Pyridazin-3-carboxamide compounds as tyk2 inhibitors

Abstract

The present invention provides pyridazine-3-carboxamide compounds of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof. The present invention also provides pharmaceutical compositions comprising said compounds, processes for their preparation and their use in the treatment or prevention of TYK2 kinase-mediated diseases.

Description

Invention Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically to pyridazine-3-carboxamide compounds, compositions containing the same, methods for their preparation, and their use as TYK2 inhibitors. Background Technology

[0002] The Janus kinase family (JAK) is a family of intracellular non-receptor tyrosine kinases that mediate the signaling and activation of various cytokines. Gain-of-function expression or mutation of JAKs is associated with many autoimmune diseases, inflammation, and cancer. This family includes JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, and TYK2 are widely distributed in various tissues and cells of the human body, while JAK3 is mainly found in bone marrow cells, thymocytes, NK cells, and activated B cells and T cells.

[0003] The JAK-mediated signaling pathway comprises three key components: cell surface cytokine receptors, JAK, and downstream proteins. Cytokines such as various interferons (IFNs) and interleukins (ILs) bind to cytokine receptors on the cell surface, bringing JAK, which binds to the receptor's intracellular domain, closer. Then, tyrosine residues of JAK are phosphorylated, increasing the activity of the kinase domain. Subsequently, the activated JAK phosphorylates tyrosine residues of the receptor, creating binding sites for proteins with SH2 domains. STAT (signal transducer and activator of transcription) binds to phosphorylated tyrosine residues on the receptor via its SH2 domain, is phosphorylated by JAK, and produces phosphorylated STAT dimers. These dimers then translocate to the nucleus to induce transcription of target genes. Furthermore, other proteins with SH2 domains can also bind to activated JAK, thereby cross-linking with other signaling pathways, such as PI3K / AKT and MAPK / ERK.

[0004] TYK2 is a non-receptor tyrosine kinase that mediates immune signaling, primarily regulating IL-23, IL-12, and type I interferon (IFNα)-driven signaling pathways. Inhibition of TYK2-mediated signal transduction allows TYK2 to act as a regulator of IL-12, IL-23, and / or IFNα. TYK2 plays a crucial role in transmitting inflammatory and immune response signals, participating 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 factor, and IL-2); therefore, TYK2 inhibitors, by not acting on other subtypes, can avoid the adverse reactions of currently marketed JAK inhibitors.

[0005] Typical small-molecule JAK inhibitors are site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (JH1) of the JAK protein. Due to the high homology of the ATP site of JAK family kinases and the similarity to the ATP-binding region of the human kinase group, they generally suffer from low selectivity.

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

[0007] There is a need for drugs with better activity that selectively inhibit TYK2 by binding to JH2, thereby providing therapeutic benefits in the treatment of the disease. Summary of the Invention

[0008] Based on this, the present invention provides a pyridazine-3-carboxamide compound that has excellent selective inhibition of TYK2 activity and can treat a variety of TYK2-mediated diseases.

[0009] This invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof:

[0010]

[0011] Wherein, each substituent is as defined in this invention.

[0012] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it further comprises other therapeutic agents.

[0013] In one embodiment, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof, and pharmaceutical compositions comprising thereof in the preparation of medicaments for treating and / or preventing TYK2-mediated diseases.

[0014] In one embodiment, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a solvate, a hydrate, a polymorph, a prodrug, or an isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising said compound for the treatment and / or prevention of TYK2 kinase-mediated diseases.

[0015] In one embodiment, the present invention provides a method of treating and / or preventing TYK2 kinase-mediated diseases in a subject with a compound as defined herein, comprising administering the subject the compound or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a solvate, a hydrate, a polymorph, a prodrug, or an isotopic variant thereof, and mixtures thereof, or pharmaceutical compositions comprising thereof.

[0016] The diseases mediated by TYK2 kinase as described in this invention are selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, and polycythemia. Further, the autoimmune diseases include lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease; the skin diseases include psoriasis, rashes, or atopic dermatitis; the allergic diseases include asthma or rhinitis; the organ transplant rejection includes allogeneic suppression rejection or graft-versus-host disease; and the cancers include 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.

[0017] In some implementations, this method relates to diseases mediated by the TYK2 kinase selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease. Detailed Implementation

[0018] definition

[0019] The compounds of the present invention, their preparation methods, and their uses are further described in detail below with reference to specific embodiments. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein means any one or a combination of one or more of the associated listed items.

[0021] The term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Alkyl groups are preferably, for example, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, and C1-C3 alkyl. Taking "C1-C3 alkyl" as an example, it refers to an alkyl group containing 1 to 3 carbon atoms, and each occurrence can be independently 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).

[0022] "Alkenyl" is an alkyl group as defined in this invention that contains at least one carbon-carbon double bond. In one example, the alkenyl group 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 groups 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 groups. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkoxy, hydroxyl, nitro, cyano, and amino groups.

[0023] "Alkynyl" is an alkyl group as defined in this invention that contains at least one carbon-carbon triple bond. In one example, the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkynyl groups 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-octyynyl, 3-nonynyl, or 4-decynyl, etc. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano, and amino.

[0024] "Carbocyclic" or "cycloalkyl" refers to a saturated or partially unsaturated cyclic carbon-containing group, such as a 5-6 member saturated carbocyclic ring and a 5-6 member partially unsaturated carbocyclic ring. In one embodiment, the carbocyclic group is a 3- to 4 member monocyclic ring, a 3- to 5 member monocyclic ring, a 3- to 6 member monocyclic ring, a 3- to 7 member monocyclic ring, a 3- to 8 member monocyclic ring, a 3- to 10 member monocyclic ring, a 5- to 8 member monocyclic ring, a 5- to 6 member monocyclic ring, a 4- to 12 member bicyclic ring, or a 10- to 15 member tricyclic ring system. The carbocyclic ring includes bridged rings or spirocyclic rings. Non-limiting examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cyclohepttrienyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl, or spiro[3.3]heptyl, etc. The carbocyclic group may optionally be substituted. When substituted, the substituents are preferably 1 to 5, and said substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkoxy, hydroxyl, nitro, cyano, and amino.

[0025] The term "halogen" refers to -F, -Cl, -Br, or -I. Further, the term "halogenated alkyl" refers to an alkyl group substituted with a halogen group, wherein the alkyl group, as defined above, is preferably C. 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl and C 1-2 Halogenated alkyl groups.

[0026] The term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom. It can be a monocyclic aryl, a fused-ring aryl, or a polycyclic aryl, preferably a 6-10 membered aryl. For polycyclic rings, at least one is an aromatic ring system. Phrases containing this term, such as "5-6 membered aryl," indicate that the aromatic ring system contains 5-6 ring atoms. Preferably, the aryl group is phenyl.

[0027] The term "heteroaryl" refers to an aryl group containing a heteroatom, which can be monocyclic or fused-ring, wherein the heteroatom is independently selected from N, O, and S, preferably a 5-12 membered heteroaryl, a 5-10 membered heteroaryl, more preferably a 5-8 membered heteroaryl, more preferably a 5-6 membered heteroaryl, and even more preferably a 5 membered heteroaryl. Heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrahydropyrroleyl, and thiadiazolyl. In one embodiment, it typically contains one or more, preferably one to three, 5-6 membered monocyclic heteroaryl groups independently selected from N, O, and S. Unless otherwise stated, “5-membered heteroaryl” refers to an exemplary 5-membered heteroaryl group containing one heteroatom, including but not limited to pyrrole, furanyl, and thiophene; an exemplary 5-membered heteroaryl group containing two heteroatoms, including but not limited to imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; an exemplary 5-membered heteroaryl group containing three heteroatoms, including but not limited to thiazolyl, oxadiazolyl, and thiadiazolyl; and an exemplary 5-membered heteroaryl group containing four heteroatoms, including but not limited to tetrazolyl.

[0028] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing heteroatoms selected from N, O, and S. Further, the term "heterocyclic group" refers to a stable 3-10 member saturated heterocyclic system in which one or more of the constituent atoms of a non-aromatic ring are heteroatoms, with the remainder being carbon. The heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. The heterocyclic group can be a 3- to 7-membered monocyclic, a 5- to 8-membered monocyclic, a 5- to 6-membered monocyclic, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic system, preferably a 3- to 10-membered heterocyclic group, and contains at least one, preferably one to four, heteroatoms selected from N, O, or S. Unless otherwise specifically indicated in this specification, heterocyclic alkyl groups may be monocyclic (“monocyclic heterocyclic alkyl”) or bicyclic, tricyclic, or more cyclic systems, which may include fused (fused), bridged (bridged ring), or spirocyclic systems (e.g., bicyclic systems (“bicyclic heterocyclic alkyl”)). Bicyclic heterocyclic alkyl systems may include one or more heteroatoms in one or both rings and are saturated. Exemplary 3-membered heterocyclic groups include, but are not limited to, azirropropyl, ethylene oxide, and thiocyclopropane, or their stereoisomers; exemplary 4-membered heterocyclic groups include, but are not limited to, azirrobutyl, propylene oxide, thiocyclobutyl, or their isomers and stereoisomers; exemplary 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, and imidazolyl. The heterocyclic group includes, but is not limited to, piperidinyl, tetrahydropyranyl, thiocyclohexyl, morpholinyl, thiomorpholinyl, dithiaalkyl, dioxaneyl, piperazine, triazineyl, or its isomers and stereoisomers. Exemplary 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thiocyclohexyl, morpholinyl, thiomorpholinyl, dithiaalkyl, dioxaneyl, piperazineyl, triazineyl, or their isomers and stereoisomers; exemplary 7-membered heterocyclic groups include, but are not limited to, azirheptanyl, oxacycloheptanyl, thiocycloheptanyl, and diazirheptanyl, or their isomers and stereoisomers. In one embodiment, a typical heterocyclic group is a 5-6 membered monocyclic heterocyclic group containing one or more, preferably 1-4, more preferably 1-3 heteroatoms independently selected from N, O, and S. In one embodiment, "heterocyclic alkyl" is a 4-6 membered heterocyclic alkyl group, wherein the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0029] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively. In some specific structures, when an alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group; for example, the alkyl in the group "-C1-C3 haloalkyl" should be understood as an alkylene group.

[0030] The term "pharmaceutically acceptable salt" refers to a compound that can be converted into a corresponding salt by conventional methods, which is chemically or physically compatible with other components constituting a pharmaceutical dosage form and physiologically compatible with receptors. This salt can be an acidic and / or basic salt formed by the compound with inorganic and / or organic acids and / or inorganic and / or organic bases, including zwitterionic salts (internal salts), and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. Alternatively, they can be obtained by appropriately mixing the compound of the present invention or its stereoisomers or solvates with a suitable amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by reacting in an aqueous medium followed by cooling and drying. Specifically, the salt is preferably a water-soluble, pharmaceutically acceptable, non-toxic acid addition salt, examples of which are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods conventional in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Where appropriate, other pharmaceutically acceptable salts may include salts derived from suitable bases, including alkali metal salts, alkaline earth metal salts, and ammonium salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include salts formed using balancing ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates with non-toxic ammonium, quaternary ammonium, and amine cations.

[0031] The term "solvent" or "solvent compound" refers to a compound containing solvent molecules, which can be bonded to the compound molecules through various mechanisms, including coordinate bonds, covalent bonds, van der Waals forces, ionic bonds, and hydrogen bonds. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, and diethyl ether. 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 can be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0032] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0033] The term "prodrug" refers to any compound that, when administered to an organism, produces a drug, i.e., an active ingredient, through spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. Prodrugs are therefore covalently modified analogs or potential forms of therapeutically active compounds. Suitable examples include, but are not limited to, carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0034] This invention also includes isotopically labeled compounds (isotope variants) that are equivalent to the general formulas or specific compounds described in this application, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、31 P, 32 P, 35 S, 18 F and 36 Cl, preferably 2 H (i.e., deuterium, D). Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Additionally, heavier isotopes such as deuterium (i.e.,...) are preferred. 2 H) substitution is preferred in some cases because its higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements. Isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0035] The compounds of this invention comprise one or more asymmetric centers and therefore can exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures 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; or preferred isomers may be prepared by asymmetric synthesis.

[0036] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, including situations where the event or environment may or may not occur. For example, "aryl group optionally substituted with alkyl group" means that the alkyl group may but does not have to be present, and the term includes cases where the aryl group is substituted with an alkyl group and cases where the aryl group is not substituted with an alkyl group.

[0037] "Pharmaceutically acceptable excipients" refers to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. As used herein, the term "pharmaceuticalally acceptable excipients" includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each excipient must be "pharmaceutically acceptable" in the sense of compatibility with other components in the formulation and harmlessness to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrins; (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 waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Rice 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.

[0038] The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a specific crystal arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0039] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning within the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail. It should be understood that the singular form used in this invention, such as "a," includes plural references unless otherwise specified.

[0040] Furthermore, the terms "comprising" and "including" are open-ended rather than closed-ended, meaning they include the contents specified in this invention but do not exclude other aspects.

[0041] Unless otherwise stated, this invention uses traditional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and the steps and conditions can be referred to conventional operating procedures and conditions in the field.

[0042] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

[0043] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...each independently" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...each independently" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0044] Specifically, the present invention relates to the following technical solutions

[0045] In one embodiment, the present invention relates to compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof:

[0046]

[0047] in:

[0048] X is either CR' or N;

[0049] Y is CR';

[0050] R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups, wherein the groups are optionally substituted with one or more deuterium groups until fully deuterated;

[0051] R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups, wherein the groups are optionally substituted with one or more deuterium groups until fully deuterated;

[0052] R3 is selected from -LC 1-6 Alkyl, -LC 1-6 Halogenated alkyl, -LC 3-7Cycloalkyl, -L-3-7-membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated;

[0053] R4 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0054] Each group in R1, R2, R3 and R4 may be optionally replaced by 1, 2, 3 or 4 Rs;

[0055] Where L is selected from bond, -C(O)- or -C(S)-;

[0056] R is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0057] R' is selected from H, D, halogen, or CN.

[0058] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a solvate, a hydrate, a polymorph, a prodrug, or an isotopic variant thereof, wherein:

[0059] X is either CR' or N;

[0060] Y is CR';

[0061] R1 is selected from C 1-6 Alkyl, C 3-7 Cycloalkyl or 3-7-membered heterocyclic groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0062] R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7-membered heterocyclic groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0063] R3 is selected from -LC 3-7 Cycloalkyl, -L-3-7-membered heterocyclic group, C 6-10 Aryl or 5-6-membered heteroaryl, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated;

[0064] R4 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0065] Each group in R1, R2, R3 and R4 may be optionally replaced by 1, 2, 3 or 4 Rs;

[0066] Where L is selected from -C(O)- or -C(S)-;

[0067] R is selected from H, D, halogen, or CN;

[0068] R' is selected from H, D, halogen, or CN.

[0069] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein X is CR', preferably CH.

[0070] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein Y is CH or CF.

[0071] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein the groups are optionally substituted with one or more deuterium groups until complete deuteration; preferably, R1 is selected from C1. 1-6 Alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups until fully deuterated; preferably, R1 is C. 1-6 Alkyl group, optionally substituted with one or more deuterium atoms, up to complete deuteration; preferably, R1 is C. 3-7 Cycloalkyl.

[0072] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, wherein the groups are optionally substituted with one or more deuterium groups until complete deuteration; preferably, R2 is selected from C. 1-6 Alkyl, C1-6 Halogenated alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups until fully deuterated; preferably, R2 is C. 1-6 Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration.

[0073] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein R3 is selected from -C(O)-C 3-7 Cycloalkyl or 5-6-membered heteroaryl groups, wherein the groups are optionally substituted with one or more deuterium groups until fully deuterated; preferably, R3 is -C(O)-C 3-7 Cycloalkyl.

[0074] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein R4 is selected from C 1-6 Alkyl or C 1-6 The alkyl group is optionally substituted with one or more deuterium groups until fully deuterated; preferably, R4 is C. 1-6 Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration.

[0075] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, having the following general formula:

[0076]

[0077] Each group is as defined in this application.

[0078] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, wherein said compound is selected from:

[0079]

[0080]

[0081]

[0082] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotope variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it further comprises other therapeutic agents.

[0083] In one embodiment, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, and mixtures thereof, and pharmaceutical compositions comprising thereof in the preparation of medicaments for treating and / or preventing TYK2 kinase-mediated diseases.

[0084] In one embodiment, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a solvate, a hydrate, a polymorph, a prodrug, or an isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising said compound for the treatment and / or prevention of TYK2 kinase-mediated diseases.

[0085] In one embodiment, the present invention provides a method of treating and / or preventing TYK2 kinase-mediated diseases in a subject with a compound as defined herein, comprising administering the subject the compound or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a solvate, a hydrate, a polymorph, a prodrug, or an isotopic variant thereof, and mixtures thereof, or pharmaceutical compositions comprising thereof.

[0086] The diseases mediated by TYK2 kinase as described in this invention are selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, and polycythemia. Further, the autoimmune diseases include lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease; the skin diseases include psoriasis, rashes, or atopic dermatitis; the allergic diseases include asthma or rhinitis; the organ transplant rejection includes allogeneic suppression rejection or graft-versus-host disease; and the cancers include 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.

[0087] In some implementations, this method relates to diseases mediated by the TYK2 kinase selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

[0088] Those skilled in the art will understand that, without violating common sense in the field, the above-mentioned preferred conditions can be arbitrarily combined to obtain various preferred embodiments of the present invention.

[0089] Dosage

[0090] The compounds of the present invention (I) may be administered by any means suitable for the disease state to be treated, depending on the need for site-specific treatment or the amount of drug to be delivered. While other delivery modalities are covered, topical administration is generally preferred for skin-related diseases, and systemic treatment is preferred for cancerous or precancerous disease states. For example, the compounds may be delivered in the following ways: orally, for example in tablets, capsules, granules, powders, or liquid formulations (including syrups); topically, for example in solutions, suspensions, gels, or ointments; sublingually; buccally; parenterally, for example by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in sterile injectable aqueous or non-aqueous or suspension forms); nasally, for example by inhalation sprays; topically, for example in creams or ointments; rectally, for example in suppositories; or liposomes. Unit-dose formulations containing non-toxic, pharmaceutically acceptable carriers or diluents may be administered. The compounds may be administered in forms suitable for immediate or prolonged release. Immediate or prolonged release can be achieved using suitable pharmaceutical compositions or, especially in the case of prolonged release, using, for example, subcutaneous implants or osmotic pump devices.

[0091] Exemplary compositions for local application include a local carrier.

[0092] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for volume impartation, alginate or sodium alginate as a suspending agent, methylcellulose as a thickener, and sweeteners or flavoring agents, such as those known in the art; and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose, and / or other excipients, binders, expanders, disintegrants, diluents, and lubricants, such as those known in the art. The compounds of the present invention can also be delivered orally via sublingual and / or buccal administration, for example, using molded, compressed, or freeze-dried tablets. Exemplary compositions may include rapidly dissolving diluents, such as mannitol, lactose, sucrose, and / or cyclodextrin. These formulations may also include high molecular weight excipients, such as cellulose. Or polyethylene glycol (PEG); excipients used to aid mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymers (e.g., ); and reagents for controlling release, such as polyacrylic acid copolymers (e.g., CARBOPOL); Lubricants, flow aids, flavoring agents, colorants, and stabilizers may also be added to facilitate preparation and use.

[0093] Exemplary compositions for nasal aerosol or inhalation administration include solutions that may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to improve absorption and / or bioavailability, and / or other solubilizers or dispersants, such as those known in the art.

[0094] Exemplary compositions for parenteral administration include injectable solutions or suspensions that may contain, for example, suitable nontoxic diluents or solvents acceptable for parenteral administration, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersants or wetting and suspending agents, including synthetic mono- or diglycerides and fatty acids, including oleic acid.

[0095] Exemplary compositions for rectal administration include suppositories that may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycol, which are solid at room temperature but liquefy and / or dissolve in the rectal lumen to release the drug.

[0096] The therapeutically effective amount of the compounds of this invention can be determined by those skilled in the art, and for mammals includes exemplary doses of the active compound of about 0.05-1000 mg / kg, 1-1000 mg / kg, 1-50 mg / kg, 5-250 mg / kg, and 250-1000 mg / kg body weight per day, which may be administered as a single dose or in individual fractionated doses (e.g., 1 to 4 times daily). It should be understood that the specific dose level and frequency of administration for any particular individual may vary and should depend on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the individual's species, age, weight, general health condition, sex and diet, administration pattern and time, excretion rate, drug combination, and the severity of the specific disease state. Preferred individuals for treatment include animals, most preferably mammalian species, such as humans and livestock, such as dogs, cats, horses, etc. Therefore, when the term "patient" is used herein, this term refers to all individuals, most preferably mammalian species suffering from TYK2 kinase-mediated diseases.

[0097] Example

[0098] The materials or reagents used in this article are commercially available or prepared by synthetic methods commonly known in the art.

[0099] Example 1

[0100] 6-(cyclopropylcarbamate)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 1)

[0101] Synthesis of intermediate 1C

[0102]

[0103] Step 1: 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)aniline

[0104]

[0105] 3-Bromo-2-methoxyaniline (10 g, 49.5 mmol) was dissolved in 1,4-dioxane (150 mL), followed by the addition of pinacol diboronate (25.1 g, 98.8 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (3.62 g, 4.95 mmol), and potassium acetate (9.72 g, 99 mmol). After nitrogen purging, the reaction mixture was reacted in an oil bath at 110 °C for 3 hours. The reaction mixture was poured into water (80 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain the title compound (7.8 g, yield: 63.4%, yellow solid).

[0106] MS(ESI): m / z 249.9 [M+H] + ;

[0107] Step 2: 2-Methoxy-3-(1-Methyl-1H-1,2,4-triazol-3-yl)aniline

[0108]

[0109] 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)aniline (5.4 g, 21.7 mmol) was dissolved in 1,4-dioxane (80 mL), and water (16 mL), 3-bromo-1-methyl-1H-1,2,4-triazole (5.27 g, 32.5 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.59 g, 2.17 mmol), and potassium carbonate (9.0 g, 65.1 mmol) were added. After nitrogen purging, the reaction was carried out in an oil bath at 110 °C for 16 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to give the title compound (3.1 g, yield: 70.1%, brown solid).

[0110] MS(ESI): m / z 205.1 [M+H] + ;

[0111] Synthesis of Compound 1

[0112]

[0113] Step 1: Lithium 4,6-dichloropyridazine-3-carboxylate

[0114]

[0115] 4,6-Dichloropyridazine-3-carboxylic acid methyl ester (10 g, 48.31 mmol) was dissolved in water (7.5 mL) and acetonitrile (50 mL), and lithium bromide (12.58 g, 144.93 mmol) and DIEA (18.7 g, 144.93 mmol) were added. The reaction mixture was reacted at room temperature for 4 hours. The reaction solution was filtered, and the filter cake was washed with acetonitrile to give the title compound (6.84 g, yield: 71.3%, white solid).

[0116] MS(ESI): m / z 192.9[M+H]+;

[0117] Step 2: 4,6-Dichloro-N-methoxypyridazine-3-carboxamide

[0118]

[0119] Lithium 4,6-dichloropyridazine-3-carboxylate (2 g, 10.4 mmol) was dissolved in thionyl chloride (20 mL), and DMF (0.5 mL) was added. The mixture was reacted at 90 °C for 1 hour. The reaction solution was evaporated to dryness, and DCM (20 mL) was added. The mixture was cooled to 0 °C, and methoxyamine (910.4 mg, 10.5 mmol) and triethylamine (5.26 g, 52.0 mmol) were added at 0 °C. The reaction solution was reacted at room temperature for 1 hour, and the solvent was removed by vacuum to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to obtain the title compound (613 mg, yield: 27.5%, yellow solid).

[0120] MS(ESI): m / z 208.9[M+H]+;

[0121] Step 3: 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide

[0122]

[0123] 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.0 g, 4.90 mmol) was dissolved in THF (40 mL). After purging with nitrogen three times, the reaction system was cooled to 0 °C. At 0 °C, bis(trimethylsilyl)aminolithium (2.46 g, 14.71 mmol) was slowly added dropwise using a syringe. The reaction solution was allowed to react at 0 °C for 1 hour. Then, at 0 °C, a tetrahydrofuran solution of 4,6-dichloro-N-methoxypyridazine-3-carboxamide (1.08 g, 4.90 mmol) was injected into the reaction solution using a syringe. After the reaction solution naturally warmed to room temperature, it was allowed to react at room temperature for 16 hours. The reaction solution was quenched by adding 10 mL of saturated ammonium chloride aqueous solution. After quenching, the reaction solution was poured into water (10 mL). The aqueous phase was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain the crude product. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the title compound (880 mg, yield: 46.3%, yellow solid).

[0124] MS(ESI): m / z 390.1 [M+H] +

[0125] Step 4: 6-(cyclopropylcarbamate)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 1)

[0126]

[0127] 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (200 mg, 0.51 mmol) was dissolved in 1,4-dioxane (8.5 mL), and cyclopropylformamide (434 mg, 5.10 mmol), tris(dibenzylacetone)dipalladium (186.8 mg, 0.204 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (235.8 mg, 0.408 mmol), and cesium carbonate (498.5 mg, 1.53 mmol) were added. After nitrogen purging, the reaction was carried out in an oil bath at 110 °C for 16 hours. The solvent was removed by vacuum rotation of the reaction solution, and the crude product was obtained by filtration with dichloromethane:methanol = 15:1. The crude product was purified by reversed-phase preparative chromatography to give the title compound (5.9 mg, yield: 2.6%, white solid).

[0128] MS(ESI): m / z 439.1 [M+H] + ;

[0129] 1 H NMR (400MHz, CD3OD) δ8.47(s,1H),8.25(s,1H),7.67(d,J=7.5Hz,1H),7.59(d,J=7.8Hz,1H), 7.29(t,J=7.9Hz,1H),4.01(s,3H),3.87(s,3H),3.74(s,3H),1.29(s,1H),0.99–0.87(m,4H).

[0130] Example 2

[0131] 6-((6-cyanopyridin-2-yl)amino)-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 2)

[0132]

[0133] 6-Chloro-N-methoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (200 mg, 0.51 mmol) was dissolved in 1,4-dioxane (3 mL), and 6-aminopyridinecarboxynitrile (303.8 mg, 2.55 mmol), tris(dibenzylacetone)dipalladium (140.1 mg, 0.153 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (147.4 mg, 0.255 mmol), and cesium carbonate (830.8 mg, 2.55 mmol) were added. After nitrogen purging, the reaction was carried out in an oil bath at 130 °C for 16 hours. The solvent was removed from the reaction solution under vacuum, and then the mixture was slurried with a 15:1 dichloromethane:methanol mixture and filtered to obtain the crude product. The crude product was purified by reversed-phase preparative chromatography to obtain the title compound (9.72 mg, yield: 4.0%, yellow powder).

[0134] MS(ESI): m / z 473.2 [M+H] + ;

[0135] 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.38(s,2H),7.92(d,J=7.6Hz,1H),7.72( s,2H),7.62-7.59(m,3H),7.38(s,1H),3.96(s,3H),3.77(s,3H),3.76(s,3H).

[0136] Example 3

[0137] 6-(cyclopropylcarbamate)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (compound 3)

[0138]

[0139] Step 1: 6-Chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide

[0140]

[0141] 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (420 mg, 2.06 mmol) was dissolved in tetrahydrofuran (10 mL), and after purging with nitrogen, the reaction solution was cooled to 0 °C. Bis(trimethylsilyl)aminolithium (1.03 g, 6.16 mmol) was slowly added dropwise at 0 °C, and the reaction was carried out at 0 °C for 1 hour. Then, a tetrahydrofuran solution (2 mL) of 4,6-dichloro-N-ethoxypyridazine-3-carboxamide (484 mg, 2.06 mmol) was added at 0 °C. After the reaction solution was allowed to naturally warm to room temperature, it was reacted at room temperature for 16 hours. The reaction solution was quenched with methanol (2 mL), and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the title compound (270 mg, yield: 32.5%, white solid).

[0142] MS(ESI): m / z 404.4 [M+H] + ;

[0143] Step 2: 6-(cyclopropylcarbamate)-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (compound 3)

[0144]

[0145] 6-Chloro-N-ethoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (140 mg, 0.347 mmol) was dissolved in 1,4-dioxane (3 mL), and cyclopropylformamide (295 mg, 3.47 mmol), tris(dibenzylacetone)dipalladium (127 mg, 0.139 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (166 mg, 0.287 mmol), and cesium carbonate (339 mg, 1.04 mmol) were added. After nitrogen purging, the mixture was reacted in an oil bath at 110 °C for 16 hours. The reaction solution was filtered and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (4 mg, yield: 2.55%, white solid).

[0146] MS(ESI): m / z 453.1 [M+H] + ;

[0147] 1H NMR (400MHz, CD3OD) δ8.47(s,1H),8.26(s,1H),7.68(d,J=7.7Hz,1H),7.60(d,J=8.0Hz,1H),7.30(t,J=7.8Hz,1H),4. 12–4.06(m,2H),4.02(s,3H),3.74(s,3H),1.37(brs,1H),1.29(brs,3H),0.97(d,J=4.4Hz,2H),0.92(d,J=8.0Hz,2H).

[0148] Example 4

[0149] 6-(cyclopropylcarbamate)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (compound 4)

[0150]

[0151] Step 1: 3-Bromo-5-fluoro-2-methoxyaniline

[0152]

[0153] 1-Bromo-5-fluoro-2-methoxy-3-nitrobenzene (2.539 g, 10.15 mmol) was dissolved in a mixture of isopropanol and water (12 ml), and ammonium chloride (2.714 g, 50.74 mmol) was added, followed by fractional addition of iron powder (2.79 g, 50.74 mmol). After nitrogen purging, the reaction was carried out in an oil bath at 80 °C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound (1.68 g, yield: 75.3%, yellow solid).

[0154] MS(ESI): m / z 221.9 [M+H] + ;

[0155] Step 2: 5-Fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)aniline

[0156]

[0157] 3-Bromo-5-fluoro-2-methoxyaniline (1.582 g, 7.19 mmol) was dissolved in 1,4-dioxane solution (12 mL), and pinacol diboronate (3.62 g, 14.25 mmol), potassium acetate (1.398 g, 14.25 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (521.7 mg, 0.713 mmol) were added. After nitrogen purging, the reaction was carried out in an oil bath at 110 °C for two hours. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the title compound (1.05 g, yield: 54.7%, yellow solid).

[0158] MS(ESI): m / z 268.0 [M+H] + ;

[0159] Step 3: 5-Fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

[0160]

[0161] 5-Fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpinecyclo-2-yl)aniline (1.05 g, 3.93 mmol) was dissolved in a mixed solution (8 mL) of 1,4-dioxane and water. 3-Bromo-1-methyl-1H-1,2,4-triazole (955 mg, 5.90 mmol), potassium carbonate (1.63 g, 11.8 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (288 mg, 0.394 mmol) were added. After nitrogen purging, the reaction was carried out in an oil bath at 110 °C for 16 hours. The reaction was stopped, and after cooling to room temperature, water (40 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give the title compound (600 mg, yield: 68.6%, yellow solid).

[0162] MS(ESI): m / z 223.1 [M+H] + ;

[0163] Step 4: ((6-chloro-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)

[0164]

[0165] 5-Fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (410 mg, 1.80 mmol) was dissolved in water (7 mL) and isopropanol (1 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (414.7 mg, 2.16 mmol) and zinc acetate (396.4 mg, 2.16 mmol) were added. After purging with nitrogen three times, the reaction was carried out in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (10 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, and the filter cake was washed with water (10 mL × 2) and tetrahydrofuran (3 mL) to give the title compound (140 mg, yield: 20.1%, yellow solid).

[0166] MS(ESI): m / z 379.0 [M+H] + ;

[0167] Step 5: ((6-(cyclopropylcarbamoyl)-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0168]

[0169] Zinc ((6-chloro-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (140 mg, 0.371 mmol)) was dissolved in toluene (2 mL) and acetonitrile (1 mL). Cyclopropylformamide (78.9 mg, 0.927 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (41.1 mg, 0.074 mmol), 1,8-diazabicycloundec-7-ene (56.5 mg, 0.371 mmol), cesium carbonate (242 mg, 0.742 mmol), and palladium acetate (8.33 mg, 0.0371 mmol) were added. After nitrogen purging, the reaction was carried out in an oil bath at 100 °C for 16 hours. After the reaction was stopped, the reaction solution was cooled to room temperature, and water (6 mL) and acetic acid (3 mL) were added. The mixture was washed with petroleum ether (10 mL × 3), and the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (110 mg, yield: 69.6%, brown solid).

[0170] MS(ESI): m / z 428.1 [M+H] + ;

[0171] Step 6: 6-(cyclopropylcarbamate)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 4)

[0172]

[0173] N-methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added to a reaction flask, followed by ((6-(cyclopropylcarbamoyl)-4-((5-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (110 mg, 0.258 mmol), O-ethylhydroxylamine hydrochloride 12 (37.7 mg, 0.387 mmol), and N-methylimidazole (63.5 mg, 0.773 mmol). The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (69.7 mg, 0.516 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (98.9 mg, 0.516 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (10 mL) was added to the reaction solution for quenching. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (6.01 mg, yield: 5.0%, yellow solid).

[0174] MS(ESI): m / z 471.0[M+H]+;

[0175] 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),8.60(s,1H),8.39(s,1H),8.25(s,1H),7.45–7.39(m,2H),4.02–3.98( m,2H),3.96(s,3H),3.74(s,3H),2.11(dd,J=12.1,5.7Hz,1H),1.23(t,J=7.0Hz,3H),0.85(d,J=5.7Hz,4H).

[0176] Example 5

[0177] 6-(cyclopropylcarbamoyl)-N-ethoxy-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 5)

[0178]

[0179] Step 1: Methyl 2-methoxy-3-nitrobenzene

[0180]

[0181] 2-Hydroxy-3-nitrobenzoic acid (2.5 g, 13.65 mmol) was dissolved in N,N-dimethylacetamide (50 mL), and iodomethane (9.7 g, 68.3 mmol) and cesium carbonate (17.8 g, 54.61 mmol) were added. The mixture was reacted at room temperature for 16 hours. Water (250 mL) was added to the reaction solution, and the mixture was stirred for 1 hour. The mixture was then filtered, and the filter cake was washed with acetonitrile (10 mL × 3). The solvent was removed under vacuum. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 4:1) to give the title compound (2.36 g, yield: 82.1%, yellow solid).

[0182] MS(ESI): m / z 212.1 [M+H] + ;

[0183] Step 2: 2-Methoxy-3-nitrobenzamide

[0184]

[0185] Methyl 2-methoxy-3-nitrobenzene (2.26 g, 10.7 mmol) was dissolved in ammonia-methanol solution (12 mL, 48 mmol), and ammonia water (9 mL) was added. The mixture was sealed and reacted at room temperature for 16 hours. The solvent was removed from the reaction solution under vacuum, and the solution was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to give the title compound (1.545 g, yield: 73.7%, yellow solid).

[0186] MS(ESI): m / z 197.0 [M+H] + ;

[0187] Step 3: 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0188]

[0189] 2-Methoxy-3-nitrobenzamide (1.62 g, 8.26 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (22 mL), and reacted in an oil bath at 95 °C for 1 hour. The solvent was then removed by vacuum rotation, and ethanol (6 mL) was added to dissolve the crude product solution. In an ice bath, ethanol (16 mL) and acetic acid (6 mL) were added to the reaction flask, and the mixture was stirred for 5 minutes. Hydrazine hydrate (12 mL) was added dropwise, and stirring continued for 15 minutes. The mixture was then added dropwise to the ethanol solution of the crude product, and the mixture was slowly brought to room temperature and stirred for 4 hours. After removing the solvent by vacuum rotation, the reaction solution was diluted with ethyl acetate (200 mL), washed with saturated sodium bicarbonate aqueous solution (200 mL × 2), and the organic phase was separated and washed with saturated brine (50 mL × 3). The solution was dried over anhydrous sodium sulfate and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain the title compound (830 mg, yield: 45.7%, yellow solid).

[0190] MS(ESI): m / z 221.0[M+H]+

[0191] Step 4: 3-(2-methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole

[0192]

[0193] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1 g, 4.55 mmol) was dissolved in N,N-dimethylacetamide (16 mL), cesium carbonate (2.96 g, 9.1 mmol) was added, and deuterated iodomethane (988.4 mg, 6.82 mmol) was added at 0 °C. The reaction mixture was slowly heated to room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution (15 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 2:3) to give the title compound (866 mg, yield: 80.3%, yellow solid).

[0194] MS(ESI): m / z 238.3 [M+H] + ;

[0195] Step 5: 2-Methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)aniline

[0196]

[0197] 3-(2-methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole (866 mg, 3.65 mmol) was dissolved in methanol (20 mL), and ammonia (1 mL) and palladium / carbon (155.6 mg) were added. After purging with hydrogen, the reaction mixture was reacted at room temperature for 2 hours. The reaction solution was filtered, washed with methanol (20 mL × 3), and the solvent was removed under vacuum to give the title compound (622 mg, yield: 82%, yellow solid).

[0198] MS(ESI): m / z 208.1 [M+H] + ;

[0199] Step 6: ((6-chloro-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)

[0200]

[0201] 2-Methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)aniline (320 mg, 1.55 mmol) and lithium 4,6-dichloropyridazine-3-carboxylate (357.1 mg, 1.86 mmol) were dissolved in a mixed solvent of isopropanol (2 mL) and water (14 mL), and zinc acetate (340 mg, 1.86 mmol) was added. The mixture was reacted in an oil bath at 65 °C for 16 hours. After the reaction was stopped, water (15 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed with water (10 mL × 2) and tetrahydrofuran (5 mL × 3). The solvent was removed by vacuum to give the title compound (420 mg, yield: 74.6%, yellow solid).

[0202] MS(ESI): m / z 364.0 [M+H] + ;

[0203] Step 7: ((6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0204]

[0205] ((6-chloro-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 1.02 mmol) was dissolved in toluene (7 mL) and acetonitrile (14 mL). Cyclopropylformamide (216 mg, 2.454 mmol), (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine (112.6 mg, 0.203 mmol), diazabicyclo(154.6 mg, 1.02 mmol), cesium carbonate (661 mg, 2.03 mmol), and palladium acetate (45.6 mg, 0.203 mmol) were added. The mixture was purged with nitrogen and reacted in an oil bath at 100 °C for 16 hours. After the reaction was stopped, water (20 mL) and acetic acid (10 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 0.5 hours. The solution was then washed with petroleum ether (15 mL × 3), the aqueous phase was extracted with dichloromethane (20 mL × 3), washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (400 mg, yield: 88.5%, brown solid).

[0206] MS(ESI): m / z 413.1 [M+H] + ;

[0207] Step 8: 6-(cyclopropylcarbamate)-N-ethoxy-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 5)

[0208]

[0209] N-methylpyrrolidone (15 mL) and acetonitrile (15 mL) were added to a reaction flask and stirred at room temperature for 10 minutes. Then, ((6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 0.9 mmol), O-ethylhydroxylamine hydrochloride (132 mg, 1.35 mmol), and N-methylimidazolium (222.3 mg, 2.71 mmol) were added. After nitrogen purging, the mixture was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (244 mg, 1.81 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (346.1 mg, 1.81 mmol) were added. After nitrogen purging, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was quenched with water (30 mL). Extraction was performed with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The crude product was purified by high-performance liquid chromatography (elution system: ammonia, water, acetonitrile) to give the title compound (11.4 mg, yield: 2.8%, white solid).

[0210] MS(ESI): m / z 456.2 [M+H] + ;

[0211] 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),11.31(s,1H),10.55(s,1H),8.56(s,1H),8.15(s,1H),7.66(d,J=6.9Hz,1H),7.51( d,J=5.8Hz,1H),7.28(d,J=6.6Hz,1H),3.99(d,J=5.4Hz,2H),3.73(s,3H),2.09(brs,1H),1.23(brs,3H),0.82(brs,4H).

[0212] Example 6

[0213] 6-(cyclopropylcarbamoyl)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (compound 6)

[0214]

[0215] Step 1: 5-Fluoro-2-methoxybenzamide

[0216]

[0217] 5-Fluoro-2-methoxybenzoic acid (7.2 g, 42.32 mmol) was dissolved in thionyl chloride (20 mL), and N,N-dimethylformamide (0.5 mL) was added. The reaction solution was reacted in an oil bath at 85 °C for 2 hours. The solvent was removed by vacuum rotation of the reaction solution, and dichloromethane (50 mL × 3) was added in portions to remove residual thionyl chloride, yielding a crude product. The crude product was dissolved in dichloromethane (20 mL) for later use. A 500 mL three-necked flask was taken, and a 1,4-dioxane solution of ammonia (0.4 M, 170 mL) was added. The mixture was cooled to 0 °C, and the prepared dichloromethane solution was slowly added dropwise. The reaction solution was stirred for 30 minutes. The reaction solution was poured into water (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL × 3), the combined organic phases were washed with saturated brine (70 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (6.25 g, yield: 87.3%, white solid).

[0218] MS(ESI): m / z 170.1 [M+H] + ;

[0219] Step 2: 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole

[0220]

[0221] 5-Fluoro-2-methoxybenzamide (6.25 g, 36.95 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (50 mL), and after nitrogen purging, the reaction was carried out in an oil bath at 95 °C for 1 hour. The solvent was removed from the reaction solution under vacuum to obtain crude DMF-DMA addition product, which was dissolved in ethanol (30 mL) for later use. Under ice bath conditions, ethanol (80 mL), acetic acid (30 mL), and hydrazine hydrate (98 wt.%, 15 mL) were added to the reaction flask, and stirring was continued for 15 minutes. Then, the ethanol solution of the crude DMF-DMA addition product was added dropwise. After the reaction solution was allowed to rise naturally to room temperature, it was stirred at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, it was diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate aqueous solution (400 mL × 3), the organic phase was washed with saturated brine (300 mL × 3), dried with anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (5.46 g, yield: 76.5%, white solid).

[0222] MS(ESI): m / z 194.1 [M+H] + ;

[0223] Step 3: 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0224]

[0225] 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (5.46 g, 28.26 mmol) was dissolved in concentrated sulfuric acid (50 mL), and nitric acid (68 wt.%, 5.24 g, 56.55 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred under ice bath conditions for 2 hours. The reaction was stopped, and the reaction solution was poured into ice water (50 mL). Ammonia was slowly added dropwise to adjust the pH to 9.0. The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (6.4 g, yield: 95.1%, yellow solid).

[0226] MS(ESI): m / z 239.1 [M+H] + ;

[0227] Step 4: 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole

[0228]

[0229] 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (3.4 g, 14.3 mmol) and cesium carbonate (5.59 g, 17.16 mmol) were added to N,N-dimethylformamide (60 mL). After nitrogen purging, the reaction system was cooled to 0 °C, and then deuterated iodomethane (3.11 g, 21.5 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction was stopped, and the reaction mixture was quenched with water (70 mL). The mixture was extracted three times with ethyl acetate (80 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (1.831 g, yield: 49%, yellow solid).

[0230] MS(ESI): m / z 256.1 [M+H] + ;

[0231] Step 5: 5-Fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)aniline

[0232]

[0233] 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole (1.831 g, 7.18 mmol) was dissolved in methanol (50 mL), and ammonia (25 wt%, 1 mL) and palladium / carbon (305.39 mg) were added. After hydrogen purging, the reaction mixture was allowed to react at room temperature for 16 hours. The reaction was stopped, the reaction mixture was filtered, washed with methanol, and the filtrates were combined, concentrated under reduced pressure, and purified by column chromatography (silica gel, dichloromethane:methanol = 92:8) to give the title compound (1.493 g, yield: 92.39%, yellow solid).

[0234] MS(ESI): m / z 226.0 [M+H] + ;

[0235] Step 6: ((6-chloro-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0236]

[0237] 5-Fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)aniline (300 mg, 1.33 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (318.06 mg, 1.60 mmol), and zinc acetate (293.29 mg, 1.60 mmol) were dissolved in 4.8 mL of water:toluene = 7:1. After nitrogen purging, the reaction was carried out at 100 °C for 16 hours. The reaction was stopped, 6 mL of water was added to the reaction solution, and the mixture was stirred for one hour. The mixture was then filtered, washed with tetrahydrofuran (2 mL), and the filter cake was dried to give the title compound (276 mg, yield: 50.12%, white solid).

[0238] MS(ESI): m / z 382.0 [M+H] + ;

[0239] Step 7: ((6-(cyclopropylcarbamoyl)-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0240]

[0241] Zinc ((6-chloro-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (200 mg, 0.48 mmol), cyclopropaneformamide (102.92 mg, 1.21 mmol), (R)-(S)-Cy2PF-PtBu2 (554.55 mg, 0.097 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (73.64 mg, 0.48 mmol), cesium carbonate (315.22 mg, 0.97 mmol), and palladium acetate (21.72 mg, 0.097 mmol) were dissolved in 1.8 mL of toluene:acetonitrile = 2:1. After nitrogen purging, the mixture was reacted at 100 °C for 16 hours. The reaction was stopped, and 6 mL of a water:acetic acid = 2:1 solution was added to the reaction solution. The mixture was extracted with petroleum ether (8 mL), and the lower aqueous phase was extracted three times with dichloromethane (10 mL). The dichloromethane organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the title compound (250 mg, purity: 77%, brown solid).

[0242] MS(ESI): m / z 431.0 [M+H] + ;

[0243] Step 8: 6-(cyclopropylcarbamate)-N-ethoxy-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 6)

[0244]

[0245] N-methylpyrrolidone (6.25 mL) and acetonitrile (6.25 mL) were added to a reaction flask, followed by ((6-(cyclopropylcarbamoyl)-4-((5-fluoro-2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (250 mg, 0.54 mmol) and O-ethylhydroxylamine hydrochloride (79.16 mg). 1-hydroxybenzotriazole (146.20 mg, 1.08 mmol) and N-methylimidazole (133.25 mg, 1.62 mmol) were added; after nitrogen purging, the mixture was reacted in an oil bath at 65 °C for 15 minutes, then 1-hydroxybenzotriazole (146.20 mg, 1.08 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (207.42 mg, 1.08 mmol) were added; after nitrogen purging, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, ethyl acetate (30 mL) was added to the reaction mixture, and then the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by reversed-phase preparative chromatography (elution system: hydrochloric acid, water, acetonitrile) to obtain the title compound (26.59 mg, yield: 10.38%, white solid).

[0246] MS(ESI): m / z 474.0 [M+H] +

[0247] Example 7

[0248] 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 7)

[0249]

[0250] Step 1: 1-Cyclopropyl-3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0251]

[0252] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (420 mg, 1.909 mmol) was dissolved in 1,4-dioxane (15 mL), followed by the addition of cyclopropylboronic acid (246 mg, 2.864 mmol), sodium carbonate (405 mg, 3.821 mmol), 2,2-bipyridine (298 mg, 1.908 mmol), and copper acetate (347 mg, 1.91 mmol). After oxygen replacement, the reaction mixture was reacted in an oil bath at 85 °C for 16 hours. The reaction was then stopped, and the reaction solution was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the title compound (270 mg, yield: 62.5%, yellow oil).

[0253] MS(ESI): m / z 261.0 [M+H] + ;

[0254] Step 2: 3-(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline

[0255]

[0256] 1-Cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (270 mg, 1.037 mmol) was dissolved in methanol (10 mL), and palladium / carbon catalyst (27 mg, 0.254 mmol) was added. After three purgings with hydrogen, the reaction was carried out at room temperature for 16 hours. The reaction was stopped, and the palladium / carbon catalyst was filtered off. The solvent in the filtrate was removed under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (200 mg, yield: 83.6%, colorless transparent oil).

[0257] MS(ESI): m / z 231.1 [M+H] + ;

[0258] Step 3: ((6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)

[0259]

[0260] 3-(1-Cyclopropyl-1H-1,2,4-Triazol-3-yl)-2-methoxyaniline (200 mg, 0.869 mmol) was dissolved in water (7 mL) and isopropanol (1 mL). Lithium 4,6-dichloropyridazine-3-carboxylate (200 mg, 1.042 mmol) and zinc acetate (191 mg, 1.041 mmol) were added. After purging with nitrogen three times, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (5 mL) was added to the reaction solution. The mixture was stirred at room temperature for 1 hour, then filtered. The filter cake was washed with water (6 mL × 2) and tetrahydrofuran (1 mL), and dried to give the title compound (170 mg, yield: 46.8%, yellow solid).

[0261] MS(ESI): m / z 387.0 [M+H] + ;

[0262] Step 4: ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0263]

[0264] ((6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (170 mg, 0.406 mmol) was dissolved in toluene (2 mL) and acetonitrile (1 mL), and then cyclopropylformamide (86.4 mg, 1.015 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (45 mg, 0.0811 mmol), 1,8-diazabicycloundec-7-ene (61.8 mg, 0.406 mmol), cesium carbonate (265 mg, 0.813 mmol), and palladium acetate (9.12 mg, 0.0406 mmol) were added. After nitrogen purging, the mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped, the reaction solution was cooled to room temperature, water (6 mL) and acetic acid (3 mL) were added, the mixture was extracted with petroleum ether (10 mL × 3), and then the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined dichloromethane organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (195 mg, brown solid).

[0265] MS(ESI): m / z 436.2 [M+H] + ;

[0266] Step 5: 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 7)

[0267]

[0268] Take a 50 mL reaction flask, add N-methylpyrrolidone (4 mL) and acetonitrile (4 mL), stir the mixed solvent at room temperature for 10 minutes, then add ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (195 mg, 0.417 mmol), O-ethylhydroxylamine hydrochloride (61 mg, 0.625 mmol), and N-methylimidazolium (103 mg, 1.255 mmol). Stir the reaction solution in an oil bath at 65 °C for 15 minutes, then add 1-hydroxybenzotriazole (113 mg, 0.836 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.836 mmol). Continue stirring the reaction solution in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (15 mL) was added to the reaction solution for quenching. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (16.03 mg, yield: 8.02%, yellow solid).

[0269] MS(ESI): m / z 479.2 [M+H] + ;

[0270] 1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.55(s,1H),8.69(s,1H),8.40(s,1H) ,8.14(s,1H),7.66(d,J=7.6Hz,1H),7.51(d,J=8.0Hz,1H),7.27(t,J=7.9Hz,1 H),3.99(q,J=7.0Hz,2H),3.90–3.84(m,1H),3.71(s,3H),2.12–2.05(m,1H),1 .23(t,J=7.0Hz,3H),1.17–1.16(m,2H),1.07–1.06(m,2H),0.86–0.80(m,4H).

[0271] Example 8

[0272] 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 8)

[0273]

[0274] Step 1: 1-Cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0275]

[0276] 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (3.1 g, 13.02 mmol) was dissolved in 50 mL of 1,4-dioxane solution. Cyclopropylboronic acid (1.68 g, 19.56 mmol), sodium carbonate (2.76 g, 26.04 mmol), 2,2-bipyridine (2.03 g, 13.0 mmol), and copper acetate (2.36 g, 13.0 mmol) were added. After oxygen replacement, the reaction was carried out in an oil bath at 85 °C for 16 hours. The reaction was stopped, and the reaction solution was poured into water (60 mL). The aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the title compound (2.1 g, yield: 58.0%, yellow oil).

[0277] MS(ESI): m / z 279.0 [M+H] + ;

[0278] Step 2: 3-(1-Cyclopropyl-1H-1,2,4-Triazol-3-yl)-5-Fluoro-2-methoxyaniline

[0279]

[0280] 1-Cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (2.1 g, 7.55 mmol) was dissolved in methanol (50 mL), and palladium / carbon catalyst (321 mg, 3.02 mmol) and ammonia (1 mL) were added. After three purgings with hydrogen, the reaction was carried out at room temperature for 16 hours. The reaction was stopped, and the palladium / carbon catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (1.5 g, yield: 80.2%, colorless transparent oil).

[0281] MS(ESI): m / z 249.2 [M+H] + ;

[0282] Step 3: ((6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)

[0283]

[0284] 3-(1-Cyclopropyl-1H-1,2,4-Triazol-3-yl)-5-fluoro-2-methoxyaniline (400 mg, 1.61 mmol) was dissolved in water (7 mL) and isopropanol (1 mL). Lithium 4,6-dichloropyridazine-3-carboxylate (371 mg, 1.93 mmol) and zinc acetate (355 mg, 1.93 mmol) were added. After purging with nitrogen three times, the mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped, and water (10 mL) was added to the reaction solution. The mixture was stirred at room temperature for 1 hour, then filtered. The filter cake was washed with water (10 mL × 2) and tetrahydrofuran (3 mL), and dried to give the title compound (310 mg, yield: 44.1%, yellow solid).

[0285] MS(ESI): m / z 405.2 [M+H] + ;

[0286] Step 4: ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0287]

[0288] Zinc ((6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (160 mg, 0.367 mmol) was dissolved in toluene (2 mL) and acetonitrile (1 mL). Cyclopropylformamide (78.1 mg, 0.918 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (40.7 mg, 0.073 mmol), 1,8-diazabicycloundec-7-ene (55.9 mg, 0.367 mmol), cesium carbonate (239 mg, 0.736 mmol), and palladium acetate (8.24 mg, 0.0367 mmol) were added. After nitrogen purging, the mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped, the reaction solution was cooled to room temperature, water (6 mL) and acetic acid (3 mL) were added, the mixture was extracted with petroleum ether (10 mL × 3), and then the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined dichloromethane organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (168 mg, yield: 94.5%, brown solid).

[0289] MS(ESI): m / z 454.3 [M+H] + ;

[0290] Step 5: 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 8)

[0291]

[0292] Take a 50 mL reaction flask, add N-methylpyrrolidone (3 mL) and acetonitrile (3 mL), mix the solvents and stir at room temperature for 10 minutes, then add ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (130 mg, 0.268 mmol) and O-ethylhydroxylamine salt. The reaction mixture was prepared with 1-hydroxybenzotriazole (39.2 mg, 0.402 mmol) and N-methylimidazole (66 mg, 0.804 mmol) in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (72.4 mg, 0.536 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.537 mmol) were added, and the mixture was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the mixture was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (7.54 mg, yield: 5.7%, yellow solid).

[0293] MS(ESI): m / z 497.2 [M+H] +

[0294] Example 9

[0295] 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 9)

[0296]

[0297] Step 1: Methyl 2-(methoxy-d3)-3-nitrobenzoate

[0298]

[0299] Methyl 2-hydroxy-3-nitrobenzene (1.7 g, 8.623 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of deuterated iodomethane (1.87 g, 12.9 mmol) and potassium carbonate (2.38 g, 17.221 mmol). The mixture was purged with nitrogen and reacted in an oil bath at 60 °C for 2 hours. The reaction was then stopped, and the reaction solution was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the title compound (1.69 g, yield: 91.5%, yellow oil).

[0300] MS(ESI): m / z 215.1 [M+H] + ;

[0301] Step 2: 2-(methoxy-d3)-3-nitrobenzamide

[0302]

[0303] Methyl 2-(methoxy-d3)-3-nitrobenzoate (1.69 g, 7.89 mmol) was dissolved in ammonia-methanol solution (30 mL), and ammonia water (15 mL) was added. After nitrogen purging, the reaction was carried out at room temperature for 16 hours. The reaction was stopped, and the solvent was removed from the reaction solution under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the title compound (1.45 g, yield: 92.2%, yellow solid).

[0304] MS(ESI): m / z 200.1 [M+H] + ;

[0305] Step 3: 3-(2-(methoxy-d3)-3-nitrophenyl)-1H-1,2,4-triazole

[0306]

[0307] 2-(methoxy-d3)-3-nitrobenzamide (1.45 g, 7.28 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (10 mL), and after nitrogen purging, the reaction was carried out in an oil bath at 95 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then dissolved in ethanol (10 mL) for later use. A 250 mL single-necked flask was taken, and ethanol (40 mL) and acetic acid (10 mL) were added to the flask. The system was cooled to 0 °C, and hydrazine hydrate (4 mL) was added dropwise. The mixture was stirred at 0 °C for 1 hour. The prepared crude product ethanol solution was added dropwise to the system, and stirring was continued for 2 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then dissolved in ethyl acetate (200 mL). The organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title compound (1.1 g, yield: 67.7%, pale yellow solid).

[0308] MS(ESI): m / z 224.1 [M+H] + ;

[0309] Step 4: 1-Cyclopropyl-3-(2-(methoxy-d3)-3-nitrophenyl)-1H-1,2,4-triazole

[0310]

[0311] 3-(2-(methoxy-d3)-3-nitrophenyl)-1H-1,2,4-triazole (1.1 g, 4.928 mmol) was dissolved in 1,4-dioxane (40 mL), and cyclopropylboronic acid (635 mg, 7.392 mmol), sodium carbonate (1.04 g, 9.812 mmol), 2,2-bipyridine (770 mg, 4.93 mmol), and copper acetate (895 mg, 4.928 mmol) were added. After oxygen replacement, the mixture was reacted in an oil bath at 85 °C for 16 hours. The reaction was stopped, and the reaction solution was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the title compound (900 mg, yield: 69.2%, yellow oil).

[0312] MS(ESI): m / z 264.0 [M+H] + ;

[0313] Step 5: 3-(1-Cyclopropyl-1H-1,2,4-Triazol-3-yl)-2-(Methoxy-d3)aniline

[0314]

[0315] 1-Cyclopropyl-3-(2-(methoxy-d3)-3-nitrophenyl)-1H-1,2,4-triazole (900 mg, 3.419 mmol) was dissolved in methanol (25 mL), and a palladium / carbon catalyst (90 mg) was added. After three purgings with hydrogen, the reaction was carried out at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, and the solvent was removed from the filtrate under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (520 mg, yield: 65.2%, colorless transparent oil).

[0316] MS(ESI): m / z 234.2 [M+H] + ;

[0317] Step 6: ((6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)

[0318]

[0319] 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)aniline (520 mg, 2.229 mmol) was dissolved in water (14 mL) and isopropanol (2 mL). Lithium 4,6-dichloropyridazine-3-carboxylate (530 mg, 2.677 mmol) and zinc acetate (491 mg, 2.676 mmol) were added. After purging 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 mixture was stirred at room temperature for 1 hour, then filtered. The filter cake was washed with water (15 mL × 3) and tetrahydrofuran (4 mL), and then dried to give the title compound (680 mg, yield: 72.3%, white solid).

[0320] MS(ESI): m / z 390.2 [M+H] + ;

[0321] Step 7: ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0322]

[0323] Zinc ((6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (680 mg, 1.613 mmol) was dissolved in toluene (8 mL) and acetonitrile (4 mL). Cyclopropylformamide (343 mg, 4.031 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (179 mg, 0.323 mmol), 1,8-diazabicycloundec-7-ene (246 mg, 1.616 mmol), cesium carbonate (1.05 g, 3.223 mmol), and palladium acetate (72.4 mg, 0.322 mmol) were added. After nitrogen purging, the mixture was reacted in an oil bath at 100 °C for 16 hours. The reaction was stopped, the reaction solution was cooled to room temperature, water (20 mL) and acetic acid (10 mL) were added, the mixture was extracted with petroleum ether (30 mL × 3), and then the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined dichloromethane organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (720 mg, yield: 94.9%, brown solid).

[0324] MS(ESI): m / z 439.3 [M+H] + ;

[0325] Step 8: 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 9)

[0326]

[0327] Take a 50 mL reaction flask, add N-methylpyrrolidone (4 mL) and acetonitrile (4 mL), mix the solvents and stir at room temperature for 10 minutes, then add ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(methoxy-d3)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (370 mg, 0.787 mmol) and O-ethylhydroxylamine hydrochloride. (153.5 mg, 1.574 mmol) and N-methylimidazole (193.8 mg, 2.361 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (212.7 mg, 1.574 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (301.7 mg, 1.574 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 3 hours. The reaction was stopped, and water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (88.36 mg, yield: 23.3%, pink solid).

[0328] MS(ESI): m / z 482.1 [M+H] + ;

[0329] 1 H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.55(s,1H),8.69(s,1H),8.38(s, 1H),8.14(s,1H),7.66(d,J=7.8Hz,1H),7.51(d,J=7.9Hz,1H),7.27(t,J= 7.9Hz,1H),4.02–3.96(m,2H),3.89–3.85(m,1H),2.11–2.07(m,1H),1.23 (t,J=7.0Hz,3H),1.17–1.15(m,2H),1.09–1.05(m,2H),0.84–0.80(m,4H).

[0330] Example 10

[0331] 6-(Cyclopropylcarbamate)-N-(2-fluoroethoxy)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 10)

[0332]

[0333] Synthesis of intermediate 10C

[0334]

[0335] Step 1: 2-(2-fluoroethoxy)isoindoline-1,3-dione

[0336]

[0337] 2-Fluoroethane-1-ol (5.0 g, 78.052 mmol) was dissolved in ultradry tetrahydrofuran solution (50 mL), and 2-hydroxyisoindoline-1,3-dione (12733 mg, 78.052 mmol) and triphenylphosphine (26.614 g, 101.468 mmol) were added. Nitrogen gas was then introduced, and diethyl azodicarbonate (17.671 g, 101.468 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction mixture was reacted at room temperature for 16 hours. The reaction was stopped, and the reaction solution was filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the title compound (8.4 g, yield: 51.4%, white solid).

[0338] 1 H NMR (400MHz, DMSO-d6) δ7.89–7.83(m,4H),4.78–4.74(m,1H),4.66–4.62(m,1H),4.46–4.41(m,1H),4.38–4.34(m,1H).

[0339] Step 2: O-(2-Fluoroethyl)hydroxylamine hydrochloride

[0340]

[0341] 2-(2-fluoroethoxy)isoindoline-1,3-dione (8.4 g, 40.157 mmol) was dissolved in dichloromethane solution (50 mL), and hydrazine hydrate (4.016 g, 80.314 mmol) was added dropwise to displace nitrogen gas. The reaction was carried out at room temperature for 16 hours. The reaction was stopped, and the reaction solution was filtered. The filtrate was washed with water (20 mL × 2), and the aqueous phase was collected. The aqueous phase was extracted with a chloroform-isopropanol (3:1) mixture (30 mL × 6). The organic phases were combined and added to a solution of dioxane (30 mL). The mixture was stirred at room temperature for 30 minutes and then evaporated to dryness to give the title compound (1.7 g, yield: 36.6%, white solid).

[0342] Synthesis of Compound 10

[0343] Step 1: ((6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)

[0344]

[0345] 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (500 mg, 2.448 mmol) was dissolved in water (35 mL) and isopropanol (5 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (974 mg, 4.896 mmol) and zinc acetate (898 mg, 4.896 mmol) were added. After purging with nitrogen three times, the reaction was carried out in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (15 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, and the filter cake was washed with water (10 mL × 2) and tetrahydrofuran (1 mL) to give the title compound (530 mg, yield: 55.2%, brown solid).

[0346] MS(ESI): m / z 361.0 [M+H] + ;

[0347] Step 2: ((6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0348]

[0349] ((6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (480 mg, 1.223 mmol) was dissolved in toluene (8 mL) and acetonitrile (4 mL). Cyclopropylformamide (260 mg, 3.058 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (136 mg, 0.245 mmol), 1,8-diazabicycloundec-7-ene (186 mg, 1.223 mmol), potassium carbonate (338 mg, 2.446 mmol), and palladium acetate (55 mg, 0.245 mmol) were added. After nitrogen purging, the mixture was reacted in an oil bath at 75 °C for 16 hours. The reaction was stopped, the reaction solution was cooled to room temperature, water (15 mL) and acetic acid (7 mL) were added, the mixture was extracted with petroleum ether (30 mL × 2), and then the aqueous phase was extracted with dichloromethane (30 mL × 2). The combined dichloromethane organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the title compound (500 mg, yield: 81.8%, brown solid).

[0350] MS(ESI): m / z 410.1 [M+H] + ;

[0351] Step 3: 6-(cyclopropylcarbamate)-N-(2-fluoroethoxy)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 10)

[0352]

[0353] Take a 50 mL reaction flask, add N-methylpyrrolidone (2 mL) and acetonitrile (2 mL), stir the mixed solvent at room temperature for 10 minutes, then add ((6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (200 mg, 0.453 mmol), O-(2-fluoroethyl)hydroxylamine hydrochloride (79 mg, 0.680 mmol), and N-methylimidazolium (111 mg, 1.359 mmol). Stir the reaction solution in an oil bath at 65 °C for 15 minutes, then add 1-hydroxybenzotriazole (122 mg, 0.906 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (174 mg, 0.906 mmol). Stir the reaction solution in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (7.64 mg, yield: 3.6%, gray solid).

[0354] MS(ESI): m / z 471.0 [M+H] + ;

[0355] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.40(s,1H),8.15(s,1H),7.66(d,J=7.7Hz,1H),7.51(d,J=7.1Hz,1H),7.28(d, J=7.9Hz,1H),4.69(d,J=48.0Hz,2H),4.29–4.07(m,2H),3.93(s,3H),3.73(s,3H),2.09(brs,1H),0.82–0.77(m,4H).

[0356] Example 11

[0357] 6-(Cyclopropylcarbamate)-N-(2,2-Difluoroethoxy)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 11)

[0358]

[0359] Step 1: 2-(2,2-difluoroethoxy)isoindole-1,3-dione

[0360]

[0361] 2,2-Difluoroethane-1-ol (5.0 g, 60.938 mmol) was dissolved in ultradry tetrahydrofuran solution (50 mL), and 2-hydroxyisoindoline-1,3-dione (9.941 g, 60.938 mmol) and triphenylphosphine (20.778 g, 79.219 mmol) were added. Nitrogen gas was then introduced, and diethyl azodicarbonate (13.796 g, 79.219 mmol) was added dropwise at 0 °C. The reaction was allowed to proceed for 16 hours at room temperature. The reaction was then stopped, and the reaction mixture was filtered. The filtrate was evaporated to dryness under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to give the title compound (11 g, yield: 79.5%, white solid).

[0362] 1 H NMR (400MHz, CDCl3) δ7.90–7.84(m,2H),7.81–7.76(m,2H),6.40–6.06(m,1H),4.38(td,J=12.7,4.2Hz,2H).

[0363] Step 2: O-(2,2-difluoroethyl)hydroxylamine hydrochloride

[0364]

[0365] 2-(2,2-difluoroethoxy)isoindole-1,3-dione (10.0 g, 44.020 mmol) was dissolved in dichloromethane solution (50 mL), and hydrazine hydrate (4.402 g, 88.040 mmol) was added dropwise to displace nitrogen gas. The reaction was carried out at room temperature for 16 hours. The reaction was stopped, and the reaction solution was filtered. The filtrate was washed with water (50 mL × 2), and the aqueous phase was collected. The aqueous phase was then extracted with a chloroform-isopropanol (3:1) mixture (30 mL × 6). The combined organic phases were added to a solution of dioxane (20 mL), and the mixture was stirred at room temperature for 1 hour. The solution was then evaporated to dryness to give the title compound (1.1 g, yield: 18.7%, white solid).

[0366] Step 3: 6-(cyclopropylcarbamate)-N-(2,2-difluoroethoxy)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 11)

[0367]

[0368] N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added to a reaction flask. The mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (200 mg, 0.453 mmol), O-(2,2-difluoroethyl)hydroxylamine hydrochloride (91 mg, 0.680 mmol), and N-methylimidazolium (111 mg, 1.359 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (122 mg, 0.906 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (174 mg, 0.906 mmol) were added. The reaction was continued 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 mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to give the title compound (15.64 mg, yield: 7.1%, white solid).

[0369] MS(ESI): m / z 489.2 [M+H] + ;

[0370] 1 H NMR (400MHz, DMSO-d6) δ8.57(s,1H),8.43(s,1H),8.13(s,1H),7.65(d,J=8.0Hz,1H),7.50(s,1H),7.27(t,J=8.0 Hz,1H),6.36(t,J=54.2Hz,1H),4.18(d,J=14.3Hz,2H),3.93(s,3H),3.73(s,3H),2.09(brs,1H),0.82(brs,4H).

[0371] Example 12

[0372] 6-(cyclopropamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(2-fluoroethoxy)pyridazine-3-carboxamide (Compound 12)

[0373]

[0374] N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, and the mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (270 mg, 0.578 mmol) and O-(2-fluoroethyl)hydroxylamine hydrochloride (1) were added. 33.6 mg (1.156 mmol) and N-methylimidazole (142.4 mg, 1.734 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (156.2 mg, 1.156 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (221.6 mg, 1.156 mmol) were added, and the reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound (11.3 mg, yield: 3.94%, yellow solid).

[0375] MS(ESI): m / z 497.1 [M+H] + ;

[0376] 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),11.34(s,1H),10.50(s,1H),8.69(s,1H),8.14(s,1 H),7.68–7.65(m,1H),7.51(dd,J=7.9,1.3Hz,1H),7.26(d,J=7.9Hz,1H),4.76–4.74(m,1 H),4.64–4.62(m,1H),4.25–4.23(m,1H),4.17–4.16(m,1H),3.88–3.86(m,1H),3.71(s,3 H),2.10–2.06(m,1H),1.18–1.16(m,2H),1.07(dd,J=6.9,1.7Hz,2H),0.83–0.81(m,4H).

[0377] Example 13

[0378] 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(2,2-difluoroethoxy)pyridazine-3-carboxamide (Compound 13)

[0379]

[0380] N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, and the mixed solvents were stirred at room temperature for 10 minutes. Then, ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (230 mg, 0.492 mmol) and O-(2,2-difluoroethyl)hydroxylamine hydrochloride were added. Salt (194.8 mg, 1.476 mmol) and N-methylimidazole (121.2 mg, 1.476 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (133 mg, 0.984 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (189 mg, 0.986 mmol) were added, and the reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: hydrochloric acid, water, acetonitrile) to obtain the title compound (17.76 mg, yield: 7.01%, yellow solid).

[0381] MS(ESI): m / z 515.0 [M+H] + ;

[0382] 1 H NMR(400MHz,DMSO-d6)δ12.68(s,1H),11.42(s,1H),10.47(s,1H),8.74(s,1H ),8.10(s,1H),7.68(d,J=7.9Hz,1H),7.52(d,J=7.6Hz,1H),7.28(t,J=7.9Hz ,1H),6.50–6.21(m,1H),4.26–4.19(m,2H),3.90–3.86(m,1H),3.72(s,3H),2 .11–2.05(m,1H),1.17(d,J=3.2Hz,2H),1.07(d,J=5.4Hz,2H),0.82(brs,4H).

[0383] Example 14

[0384] 6-(Cyclopropylcarbamate)-N-(Methoxy-d3)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 14)

[0385]

[0386] ((6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (130 mg, 0.29 mmol) and O-(methyl-d3)hydroxylamine hydrochloride (38.26 mg, 0.44 mmol) were dissolved in N-methylpyrrolidone (1 mL) and acetonitrile (1 mL). N-methylimidazolium (72.34 mg, 0.88 mmol) was added, and the reaction was heated to 65 °C and stirred for 15 minutes. Then 1-hydroxybenzotriazole (79.67 mg, 0.59 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113.02 mg, 0.59 mmol) were added, and the reaction was continued at this temperature for 2 hours. The reaction was stopped, and the reaction solution was purified by reversed-phase preparative chromatography (elution system: formic acid, acetonitrile, water) to obtain the title compound (27.15 mg, yield: 20.8%, white solid).

[0387] MS(ESI): m / z 442.3 [M+H] + ;

[0388] 1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),11.32(s,1H),10.55(s,1H),8.56(s,1H),8.15(s,1H),7.68–7.66(m, 1H),7.52–7.50(m,1H),7.29–7.25(m,1H),3.95(s,3H),3.73(s,3H),2.12–2.05(m,1H),0.83–0.81(m,4H).

[0389] Example 15

[0390] 6-(Cyclopropylcarbamate)-N-(ethoxy-d5)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 15)

[0391]

[0392] Step 1: 2-(ethoxy-d5)isoindole-1,3-dione

[0393]

[0394] 2-Hydroxyisoindoline-1,3-dione (5.5 g, 33.715 mmol) was dissolved in tetrahydrofuran (45 mL), and ethane-1,1,2,2,2-d5-1-ol-d (1.76 g, 33.775 mmol) and triphenylphosphine (11.5 g, 43.845 mmol) were added. After nitrogen purging, diethyl azodicarbonate (7.63 g, 43.813 mmol) was slowly added dropwise under ice bath conditions; the reaction mixture was stirred at room temperature for 16 hours. The reaction was stopped, and the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the title compound (2.79 g, yield: 42.1%, white solid).

[0395] MS(ESI): m / z 197.0 [M+H] + ;

[0396] Step 2: O-(ethyl-d5)hydroxylamine hydrochloride

[0397]

[0398] 2-(ethoxy-d5)isoindole-1,3-dione (2.7 g, 13.76 mmol) was dissolved in dichloromethane (30 mL), and hydrazine hydrate (1.38 g, 27.57 mmol) was added. After purging with nitrogen, the reaction mixture was stirred at room temperature for 16 hours. The reaction was stopped, and the reaction mixture was filtered. The filtrate was poured into water (40 mL), and the aqueous phase was extracted with a chloroform:isopropanol = 3:1 mixed solvent (40 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. A solution of dioxane chloride (15 mL) was added to the filtrate, and the reaction mixture was stirred at room temperature for 1 hour. Then, the mixture was concentrated under reduced pressure to give the title compound (580 mg, yield: 41.1%, white solid).

[0399] Step 3: 6-(cyclopropylcarbamate)-N-(ethoxy-d5)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 15)

[0400]

[0401] N-methylpyrrolidone (10 mL) and acetonitrile (10 mL) were added to a reaction flask, followed by ((6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (300 mg, 0.76 mmol), O-(ethyl-d5)hydroxylamine hydrochloride (117.6 mg, 1.15 mmol), and N-methylimidazole (188.3 mg, 2.29 mmol). After nitrogen purging, the mixture was reacted in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (206.6 mg, 1.53 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (293.1 mg, 1.53 mmol) were added. After nitrogen purging, 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 for quenching. The solution was then extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by reversed-phase preparative chromatography to obtain the title compound (71.89 mg, yield: 20.6%, white solid).

[0402] MS(ESI): m / z 458.2 [M+H] + ;

[0403] 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),11.32(s,1H),10.55(s,1H),8.57(s,1H),8.15(s,1H),7.67(d,J=7.5Hz,1H),7. 51(d,J=7.8Hz,1H),7.27(t,J=7.9Hz,1H),3.95(s,3H),3.73(s,3H),2.10–2.06(m,1H),0.82(brs,2H),0.81(brs,2H).

[0404] Example 16

[0405] 6-(cyclopropamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methoxy-d3)pyridazine-3-carboxamide (Compound 16)

[0406]

[0407] N-methylpyrrolidone (6 mL) and acetonitrile (6 mL) were added to a reaction flask, and the mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (300 mg, 0.642 mmol) and O-deuterated methyl hydroxylamine hydrochloride (111) were added. 7 mg (1.284 mmol) of N-methylimidazole (158.1 mg, 1.926 mmol) was added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (173.5 mg, 1.284 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (246.1 mg, 1.284 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (55.71 mg, yield: 17.5%, yellow solid).

[0408] MS(ESI): m / z 468.1 [M+H] + ;

[0409] 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),11.32(s,1H),10.55(s,1H),8.69(s,1H),8.15(s,1H),7.66(d,J=7.9Hz,1H),7.51(d,J=7.7Hz,1 H),7.27(t,J=7.9Hz,1H),3.89–3.85(m,1H),3.72(s,3H),2.11–2.06(m,1H),1.19–1.15(m,2H),1.09–1.05(m,2H),0.84–0.80(m,4H).

[0410] Example 17

[0411] 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(ethoxy-d5)pyridazine-3-carboxamide (Compound 17)

[0412]

[0413] N-methylpyrrolidone (6.5 mL) and acetonitrile (6.5 mL) were added to a reaction flask, followed by ((6-(cyclopropamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (200 mg, 0.43 mmol), O-(ethyl-d5)hydroxylamine hydrochloride (65.2 mg, 0.64 mmol), and N-methylimidazole (105.45 mg, 1.28 mmol). After purging with nitrogen, the mixture was reacted in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (115.7 mg, 0.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164.15 mg, 0.86 mmol) were added. After purging 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 for quenching. The solution was then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under vacuum to obtain the crude product. The crude product was purified by reversed-phase preparative chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (65.3 mg, yield: 31.7%, white solid).

[0414] MS(ESI): m / z 484.3 [M+H] + ;

[0415] 1 H NMR (400MHz, DMSO-d6) δ12.26(s,1H),11.32(s,1H),10.56(s,1H),8.69(s,1H),8.15(s,1H),7.66(dd,J=7.8,1.3Hz,1H),7.51( d,J=7.9Hz,1H),7.27(t,J=7.9Hz,1H),3.90–3.84(m,1H),3.72(s,3H),2.13–2.04(m,1H),1.21–1.04(m,4H),0.87–0.79(m,4H).

[0416] Example 18

[0417] 6-(cyclopropamido)-N-cyclopropoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 18)

[0418]

[0419] Step 1: 2-(vinyl)isoindoline-1,3-dione

[0420]

[0421] 2-Hydroxyisoindoline-1,3-dione (900 mg, 5.517 mmol) was dissolved in ultradry tetrahydrofuran (20 mL), and ethylene boric anhydride pyridine complex (876 mg, 3.641 mmol), 1,3-diethylurea (256 mg, 2.207 mmol), copper trifluoromethanesulfonate (798 mg, 2.207 mmol), and triethylamine (1114 mg, 11.034 mmol) were added. After oxygen replacement, the reaction was carried out at 50 °C for 16 hours. The reaction was stopped, the reaction solution was filtered, and the filtrate was collected and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give the title compound (950 mg, yield: 91.1%, white solid).

[0422] 1 H NMR (400MHz, DMSO-d6) δ7.92–7.86(m,4H),6.92(dd,J=13.6,6.4Hz,1H),4.73(dd,J=13.6,3.5Hz,1H),4.40(dd,J=6.4,3.5Hz,1H).

[0423] Step 2: 2-Cyclopropoxyisoindoline-1,3-dione

[0424]

[0425] Diethylzinc (19 mL, 19.0 mmol, 1.0 M hexane solution) was added dropwise to 16 mL of ultra-dry dichloromethane at 0 °C, purging with nitrogen and maintaining the temperature at 0 °C. Trifluoroacetic acid (2.172 g, 19.048 mmol) was dissolved in 8 mL of ultra-dry dichloromethane and slowly added dropwise to the above solution, stirring for 20 minutes. Diiodomethane (5.101 g, 19.048 mmol) was dissolved in 8 mL of ultra-dry dichloromethane and slowly added dropwise, stirring for another 20 minutes. 2-(vinyl)isoindoline-1,3-dione (900 mg, 4.762 mmol) was dissolved in 5.5 mL of ultra-dry dichloromethane solution and slowly added dropwise, purging with nitrogen and reacting at room temperature for 16 hours. The reaction was stopped, and dilute hydrochloric acid (0.1N, 16mL) was added to the reaction solution. The mixture was separated, and the organic phase was collected and washed successively with saturated sodium bicarbonate solution (17mL) and saturated saline solution (10mL). The solution was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the title compound (850mg, yield: 87.9%, white solid).

[0426] Step 3: O-Cyclopropylhydroxylamine hydrochloride

[0427]

[0428] 2-Cyclopropoxyisoindoline-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 purging with nitrogen, the reaction mixture was allowed to react at room temperature for 16 hours. The reaction was stopped, and the reaction mixture was filtered. The filtrate was washed with water (20 mL × 2). The aqueous phase was collected and extracted with a chloroform / isopropanol mixture (3:1, 15 mL × 6). The organic phases were combined and dried. A solution of 1,4-dioxane in hydrogen chloride (1 mL) was added, and the mixture was stirred for 1 h and then evaporated to dryness to give the title compound (130 mg, yield: 53.5%, white solid).

[0429] Step 4: 6-(cyclopropamido)-N-cyclopropoxy-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 18)

[0430]

[0431] N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, followed by ((6-(cyclopropamido)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (255 mg, 0.578 mmol), O-cyclopropylhydroxylamine hydrochloride (95.37 mg, 0.867 mmol), and N-methylimidazolium (142.4 mg, 1.734 mmol). The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (156.2 mg, 1.156 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (221.6 mg, 1.156 mmol) were added, and the reaction solution was stirred in an oil bath at 65 °C for 2 hours. The reaction was stopped, and water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (16.22 mg, yield: 6.03%, yellow solid).

[0432] MS(ESI): m / z 465.0 [M+H] + ;

[0433] 1H NMR (400MHz, DMSO-d6) δ12.37(s,1H),11.32(s,1H),10.54(s,1H),8.56(s,1H),8.16(s,1H),7.69–7.65(m,1H),7.52(d,J=7.7Hz,1H),7 .27(t,J=7.9Hz,1H),4.12–4.07(m,1H),3.95(s,3H),3.73(s,3H),2.13–2.06(m,1H),0.90(brs,2H),0.82(brs,4H),0.61–0.56(m,2H).

[0434] Example 19

[0435] 6-(Cyclopropylcarbamate)-N-Cyclopropoxy-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 19)

[0436]

[0437] Step 1: 1-Ethyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0438]

[0439] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (450 mg, 2.044 mmol) was dissolved in ultradry N,N-dimethylformamide (10 mL), and cesium carbonate (1.998 g, 6.132 mmol) was added. After nitrogen purging, iodoethane (478 mg, 3.066 mmol) was slowly added dropwise in an ice bath at 0 °C, and then the mixture was transferred to room temperature for 2 hours. The reaction was stopped, and the reaction solution was filtered and poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under vacuum to obtain the title compound (530 mg, pale yellow oil), which was directly added to the next reaction.

[0440] MS(ESI): m / z 249.0 [M+H] + ;

[0441] Step 2: 3-(1-Ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline

[0442]

[0443] 1-Ethyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole 3 (530 mg, 2.135 mmol) was dissolved in methanol (20 mL), and palladium / carbon (91 mg, 0.854 mmol) was added. Hydrogen was purged three times, and the reaction was carried out at room temperature for 2 hours. The reaction was stopped, and the reaction solution was filtered and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to give the title compound (335 mg, yield: 71.9%, pale yellow solid).

[0444] MS(ESI): m / z 219.2 [M+H] + ;

[0445] Step 3: ((6-chloro-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)

[0446]

[0447] 3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (300 mg, 1.375 mmol) was dissolved in water (14 mL) and isopropanol (2 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (410 mg, 2.063 mmol) and zinc acetate (379 mg, 2.063 mmol) were added. After purging with nitrogen three times, the reaction was carried out in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (10 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, and the filter cake was washed with water (6 mL × 2) and tetrahydrofuran (1 mL). The filter cake was dried to give the title compound (440 mg, yield: 79.0%, pale yellow solid).

[0448] MS(ESI): m / z 375.3 [M+H] + ;

[0449] Step 4: ((6-(cyclopropamido)-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0450]

[0451] ((6-chloro-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 0.984 mmol) was dissolved in toluene (8 mL) and acetonitrile (4 mL), and cyclopropaneformamide (209 mg, 2.460 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (109 mg, 0.197 mmol), 1,8-diazabicycloundec-7-ene (150 mg, 0.984 mmol), potassium carbonate (273 mg, 1.974 mmol), and palladium acetate (44 mg, 0.197 mmol) were added. After nitrogen purging, the mixture was reacted in an oil bath at 75 °C for 16 hours. The reaction was stopped, the reaction solution was cooled to room temperature, water (15 mL) and acetic acid (7.5 mL) were added, the mixture was washed with petroleum ether (30 mL × 2), the aqueous phase was extracted with dichloromethane (15 mL × 3), the combined dichloromethane organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum to obtain the title compound (750 mg, brown solid).

[0452] MS(ESI): m / z 424.1 [M+H] + ;

[0453] Step 5: 6-(cyclopropylcarbamate)-N-cyclopropoxy-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 19)

[0454]

[0455] N-methylpyrrolidone (8 mL) and acetonitrile (8 mL) were added to a reaction flask. The mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(cyclopropamido)-4-((3-(1-ethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (750 mg, 1.648 mmol), O-cyclopropylhydroxylamine hydrochloride (271 mg, 2.472 mmol), and N-methylimidazolium (404 mg, 4.944 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (445 mg, 3.296 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (632 mg, 3.296 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, the reaction solution was filtered, and the crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (21.82 mg, yield: 3.7%, pale yellow solid).

[0456] MS(ESI): m / z 479.2 [M+H] + ;

[0457] 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),11.33(s,1H),10.56(s,1H),8.61(s,1H), 8.17(s,1H),7.68(dd,J=7.8,1.5Hz,1H),7.52(dd,J=7.9,1.4Hz,1H),7.28(t,J= 7.9Hz,1H),4.28(q,J=7.3Hz,2H),4.11–4.08(m,1H),3.73(s,3H),2.14–2.05(m, 1H), 1.46 (t, J = 7.3Hz, 3H), 0.90 (brs, 2H), 0.85–0.79 (m, 4H), 0.62–0.55 (m, 2H).

[0458] Example 20

[0459] 6-(cyclopropylcarbamate)-N-cyclopropoxy-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 20)

[0460]

[0461] N-methylpyrrolidone (1 mL) and acetonitrile (1 mL) were added to a reaction flask, followed by ((6-(cyclopropamido)-4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (155 mg, 0.349 mmol), O-cyclopropylhydroxylamine hydrochloride (57 mg, 0.524 mmol), and N-methylimidazolium (86 mg, 1.047 mmol). The reaction mixture was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (94 mg, 0.698 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (137 mg, 0.698 mmol) were added. The reaction mixture was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, the reaction solution was filtered, and the crude filtrate was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (53.77 mg, yield: 33.0%, pale yellow solid).

[0462] MS(ESI): m / z 468.4 [M+H] + ;

[0463] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),11.50(s,1H),10.61(s,1H),8.69(s,1H),8.06(s,1H),7.69(dd,J=7.8,1.5Hz,1H),7.53(dd,J=8.0,1. 4Hz,1H),7.29(t,J=7.9Hz,1H),4.12–4.05(m,1H),3.72(s,3H),2.10– 2.02(m,1H),0.91–0.86(m,2H),0.85–0.82(m,4H),0.61–0.54(m,2H).

[0464] Example 21

[0465] 6-(cyclopropylcarbamate)-N-cyclopropoxy-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 21)

[0466]

[0467] Step 1: 1-Bromo-2-(methoxy-d3)-3-nitrobenzene

[0468]

[0469] 2-Bromo-6-nitrophenol (1000 mg, 4.587 mmol) was dissolved in ultradry N,N-dimethylformamide (15 mL), potassium carbonate (1.268 g, 9.174 mmol) was added, and after nitrogen purging, deuterated iodomethane (997 mg, 6.881 mmol) was slowly added dropwise in an ice bath at 0 °C. The mixture was then transferred to 60 °C and reacted for 3 hours. The reaction was stopped, and the reaction solution was filtered and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to give the crude title compound (1000 mg, yield: 77.5%, pale yellow oil).

[0470] 1 H NMR (400MHz, DMSO-d6) δ8.01 (dd, J=8.1, 1.5Hz, 1H), 7.95 (dd, J=8.2, 1.5Hz, 1H), 7.31 (t, J=8.1Hz, 1H).

[0471] Step 2: 3-Bromo-2-(methoxy-d3)aniline

[0472]

[0473] 1-Bromo-2-(methoxy-d3)-3-nitrobenzene (1000 mg, 4.254 mmol) was dissolved in isopropanol (9 mL) and water (0.9 mL). Iron powder (1188 mg, 21.270 mmol) and ammonium chloride (1138 mg, 21.270 mmol) were added, and nitrogen was introduced to replace the nitrogen atmosphere. The reaction was carried out at 80 °C for 2 hours. The reaction was stopped, and the reaction solution was filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (730 mg, yield: 83.7%, pale yellow solid).

[0474] MS(ESI): m / z 205.2 [M+H] + ;

[0475] Step 3: 2-(methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline

[0476]

[0477] 3-Bromo-2-(methoxy-d3)aniline (730 mg, 3.560 mmol) and pinacol diborate (1808 mg, 7.12 mmol) were dissolved in ultra-dry dioxane (20 mL), and potassium acetate (699 mg, 7.12 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (260 mg, 0.356 mmol) were added. After purging with nitrogen three times, the mixture was reacted in an oil bath at 110 °C for 3 hours. The reaction was stopped, and the reaction solution was filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (783 mg, yield: 87.2%, pale yellow solid).

[0478] MS(ESI): m / z 254.2 [M+H] + ;

[0479] Step 4: 2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

[0480]

[0481] 2-(methoxy-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpine-2-yl)aniline (783 mg, 3.105 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (755 mg, 4.658 mmol) were dissolved in dioxane solution (20 mL) and water (4 mL). Potassium carbonate (1287 mg, 9.315 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (228 mg, 0.311 mmol) were added. After purging with nitrogen three times, the mixture was reacted in an oil bath at 110 °C for 16 hours. The reaction was stopped, and the reaction solution was filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (550 mg, yield: 85.5%, pale yellow solid).

[0482] MS(ESI): m / z 208.2 [M+H] + ;

[0483] Step 5: ((6-chloro-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(05)

[0484]

[0485] 2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (550 mg, 2.654 mmol) was dissolved in water (21 mL) and isopropanol (3 mL), and lithium 4,6-dichloropyridazine-3-carboxylate (612 mg, 3.185 mmol) and zinc acetate (854 mg, 3.185 mmol) were added. After purging with nitrogen three times, the reaction was carried out in an oil bath at 65 °C for 16 hours. The reaction was stopped, water (20 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, and the filter cake was washed with water (6 mL × 2) and tetrahydrofuran (1 mL). After drying, the title compound (400 mg, yield: 38.1%, yellow solid) was obtained.

[0486] MS(ESI): m / z 364.2 [M+H] + ;

[0487] Step 6: ((6-(cyclopropylcarbamoyl)-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0488]

[0489] Zinc ((6-chloro-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (180 mg, 0.455 mmol) was dissolved in ultra-dry NN-dimethylformamide (5 mL), cyclopropaneformamide (97 mg, 1.138 mmol), cesium carbonate (296 mg, 0.91 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (115 mg, 0.137 mmol) were added, nitrogen was purged, and the reaction was carried out at 100 °C for 16 hours. The reaction was stopped, and the reaction solution was filtered and purified by reverse column chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (50 mg, yield: 24.8%, pale yellow solid).

[0490] MS(ESI): m / z 413.3 [M+H] + ;

[0491] Step 7: 6-(cyclopropylcarbamate)-N-cyclopropoxy-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 21)

[0492]

[0493] N-methylpyrrolidone (1 mL) and acetonitrile (1 mL) were added to a reaction flask, followed by ((6-(cyclopropylcarbamoyl)-4-((2-(methoxy-d3)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (75 mg, 0.169 mmol), O-cyclopropylhydroxylamine hydrochloride (29 mg, 0.254 mmol), and N-methylimidazolium (41 mg, 0.507 mmol). The reaction mixture was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (46 mg, 0.338 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg, 0.338 mmol) were added. The reaction mixture was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, the reaction solution was filtered, and the crude filtrate was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (20.86 mg, yield: 26.4%, pale yellow solid).

[0494] MS(ESI): m / z 468.2 [M+H] + ;

[0495] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),11.35(s,1H),10.55(s,1H),8.59(s,1H),8.12(s,1H),7.66(dd,J=7.8,1.5Hz,1H),7.51(dd,J=8.0,1. 5Hz,1H),7.27(t,J=7.9Hz,1H),4.09–4.08(m,1H),3.94(s,3H),2.11– 2.03(m,1H),0.91–0.86(m,2H),0.85–0.78(m,4H),0.61–0.54(m,2H).

[0496] Example 22

[0497] N-Cyclobutoxy-6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 22)

[0498]

[0499] Step 1: 2-Cyclobutoxyisoindoline-1,3-dione

[0500]

[0501] 2-Hydroxyisoindoline-1,3-dione (10 g, 61.3 mmol) was dissolved in N,N-dimethylformamide (100 mL), and cyclobutyl bromide (12.4 g, 91.85 mmol), 18-crown ether-6 (3.24 g, 12.258 mmol), and potassium carbonate (16.9 g, 122.3 mmol) were added. After nitrogen purging, the reaction mixture was stirred in an oil bath at 80 °C for 16 hours. The reaction was stopped, and the reaction mixture was poured into water (80 mL). The aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the title compound (8.2 g, yield: 61.7%, white solid).

[0502] MS(ESI): m / z 218.1 [M+H] + ;

[0503] Step 2: O-Cyclobutyridine hydrochloride

[0504]

[0505] 2-Cyclobutoxyisoindoline-1,3-dione (500 mg, 2.304 mmol) was dissolved in dichloromethane (8 mL), and hydrazine hydrate (230.7 mg, 4.608 mmol) was added. After purging with nitrogen, the reaction mixture was stirred at room temperature for 16 hours. TLC monitoring showed the starting material had disappeared. The reaction mixture was filtered, and the filtrate was poured into water (20 mL). The aqueous phase was extracted with a chloroform:isopropanol = 3:1 mixed solvent (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. A 1,4-dioxane solution of hydrogen chloride (2 mL) was added to the filtrate, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (180 mg, yield: 63.2%, white solid).

[0506] Step 3: N-Cyclobutoxy-6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 22)

[0507]

[0508] N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask. The mixed solvent was stirred at room temperature for 10 minutes. Then, ((6-(cyclopropamido)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (230 mg, 0.521 mmol), O-cyclobutylhydroxylamine hydrochloride (96.6 mg, 0.782 mmol), and N-methylimidazolium (128.3 mg, 1.563 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (140.8 mg, 1.042 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (199.8 mg, 1.042 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 2 hours. The reaction was stopped, and water (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (11.86 mg, yield: 4.7%, white solid).

[0509] MS(ESI): m / z 479.0 [M+H] + ;

[0510] 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),11.31(s,1H),10.54(s,1H),8.56(s,1H),8.33(s,1H),7.66(d,J=7.4Hz,1H),7.51(d,J=7.6Hz,1H),7 .27(t,J=7.9Hz,1H),4.58–4.51(m,1H),3.95(s,3H),3.72(s,3H),2.19–2.08(m,5H),1.76–1.69(m,1H),1.55–1.48(m,1H),0.82(brs,4H).

[0511] Biological testing evaluation

[0512] Test Example A: In vitro enzyme binding experiment of compound TYK2JH2 of the present invention.

[0513] Experimental objective: The purpose of this test case is to use fluorescence resonance energy transfer (TR-FRET) to test the binding effect of the compound on the TYK2 JH2 pseudokinase, and thus evaluate the affinity of the compound for TYK2 JH2.

[0514] Experimental methods:

[0515] The compound was dissolved in DMSO to prepare a 10 mM stock solution. Different concentration gradients of the compound were then prepared in 200X dilution plates and transferred to Echo plates. Using an Echo instrument, 75 nL of the compound was transferred from the Echo plate to a 384-well plate. 5 μL of 3X TYK2 JH2 kinase (Bioduro), 5 μL of 3X Tb antibody (Cisbio), and 5 μL of 3X TRACER (Bioduro) were added to each well of the 384-well plate, respectively. The plates were centrifuged for 30 seconds and incubated at room temperature for 60 minutes. The fluorescence signal ratio at 495 nm / 520 nm was read using an Envision microplate reader (PerkinElmer). Data analysis was performed using XL-Fit software, and the IC50 of the compound was calculated. 50 .

[0516] Experimental results:

[0517] Compound numbering <![CDATA[TYK2 JH2 Binding Experiment (IC 50 , nM)]]> Compound 1 0.17 Compound 2 0.16 Compound 3 0.13 Compound 4 0.20 Compound 5 0.26 Compound 6 0.30 Compound 7 0.17 Compound 8 0.33 Compound 9 0.22 Compound 14 0.27 Compound 15 0.14 Compound 16 0.29 Compound 17 0.19 BMS-986165 0.25

[0518] The experimental data show that the compound of this invention has a good binding effect on TYK2 JH2 pseudokinase.

[0519] Test Example B: Determination of the effect of the compound of the present invention on IL-2-induced STAT5 phosphorylation of CD3+ cell subsets in human PBMCs (JAK1 / 3).

[0520] Experimental objective: The purpose of this test case is to detect the inhibitory effect of the compound on IL-2-induced STAT5 phosphorylation using protein phosphorylation flow cytometry.

[0521] Experimental methods:

[0522] Human PBMCs were pre-incubated with the compound to induce STAT5 phosphorylation under appropriate stimulation conditions. Corresponding cell subsets and targets were stained, and cell data were read using flow cytometry to analyze the intensity of phosphorylated antibody signals under different compound concentrations. PBMCs were resuspended and aliquoted into 96-well plates (62.5 μL / well); 3.5 μL of 20X compound working solution was added, and the plates were incubated at 37°C for 30 min; 5 μL of PE Mouse Anti-Human CD3 (BD) was added, and the plates were incubated at 37°C in the dark for 30 min; 4 μL of 20X IL-2 (R&D) was added to each well, and the plates were incubated at 37°C in the dark for 20 min; all cells in the 96-well plates were transferred to deep-well plates, and 400 μL of fixation working solution (Biolegend) was added to each well, and the plates were incubated at room temperature in the dark for 20 min. Wash cells twice with PBS, add 400 μL of Perm Buffer III (BD), and incubate at 4°C in the dark for 40 minutes. Wash cells twice with PBS, add 100 μL of STAT5 pY694 antibody working solution (BD), and incubate at room temperature for 40 minutes. Wash cells once with PBS, resuspend cells in 200 μL of staining buffer, transfer to a sample plate, analyze antibody fluorescence intensity using FlowJo software, and calculate the IC50 of the compound using XL-Fit software. 50 .

[0523] Experimental conclusion:

[0524] Compound numbering <![CDATA[pSTAT5 (JAK1 / 3) (IC induced by IL-2 in hPBMC 50 , μM)]]> Compound 7 >30 Compound 9 >30 Compound 17 >30 BMS-986165 0.409

[0525] The experimental data show that the compound of this invention has lower inhibitory activity on the JAK1 / 3 signaling pathway and better selectivity.

[0526] Test Example C: Quantitative pharmacokinetic evaluation of the compounds of this invention by intravenous injection or gavage in mice.

[0527] Experimental objective: The purpose of this test case is to evaluate the pharmacokinetic properties of the compounds of this invention.

[0528] The inventors conducted pharmacokinetic evaluations of the compounds of this invention in mice. Animal information is detailed in Table 1.

[0529] Table 1: Information on test animals for this invention

[0530] phylogenetic grade gender weight age source ICR mice SPF male 26-32g 6-8 weeks Shanghai Xipu-Bikai Experimental Animal Co., Ltd.

[0531] Experimental methods:

[0532] The compounds of this invention were administered to test animals in the form of 5% DMA + 5% Solutol + 90% physiological saline or 5% ethanol + 5% TPGS + 90% PEG300 solvent. Animals were fasted for 12 hours prior to administration but had free access to water. For intravenous administration, the dose was 1 mg / kg; for gavage administration, the dose was 10 mg / kg. Blood samples (approximately 0.3 mL) were collected from the animals at the following time points after administration: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours. EDTA-K2 was pre-added to the blood collection vessels as an anticoagulant. Blood samples were centrifuged at 6800g for 6 minutes, and plasma was collected and stored at -80°C.

[0533] Sample preparation for LC-MS / MS assay: 15 μL of plasma sample was used for protein precipitation with 300 μL of methanol containing 100 ng / mL IS (IS is tolbutamide). The mixture was vortexed for 1 minute and then centrifuged at 18000 g for 10 minutes. 300 μL of the supernatant was transferred to a 96-well plate. 2 μL of the supernatant was analyzed by LC-MS / MS. The results showed that the compounds of the present invention all exhibited good pharmacokinetic properties in mice.

[0534]

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof: (I) in: X is either CR' or N; Y is CR'; R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups, wherein the groups are optionally substituted with one or more deuterium groups until fully deuterated; R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups, wherein the groups are optionally substituted with one or more deuterium groups until fully deuterated; R3 is selected from -LC 1-6 Alkyl, -LC 1-6 Halogenated alkyl, -LC 3-7 Cycloalkyl, -L-3-7-membered heterocyclic groups, -LC 6-10 Aryl or -L-5-10 heteroaryl, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated; R4 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; Each group in R1, R2, R3 and R4 may be optionally replaced by 1, 2, 3 or 4 Rs; Where L is selected from bond, -C(O)- or -C(S)-; R is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R' is selected from H, D, halogen, or CN; The compound mentioned is not .

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is either CR' or N; Y is CR'; R1 is selected from C 1-6 Alkyl, C 3-7 Cycloalkyl or 3-7-membered heterocyclic groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl or 3-7-membered heterocyclic groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; R3 is selected from -LC 3-7 Cycloalkyl, -L-3-7-membered heterocyclic group, C 6-10 Aryl or 5-6-membered heteroaryl, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated; R4 is selected from H and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; Each group in R1, R2, R3 and R4 may be optionally replaced by 1, 2, 3 or 4 Rs; Where L is selected from -C(O)- or -C(S)-; R is selected from H, D, halogen, or CN; R' is selected from H, D, halogen, or CN.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, X is CR'.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, X is CH.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, Y represents CH or CF.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-7-membered heterocyclic groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from C 1-6 Alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R1 is C 1-6 Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration.

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R1 is C 3-7 Cycloalkyl.

10. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-7-membered heterocyclic groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

11. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

12. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R2 is C 1-6 Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration.

13. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from -C(O)-C 3-7 Cycloalkyl or 5-6-membered heteroaryl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

14. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R3 is -C(O)-C 3-7 Cycloalkyl.

15. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

16. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R4 is C 1-6 Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (II) (III) (IV), Each of the groups is defined as described in any one of claims 1-16.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: , , , , , , , , , , , , , , , , , , , , or .

19. A pharmaceutical composition comprising a compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable excipient.

20. The pharmaceutical composition of claim 19, further comprising other therapeutic agents.

21. Use of any compound of claims 1-18 or a pharmaceutically acceptable salt thereof, or a mixture thereof, or the pharmaceutical composition of claim 19 or 20, in the preparation of a medicament for treating and / or preventing TYK2 kinase-mediated diseases.

22. The use of claim 21, wherein the TYK2 kinase-mediated disease is selected from autoimmune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, and polycythemia vera; the skin disease is psoriasis, rash, or atopic dermatitis; the allergic disease is asthma or rhinitis; the organ rejection is allogeneic suppression 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.

23. The use of claim 22, wherein the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease.

24. The use of claim 21, wherein the TYK2 kinase-mediated disease is selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

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