Substituted pyridazine-3-carboxamide compounds that function 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, polymorph, prodrug, or isotope variant thereof. The present invention also provides a pharmaceutical composition comprising the compound, a method for preparing the same, and its use in the treatment or prevention of TYK2 kinase-mediated diseases. TIFF2025521070000079.tif42128

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular, to substituted pyridazine-3-carboxamide compounds, compositions containing the same, methods for preparing the same, 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 and bring JAKs that bind to the intracellular domain of the receptor into proximity. Then, the tyrosine residues of JAKs are phosphorylated, increasing the activity of the kinase domain. Next, the activated JAK phosphorylates the tyrosine residues of the receptor, generating binding sites for proteins with SH2 domains. Signal Transducer and Activator of Transcription (STAT) binds to phosphorylated tyrosine on the receptor through its SH2 domain, is phosphorylated by JAK, producing 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 cross-linking with other signal transduction pathways such as PI3K / AKT and 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 regulatory factor by inhibiting TYK2-mediated signal transduction. TYK2 plays an important role in the transmission of 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, etc.). 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-specific 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, there is generally a problem of low selectivity.

[0006] Research has shown that the pseudokinase domain (JH2) in the JAK family, which exhibits significant catalytic activity, may 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 the JH2 of TYK2 and inhibit TYK2 kinase function through an allosteric effect.

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

[0008] In view of the above, the present invention provides substituted pyridazine-3-carboxamide compounds having excellent activity for 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, and mixtures thereof, TIFF2025521070000002.tif42128wherein 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 as defined herein, and a pharmaceutically acceptable excipient, preferably the pharmaceutical composition further comprises another therapeutic agent.

[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, or a pharmaceutical composition comprising the same as defined herein, 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 comprising the compound as defined herein, in the treatment and / or prevention of TYK2 kinase-mediated diseases.

[0013] In one embodiment, the present invention is 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 isotopic 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 for the present method is selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

Mode for Carrying Out the Invention

[0016] Detailed Description Definition 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 may be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, 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 in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terms used in this specification are for the purpose of describing specific embodiments only and are not intended to limit the invention. As used in this specification, 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 primary (usually), secondary, tertiary, quaternary carbon atoms, or combinations 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, the 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), and 2-propyl (i-Pr, i-propyl, -CH(CH3)2).

[0019] "Alkylene" refers to a divalent group formed by removing another hydrogen from an alkyl, and can be substituted or unsubstituted. In some embodiments, C 1~6 alkylene, C 1~4 alkylene, C 2~4 alkylene, and C 1~3Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), etc. Exemplary substituted alkylene such as those substituted with one or more alkyl (methyl) groups includes substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2), etc., but is not limited to these.

[0020] "Alkenyl" is alkyl as defined herein that contains at least one carbon-carbon double bond. In one embodiment, 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, etc. When alkenyl is substituted, preferably 1 to 5 substituents are present, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0021] "Alkynyl" is an alkyl as defined herein that contains at least one carbon-carbon triple bond. In one embodiment, alkynyl contains from 2 to 20 carbon atoms, preferably from 2 to 12 carbon atoms, more preferably from 2 to 8 carbon atoms, and even more preferably from 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. When alkynyl is substituted, preferably 1 to 5 substituents are present, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0022] "Carbocyclic" or "cycloalkyl" refers to a saturated or partially unsaturated cyclic carbon-containing group such as a 5- to 6-membered saturated carbon ring and a 5- to 6-membered partially unsaturated carbon 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 carbon ring includes a bridged or spiro ring. Non-limiting examples of carbocyclic include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl, or spiro[3.3]heptyl. Carbocyclic may be substituted. When carbocyclic is substituted, preferably 1 to 5 substituents are present, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0023] 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.

[0024] The term "aryl" refers to an aromatic hydrocarbon group obtained 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.

[0025] The term "heteroaryl" refers to an aryl containing heteroatoms, which can be monocyclic or fused rings, and the heteroatoms are independently selected from N, O, and S. 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. Heteroaryl includes, but is 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, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl; and exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.

[0026] "Heterocyclyl" or "heterocyclic" refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing a heteroatom selected from N, O, and S. Further, the term "heterocyclyl" refers to a group having a stable 3- to 10-membered saturated heterocyclic ring system in which one or more atoms constituting the non-aromatic ring are heteroatoms and the rest are carbon. 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")), a bicyclic system, a tricyclic system, or a polycyclic system having more rings. The ring system of a 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 an independent 5- or 6-membered monocyclic heterocyclyl containing one or more, preferably 1 to 4, more preferably 1 to 3 heteroatoms 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.

[0027] 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 of that variable lists "alkyl" or "aryl", it is understood that "alkyl" or "aryl" represents a linking alkylene group or 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 group "-C1-C3 haloalkyl" should be understood as alkylene.

[0028] The term "pharmaceutically acceptable salt" means that the compound can be converted to the corresponding salt by conventional methods, and the salt is chemically and physically compatible with the other components that make up the pharmaceutical dosage form and is physiologically compatible with the receptor. The salts can be acidic and / or basic salts formed from the compound, as well as inorganic and / or organic acids and / or inorganic and / or organic bases, and also include zwitterionic salts (inner salts), and further include 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 certain amount of acid or base. These salts can be precipitated from the solution, collected by filtration, or recovered after evaporation of the solvent, or obtained by reaction in an aqueous medium followed by cooling and drying. In particular, the salts are preferably water-soluble pharmaceutically acceptable non-toxic acid addition salts, examples of which are salts formed from amino 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, cyclopentanepropionate, diglucosate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactoate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, niacin, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Additional pharmaceutically acceptable salts may 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, etc. Additional pharmaceutically acceptable salts may include, where appropriate, salts formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates, together with non-toxic ammonium, quaternary ammonium, and amine cations.

[0029] The term "solvate" can 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, 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, the solvate may be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0030] 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 the compound to the number of molecules of the compound in the hydrate is predefined. Thus, the 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 more than one type of hydrate, including, for example, a monohydrate (where x = 1), a lower hydrate (where x is a number greater than 0 and less than 1, for example, a hemihydrate (R·0.5H2O)), and a polyhydrate (where x is a number greater than 1, for example, a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0031] The term "prodrug" refers to any compound that, when administered to a living being, produces a drug, i.e., the active ingredient, as a result of natural 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.

[0032] The present invention further includes isotope-labeled compounds (isotope variants) that are equivalent to the general formula 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 incorporated 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 isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H (i.e., deuterium, D). Compounds of the present invention, prodrugs of the compounds, and pharmaceutically acceptable salts of the compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are all within the scope of the present invention. 3 H and 14 Certain specific isotope-labeled compounds of the present invention, such as those incorporating radioactive isotopes such as 3 H) and carbon-14 (i.e., 14C) Isotopes are particularly preferred due to ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e., 2 H) may be preferred in some cases because the substituted compound can provide therapeutic advantages such as an extended in vivo half-life due to better metabolic stability or a reduction in the required dose. The isotope-labeled compounds and prodrugs thereof of the present invention can generally be prepared by using readily available isotope-labeled reagents in place of non-isotope-labeled reagents when carrying out the following procedures and / or examples and the processes disclosed in the preparation examples.

[0033] The compounds of the present invention contain one or more chiral centers and thus can have multiple stereoisomeric forms, for example, 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 stereoisomers, including a racemic mixture 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.

[0034] "Optional" or "optionally" means that the event or situation described thereafter may occur but does not necessarily occur, including the case where the event or situation occurs or does not occur. For example, "aryl may be substituted with alkyl" means that alkyl may be present but does not necessarily be present, and the term includes the case where aryl is substituted with alkyl and the case where aryl is not substituted with alkyl.

[0035] "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, etc. 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) cellulose and its 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, and 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.

[0036] 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 crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optoelectronic properties, stabilities, and solubilities. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can favor one crystal form. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0037] 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 there are multiple definitions for a term, the definition in this document shall prevail. The singular forms (e.g., "a" and "an") used in the present invention are to be understood to include plural references unless otherwise specified.

[0038] In addition, the terms "comprise" and "include" are not of a closed limitation but are unrestricted, that is, they include what is specified in the present invention but do not exclude other aspects.

[0039] Unless otherwise specified, the present invention can identify compounds using conventional methods such as mass spectrometry and nuclear magnetic resonance, and for steps and conditions, reference can be made to the conventional operating steps and conditions in the technical field.

[0040] Unless otherwise indicated, the present invention uses standard nomenclature and standard inspection procedures and techniques in analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used in chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

[0041] In addition, unless otherwise specified, the description "each independently" used in the present invention should be understood in a broad sense, noting 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 the specific options represented by the same symbol do not affect each other between different groups, or that the specific options represented by the same symbol do not affect each other within the same group.

[0042] Specifically, the present invention relates to the following technical solutions.

[0043] 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, and mixtures thereof, TIFF2025521070000003.tif42128wherein, R1 is H, C 1~6 haloalkyl, C 1~6 alkylene-OR a 、C 1~6 alkylene-SR a 、C 1~6 alkylene-NR b R c 、C 1~6 alkylene-C(O)R a 、C 1~6 alkylene-C(O)OR a 、C 1~6 alkylene-C(O)NR b R c 、C 1~6 alkylene-OC(O)R a 、C 1~6 alkylene-NR b C(O)R a 、C 1~6 alkylene-S(O) m R a 、C 1~6 alkylene-S(O) m NR b R c or C 1~6 alkylene-NR b S(O) m R a selected from, 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 selected from, and the group may be substituted with one or more deuteriums until it is fully deuterated, R3 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, and R3 may be substituted with 1, 2, 3, or 4 Rs, R a , R b , and R c are independently selected from H, 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, m is 1 or 2, R is H, D, halogen, CN, C 1~6 alkyl, or C 1~6 haloalkyl.

[0044] In a more specific embodiment, the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, wherein R1 is H, C 1~6 haloalkyl, C 1~6 alkylene-OR a , C 1~6 alkylene-SR a , C 1~6 alkylene-NR b R c , C 1~6 alkylene-C(O)R a , C 1~6 alkylene-C(O)OR a , C 1~6 alkylene-C(O)NR b R c , C 1~6 alkylene-OC(O)R a , or C 1~6 alkylene-NR b C(O)R aselected from, and the group may be substituted with one or more deuteriums until it is fully deuterated. Preferably, R1 is H, C 1~6 haloalkyl, C 1~6 alkylene-OR a 、C 1~6 alkylene-SR a 、C 1~6 alkylene-NR b R c 、C 1~6 alkylene-C(O)OR a 、or C 1~6 alkylene-C(O)NR b R c selected from, and the group may be substituted with one or more deuteriums until it is fully deuterated. Preferably, R1 is H, C 1~6 haloalkyl, C 1~6 alkylene-OH, C 1~6 alkylene-SH, C 1~6 alkylene-NH2, C 1~6 alkylene-C(O)OH, or C 1~6 alkylene-C(O)NH2 selected from, and the group may be substituted with one or more deuteriums until it is fully deuterated. Preferably, R1 is H or C 1~6 selected from haloalkyl, and the group may be substituted with one or more deuteriums until it is fully deuterated. Preferably, R1 is C 1~6 alkylene-OR a wherein, R a is selected from C 1~6 alkyl or C 1~6 haloalkyl.

[0045] 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 mixtures thereof, wherein R2 is C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7Selected from cycloalkyl or 3- to 7-membered heterocyclyl, which group may be substituted with one or more deuteriums until fully deuterated, preferably, R2 is C 1~6 alkyl, C 1~6 haloalkyl, C 3~7 Selected from cycloalkyl or 3- to 7-membered heterocyclyl, which group may be substituted with one or more deuteriums until fully deuterated, preferably, R2 is C 1~6 alkyl or C 3~7 Selected from cycloalkyl, which group may be substituted with one or more deuteriums until fully deuterated.

[0046] 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 mixtures thereof, wherein R3 is C 1~6 alkyl or C 1~6 Selected from haloalkyl, which group may be substituted with one or more deuteriums until fully deuterated, preferably, R3 is methyl which may be substituted with one or more deuteriums until fully deuterated.

[0047] 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 mixtures thereof, R1 is H, C 1~6 haloalkyl, C 1~6 alkylene-OR a , C 1~6 alkylene-SR a , or C 1~6 alkylene-C(O)OR a Selected from, which group may be substituted with one or more deuteriums until fully deuterated, R2 is C 1~6 alkyl, C 1~6 haloalkyl, C3~7 Selected from cycloalkyl or 3- to 7-membered heterocyclyl, which group may be substituted with one or more deuteriums until it is completely deuterated. R3 is H, C 1~6 alkyl, or C 1~6 selected from haloalkyl, which group may be substituted with one or more deuteriums until it is completely deuterated. Each of the groups R1, R2, and R3 may be substituted with 1, 2, 3, or 4 Rs. R a is H, C 1~6 alkyl, or C 1~6 selected from haloalkyl. R is H, D, halogen, CN, C 1~6 alkyl, or C 1~6 selected from haloalkyl.

[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, and mixtures thereof. R1 is H, C 1~4 haloalkyl, C 1~4 alkylene-OR a , or C 1~4 selected from alkylene-C(O)OH, which group may be substituted with one or more deuteriums until it is completely deuterated. R2 is C 1~4 alkyl, C 1~4 haloalkyl, or C 3~7 selected from cycloalkyl, which group may be substituted with one or more deuteriums until it is completely deuterated. R3 is C 1~4 alkyl or C 1~4 selected from haloalkyl, which group may be substituted with one or more deuteriums until it is completely deuterated. R a is H, C 1~4 alkyl, or C 1~4 selected from haloalkyl.

[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, and mixtures thereof, R1 is C, which may be substituted with one or more deuteriums until it is completely deuterated 1~4 alkylene-OR a wherein R2 is selected from C 1~4 alkyl, C 1~4 haloalkyl, or C 3~7 cycloalkyl, and the group may be substituted with one or more deuteriums until it is completely deuterated, preferably C 1~4 alkyl which may be substituted with one or more deuteriums until it is completely deuterated, R3 is selected from C 1~4 alkyl or C 1~4 haloalkyl, and the group may be substituted with one or more deuteriums until it is completely deuterated, R a is selected from C 1~4 alkyl or C 1~4 haloalkyl.

[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, and mixtures thereof, R1 is H, C 1~4 haloalkyl, C 1~4 alkylene-OH or C 1~4 alkylene-C(O)OH, and the group may be substituted with one or more deuteriums until it is completely deuterated, R2 is C 1~4 alkyl, C 1~4 haloalkyl, or C 3~7Selected from cycloalkyl, which may be substituted with one or more deuteriums until fully deuterated, preferably may be substituted with one or more deuteriums until fully deuterated, C 1~4 alkyl, R3 is C 1~4 alkyl or C 1~4 haloalkyl, which may be substituted with one or more deuteriums until fully deuterated.

[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 mixtures thereof, R1 is H, C 1~6 alkylene-OR a and C 1~6 alkylene-SR a selected from, which may be substituted with one or more deuteriums until fully deuterated, R2 is C 1~6 alkyl and C 1~6 haloalkyl, which may be substituted with one or more deuteriums until fully deuterated, R3 is H, C 1~6 alkyl, or C 1~6 haloalkyl, which may be substituted with one or more deuteriums until fully deuterated, Each group of R1, R2, and R3 may be substituted with 1, 2, 3, or 4 Rs, R a is selected from H, C 1~6 alkyl, and C 1~6 haloalkyl, R is selected from H, D, halogen, CN, C 1~6 alkyl, or C 1~6 haloalkyl.

[0052] 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 mixtures thereof, R1 is selected from H and C 1~6 alkylene-OR a and the group may be substituted with one or more deuteriums until it is fully deuterated, R2 is selected from C 1~6 alkyl and C 1~6 haloalkyl, R3 is C 1~6 alkyl, and the group may be substituted with one or more deuteriums until it is fully deuterated, R a is selected from H and C 1~6 alkyl.

[0053] 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 mixtures thereof, R1 is selected from H and C 1~4 alkylene-OR a and the group may be substituted with one or more deuteriums until it is fully deuterated, R2 is C 1~4 alkyl, and the group may be substituted with one or more deuteriums until it is fully deuterated, R3 is C 1~4 alkyl, and the group may be substituted with one or more deuteriums until it is fully deuterated, R a is C 1~4 alkyl. 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 mixtures thereof, and the compound is Selected from TIFF2025521070000004.tif237166.

[0054] 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 as defined herein, and a pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition further comprises another therapeutic agent.

[0055] 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 the same, in the preparation of a medicament for treating and / or preventing a TYK2 kinase-mediated disease.

[0056] In one embodiment, the present invention provides the use of 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 a compound as defined herein, in the treatment and / or prevention of a TYK2 kinase-mediated disease.

[0057] 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.

[0058] 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.

[0059] In some embodiments, the TYK2 kinase-mediated disease related to the method is selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

[0060] Those skilled in the art will understand that various preferred conditions described above can be arbitrarily combined to obtain various preferred embodiments of the present invention without departing from the common general knowledge in the art.

[0061] Administration The compounds represented by formula (I) of the present invention can be administered by any means suitable for the condition of the disease to be treated. Such means may depend on the need for site-specific treatment or the amount of medicament to be delivered. Although other modes of delivery 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 compounds can be administered orally, e.g., in the form of tablets, capsules, granules, powders, or liquid formulations (including syrups); topically, e.g., in the form of solutions, suspensions, gels, or ointments; sublingually; buccally; parenterally, e.g., by subcutaneous, intravenous, intramuscular, or intracostal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, e.g., by inhalation of a spray; topically, e.g., in the form of creams or ointments; rectally, e.g., in the form of suppositories; or delivered by liposomes. Unit dosage formulations containing non-toxic pharmaceutically acceptable carriers or diluents can be administered. The compounds can be administered in forms 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, devices such as subcutaneous implants or osmotic pumps.

[0062] Exemplary compositions for topical administration include topical carriers.

[0063] Exemplary compositions for oral administration may include, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a tackifier, and sweetening or flavoring agents such as those known in the art, a suspending agent, and, 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, immediate release tablets. The compounds of the present invention may also be orally delivered 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.

[0064] Exemplary compositions for nasal aerosol or inhalation administration may 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.

[0065] 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 other suitable dispersing or wetting agents and suspending agents including synthetic mono- or diglycerides and fatty acids including oleic acid, and may include injectable solutions or suspensions.

[0066] Exemplary compositions for rectal administration include, for example, suppositories which may contain suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycol, which are solid at ambient temperature but liquefy and / or dissolve in the rectal cavity to release the medicament.

[0067] 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 to 1000 mg / kg, 1 to 1000 mg / kg, 1 to 50 mg / kg, 5 to 250 mg / kg, and 250 to 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 to 4 times per day). The specific dosage level and frequency of administration for any particular subject can vary and will 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, 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, as well as mammalian species such as domestic animals like dogs, cats, horses, etc. Thus, when the term "patient" is used herein, it is intended to include all subjects, most preferably mammalian species suffering from a TYK2 kinase-mediated disease.

Examples

[0068] The materials and reagents used herein are either commercially available or prepared by synthetic methods generally known in the art.

[0069] Example 1 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 1) TIFF2025521070000005.tif132153

[0070] Step 1: Methyl 2-methoxy-3-nitrobenzoate TIFF2025521070000006.tif161283-Nitrosalicylic acid (15 g, 81.91 mmol) and cesium carbonate (106.756 g, 327.65 mmol) were dissolved in N,N-dimethylformamide (300 mL), and iodomethane (58.54 g, 409.57 mmol) was added to the reaction system. The reaction solution was stirred and reacted at room temperature for 16 hours. The reaction was stopped, and water (1.5 L) was added to the reaction solution to quench it. After filtration, the filter cake was dried to obtain the title compound (12.886 g, yield: 74.5%, white solid). MS(ESI): m / z 212.1[M+H]+.

[0071] Step 2: 2-Methoxy-3-nitrobenzamide TIFF2025521070000007.tif16128Methyl 2-methoxy-3-nitrobenzoate (6.66 g, 31.54 mmol) was dissolved in methanol (36.63 mL), and aqueous ammonia (27.3 mL) was added. The mixture was reacted at room temperature for 16 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure and then separated and purified by column chromatography (silica gel, dichloromethane:methanol = 95:5) to obtain the title compound (5.2 g, yield: 84%, yellow solid). MS(ESI): m / z 197.0[M+H]+.

[0072] Step 3: 3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025521070000008.tif211282-Methoxy-3-nitrobenzamide (5.2 g, 26.53 mmol) was dissolved in N,N-dimethylformamide dimethylacetal (67.6 mL), and the mixture was reacted at 95 °C for 1 hour. The reaction solution was rotated in vacuo to remove the solvent, and ethanol (13 mL) was used for dissolution to obtain the crude product. Ethanol (110 mL) and acetic acid (26 mL) were stirred at 0 °C for 5 minutes, and hydrazine hydrate (13.18 mL) was added thereto. The mixture was stirred and reacted for 15 minutes, then the crude product solution was added, and the mixture was warmed to room temperature, stirred, and reacted for 1 hour. The reaction was stopped, the reaction solution was concentrated under reduced pressure, then extracted using added ethyl acetate (451 mL), then washed twice using saturated sodium bicarbonate solution (451 mL), washed using saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 9:1) to obtain the title compound (3.71 g, yield: 63.5%, yellow solid). MS(ESI): m / z 221.1[M+H]+.

[0073] Step 4: 3-(2-Methoxy-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole TIFF2025521070000009.tif251283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.3 g, 5.9 mmol), 3,4-dihydro-2H-pyran (2.5 g, 29.52 mmol), and 4-methylbenzenesulfonic acid (224.61 mg, 1.18 mmol) were dissolved in tetrahydrofuran (52 mL), and the reaction solution was stirred at 80 °C for 16 h. The reaction was stopped, and water (50 mL) was added to the reaction solution to quench it. Then, extraction was performed three times using ethyl acetate (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (1.8 g, yield: 100%, yellow oil). MS(ESI): m / z 305.1[M+H]+.

[0074] Step 5: 2-Methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)aniline TIFF2025521070000010.tif221283-(2-Methoxy-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (1.8 g, 5.92 mmol) was dissolved in methanol (50 mL), aqueous ammonia (0.85 mL) was added, and then palladium / carbon (251.8 mg, 2.4 mmol) was added in one batch. After replacing with hydrogen, the mixture was reacted at room temperature for 16 h. The reaction was stopped. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Then, it was separated and purified by column chromatography (silica gel, dichloromethane:methanol = 100:1) to obtain the title compound (1.572 g, yield: 97%, yellow oil). MS(ESI): m / z 275.1[M+H]+.

[0075] Step 6: ((6-Chloro-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000011.tif381282-Methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)aniline (400 mg, 1.46 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (348.21 mg, 1.75 mmol), and zinc acetate (321.08 mg, 1.75 mmol) were dissolved in 10 mL of a solvent of water:isopropanol = 7:1. After replacement with nitrogen, the mixture was reacted at 65 °C for 16 hours. The reaction was stopped, 15 mL of water was added to the reaction solution, the mixture was stirred for 1 hour, then filtered by suction and washed with tetrahydrofuran (0.5 mL). The filter cake was dried to obtain the title compound (365 mg, yield: 54%, white solid). MS(ESI): m / z 431.1 [M+H]+.

[0076] Step 7: ((6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino))pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000012.tif39128((6-chloro-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (335 mg, 0.724 mmol), cyclopropylcarboxamide (308.18 mg, 3.62 mmol), (2R)-1-[(1R)-1-[bis(1,1-di-tert-butyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (120.49 mg, 0.217 mmol), tris[dibenzylideneacetone]dipalladium (132.64 mg, 0.145 mmol), and cesium carbonate (471.97 mg, 1.45 mmol) were dissolved in N,N-dimethylacetamide (5 mL). After replacement with nitrogen, the mixture was reacted at 140 °C for 1 hour. The reaction was stopped, the reaction solution was filtered, and then the filtrate was separated and purified by reverse-phase column chromatography (C18, water / 0.1% TFA:acetonitrile = 70:30) to obtain the title compound (216 mg, yield: 58%, yellow solid). MS(ESI): m / z 480.4[M+H]+.

[0077] Step 8: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide TIFF2025521070000013.tif36128N-methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added to a reaction flask, and then ((6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino))pyridazine-3-carbonyl)oxy)zinc(0.5) (100 mg, 0.196 mmol), O-ethylhydroxylamine hydrochloride (28.62 mg, 0.293 mmol), and N-methylimidazole (48.18 mg, 0.587 mmol) were added. After purging with nitrogen, the mixture was reacted in an oil bath at 65 °C for 15 minutes, and finally, 1-hydroxybenzotriazole (52.87 mg, 0.39 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol) were added. After purging with nitrogen, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped and quenched by adding water (10 mL) to the reaction solution, and then extraction was carried out using ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent, and the title compound (124 mg, brown oil) was obtained. MS(ESI): m / z 523.2[M+H]+.

[0078] Step 9: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 1) (Cyclopropanecarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (114 mg) was dissolved in methanol (2 mL), and hydrogen chloride dioxane solution (2 mL) was added thereto, and the mixture was reacted at room temperature for 1 hour. The reaction was stopped, and the reaction solution was rotated in vacuo to remove the solvent to obtain a crude product. The crude product was separated and purified by reversed-phase preparative chromatography (formic acid system) to obtain the title compound (12.71 mg, yield: 13.38%, white solid). MS (ESI): m / z 439.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 11.34 (s, 1H), 10.57 (s, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 6.6 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.70 (s, 3H), 2.08 (t, J = 5.8 Hz, 1H), 1.23 (t, J = 7.0 Hz, 3H), 0.83 - 0.81 (m, 4H).

[0079] Example 2 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 2) TIFF2025521070000015.tif67155

[0080] Step 1: 3-(2-Methoxy-3-nitrophenyl)-1-(2-methoxyethyl)-1H-1,2,4-triazole TIFF2025521070000016.tifDissolve (2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.0 g, 4.542 mmol) in ultra-dry N,N-dimethylformamide (10 mL), and add cesium carbonate (4439 mg, 13.626 mmol). After purging with nitrogen, slowly add 1-bromo-2-methoxyethane (947 mg, 6.813 mmol) dropwise, and react the mixture at room temperature for 2 hours. Stop the reaction, filter the reaction solution, and then pour it into water (30 mL). Extract the aqueous phase with ethyl acetate (15 mL×3), wash the combined organic phases with saturated brine (20 mL×2), dry over anhydrous sodium sulfate, filter, and rotate the filtrate in vacuo to remove the solvent to obtain the title compound (1.33 g, pale yellow oil). MS(ESI): m / z 279.0 [M+H]+.

[0081] Step 2: 2-Methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)aniline TIFF2025521070000017.tifDissolve 2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)nitrobenzene (1.3 g, 4.672 mmol) in methanol (30 mL), and add palladium / carbon (198 mg, 1.869 mmol). After purging with hydrogen three times, react the mixture at room temperature for 16 hours. Stop the reaction, filter the reaction solution, and then centrifuge. Separate and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain the title compound (830 mg, yield: 71.6%, colorless oil). MS(ESI): m / z 249.1 [M+H]+.

[0082] Step 3: ((6-Chloro-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) Dissolve 3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)-4-methoxyaniline (750 mg, 3.021 mmol) in water (21 mL) and isopropanol (3 mL), and add lithium 4,6-dichloropyridine-3-carboxylate (722 mg, 3.625 mmol) and zinc acetate (665 mg, 3.625 mmol). 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 (21 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 (6 mL × 2) and tetrahydrofuran (1 mL) and dried to obtain the title compound (730 mg, yield: 55.3%, pale yellow solid). MS(ESI): m / z 404.9 [M+H]+.

[0083] Step 4: ((6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000019.tif41128((6-chloro-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (730 mg, 1.672 mmol) was dissolved in toluene (8 mL) and acetonitrile (4 mL), and cyclopropylcarboxamide (356 mg, 4.180 mmol), (R)-(-)-1-[(S-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (185 mg, 0.334 mmol), 1,8-diazabicycloundec-7-ene (254 mg, 1.672 mmol), potassium carbonate (462 mg, 3.344 mmol), and palladium acetate (75 mg, 0.334 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 dried over anhydrous sodium sulfate and filtered. The filtrate was rotated in vacuo to remove the solvent, and the title compound (1410 mg, brown solid) was obtained and used directly in the next step. MS(ESI): m / z 454.6 [M+H]+.

[0084] Step 5: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 2) TIFF2025521070000020.tifA 3912850 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-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 0.825 mmol), O-ethylhydroxylamine hydrochloride (121 mg, 1.238 mmol), and N-methylimidazole (202 mg, 2.475 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (223 mg, 1.650 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (316 mg, 1.650 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 (79.51 mg, yield: 19.4%, white solid). MS(ESI): m / z 497.3[M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 12.25(s, 1H), 11.31(s, 1H), 10.55(s, 1H), 8.57(s, 1H), 8.15(s, 1H), 7.66(dd, J = 7.8, 1.5 Hz, 1H), 7.50(dd, J = 7.9, 1.4 Hz, 1H), 7.27(t, J = 7.9 Hz, 1H), 4.40(t, J = 5.2 Hz, 2H), 3.98(q, J = 7.0 Hz, 2H), 3.78 - 3.69(m, 5H), 3.25(s, 3H), 2.13 - 2.02(m, 1H), 1.22(t, J = 7.0 Hz, 3H), 0.81(d, J = 5.4 Hz, 4H).

[0085] Example 3 6-(Cyclopropylcarboxamido)-N-cyclopropyloxy-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 3) TIFF2025521070000021.tif63148

[0086] Step 1: 2-(Vinyl)isoindoline-1,3-dione TIFF2025521070000022.tif161282-Hydroxyisoindoline-1,3-dione (900 mg, 5.517 mmol) was dissolved in ultra-dry tetrahydrofuran (20 mL), and anhydrous ethylene borate pyridine complex (876 mg, 3.641 mmol), diethyl urea (256 mg, 2.207 mmol), bis(((trifluoromethyl)sulfonyl)oxy)copper (798 mg, 2.207 mmol), and trimethylamine (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, then the filtrate was collected, centrifuged, and 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). 1H NMR (400 MHz, DMSO-d6) δ 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).

[0087] Step 2: 2-Cyclopropyloxyisoindoline-1,3-dione TIFF2025521070000023.tif16128Diethylzinc (19 mL, 19.0 mmol, 1.0 M solution in hexane) was added dropwise into ultradry 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 ultradry dichloromethane (8 mL), and then the resulting solution was slowly added dropwise into the above solution, and stirring was carried out for 20 minutes. Diiodomethane (5.101 g, 19.048 mmol) was dissolved in ultradry dichloromethane (8 mL), and then 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 ultradry dichloromethane solution (5.5 mL), and then 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, then washed successively with saturated sodium bicarbonate solution (17 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and centrifuged to obtain the 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).

[0088] Step 3: O-Cyclopropylhydroxylamine hydrochloride TIFF2025521070000024.tif131282-Cyclopropyloxyisoindoline-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 hours. 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 extraction was carried out using a mixed chloroform / isopropanol 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 hour and then centrifuged to obtain the title compound (130 mg, yield: 53.5%, white solid).

[0089] Step 4: 6-(Cyclopropylcarboxamido)-N-cyclopropyloxy-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 3) TIFF2025521070000025.tif37128N-Methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added to a reaction flask, and then ((6-(Cyclopropylcarboxamido)-4-((2-(methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (400 mg, 0.825 mmol), O-cyclopropylhydroxylamine hydrochloride (136 mg, 1.238 mmol), and N-methylimidazole (202 mg, 2.475 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (223 mg, 1.650 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (316 mg, 1.650 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 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 (57 mg, yield: 13.6%, white solid). MS(ESI): m / z 509.2[M+H]+. 1H NMR(400 MHz, DMSO-d6)δ12.46(s, 1H), 11.33(s, 1H), 10.56(s, 1H), 8.58(s, 1H), 8.17(s, 1H), 7.68(dd, J = 7.8, 1.5 Hz, 1H), 7.52(dd, J = 8.0, 1.5 Hz, 1H), 7.30 - 7.26(m, 1H), 4.42(t, J = 5.2 Hz, 2H), 4.13 - 4.06(m, 1H), 3.78 - 3.71(m, 5H), 3.26(s, 3H), 2.14 - 2.05(m, 1H), 0.90(brs, 2H), 0.82(d, J = 5.4 Hz, 4H), 0.62 - 0.55(m, 2H).

[0090] Example 4 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 4) TIFF2025521070000026.tif128137

[0091] Step 1: 1-(2-Fluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025521070000027.tif261283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1 g, 4.54 mmol), 1-fluoro-2-iodoethane (1.2 g, 6.81 mmol), and cesium carbonate (4.44 g, 13.62 mmol) were dissolved in N,N-dimethylformamide (10 mL), the reaction solution was stirred, and reacted at room temperature for 2 hours. The reaction was stopped, water (10 mL) was added to the reaction solution to quench it, and then extraction was carried out using ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, then the filtrate was concentrated under reduced pressure, and then separated and purified by column chromatography (silica gel, petroleum ether:methanol = 97:3) to obtain the title compound (1.16 g, yield: 91.37%, yellow solid). MS(ESI): m / z 267.0[M+H]+.

[0092] Step 2: 3-(1-(2-Fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline TIFF2025521070000028.tif261281-(2-Fluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.11 g, 4.17 mmol) was dissolved in tetrahydrofuran (12 mL), methanol (20 mL) and aqueous ammonia (0.6 mL) were added, and then palladium / carbon (177.48 mg, 1.67 mmol) was added in one portion. After replacing with hydrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped. The reaction solution was filtered and concentrated under reduced pressure, and then separated and purified by column chromatography (silica gel, dichloromethane:methanol = 98:2) to obtain the title compound (728 mg, yield: 70.75%, white solid). MS(ESI): m / z 237.1[M+H]+.

[0093] Step 3: ((6-Chloro-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc TIFF2025521070000029.tif391283-(1-(2-Fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (300 mg, 1.27 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (303.24 mg, 1.52 mmol), and zinc acetate (279.62 mg, 1.52 mmol) were dissolved in 9 mL of a solvent of water:toluene = 7:1. After replacing with nitrogen, the mixture was reacted at 65 °C for 16 hours. The reaction was stopped, 12 mL of water was added to the reaction solution, the mixture was stirred for 1 hour, then filtered by suction and washed with tetrahydrofuran (0.5 mL). The filter cake was dried to obtain the title compound (360 mg, yield: 66.8%, white solid). MS(ESI): m / z 393.0[M+H]+.

[0094] Step 4: ((6-(Cyclopropylcarboxamido)-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000030.tif42128 ((6-Chloro-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (360 mg, 0.848 mmol), cyclopropylcarboxamide (216.53 mg, 2.544 mmol), (2R-1-[(1R)-1-[Bis(1,1-di-tert-butyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (94.07 mg, 0.17 mmol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (129.12 mg, 0.848 mmol), potassium carbonate (351.66 mg, 2.544 mmol), and palladium acetate (38.08 mg, 0.17 mmol) were dissolved in 6 mL of a solvent of toluene:acetonitrile = 2:1. After replacing with nitrogen, the mixture was reacted at 75 °C for 16 hours. The reaction was stopped, 12 mL of a solution of water:acetic acid = 2:1 was added to the reaction solution, and it was washed with petroleum ether (20 mL). The aqueous phase was extracted with dichloromethane (20 mL × 3), the combined dichloromethane organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent to obtain the title compound (382 mg, yield: 95.2%, brown solid). MS(ESI): m / z 442.2 [M+H]+.

[0095] Step 5: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 4) TIFF2025521070000031.tif40128N-methylpyrrolidone (11.4 mL) and acetonitrile (11.4 mL) were added to a reaction flask, and bis((6-(cyclopropanecarboxamido)-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (380 mg, 0.803 mmol), O-ethylhydroxylamine hydrochloride (117.52 mg, 1.205 mmol), and N-methylimidazole (197.83 mg, 2.41 mmol) were added. After replacement with nitrogen, the mixture was reacted in an oil bath at 65 °C for 15 minutes, and finally, 1-hydroxybenzotriazole (217.06 mg, 1.61 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (307.95 mg, 1.61 mmol) were added. After replacement with nitrogen, the mixture then continued to react in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (20 mL) was added to the reaction solution to quench it. Then, extraction was carried out using ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and rotated 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 (29.6 mg, yield: 7.6%, white solid). MS (ESI): m / z 485.2 [M+H]+. 1H NMR (400 MHz, DMSO) δ 12.22 (s, 1H), 11.33 (s, 1H), 10.57 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 4.91 (t, J = 4.6 Hz, 1H), 4.79 (t, J = 4.6 Hz, 1H), 4.64 (t, J = 4.6 Hz, 1H), 4.57 (t, J = 4.6 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 3.73 (s, 3H), 2.15 - 2.01 (m, 1H), 1.23 (t, J = 7.0 Hz, 3H), 0.82 (d, J = 5.4 Hz, 4H).

[0096] Example 5 6-(Cyclopropylcarboxamido)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 5) TIFF2025521070000032.tif72155

[0097] Step 1: 1-(2,2-Difluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole TIFF2025521070000033.tif261283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (900 mg, 4.087 mmol) was dissolved in N,N-dimethylformamide (8 mL), cesium carbonate (3.995 g, 12.261 mmol) was added, and then 1,1-difluoro-2-iodoethane (1.177 g, 6.131 mmol) was added at 0 °C. After replacing with nitrogen, the mixture was reacted at 65 °C for 5 hours. The reaction was stopped, the reaction solution was filtered, then water (20 mL) was added thereto, and extraction was subsequently performed using ethyl acetate (10 mL × 3). The organic phases were combined, then washed using saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and then the filtrate was centrifuged to obtain the title compound (1.05 g, yield: 90.3%, pale yellow oil). MS(ESI): m / z 285.2 [M+H]+.

[0098] Step 2: 3-(1-(2,2-Difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline TIFF2025521070000034.tif301281-(2,2-Difluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (950 mg, 3.339 mmol) was dissolved in MeOH (20 mL), and palladium / carbon (146 mg, 1.336 mmol) was added. After replacing with hydrogen, the mixture was reacted at room temperature for 2 hours. The reaction was stopped, the reaction solution was filtered, and then centrifuged. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (910 mg, yield: 83.6%, pale yellow oil). MS (ESI): m / z 255.0 [M+H]+.

[0099] Step 3: ((6-Chloro-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000035.tif401283-(1-(2,2-Difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (830 mg, 3.264 mmol) was dissolved in water (21 mL) and isopropanol (3 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (779 mg, 3.917 mmol) and zinc acetate (719 mg, 3.917 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 (25 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 (5 mL×2) and tetrahydrofuran (1 mL) and dried to obtain the title compound (940 mg, yield: 65.1%, white solid). MS (ESI): m / z 411.0 [M+H]+.

[0100] Step 4: ((6-(Cyclopropylcarboxamido)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000036.tif42128 ((6-Chloro-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (420 mg, 0.949 mmol) was dissolved in toluene (4 mL) and acetonitrile (2 mL), then cyclopropylcarboxamide (202 mg, 2.373 mmol), potassium carbonate (262 mg, 1.898 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (144 mg, 0.949 mmol), (R-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (105 mg, 0.190 mmol), and palladium acetate (43 mg, 0.190 mmol) were added. After replacement with nitrogen, the mixture was reacted at 75 °C for 16 h. The reaction was stopped, water (15 mL) and acetic acid (7.5 mL) were added to the reaction solution, which was washed with petroleum ether (30 mL × 2), and then the aqueous phase was extracted with dichloromethane (10 mL × 3). The dichloromethane extracts were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and centrifuged to obtain the crude title compound (520 mg, brown oil), which was used directly in the next step. MS(ESI): m / z 460.0 [M+H]+.

[0101] Step 5: 6-(Cyclopropylcarboxamido)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 5) TIFF2025521070000037.tif 41128 N-methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added to a reaction flask, and then ((6-(cyclopropylcarboxamido)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5) (470 mg, 0.957 mmol), O-ethylhydroxylamine hydrochloride (140 mg, 1.436 mmol), and N-methylimidazole (235 mg, 2.871 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (259 mg, 1.914 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (367 mg, 1.914 mmol) were added. The reaction solution was stirred and reacted in an oil bath at 65 °C for 5 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: trifluoroacetic acid, water, and acetonitrile) to obtain the title compound (13.54 mg, yield: 2.8%, white solid). MS(ESI): m / z 503.0 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 12.27 (s, 1H), 11.33 (s, 1H), 10.57 (s, 1H), 8.69 (s, 1H), 8.16 (s, 1H), 7.68 (dd, J = 7.8, 1.3 Hz, 1H), 7.54 (d, J = 6.7 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 6.64 - 6.32 (m, 1H), 4.83 (td, J = 15.2, 3.4 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.72 (s, 3H), 2.12 - 2.04 (m, 1H), 1.23 (t, J = 7.0 Hz, 3H), 0.82 (d, J = 4.6 Hz, 4H).

[0102] Example 6 6-(Cyclopropylcarboxamido)-N-cyclopropyloxy-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 6) TIFF2025521070000038.tif45128N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, and ((6-(cyclopropylcarboxamido)-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (830 mg, 1.754 mmol), O-cyclopropylhydroxylamine hydrochloride (288 mg, 2.631 mmol), and N-methylimidazole (430 mg, 5.262 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, then 1-hydroxybenzotriazole (474 mg, 3.508 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (672 mg, 3.508 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 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 (82.74 mg, yield: 63.3%, gray solid). MS(ESI): m / z 497.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 11.32 (s, 1H), 10.55 (s, 1H), 8.65 (s, 1H), 8.16 (s, 1H), 7.68 (dd, J = 7.8, 1.4 Hz, 1H), 7.52 (dd, J = 7.9, 1.3 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 4.90 (t, J = 4.6 Hz, 1H), 4.78 (t, J = 4.6 Hz, 1H), 4.63 (t, J = 4.6 Hz, 1H), 4.56 (t, J = 4.6 Hz, 1H), 4.09 (brs, 1H), 3.72 (s, 3H), 2.10 - 2.05 (m, 1H), 0.89 (brs, 2H), 0.81 (d, J = 5.3 Hz, 4H), 0.61 - 0.54 (m, 2H).

[0103] Example 7 2-(3-(3-((6-(Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)acetic acid (Compound 7) TIFF2025521070000039.tif142151

[0104] Step 1: tert-Butyl 2-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)acetate TIFF2025521070000040.tif291283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (550 mg, 2.50 mmol), tert-butyl 2-bromoacetate (730.8 mg, 3.75 mmol), and cesium carbonate (1.63 g, 5.00 mmol) were dissolved in N,N-dimethylformamide (5.5 mL). The reaction solution was stirred and reacted at 50 °C for 1 hour. The reaction was stopped, and water (5 mL) was added to the reaction solution for quenching. Then, extraction was carried out using ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure and then separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 4:1) to obtain the title compound (554 mg, yield: 66.34%, white solid). MS(ESI): m / z 335.0 [M+H]+.

[0105] Step 2: tert-Butyl 2-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)acetate TIFF2025521070000041.tif301282-(3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)acetic acid tert-butyl (554 mg, 1.66 mmol) was dissolved in methanol (20 mL), ammonium hydroxide (0.3 mL) was added, and then palladium / carbon (70.54 mg, 0.66 mmol) was added in one portion. After replacing with hydrogen, the mixture was reacted at room temperature for 16 h. The reaction was stopped, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 3:7) to obtain the title compound (300 mg, yield: 59.49%, yellow solid). MS(ESI): m / z 305.1[M+H]+.

[0106] Step 3: ((4-((3-(1-(2-(tert-Butyloxy)-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazin-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000042.tif401282-(3-(3-Amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)acetic acid tert-butyl (200 mg, 0.657 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (156.93 mg, 0.789 mmol), and zinc acetate (144.7 mg, 0.789 mmol) were dissolved in 6 mL of a solvent of water:acetonitrile = 7:1. After replacing with nitrogen, the mixture was reacted in an oil bath at 65 °C for 16 h. The reaction was stopped, 8 mL of water was added to the reaction solution, the mixture was stirred for 1 h, then filtered by suction, and washed with tetrahydrofuran (0.5 mL). The filter cake was dried to obtain the title compound (185 mg, yield: 57.4%, white solid). MS(ESI): m / z 461.1[M+H]+.

[0107] Step 4: ((4 - ((3 - (1 - (2 - (tert - butoxy) - 2 - oxoethyl) - 1H - 1,2,4 - triazol - 3 - yl) - 2 - methoxyphenyl)amino) - 6 - (cyclopropanecarboxamido)pyridazine - 3 - carbonyl)oxy)zinc(0.5) TIFF2025521070000043.tif42128((4 - ((3 - (1 - (2 - (tert - butyloxy) - 2 - oxoethyl) - 1H - 1,2,4 - triazol - 3 - yl) - 2 - methoxyphenyl)amino) - 6 - chloropyridazine - 3 - carbonyl)oxy)zinc(0.5) (140 mg, 0.285 mmol), cyclopropylcarboxamide (72.86 mg, 0.856 mmol), (2R) - 1 - [(1R) - 1 - [bis(1,1 - di - tert - butyl)phosphino]ethyl] - 2 - (dicyclohexylphosphino)ferrocene (31.65 mg, 0.0571 mmol), 1,8 - diazabicyclo[5.4.0]undec - 7 - ene (43.45 mg, 0.285 mmol), potassium carbonate (118.33 mg, 0.856 mmol), and palladium acetate (12.81 mg, 0.0571 mmol) were dissolved in 2 mL of a solvent of toluene:acetonitrile = 2:1. After purging with nitrogen, the mixture was reacted at 75 °C for 16 h. The reaction was stopped, 4.5 mL of a solution of water:acetic acid = 2:1 was added to the reaction solution, washed with petroleum ether (8 mL), and then extracted with dichloromethane (16 mL × 3). The combined dichloromethane organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent to obtain the title compound (104 mg, yield: 67.3%, brown oil). MS(ESI): m / z 510.1 [M + H]+.

[0108] Step 5: 2 - (3 - (3 - ((6 - (cyclopropanecarboxamido) - 3 - (ethoxycarbonyl)pyridazin - 4 - yl)amino) - 2 - methoxyphenyl) - 1H - 1,2,4 - triazole - 1 - acetic acid tert - butyl TIFF2025521070000044.tif43128N-Methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added to a reaction flask, and ((4-((3-(1-(2-(tert-Butyloxy)-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-carbonyl)oxy)zinc(0.5) (84 mg, 0.155 mmol), O-ethylhydroxylamine hydrochloride (22.91 mg, 0.233 mmol), and N-methylimidazole (38.23 mg, 0.466 mmol) were added. After purging with nitrogen, the mixture was reacted in an oil bath at 65 °C for 15 minutes. Finally, 1-hydroxybenzotriazole (41.94 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59.51 mg, 0.31 mmol) were added, and after purging with nitrogen, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was extracted with ethyl acetate (8 mL × 3). The combined dichloromethane organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was dried in vacuo to remove the solvent, obtaining the title compound (305 mg, purity: 73.73%, brown oil). MS(ESI): m / z 553.1[M+H]+.

[0109] Step 6: 2-(3-(3-((6-(Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)acetic acid (Compound 7) TIFF2025521070000045.tif 401282 - (3 - (3 - ((6 - (Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin - 4 - yl)amino)-2 - methoxyphenyl)-1H - 1,2,4 - triazole - 1 - acetic acid tert - butyl (300 mg) was dissolved in 10 mL of a solvent of trifluoroacetic acid:1,2 - dichloroethane = 1:1 and reacted at room temperature for 5 hours. The reaction was stopped, and the reaction solution was rotated 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 (5 mg, yield: 1.8%, white solid). MS(ESI): m / z 497.1[M + H]+. 1H NMR(400 MHz, DMSO - d6)δ11.32(s, 1H), 10.55(s, 1H), 8.49(s, 1H), 8.16(s, 1H), 7.67(d, J = 7.7 Hz, 1H), 7.49(d, J = 7.6 Hz, 1H), 7.26(t, J = 7.9 Hz, 1H), 4.71(s, 2H), 3.99(q, J = 7.0 Hz, 2H), 3.71(s, 3H), 2.14 - 2.01(m, 1H), 1.23(t, J = 7.0 Hz, 3H), 0.82(d, J = 5.5 Hz, 4H).

[0110] Example 8 3-(3-(3-((6-(Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin - 4 - yl)amino)-2 - methoxyphenyl)-1H - 1,2,4 - triazol - 1 - yl)propanoic acid (Compound 8) TIFF2025521070000046.tif 83159

[0111] Step 1: tert - Butyl 3-(3-(2 - methoxy - 3 - nitrophenyl)-1H - 1,2,4 - triazol - 1 - yl)propanoate TIFF2025521070000047.tif371283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (400 mg, 1.818 mmol) was dissolved in ultra-dry N,N-dimethylformamide (5 mL), and cesium carbonate (1.78 g, 5.454 mmol) was added. After replacing with nitrogen, tert-butyl 3-bromopropionate (570 mg, 2.727 mmol) was slowly added dropwise in an ice bath at 0 °C, and then the reaction was carried out at 50 °C for 16 h. The reaction was stopped and the reaction solution was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3), the combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the title compound (490 mg, yield: 77.5%, pale yellow oil). MS(ESI): m / z 349.0[M+H]+.

[0112] Step 2: tert-Butyl 3-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propanoate TIFF2025521070000048.tif341283-(3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)propanoic acid tert-butyl (490 mg, 1.408 mmol) was dissolved in methanol (20 mL), and palladium / carbon catalyst (37 mg, 0.352 mmol) was added. After replacing with hydrogen three times, the mixture was reacted at room temperature for 2 h. The reaction was stopped and filtration was carried out to remove palladium / carbon. The filtrate was rotated in vacuo to remove the solvent to obtain the crude product, and the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound (420 mg, yield: 93.8%, pale yellow oil). MS(ESI): m / z 319.4[M+H]+.

[0113] Step 3: ((4-((3-(1-(3-(tert-Butyloxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000049.tif431283-(3-(3-Amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propanoic acid tert-butyl (420 mg, 1.321 mmol) was dissolved in water (7 mL) and isopropanol (1 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (304 mg, 1.585 mmol) and zinc acetate (291 mg, 1.585 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 (320 mg, yield: 47.9%, brown solid). MS(ESI): m / z 475.1 [M+H]+.

[0114] Step 4: ((4-((3-(1-(3-(tert-Butyloxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000050.tif46128((4-((3-(1-(3-(tert-Butoxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc(0.5)(320 mg, 0.632 mmol) was dissolved in toluene (4 mL) and acetonitrile (2 mL), and cyclopropylcarboxamide (134 mg, 1.580 mmol), (R)-(-)-1-[(S-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (70 mg, 0.126 mmol), 1,8-diazabicycloundec-7-ene (96 mg, 0.632 mmol), cesium carbonate (174 mg, 1.264 mmol), and palladium acetate (28 mg, 0.126 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 and the reaction solution was cooled to room temperature. Water (8 mL) and acetic acid (4 mL) were added, and the mixture was washed with petroleum ether (15 mL × 2). The aqueous phase was extracted with dichloromethane (20 mL × 3), and the combined dichloromethane organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent to obtain the title compound (275 mg, yield: 78.4%, brown solid). MS(ESI): m / z 524.2[M+H]+.

[0115] Step 5: tert-Butyl 3-(3-(6-(cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propanoate TIFF2025521070000051.tif46128N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added to a reaction flask, and ((4-((3-(1-(3-(tert-butyloxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc(0.5) (275 mg, 0.495 mmol), O-ethylhydroxylamine hydrochloride (72 mg, 0.743 mmol), and N-methylimidazole (121 mg, 1.485 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, then 1-hydroxybenzotriazole (134 mg, 0.990 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg, 0.990 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 (10 mL × 3), the combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent to obtain the title compound (300 mg, yield: 8.02%, yellow solid). MS(ESI): m / z 567.1[M+H]+.

[0116] Step 6: 3-(3-(3-((6-(cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propanoic acid (Compound 8) tert-Butyl (3-(3-((6-(Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propanoate (300 mg, 0.531 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped and the reaction solution was centrifuged. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, water, and acetonitrile) to obtain the title compound (37.98 mg, yield: 14.0%, pale yellow solid). MS (ESI): m / z 511.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 11.32 (s, 1H), 10.57 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 4.45 (t, J = 6.5 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.71 (s, 3H), 2.89 (t, J = 6.5 Hz, 2H), 2.12 - 2.04 (m, 1H), 1.23 (t, J = 7.0 Hz, 3H), 0.82 (d, J = 5.5 Hz, 4H).

[0117] Example 9 4-(3-(3-((6-(Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butanoic acid (Compound 9) TIFF2025521070000053.tif70160

[0118] Step 1: tert-Butyl 4-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)butanoate TIFF2025521070000054.tif311283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole 1 (500 mg, 2.27 mmol) was dissolved in N,N-dimethylformamide (10 mL), and tert-butyl 4-bromobutyrate (760 mg, 3.41 mmol) and cesium carbonate (1.48 g, 4.54 mmol) were added. After replacing with nitrogen three times, the reaction solution was stirred in an oil bath at 50 °C for 2 hours. The reaction was stopped, and the reaction solution was poured into water (40 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (720 mg, yield: 87.4%, yellow oil). MS (ESI): m / z 363.1 [M+H]+.

[0119] Step 2: tert-Butyl 4-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butanoate TIFF2025521070000055.tif311284-Tert-butyl 4-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)butanoate (720 mg, 1.987 mmol) was dissolved in methanol (12 mL), and palladium / carbon catalyst (72 mg) was added. After replacing with hydrogen three times, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, filtration was carried out to remove palladium / carbon by suction, and the filtrate was rotated in vacuo to remove the solvent to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (500 mg, yield: 75.8%, colorless and transparent oil). MS (ESI): m / z 333.2 [M+H]+.

[0120] Step 3: ((4 - ((3 - (1 - (4 - (tert - butyloxy) - 4 - oxobutyl) - 1H - 1,2,4 - triazol - 3 - yl) - 2 - methoxyphenyl)amino) - 6 - chloropyridazine - 3 - carbonyl)oxy)zinc(0.5) TIFF2025521070000056.tif391284 - (3 - (3 - Amino - 2 - methoxyphenyl) - 1H - 1,2,4 - triazol - 1 - yl)butanoic acid tert - butyl (500 mg, 1.504 mmol) was dissolved in isopropanol (3 mL) and water (21 mL), and lithium 4,6 - dichloropyridazine - 3 - carboxylate (357.4 mg, 1.805 mmol) and zinc acetate (331.2 mg, 1.805 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 (10 mL × 2) and tetrahydrofuran (2 mL) and dried to obtain the title compound (620 mg, yield: 79.2%, white solid). MS(ESI): m / z 489.1 [M + H]+.

[0121] Step 4: ((4 - ((3 - (1 - (4 - (tert - butyloxy) - 4 - oxobutyl) - 1H - 1,2,4 - triazol - 3 - yl) - 2 - methoxyphenyl)amino) - 6 - (cyclopropylcarboxamido)pyridazine - 3 - carbonyl)oxy)zinc(0.5) TIFF2025521070000057.tif46128((4-((3-(1-(4-(tert-Butyloxy)-4-oxobutyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc(0.5)(620 mg, 1.191 mmol) was dissolved in toluene (6 mL) and acetonitrile (3 mL), and cyclopropylcarboxamide (253.4 mg, 2.978 mmol), (R)-(-)-1-[(S-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (132.1 mg, 0.238 mmol), 1,8-diazabicycloundec-7-ene (181.3 mg, 1.191 mmol), potassium carbonate (329.2 mg, 2.382 mmol), and palladium acetate (53.5 mg, 0.238 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, the reaction solution was cooled to room temperature, and water (20 mL) and acetic acid (10 mL) were added. The mixture was washed with petroleum ether (30 mL × 3), the aqueous phase was extracted with dichloromethane (40 mL × 3), the combined dichloromethane organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated in vacuo to remove the solvent to obtain the title compound (650 mg, yield: 95.9%, brown solid). MS(ESI): m / z 538.1[M+H]+.

[0122] Step 5: 4-(3-((6-(Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butanoic acid tert-butyl TIFF2025521070000058.tif44128N-methylpyrrolidone (6 mL) and acetonitrile (6 mL) were added to a reaction flask, and ((4-((3-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc (0.5) (650 mg, 1.142 mmol), O-ethylhydroxylamine hydrochloride (334.2 mg, 3.426 mmol), and N-methylimidazole (281.3 mg, 3.426 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, then 1-hydroxybenzotriazole (308.6 mg, 2.284 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (437.8 mg, 2.284 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 (40 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated brine (40 mL × 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was rotated in vacuo to remove the solvent, and the crude title compound (1 g, yellow oil) was obtained and used directly in the next step. MS (ESI): m / z 581.1 [M+H]+.

[0123] Step 6: 4-(3-(3-((6-(Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butanoic acid (Compound 9) TIFF2025521070000059.tif401284 - (3 - ((6 - (Cyclopropylcarboxamido)-3-(ethoxycarbonyl)pyridazin - 4 - yl)amino)-2 - methoxyphenyl)-1H - 1,2,4 - triazol - 1 - yl)butanoic acid tert - butyl (1 g, 1.722 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. After replacing with nitrogen three times, the mixture was reacted at room temperature for 8 hours. The reaction was stopped, and the reaction solution was rotated 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), obtaining the title compound (85.41 mg, yield: 9.46%, yellow solid). MS(ESI): m / z 525.0[M + H]+. 1H NMR(400 MHz, DMSO - d6)δ12.25(s, 1H), 11.31(s, 1H), 10.56(s, 1H), 8.61(s, 1H), 8.16(s, 1H), 7.68(dd, J = 7.7, 1.0 Hz, 1H), 7.51(d, J = 8.0 Hz, 1H), 7.28(t, J = 7.9 Hz, 1H), 4.28(t, J = 6.8 Hz, 2H), 4.02 - 3.97(m, 2H), 3.72(s, 3H), 2.29(t, J = 7.3 Hz, 2H), 2.10 - 2.04(m, 3H), 1.23(t, J = 7.0 Hz, 3H), 0.82(d, J = 6.0 Hz, 4H).

[0124] Example 10 6 - (Cyclopropylcarboxamido)-N - ethoxy - 4 - ((3-(1-(2 - hydroxyethyl)-1H - 1,2,4 - triazol - 3 - yl)-2 - methoxyphenyl)amino)pyridazine - 3 - carboxamide (Compound 10) TIFF2025521070000060.tif66149

[0125] Step 1: 1-(2 - (Benzyloxy)ethyl)-3-(2 - methoxy - 3 - nitrophenyl)-1H - 1,2,4 - triazole TIFF2025521070000061.tif 291283-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1000 mg, 4.542 mmol) was dissolved in ultra-dry N,N-dimethylformamide (10 mL), and cesium carbonate (4440 mg, 13.626 mmol) and ((2-bromoethoxy)methyl)benzene (1465 mg, 6.813 mmol) were added. The mixture was reacted at 50 °C for 1 hour. The reaction was stopped, the reaction solution was filtered, and then poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3), the combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent to obtain the 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 (1.5 g, yield: 93.3%, pale yellow oil). MS(ESI): m / z 355.5[M+H]+.

[0126] Step 2: 3-(1-(2-(Benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline TIFF2025521070000062.tif 271281-(2-(Benzyloxy)ethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.5 g, 4.233 mmol) was dissolved in isopropanol (10 mL) and water (0.8 mL), and iron powder (233 mg, 21.165 mmol) and ammonium chloride (1132 mg, 21.165) were added. After replacing with nitrogen three times, the mixture was reacted at 70 °C for 1 hour. The reaction was stopped, the reaction solution was filtered, and then centrifuged. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:5) to obtain the title compound (1.32 g, yield: 96.1%, colorless oil). MS(ESI): m / z 325.0[M+H]+.

[0127] Step 3: ((4 - ((3 - (1 - (2 - (Benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000063.tif361283-(1-(2-(Benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (1.2 g, 3.699 mmol) was dissolved in water (35 mL) and isopropanol (5 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (879 mg, 4.439 mmol) and zinc acetate (815 mg, 4.439 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 (40 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 (1 mL) and dried to obtain the title compound (1.2 g, yield: 63.3%, gray solid). MS(ESI): m / z 481.1 [M+H]+.

[0128] Step 4: ((4 - ((3 - (1 - (2 - (Benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc(0.5) TIFF2025521070000064.tif39128((4 - ((3 - (1 - (2 - (benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc(0.5)(1.2 g, 2.138 mmol) was dissolved in toluene (24 mL) and acetonitrile (12 mL), and cyclopropylcarboxamide (454 mg, 5.345 mmol), (R-(-)-1-[(S-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (237 mg, 0.428 mmol), 1,8-diazabicycloundec-7-ene (325 mg, 2.138 mmol), potassium carbonate (590 mg, 4.276 mmol), and palladium acetate (96 mg, 0.428 mmol) were added. After purging 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 (30 mL) and acetic acid (15 mL) were added, and the mixture was washed with petroleum ether (50 mL × 2). The aqueous phase was extracted with dichloromethane (10 mL × 3), and the combined dichloromethane organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent to give the title compound (1.8 g, brown oil), which was used directly in the next step reaction. MS(ESI): m / z 530.0[M+H]+.

[0129] Step 5: 4 - ((3 - (1 - (2 - (benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)-N-ethoxypyridazine-3-carboxamide Take a 4212825 mL reaction flask, add N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) thereto, and then add ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc(0.5) (400 mg, 0.713 mmol), O-ethylhydroxylamine hydrochloride (104 mg, 1.070 mmol), and N-methylimidazole (175 mg, 2.139 mmol). Stir the reaction solution in an oil bath at 65 °C for 15 minutes, then add 1-hydroxybenzotriazole (193 mg, 1.426 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (273 mg, 1.426 mmol). Stir the reaction solution in an oil bath at 65 °C for 16 hours. Stop the reaction, add water (20 mL) to the reaction solution, and then perform extraction using ethyl acetate (10 mL × 3). Combine the organic phases, then wash with saturated brine (10 mL × 3), dry over anhydrous sodium sulfate, filter, and then centrifuge the filtrate to obtain the title compound (510 mg, brown oil), which was used directly in the reaction in the next step. MS(ESI): m / z 573.1[M+H]+.

[0130] Step 6: 6-(Cyclopropylcarboxamido)-N-ethoxy-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 10) TIFF2025521070000066.tif411284 - ((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-ethoxypyridazine-3-carboxamide (510 mg, 0.891 mmol) was dissolved in methanol (20 mL), and palladium carbon (38 mg, 0.356 mmol) was added. After replacing with hydrogen, the mixture was reacted at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, and then centrifuged. The crude product was separated and purified by high performance liquid chromatography (elution system: formic acid, acetonitrile, and water) to obtain the title compound (20.4 mg, yield: 4.7%, white solid). MS(ESI): m / z 483.0 [M + H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.10 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 5.00 (s, 1H), 4.26 (d, J = 4.9 Hz, 2H), 3.94 (d, J = 6.4 Hz, 2H), 3.78 (brs, 2H), 3.72 (s, 3H), 2.05 (brs, 1H), 1.20 (t, J = 6.7 Hz, 3H), 0.80 (d, J = 5.7 Hz, 4H).

[0131] Example 11 6-(Cyclopropylcarboxamido)-N-(2-fluoroethoxy)-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 11) TIFF2025521070000067.tif34146

[0132] Step 1: 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)-N-(2-fluoroethoxy)pyridazine-3-carboxamide TIFF2025521070000068.tif39128N-methylpyrrolidone (9 mL) and acetonitrile (9 mL) were stirred at room temperature for 10 minutes, and ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc(0.5) (300 mg, 0.64 mmol), O-(2-fluoroethyl)hydroxylamine hydrochloride (110.91 mg, 0.96 mmol), and N-methylimidazole (158.45 mg, 1.93 mmol) were added. After replacement with nitrogen, the mixture was reacted in an oil bath at 65 °C for 15 minutes, and finally, 1-hydroxybenzotriazole (172.95 mg, 1.28 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (245.38 mg, 1.28 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, and water (20 mL) was added to the reaction solution to quench it, and then extraction was carried out using ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was rotated in vacuo to remove the solvent, and the title compound (300 mg, yield: 95.1%, brown solid) was obtained. MS(ESI): m / z 591.3[M+H]+.

[0133] Step 2: 6-(Cyclopropylcarboxamido)-N-(2-fluoroethoxy)-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 11) TIFF2025521070000069.tif381284 - ((3 - (1 - (2 - (benzyloxy)ethyl)-1H - 1,2,4 - triazol - 3 - yl)-2 - methoxyphenyl)amino)-6 - (cyclopropylcarboxamido)-N-(2 - fluoroethoxy)pyridazine - 3 - carboxamide (158 mg, 0.268 mmol) was dissolved in acetonitrile (3 mL), and then trimethylsilyl iodide (267.64 mg, 1.338 mmol) was added. The mixture was reacted at room temperature for 4 hours. The reaction was stopped and the solvent was removed by rotary evaporation in vacuo to obtain the crude product. The crude product was separated and purified by reverse - phase preparative chromatography (elution system: formic acid, acetonitrile, and water) to obtain the title compound (27.91 mg, yield: 20.85%, white solid). MS(ESI): m / z 501.1[M + H]+. 1H NMR(400 MHz, DMSO - d6)δ12.46(s, 1H), 11.34(s, 1H), 10.51(s, 1H), 8.56(s, 1H), 8.15(s, 1H), 7.70(dd, J = 7.8, 1.3 Hz, 1H), 7.51(d, J = 6.7 Hz, 1H), 7.28(t, J = 7.9 Hz, 1H), 4.77 - 4.73(m, 1H), 4.65 - 4.59(m, 1H), 4.29(t, J = 5.3 Hz, 2H), 4.26 - 4.23(m, 1H), 4.19 - 4.14(m, 1H), 3.80(t, J = 5.4 Hz, 2H), 3.73(s, 3H), 2.12 - 2.05(m, 1H), 0.85 - 0.80(m, 4H).

[0134] Example 12 6 - (cyclopropylcarboxamido)-N-(2,2 - difluoroethoxy)-4 - ((3 - (1 - (2 - hydroxyethyl)-1H - 1,2,4 - triazol - 3 - yl)-2 - methoxyphenyl)amino)pyridazine - 3 - carboxamide (Compound 12) TIFF2025521070000070.tif37156

[0135] Step 1: 4-((3-(1-(2-(Benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(2,2-difluoroethoxy)pyridazine-3-carboxamide TIFF2025521070000071.tif37128N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added to a reaction flask, and then ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 0.713 mmol), O-(2,2-difluoroethyl)hydroxylamine hydrochloride (143 mg, 1.070 mmol), and N-methylimidazole (175 mg, 2.139 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes, and then 1-hydroxybenzotriazole (193 mg, 1.426 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (273 mg, 1.426 mmol) were added. The reaction solution was stirred and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (20 mL) was added to the reaction solution, and then extraction was performed using ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and then the filtrate was centrifuged to obtain the title compound (290 mg, yield: 66.8%, brown oil). MS(ESI): m / z 609.0[M+H]+.

[0136] Step 2: 6-(Cyclopropylcarboxamido)-N-(2,2-difluoroethoxy)-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 12) Take a 3912850 mL reaction flask and dissolve 4 - ((3 - (1 - (2 - (benzyloxy)ethyl)-1H - 1,2,4 - triazol - 3 - yl)-2 - methoxyphenyl)amino)-6 - (cyclopropylcarboxamido)-N-(2,2 - difluoroethoxy)pyridazine - 3 - carboxamide (260 mg, 0.427 mmol) in methanol (20 mL), then add palladium / carbon (18 mg, 0.171 mmol). After replacing with hydrogen, stir the reaction solution and react at room temperature for 40 hours. Stop the reaction, filter the reaction solution, and then centrifuge to dehydrate. Separate and purify the crude product by high - performance liquid chromatography (elution system: formic acid, acetonitrile, and water) to obtain the title compound (7.65 mg, yield: 3.5%, white solid). MS(ESI): m / z 519.1[M + H]+. 1H NMR(400 MHz, DMSO - d6)δ11.31(s, 1H), 10.48(s, 1H), 8.54(s, 1H), 8.13(s, 1H), 7.68(d, J = 7.5 Hz, 1H), 7.50(d, J = 8.0 Hz, 1H), 7.27(t, J = 7.9 Hz, 1H), 6.34(t, J = 54.5 Hz, 1H), 5.00(s, 1H), 4.29 - 4.21(m, 4H), 3.82 - 3.70(m, 5H), 2.13 - 2.01(m, 1H), 0.81(d, J = 5.2 Hz, 4H).

[0137] Biological test evaluation Test Example A: In vitro TYK2 JH2 enzyme - binding assay of the compounds of the present invention Objective: The objective of this test example was to test the binding effect of the compounds on TYK2 JH2 pseudokinase using the time - resolved fluorescence resonance energy transfer (TR - FRET) method and then evaluate the affinity of the compounds for TYK2 JH2.

[0138] Experimental method: Using DMSO-dissolved compounds, a 10 mM stock solution was prepared. Subsequently, 200X compounds with different gradient concentrations were prepared in a compound dilution plate and transferred to an Echo plate. Using an Echo instrument, 75 nL of the compound was transferred from the Echo plate to a 384-well assay plate, and 5 μL of 3X TYK2 JH2 pseudokinase (Bioduro), 5 μL of 3X Tb antibody (Cisbio), and 5 μL of 3X TRACER (Bioduro) were added to the 384-well assay plate. The mixture was 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.

[0139] Experimental results: TIFF2025521070000073.tif51128

[0140] It can be seen from the experimental data that the compounds of the present invention had a good binding effect on TYK2 JH2 pseudokinase.

[0141] Test Example B: Determination of the effect of the compounds 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 case was to test the inhibitory effect of the compound on IL-2-induced STAT5 phosphorylation using protein phosphorylation flow cytometry analysis technology.

[0142] Experimental method: Human PBMCs 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. The PBMCs were resuspended and dispensed into 96-well plates at 62.5 μL / well. 3.5 μL of a 20X compound dilution 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 dilution 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 dilution standard solution (BD) was added, and incubated at room temperature for 40 minutes. After washing once with PBS, the cells 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.

[0143] Experimental results: TIFF2025521070000074.tif21130

[0144] From the results of the experimental data, 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.

[0145] Test Example C: Determination of JAK1 JH1 / JAK2 JH1 / JAK3 JH1 / TYK2 JH1 kinase inhibition by the compound of the present invention Objective: The objective of this test example was to examine the inhibitory effect of a compound on the kinase activities of JAK1 JH1 / JAK2 JH1 / JAK3 JH1 / TYK2 JH1 using the homogeneous time-resolved fluorescence resonance energy transfer (HTRF) technology.

[0146] Experimental method: Using an automatic micropipette system, a 100 nL / well compound dilution standard solution was transferred to a 384-well assay plate, and 5 μL / well of 2X JAK1 JH1 / JAK2 JH1 / JAK3 JH1 / TYK2 JH1 kinase solution or assay buffer was added, mixed uniformly by centrifugation, and incubated at room temperature (25 °C) for 15 minutes. After the incubation was completed, 5 μL of a mixed solution containing 2X TK-SUB-biotin substrate and ATP was added to each well, mixed uniformly by centrifugation, and incubated at 25 °C for 45 minutes (for JAK1 / JAK2) or 60 minutes (for JAK3 / TYK2). After the incubation was completed, 10 μL of an assay mixture (TK antibody-EU and streptavidin-XL mixture) was added to each well, mixed uniformly by centrifugation, and incubated at 25 °C for 60 minutes (for JAK1 / JAK2) or 120 minutes (for JAK3 / TYK2). After the incubation was completed, the solution was transferred to a 4 °C refrigerator for overnight incubation, the fluorescence value was read with an Envision 2104 Multilabel Reader, and the IC of the compound was calculated using XL-Fit software. 50 was calculated.

[0147] Experimental results: TIFF2025521070000075.tif26140

[0148] From the results of the experimental data, it can be seen that the compound of the present invention had lower inhibitory activity against JAK1 JH1 / JAK2 JH1 / JAK3 JH1 and had better selectivity.

Claims

1. Compounds represented by general formula (I), or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants, and mixtures thereof: During the ceremony, R １ is H, C １～６ haloalkyl, C １～６ alkylene - OR ａ , C １～６ alkylene - SR ａ , C １～６ alkylene - NR ｂ R ｃ , C １～６ alkylene - C(O)R ａ , C １～６ alkylene - C(O)OR ａ , C １～６ alkylene - C(O)NR ｂ R ｃ , C １～６ alkylene - OC(O)R ａ , C １～６ alkylene - NR ｂ C(O)R ａ , C １～６ alkylene - S(O) ｍ R ａ , C １～６ alkylene - S(O) ｍ NR ｂ R ｃ , or C １～６ alkylene - NR ｂ S(O) ｍ R ａ selected from, and the group may be substituted with one or more deuteriums until fully deuterated, R ２ C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～７ Cycloalkyl, 3-7 membered heterocyclyl, C ６～１０ Selected from aryl or 5- to 10-membered heteroaryl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ H, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R １ , R ２ , and R ３ Each of the groups may be substituted with 1, 2, 3, or 4 R groups. R ａ , R ｂ , and R ｃ H and C are independent of each other. １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～７ Cycloalkyl, 3-7 membered heterocyclyl, C ６～１０ Selected from aryls or 5- to 10-membered heteroaryls, m is either 1 or 2. R stands for H, D, halogen, CN, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups.

2. R １ is H, C １～６ haloalkyl, C １～６ alkylene - OR ａ , C １～６ alkylene - SR ａ , C １～６ alkylene - NR ｂ R ｃ , C １～６ alkylene - C(O)R ａ , C １～６ alkylene - C(O)OR ａ , C １～６ alkylene - C(O)NR ｂ R ｃ , C １～６ alkylene - OC(O)R ａ , or C １～６ alkylene - NR ｂ C(O)R ａ selected from, and the group may be substituted with one or more deuteriums until it is fully deuterated; preferably, R １ is H, C １～６ haloalkyl, C １～６ alkylene - OR ａ , C １～６ alkylene - SR ａ , C １～６ alkylene - NR ｂ R ｃ , C １～６ alkylene - C(O)OR ａ , or C １～６ alkylene - C(O)NR ｂ R ｃ selected from, and the group may be substituted with one or more deuteriums until it is fully deuterated; preferably, R １ is H, C １～６ haloalkyl, C １～６ alkylene - OH, C １～６ alkylene - SH, C １～６ alkylene - NH ２ , C １～６ alkylene - C(O)OH, or C １～６ alkylene - C(O)NH ２ selected from, and the group may be substituted with one or more deuteriums until it is fully deuterated; preferably, R １ However, H or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated; and preferably, R １ However, C １～６ Alkylene-OR ａ And R ａ However, C １～６ Alkyl or C １～６ A compound according to claim 1, selected from haloalkyls, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

3. R ２ However, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～７ Selected from cycloalkyl or 3- to 7-membered heterocyclyl, the group may be substituted with one or more deuterium atoms until it is completely deuterated; preferably, R ２ However, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Selected from cycloalkyl or 3- to 7-membered heterocyclyl, the group may be substituted with one or more deuterium atoms until it is completely deuterated; and preferably, R ２ However, C １～６ Alkyl or C ３～７ A compound according to claim 1, selected from cycloalkyl groups, wherein the group may be substituted with one or more deuterium atoms until it is completely deuterated, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

4. R ３ However, C １～６ Alkyl or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated; and preferably, R ３ The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

5. R １ However, H, C １～６ Haloalkyl, C １～６ Alkylene-OR ａ , C １～６ Alkilen-SR ａ , or C １～６ Alkylene-C(O)OR ａ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ However, C １～６ Alkyl, C １～６ Haloalkyl, C ３～７ Selected from cycloalkyl or 3- to 7-membered heterocyclyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ However, H, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R １ , R ２ , and R ３ Each of the groups may be substituted with 1, 2, 3, or 4 R groups. R ａ However, H, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, R stands for H, D, halogen, CN, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

6. R １ However, H, C １～４ Haloalkyl, C １～４ Alkylene-OR ａ , or C １～４ Selected from alkylene-C(O)OH, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ However, C １～４ Alkyl, C １～４ Haloalkyl, or C ３～７ Selected from cycloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ However, C １～４ Alkyl or C １～４ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ａ However, H, C １～４ Alkyl, or C １～４ Selected from haloalkyl groups, The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

7. R １ However, C may be substituted with one or more deuterium atoms until it is completely deuterated. １～４ Alkylene-OR ａ And, R ２ However, C １～４ Alkyl, C １～４ Haloalkyl, or C ３～７ Selected from cycloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated; preferably, C may be substituted with one or more deuterium atoms until it is completely deuterated. １～４ It is alkyl, R ３ However, C １～４ Alkyl or C １～４ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ａ However, C １～４ Alkyl or C １～４ Selected from haloalkyl groups, The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

8. R １ However, H, C １～４ Haloalkyl, C １～４ Alkylene-OH or C １～４ Selected from alkylene-C(O)OH, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ However, C １～４ Alkyl, C １～４ Haloalkyl, or C ３～７ Selected from cycloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated; preferably, C may be substituted with one or more deuterium atoms until it is completely deuterated. １～４ It is alkyl, R ３ However, C １～４ Alkyl or C １～４ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

9. R １ However, H, C １～６ Alkylene-OR ａ and C １～６ Alkilen-SR ａ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ However, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ However, H, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R １ , R ２ , and R ３ Each of the groups may be substituted with 1, 2, 3, or 4 R groups. R ａ However, H, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, R stands for H, D, halogen, CN, C １～６ Alkyl, or C １～６ Selected from haloalkyl groups, The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

10. R １ However, H and C １～６ Alkylene-OR ａ Selected from, the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ２ However, C １～６ Alkyl and C １～６ Selected from haloalkyl groups, R ３ However, C １～６ It is alkyl, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ａ However, H and C １～６ Selected from alkyl groups, The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

11. R １ However, H and C １～４ Alkylene-OR ａ Selected from, the group may be substituted with one or more deuterium groups until it is completely deuterated. R ２ However, C １～４ It is alkyl, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ３ However, C １～４ It is alkyl, and the group may be substituted with one or more deuterium atoms until it is completely deuterated. R ａ However, C １～４ It is alkyl. The compound described in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

12. The aforementioned compound, A compound according to claim 1, selected from, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient, preferably further comprising other therapeutic agents.

14. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, in the preparation of a medicament for the treatment and / or prevention of TYK2 kinase-mediated diseases.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, and mixtures thereof, for treating and / or preventing TYK2 kinase-mediated diseases in a subject.

16. The TYK2 kinase-mediated disease is selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye diseases, myelofibrosis, and polycythemia vera, preferably 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, stomach cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma, or leukemia, according to claim 15.

17. The pharmaceutical composition according to claim 15, wherein the TYK2 kinase-mediated disease is selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

Images