield: 55.2%, brown solid). MS(ESI): m / z 361.0 [M+H] + 。

[0129] Step 2: ((6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000070.tif38128 ((6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (480 mg, 1.223 mmol) was dissolved in toluene (8 mL) and acetonitrile (4 mL), and cyclopropylcarboxamide (260 mg, 3.058 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (136 mg, 0.245 mmol), 1,8-diazabicycloundec-7-ene (186 mg, 1.223 mmol), potassium carbonate (338 mg, 2.446 mmol), and palladium acetate (55 mg, 0.245 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 75 °C for 16 h. The reaction was stopped and the reaction solution was cooled to room temperature. Water (15 mL) and acetic acid (7 mL) were added, and the mixture was extracted with petroleum ether (30 mL × 2), then the aqueous phase was extracted with dichloromethane (30 mL × 2). The combined dichloromethane organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, giving the title compound (500 mg, yield: 81.8%, brown solid). MS(ESI): m / z 410.1 [M+H] + 。

[0130] Step 3: 6-(Cyclopropylcarboxamido)-N-(2-fluoroethoxy)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 10). TIFF2025518997000071.tifA 3712850 mL reaction flask was taken, and N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added thereto. The mixed solvent was stirred at room temperature for 10 minutes, and then ((6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (200 mg, 0.453 mmol), O-(2-fluoroethyl)hydroxylamine hydrochloride (79 mg, 0.680 mmol), and N-methylimidazole (111 mg, 1.359 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (122 mg, 0.906 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (174 mg, 0.906 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (10 mL) was added to the reaction solution, and extraction was performed using ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (7.64 mg, yield: 3.6%, gray solid). MS(ESI):m / z 471.0[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.40(s,1H),8.15(s,1H),7.66(d,J=7.7Hz,1H),7.51(d,J=7.1Hz,1H),7.28(d,J=7.9Hz,1H),4.69(d,J=48.0Hz,2H),4.29-4.07(m,2H),3.93(s,3H),3.73(s,3H),2.09(brs,1H),0.82-0.77(m,4H).

[0131] Example 11 6-(Cyclopropylcarboxamido)-N-(2,2-difluoroethoxy)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 11) TIFF2025518997000072.tif70128

[0132] Step 1: 2-(2,2-Difluoroethoxy)isoindole-1,3-dione TIFF2025518997000073.tif171282,2-Difluoroethanol (5.0 g, 60.938 mmol) was dissolved in an over-dried tetrahydrofuran solution (50 mL), and 2-hydroxyisoindoline-1,3-dione (9.941 g, 60.938 mmol) and triphenylphosphine (20.778 g, 79.219 mmol) were added. After replacing with nitrogen, diethyl azodicarboxylate (13.796 g, 79.219 mmol) was added dropwise at 0 °C, and the mixture was reacted at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, and then the filtrate was spin-dried in vacuo. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain the title compound (11 g, yield: 79.5%, white solid). 1 H NMR (400 MHz, CDCl3) δ 7.90 - 7.84 (m, 2H), 7.81 - 7.76 (m, 2H), 6.40 - 6.06 (m, 1H), 4.38 (td, J = 12.7, 4.2 Hz, 2H).

[0133] Step 2: O-(2,2-Difluoroethyl)hydroxylamine hydrochloride TIFF2025518997000074.tif111282 - (2,2 - Difluoroethoxy)isoindole - 1,3 - dione (10.0 g, 44.020 mmol) was dissolved in dichloromethane solution (50 mL), and hydrazine hydrate (4.402 g, 88.040 mmol) was added dropwise. After replacing with nitrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, the filtrate was washed with water (50 mL × 2), and the aqueous phase was collected. Then, the aqueous phase was extracted with a mixed solution of chloroform and isopropanol (3:1) (30 mL × 6). The organic phases were combined, and then a solution of hydrogen chloride in dioxane (20 mL) was added. The resulting solution was stirred at room temperature for 1 hour and then spin - dried to obtain the title compound (1.1 g, yield: 18.7%, white solid).

[0134] Step 3: 6 - (Cyclopropylcarboxamido)-N-(2,2 - difluoroethoxy)-4 - ((2 - methoxy - 3-(1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide (Compound 11) TIFF2025518997000075.tif35128N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added to a reaction flask, and the mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (200 mg, 0.453 mmol), O-(2,2-difluoroethyl)hydroxylamine hydrochloride (91 mg, 0.680 mmol), and N-methylimidazole (111 mg, 1.359 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (122 mg, 0.906 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (174 mg, 0.906 mmol) were added. The reaction was continued with stirring in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (10 mL) was added to the reaction solution, and extraction was performed using ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by high-performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (15.64 mg, yield: 7.1%, white solid). MS(ESI): m / z 489.2[M+H] + 。 1 H NMR(400 MHz, DMSO-d6) δ 8.57(s, 1H), 8.43(s, 1H), 8.13(s, 1H), 7.65(d, J = 8.0 Hz, 1H), 7.50(s, 1H), 7.27(t, J = 8.0 Hz, 1H), 6.36(t, J = 54.2 Hz, 1H), 4.18(d, J = 14.3 Hz, 2H), 3.93(s, 3H), 3.73(s, 3H), 2.09(brs, 1H), 0.82(brs, 4H).

[0135] Example 12 6-(Cyclopropanamide)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(2-fluoroethoxy)pyridazine-3-carboxamide (Compound 12) TIFF2025518997000076.tif46128N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, and the mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(Cyclopropylcarboxamide)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (270 mg, 0.578 mmol), O-(2-fluoroethyl)hydroxylamine hydrochloride (133.6 mg, 1.156 mmol), and N-methylimidazole (142.4 mg, 1.734 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (156.2 mg, 1.156 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (221.6 mg, 1.156 mmol) were added. The reaction solution was stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by high performance liquid chromatography (elution system: trifluoroacetic acid, water, and acetonitrile) to obtain the title compound (11.3 mg, yield: 3.94%, yellow solid). MS(ESI): m / z 497.1[M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 11.34 (s, 1H), 10.50 (s, 1H), 8.69 (s, 1H), 8.14 (s, 1H), 7.68 - 7.65 (m, 1H), 7.51 (dd, J = 7.9, 1.3 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 4.76 - 4.74 (m, 1H), 4.64 - 4.62 (m, 1H), 4.25 - 4.23 (m, 1H), 4.17 - 4.16 (m, 1H), 3.88 - 3.86 (m, 1H), 3.71 (s, 3H), 2.10 - 2.06 (m, 1H), 1.18 - 1.16 (m, 2H), 1.07 (dd, J = 6.9, 1.7 Hz, 2H), 0.83 - 0.81 (m, 4H).

[0136] Example 13 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(2,2-difluoroethoxy)pyridazine-3-carboxamide (Compound 13) TIFF2025518997000077.tif43128N-Methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, and the mixed solvent was stirred at room temperature for 10 minutes. Subsequently, ((6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (230 mg, 0.492 mmol), O-(2,2-difluoroethyl)hydroxylamine hydrochloride (194.8 mg, 1.476 mmol), and N-methylimidazole (121.2 mg, 1.476 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (133 mg, 0.984 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (189 mg, 0.986 mmol) were added. The reaction solution was stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by high-performance liquid chromatography (elution system: hydrochloric acid, water, and acetonitrile) to obtain the title compound (17.76 mg, yield: 7.01%, yellow solid). MS(ESI):m / z 515.0[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ12.68(s,1H),11.42(s,1H),10.47(s,1H),8.74(s,1H),8.10(s,1H),7.68(d,J=7.9Hz,1H),7.52(d,J=7.6Hz,1H),7.28(t,J=7.9Hz,1H),6.50-6.21(m,1H),4.26-4.19(m,2H),3.90-3.86(m,1H),3.72(s,3H),2.11-2.05(m,1H),1.17(d,J=3.2Hz,2H),1.07(d,J=5.4Hz,2H),0.82(brs,4H).

[0137] Example 14 6-(Cyclopropylcarboxamido)-N-(methoxy-d3)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 14) TIFF2025518997000078.tif43128 Zinc(0.5) ((6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy) (130 mg, 0.29 mmol) and O-(methyl-d3)hydroxylamine hydrochloride (38.26 mg, 0.44 mmol) were dissolved in N-methylpyrrolidone (1 mL) and acetonitrile (1 mL), and N-methylimidazole (72.34 mg, 0.88 mmol) was added. The reaction temperature was raised to 65 °C and the solution was stirred for 15 minutes. Then, 1-hydroxybenzotriazole (79.67 mg, 0.59 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113.02 mg, 0.59 mmol) were added and the reaction was continued at that temperature for 2 hours. The reaction was stopped and the reaction solution was separated and purified by reverse-phase preparative chromatography (elution system: formic acid, acetonitrile, and water) to obtain the title compound (27.15 mg, yield: 20.8%, white solid). MS(ESI): m / z 442.3 [M+H] + 。 1 H NMR(400 MHz, DMSO-d6) δ 12.35 (s, 1H), 11.32 (s, 1H), 10.55 (s, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 7.68 - 7.66 (m, 1H), 7.52 - 7.50 (m, 1H), 7.29 - 7.25 (m, 1H), 3.95 (s, 3H), 3.73 (s, 3H), 2.12 - 2.05 (m, 1H), 0.83 - 0.81 (m, 4H).

[0138] Example 15 6-(Cyclopropylcarboxamido)-N-(ethoxy-d5)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 15) TIFF2025518997000079.tif78128

[0139] Step 1: 2-(Ethoxy-d5)isoindole-1,3-dione TIFF2025518997000080.tif151282-Hydroxyisoindoline-1,3-dione (5.5 g, 33.715 mmol) was dissolved in tetrahydrofuran (45 mL), and ethane-1,1,2,2,2-d5-1-ol-d (1.76 g, 33.775 mmol) and triphenylphosphine (11.5 g, 43.845 mmol) were added. After replacing with nitrogen, diethyl azodicarboxylate (7.63 g, 43.813 mmol) was slowly added dropwise in an ice bath. The reaction solution was stirred and reacted at room temperature for 16 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (2.79 g, yield: 42.1%, white solid). MS(ESI): m / z 197.0[M+H] + 。

[0140] Step 2: O-(Ethyl-d5)hydroxylamine hydrochloride TIFF2025518997000081.tif91282 - (Ethoxy - d5)isoindole - 1,3 - dione (2.7 g, 13.76 mmol) was dissolved in dichloromethane (30 mL), and hydrazine hydrate (1.38 g, 27.57 mmol) was added. After replacing with nitrogen, the reaction solution was stirred and reacted at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, and the filtrate was poured into water (40 mL). The aqueous phase was extracted using a mixed solvent of chloroform:isopropanol = 3:1 (40 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. A hydrogen chloride dioxane solution (15 mL) was added to the filtrate, the reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain the title compound (580 mg, yield: 41.1%, white solid).

[0141] Step 3: 6 - (Cyclopropylcarboxamido)-N-(ethoxy - d5)-4-((2 - methoxy - 3-(1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino)pyridazine - 3 - carboxamide (Compound 15) TIFF2025518997000082.tif37128N-methylpyrrolidone (10 mL) and acetonitrile (10 mL) were added to a reaction flask, and ((6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (300 mg, 0.76 mmol), O-(ethyl-d5)hydroxylamine hydrochloride (117.6 mg, 1.15 mmol), and N-methylimidazole (188.3 mg, 2.29 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 65 °C for 15 minutes, then 1-hydroxybenzotriazole (206.6 mg, 1.53 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (293.1 mg, 1.53 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (20 mL) was added to the reaction solution to quench it, and then extraction was performed using ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by reverse-phase preparative chromatography to obtain the title compound (71.89 mg, yield: 20.6%, white solid). MS(ESI): m / z 458.2[M+H] + 。 1 H NMR(400 MHz, DMSO-d6) δ 12.25(s, 1H), 11.32(s, 1H), 10.55(s, 1H), 8.57(s, 1H), 8.15(s, 1H), 7.67(d, J = 7.5 Hz, 1H), 7.51(d, J = 7.8 Hz, 1H), 7.27(t, J = 7.9 Hz, 1H), 3.95(s, 3H), 3.73(s, 3H), 2.10 - 2.06(m, 1H), 0.82(brs, 2H), 0.81(brs, 2H).

[0142] Example 16 6-(Cyclopropanamide)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methoxy-d3)pyridazine-3-carboxamide (Compound 16) TIFF2025518997000083.tif50128N-methylpyrrolidone (6 mL) and acetonitrile (6 mL) were added to a reaction flask, and the mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(cyclopropylcarboxamide)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (300 mg, 0.642 mmol), O-deuterated methylhydroxylamine hydrochloride (111.7 mg, 1.284 mmol), and N-methylimidazole (158.1 mg, 1.926 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (173.5 mg, 1.284 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (246.1 mg, 1.284 mmol) were added. The reaction solution was continuously stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by high-performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (55.71 mg, yield: 17.5%, yellow solid). MS(ESI): m / z 468.1 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 11.32 (s, 1H), 10.55 (s, 1H), 8.69 (s, 1H), 8.15 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 3.89 - 3.85 (m, 1H), 3.72 (s, 3H), 2.11 - 2.06 (m, 1H), 1.19 - 1.15 (m, 2H), 1.09 - 1.05 (m, 2H), 0.84 - 0.80 (m, 4H).

[0143] Example 17 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(ethoxy-d5)pyridazine-3-carboxamide (Compound 17) TIFF2025518997000084.tif47128N-methylpyrrolidone (6.5 mL) and acetonitrile (6.5 mL) were added to a reaction flask, and ((6-(cyclopropionamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (200 mg, 0.43 mmol), O-(ethyl-d5)hydroxylamine hydrochloride (65.2 mg, 0.64 mmol), and N-methylimidazole (105.45 mg, 1.28 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (115.7 mg, 0.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164.15 mg, 0.86 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (20 mL) was added to the reaction solution to quench it, and then extraction was performed using ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by reverse-phase preparative chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (65.3 mg, yield: 31.7%, white solid). MS(ESI):m / z 484.3[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H),11.32(s,1H),10.56(s,1H),8.69(s,1H),8.15(s,1H),7.66(dd,J=7.8,1.3Hz,1H),7.51(d,J=7.9Hz,1H),7.27(t,J=7.9Hz,1H),3.90-3.84(m,1H),3.72(s,3H),2.13-2.04(m,1H),1.21-1.04(m,4H),0.87-0.79(m,4H).

[0144] Example 18 6-(Cyclopropanamide)-N-cyclopropoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 18) TIFF2025518997000085.tif64148

[0145] Step 1: 2-(Vinyl)isoindoline-1,3-dione TIFF2025518997000086.tif161282-Hydroxyisoindoline-1,3-dione (900 mg, 5.517 mmol) was dissolved in ultradry tetrahydrofuran (20 mL), and ethylene borate pyridine complex (876 mg, 3.641 mmol), 1,3-diethylurea (256 mg, 2.207 mmol), copper trifluoromethanesulfonate (798 mg, 2.207 mmol), and triethylamine (1114 mg, 11.034 mmol) were added. After replacing with oxygen, the mixture was reacted at 50 °C for 16 h. The reaction was stopped, the reaction solution was filtered, and then the filtrate was collected and spin-dried. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain the title compound (950 mg, yield: 91.1%, white solid). 1 H NMR (400 MHz, DMSO-d6) 7.92 - 7.86 (m, 4H), 6.92 (dd, J = 13.6, 6.4 Hz, 1H), 4.73 (dd, J = 13.6, 3.5 Hz, 1H), 4.40 (dd, J = 6.4, 3.5 Hz, 1H).

[0146] Step 2: 2-Cyclopropyloxyisoindoline-1,3-dione TIFF2025518997000087.tifDiethylzinc (19 mL, 19.0 mmol, 1.0 M hexane solution) was added dropwise to ultra-dry dichloromethane (16 mL) at 0 °C. After replacing with nitrogen, the temperature was maintained at 0 °C. Trifluoroacetic acid (2.172 g, 19.048 mmol) was dissolved in ultra-dry dichloromethane (8 mL), and the resulting solution was slowly added dropwise to the above solution, followed by stirring for 20 minutes. Diiodomethane (5.101 g, 19.048 mmol) was dissolved in ultra-dry dichloromethane (8 mL), and the resulting solution was slowly added dropwise, and stirring was continued for 20 minutes. 2-(Vinyl)isoindoline-1,3-dione (900 mg, 4.762 mmol) was dissolved in an ultra-dry dichloromethane solution (5.5 mL), and the resulting solution was slowly added dropwise. After replacing with nitrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, dilute hydrochloric acid (0.1 N, 16 mL) was added to the reaction solution, and this was separated. The organic phase was collected and then washed successively with saturated sodium bicarbonate solution (17 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the title compound (850 mg, yield: 87.9%, white solid).

[0147] Step 3: O-Cyclopropylhydroxylamine hydrochloride Cyclopropylmethoxyisoindoline-1,3-dione (450 mg, 2.217 mmol) was dissolved in dichloromethane (20 mL), and hydrazine hydrate (222 mg, 4.434 mmol) was added. After replacing with nitrogen, the mixture was reacted at room temperature for 16 h. The reaction was stopped, the reaction solution was filtered, and the filtrate was washed with water (20 mL×2). The aqueous phase was collected and extracted with a chloroform / isopropanol mixed solution (3:1, 15 mL×6). The organic phases were combined, then dried, and a solution of hydrogen chloride in 1,4-dioxane (1 mL) was added. The resulting solution was stirred for 1 h and then spin-dried to obtain the title compound (130 mg, yield: 53.5%, white solid).

[0148] Step 4: 6-(Cyclopropanecarboxamido)-N-cyclopropanemethoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 18) TIFF2025518997000089.tif36128N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, and then ((6-(cyclopropionamide)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (255 mg, 0.578 mmol), O-cyclopropylhydroxylamine hydrochloride (95.37 mg, 0.867 mmol), and N-methylimidazole (142.4 mg, 1.734 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (156.2 mg, 1.156 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (221.6 mg, 1.156 mmol) were added. The reaction solution was stirred and reacted in an oil bath at 65 °C for 2 hours. The reaction was stopped, and water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (16.22 mg, yield: 6.03%, yellow solid). MS(ESI):m / z 465.0[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ12.37(s,1H),11.32(s,1H),10.54(s,1H),8.56(s,1H),8.16(s,1H),7.69-7.65(m,1H),7.52(d,J=7.7Hz,1H),7.27(t,J=7.9Hz,1H),4.12-4.07(m,1H),3.95(s,3H),3.73(s,3H),2.13-2.06(m,1H),0.90(brs,2H),0.82(brs,4H),0.61-0.56(m,2H).

[0149] Example 19 6-(Cyclopropylcarboxamido)-N-cyclopropyloxy-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 19) TIFF2025518997000090.tif69128

[0150] Step 1: 1-Ethyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025518997000091.tif221283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (450 mg, 2.044 mmol) was dissolved in ultra-dry N,N-dimethylformamide (10 mL), and cesium carbonate (1.998 g, 6.132 mmol) was added. After replacing with nitrogen, iodoethane (478 mg, 3.066 mmol) was slowly added dropwise in an ice bath at 0 °C, then the reaction was transferred to room temperature and allowed to react for 2 hours. The reaction was stopped, the reaction solution was filtered, and then poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3), the combined organic phases were washed with saturated brine (20 mL × 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was spun in vacuo to remove the solvent, and the title compound (530 mg, pale yellow oil) was obtained and used directly in the next step reaction. MS(ESI): m / z 249.0 [M+H] + 。

[0151] Step 2: 3-(1-Ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline TIFF2025518997000092.tif 221281-Ethyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole 3 (530 mg, 2.135 mmol) was dissolved in methanol (20 mL), and palladium / carbon (91 mg, 0.854 mmol) was added. After replacing with hydrogen three times, the mixture was reacted at room temperature for 2 hours. The reaction was stopped, the reaction solution was filtered, and then spin-dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain the title compound (335 mg, yield: 71.9%, pale yellow solid). MS(ESI): m / z 219.2[M+H] + 。

[0152] Step 3: ((6-Chloro-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000093.tif 37128 3-(1-Ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (300 mg, 1.375 mmol) was dissolved in water (14 mL) and isopropanol (2 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (410 mg, 2.063 mmol) and zinc acetate (379 mg, 2.063 mmol) were added. After replacing with nitrogen three times, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (10 mL) was added to the reaction solution. The solution was stirred at room temperature for 1 hour and then filtered by suction. The filter cake was washed with water (6 mL×2) and tetrahydrofuran (1 mL) and dried to obtain the title compound (440 mg, yield: 79.0%, pale yellow solid). MS(ESI): m / z 375.3[M+H] + 。

[0153] Step 4: ((6-(Cyclopropanecarboxamido)-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000094.tif39128 ((6-chloro-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (400 mg, 0.984 mmol) was dissolved in toluene (8 mL) and acetonitrile (4 mL), and cyclopropylcarboxamide (209 mg, 2.460 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (109 mg, 0.197 mmol), 1,8-diazabicycloundec-7-ene (150 mg, 0.984 mmol), potassium carbonate (273 mg, 1.974 mmol), and palladium acetate (44 mg, 0.197 mmol) were added. After replacing with nitrogen, the mixture was reacted in an oil bath at 75 °C for 16 h. The reaction was stopped and the reaction solution was cooled to room temperature. Water (15 mL) and acetic acid (7.5 mL) were added, and the mixture was washed with petroleum ether (30 mL × 2). The aqueous phase was extracted with dichloromethane (15 mL × 3), and the combined dichloromethane organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spun in vacuo to remove the solvent, giving the title compound (750 mg, brown solid). MS(ESI): m / z 424.1 [M+H] + 。

[0154] Step 5: 6-(Cyclopropylcarboxamido)-N-cyclopropyloxy-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 19) TIFF2025518997000095.tif35128N-methylpyrrolidone (8 mL) and acetonitrile (8 mL) were added to a reaction flask, and the mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(cyclopropionamide)-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (750 mg, 1.648 mmol), O-cyclopropylhydroxylamine hydrochloride (271 mg, 2.472 mmol), and N-methylimidazole (404 mg, 4.944 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (445 mg, 3.296 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (632 mg, 3.296 mmol) were added. The reaction solution was continuously stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped and the reaction solution was filtered. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (21.82 mg, yield: 3.7%, pale yellow solid). MS(ESI):m / z 479.2[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),11.33(s,1H),10.56(s,1H),8.61(s,1H),8.17(s,1H),7.68(dd,J=7.8,1.5Hz,1H),7.52(dd,J=7.9,1.4Hz,1H),7.28(t,J=7.9Hz,1H),4.28(q,J=7.3Hz,2H),4.11-4.08(m,1H),3.73(s,3H),2.14-2.05(m,1H),1.46(t,J=7.3Hz,3H),0.90(brs,2H),0.85-0.79(m,4H),0.62-0.55(m,2H).

[0155] Example 20 6-(Cyclopropylcarboxamido)-N-cyclopropyloxy-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 20) TIFF2025518997000096.tif46136N-methylpyrrolidone (1 mL) and acetonitrile (1 mL) were added to a reaction flask, and then ((6-(cyclopropionamide)-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (155 mg, 0.349 mmol), O-cyclopropylhydroxylamine hydrochloride (57 mg, 0.524 mmol), and N-methylimidazole (86 mg, 1.047 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (94 mg, 0.698 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (137 mg, 0.698 mmol) were added. The reaction solution was continuously stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped and the reaction solution was filtered. The crude product of the filtrate was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (53.77 mg, yield: 33.0%, pale yellow solid). MS(ESI): m / z 468.4[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ12.49(s,1H),11.50(s,1H),10.61(s,1H),8.69(s,1H),8.06(s,1H),7.69(dd,J=7.8,1.5Hz,1H),7.53(dd,J=8.0,1.4Hz,1H),7.29(t,J=7.9Hz,1H),4.12-4.05(m,1H),3.72(s,3H),2.10-2.02(m,1H),0.91-0.86(m,2H),0.85-0.82(m,4H),0.61-0.54(m,2H).

[0156] Example 21 6-(Cyclopropylcarboxamido)-N-cyclopropyloxy-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 21) TIFF2025518997000097.tif58160

[0157] Step 1: 1-Bromo-2-(methoxy-d3)-3-nitrobenzene TIFF2025518997000098.tif171282-Bromo-6-nitrophenol (1000 mg, 4.587 mmol) was dissolved in ultradry N,N-dimethylformamide (15 mL), and potassium carbonate (1.268 g, 9.174 mmol) was added. After replacement with nitrogen, deuterated iodomethane (997 mg, 6.881 mmol) was slowly added dropwise in an ice bath at 0 °C, and then the mixture was transferred to 60 °C and reacted for 3 hours. The reaction was stopped, the reaction solution was filtered, and then poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, giving the crude title compound (1000 mg, yield: 77.5%, pale yellow oil). 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (dd, J = 8.1, 1.5 Hz, 1H), 7.95 (dd, J = 8.2, 1.5 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H).

[0158] Step 2: 3-Bromo-2-(methoxy-d3)aniline TIFF2025518997000099.tif151281-Bromo-2-(methoxy-d3)-3-nitrobenzene (1000 mg, 4.254 mmol) was dissolved in isopropanol (9 mL) and water (0.9 mL), and iron powder (1188 mg, 21.270 mmol) and ammonium chloride (1138 mg, 21.270 mmol) were added. After replacing with nitrogen, the mixture was reacted at 80 °C for 2 hours. The reaction was stopped, the reaction solution was filtered, and then spin-dried to obtain the crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (730 mg, yield: 83.7%, pale yellow solid). MS(ESI): m / z 205.2[M+H] + 。

[0159] Step 3: 2-(Methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline TIFF2025518997000100.tif221283-Bromo-2-(methoxy-d3)aniline (730 mg, 3.560 mmol) and pinacol diboronate (1808 mg, 7.12 mmol) were dissolved in ultra-dry dioxane (20 mL), and potassium acetate (699 mg, 7.12 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (260 mg, 0.356 mmol) were added. After replacing with nitrogen three times, the mixture was reacted in an oil bath at 110 °C for 3 hours. The reaction was stopped, the reaction solution was filtered, and then spin-dried. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (783 mg, yield: 87.2%, pale yellow solid). MS(ESI): m / z 254.2[M+H] + 。

[0160] Step 4: 2-(Methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline TIFF2025518997000101.tif 231282-(Methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (783 mg, 3.105 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (755 mg, 4.658 mmol) were dissolved in dioxane solution (20 mL) and water (4 mL), and potassium carbonate (1287 mg, 9.315 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (228 mg, 0.311 mmol) were added. After replacing with nitrogen three times, the reaction was carried out in an oil bath at 110 °C for 16 hours. The reaction was stopped, the reaction solution was filtered, and then spin-dried. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (550 mg, yield: 85.5%, pale yellow solid). MS(ESI): m / z 208.2[M+H] + 。

[0161] Step 5: ((6-Chloro-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000102.tif 351282-(Methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (550 mg, 2.654 mmol) was dissolved in water (21 mL) and isopropanol (3 mL), and lithium 4,6-dichloropyridazine-3-carboxylate 5 (612 mg, 3.185 mmol) and zinc acetate (854 mg, 3.185 mmol) were added. After replacing with nitrogen three times, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (20 mL) was added to the reaction solution. The solution was stirred at room temperature for 1 hour and then filtered by suction. The filter cake was washed with water (6 mL×2) and tetrahydrofuran (1 mL) and dried to obtain the title compound (400 mg, yield: 38.1%, yellow solid). MS(ESI): m / z 364.2[M+H] +。

[0162] Step 6: ((6-(Cyclopropylcarboxamido)-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025518997000103.tif36128 ((6-Chloro-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (180 mg, 0.455 mmol) was dissolved in ultra-dry N,N-dimethylformamide (5 mL), and cyclopropylcarboxamide (97 mg, 1.138 mmol), cesium carbonate (296 mg, 0.91 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)(2-amino-1,1’-biphenyl-2-yl)palladium(II) (115 mg, 0.137 mmol) were added. After replacing with nitrogen, the mixture was reacted at 100 °C for 16 hours. The reaction was stopped, the reaction solution was filtered, and then separated and purified by reverse column chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (50 mg, yield: 24.8%, pale yellow solid). MS(ESI): m / z 413.3 [M+H] + 。

[0163] Step 7: 6-(Cyclopropylcarboxamido)-N-cyclopropyloxy-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 21) TIFF2025518997000104.tif31128N-methylpyrrolidone (1 mL) and acetonitrile (1 mL) were added to a reaction flask, and then ((6-(cyclopropylcarboxamido)-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (75 mg, 0.169 mmol), O-cyclopropylhydroxylamine hydrochloride (29 mg, 0.254 mmol), and N-methylimidazole (41 mg, 0.507 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (46 mg, 0.338 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg, 0.338 mmol) were added. The reaction solution was continuously stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped and the reaction solution was filtered. The crude product of the filtrate was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (20.86 mg, yield: 26.4%, pale yellow solid). MS(ESI):m / z 468.2[M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),11.35(s,1H),10.55(s,1H),8.59(s,1H),8.12(s,1H),7.66(dd,J=7.8,1.5Hz,1H),7.51(dd,J=8.0,1.5Hz,1H),7.27(t,J=7.9Hz,1H),4.09-4.08(m,1H),3.94(s,3H),2.11-2.03(m,1H),0.91-0.86(m,2H),0.85-0.78(m,4H),0.61-0.54(m,2H)。

[0164] Example 22 N-cyclobutyloxy-6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 22) TIFF2025518997000105.tif43146

[0165] Project 1: 2-Cyclobutanoxyisoindoline-1,3-dione TIFF2025518997000106.tif151282-Hydroxyisoindoline-1,3-dione (10 g, 61.3 mmol) was dissolved in N,N-dimethylformamide (100 mL), and cyclobutyl bromide (12.4 g, 91.85 mmol), 18-crown-ether-6 (3.24 g, 12.258 mmol) and potassium carbonate (16.9 g, 122.3 mmol) were added. After replacing with nitrogen, the reaction solution was stirred and reacted in an oil bath at 80 °C for 16 hours. The reaction was stopped and the reaction solution was poured into water (80 mL). The aqueous phase was extracted with ethyl acetate (80 mL × 3), the combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound (8.2 g, yield: 61.7%, white solid). MS(ESI): m / z 218.1[M+H] + 。

[0166] Project 2: O-Cyclobutanolamine hydrochloride TIFF2025518997000107.tif111282-Cyclobutanoxyisatoic anhydride (500 mg, 2.304 mmol) was dissolved in dichloromethane (8 mL), and hydrazine hydrate (230.7 mg, 4.608 mmol) was added. After replacing with nitrogen, the reaction solution was stirred at room temperature for 16 hours. TLC plate monitoring indicated the disappearance of the starting material. The reaction solution was filtered, and the filtrate was poured into water (20 mL). The aqueous phase was extracted with a mixed solvent of chloroform:isopropanol = 3:1 (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. A solution of hydrogen chloride in 1,4-dioxane (2 mL) was added to the filtrate. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title compound (180 mg, yield: 63.2%, white solid).

[0167] Step 3: N-Cyclobutyloxy-6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 22) TIFF2025518997000108.tif35128N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, and the mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(cyclopropionamide)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (230 mg, 0.521 mmol), O-cyclobutylhydroxylamine hydrochloride (96.6 mg, 0.782 mmol), and N-methylimidazole (128.3 mg, 1.563 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (140.8 mg, 1.042 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (199.8 mg, 1.042 mmol) were added, and the reaction solution was stirred in an oil bath at 65 °C for 2 hours. The reaction was stopped, and water (30 mL) was added to the reaction solution. The aqueous phase was extracted using ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and spun in vacuo to remove the solvent, obtaining a crude product. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (11.86 mg, yield: 4.7%, white solid). MS(ESI): m / z 479.0[M+H] + 。 1 H NMR(400 MHz, DMSO-d6) δ 12.21(s, 1H), 11.31(s, 1H), 10.54(s, 1H), 8.56(s, 1H), 8.33(s, 1H), 7.66(d, J = 7.4 Hz, 1H), 7.51(d, J = 7.6 Hz, 1H), 7.27(t, J = 7.9 Hz, 1H), 4.58 - 4.51(m, 1H), 3.95(s, 3H), 3.72(s, 3H), 2.19 - 2.08(m, 5H), 1.76 - 1.69(m, 1H), 1.55 - 1.48(m, 1H), 0.82(brs, 4H).

[0168] Biological Test Evaluation Test Example A: In Vitro Enzyme Binding Assay of the Compound TYK2 JH2 of the Present Invention Objective: The objective of this test example was to test the binding effect of the compound on TYK2 JH2 pseudokinase using the time-resolved fluorescence resonance energy transfer (TR-FRET) method, and then evaluate the affinity of the compound for TYK2 JH2.

[0169] Experimental method: A 10 mM stock solution was prepared using the DMSO-dissolved compound, and then 200X compounds with different gradient concentrations were prepared in a compound dilution plate and transferred to an Echo plate. 75 nL of the compound was transferred from the Echo plate to a 384-well assay plate using an Echo instrument, and 5 μL of 3X TYK2 JH2 kinase (Bioduro), 5 μL of 3X Tb antibody (Cisbio), and 5 μL of 3X TRACER (Bioduro) were added to the 384-well assay plate, centrifuged for 30 seconds, and incubated at room temperature for 60 minutes. The fluorescence signal ratio of 495 nm / 520 nm was read by an Envision microplate reader (PerkinElmer), and the data was analyzed using XL-Fit software to calculate the IC 50 of the compound.

[0170] Experimental results: TIFF2025518997000109.tif76128

[0171] It can be seen from the experimental data that the compound of the present invention had a good binding effect on TYK2 JH2 pseudokinase.

[0172] Test Example B: Determination of the Effect of the Compound of the Present Invention on IL-2-Induced STAT5 Phosphorylation (JAK1 / 3) in CD3+ Cell Subpopulations in Human PBMC Objective: The objective of this test example was to test the inhibitory effect of the compound on IL-2-induced STAT5 phosphorylation using protein phosphorylation flow cytometry analysis technology.

[0173] Experimental method: Human PBMC cells were pre-incubated with the compound, induced to phosphorylate STAT5 under appropriate stimulation conditions, and the corresponding cell subpopulations and targets were stained. Flow cytometry was used to read the cell data and analyze the intensity of the phosphorylated antibody signal at different compound concentrations. PBMCs were resuspended and dispensed into 96-well plates at 62.5 μL / well. 3.5 μL of a 20X compound standard solution was added and incubated at 37 °C for 30 minutes. 5 μL of PE mouse anti-human CD3 (BD) was added and incubated at 37 °C for 30 minutes in the dark. 4 μL of 20X IL-2 (R&D) was added to each well and incubated at 37 °C for 20 minutes in the dark. All the cells in the 96-well plate were transferred to a deep-well plate, 400 μL of a fixation standard solution (Biolegend) was added to each well, and incubated at room temperature for 20 minutes in the dark. The cells were washed twice with PBS, 400 μL of Perm Buffer III (BD) was added, and incubated at 4 °C for 40 minutes in the dark. The cells were washed twice with PBS, 100 μL of a STAT5 pY694 antibody standard solution (BD) was added, and incubated at room temperature for 40 minutes. After washing once with PBS, they were resuspended in 200 μL of staining buffer and transferred to a sample plate. The antibody fluorescence intensity was analyzed using FlowJo software, and the IC 50 of the compound was calculated using XL-Fit software.

[0174] Experimental results: TIFF2025518997000110.tif26128

[0175] From the experimental data results, it can be seen that the compound of the present invention had lower inhibitory activity against the JAK1 / 3 signaling pathway and had better selectivity.

[0176] Test Example C: Pharmacokinetic evaluation of the compound of the present invention by intravenous injection or forced oral administration in mice Objective: The objective of this test example was to evaluate the pharmacokinetic properties of the compound of the present invention.

[0177] The inventors evaluated the pharmacokinetic properties of the compounds of the present invention in mice. The animal information is shown in Table 1.

[0178] (Table 1) Information table of test animals of the present invention TIFF2025518997000111.tif13170

[0179] Experimental method: The compounds of the present invention were administered to the test animals in the form of 5% DMA + 5% Solutol + 90% physiological saline or 5% ethanol + 5% TPGS + 90% PEG300 solvent. The animals were fasted for 12 hours before administration and allowed free access to water. For the intravenous administration group, the dose was 1 mg / kg. The drug was administered by intragastric administration at a dose of 10 mg / kg. After drug administration, blood was collected intravenously from the animals at the following time points (the blood volume was approximately 0.3 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours. EDTA-K2 was pre-added to the blood collection tube as an anticoagulant, and the blood samples were centrifuged at 6800 g for 6 minutes to collect plasma, which was then stored at -80°C.

[0180] Sample preparation for LC-MS / MS assay: 15 μL of plasma sample was used for protein precipitation using 300 μL of methanol containing 100 ng / mL of IS (the IS was tolbutamide). The mixture was vortexed for 1 minute and then centrifuged at 18000 g for 10 minutes. 300 μL of the supernatant was transferred to a 96-well plate. 2 μL of the supernatant was subjected to LC-MS / MS analysis. The analysis results showed that the compounds of the present invention had good pharmacokinetic properties in mice. TIFF2025518997000112.tif41163

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