Substituded pyridazin-3-formamide 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 particularly to substituted pyridazine-3-carboxamide compounds, compositions comprising 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 substituted 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, and mixtures 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] "Alkylene" refers to a divalent group formed by removing another hydrogen atom from an alkyl group, and can be substituted or unsubstituted. In some embodiments, C 1-6 Alkylene, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0023] "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.

[0024] "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.

[0025] "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.

[0026] 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 groups and C 1-2 Halogenated alkyl groups.

[0027] 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.

[0028] 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.

[0029] "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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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)).

[0034] 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.

[0035] 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.

[0036] 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.

[0037] "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.

[0038] "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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] Specifically, the present invention relates to the following technical solutions

[0046] 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, and mixtures thereof:

[0047]

[0048] in:

[0049] R1 is selected from H and C. 1-6 Haloalkyl, C 1-6 Alkylene-OR a C 1-6 Alkylene-SR a C 1-6 Alkylene-NR b R c C 1-6 Alkylene-C(O)R a C 1-6 Alkylene-C(O)OR a C 1-6 Alkylene-C(O)NR b R c C 1-6 Alkylene-OC(O)R a C 1-6 Alkylene-NR b C(O)R a C 1-6 Alkylene-S(O) m R a C 1-6 Alkylene-S(O) m NR bR c Or C 1-6 Alkylene-NR b S(O) m R a The group is optionally substituted with one or more deuterium groups until it is completely deuterated;

[0050] 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;

[0051] R3 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;

[0052] Each group in R1, R2 and R3 may be optionally replaced by 1, 2, 3 or 4 Rs;

[0053] Where R a R b and R c Independently selected from H and 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;

[0054] m = 1 or 2;

[0055] R is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0056] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein R1 is selected from H, C 1-6 Haloalkyl, C 1-6 Alkylene-OR a C 1-6 Alkylene-SR a C 1-6 Alkylene-NR b R c C1-6 Alkylene-C(O)R a C 1-6 Alkylene-C(O)OR a C 1-6 Alkylene-C(O)NR b R c C 1-6 Alkylene-OC(O)R a Or C 1-6 Alkylene-NR b C(O)R a The group is optionally substituted with one or more deuterium groups until complete deuteration; preferably, R1 is selected from H, C. 1-6 Haloalkyl, C 1-6 Alkylene-OR a C 1-6 Alkylene-SR a C 1-6 Alkylene-NR b R c C 1-6 Alkylene-C(O)OR a Or C 1-6 Alkylene-C(O)NR b R c The group is optionally substituted with one or more deuterium groups until complete deuteration; preferably, R1 is selected from H, C. 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-SH, C 1-6 Alkylene-NH2, C 1-6 alkylene-C(O)OH or C 1-6 Alkylene-C(O)NH2, wherein the group is optionally substituted with one or more deuterium groups until complete deuteration; preferably, R1 is selected from H or C. 1-6 The alkyl group is optionally substituted with one or more deuterium groups until fully deuterated; preferably, R1 is C. 1-6 Alkylene-OR a , where R a Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0057] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6alkynyl 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, 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 until complete deuteration; preferably, R2 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.

[0058] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein R3 is selected from C 1-6 Alkyl or C 1-6 The haloalkyl group is optionally substituted with one or more deuterium groups until fully deuterated; preferably, R3 is a methyl group, which is optionally substituted with one or more deuterium groups until fully deuterated.

[0059] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein:

[0060] R1 is selected from H and C. 1-6 Haloalkyl, C 1-6 Alkylene-OR a C 1-6 Alkylene-SR a Or C 1-6 Alkylene-C(O)OR a The group is optionally substituted with one or more deuterium groups until it is completely deuterated;

[0061] 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;

[0062] R3 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;

[0063] Each group in R1, R2 and R3 may be optionally replaced by 1, 2, 3 or 4 Rs;

[0064] Where R a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0065] R is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0066] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein:

[0067] R1 is selected from H and C. 1-4 Haloalkyl, C 1-4 Alkylene-OR a Or C 1-4 Alkylene-C(O)OH, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated;

[0068] R2 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0069] R3 is selected from C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0070] Where R a Selected from H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0071] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein:

[0072] R1 is C 1-4 Alkylene-OR a It may be optionally replaced by one or more deuteriums, up to complete deuteration;

[0073] R2 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; preferably C. 1-4Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0074] R3 is selected from C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0075] Where R a Selected from C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0076] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein:

[0077] R1 is selected from H and C. 1-4 Haloalkyl, C 1-4 alkylene-OH or C 1-4 Alkylene-C(O)OH, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated;

[0078] R2 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; preferably C. 1-4 Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0079] R3 is selected from C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

[0080] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein:

[0081] R1 is selected from H and C. 1-6 Alkylene-OR a and C 1-6 Alkylene-SR a The group is optionally substituted with one or more deuterium groups until it is completely deuterated;

[0082] R2 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0083] R3 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;

[0084] Each group in R1, R2 and R3 may be optionally replaced by 1, 2, 3 or 4 Rs;

[0085] Where R a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0086] R is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0087] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein:

[0088] R1 is selected from H and C. 1-6 Alkylene-OR a The group is optionally substituted with one or more deuterium groups until it is completely deuterated;

[0089] R2 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0090] R3 is C 1-6 Alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0091] Where R a Selected from H and C 1-6 alkyl.

[0092] In a more specific embodiment, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein:

[0093] R1 is selected from H and C. 1-4 Alkylene-OR a The group is optionally substituted with one or more deuterium groups until it is completely deuterated;

[0094] R2 is C 1-4 Alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration;

[0095] R3 is C 1-4 Alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

[0096] Where R a C 1-4 Alkyl groups. In more specific embodiments, the present invention provides compounds of formula (I) above, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein said compounds are selected from:

[0097]

[0098]

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] In some implementations, this method relates to diseases mediated by the TYK2 kinase selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

[0105] 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.

[0106] Dosage

[0107] 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.

[0108] Exemplary compositions for local application include a local carrier.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] Example

[0115] The materials or reagents used in this article are commercially available or prepared by synthetic methods commonly known in the art.

[0116] Example 1

[0117] 6-(cyclopropylcarbamate)-N-ethoxy-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 1)

[0118]

[0119] Step 1: Methyl 2-methoxy-3-nitrobenzene

[0120]

[0121] 3-Nitrosalicylic acid (15 g, 81.91 mmol) and cesium carbonate (106.756 g, 327.65 mmol) were dissolved in N,N dimethylformamide (300 mL). Iodomethane (58.54 g, 409.57 mmol) was added to the reaction system, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was stopped, and water (1.5 L) was added to the reaction solution for quenching. After filtration, the filter cake was dried to give the title compound (12.886 g, yield: 74.5%, white solid).

[0122] MS(ESI): m / z 212.1[M+H]+;

[0123] Step 2: 2-Methoxy-3-nitrobenzamide

[0124]

[0125] Methyl 2-methoxy-3-nitrobenzene (6.66 g, 31.54 mmol) was dissolved in methanol (36.63 mL), and ammonia (27.3 mL) was added. The reaction was carried out at room temperature for 16 hours. The reaction was stopped, and the reaction solution was concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane:methanol = 95:5) to give the title compound (5.2 g, yield: 84%, yellow solid).

[0126] MS(ESI): m / z 197.0[M+H]+;

[0127] Step 3: 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0128]

[0129] 2-Methoxy-3-nitrobenzamide (5.2 g, 26.53 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (67.6 mL) and reacted at 95 °C for 1 h. The solvent was removed from the reaction solution under vacuum, and the crude product was dissolved in ethanol (13 mL) to obtain the crude product. Ethanol (110 mL) and acetic acid (26 mL) were stirred at 0 °C for 5 min, and then hydrazine hydrate (13.18 mL) was added. After stirring for 15 min, the crude product solution was added, and the mixture was brought to room temperature and stirred for 1 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. It was then extracted with ethyl acetate (451 mL), washed twice with saturated sodium bicarbonate solution (451 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 9:1) to obtain the title compound (3.71 g, yield: 63.5%, yellow solid).

[0130] MS(ESI): m / z 221.1[M+H]+;

[0131] Step 4: 3-(2-methoxy-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole

[0132]

[0133] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.3 g, 5.9 mmol), 3,4-dihydro-2H-pyran (2.5 g, 29.52 mmol), and 4-methylbenzenesulfonic acid (224.61 mg, 1.18 mmol) were dissolved in tetrahydrofuran (52 mL), and the reaction mixture was stirred at 80 °C for 16 hours. The reaction was stopped, and the mixture was quenched with water (50 mL). The mixture was then extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to give the title compound (1.8 g, yield: 100%, yellow oil).

[0134] MS(ESI): m / z 305.1[M+H]+;

[0135] Step 5: 2-Methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)aniline

[0136]

[0137] 3-(2-methoxy-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (1.8 g, 5.92 mmol) was dissolved in methanol (50 mL), ammonia (0.85 mL) was added, and then palladium / carbon (251.8 mg, 2.4 mmol) was added in portions. After hydrogen purging, the reaction was carried out at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane:methanol = 100:1) to obtain the title compound (1.572 g, yield: 97%, yellow oil).

[0138] MS(ESI): m / z 275.1[M+H]+;

[0139] Step 6: ((6-chloro-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0140]

[0141] 2-Methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)aniline (400 mg, 1.46 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (348.21 mg, 1.75 mmol), and zinc acetate (321.08 mg, 1.75 mmol) were dissolved in 10 mL of water:isopropanol = 7:1. After nitrogen purging, the reaction mixture was reacted at 65 °C for 16 hours. The reaction was stopped, 15 mL of water was added to the reaction mixture, and the mixture was stirred for one hour. The mixture was then filtered, washed with tetrahydrofuran (0.5 mL), and the filter cake was dried to give the title compound (365 mg, yield: 54%, white solid).

[0142] MS(ESI): m / z 431.1[M+H]+;

[0143] Step 7: ((6-(cyclopropaneformamido)-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino))pyridazine-3-carbonyl)oxy)zinc(0.5)

[0144]

[0145] ((6-chloro-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (335 mg, 0.724 mmol), cyclopropaneformamide (308.18 mg, 3.62 mmol), (2R)-1-[(1R)-1-[bis(1,1-di-tert-butyl)phosphine]ethyl]-2-(dicyclohexylphosphine)ferrocene (120.49 mg, 0.217 mmol), tris[dibenzylideneacetone]palladium (132.64 mg, 0.145 mmol) and cesium carbonate (471.97 mg, 1.45 mmol) were dissolved in N,N-dimethylacetamide (5 mL), and after nitrogen purging, the reaction was carried out at 140 °C for 1 hour. The reaction was stopped, and the reaction solution was filtered. The filtrate was purified by reversed-phase column chromatography (C18, water / 0.1% TFA: acetonitrile = 70:30) to obtain the title compound (216 mg, yield: 58%, yellow solid).

[0146] MS(ESI): m / z 480.4[M+H]+;

[0147] Step 8: 6-(cyclopropylcarbamate)-N-ethoxy-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide

[0148]

[0149] N-methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added to a reaction flask, followed by ((6-(cyclopropaneformamido)-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino))pyridazine-3-carbonyl)oxy)zinc (0.5 mg) (100 mg, 0.196 mmol), and O-ethylhydroxylamine hydrochloride (28.62 mg). The reaction mixture was initially prepared with 1-hydroxybenzotriazole (52.87 mg, 0.39 mmol) and N-methylimidazole (48.18 mg, 0.587 mmol). After nitrogen purging, the mixture was reacted in an oil bath at 65 °C for 15 minutes. Finally, 1-hydroxybenzotriazole (52.87 mg, 0.39 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg, 0.39 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 (10 mL) was added to quench the reaction mixture. The mixture was then extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under vacuum to obtain the title compound (124 mg, brown oil).

[0150] MS(ESI): m / z 523.2[M+H]+;

[0151] Step 9: 6-(cyclopropylcarbamate)-N-ethoxy-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 1)

[0152]

[0153] 114 mg of 6-(cyclopropanecarbamate)-N-ethoxy-4-((2-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl))amino)pyridazine-3-carboxamide was dissolved in 2 mL of methanol, and 2 mL of dioxane chloride solution was added. The mixture was reacted at room temperature for 1 hour. 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 reversed-phase preparative chromatography (formic acid system) to obtain the title compound (12.71 mg, yield: 13.38%, white solid).

[0154] MS(ESI): m / z 439.1[M+H]+;

[0155] 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),11.34(s,1H),10.57(s,1H),8.35(s,1H),8.14(s,1H),7.77(d,J=7.6Hz,1H),7.56(d,J=6.6 Hz,1H),7.33(t,J=7.9Hz,1H),3.99(q,J=7.0Hz,2H),3.70(s,3H),2.08(t,J=5.8Hz,1H),1.23(t,J=7.0Hz,3H),0.83-0.81(m,4H).

[0156] Example 2

[0157] 6-(cyclopropylcarbamate)-N-ethoxy-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 2)

[0158]

[0159] Step 1: 3-(2-methoxy-3-nitrophenyl)-1-(2-methoxyethyl)-1H-1,2,4-triazole

[0160]

[0161] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.0 g, 4.542 mmol) was dissolved in ultradry N,N-dimethylformamide (10 mL), and cesium carbonate (4439 mg, 13.626 mmol) was added. After purging with nitrogen, 1-bromo-2-methoxyethane (947 mg, 6.813 mmol) was slowly added dropwise, and the reaction was carried out at 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, filtered, and the solvent was removed from the filtrate under vacuum to give the title compound (1.33 g, pale yellow oil).

[0162] MS(ESI): m / z 279.0 [M+H]+;

[0163] Step 2: 2-Methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)aniline

[0164]

[0165] 3-(2-methoxy-3-nitrophenyl)-1-(2-methoxyethyl)-1H-1,2,4-triazole (1.3 g, 4.672 mmol) was dissolved in methanol (30 mL), and palladium / carbon (198 mg, 1.869 mmol) was added. Hydrogen was purged three times, and the reaction was carried out 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 = 1:3) to give the title compound (830 mg, yield: 71.6%, colorless oil).

[0166] MS(ESI): m / z 249.1 [M+H]+;

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

[0168]

[0169] 2-Methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)aniline (750 mg, 3.021 mmol) was dissolved in water (21 mL) and isopropanol (3 mL). Lithium 4,6-dichloropyridazine-3-carboxylate (722 mg, 3.625 mmol) and zinc acetate (665 mg, 3.625 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, and water (21 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). The filter cake was dried to give the title compound (730 mg, yield: 55.3%, pale yellow solid).

[0170] MS(ESI): m / z 404.9[M+H]+;

[0171] Step 4: ((6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0172]

[0173] Zinc ((6-chloro-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (730 mg, 1.672 mmol)) was dissolved in toluene (8 mL) and acetonitrile (4 mL). Cyclopropylformamide (356 mg, 4.180 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (185 mg, 0.334 mmol), 1,8-diazabicycloundec-7-ene (254 mg, 1.672 mmol), potassium carbonate (462 mg, 3.344 mmol), and palladium acetate (75 mg, 0.334 mmol) were added. After 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 dried over anhydrous sodium sulfate and filtered, the solvent was removed from the filtrate under vacuum to obtain the title compound (1410 mg, brown solid), which was directly added to the next step.

[0174] MS(ESI): m / z 454.6[M+H]+;

[0175] Step 5: 6-(cyclopropylcarbamate)-N-ethoxy-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 2)

[0176]

[0177] 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-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 0.825 mmol) and O-ethylhydroxy Amino acid hydrochloride (121 mg, 1.238 mmol) and N-methylimidazole (202 mg, 2.475 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (223 mg, 1.650 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (316 mg, 1.650 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, and the reaction solution was filtered. The crude product of the filtrate was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (79.51 mg, yield: 19.4%, white solid).

[0178] MS(ESI): m / z 497.3[M+H]+;

[0179] 1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),11.31(s,1H),10.55(s,1H),8.57(s,1H) ,8.15(s,1H),7.66(dd,J=7.8,1.5Hz,1H),7.50(dd,J=7.9,1.4Hz,1H),7.27(t ,J=7.9Hz,1H),4.40(t,J=5.2Hz,2H),3.98(q,J=7.0Hz,2H),3.78–3.69(m,5H) ,3.25(s,3H),2.13–2.02(m,1H),1.22(t,J=7.0Hz,3H),0.81(d,J=5.4Hz,4H).

[0180] Example 3

[0181] 6-(cyclopropylcarbamate)-N-cyclopropoxy-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (compound 3)

[0182]

[0183] Step 1: 2-(vinyl)isoindoline-1,3-dione

[0184]

[0185] 2-Hydroxyisoindoline-1,3-dione (900 mg, 5.517 mmol) was dissolved in ultradry tetrahydrofuran (20 mL). Ethyleneborane pyridine complex (876 mg, 3.641 mmol), diethylurea (256 mg, 2.207 mmol), bis(((trifluoromethyl)sulfonyl)oxy)copper (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).

[0186] 1H 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).

[0187] Step 2: 2-Cyclopropoxyisoindoline-1,3-dione

[0188]

[0189] Diethylzinc (19 mL, 19.0 mmol, 1.0 M solution in Hexanes) 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 (0.1 N, 16 mL) was added to the reaction solution. The mixture was separated, and the organic phase was collected and washed successively with saturated sodium bicarbonate solution (17 mL) and saturated saline solution (10 mL). 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 (850 mg, yield: 87.9%, white solid).

[0190] Step 3: O-Cyclopropylhydroxylamine hydrochloride

[0191]

[0192] 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 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). 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 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).

[0193] Step 4: 6-(cyclopropylcarbamate)-N-cyclopropoxy-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (Compound 3)

[0194]

[0195] N-methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added to a reaction flask, followed by ((6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 0.825 mmol), O-cyclopropylhydroxylamine hydrochloride (136 mg, 1.238 mmol), and N-methylimidazole (202 mg, 2.475 mmol). The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (223 mg, 1.650 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (316 mg, 1.650 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, the reaction solution was filtered, and the crude filtrate was separated and purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (57 mg, yield: 13.6%, white solid).

[0196] MS(ESI): m / z 509.2[M+H]+;

[0197] 1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),11.33(s,1H),10.56(s,1H),8.58(s,1H), 8.17(s,1H),7.68(dd,J=7.8,1.5Hz,1H),7.52(dd,J=8.0,1.5Hz,1H),7.30–7.2 6(m,1H),4.42(t,J=5.2Hz,2H),4.13–4.06(m,1H),3.78–3.71(m,5H),3.26(s,3 H),2.14–2.05(m,1H),0.90(brs,2H),0.82(d,J=5.4Hz,4H),0.62–0.55(m,2H).

[0198] Example 4

[0199] 6-(cyclopropylcarbamate)-N-ethoxy-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (compound 4)

[0200]

[0201] Step 1: 1-(2-Fluoroethyl)-3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0202]

[0203] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1 g, 4.54 mmol), 1-fluoro-2-iodoethane (1.2 g, 6.81 mmol), and cesium carbonate (4.44 g, 13.62 mmol) were dissolved in N,N dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was stopped, and the mixture was quenched with water (10 mL). The mixture 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 filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, dichloromethane:methanol = 97:3) to give the title compound (1.16 g, yield: 91.37%, yellow solid).

[0204] MS(ESI): m / z 267.0[M+H]+;

[0205] Step 2: 3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline

[0206]

[0207] 1-(2-fluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.11 g, 4.17 mmol) was dissolved in tetrahydrofuran (12 mL), followed by the addition of methanol (20 mL) and ammonia (0.6 mL). Palladium / carbon (177.48 mg, 1.67 mmol) was then added in portions. After hydrogen purging, the reaction mixture was allowed to react at room temperature for 16 hours. The reaction was then stopped, the reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography (silica gel, dichloromethane:methanol = 98:2) to obtain the title compound (728 mg, yield: 70.75%, white solid).

[0208] MS(ESI): m / z 237.1[M+H]+;

[0209] Step 3: ((6-chloro-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc

[0210]

[0211] 3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (300 mg, 1.27 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (303.24 mg, 1.52 mmol), and zinc acetate (279.62 mg, 1.52 mmol) were dissolved in 9 mL of water:toluene = 7:1. After nitrogen purging, the reaction mixture was reacted at 65 °C for 16 hours. The reaction was stopped, 12 mL of water was added to the reaction mixture, and the mixture was stirred for one hour. The mixture was then filtered, washed with tetrahydrofuran (0.5 mL), and the filter cake was dried to give the title compound (360 mg, yield: 66.8%, white solid).

[0212] MS(ESI): m / z 393.0[M+H]+;

[0213] Step 4: ((6-(cyclopropylcarbamoyl)-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0214]

[0215] Zinc ((6-chloro-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (360 mg, 0.848 mmol), cyclopropaneformamide (216.53 mg, 2.544 mmol), (2R)-1-[(1R)-1-[bis(1,1-di-tert-butyl)phosphine]ethyl]-2-(bicyclo) Hexylphosphine (ferrocene) (94.07 mg, 0.17 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (129.12 mg, 0.848 mmol), potassium carbonate (351.66 mg, 2.544 mmol), and palladium acetate (38.08 mg, 0.17 mmol) were dissolved in 6 mL of toluene:acetonitrile (2:1). After nitrogen purging, the mixture was reacted at 75 °C for 16 hours. The reaction was stopped, and 12 mL of water:acetic acid (2:1) solution was added to the reaction mixture. The mixture was washed with petroleum ether (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined dichloromethane organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under vacuum to give the title compound (382 mg, yield: 95.2%, brown solid).

[0216] MS(ESI): m / z 442.2[M+H]+;

[0217] Step 5: 6-(cyclopropylcarbamate)-N-ethoxy-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 4)

[0218]

[0219] N-methylpyrrolidone (11.4 mL) and acetonitrile (11.4 mL) were added to a reaction flask, followed by di((6-(cyclopropaneformamido)-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (380 mg, 0.803 mmol) and O-ethylhydroxylamine hydrochloride (117.52 mg, 1.2 mmol). 0.05 mmol) and N-methylimidazole (197.83 mg, 2.41 mmol) were added, and after nitrogen purging, the mixture was reacted in an oil bath at 65 °C for 15 minutes. Finally, 1-hydroxybenzotriazole (217.06 mg, 1.61 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (307.95 mg, 1.61 mmol) were added, and 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 (20 mL). The solution was then extracted with ethyl acetate (25 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 (29.6 mg, yield: 7.6%, white solid).

[0220] MS(ESI): m / z 485.2[M+H]+;

[0221] 1H NMR(400MHz,DMSO)δ12.22(s,1H),11.33(s,1H),10.57(s,1H),8.66(s,1H),8.16(s,1H ),7.69(d,J=7.7Hz,1H),7.53(d,J=7.8Hz,1H),7.29(t,J=7.9Hz,1H),4.91(t,J=4.6Hz ,1H),4.79(t,J=4.6Hz,1H),4.64(t,J=4.6Hz,1H),4.57(t,J=4.6Hz,1H),3.99(q,J=7. 0Hz, 2H), 3.73 (s, 3H), 2.15–2.01 (m, 1H), 1.23 (t, J = 7.0Hz, 3H), 0.82 (d, J = 5.4Hz, 4H).

[0222] Example 5

[0223] 6-(cyclopropylcarbamoyl)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 5)

[0224]

[0225] Step 1: 1-(2,2-difluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0226]

[0227] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (900 mg, 4.087 mmol) was dissolved in N,N-dimethylformamide (8 mL), and cesium carbonate (3.995 g, 12.261 mmol) was added. Then, 1,1-difluoro-2-iodoethane (1.177 g, 6.131 mmol) was added at 0 °C. After nitrogen purging, the reaction was carried out at 65 °C for 5 hours. The reaction was stopped, and the reaction solution was filtered and water (20 mL) was added. The solution was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the title compound (1.05 g, yield: 90.3%, pale yellow oil).

[0228] MS(ESI): m / z 285.2[M+H]+;

[0229] Step 2: 3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline

[0230]

[0231] 1-(2,2-difluoroethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (950 mg, 3.339 mmol) was dissolved in MeOH (20 mL), and palladium / carbon (146 mg, 1.336 mmol) was added. After purging with hydrogen, 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. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the title compound (910 mg, yield: 83.6%, pale yellow oil).

[0232] MS(ESI): m / z 255.0[M+H]+;

[0233] Step 3: ((6-chloro-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5)

[0234]

[0235] 3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (830 mg, 3.264 mmol) was dissolved in water (21 mL) and isopropanol (3 mL). Lithium 4,6-dichloropyridazine-3-carboxylate (779 mg, 3.917 mmol) and zinc acetate (719 mg, 3.917 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 (25 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 (5 mL × 2) and tetrahydrofuran (1 mL). The filter cake was dried to give the title compound (940 mg, yield: 65.1%, white solid).

[0236] MS(ESI): m / z 411.0[M+H]+;

[0237] Step 4: ((6-(cyclopropylcarbamoyl)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0238]

[0239] Zinc ((6-chloro-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (420 mg, 0.949 mmol) was dissolved in toluene (4 mL) and acetonitrile (2 mL), and then cyclopropaneformamide (202 mg, 2.373 mmol), potassium carbonate (262 mg, 1.898 mmol), 1,8-diazahexacyclic[5.4.0]undec-7-ene (144 mg, 0.949 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (105 mg, 0.190 mmol) and palladium acetate (43 mg, 0.190 mmol) were added, nitrogen was substituted, and the reaction was carried out at 75 °C for 16 hours. Stop the reaction, add water (15 mL) and acetic acid (7.5 mL) to the reaction solution, wash with petroleum ether (30 mL × 2), and extract the aqueous phase with dichloromethane (10 mL × 3); combine the dichloromethanes and dry with anhydrous sodium sulfate, filter the filtrate and evaporate to dryness to obtain the crude title compound (520 mg, brown oil), and proceed directly to the next step.

[0240] MS(ESI): m / z 460.0[M+H]+;

[0241] Step 5: 6-(cyclopropylcarbamate)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-ethoxypyridazine-3-carboxamide (Compound 5)

[0242]

[0243] N-methylpyrrolidone (3 mL) and acetonitrile (3 mL) were added to a reaction flask, followed by ((6-(cyclopropylcarbamoyl)-4-((3-(1-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (0.5) (470 mg, 0.957 mmol), O-ethylhydroxylamine hydrochloride (140 mg, 1.436 mmol), and N-methylimidazole (235 mg, 2.871 mmol). The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (259 mg, 1.914 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (367 mg, 1.914 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 5 hours. The reaction was stopped, the reaction solution was filtered, and the crude product of the filtrate was separated and purified by high performance liquid chromatography (elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound (13.54 mg, yield: 2.8%, white solid).

[0244] MS(ESI): m / z 503.0[M+H]+;

[0245] 1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),11.33(s,1H),10.57(s,1H),8.69(s,1H) ,8.16(s,1H),7.68(dd,J=7.8,1.3Hz,1H),7.54(d,J=6.7Hz,1H),7.29(t,J=7. 9Hz,1H),6.64–6.32(m,1H),4.83(td,J=15.2,3.4Hz,2H),3.99(q,J=7.0Hz,2H ),3.72(s,3H),2.12–2.04(m,1H),1.23(t,J=7.0Hz,3H),0.82(d,J=4.6Hz,4H).

[0246] Example 6

[0247] 6-(cyclopropylcarbamate)-N-cyclopropoxy-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (compound 6)

[0248]

[0249] N-methylpyrrolidone (4 mL) and acetonitrile (4 mL) were added to a reaction flask, followed by ((6-(cyclopropylcarbamoyl)-4-((3-(1-(2-fluoroethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carbonyl)oxy)zinc (830 mg, 1.754 mmol), O-cyclopropylhydroxylamine hydrochloride (288 mg, 2.631 mmol), and N-methylimidazole (430 mg, 5.262 mmol). The reaction mixture was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (474 ​​mg, 3.508 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (672 mg, 3.508 mmol) were added. The reaction 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 (82.74 mg, yield: 63.3%, gray solid).

[0250] MS(ESI): m / z 497.3[M+H]+;

[0251] 1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),11.32(s,1H),10.55(s,1H),8.65(s,1H),8.16(s,1H) ,7.68(dd,J=7.8,1.4Hz,1H),7.52(dd,J=7.9,1.3Hz,1H),7.28(t,J=7.9Hz,1H),4.90(t,J= 4.6Hz,1H),4.78(t,J=4.6Hz,1H),4.63(t,J=4.6Hz,1H),4.56(t,J=4.6Hz,1H),4.09(brs,1 H),3.72(s,3H),2.10–2.05(m,1H),0.89(brs,2H),0.81(d,J=5.3Hz,4H),0.61–0.54(m,2H).

[0252] Example 7

[0253] 2-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)acetic acid (compound 7)

[0254]

[0255] Step 1: 2-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)tert-butyl acetate

[0256]

[0257] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (550 mg, 2.50 mmol), tert-butyl 2-bromoacetate (730.8 mg, 3.75 mmol), and cesium carbonate (1.63 g, 5.00 mmol) were dissolved in N,N dimethylformamide (5.5 mL). The reaction mixture was stirred at 50 °C for 1 hour. The reaction was stopped, and water (5 mL) was added to quench the reaction mixture. The mixture was then extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 4:1) to obtain the title compound (554 mg, yield: 66.34%, white solid).

[0258] MS(ESI): m / z 335.0[M+H]+;

[0259] Step 2: 2-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)tert-butyl acetate

[0260]

[0261] 2-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)tert-butyl acetate (554 mg, 1.66 mmol) was dissolved in methanol (20 mL), ammonium hydroxide (0.3 mL) was added, followed by the addition of palladium / carbon (70.54 mg, 0.66 mmol) in portions. After hydrogen purging, the reaction was carried out at room temperature for 16 hours. The reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 3:7) to obtain the title compound (300 mg, yield: 59.49%, yellow solid).

[0262] MS(ESI): m / z 305.1[M+H]+;

[0263] Step 3: ((4-((3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5)

[0264]

[0265] 2-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)tert-butyl acetate (200 mg, 0.657 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (156.93 mg, 0.789 mmol), and zinc acetate (144.7 mg, 0.789 mmol) were dissolved in 6 mL of water:toluene = 7:1. After nitrogen purging, the mixture was reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, 8 mL of water was added to the reaction mixture, and the mixture was stirred for one hour. The mixture was then filtered, washed with tetrahydrofuran (0.5 mL), and the filter cake was dried to give the title compound (185 mg, yield: 57.4%, white solid).

[0266] MS(ESI): m / z 461.1[M+H]+;

[0267] Step 4: ((4-((3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropaneformylamino)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0268]

[0269] Zinc ((4-((3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5) (140 mg, 0.285 mmol), cyclopropaneformamide (72.86 mg, 0.856 mmol), (2R)-1-[(1R)-1-[bis(1,1-di-tert-butyl)phosphine]ethyl]-2- (Dicyclohexylphosphine)ferrocene (31.65 mg, 0.0571 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (43.45 mg, 0.285 mmol), potassium carbonate (118.33 mg, 0.856 mmol), and palladium acetate (12.81 mg, 0.0571 mmol) were dissolved in 2 mL of toluene:acetonitrile = 2:1. After nitrogen purging, the reaction mixture was reacted at 75 °C for 16 hours. The reaction was stopped, and 4.5 mL of water:acetic acid = 2:1 solution was added to the reaction mixture. The mixture was washed with petroleum ether (8 mL) and then extracted with dichloromethane (16 mL × 3). The combined dichloromethane organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under vacuum to give the title compound (104 mg, yield: 67.3%, brown oil).

[0270] MS(ESI): m / z 510.1[M+H]+;

[0271] Step 5: 2-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazole-1-tert-butyl acetate

[0272]

[0273] N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added to a reaction flask, followed by ((4-((3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropaneformylamino)pyridazine-3-carbonyl)oxy)zinc (0.5) (84 mg, 0.155 mmol), and O-ethylhydroxylamine hydrochloride (22.91 mL). After nitrogen purging of N-methylimidazole (38.23 mg, 0.466 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59.51 mg, 0.31 mmol), the reaction was carried out in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (41.94 mg, 0.31 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59.51 mg, 0.31 mmol) were added, and the reaction was carried out in an oil bath at 65 °C for 16 hours after nitrogen purging. The reaction was stopped, and the reaction solution was extracted with ethyl acetate (8 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 give the title compound (305 mg, purity: 73.73%, brown oil).

[0274] MS(ESI): m / z 553.1[M+H]+;

[0275] Step 6: 2-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)acetic acid (compound 7)

[0276]

[0277] 300 mg of 2-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-acetic acid tert-butyl ester was dissolved in 10 mL of a solvent of trifluoroacetic acid and 1,2-dichloroethane in a 1:1 ratio, and the reaction was carried out at room temperature for 5 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 reversed-phase preparative chromatography to obtain the title compound (5 mg, yield: 1.8%, white solid).

[0278] MS(ESI): m / z 497.1[M+H]+;

[0279] 1H NMR (400MHz, DMSO-d6) δ11.32(s,1H),10.55(s,1H),8.49(s,1H),8.16(s,1H),7.67(d,J=7.7Hz,1H),7.49(d,J=7.6Hz,1H),7.26( t,J=7.9Hz,1H),4.71(s,2H),3.99(q,J=7.0Hz,2H),3.71(s,3H),2.14–2.01(m,1H),1.23(t,J=7.0Hz,3H),0.82(d,J=5.5Hz,4H).

[0280] Example 8

[0281] 3-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propionic acid (compound 8)

[0282]

[0283] Step 1: tert-butyl 3-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)propionate

[0284]

[0285] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (400 mg, 1.818 mmol) was dissolved in ultradry N,N-dimethylformamide (5 mL), and cesium carbonate (1.78 g, 5.454 mmol) was added. After nitrogen purging, tert-butyl 3-bromopropionate (570 mg, 2.727 mmol) was slowly added dropwise in an ice bath at 0 °C, and the reaction was carried out at 50 °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 (10 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), 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 silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain the title compound (490 mg, yield: 77.5%, pale yellow oil).

[0286] MS(ESI): m / z 349.0[M+H]+;

[0287] Step 2: Tert-butyl 3-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propionate

[0288]

[0289] 3-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)propionate tert-butyl ester (490 mg, 1.408 mmol) was dissolved in methanol (20 mL), and palladium / carbon catalyst (37 mg, 0.352 mmol) was added. After three hydrogen purgings, the reaction was carried out at room temperature for 2 hours. The reaction was stopped, and the palladium / carbon catalyst was filtered off. 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 = 10:1) to obtain the title compound (420 mg, yield: 93.8%, pale yellow oil).

[0290] MS(ESI): m / z 319.4[M+H]+;

[0291] Step 3: ((4-((3-(1-(3-(tert-butoxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc(0.5)

[0292]

[0293] 3-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)tert-butyl propionate (420 mg, 1.321 mmol) was dissolved in water (7 mL) and isopropanol (1 mL). Lithium 4,6-dichloropyridazine-3-carboxylate (304 mg, 1.585 mmol) and zinc acetate (291 mg, 1.585 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, 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 (6 mL × 2) and tetrahydrofuran (1 mL). The filter cake was dried to give the title compound (320 mg, yield: 47.9%, brown solid).

[0294] MS(ESI): m / z 475.1[M+H]+;

[0295] Step 4: ((4-((3-(1-(3-(tert-butoxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0296]

[0297] Zinc ((4-((3-(1-(3-(tert-butoxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5) (320 mg, 0.632 mmol) was dissolved in toluene (4 mL) and acetonitrile (2 mL). Cyclopropylformamide (134 mg, 1.580 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (70 mg, 0.126 mmol), 1,8-diazabicycloundec-7-ene (96 mg, 0.632 mmol), potassium carbonate (174 mg, 1.264 mmol), and palladium acetate (28 mg, 0.126 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 (8 mL) and acetic acid (4 mL) were added, the mixture was washed with petroleum ether (15 mL × 2), the aqueous phase was extracted with dichloromethane (20 mL × 3), the combined dichloromethane organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under vacuum to give the title compound (275 mg, yield: 78.4%, brown solid).

[0298] MS(ESI): m / z 524.2[M+H]+;

[0299] Step 5: 3-(3-(6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)tert-butyl propionate

[0300]

[0301] N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added to a reaction flask, followed by ((4-((3-(1-(3-(tert-butoxy)-3-oxopropyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)pyridazine-3-carbonyl)oxy)zinc (0.5) (275 mg, 0.495 mmol), O-ethylhydroxylamine hydrochloride (72 mg, 0.743 mmol), and N-methylimidazolium (121 mg, 1.485 mmol). The reaction solution was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (134 mg, 0.990 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg, 0.990 mmol) were added. The reaction solution was stirred in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (10 mL) was added to the reaction solution for quenching. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under vacuum to give the title compound (300 mg, yield: 8.02%, yellow solid).

[0302] MS(ESI): m / z 567.1[M+H]+;

[0303] Step 6: 3-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propionic acid (compound 8)

[0304]

[0305] 10g (300mg, 0.531mmol) of tert-butyl 3-(3-(6-(cyclopropaneformamide)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)propionate was dissolved in dichloromethane (1mL), and trifluoroacetic acid (1mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was stopped, and the reaction solution was evaporated to dryness. The crude product was purified by high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (37.98mg, yield: 14.0%, pale yellow solid).

[0306] MS(ESI): m / z 511.2[M+H]+;

[0307] 1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),11.32(s,1H),10.57(s,1H),8.59(s,1 H),8.16(s,1H),7.67(d,J=7.8Hz,1H),7.51(d,J=7.9Hz,1H),7.27(t,J=7.9 Hz,1H),4.45(t,J=6.5Hz,2H),3.99(q,J=7.0Hz,2H),3.71(s,3H),2.89(t,J =6.5Hz,2H),2.12–2.04(m,1H),1.23(t,J=7.0Hz,3H),0.82(d,J=5.5Hz,4H).

[0308] Example 9

[0309] 4-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butyric acid (compound 9)

[0310]

[0311] Step 1: 4-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)tert-butyl butyrate

[0312]

[0313] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole 1 (500 mg, 2.27 mmol) was dissolved in N,N-dimethylformamide (10 mL), and tert-butyl 4-bromobutyrate (760 mg, 3.41 mmol) and cesium carbonate (1.48 g, 4.54 mmol) were added. After purging with nitrogen three times, the reaction solution was stirred in an oil bath at 50 °C for 2 hours. The reaction was stopped, and the reaction solution was poured into water (40 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), 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 silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the title compound (720 mg, yield: 87.4%, yellow oil).

[0314] MS(ESI): m / z 363.1[M+H]+;

[0315] Step 2: Tert-butyl 4-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butyrate

[0316]

[0317] 720 mg (1.987 mmol) of tert-butyl 4-(3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazol-1-yl)butyrate was dissolved in 12 mL of methanol. A palladium / carbon catalyst (72 mg) was added, and the mixture was purged three times with hydrogen. The reaction was then 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 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 (500 mg, yield: 75.8%, colorless transparent oil).

[0318] MS(ESI): m / z 333.2[M+H]+;

[0319] Step 3: ((4-((3-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5)

[0320]

[0321] 4-(3-(3-amino-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)tert-butyl butyrate (500 mg, 1.504 mmol) was dissolved in isopropanol (3 mL) and water (21 mL). Lithium 4,6-dichloropyridazine-3-carboxylate (357.4 mg, 1.805 mmol) and zinc acetate (331.2 mg, 1.805 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, 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 (2 mL). After drying, the title compound (620 mg, yield: 79.2%, white solid) was obtained.

[0322] MS(ESI): m / z 489.1[M+H]+;

[0323] Step 4: ((4-((3-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0324]

[0325] Zinc ((4-((3-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5) (620 mg, 1.191 mmol) was dissolved in toluene (6 mL) and acetonitrile (3 mL), and cyclopropylformamide (253.4 mg, 2.978 mmol) and (R)-(-) were added. -1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (132.1 mg, 0.238 mmol), 1,8-diazabicycloundec-7-ene (181.3 mg, 1.191 mmol), potassium carbonate (329.2 mg, 2.382 mmol), and palladium acetate (53.5 mg, 0.238 mmol) were reacted in an oil bath at 75 °C for 16 hours after nitrogen purging. The reaction was stopped, the reaction solution was cooled to room temperature, and water (20 mL) and acetic acid (10 mL) were added. The mixture was washed with petroleum ether (30 mL × 3), and the aqueous phase was extracted with dichloromethane (40 mL × 3). The combined dichloromethane organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under vacuum to give the title compound (650 mg, yield: 95.9%, brown solid).

[0326] MS(ESI): m / z 538.1[M+H]+;

[0327] Step 5: 4-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazine-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)tert-butyl butyrate

[0328]

[0329] N-methylpyrrolidone (6 mL) and acetonitrile (6 mL) were added to a reaction flask, followed by ((4-((3-(1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)pyridazine-3-carbonyl)oxy)zinc (0.5 mg) (650 mg, 1.142 mmol) and O-ethylhydroxylamine hydrochloride (334.2 mL). The reaction mixture was stirred in an oil bath at 65°C for 15 minutes with N-methylimidazole (308.6 mg, 2.284 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (437.8 mg, 2.284 mmol). The reaction mixture was then stirred in an oil bath at 65°C for 16 hours. The reaction mixture was then stopped, and the solution was poured into water (40 mL). 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 filtered. The solvent was removed from the filtrate under vacuum to obtain the crude title compound (1 g, yellow oil), which was directly added to the next step.

[0330] MS(ESI): m / z 581.1[M+H]+;

[0331] Step 6: 4-(3-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butyric acid (compound 9)

[0332]

[0333] 1 g (1.722 mmol) of tert-butyl 4-(3-((6-(cyclopropylcarbamoyl)-3-(ethoxycarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)butyrate was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added. After purging with nitrogen three times, the reaction was carried out at room temperature for 8 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 high performance liquid chromatography (elution system: formic acid, water, acetonitrile) to obtain the title compound (85.41 mg, yield: 9.46%, yellow solid).

[0334] MS(ESI): m / z 525.0[M+H]+;

[0335] 1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),11.31(s,1H),10.56(s,1H),8.61(s,1 H),8.16(s,1H),7.68(dd,J=7.7,1.0Hz,1H),7.51(d,J=8.0Hz,1H),7.28(t,J =7.9Hz,1H),4.28(t,J=6.8Hz,2H),4.02–3.97(m,2H),3.72(s,3H),2.29(t,J =7.3Hz,2H),2.10–2.04(m,3H),1.23(t,J=7.0Hz,3H),0.82(d,J=6.0Hz,4H).

[0336] Example 10

[0337] 6-(Cyclopropylcarboxamide)-N-ethoxy-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 10)

[0338]

[0339] Step 1: 1-(2-(benzyloxy)ethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0340]

[0341] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1000 mg, 4.542 mmol) was dissolved in ultradry N,N-dimethylformamide (10 mL), and cesium carbonate (4440 mg, 13.626 mmol) and ((2-bromoethoxy)methyl)benzene (1465 mg, 6.813 mmol) were added. The reaction was carried out at 50 °C for 1 hour. The reaction was stopped, and the reaction solution was filtered and poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. The filtrate was filtered, 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 obtain the title compound (1.5 g, yield: 93.3%, pale yellow oil).

[0342] MS(ESI): m / z 355.5[M+H]+;

[0343] Step 2: 3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline

[0344]

[0345] 1-(2-(benzyloxy)ethyl)-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.5 g, 4.233 mmol) was dissolved in isopropanol (10 mL) and water (0.8 mL). Iron powder (233 mg, 21.165 mmol) and ammonium chloride (1132 mg, 21.165 mmol) were added, and the mixture was purged with nitrogen three times. The reaction was carried out at 70 °C for 1 hour. 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 = 1:5) to obtain the title compound (1.32 g, yield: 96.1%, colorless oil).

[0346] MS(ESI): m / z 325.0[M+H]+;

[0347] Step 3: ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5)

[0348]

[0349] 3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (1.2 g, 3.699 mmol) was dissolved in water (35 mL) and isopropanol (5 mL). Lithium 4,6-dichloropyridazine-3-carboxylate (879 mg, 4.439 mmol) and zinc acetate (815 mg, 4.439 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 (40 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 (1 mL). After drying, the title compound (1.2 g, yield: 63.3%, gray solid) was obtained.

[0350] MS(ESI): m / z 481.1[M+H]+;

[0351] Step 4: ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)pyridazine-3-carbonyl)oxy)zinc(0.5)

[0352]

[0353] Zinc ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-chloropyridazine-3-carbonyl)oxy)zinc (0.5 g) (1.2 g, 2.138 mmol) was dissolved in toluene (24 mL) and acetonitrile (12 mL). Cyclopropylformamide (454 mg, 5.345 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (237 mg, 0.428 mmol), 1,8-diazabicycloundec-7-ene (325 mg, 2.138 mmol), potassium carbonate (590 mg, 4.276 mmol), and palladium acetate (96 mg, 0.428 mmol) were added. After 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 (30 mL) and acetic acid (15 mL) were added, the mixture was washed with petroleum ether (50 mL × 2), the aqueous phase was extracted with dichloromethane (10 mL × 3), the combined dichloromethane organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate, the filtrate was filtered and the solvent was removed by vacuum to obtain the title compound (1.8 g, brown oil), which was directly added to the next reaction.

[0354] MS(ESI): m / z 530.0[M+H]+;

[0355] Step 5: 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-ethoxypyridazine-3-carboxamide

[0356]

[0357] Take a 25 mL reaction flask, add N-methylpyrrolidone (2 mL) and acetonitrile (2 mL), then add ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 0.713 mmol), O-ethylhydroxylamine hydrochloride (104 mg, 1.070 mmol), and N-methylimidazolium (175 mg, 2.139 mmol). Stir the reaction solution in an oil bath at 65 °C for 15 minutes, then add 1-hydroxybenzotriazole (193 mg, 1.426 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (273 mg, 1.426 mmol). Stir the reaction solution in an oil bath at 65 °C for 16 hours. The reaction was stopped, and water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the title compound (510 mg, brown oil). This compound was then directly added to the next reaction.

[0358] MS(ESI): m / z 573.1[M+H]+;

[0359] Step 6: 6-(cyclopropylcarboxamide)-N-ethoxy-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 10)

[0360]

[0361] 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarbamate)-N-ethoxypyridazine-3-carboxamide (510 mg, 0.891 mmol) was dissolved in methanol (20 mL), and palladium on carbon (38 mg, 0.356 mmol) was added. After purging with hydrogen, the reaction was carried out 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 high performance liquid chromatography (elution system: ammonia, acetonitrile, water) to obtain the title compound (20.4 mg, yield: 4.7%, white solid).

[0362] MS(ESI): m / z 483.0[M+H]+;

[0363] 1H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.10(s,1H),7.63(d,J=7.7Hz,1H),7.47(d,J=8.0Hz,1H),7.24(t,J=8.0Hz,1H),5.00(s,1H),4 .26(d,J=4.9Hz,2H),3.94(d,J=6.4Hz,2H),3.78(brs,2H),3.72(s,3H),2.05(brs,1H),1.20(t,J=6.7Hz,3H),0.80(d,J=5.7Hz,4H).

[0364] Example 11

[0365] 6-(Cyclopropylcarbamate)-N-(2-Fluoroethoxy)-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 11)

[0366]

[0367] Step 1: 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(2-fluoroethoxy)pyridazine-3-carboxamide

[0368]

[0369] N-methylpyrrolidone (9 mL) and acetonitrile (9 mL) were stirred at room temperature for ten minutes. Then, ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)pyridazine-3-carbonyl)oxy)zinc (0.5 mg) (300 mg, 0.64 mmol) and O-(2-fluoroethyl)hydroxylamine hydrochloride (110.91 mg) were added. The reaction mixture was initially prepared with 1-hydroxybenzotriazole (172.95 mg, 1.28 mmol) and N-methylimidazole (158.45 mg, 1.93 mmol), purged with nitrogen, and reacted in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (172.95 mg, 1.28 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (245.38 mg, 1.28 mmol) were added, purged with nitrogen, and reacted in an oil bath at 65 °C for 16 hours. The reaction was stopped, quenched with water (20 mL), and extracted with ethyl acetate (30 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 give the title compound (300 mg, yield: 95.1%, brown solid).

[0370] MS(ESI): m / z 591.3[M+H]+;

[0371] Step 2: 6-(cyclopropylcarbamate)-N-(2-fluoroethoxy)-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 11)

[0372]

[0373] 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(2-fluoroethoxy)pyridazine-3-carboxamide (158 mg, 0.268 mmol) was dissolved in acetonitrile (3 mL), followed by the addition of trimethyliodosilane (267.64 mg, 1.338 mmol). The reaction was carried out at room temperature for 4 hours. The reaction was stopped, and the solvent was removed under vacuum to obtain the crude product. The crude product was purified by reversed-phase preparative chromatography (elution system: formic acid, acetonitrile, water) to obtain the title compound (27.91 mg, yield: 20.85%, white solid).

[0374] MS(ESI): m / z 501.1[M+H]+;

[0375] 1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),11.34(s,1H),10.51(s,1H),8.56(s,1H),8.15 (s,1H),7.70(dd,J=7.8,1.3Hz,1H),7.51(d,J=6.7Hz,1H),7.28(t,J=7.9Hz,1H),4. 77–4.73(m,1H),4.65–4.59(m,1H),4.29(t,J=5.3Hz,2H),4.26–4.23(m,1H),4.19–4 .14(m,1H),3.80(t,J=5.4Hz,2H),3.73(s,3H),2.12–2.05(m,1H),0.85–0.80(m,4H).

[0376] Example 12

[0377] 6-(cyclopropylcarbamoyl)-N-(2,2-difluoroethoxy)-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 12)

[0378]

[0379] Step 1: 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamide)-N-(2,2-difluoroethoxy)pyridazine-3-carboxamide

[0380]

[0381] N-methylpyrrolidone (2 mL) and acetonitrile (2 mL) were added to a reaction flask, followed by ((4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)pyridazine-3-carbonyl)oxy)zinc (0.5) (400 mg, 0.713 mmol), O-(2,2-difluoroethyl)hydroxylamine hydrochloride (143 mg, 1.070 mmol), and N-methylimidazolium (175 mg, 2.139 mmol). The reaction mixture was stirred in an oil bath at 65 °C for 15 minutes. Then, 1-hydroxybenzotriazole (193 mg, 1.426 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (273 mg, 1.426 mmol) were added. The reaction mixture was stirred 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 extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give the title compound (290 mg, yield: 66.8%, brown oil).

[0382] MS(ESI): m / z 609.0[M+H]+;

[0383] Step 2: 6-(cyclopropylcarbamate)-N-(2,2-difluoroethoxy)-4-((3-(1-(2-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide (Compound 12)

[0384]

[0385] Take a 50 mL reaction flask, dissolve 260 mg (0.427 mmol) of 4-((3-(1-(2-(benzyloxy)ethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamide)-N-(2,2-difluoroethoxy)pyridazine-3-carboxamide in methanol (20 mL), add palladium / carbon (18 mg, 0.171 mmol), replace with hydrogen gas, and stir the reaction at room temperature for 40 hours. Stop the reaction, filter the reaction solution, and evaporate the filtrate to dryness. The crude product is purified by high performance liquid chromatography (elution system: formic acid, acetonitrile, water) to obtain the title compound (7.65 mg, yield: 3.5%, white solid).

[0386] MS(ESI): m / z 519.1[M+H]+;

[0387] 1H NMR (400MHz, DMSO-d6) δ11.31(s,1H),10.48(s,1H),8.54(s,1H),8.13(s,1H),7.68(d,J=7.5Hz,1H),7.50(d,J=8.0Hz,1H),7.27(t ,J=7.9Hz,1H),6.34(t,J=54.5Hz,1H),5.00(s,1H),4.29–4.21(m,4H),3.82–3.70(m,5H),2.13–2.01(m,1H),0.81(d,J=5.2Hz,4H).

[0388] Biological testing evaluation

[0389] Test Example A: In vitro enzyme binding experiment of compound TYK2 JH2 of the present invention.

[0390] 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.

[0391] Experimental methods:

[0392] 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 pseudokinase (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 .

[0393] Experimental results:

[0394]

[0395]

[0396] The experimental data show that the compound of this invention has a good binding effect on TYK2 JH2 pseudokinase.

[0397] Test Example B: Determination of the effect of the compound of the present invention on STAT5 phosphorylation of CD3+ cell subsets (JAK1 / 3) in human PBMCs induced by IL-2.

[0398] 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.

[0399] Experimental methods:

[0400] 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 PermBuffer III (BD), and incubate at 4°C in the dark for 40 minutes. Wash cells twice with PBS, add 100 μL STAT5 pY694 antibody working solution (BD), and incubate at room temperature for 40 minutes. Wash cells once with PBS, add 200 μL staining buffer to resuspend cells, transfer to a sample plate, analyze antibody fluorescence intensity using FlowJo software, and calculate the IC50 of the compound using XL-Fit software. 50 .

[0401] Experimental conclusion:

[0402] Compound numbering <![CDATA[pSTAT5 (JAK1 / 3) (IC induced by IL-2 in hPBMC 50 , μM)]]> Compound 1 >30 Compound 2 >30 BMS-986165 0.409

[0403] The experimental data show that the compound of this invention has lower inhibitory activity on the JAK1 / 3 signaling pathway and better selectivity.

[0404] Test Example C: Determination of the inhibitory effect of the compounds of the present invention on JAK1 JH1 / JAK2 JH1 / JAK3 JH1 / TYK2 JH1 kinases.

[0405] Experimental objective: The purpose of this test case is to detect the inhibitory effect of the compound on the activity of JAK1 JH1 / JAK2 JH1 / JAK3 JH1 / TYK2 JH1 kinases using homogeneous time-resolved fluorescence resonance energy transfer (HTRF).

[0406] Experimental methods:

[0407] Using an automated micropipette system, transfer the compound working solution to a 384-well plate at 100 nL per well. Add 5 μL of 2X JAK1 JH1 / JAK2 JH1 / JAK3 JH1 / TYK2 JH1 kinase solution or reaction buffer to each well, centrifuge to mix, and incubate at 25°C for 15 minutes. After incubation, add 5 μL of 2X TK-SUB-biotin substrate and ATP mixture to each well, centrifuge to mix, and incubate at 25°C for 45 minutes (JAK1 / JAK2) or 60 minutes (JAK3 / TYK2). After incubation, add 10 μL of detection mixture (TK Antibody-EU and Streptavidin-XL mixture) to each well, centrifuge to mix, and incubate at 25°C for 60 minutes (JAK1 / JAK2) or 120 minutes (JAK3 / TYK2). After incubation, the cells were transferred to a 4°C refrigerator for overnight incubation. Fluorescence values ​​were read on an Envision 2104 Multilabel Reader, and the IC50 of the compounds was calculated using XL-Fit software. 50 .

[0408] Experimental conclusion:

[0409]

[0410] The experimental data show that the compound of the present invention has lower inhibitory activity against JAK1 JH1 / JAK2 JH1 / JAK3 JH1 and has better selectivity.

Claims

1. Compounds of general formula (I), or pharmaceutically acceptable salts thereof, and mixtures thereof: (I) in: R1 is selected from H and C. 1-6 Haloalkyl, C 1-6 Alkylene-OR a C 1-6 Alkylene-SR a C 1-6 Alkylene-NR b R c C 1-6 Alkylene-C(O)R a C 1-6 Alkylene-C(O)OR a C 1-6 Alkylene-C(O)NR b R c C 1-6 Alkylene-OC(O)R a C 1-6 Alkylene-NR b C(O)R a C 1-6 Alkylene-S(O) m R a C 1-6 Alkylene-S(O) m NR b R c Or C 1-6 Alkylene-NR b S(O) m R a The group is optionally substituted with one or more deuterium groups until it is completely 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 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 and R3 may be optionally replaced by 1, 2, 3 or 4 Rs; Where R a R b and R c Independently selected from H and 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; m = 1 or 2; R is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, R1 is selected from H and C. 1-6 Haloalkyl, C 1-6 Alkylene-OR a C 1-6 Alkylene-SR a C 1-6 Alkylene-NR b R c C 1-6 Alkylene-C(O)R a C 1-6 Alkylene-C(O)OR a C 1-6 Alkylene-C(O)NR b R c C 1-6 Alkylene-OC(O)R a Or C 1-6 Alkylene-NR b C(O)R a The group is optionally substituted with one or more deuterium groups, up to complete deuteration.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, R1 is selected from H and C. 1-6 Haloalkyl, C 1-6 Alkylene-OR a C 1-6 Alkylene-SR a C 1-6 Alkylene-NR b R c C 1-6 Alkylene-C(O)OR a Or C 1-6 Alkylene-C(O)NR b R c The group is optionally substituted with one or more deuterium groups, up to complete deuteration.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, R1 is selected from H and C. 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene-SH, C 1-6 Alkylene-NH2, C 1-6 alkylene-C(O)OH or C 1-6 Alkylene-C(O)NH2, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated.

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, R1 is selected from H or C. 1-6 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, R1 is C 1-6 Alkylene-OR a , where R a Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and mixtures 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.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, 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.

9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, R2 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.

10. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, R3 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.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein, R3 is a methyl group, which is optionally substituted with one or more deuterium groups, up to complete deuteration.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R1 is selected from H and C. 1-6 Haloalkyl, C 1-6 Alkylene-OR a C 1-6 Alkylene-SR a Or C 1-6 Alkylene-C(O)OR a The group is optionally substituted with one or more deuterium groups until it is completely deuterated; 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 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 and R3 may be optionally replaced by 1, 2, 3 or 4 Rs; Where R a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R1 is selected from H and C. 1-4 Haloalkyl, C 1-4 Alkylene-OR a Or C 1-4 Alkylene-C(O)OH, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated; R2 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; R3 is selected from C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; Where R a Selected from H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R1 is C 1-4 Alkylene-OR a It may be optionally replaced by one or more deuteriums, up to complete deuteration; R2 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; R3 is selected from C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; Where R a Selected from C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R2 is C 1-4 Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R1 is selected from H and C. 1-4 Haloalkyl, C 1-4 alkylene-OH or C 1-4 Alkylene-C(O)OH, wherein the group is optionally substituted with one or more deuterium groups until fully deuterated; R2 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-7 Cycloalkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; R3 is selected from C 1-4 Alkyl or C 1-4 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R2 is C 1-4 Alkyl groups, which are optionally substituted with one or more deuterium groups, up to complete deuteration.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R1 is selected from H and C. 1-6 Alkylene-OR a and C 1-6 Alkylene-SR a The group is optionally substituted with one or more deuterium groups until it is completely deuterated; R2 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; R3 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 and R3 may be optionally replaced by 1, 2, 3 or 4 Rs; Where R a Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R is selected from H, D, halogen, CN, C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R1 is selected from H and C. 1-6 Alkylene-OR a The group is optionally substituted with one or more deuterium groups until it is completely deuterated; R2 is selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R3 is C 1-6 Alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; Where R a Selected from H and C 1-6 alkyl.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, and mixtures thereof, wherein: R1 is selected from H and C. 1-4 Alkylene-OR a The group is optionally substituted with one or more deuterium groups until it is completely deuterated; R2 is C 1-4 Alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration; R3 is C 1-4 Alkyl groups, wherein the groups are optionally substituted with one or more deuterium groups, up to complete deuteration. Where R a C 1-4 alkyl.

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

22. A pharmaceutical composition comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition of claim 22, further comprising other therapeutic agents.

24. Use of any compound of claims 1-21 or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition of claim 22 or 23, in the preparation of a medicament for treating and / or preventing TYK2 kinase-mediated diseases.

25. The use of claim 24, 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.

26. The use of claim 25, wherein the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease.

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