Pyridazine derivative inhibitors, their preparation and use

Abstract

The present invention relates to a pyridazine derivative inhibitor, its preparation method and use. In particular, the present invention relates to a compound represented by general formula (I), a preparation method and a pharmaceutical composition containing the compound, and its use in the preparation of a TYK2 inhibitor drug. TIFF2022524279000262.tif87170TIFF2022524279000263.tif79170

Description

[Technical field]

[0001] The present invention relates to the field of drug synthesis, specifically to pyridazine derivative inhibitors, their preparation methods and uses. [Background technology]

[0002] Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signal transduction and activation of various cytokines. The JAK kinase family is divided into four subtypes, JAK1, JAK2, JAK3 and TYK2, each of which mediates the signal transduction pathway of different types of cytokines, respectively. JAK-1, JAK-2 and TYK-2 are all expressed in various tissue cells of the human body, while JAK-3 is mainly expressed in various hematopoietic tissue cells. A common feature of cytokine receptors is that the receptor itself has no kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. After the cytokine receptor binds to its ligand, it activates the receptor-bound JAKs, which further phosphorylates the receptor, and the phosphorylated tyrosine site can bind to STAT proteins containing SH2 domains. Thus, STATs are recruited to receptors and phosphorylated by JAKs, followed by phosphotyrosine-mediated STAT dimerization, and the activated STAT dimers translocate into the cell nucleus and activate their target gene transcription, further regulating various functions such as the growth, activation, and differentiation of various cells.

[0003] TYK2 is the earliest discovered subtype of the JAK family and mediates the functions of cytokines such as IFN-α, IL-6, IL-10, IL-12 and IL-23. Research has shown that TYK2 deletion mutations can effectively inhibit the development of immune diseases such as allergies, autoimmunity and inflammation. IL-23 plays a very important role in the development process of psoriasis, and the latest research shows that the pathogenesis of psoriasis is that endogenous unknown antigens activate antigen-presenting cells (APCs) to secrete IL-23, which in turn activates Th17 cells to secrete cytokines such as IL-17, which induces the differentiation and division of keratinocytes to secrete IL-23, which in turn stimulates inflammation and keratinocyte proliferation to cause psoriasis. TYK2 and JAK2 both mediate the downstream signaling pathway of IL-23, and inhibiting JAK2 leads to anemia and other blood-related side effects, so targeting TYK2 to suppress the IL-23 signaling pathway is a good policy for treating psoriasis.

[0004] Early TYK2 inhibitors, such as Tofacitinib, all belong to JAK non-selective inhibitors and are the first oral JAK inhibitors, all of which have significant inhibitory activity against JAK1, 2, and 3 subtypes. Inhibition of activity against other subtypes, such as JAK1, JAK2, and JAK3, enhances the therapeutic effect of tofacitinib, but at the same time brings serious side effects, including infection, tuberculosis, tumor, anemia, liver damage, and cholesterol increase. Since JAK2 activity is related to the differentiation of erythroid cells and lipid metabolism process, some of the above-mentioned adverse reactions, such as anemia, may be related to the insufficient selectivity of Tofacitinib against JAK-2, and are thought to be caused by the non-selective inhibition of the drug. At present, there are no TYK2 selective inhibitors on the market, and early JAK inhibitors mainly act by competing with the kinase domain for binding to ATP, so there is a problem that they generally have low selectivity.

[0005] Considering the good therapeutic effect of JAK non-selective inhibitors and the serious side effects of various targets, developing a safer TYK2 selective inhibitor drug for the treatment of inflammatory diseases such as psoriasis has great clinical potential. BMS's international applications WO2015069310A1 and WO2018081488A1 report a TYK2 selective inhibitor, and the developed BMS-986165 has now achieved good therapeutic effect in phase II clinical trials and entered phase III clinical studies, demonstrating the advantages of TYK2 selective inhibitors and having important clinical value. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Application No. 2015 / 069310 [Patent Document 2] International Application No. 2018 / 081488 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R is hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR aa , -SR aa , -C(O)R aa , -C(O)OR aa , -S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb, -NR aa C(O)R bb or -NR aa S(O) m1 R bb is selected from R1 is a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -R aa , -(CH2) n1 OR bb , -(CH2) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m1 R bb , -NR aa CR bb =NR cc , -NR aa CR bb =CR cc R dd , -(CH2) n1 S(O) m1 NR aa R bb , -(CH2) n1 C(O)R aa , -NRaaC(O)OR bb , -(CH2) n1 S(O) m1 R aa , -(CH2) n1 NR aa C(O)C(O)R aa or -(CH2) n1 NR aa S(O) m1 R bbwherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted with one or more substituents selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, a halogen, an amino group, an oxo group, a thio group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R2 is a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -R aa , -C(O)R aa , -(CH2) n1 OR bb , -(CH2) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m1 R bb , -NR aa CR bb =NR cc , -NR aa CR bb =CR cc R dd , -(CH2) n1 S(O) m1 NR aa R bb , -(CH2) n1 C(O)R aa , -NR aa C(O)OR bb , -(CH2) n1 S(O) m1 R aa or -(CH2) n1 NR aa S(O) m1 R bbwherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted with one or more substituents selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, a halogen, an amino group, an oxo group, a thio group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R3 is selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an alkenyl group, or an alkynyl group; R4, R5, R6 and R7 are either present or absent, and when present, are selected from the group consisting of hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxy group, a cyano group, an oxo group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -C(O)OR aa , -S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb or -NR aa S(O) m1 R bb is selected from Alternatively, R4 and R6 or R6 and R7 combine to form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted with one or more substituents selected from hydrogen, deuterium, an alkyl group, a halogenated alkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the alkyl group, the deuterated alkyl group, the halogenated alkyl group, the alkoxy group, the hydroxyalkyl group, the haloalkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted with one or more substituents selected from hydrogen, deuterium, a substituted or unsubstituted alkyl group, a halogen, a hydroxy group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; Or any two adjacent or non-adjacent R aa , R bb , R cc and R ddare bonded to form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group being optionally further substituted with one or more substituents selected from hydrogen, deuterium, an alkyl group, a halogenated alkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; x is an integer of 0, 1, 2 or 3; m1 is an integer of 0, 1 or 2; n1 is an integer of 0, 1, 2, 3, 4, or 5. [Means for solving the problem]

[0008] In a preferred embodiment, R is hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, halogen, amino group, mercapto group, -OR aa , -SR aa , -S(O) m1 R aa or -NR aa R bb Preferably, hydrogen, C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Haloalkoxy groups, fluorine, chlorine, bromine, -OR aa , -SR aa , -S(O) m1 R aa or -NR aa R bb and more preferably hydrogen, a methyl group, an ethyl group, a propyl group, FCH2-, F2CH-, F3C-, ClCH2-, Cl2CH-, Cl3C-, CH3O-, CH3CH2O-, CH3CH2CH2O-, FCH2O-, F2CHO-, F3CO-, fluorine, chlorine, -OR aa , -SR aa, -S(O) m1 R aa or -NR aa R bb and more preferably CH3O-, (CH3)2N-, CH3S-, F3CO-, F2HCO-, F- or CH3S(O)2-; Here, R aa or R bb are each independently hydrogen, deuterium, a hydroxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, cyano group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-7 is selected from a cycloalkyl group or a 3- to 7-membered heterocyclic group, and is preferably hydrogen, a hydroxy group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, cyano group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 a cycloalkyl group, or a 3-6-membered heterocyclic group containing 1 to 3 N, O or S atoms, more preferably a hydrogen atom, a methyl group, an ethyl group, -CD3, -CD2CD3, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, FCH2-, F2CH-, F3C-, a cyano group, a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, an oxiranyl group, an epoxypropyl group, an epoxybutyl group, an epoxypentyl group, a pyrrolidine group or a piperidyl group, and still more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, a cyclopropyl group or a cyclobutyl group; R1 is C 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 Aryl groups, 3- to 7-membered heteroaryl groups, -NR c C(O)R d , -NR c C(O)NR d R e, -NR c S(O) m1 R d , -NR c CR d =NRe, -NR c CR d =CR e R f , -NR c C(O)OR d , -(CH2) n1 S(O) m1 R c , -(CH2) n1 NR c C(O)C(O)R g or -(CH2) n1 NR c S(O) m1 R d , -NR c CR d R e R f , -NR c C(S)R d , -OC=ONR c R d or -CR e R f C=ONR c R d Preferably, 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-10 Aryl groups, 3-6 membered heteroaryl groups, -NR c C(O)R d , -NR c C(O)NR d R e , -NR c S(O) m1 R d , -NR c CR d =NR e , -NR c CR d =CR e R f , -NR c C(O)OR d , -(CH2) n1 S(O) m1 R c , -(CH2) n1 NR cC(O)C(O)R g or -(CH2) n1 NR c S(O) m1 R d , -NR c CR d R e R f , -NR c C(S)R d , -OC=ONR c R d or -CR e R f C=ONR c R d and more preferably, C 3-6 a cycloalkyl group, a 3- to 6-membered heterocyclic group containing 1 to 3 N, O or S atoms, a phenyl group, a naphthyl group, a 3- to 6-membered heteroaryl group containing 1 to 3 N, O or S atoms, -NR c C(O)R d , -NR c C(O)NR d R e , -NR c S(O) m1 R d , -NR c CR d =NR e , -NR c CR d =CR e R f , -NR c C(O)OR d , -(CH2) n1 S(O) m1 R c , -(CH2) n1 NR c C(O)C(O)R g or -(CH2) n1 NR c S(O) m1 R d , -NR c CR d R e R f , -NR c C(S)R d , -OC=ONR c R d or -CR e Rf C=ONR c R d and more preferably [ka] [ka] and R c , R d , R e , R f or R g are each independently hydrogen, deuterium, a hydroxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, halogen, cyano group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-12 aryl group and 3- to 7-membered heteroaryl group, preferably hydrogen, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, fluorine, chlorine, bromine, cyano group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10An aryl group and a 3-6 membered heteroaryl group containing 1 to 3 N, O or S atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, -CD3, -CD2CD3, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, FCH2-, F2CH-, F3C-, a cyano group, a fluorine group, a chlorine group, CHO-, CH3CHO-, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, [ka] and more preferably hydrogen, a methyl group, an ethyl group, -CD3, -CD2CD3, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, FCH2-, F2CH-, F3C-, a cyano group, fluorine, chlorine, CHO-, CH3CHO-, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, [ka] and Or any two adjacent or non-adjacent R c , R d , R e or R f is combined with C 3-7 A cycloalkyl group, a 3- to 7-membered heterocyclic group, an aryl group, or a 3- to 7-membered heteroaryl group, preferably C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-12 Aryl groups and 3- to 6-membered heteroaryl groups, more preferably C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 An aryl group and a 3- to 6-membered heteroaryl group containing 1 to 2 N, O or S atoms, more preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, [ka] and even more preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, [ka] and R2 is C 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 Aryl groups, 3- to 7-membered heteroaryl groups, C 1-6 Hydroxyalkyl groups of -C(O)R hh , -(CH2) n1 OR ii , -(CH2) n1 NR hh R ii , -NR hh C(O)R ii , -NR hh C(O)NR ii R jj , -C(O)NR hh R ii , -NR hh S(O) m1 R ii , -NR hh CR ii =NR ii , -NR hh CR ii =CR jj R kk , -(CH2) n1 S(O) m1 NR hh R ii , -(CH2) n1 C(O)R hh , -NR hh C(O)OR ii , -(CH2) n1 S(O) m1 R hh or -(CH2) n1 NR hh S(O) m1 R ii C is selected from 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 The aryl group or the 3- to 7-membered heteroaryl group may be selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 Alkyl group, C 1-6Alkoxy group or C 3-6 The cycloalkyl group may be substituted with one or more substituents, preferably C 3-6 Cycloalkyl groups, substituted or unsubstituted 3- to 6-membered heterocyclic groups, C 6-10 Aryl group, substituted or unsubstituted 3- to 6-membered heteroaryl group, C 1-3 Hydroxyalkyl group, -C(O)R hh , -(CH2) n1 OR ii , -(CH2) n1 NR hh R ii , -NR hh C(O)R ii , -NR hh C(O)NR ii R jj , -C(O)NR hh R ii , -NR hh S(O) m1 R ii , -NR hh CR ii =NR jj , -NR hh CR ii =CR jj R kk , -(CH2) n1 S(O) m1 NR hh R ii , -(CH2) n1 C(O)R hh , -NR hh C(O)OR ii , -(CH2) n1 S(O) m1 R hh or -(CH2) n1 NR hh S(O) m1 R ii and C 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 The aryl group or the 3- to 7-membered heteroaryl group is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 Alkyl group or C 3-5 The cycloalkyl group may be substituted with one or more substituents, more preferably C 3-6a cycloalkyl group, a 3- to 6-membered heterocyclic group containing 1 to 3 N, O or S atoms, a phenyl group, a naphthyl group, a 3- to 6-membered heteroaryl group containing 1 to 3 N, O or S atoms, C 1-3 Hydroxyalkyl group, -C(O)R hh , -(CH2) n1 OR ii , -(CH2) n1 NR hh R ii , -C(O)NR hh R ii , -(CH2) n1 S(O) m1 NR hh R ii , -(CH2) n1 C(O)R hh , -(CH2) n1 S(O) m1 R hh or -(CH2) n1 NR hh S(O) m1 R ii and C 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 The aryl group or the 3- to 7-membered heteroaryl group may be substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group, and more preferably, HOCH2-, HOCH2CH2-, HOCH2C(O)-, CH3NHC(O)-, D3CNHC(O)-, CH3NHS(O)2-, D3CNHS(O)2-, [ka] and R hh , R ii , R jj or R kk are each independently hydrogen, deuterium, a hydroxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C1-6 Haloalkoxy group, halogen, cyano group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 A cycloalkyl group or a 3- to 6-membered heterocyclic group is preferably selected from hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, fluorine, chlorine, bromine, cyano group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 a cycloalkyl group, or a 3-6-membered heterocyclic group containing 1 to 3 N, O or S atoms, and more preferably hydrogen, deuterium, a methyl group, an ethyl group, -CD3, -CD2CD3, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, FCH2-, F2CH-, F3C-, a cyano group, fluorine, chlorine, CHO-, CH3CHO-, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an epoxypropyl group, an epoxybutyl group, an epoxypentyl group, an epoxyhexyl group, a pyrrolidine group or a piperidyl group; R3 is hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 is selected from haloalkoxy groups, fluorine, chlorine, bromine, amino groups, mercapto groups, nitro groups, hydroxy groups, and cyano groups, and is preferably selected from hydrogen, deuterium, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3haloalkoxy group, fluorine, chlorine, bromine, amino group, mercapto group, nitro group, hydroxy group or cyano group, more preferably hydrogen, deuterium, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, fluorine, chlorine, hydroxy group or cyano group; R4, R5, R6 and R7 are present or absent, and when present, are selected from hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, fluorine, chlorine, bromine, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-7 A cycloalkyl group, a 3- to 7-membered heterocyclic group, an aryl group, a 3- to 7-membered heteroaryl group, -(CH2) n1 R ll , -(CH2) n1 OR ll , -SR ll , -(CH2) n1 C(O)R ll , -C(O)OR ll , -S(O) m1 R ll , -NR ll R mm , -C(O)NR ll R mm , -NR ll C(O)R mm or -NR ll S(O) m1 R mm Preferably, hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, fluorine, chlorine, bromine, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 an aryl group, a 3-6 membered heteroaryl group containing 1-3 N, O or S atoms, -(CH2) n1 R ll , -(CH2) n1 OR ll , -SR ll , -(CH2) n1 C(O)R ll , -C(O)OR ll , -S(O) m1 R ll , -NR ll R mm , -C(O)NR ll R mm , -NR ll C(O)R mm or -NR ll S(O) m1 R mm More preferably, hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, fluorine, chlorine, bromine, amino group, mercapto group, nitro group, hydroxy group, cyano group, oxo group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 an aryl group, a 3-6 membered heteroaryl group containing 1-3 N, O or S atoms, -(CH2) n1 R ll , -(CH2) n1 OR ll or -NR ll R mm and more preferably hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, (CH3)3C-, CF3CH2-, fluorine, chlorine, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclobutyl group, a vinyl group, CH2=CHCH2-, an ethynyl group, [ka] Cyano group, CNCH2-, CNCH2CH2-, CH3OCH2-, CH3OCH2CH2-, CF3C(CH3)2-, [ka] and R ll or R mm are each independently hydrogen, deuterium, a hydroxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, halogen, cyano group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 A cycloalkyl group or a 3- to 6-membered heterocyclic group is preferably selected from hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Haloalkoxy group, fluorine, chlorine, bromine, cyano group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 a cycloalkyl group, or a 3-6-membered heterocyclic group containing 1 to 3 N, O or S atoms, and more preferably hydrogen, deuterium, a methyl group, an ethyl group, -CD3, -CD2CD3, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, FCH2-, F2CH-, F3C-, a cyano group, fluorine, chlorine, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an epoxypropyl group, an epoxybutyl group, an epoxypentyl group, an epoxyhexyl group, a pyrrolidine group or a piperidyl group; Alternatively, R4 and R6 or R6 and R7 may be joined to form a heterocyclic or heteroaryl group, the heterocyclic or heteroaryl group being selected from the group consisting of hydrogen, deuterium, halogen, C1-6 Alkyl group or C 3-6 The cycloalkyl group may be substituted with one or more substituents, and is preferably a 3- to 6-membered heterocyclic group or a 3- to 7-membered heteroaryl group, and the heterocyclic group or heteroaryl group may be substituted with hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 Alkyl group or C 3-5 It may be substituted with one or more substituents selected from the group consisting of a cycloalkyl group, and more preferably a 3-6 membered heterocyclic group containing 1 to 3 N, O or S atoms, or a 3-7 membered heteroaryl group containing 1 to 3 N, O or S atoms, and the heterocyclic group or heteroaryl group may be substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group, and more preferably [ka] It is.

[0009] Optionally, the compound of formula I is [ka] isn't it.

[0010] In a preferred embodiment of the present invention, in the compound represented by the general formula (I), its stereoisomer, or its pharma- ceutically acceptable salt, the general formula (I) is further represented by general formula (II): [ka] During the ceremony, R to R6 and x are as defined in general formula (I).

[0011] In a further preferred embodiment according to the present invention, in the compound represented by the general formula (I), its stereoisomer, or its pharma- ceutically acceptable salt, the general formula (I) is further represented by general formula (III): [ka] During the ceremony, R, R1, R3 to R6, and x are as defined in general formula (I).

[0012] In yet another preferred embodiment of the present invention, in the compound represented by the general formula (I), its stereoisomer or its pharma- ceutically acceptable salt, the general formula (I) is further represented by general formula (IV): [ka] During the ceremony, Ring A is selected from a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, and is preferably a heteroaryl group; R8 is selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogen, a cyano group, a nitro group, a halogenated alkyl group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the alkyl group, the halogenated alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted with one or more substituents selected from hydrogen, deuterium, an alkyl group, a halogen, a hydroxy group, an amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and is preferably hydrogen, a halogen, an amino group, a cyano group, an alkyl group, a halogenated alkyl group, or a cycloalkyl group; y is 0, 1, 2 or 3; R, R1, R3 to R6 and x are as described in general formula (I). In a preferred embodiment, the ring A is 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 aryl group or 3- to 7-membered heteroaryl group, preferably 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-10 An aryl group or a 3- to 6-membered heteroaryl group, more preferably C 3-6a cycloalkyl group, a 3-6 membered heterocyclic group containing 1 to 3 N, O or S atoms, a phenyl group, a naphthyl group, a 3-6 membered heteroaryl group containing 1 to 3 N, O or S atoms, and more preferably [ka] and Even more preferably, [ka] and R8 is hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, fluorine, chlorine, bromine, cyano groups, nitro groups, C 1-6 Halogenated alkyl group, hydroxy group, amino group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 aryl group and 3- to 7-membered heteroaryl group, preferably hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, fluorine, chlorine, bromine, cyano groups, nitro groups, C 1-3 Halogenated alkyl group, hydroxy group, amino group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 An aryl group and a 3-6 membered heteroaryl group containing 1 to 3 N, O or S atoms are more preferred, and hydrogen, deuterium, a methyl group, an ethyl group, a propyl group, a chlorine-substituted methyl group, a chlorine-substituted ethyl group, a fluorine-substituted methyl group, a fluorine-substituted ethyl group, fluorine, chlorine, bromine, a cyano group, a nitro group, a hydroxy group, an amino group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, [ka] It is.

[0013] In a further preferred embodiment of the present invention, in the compound represented by the general formula (I), its stereoisomer, or its pharma- ceutically acceptable salt, the general formula (I) is further represented by general formula (V): [ka] During the ceremony, R9 is hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogen, a cyano group, a nitro group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -C(O)OR aa , -S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb Or-NR aa S(O) m1 R bb wherein the alkyl group, the halogenated alkyl group, the amino group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted with one or more substituents selected from hydrogen, deuterium, an alkyl group, a halogenated alkyl group, a halogen, a hydroxy group, an amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R, R3 to R6, R aa , R bb and x are as defined in general formula (I).

[0014] In a preferred embodiment, R9 is hydrogen, deuterium, C1-6 Alkyl group, C 1-6 Deuterated alkyl groups, fluorine, chlorine, bromine, cyano groups, nitro groups, C 1-6 Halogenated alkyl group, hydroxy group, amino group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 An aryl group or a 3- to 7-membered heteroaryl group, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -C(O)OR aa , -S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb or -NR aa S(O) m1 R bb Preferably, hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, fluorine, chlorine, bromine, cyano groups, nitro groups, C 1-3 Halogenated alkyl group, hydroxy group, amino group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, C 6-10 An aryl group or a 3- to 6-membered heteroaryl group, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -C(O)OR aa , -S(O) m1 R aa , -NR aa R bb , -C(O)NR aa Rbb , -NR aa C(O)R bb or -NR aa S(O) m1 R bb More preferably, C substituted with hydrogen, deuterium, or a hydroxyl group 1-3 Alkyl group, C 1-3 Cycloalkyl-substituted C 1-3 C substituted with alkyl or hydroxy groups 1-3 Deuterated alkyl groups, fluorine, chlorine, bromine, cyano groups, nitro groups, C 1-3 Halogenated alkyl groups, hydroxy groups, C 3-6 Amino group substituted with cycloalkyl group, C substituted with halogen 2-5 Alkenyl group, halogen-substituted C 2-5 Alkynyl group, halogen-substituted C 3-6 Cycloalkyl groups, C 1-3 Alkyl-substituted C 3-6 Cycloalkyl, cyano-substituted C 3-6 Cycloalkyl groups, C 1-3 Alkoxy-substituted C 3-6 Cycloalkyl groups, C 1-3 C substituted with halogenated alkyl groups 3-6 a cycloalkyl group, a 3-7 membered heterocyclic group containing 1-3 N, O or S atoms, a phenyl group, a naphthyl group or a 3-7 membered heteroaryl group containing 1-3 N, O or S atoms, -(CH2) n1 R aa , -(CH2) n1 OR aa , -(CH2) n1 C(O)R aa or -NR aa R bb and even more preferably [ka] and R aa or R bb are independently hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6Deuterated alkyl groups, halogens, cyano groups, nitro groups, C 1-6 Halogenated alkyl group, hydroxy group, amino group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 aryl group or 3- to 7-membered heteroaryl group, preferably hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, fluorine, chlorine, bromine, cyano groups, nitro groups, C 1-3 Halogenated alkyl group, hydroxy group, amino group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 an aryl group or a 3-7 membered heteroaryl group containing 1-3 N, O or S atoms, more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, a fluorine atom, a chlorine atom, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a naphthyl group or a biphenyl group; m1 is 0, 1, 2 or 3; n1 is 0, 1, 2 or 3.

[0015] In a further preferred embodiment of the present invention, in the compound represented by the general formula (I), its stereoisomer, or its pharma- ceutically acceptable salt, the general formula (I) is further represented by general formula (VI): [ka] During the ceremony, Ring B is selected from a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, preferably a heteroaryl group; R 10is selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogen, a cyano group, a nitro group, a halogenated alkyl group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the alkyl group, the deuterated alkyl group, the halogenated alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted with one or more substituents selected from hydrogen, deuterium, an alkyl group, a halogen, a hydroxy group, an amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and is preferably hydrogen, a halogen, an amino group, a cyano group, an alkyl group, a halogenated alkyl group, or a cycloalkyl group; z is 0, 1, 2 or 3; R, R3 to R6 and x are as defined in formula (I). In a preferred embodiment, ring B is 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 aryl group or 3- to 7-membered heteroaryl group, preferably 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-10 An aryl group or a 3- to 6-membered heteroaryl group, more preferably C 3-6 a cycloalkyl group, a 3-6 membered heterocyclic group containing 1 to 3 N, O or S atoms, a phenyl group, a naphthyl group or a 3-6 membered heteroaryl group containing 1 to 3 N, O or S atoms, more preferably [ka] and even more preferably [ka] and Chlorine R 10 is hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, fluorine, chlorine, bromine, cyano groups, nitro groups, C 1-6Halogenated alkyl groups, hydroxy groups, amino groups, alkenyl groups, alkynyl groups, C 3-7 Cycloalkyl groups, 3- to 7-membered heterocyclic groups, C 6-12 aryl group and 3- to 7-membered heteroaryl group, preferably hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, fluorine, chlorine, bromine, cyano groups, nitro groups, C 1-3 Halogenated alkyl groups, hydroxy groups, amino groups, alkenyl groups, alkynyl groups, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 It is an aryl group or a 3-6 membered heteroaryl group containing 1 to 3 N, O or S atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, a fluorine group, a chlorine group, a hydroxyl group, an amino group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0016] In a further preferred embodiment of the present invention, in the compound represented by the general formula (I), its stereoisomer, or its pharma- ceutically acceptable salt, the general formula (I) is further represented by general formula (VII): [ka] During the ceremony, M, S, NR cc or CR cc R dd and R 11is selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogen, a cyano group, a nitro group, a halogenated alkyl group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the alkyl group, the halogenated alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be further substituted with one or more substituents selected from a deuterated alkyl group, a deuterium, an alkyl group, a halogen, a hydroxy group, an amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and is preferably hydrogen, a halogen, an amino group, a cyano group, an alkyl group, a halogenated alkyl group, or a cycloalkyl group; R cc and R dd are each independently selected from hydrogen, deuterium, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxy group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Or, R cc and R dd are bonded to form a cycloalkyl group or a heterocyclic group, the cycloalkyl group or the heterocyclic group being optionally further substituted with one or more substituents selected from a deuterated alkyl group, a deuterium, an alkyl group, a halogen, a hydroxy group, an amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R, R3 to R6 and x are as defined in general formula (I).

[0017] In a preferred embodiment, M is S, NR cc or CR cc R dd and preferably S, NCH3, NOCH3, NCN, CH2, CHCH3 or [ka] and R 11 is hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, halogens, cyano groups, nitro groups, C 1-6 Halogenated alkyl group, hydroxy group, amino group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-12 aryl group and 3-8 membered heteroaryl group, preferably hydrogen, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, halogens, amino groups, cyano groups, alkyl groups, C 1-3 Halogenated alkyl group or C 3-5 a cycloalkyl group, more preferably a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, fluorine, chlorine, bromine, a difluoromethyl group, a difluoroethyl group, a trifluoromethyl group, or a trifluoroethyl group; R cc and R dd are independently hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 1-6 Haloalkoxy group, fluorine, chlorine, bromine, cyano group, nitro group, hydroxy group, amino group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, C 6-12 aryl group or 3-6 membered heteroaryl group, preferably hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3Hydroxyalkyl group, C 1-3 Haloalkoxy group, fluorine, chlorine, bromine, cyano group, nitro group, hydroxy group, amino group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S, C 6-10 an aryl group or a 3-6 membered heteroaryl group containing 1-3 N, O or S, more preferably hydrogen, a methyl group, an ethyl group, a propyl group, fluorine, chlorine, a methoxy group, an ethoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an amino group, a hydroxy group or a cyano group; Or, R cc and R dd are combined into one C 3-6 Forms a cycloalkyl group or a 3- to 6-membered heterocyclic group, preferably 3-6 A cycloalkyl group or a 3-6 membered heterocyclic group containing 1-3 N, O or S, more preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, [ka] It is.

[0018] In a further preferred embodiment of the present invention, in the compound represented by the general formula (I), its stereoisomer, or its pharma- ceutically acceptable salt, the general formula (I) is further represented by general formula (VIII): [ka] During the ceremony, R3 to R6 and x are as defined in general formula (I).

[0019] In a preferred form, R3 is selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine; R4 is C 1-6 Alkyl group, C 2-6Alkenyl group, C 2-6 Alkynyl group, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocyclic group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 The cycloalkyl group and the 3- to 6-membered heterocyclic group may be further substituted with one or more substituents selected from a methyl group, an ethyl group, a fluorine group, and a chlorine group, and preferably, 1-3 Alkyl group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-5 A cycloalkyl group or a 3- to 5-membered heterocyclic group, more preferably C 1-3 Alkyl group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-5 a cycloalkyl group, or a 3-5 membered heterocyclic group containing 1 to 3 N, O or S atoms, more preferably a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a vinyl group, a propenyl group, an allyl group, an ethynyl group, a propynyl group, a propargyl group, [ka] and R5 and R6 are each independently hydrogen or deuterium; x is 0, 1, 2 or 3.

[0020] In a further preferred embodiment according to the present invention, in the compound represented by any one of the general formulae, its stereoisomers, or its pharma- ceutically acceptable salts, Ring A and ring B are [ka] is selected from the group:

[0021] In a further preferred embodiment according to the present invention, in the compound represented by any one of the general formulae, its stereoisomers, or its pharma- ceutically acceptable salts, R is hydrogen, C1-6 Alkoxy group, C 1-6 Haloalkoxy group, -OR aa , -SR aa or -NR aa R bb is selected from R1 is a 3- to 8-membered heterocyclic group, a 5- to 8-membered heteroaryl group, -(CH2) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(=S)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa C(O)OR bb , -NR aa S(O) m1 R bb , -(CH2) n1 NR aa C(O)C(O)R aa , -NR aa CR bb =NR cc Or-NR aa CR bb =CR cc R dd The 3- to 8-membered heterocyclic group and the 5- to 8-membered heteroaryl group may further include hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, halogens, hydroxy groups, amino groups, cyano groups, oxo groups and C 3-8 may be substituted with one or more substituents selected from cycloalkyl groups; R2 is a 3- to 8-membered heterocyclic group, a 5- to 8-membered heteroaryl group, -C(O)R aa , -(CH2) n1 OR aa , -C(O)NR aa R bb Or -S(O) m1 NR aa R bb The 3- to 8-membered heterocyclic group and the 5- to 8-membered heteroaryl group may further include hydrogen, deuterium, C1-6 Alkyl group, C 1-6 Halogenated alkyl groups, halogens, hydroxy groups, amino groups, cyano groups and C 3-8 may be substituted with one or more substituents selected from cycloalkyl groups; R3 is hydrogen, halogen, cyano group, C 1-6 Alkyl group or C 1-6 selected from halogenated alkyl groups, R5 is hydrogen, halogen, cyano group, C 1-6 Alkyl group or C 1-6 selected from halogenated alkyl groups, R4 and R6 are each independently hydrogen, halogen, cyano, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Halogenated alkyl groups, C 3-8 A cycloalkyl group, a 3-8 membered heterocyclic group or -(CH2) n1 R aa is preferably selected from hydrogen, a cyclopropyl group or [ka] and Alternatively, R4 and R6 may be combined to form a single C 3-8 forms a cycloalkyl group, preferably a cyclopentane group, R7 is present or absent, and when present, is selected from hydrogen, halogen, cyano, C 1-6 Alkyl group or C 1-6 selected from halogenated alkyl groups, Alternatively, R6 and R7 may be combined to form one C 3-8 forms a cycloalkyl group, preferably a cyclopentane group, R8 and R 10 are each independently hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 1-6 Halogenated alkyl group or C 3-8 cycloalkyl groups, R9 is hydrogen, C 1-6 Alkyl group, C3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, -(CH2) n1 R aa , -(CH2) n1 OR aa , -(CH2) n1 C(O)R aa , -C(O)OR aa , -NR aa R bb or -C(O)Nr aa R bb C is selected from 1-6 Alkyl group, C 3-8 The cycloalkyl group and the 3- to 8-membered heterocyclic group may further include hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, halogens, hydroxy groups, amino groups, oxo groups, nitro groups, cyano groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 6-10 may be substituted with one or more substituents selected from an aryl group and a 5- to 8-membered heteroaryl group; R 11 is hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, halogens, cyano groups, C 1-6 Halogenated alkyl groups, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 6-10 an aryl group or a 5- to 8-membered heteroaryl group; R aa , R bb , R cc and R dd are each independently hydrogen, deuterium, cyano group, halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8a cycloalkyl group, a 3- to 8-membered heterocyclic group, or a 5- to 8-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocyclic group, and the 5- to 8-membered heteroaryl group may further include hydrogen, deuterium, C 1-6 Alkyl group, halogen, hydroxyl group, amino group, oxo group, cyano group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 6-10 may be substituted with one or more substituents selected from an aryl group and a 5- to 8-membered heteroaryl group; Or, R cc and R dd are combined into one C 3-8 Forming a cycloalkyl group, 3-8 Cycloalkyl groups are hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, halogens, amino groups, oxo groups, cyano groups, hydroxy groups, C 1-6 Alkoxy group, C 1-6 Haloalkoxy groups and C 1-6 It may be substituted with one or more substituents selected from hydroxyalkyl groups.

[0022] In a further technical solution according to the present invention, a compound represented by general formula (IX), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof is provided, [ka] During the ceremony,

[0023] Ring C is [ka] is selected from the group R 12 are independently -OR ee , -C(O)NR ee R ff , -(CH2) n1 NR ee R ff Or -S(O) m2 NR ee R ff is selected from R 17 is hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Halogenated alkyl groups, C 3-8 A cycloalkyl group, a 3-8 membered heterocyclic group or -(CH2) n1 R aa is selected from R ee and R ff are independently hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 3-8 a cycloalkyl group, a 3- to 8-membered heterocyclic group, or a 5- to 8-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocyclic group, and the 5- to 8-membered heteroaryl group may further include hydrogen, deuterium, C 1-6 Alkyl group, halogen, hydroxyl group, amino group, oxo group, cyano group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 6-10 may be substituted with one or more substituents selected from an aryl group and a 5- to 8-membered heteroaryl group; n1 is 0, 1 or 2; m2 is 0, 1 or 2; q is 0, 1, 2 or 3.

[0024] In a preferred form, R 12 are CD3NHC(O)-, CH3NHC(O)-, CH3NHS(O)2-, CH3O-, D3CNHS(O)2-, [ka] is selected from R 17 is hydrogen, halogen, cyano group, C 1-3 Alkyl group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 1-3 Halogenated alkyl groups, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocyclic group, or -(CH2) n1 R aa Preferably, hydrogen, halogen, cyano group, C 1-3 Alkyl group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C substituted with 1 to 3 fluorine, chlorine or bromine atoms 1-3 Alkyl group, C 3-6 A cycloalkyl group, a 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, or -(CH2) n1 R aa and more preferably hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxacyclobutyl group, an oxacyclopentyl group, an oxacyclohexyl group, an azacyclobutyl group, an azacyclopentyl group, an azacyclohexyl group, a thiocyclobutyl group, a thiocyclopentyl group, a thiocyclohexyl group, an allyl group, a propargyl group, CF3CH2-, (CH3)2CF3C-, CN-, CNCH2-, CNCH2CH2-, [ka] and R aais selected from an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a nitro group, a hydroxy group, a cyano group, an amino group, an aryl group or a heteroaryl group, preferably 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 1-6 Haloalkoxy group, nitro group, hydroxy group, cyano group, amino group, C 6-12 An aryl group or a 3- to 12-membered heteroaryl group, more preferably C 1-3 Alkoxy group, C 1-3 Hydroxyalkyl group, C 1-3 Haloalkoxy group, nitro group, hydroxy group, cyano group, amino group, C 6-10 An aryl group or a 5-8 membered heteroaryl group, more preferably a methoxy group, an ethoxy group, a propoxy group, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a C substituted with 1 to 3 fluorine, chlorine or bromine atoms. 1-3 an alkoxy group, a nitro group, a hydroxy group, a cyano group, an amino group, an aryl group, or a 3-6 membered heteroaryl group containing 1-3 N, O or S atoms; n1 is 1 or 2.

[0025] In a further technical means according to the present invention, a compound represented by general formula (X), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof is [ka] During the ceremony, R 13 and R 14 are independently hydrogen, deuterium, and C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 3-8 is selected from a cycloalkyl group, a 3- to 8-membered heterocyclic group, or a 5- to 8-membered heteroaryl group; R 15 is a 3- to 8-membered heterocyclic group, a 5- to 8-membered heteroaryl group, -(CH2) n1 NR aa R bb , -NRaa C(O)R bb , -NR aa C(=S)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa C(O)OR bb , -NR aa S(O) m1 R bb , -(CH2) n1 NR aa C(O)C(O)R aa , -NR aa CR bb =NR cc Or-NR aa CR bb =CR cc R dd The 3- to 8-membered heterocyclic group and the 5- to 8-membered heteroaryl group may further include hydrogen, deuterium, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, halogens, hydroxy groups, amino groups, cyano groups and C 3-8 may be substituted with one or more substituents selected from cycloalkyl groups; R 16 is hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Halogenated alkyl groups, C 3-8 A cycloalkyl group, a 3-membered heterocyclic group or -(CH2) n1 R aa is selected from R aa , R bb , R cc and R dd are each independently hydrogen, deuterium, cyano group, halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8a cycloalkyl group, a 3- to 8-membered heterocyclic group, or a 5- to 8-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8 The cycloalkyl group, the 3- to 8-membered heterocyclic group, and the 5- to 8-membered heteroaryl group may further include hydrogen, deuterium, C 1-6 Alkyl group, halogen, hydroxyl group, amino group, oxo group, cyano group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups, C 6-10 may be substituted with one or more substituents selected from an aryl group and a 5- to 8-membered heteroaryl group; n1 is 0, 1 or 2; m1 is 0, 1 or 2.

[0026] In a further technical means according to the present invention, a compound represented by general formula (XI), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof is provided, [ka] During the ceremony, R 18 is hydrogen, deuterium, halogen, hydroxyl group, cyano group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Haloalkoxy group, C 3-8 A cycloalkyl group, a 3-8 membered heterocyclic group or -(CH2) n1 R aa Preferably, hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3Alkoxy group, C 1-3 Haloalkoxy group, fluorine, chlorine, bromine, hydroxy group, cyano group, C 2-5 Alkenyl group, C 2-5 Alkynyl group, C 3-6 A cycloalkyl group, a 3- to 6-membered heterocyclic group, or -(CH2) n1 R aa and more preferably hydrogen, a methyl group, a cyclopropyl group, [ka] and R 19 are hydrogen, deuterium, halogens, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 haloalkoxy, amino, hydroxy or cyano groups, preferably hydrogen, deuterium, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 haloalkoxy group, fluorine, chlorine, bromine, amino group, hydroxy group or cyano group, more preferably hydrogen, deuterium, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, fluorine, chlorine, hydroxy group or cyano group; R aa is hydrogen, deuterium, cyano group, hydroxyl group, halogen, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 A cycloalkyl group or a 3-8 membered heterocyclic group is preferably selected from hydrogen, deuterium, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, fluorine, chlorine, bromine, cyano group, C 2-5 Alkenyl group, C 2-5 Alkynyl group or C 3-6 is a cycloalkyl group, more preferably a hydrogen atom, a methyl group, an ethynyl group or a cyclopropyl group; n1 is 0, 1 or 2; r is 0, 1, 2 or 3.

[0027] In a further technical aspect of the present invention, a method for preparing a compound represented by general formula (V) or its stereoisomer and its pharma- ceutically acceptable salt comprises the steps of: The method includes the steps of reacting general formula (V-1) with general formula (V-2) to obtain general formula (V-3), and further reacting general formula (V-3) to obtain a compound represented by general formula (V) or a stereoisomer thereof and a pharma- ceutically acceptable salt thereof; [ka] During the ceremony, X is selected from halogens; R3 to R6, R9 and x are as defined in general formula (V).

[0028] In a further technical aspect of the present invention, a method for producing the compound represented by the general formula (V) or its stereoisomer and its pharma- ceutically acceptable salt comprises the steps of: The method includes the steps of reacting general formula (V-4) with general formula (V-5) to obtain general formula (V-6), and further reacting general formula (V-6) with general formula (V-2) to obtain a compound represented by general formula (V) or a stereoisomer thereof and a pharma- ceutically acceptable salt thereof, [ka] During the ceremony, X is selected from halogens; R3 to R6, R9 and x are as defined in general formula (V).

[0029] A further technical solution according to the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) according to any one of claims, a compound represented by general formula (IX) according to any one of claims, and a compound represented by general formula (X) according to any one of claims, a stereoisomer thereof, or a pharmacologically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0030] A further technical solution according to the present invention is the use of a compound represented by any one of general formula (I), a compound represented by general formula (IX), and a compound represented by general formula (X), their stereoisomers, or pharmacologically acceptable salts thereof, or the pharmaceutical composition in the manufacture of a TYK2 inhibitor drug.

[0031] A further technical means according to the present invention is the use of a compound represented by any one of the general formula (I), a compound represented by any one of the general formula (IX), and a compound represented by any one of the general formula (X), their stereoisomers, or pharma- ceutically acceptable salts, or the pharmaceutical composition thereof, in the treatment of an inflammatory disease and an autoimmune disease selected from rheumatoid arthritis, dermatitis, psoriasis, or inflammatory bowel disease (ulcerative colitis and Crohn's disease).

[0032] The present invention further relates to a method for treating inflammatory diseases with a compound represented by general formula (I), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0033] The present invention further relates to a method for preventing and / or treating an autoimmune disease, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0034] The present invention also provides methods of treating disease conditions, including but not limited to conditions associated with impaired TYK2 kinase function, using the compounds or pharmaceutical compositions of the present invention.

[0035] The present invention also relates to a method for treating a hyperproliferative disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0036] In some embodiments, the methods relate to the treatment of conditions such as cancer, bone diseases, inflammatory diseases, immune diseases, neurological diseases, metabolic diseases, respiratory diseases, and cardiac diseases.

[0037] In some embodiments, the inflammatory and autoimmune diseases of the present methods are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease).

[0038] The therapeutic methods provided herein comprise administering to a subject a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention provides a method for treating an inflammatory disorder, including an autoimmune disease, in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. [Brief description of the drawings]

[0039] [Figure 1] FIG. 1 shows the PASI scoring results of different compounds in a mouse psoriasis model induced by imiquimod. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Unless otherwise specified to the contrary, terms used in the specification and claims have the following meanings.

[0041] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43-methylhexyl, 44-methylhexyl, 45-methylhex Examples of such groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups, and in the present invention is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a halogenated alkyl group, a deuterated alkyl group, an alkyl group substituted with an alkoxy group, and an alkyl group substituted with a hydroxy group.

[0042] The term "alkylene group" refers to an alkyl group in which one hydrogen atom has been further substituted, for example, a "methylene group" refers to -CH2-, an "ethylene group" refers to -(CH2)2-, a "propylidene group" refers to -(CH2)3-, and a "butylidene group" refers to -(CH2)4-. The term "alkenyl group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups. An alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0043] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spiro, fused, and bridged cyclic cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0044] The term "spirocycloalkyl group" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5-20 membered monocyclic rings and may contain one or more double bonds, but no ring has a fully conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into monocyclic spirocycloalkyl groups, bicyclic spirocycloalkyl groups or polycyclic spirocycloalkyl groups, with monocyclic spirocycloalkyl groups and bicyclic spirocycloalkyl groups being preferred. More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monocyclic spirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0045] Also included are spirocycloalkyl groups in which the monocyclic spirocycloalkyl groups and heterocycloalkyl groups share a spiro atom, non-limiting examples of which are: [ka] Includes.

[0046] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, and one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, but is preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes.

[0047] The term "bridged cyclic cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly bonded, and may contain one or more double bonds, but no ring has a completely conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of rings that it comprises, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cyclic cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cyclic cycloalkyl groups are: [ka] Includes.

[0048] The cycloalkyl ring may be fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, in which the ring attached to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptane, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0049] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is nitrogen, oxygen or S(O). m(wherein m is an integer of 0 to 2), but does not include a ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 ring atoms are heteroatoms, more preferably contains 3 to 8 ring atoms, and most preferably contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolo, dihydropyrrole, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidone, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spirocyclic, fused and bridged heterocyclic groups, which may be connected to other groups via a single bond or may be further connected in parallel rings to other cycloalkyl, heterocyclic, aryl and heteroaryl groups via any two or more atoms on the ring.

[0050] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group having 3 to 20 members and sharing one atom (called a spiro atom) between the monocyclic rings, where one or more of the ring atoms is nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but there is no ring with a completely conjugated π-electron system. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of spiro atoms shared by the rings, the spiro heterocyclic group is divided into a monocyclic spiro heterocyclic group, a bicyclic spiro heterocyclic group, or a polycyclic spiro heterocyclic group, and is preferably a monocyclic spiro heterocyclic group and a bicyclic spiro heterocyclic group. More preferably, it is a 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monocyclic spiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups are: [ka] Includes.

[0051] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with each other ring in the system, one or more of the rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and one or more of the ring atoms is nitrogen, oxygen, or S(O). m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 3-membered / 5-membered, 4-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups are: [ka] Includes.

[0052] The term "bridged heterocyclic group" refers to a 5-14 membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded and may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and one or more of the ring atoms is nitrogen, oxygen, or S(O). m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups are: [ka] Includes.

[0053] The heterocyclic ring may be fused to an aryl group, a heteroaryl group, or a cycloalkyl ring, where the ring attached to the parent structure is a heterocyclic group, non-limiting examples include: [ka] etc.

[0054] The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0055] The term "aryl group" refers to a 6-14 membered all carbon monocyclic or fused polycyclic (i.e. rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6-10 membered, such as phenyl and naphthyl groups. More preferably, it is a phenyl group. The aryl ring may be fused to a heteroaryl group, heterocyclic group, or cycloalkyl ring, in which the ring bonded to the parent structure is an aryl ring, non-limiting examples are: [ka] Includes.

[0056] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a carboxyl group, or a carboxylate group.

[0057] The term "heteroaryl group" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, the heteroatoms being selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5-10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazole, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and thiazolyl, more preferably triazole, pyrrolyl, thienyl, thiazolyl, pyridyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, in which the ring bonded to the parent structure is an aryl ring, non-limiting examples are: [ka] Includes.

[0058] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0059] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the alkyl group is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0060] "Halogenated alkyl group" refers to an alkyl group that is substituted with one or more halogens, where alkyl group is as defined above.

[0061] A "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0062] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where alkyl group is as defined above.

[0063] "Alkenyl group" refers to an olefin also referred to as an alkene, which may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0064] "Alkynyl group" refers to (CH≡C-), which may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0065] "Hydroxy" refers to an -OH group.

[0066] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0067] An "amino group" refers to -NH2.

[0068] A "cyano group" refers to -CN.

[0069] A "nitro group" refers to --NO.sub.2.

[0070] A "carboxyl group" refers to -C(O)OH.

[0071] "THF" refers to tetrahydrofuran.

[0072] "EtOAc" refers to ethyl acetate.

[0073] "MeOH" refers to methanol.

[0074] "DMF" refers to N,N-dimethylformamide.

[0075] "DIPEA" refers to diisopropylethylamine.

[0076] "TFA" refers to trifluoroacetic acid.

[0077] "MeCN" refers to acetonitrile.

[0078] "DMA" refers to N,N-dimethylacetamide.

[0079] "Et2O" refers to ethyl ether.

[0080] "DCE" refers to 1,2 dichloroethane.

[0081] "DIPEA" refers to N,N-diisopropylethylamine.

[0082] "NBS" refers to N-bromosuccinimide.

[0083] "NIS" refers to N-iodosuccinimide.

[0084] "Cbz-Cl" refers to benzyl chloroformate.

[0085] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0086] "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0087] "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0088] "KHMDS" refers to potassium hexamethyldisilazide.

[0089] "LiHMDS" refers to lithium bis(trimethylsilyl)amide.

[0090] "MeLi" refers to methyllithium.

[0091] "n-BuLi" refers to n-butyllithium.

[0092] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0093] "DMAP" refers to 4-dimethylaminopyridine.

[0094] "SEM-Cl" refers to chloromethyltrimethylsilyl ethyl ether;

[0095] "Xantphos" refers to 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.

[0096] "DCM" refers to dichloromethane;

[0097] The terms "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all have the same meaning, i.e., X can be any one or more of A, B, and C.

[0098] Any of the hydrogen atoms of the present invention may be replaced with its isotope, deuterium, and any one of the hydrogen atoms of the compounds of the examples of the present invention may be replaced with a deuterium atom.

[0099] "May" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes cases where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be present, but is not necessarily present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0100] "Substitution" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, each independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only present at possible chemical sites, and a person skilled in the art can easily determine (by experiment or theory) possible or impossible substitutions. For example, when an amino or hydroxyl group having free hydrogen is bonded to a carbon atom having an unsaturated (e.g., ethylenic) bond, instability may result.

[0101] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutical acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically / pharmaceutical acceptable carriers and excipients. Pharmaceutical compositions are intended to exert biological activity by facilitating administration to a living body and facilitating absorption of the active ingredients.

[0102] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when administered to a mammalian body, and which possesses the desired biological activity. EXAMPLES

[0103] The present invention will be further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0104] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetometer, with deuterated dimethylsulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as internal standard.

[0105] For liquid chromatography-mass spectrometry (LC-MS), an Agilent 1200 Infinity Series mass spectrometer is used. For HPLC, an Agilent 1200DAD high performance liquid chromatograph (Sunfire C18 150×4.6 mm chromatography column) and a Waters 2695-2996 high performance liquid chromatograph (Gimini C18 150×4.6 mm chromatography column) are used.

[0106] Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, the silica gel plate used in TLC has a size of 0.15mm-0.20mm, and the silica gel plate used to separate and purify products by thin layer chromatography has a size of 0.4mm-0.5mm. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0107] The starting materials for the examples of the present invention are known and commercially available or can be synthesized using or according to methods known in the art.

[0108] Unless otherwise stated, all reactions of the present invention are carried out under a dry nitrogen or argon gas atmosphere with continuous magnetic stirring, the solvents are dry solvents, and the reaction temperatures are in degrees Celsius.

[0109] Example 1 Preparation of 6-(bicyclo[1,1,1]pentane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] Step 1: Preparation of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [ka] 3-Bromo-2-methoxyaniline (2.02g, 10mmol), bis(pinacolato)diboron (3.05g, 12mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (816.6mg, 1mmol), potassium acetate (2.45g, 25mmol) were mixed in dioxane (20mL), the reaction system was replaced with nitrogen gas three times, reacted at 100℃ overnight, cooled to room temperature, concentrated under reduced pressure, the residue was separated with water and CHCl, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the title compound 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0g, 80%) was obtained by column chromatography.

[0110] 1 H NMR (400MHz, CDCl3) δ1.36 (s, 12H), 3.83 (s, 3H), 6.92-6.99 (m, 2H), 7.16-7.20 (m, 2H).

[0111] MS m / z(ESI):250.1[M+H] + .

[0112] Step 2: Preparation of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline [ka] 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 8 mmol), 3-bromo-1-methyl-1H-1,2,4-triazole (1.61 g, 10 mmol), Cs2CO3 (7.6 g, 20 mmol), tetrakis(triphenylphosphine)palladium (924.5 mg, 0.8 mmol) were mixed in 1,4-dioxane (40 mL) and water (5 mL) and reacted. The system was replaced with nitrogen gas three times, reacted at 100°C overnight, cooled to room temperature, concentrated under reduced pressure, the residue was partitioned between water and CHCl, the organic phase was separated and washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.14 g, 70%).

[0113] 1 H NMR (400MHz, CDCl3) δ3.77(s,3H),3.99(s,3H),6.81-6.86(m,1H),6.96-7.02(m,1H),7.32-7.37(m,1H),8.1(s,1H).

[0114] MS m / z(ESI):205.1[M+H] + .

[0115] Step 3: Preparation of lithium 4,6-dichloropyridazine-3-carboxylate [ka] Methyl 4,6-dichloropyridazine-3-carboxylate (2.07 g, 10 mmol), lithium bromide (2.6 g, 30 mmol) were dissolved in acetonitrile (20 mL) and water (2 mL), cooled to 0° C., DIPEA (5.2 mL, 30 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and react for 1 hour. The reaction solution was filtered, and the filter cake was washed with acetonitrile (2 mL×4). The filter cake was collected and dried to obtain the title compound lithium 4,6-dichloropyridazine-3-carboxylate (1.73 g, 87%).

[0116] MS m / z(ESI):193.1[M+H] + .

[0117] Step 4: Preparation of ((6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc [ka] 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.02 g, 5.0 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (1.19 g, 6.0 mmol) and zinc acetate (1.1 g, 6.0 mmol) were mixed in isopropanol (1 mL) and water (7 mL) and reacted overnight at 65 ° C. The reaction system was cooled to room temperature, water (6 mL) was added, stirred for 1 h, the reaction solution was filtered, the filter cake was washed with water (6 mL × 2) and THF (6 mL), the filter cake was collected and dried to obtain the title compound ((6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc (1.44 g, 73%).

[0118] MS m / z(ESI):361.1[M+H] + .

[0119] Step 5: Preparation of ((6-(bicyclo[1,1,1]pentane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc [ka] ((6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc (157 mg, 0.4 mmol), bicyclo[1,1,1]pentane-1-formamide (111 mg, 1.0 mmol), DBU (61 mg, 0.4 mmol), potassium carbonate (110 mg, 0.8 mmol) were mixed in toluene (1.2 mL) and acetonitrile (0.6 mL), palladium acetate (4.5 mg, 0.02 mmol) and (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (22 mg, 0.04 mmol) were added, the reaction system was replaced with nitrogen gas three times, and the reaction was carried out at 75 ° C. overnight. The reaction was cooled to room temperature, water (4 mL) and acetic acid (2 mL) were added, and the mixture was washed with petroleum ether (6 mL x 2), then the aqueous phase was separated, water (2 mL) was added to the aqueous phase, and the mixture was extracted with CHCl (5 mL x 3), the organic phases were combined, washed with saturated aqueous NaCl solution, the organic phase was separated and dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to give the title compound ((6-(bicyclo[1,1,1]pentane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc (122 mg, 65.2%).

[0120] MS m / z(ESI):436.2[M+H] + .

[0121] Step 6: Preparation of 6-(bicyclo[1,1,1]pentane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] ((6-(bicyclo[1,1,1]pentane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc (94 mg, 0.2 mmol), deuterated methylamine hydrochloride (71 mg, 1.0 mmol), and DIPEA (258 mg, 2.0 mmol) were mixed in DMF (1 mL), and HATU (380 mg, 1.0 mmol) was added and reacted at 40° C. overnight. The reaction system was cooled to room temperature, separated with saturated aqueous sodium bicarbonate and CHCl, the organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by column chromatography to obtain the title compound 6-(bicyclo[1,1,1]pentane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d)pyridazine-3-carboxamide (41 mg, 45%).

[0122] 1 H NMR (400 MHz, CDCl 3 )δ2.17(s,6H),2.53(s,1H),3.80(s,3H),4.00(s,3H),7.23-7.29(m,1H),7.51(dd,J=7.9,1.3H z,1H),7.81(dd,J=7.9,1.4Hz,1H),8.09-8.14(m,2H),8.21(s,1H),8.39(s,1H),11.03(s,1H).

[0123] MS m / z(ESI):452.2[M+H] + .

[0124] Example 2 Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(oxetane-3-carboxamide)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(oxetane-3-carboxamide)pyridazine-3-carboxamide, see Example 1.

[0125] MS m / z(ESI):442.2[M+H] + .

[0126] Example 3 Preparation of 6-(cyclobutanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclobutanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0127] 1 H NMR(400MHz,CDCl3)δ1.85-2.05(m,2H),2.16-2.27(m,2H),2.45-2.33(m,2H),3.33-3.43(m,1H),3.82(s,3H),4.01(s,3H),7.2 6-7.33(m,1H),7.55(dd,J=7.0Hz,1H),7.83(dd,J=7.8,1.1Hz,1H),8.03-8.15(m,2H),8.29(s,1H),9.18(s,1H),11.06(s,1H).

[0128] MS m / z(ESI):440.2[M+H] + .

[0129] Example 4 Preparation of 6-((1R,2R)-2-fluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-((1R,2R)-2-fluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0130] 1 H NMR(400MHz,CDCl3)δ1.18-1.28(m,1H),1.88-2.06(m,2H),3.81(s,3H),4.01(s,3H),4.65-4.95(m,1H),7.24-7.30(m,1H), 7.53(dd,J=7.9,1.3Hz,1H),7.81(dd,J=7.9,1.4Hz,1H),8.02(s,1H),8.11(s,1H),8.27(s,1H),9.82(s,1H),11.07(s,1H).

[0131] MS m / z(ESI):444.2[M+H] + .

[0132] Example 5 Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1S,2R)-2-methylcyclopropane-1-carboxamide)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1S,2R)-2-methylcyclopropane-1-carboxamide)pyridazine-3-carboxamide, see Example 1.

[0133] MS m / z(ESI):440.2[M+H] + .

[0134] Example 6 Preparation of 6-((3-cyclopropyloxobutan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-((3-cyclopropyloxobutan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0135] MS m / z(ESI):454.2[M+H] + .

[0136] Example 7 Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-methyloxobutacyclo-3-yl)amino)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-methyloxobutacyclo-3-yl)amino)pyridazine-3-carboxamide, see Example 1.

[0137] MS m / z(ESI):428.2[M+H] + .

[0138] Example 8 Preparation of 6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0139] MS m / z(ESI):480.2[M+H] + .

[0140] Example 9 Preparation of (R)-6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (R)-6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0141] MS m / z(ESI):480.2[M+H] + .

[0142] Example 10 Preparation of (S)-6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (S)-6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0143] MS m / z(ESI):480.2[M+H] + .

[0144] Example 11 Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide, see Example 1.

[0145] MS m / z(ESI):454.2[M+H] + .

[0146] Example 12 Preparation of (R)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide [ka] For the preparation of (R)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide, see Example 1.

[0147] MS m / z(ESI):454.2[M+H] + .

[0148] Example 13 Preparation of (S)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide [ka] For the preparation of (S)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide, see Example 1.

[0149] MS m / z(ESI):454.2[M+H] + .

[0150] Example 14 Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(1-methylcyclopropane-1-carboxamide)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(1-methylcyclopropane-1-carboxamide)pyridazine-3-carboxamide, see Example 1.

[0151] 1 H NMR(400MHz,CD3OD)δ0.77-0.78(m,2H),1.23-1.25(m,2H),1.48(s,3H),3.73(s,3H),4.01(s,3H),7.3 2(t,J=8.0Hz,1H),7.58(dd,J=8.0,1.2Hz,1H),7.68(dd,J=8.0,1.2Hz,1H),8.18(s,1H),8.47(s,1H).

[0152] MS m / z(ESI):440.2[M+H] + .

[0153] Example 15 Preparation of 6-(1-cyanocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(1-cyanocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0154] 1H NMR(400MHz,CDCl3)δ1.20-1.31(m,2H),1.63-1.67(m,2H),3.76(s,3H),4.01(s,3H),7.23-7.27( m,1H),7.45(dd,J=8.0,1.2Hz,1H),7.80(dd,J=8.0,1.2Hz,1H),7.96(s,1H),8.11(s,1H),8.16(br s,1H),9.00(br s,1H),10.99(br s,1H).

[0155] MS m / z(ESI):451.2[M+H] + .

[0156] Example 16 Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(1-(trifluoromethyl)cyclopropane-1-carboxamide)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(1-(trifluoromethyl)cyclopropane-1-carboxamide)pyridazine-3-carboxamide, see Example 1.

[0157] 1 H NMR(400MHz,CD3OD)δ1.28-1.38(m,2H),1.40-1.48(m,2H),3.73(s,3H),4.01(s,3H),7.29-7. 33(m,1H),7.58(dd,J=8.0,1.2Hz,1H),7.70(dd,J=8.0,1.2Hz,1H),8.12(s,1H),8.48(s,1H).

[0158] MS m / z(ESI):494.2[M+H] + .

[0159] Example 17 Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1-methoxycyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1-methoxycyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0160] MS m / z(ESI):456.2[M+H] + .

[0161] Example 18 Preparation of (S)-6-(2,2-dimethylcyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (S)-6-(2,2-dimethylcyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0162] MS m / z(ESI):454.2[M+H] + .

[0163] Example 19 Preparation of (R)-6-(2,2-dimethylcyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (R)-6-(2,2-dimethylcyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0164] MS m / z(ESI):454.2[M+H] + .

[0165] Example 20 Preparation of (R)-6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri(azol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (R)-6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri(azol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0166] MS m / z(ESI):462.2[M+H] + .

[0167] Example 21 Preparation of (S)-6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri(azol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (S)-6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri(azol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0168] MS m / z(ESI):462.2[M+H] + .

[0169] Example 22 Preparation of 6-(cyclopropanesulfonylamino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropanesulfonylamino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0170] 1 H NMR(400MHz,CD3OD)δ0.80-0.87(m,2H),0.90-0.93(m,2H),2.51-2.55(m,1H),3.65(s,3H),3.92(s,3H),7 .08(s,1H),7.21(t,J=8.20Hz,1H),7.48(dd,J=8.0,1.2Hz,1H),7.62(dd,J=8.0,1.2Hz,1H),8.38(s,1H).

[0171] MS m / z(ESI):462.2[M+H] + .

[0172] Example 23 Preparation of N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)morpholine-4-carboxamide [ka] For the preparation of N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)morpholine-4-carboxamide, see Example 1.

[0173] MS m / z(ESI):471.2[M+H] + .

[0174] Example 24 Preparation of 6-(3-cyclopropylureido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(3-cyclopropylureido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0175] 1 H NMR(400MHz,CDCl3)δ0.64-0.66(m,2H),0.82-0.87(m,2H),2.71-2.73(m,1H),3.79(s,3H),4.01(s,3 H),7.23-7.27(m,1H),7.45(dd,J=8.0,1.2Hz,1H),7.84(dd,J=8.0,1.2Hz,1H),8.11(s,1H),11.01(br s,1H).

[0176] MS m / z(ESI):441.2[M+H] + .

[0177] Example 25 Preparation of cyclopropyl (5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate [ka] For the preparation of cyclopropyl(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate, see Example 1.

[0178] MS m / z(ESI):442.2[M+H] + .

[0179] Example 26 Preparation of 6-(2-cyclopropylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(2-cyclopropylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0180] 1 H NMR(400MHz,CD3OD)δ0.24-0.28(m,2H),0.57-0.61(m,2H),1.12-1.15(m,1H),2.37(d,J=8.0Hz,2H),3.76(s,3H),4. 04(s,3H),7.32(t,J=8.0Hz,1H),7.64(dd,J=8.0,1.2Hz,1H),7.70(dd,J=8.0,1.2Hz,1H),8.20(s,1H),8.50(s,1H).

[0181] MS m / z(ESI):440.2[M+H] + .

[0182] Example 27 Preparation of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl(oxycyclopropimidylamino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl(oxycyclopropimidylamino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0183] MS m / z(ESI):455.2[M+H] + .

[0184] Example 28 Preparation of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyloxyacetylimidamide)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyloxyacetylimidamide)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0185] MS m / z(ESI):429.2[M+H] + .

[0186] Example 29 Preparation of (Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl(oxycyclopropimidylamino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl(oxycyclopropimidylamino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0187] MS m / z(ESI):455.2[M+H] + .

[0188] Example 30 Preparation of (Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyloxyacetylimidamide)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyloxyacetylimidamide)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0189] MS m / z(ESI):429.2[M+H] + .

[0190] Example 31 Preparation of (E)-6-(N'-cyanocyclopropylcarboximide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (E)-6-(N'-cyanocyclopropylcarboximide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0191] MS m / z(ESI):450.2[M+H] + .

[0192] Example 32 Preparation of (E)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (E)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0193] MS m / z(ESI):424.2[M+H] + .

[0194] Example 33 Preparation of (Z)-6-(N'-cyanocyclopropylcarboximide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (Z)-6-(N'-cyanocyclopropylcarboximide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0195] MS m / z(ESI):450.2[M+H] + .

[0196] Example 34 Preparation of (Z)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (Z)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0197] MS m / z(ESI):424.2[M+H] + .

[0198] Example 35 Preparation of 6-((cyclopropylenefluoromethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-((cyclopropylenefluoromethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0199] MS m / z(ESI):428.2[M+H] + .

[0200] Example 36 Preparation of (Z)-6-((1-fluoroprop-1-en-1-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (Z)-6-((1-fluoroprop-1-en-1-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0201] MS m / z(ESI):416.2[M+H] + .

[0202] Example 37 Preparation of 6-((1-cyclopropylene-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-((1-cyclopropylene-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0203] MS m / z(ESI):478.2[M+H] + .

[0204] Example 38 Preparation of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluorobut-2-en-2-yl)amino)pyridazine-3-carboxamide [ka] For the preparation of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluorobut-2-en-2-yl)amino)pyridazine-3-carboxamide, see Example 1.

[0205] MS m / z(ESI):466.2[M+H] + .

[0206] Example 39 Preparation of 6-((1-cyclopropylene-2,2-difluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-((1-cyclopropylene-2,2-difluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0207] MS m / z(ESI):460.2[M+H] + .

[0208] Example 40 Preparation of (E)-6-((1,1-difluorobut-2-en-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (E)-6-((1,1-difluorobut-2-en-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0209] MS m / z(ESI):448.2[M+H] + .

[0210] Example 41 Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1-methylcyclopropyl)amino)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1-methylcyclopropyl)amino)pyridazine-3-carboxamide, see Example 1.

[0211] MS m / z(ESI):412.2[M+H] + .

[0212] Example 42 6-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0213] MS m / z(ESI):450.2[M+H] + .

[0214] Example 43 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridazine-3-carboxamide, see Example 1.

[0215] MS m / z(ESI):424.2[M+H] + .

[0216] Example 44 6-(5-cyclopropyl-1H-imidazol-2-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(5-cyclopropyl-1H-imidazol-2-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0217] MS m / z(ESI):449.2[M+H] + .

[0218] Example 45 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(5-methyl-1H-imidazol-2-yl)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(5-methyl-1H-imidazol-2-yl)pyridazine-3-carboxamide, see Example 1.

[0219] MS m / z(ESI):423.2[M+H] + .

[0220] Example 46 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(pyridine-2-sulfonylamino)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(pyridine-2-sulfonylamino)pyridazine-3-carboxamide, see Example 1.

[0221] MS m / z(ESI):499.2[M+H] + .

[0222] Example 47 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1-methyl-1H-pyrazole)-3-sulfonamido)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1-methyl-1H-pyrazole)-3-sulfonamido)pyridazine-3-carboxamide, see Example 1.

[0223] MS m / z(ESI):502.2[M+H] + .

[0224] Example 48 6-(cyclopropylcarboxamido)-4-((2-(dimethylamino)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-(dimethylamino)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0225] MS m / z(ESI):439.2[M+H] + .

[0226] Example 49 6-(cyclopropylcarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methylthio)phenyl)amino)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methylthio)phenyl)amino)pyridazine-3-carboxamide, see Example 1.

[0227] 1 H NMR(400MHz,CDCl3)δ0.87-0.92(m,2H),1.09-1.12(m,2H),1.88-1.96(m,1H),2.27(s,3H),3.99(s,3H), 7.41-7.49(m,2H),7.57-7.59(m,1H),8.04(s,1H),8.14(s,1H),8.30(s,1H),10.20(s,1H),11.30(s,1H).

[0228] MS m / z(ESI):442.2[M+H] + .

[0229] Example 50 6-(cyclopropylcarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide, see Example 1.

[0230] MS m / z(ESI):480.2[M+H] + .

[0231] Example 51 6-(cyclopropylcarboxamido)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0232] 1 H NMR(400MHz,CDCl3)δ0.85-0.99(m,2H),1.03-1.12(m,2H),1.73-1.81(m,1H),4.00(s,3H),6.63-7.01(m,1 H),7.43-7.48(m,1H),7.54-7.58(m,1H),7.92-7.99(m,2H),8.08-8.16(m,2H),9.83(s,1H),11.16(s,1H).

[0233] MS m / z(ESI):462.2[M+H] + .

[0234] Example 52 6-(cyclopropylcarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamide)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0235] 1H NMR(400MHz,CDCl3)δ0.84-0.95(m,2H),1.02-1.11(m,2H),1.67-1.76(m,1H),3.78(s,3H),4.00(s,3H),7.06-7. 13(m,1H),7.63-7.67(m,1H),7.91-7.97(m,1H),7.98-8.02(m,1H),8.08-8.12(m,1H),9.77(s,1H),10.80(s,1H).

[0236] MS m / z(ESI):444.2[M+H] + .

[0237] Example 53 6-(cyclopropylcarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamide)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0238] 1 H NMR(400MHz,CDCl3)δ0.89-0.94(m,2H),1.11-1.15(m,2H),1.78-1.84(m,1H),3.81(s,3H),4.01(s,3H), 7.23-7.26(m,1H),7.53-7.56(m,1H),8.04(s,1H),8.11(s,1H),8.30(s,1H),9.73(s,1H),11.17(s,1H).

[0239] MS m / z(ESI):444.2[M+H] + .

[0240] Example 54 6-(cyclopropylcarboxamido)-4-((4-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((4-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0241] MS m / z(ESI):444.2[M+H] + .

[0242] Example 55 4-((6-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethylamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 4-((6-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethylamido)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0243] MS m / z(ESI):451.2[M+H] + .

[0244] Example 56 4-((5-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethylamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 4-((5-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethylamido)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0245] MS m / z(ESI):451.2[M+H] + .

[0246] Example 57 4-((4-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethylamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 4-((4-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethylamido)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0247] MS m / z(ESI):451.2[M+H] + .

[0248] Example 58 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] Step 1: Preparation of 2-methoxy-3-nitrobenzamide [ka] At room temperature, methyl 2-methoxy-3-nitrophenyl ester (5g, 23.7mmol) was dissolved in ammonia methanol solution (100mL, 7M), ammonia water (28wt%, 50mL) was added, the mixture was stirred at room temperature overnight, diluted with ethyl acetate (300mL), and then the organic phase was washed with saturated NaHCO3 aqueous solution (300mL x 2) and saturated saline in sequence. The organic phase was separated and dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the title compound 2-methoxy-3-nitrobenzamide (4.3g, 92%).

[0249] MS m / z(ESI):197.1[M+H] + .

[0250] Step 2: Preparation of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole [ka] 2-Methoxy-3-nitrobenzamide (4.2 g, 21.4 mmol) was dissolved in DMF-DMA (28.6 ml), heated to 95° C. and reacted for 1 hour, concentrated under reduced pressure to obtain a crude DMF-DMA adduct, which was dissolved in ethanol (20 mL) for use. In an ice bath, ethanol (70 mL) and acetic acid (21 mL) were added to the reaction flask, stirred for 5 minutes, then hydrazine hydrate (80 wt.%, 10.5 mL) was gradually added dropwise, and the mixture was stirred for 15 minutes, after which the ethanol solution of the crude DMF-DMA adduct was added dropwise, gradually warmed to room temperature, and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, then diluted with ethyl acetate (300 mL), and the organic phase was washed successively with saturated aqueous NaHCO3 solution (300 mL x 2) and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound, 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (4.5 g, 95%).

[0251] MS m / z(ESI):221.1[M+H] + .

[0252] Step 3: Preparation of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole [ka] 3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (200mg, 0.91mmol), copper acetate (198mg, 1.1mmol), 2,2'-bipyridine (170mg, 1.1mmol), sodium carbonate (192mg, 1.8mmol) were mixed in 1,2-dichloroethane (5mL), cyclopropylboronic acid (234mg, 2.72mmol) was added at room temperature, heated to 85℃ and stirred overnight. After cooling the reaction solution to room temperature, a large amount of ethyl acetate was added to dilute it. The organic phase was washed several times with saturated saline, then the organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the title compound 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (125mg, 53%) was obtained.

[0253] 1 H NMR(400MHz,CDCl3)δ1.15-1.21(m,2H),1.24-1.29(m,2H),3.70-3.79(m,1H),3. 94(s,3H),7.23-7.31(m,1H),7.78-7.81(m,1H),8.20-8.23(m,1H),8.36(s,1H).

[0254] MS m / z(ESI):261.1[M+H] + .

[0255] Step 4: Preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline [ka] Palladium / charcoal (30 mg) was added to a solution of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (120 mg, 0.46 mmol) in methanol (5 mL), and the mixture was reacted at room temperature and pressure under a hydrogen atmosphere for 12 hours, after which the catalyst was filtered off with diatomaceous earth. After filtering the filtrate, the organic solvent was concentrated under reduced pressure to obtain the title compound 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (102 mg), which was used directly in the next reaction.

[0256] MS m / z(ESI):231.1[M+H] + .

[0257] Step 5: Preparation of zinc 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate [ka] 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (100 mg, 0.4 mmol), lithium 4,6-dichloropyridazine-3-carboxylate (103.7 mg, 0.5 mmol) and zinc acetate (95.6 mg, 0.5 mmol) were mixed in isopropanol (0.5 mL) and water (3.5 mL) and heated to 80 ° C. overnight. The reaction system was cooled to room temperature, water (3 mL) was added, stirred for 1 h, the reaction solution was filtered, the filter cake was washed with water (3 mL × 2) and THF (2 mL), the filter cake was collected and dried to obtain the title compound 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate zinc (130 mg, 78%).

[0258] MS m / z(ESI):387.1[M+H] + .

[0259] Step 6: Preparation of zinc 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate [ka] 6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-zinc carboxylate (130 mg, 0.31 mmol), cyclopropylamide (86 mg, 1.0 mmol), DBU (61 mg, 0.4 mmol), potassium carbonate (110 mg, 0.8 mmol) were mixed in toluene (1.2 mL) and acetonitrile (0.6 mL), palladium acetate (4.5 mg, 0.02 mmol) and (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine (22 mg, 0.04 mmol) were added, the reaction system was replaced with nitrogen gas three times, and the reaction was heated to 75 ° C. overnight. The reaction was cooled to room temperature, water (4 mL) and acetic acid (2 mL) were added, and the mixture was washed with petroleum ether (6 mL×2), then the aqueous phase was separated, water (2 mL) was added to the aqueous phase, extracted with CHCl (5 mL×3), the organic phases were combined, washed with saturated aqueous NaCl solution, the organic phase was separated and dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to give the title compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-zinc carboxylate (109 mg, 75%).

[0260] MS m / z(ESI):436.1[M+H] + .

[0261] Step 7: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine zinc-3-carboxylate (90 mg, 0.19 mmol), deuterated methylamine hydrochloride (71 mg, 1.0 mmol), DIPEA (258 mg, 2.0 mmol) were mixed in DMF (1 mL), HATU (380 mg, 1.0 mmol) was added, and the mixture was allowed to react at 50° C. overnight. The reaction system was cooled to room temperature, separated with saturated aqueous sodium bicarbonate and CH2Cl2, the organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and then the title compound 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (35 mg, 38%) was obtained by column chromatography.

[0262] 1 H NMR(400MHz,CDCl3)δ0.86-0.99(m,2H),1.07-1.18(m,4H),1.22-1.26(m,2H),1.73-1.82(m,1H),3.65-3.72(m,1H),3.81( s,3H),7.27-7.29(m,1H),7.48-7.52(m,1H),7.81-7.84(m,1H),7.96(s,1H),8.17-8.24(m,2H),9.87(s,1H),11.27(s,1H).

[0263] MS m / z(ESI):452.2[M+H] + .

[0264] Example 59 6-(cyclopropylcarboxamido)-4-((3-(1-isopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] See Example 58 for the preparation of 6-(cyclopropylcarboxamido)-4-((3-(1-isopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0265] MS m / z(ESI):454.2[M+H] + .

[0266] Example 60 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(oxobutan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] See Example 58 for the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(oxobutan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0267] 1 H NMR(400MHz,CDCl3)δ0.90-0.96(m,2H),1.08-1.13(m,2H),1.74-1.80(m,1H),3.87(s,3H),5.07-5.09(m,2H),5.17-5.21(m,2H),5. 57-5.64(m,1H),7.27-7.32(m,1H),7.53-7.56(m,1H),7.84-7.87(m,1H),8.02(s,1H),8.23-8.27(m,2H),9.64(s,1H),11.21(s,1H).

[0268] MS m / z(ESI):468.2[M+H] + .

[0269] Example 61 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] See Example 58 for the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0270] 1 H NMR(400MHz,CDCl3)δ0.80-0.95(m,2H),1.05-1.15(m,2H),1.85-1.93(m,1H),3.35(s,3H),3.77-3.86(m,5H),4.36-4.44(m,2H) ,7.23-7.30(m,1H),7.52(dd,J=7.6Hz,1H),7.82(dd,J=7.7Hz,1H),8.02(s,1H),8.17-8.30(m,2H),10.14(s,1H),11.06(s,1H).

[0271] MS m / z(ESI):470.2[M+H] + .

[0272] Example 62 4-((3-(1-(2-cyanoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylmethylamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] See Example 58 for the preparation of 4-((3-(1-(2-cyanoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylmethylamido)-N-(methyl-d3)pyridazine-3-carboxamide.

[0273] 1 H NMR(400MHz,CDCl3)δ0.86-0.94(m,2H),1.07-1.12(m,2H),1.22-1.26(m,2H),1.74-1.80(m,1H),3.08(t,J=8.0Hz,2H),3.81(s,3 H),4.53(t,J=8.0Hz,2H),7.27-7.31(m,1H),7.53-7.55(m,1H),7.81-7.83(m,1H),8.05(s,1H),8.23(s,1H),8.26(s,1H),9.57(br s,1H),11.11(br s,1H).

[0274] MS m / z(ESI):465.2[M+H] + .

[0275] Example 63 6-(cyclopropylcarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0276] 1 H NMR(400MHz,CDCl3)δ0.90-0.95(m,2H),1.08-1.12(m,2H),1.68-1.75(m,1H),2.72-2.79(m,2H),2.98-3.05(m,2H),3.80(s,3H), 4.21-4.27(m,2H),7.23-7.28(m,1H),7.46-7.49(m,1H),7.81-7.84(m,1H),8.00(s,1H),8.19(s,1H),9.42(s,1H),11.12(s,1H).

[0277] MS m / z(ESI):452.2[M+H] + .

[0278] Example 64 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0279] 1 H NMR(400MHz,CDCl3)δ0.94-1.02(m,2H),1.07-1.11(m,2H),1.76-1.84(m,1H),3.48(s,3H),3.83(s,3 H),7.30-7.42(m,2H),7.57-7.61(m,1H),7.97-8.02(m,2H),8.19(s,1H),9.97(s,1H),11.28(s,1H).

[0280] MS m / z(ESI):426.2[M+H] + .

[0281] Example 65 6-(cyclopropylcarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0282] 1 H NMR(400MHz,CDCl3)δ0.91-0.97(m,2H),1.08-1.12(m,2H),1.96-2.02(m,2H),1.71-1.76(m,1H),2.76-2.80(m,2H),3.13-3.16(m,2 H),3.57(s,3H),4.16-4.19(m,2H),7.41-7.43(m,1H),7.50-7.52(m,1H),7.69-7.71(m,1H),7.79(s,1H),8.09(s,1H),11.84(s,1H).

[0283] MS m / z(ESI):452.2[M+H] + .

[0284] Example 66 6-(cyclopropylcarboxamido)-4-((3-(5-fluoro-1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((3-(5-fluoro-1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0285] MS m / z(ESI):444.2[M+H] + .

[0286] Example 67 6-(cyclopropylcarboxamido)-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0287] MS m / z(ESI):444.2[M+H] + .

[0288] Example 68 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-methyl-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-methyl-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0289] MS m / z(ESI):440.2[M+H] + .

[0290] Example 69 5-Cyano-6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 5-cyano-6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0291] MS m / z(ESI):451.2[M+H] + .

[0292] Example 70 N-(6-(1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(6-(1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide, see Example 1.

[0293] MS m / z(ESI):432.2[M+H] + .

[0294] Example 71 N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(4H-1,2,4-triazol-3-yl)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(4H-1,2,4-triazol-3-yl)pyridazin-3-yl)cyclopropanamide, see Example 1.

[0295] MS m / z(ESI):433.2[M+H] + .

[0296] Example 72 N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1H-tetrazol-5-yl)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1H-tetrazol-5-yl)pyridazin-3-yl)cyclopropanamide, see Example 1.

[0297] MS m / z(ESI):434.2[M+H] + .

[0298] Example 73 N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl-1H-imidazol-2-yl)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl-1H-imidazol-2-yl)pyridazin-3-yl)cyclopropanamide, see Example 1.

[0299] MS m / z(ESI):446.2[M+H] + .

[0300] Example 74 N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridazin-3-yl)cyclopropanamide, refer to Example 1.

[0301] MS m / z(ESI):447.2[M+H] + .

[0302] Example 75 N-(6-(5-cyclopropyl-1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(6-(5-cyclopropyl-1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide, see Example 1.

[0303] MS m / z(ESI):472.2[M+H] + .

[0304] Example 76 N-(6-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(6-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide, refer to Example 1.

[0305] MS m / z(ESI):473.2[M+H] + .

[0306] Example 77 N 6 -Cyclopropyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N 3 -(Methyl-d3)pyridazine-3,6-dimethylamide [ka] N 6 -Cyclopropyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N 3 For the preparation of -(methyl-d3)pyridazine-3,6-dimethylamide, see Example 1.

[0307] 1 H NMR(400MHz,CDCl3)δ0.67-0.72(m,2H).0.86-0.90(m,2H),2.92-2.99(m,1H),3.79(s,3H),4.02(s,3H),7. 23-7.27(m,1H),7.43-7.45(m,1H),7.88-7.90(m,2H),8.16(s,1H),8.22(s,1H),8.29(s,1H),11.15(s,1H).

[0308] MS m / z(ESI):426.2[M+H] + .

[0309] Example 78 N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N-(methyl-d3)sulfamoyl)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N-(methyl-d3)sulfamoyl)pyridazin-3-yl)cyclopropanamide, see Example 1.

[0310] MS m / z(ESI):462.2[M+H] + .

[0311] Example 79 N-(6-(hydroxymethyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(6-(hydroxymethyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide, see Example 1.

[0312] MS m / z(ESI):396.2[M+H] + .

[0313] Example 80 N-(6-(2-hydroxyacetyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide [ka] For the preparation of N-(6-(2-hydroxyacetyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide, see Example 1.

[0314] MS m / z(ESI):424.2[M+H] + .

[0315] Example 81 2-(Cyclopropylcarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide [ka] For the preparation of 2-(cyclopropylcarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide, see Example 1.

[0316] MS m / z(ESI):426.2[M+H] + .

[0317] Example 82 3-(Cyclopropylcarboxamide)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-1,2,4-triazine-6-carboxamide [ka] For the preparation of 3-(cyclopropylcarboxamide)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-1,2,4-triazine-6-carboxamide, see Example 1.

[0318] MS m / z(ESI):427.2[M+H]+ .

[0319] Example 83 6-Methoxy-N 2 -(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N 4 -(5-Methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine [ka] 6-Methoxy-N 2 -(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N 4 For the preparation of -(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine, see Example 1.

[0320] MS m / z(ESI):408.2[M+H] + .

[0321] Example 84 2-(Cyclopropylcarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyrimidine-5-carboxamide [ka] For the preparation of 2-(cyclopropylcarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyrimidine-5-carboxamide, see Example 1.

[0322] 1H NMR(400MHz,DMSO-d6)δ0.76-0.95(m,4H),2.09-2.21(m,1H),2.82(d,J=4.4Hz,3H),3.80(s,3H),3.95(s,3H),7.15(t, J=8.1Hz,1H),7.49(dd,J=7.8,1.6Hz,1H),8.55(s,1H),8.67(d,J=4.7Hz,1H),8.75(s,1H),10.92(s,1H),11.90(s,1H).

[0323] MS m / z(ESI):423.2[M+H] + .

[0324] Example 85 N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(N-methylaminosulfonyl)pyridin-2-yl)cyclopropanamide [ka] For the preparation of N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(N-methylaminosulfonyl)pyridin-2-yl)cyclopropanamide, see Example 1.

[0325] MS m / z(ESI):458.2[M+H] + .

[0326] Example 86 3-(Cyclopropylcarboxamide)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-1,2,4-triazine-6-carboxamide [ka] For the preparation of 3-(cyclopropylcarboxamide)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-1,2,4-triazine-6-carboxamide, see Example 1.

[0327] MS m / z(ESI):424.2[M+H] + .

[0328] Example 87 6-(2-cyclopropyl-2-carbonylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(2-cyclopropyl-2-carbonylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0329] MS m / z(ESI):454.2[M+H] + .

[0330] Example 88 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] Step 1: Preparation of 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole [ka] 5-Fluoro-2-methoxybenzenamide (3.5 g, 20.7 mmol) was dissolved in DMF-DMA (25 ml), heated to 95° C. and reacted for 1 hour, concentrated under reduced pressure to obtain a crude DMF-DMA adduct, which was dissolved in ethanol (20 mL) for use. In an ice bath, ethanol (56 mL) and acetic acid (17 mL) were added to the reaction flask, stirred for 5 minutes, then hydrazine hydrate (80 wt.%, 8.4 mL) was added dropwise, and the mixture was stirred for 15 minutes, after which the ethanol solution of the crude DMF-DMA adduct was added dropwise, gradually warmed to room temperature, and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, then diluted with ethyl acetate (300 mL), washed with saturated aqueous NaHCO3 solution (300 mL x 2), the organic phase was separated and washed with saturated saline solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the title compound 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (3.1 g, 77%).

[0331] MS m / z(ESI):194.2[M+H] + .

[0332] Step 2: Preparation of 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole [ka] 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (1.1 g, 5.69 mmol) was dissolved in concentrated sulfuric acid (10 mL), and nitric acid (68 wt.%, 1.05 g, 11.39 mmol) was added dropwise in an ice bath. After the addition was completed, the mixture was stirred in an ice bath for 2 hours. The reaction mixture was poured into ice water, and ammonia water was gradually added dropwise to adjust the pH value to about 9. The mixture was extracted with ethyl acetate, and the organic phase was separated and dried. The organic solvent was concentrated under reduced pressure to obtain the title compound 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole crude product (1.26 g), which was used directly in the next reaction.

[0333] MS m / z(ESI):239.2[M+H] + .

[0334] Step 3: Preparation of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole [ka] 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (600 mg, 2.52 mmol), copper acetate (688 mg, 3.8 mmol), 2,2'-bipyridine (590 mg, 3.8 mmol), sodium carbonate (534 mg, 5.0 mmol) were mixed in 1,2-dichloroethane (5 mL), cyclopropylboronic acid (865 mg, 10.0 mmol) was added at room temperature, and the mixture was heated to 85 ° C. and stirred overnight. After the reaction solution was cooled to room temperature, a large amount of ethyl acetate was added to dilute it. The organic phase was washed several times with saturated saline, then the organic phase was separated and dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the title compound 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 38%).

[0335] 1 H NMR (400MHz, CDCl3) δ1.16-1.20(m,2H),1.24-1.27(m,2H),3.64-3.73(m,1H),3.94(s,3H),7.52-7.54(m,1H),7.98-8.01(m,1H),8.23(s,1H).

[0336] MS m / z(ESI):279.0[M+H] + .

[0337] Step 4: Preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline [ka] Palladium / carbon (60 mg) was added to a solution of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 0.93 mmol) in methanol (5 mL), and the mixture was reacted at room temperature and pressure under hydrogen atmosphere for 8 hours, after which the catalyst was filtered off with diatomaceous earth. After filtration, the organic solvent was concentrated under reduced pressure to obtain the title compound 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (230 mg), which was used directly in the next reaction.

[0338] MS m / z(ESI):249.2[M+H] + .

[0339] Step 5: Preparation of 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] At room temperature, a solution of LiHMDS (1M, 2.78 mL, 2.78 mmol) in tetrahydrofuran was added dropwise to a solution of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (230 mg, 0.93 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (194 mg, 0.93 mmol) in tetrahydrofuran (8 mL), and the reaction was stirred at room temperature for 2 hours and then quenched with saturated aqueous ammonium chloride solution. The reaction solution was diluted with dichloromethane, and the organic phase was washed several times with saturated saline solution. The organic phase was then separated and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (290 mg, 74%).

[0340] MS m / z(ESI):421.2[M+H] + .

[0341] Step 6: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (155 mg, 0.37 mmol), cyclopropylamide (62 mg, 0.74 mmol), cesium carbonate (360 mg, 1.1 mmol) were mixed in dioxane (5 mL), tris(dibenzylideneacetone)dipalladium (101 mg, 0.11 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (127 mg, 0.22 mmol) were added, oxygen was removed with nitrogen gas for 5 minutes, and the reaction was carried out at 145 ° C. in a microwave for 2 hours. The reaction solution was diluted with dichloromethane, and the organic phase was washed several times with saturated saline solution. The organic phase was then separated and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure, and then separated by column chromatography to obtain the title compound 6-(cyclopropylcarboxamide)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (116 mg, 67%).

[0342] 1H NMR(400MHz,CDCl3)δ0.90-0.95(m,2H),1.11-1.16(m,4H),1.21-1.26(m,2H),1.74-1.80(m,1H),3.65-3.71(m,1H), 3.80(s,3H),7.22-7.25(m,1H),7.51-7.54(m,1H),8.03(s,1H),8.19(s,1H),8.29(s,1H),9.59(s,1H),11.21(s,1H).

[0343] MS m / z(ESI):470.2[M+H] + .

[0344] Example 89 6-(cyclopropylcarboxamido)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0345] MS m / z(ESI):440.2[M+H] + .

[0346] Example 90 6-(cyclopropylcarboxamido)-4-((2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0347] 1 H NMR(400MHz,CDCl3)δ0.86-0.93(m,2H),1.06-1.11(m,2H),1.78-1.87(m,1H),4.04(s,3H),7.27-7.33( m,1H),7.46-7.52(m,1H),7.90-7.96(m,1H),8.03(s,1H),8.08-8.15(m,2H),9.99(s,1H),10.95(s,1H).

[0348] MS m / z(ESI):414.2[M+H] + .

[0349] Example 91 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole [ka] At -20°C, a dichloromethane solution (20mL) of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00g, 4.54mmol), DMAP (55.0mg, 0.454mmol) and DIPEA (1.05mL, 6.36mmol) was slowly added dropwise to a dichloromethane solution (10mL) of SEM-Cl (0.964mL, 5.45mmol). After the addition was completed, the temperature was gradually raised to -10°C and stirred at this temperature overnight. The reaction solution was washed with saturated saline, the organic phase was separated and dried, and after filtration, the organic solvent was concentrated under reduced pressure, and the resulting crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next reaction.

[0350] MS m / z(ESI):351.2[M+H] + .

[0351] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline [ka] The crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added in sequence, and the mixture was stirred at 50° C. for 2 hours. The reaction system was then cooled, and the insoluble matter was filtered off with diatomaceous earth. The filtrate was concentrated, and the residue was dissolved in dichloromethane, and further washed with saturated saline. The organic phase was separated and dried with a desiccant, and after filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, yield in two steps: 45%).

[0352] MS m / z(ESI):321.2[M+H] + .

[0353] Step 3: Preparation of 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] At 0°C, LiHMDS (1M in THF, 5.00mL) was added dropwise to a THF solution (20mL) of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (640mg, 2.00mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417mg, 2.00mmol), and after the addition was completed, the temperature was gradually raised to room temperature and the mixture was stirred at room temperature for 2 hours. It was quenched by adding saturated brine, then extracted twice with DCM, the organic phases were combined and dried, after which the organic solvent was concentrated under reduced pressure and separated by column chromatography to give the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

[0354] MS m / z(ESI):493.2[M+H] + .

[0355] Step 4: Preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] 6-Chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850 mg, 1.73 mmol), cyclopropylamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4-dioxane (20 mL), and the reaction solution was eluted with nitrogen gas to remove oxygen for 5 minutes, and Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added in that order. The reaction was heated under nitrogen gas protection at 130°C in a microwave for 90 minutes, cooled to room temperature, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the title compound 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (680 mg, 73%).

[0356] MS m / z(ESI):542.3[M+H] + .

[0357] Step 5: Preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] TFA (6.0 mL) was added to a solution of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (6, 1.16 mmol) in DCM at 0° C., then stirred at room temperature overnight. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and further washed with saturated aqueous sodium bicarbonate and saturated saline in that order. The organic phase was dried and then concentrated under reduced pressure. The product was separated by column chromatography to obtain the title compound 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (270 mg, 57%).

[0358] 1 H NMR(400MHz,CDCl3)δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H), 3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H).

[0359] MS m / z(ESI):412.2[M+H] + .

[0360] Step 6: Preparation of 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (30 mg, 0.073 mmol), allyl bromide (8.7 mg, 0.073 mmol) and potassium carbonate (20 mg, 0.15 mmol) were mixed in MeCN (3 mL) and stirred at 0° C. for 2 days. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (12 mg, 39%).

[0361] 1 H NMR(400MHz,CDCl3)δ0.88-0.92(m,2H),1.10-1.12(m,2H),1.80-1.85(m,1H),3.80(s,3H),4.86-4.88(m,2H),5.35-5.38(m,2H), 6.03-6.11(m,1H),7.27-7.31(m,1H),7.52(d,J=8.0Hz,1H),7.80(d,J=8.0Hz,1H),8.03(s,1H),8.15(s,1H),8.24(s,1H),9.88(br s,1H),11.05(s,1H).

[0362] MS m / z(ESI):452.2[M+H] + .

[0363] Example 92 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole [ka] At -20°C, a dichloromethane solution (20mL) of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00g, 4.54mmol), DMAP (55.0mg, 0.454mmol) and DIPEA (1.05mL, 6.36mmol) was slowly added dropwise to a dichloromethane solution (10mL) of SEM-Cl (0.964mL, 5.45mmol). After the addition was completed, the temperature was gradually raised to -10°C and stirred at this temperature overnight. The reaction solution was washed with saturated saline, the organic phase was separated and dried, and after filtration, the organic solvent was concentrated under reduced pressure, and the resulting crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next reaction.

[0364] MS m / z(ESI):351.2[M+H] + .

[0365] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline [ka] The crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added in sequence, and the mixture was stirred at 50° C. for 2 hours. The reaction system was then cooled, and the insoluble matter was filtered off with diatomaceous earth. The filtrate was concentrated, and the residue was dissolved in dichloromethane, and further washed with saturated saline. The organic phase was separated and dried with a desiccant, and after filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, yield in two steps: 45%).

[0366] MS m / z(ESI):321.2[M+H] + .

[0367] Step 3: Preparation of 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] At 0°C, 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (640 mg, 2.00 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417 mg, 2.00 mmol) were added dropwise to a THF solution (20 mL) and, after the addition was completed, the temperature was gradually raised to room temperature and the mixture was stirred at room temperature for 2 hours. It was quenched by adding saturated brine, then extracted twice with DCM, the organic phases were combined and dried, after which the organic solvent was concentrated under reduced pressure and separated by column chromatography to give the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

[0368] MS m / z(ESI):493.2[M+H] + .

[0369] Step 4: Preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] 6-Chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850 mg, 1.73 mmol), cyclopropylamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4-dioxane (20 mL), and the reaction solution was eluted with nitrogen gas to remove oxygen for 5 minutes, and Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added in that order. The reaction was heated under nitrogen gas protection at 130°C in a microwave for 90 minutes, cooled to room temperature, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the title compound 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (680 mg, 73%).

[0370] MS m / z(ESI):542.3[M+H] + .

[0371] Step 5: Preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] To a solution of 6-(cyclopropylcarboxamide)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (6, 1.16 mmol) in DCM (20 mL) at 0° C. was added TFA (6.0 mL) and then stirred at room temperature overnight. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and further washed with saturated aqueous sodium bicarbonate and saturated saline in that order. The organic phase was dried and then concentrated under reduced pressure. The product was separated by column chromatography to obtain the title compound 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (270 mg, 57%).

[0372] 1 H NMR(400MHz,CDCl3)δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H), 3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H).

[0373] MS m / z(ESI):412.2[M+H] + .

[0374] Step 6: Preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] 6-(cyclopropylcarboxamide)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (30 mg, 0.073 mmol), propargyl bromide (8.7 mg, 0.073 mmol) and potassium carbonate (20 mg, 0.15 mmol) were mixed in MeCN (3 mL) and stirred at 0° C. for 2 days. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarboxamide)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (10 mg, 31%).

[0375] 1 H NMR(400MHz,CDCl3)δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.62(s,1H),3.81(s,3H),5.07(s,2) H),7.26-7.30(m,1H),7.52(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),8.00(s,1H),8.23(s,1H),8.38(s,1H),9.88(br s,1H),11.13(s,1H).

[0376] MS m / z(ESI):450.2[M+H] + .

[0377] Example 93 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0378] MS m / z(ESI):494.2[M+H] + .

[0379] Example 94 4-((3-(1-(tert-butyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 4-((3-(1-(tert-butyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamido)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0380] MS m / z(ESI):468.2[M+H] + .

[0381] Example 95 6-(Cyclopropanamido)-4-((2-methoxy-3-(1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0382] MS m / z(ESI):522.2[M+H] + .

[0383] Example 96 4-((3-(1-(bicyclo[1,1,1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 4-((3-(1-(bicyclo[1,1,1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0384] MS m / z(ESI):478.2[M+H] + .

[0385] Example 97 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(thiobutan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamide)-4-((2-methoxy-3-(1-(thiobutan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0386] MS m / z(ESI):484.2[M+H] + .

[0387] Example 98 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(3-methyloxobutan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(3-methyloxobutan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0388] 1 H NMR(400MHz,CDCl3)δ0.91-0.93(m,2H),1.08-1.13(m,2H),1.72-1.75(m,1H),2.07(s,3H),3.86(s,3H),4.71(d,J=6.6Hz,2H),5.25 (d,J=6.4Hz,2H),7.28-7.30(m,1H),7.52-7.55(m,1H),7.82-7.85(m,1H)8.05(s,1H),8.23-8.25(m,2H),9.31(s,1H),11.16(s,1H).

[0389] MS m / z(ESI):482.2[M+H] + .

[0390] Example 99 6-(cyclopropylmethylthioamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylmethylthioamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0391] MS m / z(ESI):442.2[M+H] + .

[0392] Example 100 6-(cyclopropylcarboxamido)-4-((2-(dimethyllin)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-(dimethyllin)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0393] MS m / z(ESI):472.2[M+H] + .

[0394] Example 101

[0395] 6-(cyclopropylcarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methanesulfonyl)phenyl)amino)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methanesulfonyl)phenyl)amino)pyridazine-3-carboxamide, see Example 1.

[0396] MS m / z(ESI):474.2[M+H] + .

[0397] Example 102 4-((3-(1-(cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 4-((3-(1-(cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamido)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0398] MS m / z(ESI):451.2[M+H] + .

[0399] Example 103 4-((3-(1-(bicyclo[1,1,1]pentan-1-ylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 4-((3-(1-(bicyclo[1,1,1]pentan-1-ylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0400] MS m / z(ESI):492.2[M+H] + .

[0401] Example 104 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(oxobutacyclo-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(oxobutacyclo-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 92.

[0402] 1 H NMR(400MHz,CDCl3)δ0.91-0.94(m,2H),1.08-1.14(m,2H),3.55-3.62(m,1H),3.81(s,3H),4.54-4.59(m,4H),4.80-4.90(m,2 H),7.27-7.29(m,1H),7.50-7.52(m,1H),7.80-7.82(m,1H),8.06(s,1H),8.13(s,1H),8.20(s,1H),9.14(s,1H),11.09(s,1H).

[0403] MS m / z(ESI):482.2[M+H] + .

[0404] Example 105 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(4-carbonyl-5-azaspiro[2,4]heptan-5-yl)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(4-carbonyl-5-azaspiro[2,4]heptan-5-yl)pyridazine-3-carboxamide, see Example 1.

[0405] MS m / z(ESI):452.2[M+H] + .

[0406] Example 106 6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0407] MS m / z(ESI):437.2[M+H] + .

[0408] Example 107 (R)-6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (R)-6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0409] MS m / z(ESI):437.2[M+H] + .

[0410] Example 108 (S)-6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of (S)-6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0411] MS m / z(ESI):437.2[M+H] + .

[0412] Example 109 6-(1-fluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(1-fluorocyclopropane-1-carboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0413] 1 H NMR(400MHz,CDCl3)δ1.38-1.50(m,4H),3.81(s,3H),4.00(s,3H),7.23-7.29(m,1H),7.49(dd ,J=7.9,1.4Hz,1H),7.81(dd,J=7.9,1.5Hz,1H),8.09-8.22(m,3H),9.09(s,1H),11.00(s,1H).

[0414] MS m / z(ESI):444.2[M+H] + .

[0415] Example 110 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-vinyloxobutacyclo-3-yl)amino)pyridazine-3-carboxamide [ka] For the preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-vinyloxobutacyclo-3-yl)amino)pyridazine-3-carboxamide, see Example 1.

[0416] MS m / z(ESI):440.2[M+H] + .

[0417] Example 111

[0418] 6-((3-ethynyloxobutan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-((3-ethynyloxobutan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0419] MS m / z(ESI):438.2[M+H] + .

[0420] Example 112 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole [ka] At -20°C, a dichloromethane solution (20mL) of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00g, 4.54mmol), DMAP (55.0mg, 0.454mmol) and DIPEA (1.05mL, 6.36mmol) was slowly added dropwise to a dichloromethane solution (10mL) of SEM-Cl (0.964mL, 5.45mmol). After the addition was completed, the temperature was gradually raised to -10°C and stirred at this temperature overnight. The reaction solution was washed with saturated saline, the organic phase was separated and dried, and after filtration, the organic solvent was concentrated under reduced pressure, and the resulting crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next reaction.

[0421] MS m / z(ESI):351.2[M+H] + .

[0422] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline [ka] The crude product was dissolved in a mixture of ethanol (30 mL) and water (5 mL), and then ammonium chloride solid (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added in sequence, and the mixture was stirred at 50° C. for 2 hours. The reaction system was then cooled, and the insoluble matter was filtered off with diatomaceous earth. The filtrate was concentrated, and the residue was dissolved in dichloromethylalkane, and further washed with saturated saline. The organic phase was separated and dried with a desiccant, and after filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, yield in two steps: 45%).

[0423] MS m / z(ESI):321.2[M+H] + .

[0424] Step 3: Preparation of 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] At 0°C, 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (640 mg, 2.00 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417 mg, 2.00 mmol) were added dropwise to a THF solution (20 mL) and, after the addition was completed, the temperature was gradually raised to room temperature and the mixture was stirred at room temperature for 2 hours. It was quenched by adding saturated brine, then extracted twice with DCM, the organic phases were combined and dried, after which the organic solvent was concentrated under reduced pressure and separated by column chromatography to give the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

[0425] MS m / z(ESI):493.2[M+H] + .

[0426] Step 4: Preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] 6-Chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850 mg, 1.73 mmol), cyclopropylamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4-dioxane (20 mL), and the reaction solution was eluted with nitrogen gas to remove oxygen for 5 minutes, and Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added in that order. Under the protection of nitrogen gas, the reaction was carried out in a microwave at 130°C for 90 minutes, cooled to room temperature, and the organic solvent was concentrated under reduced pressure, followed by separation by column chromatography to obtain the title compound 6-(cyclopropylcarboxamide)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (680 mg, 73%).

[0427] MS m / z(ESI):542.3[M+H] + .

[0428] Step 5: Preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] TFA (6.0 mL) was added to a solution of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (6, 1.16 mmol) in DCM at 0° C., then stirred at room temperature overnight. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and further washed with saturated aqueous sodium bicarbonate and saturated saline in that order. The organic phase was dried and then concentrated under reduced pressure. The product was separated by column chromatography to obtain the title compound 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (270 mg, 57%).

[0429] 1 H NMR(400MHz,CDCl3)δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H), 3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H).

[0430] MS m / z(ESI):412.2[M+H] + .

[0431] Example 113 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide, see Example 1.

[0432] 1H NMR(400MHz,DMSO)δ0.79-0.86(m,4H),2.04-2.12(m,1H),3.71(s,3H),3.95(s,3H),7.24-7.25(m,1H),7.4 9-7.52(m,1H),7.63-7.67(m,1H),7.89(s,1H),8.16(s,1H),8.53-8.58(m,2H),11.06(s,1H),11.33(s,1H).

[0433] MS m / z(ESI):409.2[M+H] + .

[0434] Example 114 6-(cyclopropylcarboxamido)-4-((5-fluoro-2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-methylamide [ka] See Example 92 for the preparation of 6-(cyclopropylcarboxamido)-4-((5-fluoro-2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-methylamide.

[0435] 1 H NMR(400MHz,DMSO-d6)δ0.84-0.87(m,2H),1.23-1.34(m,2H),2.09-2.12(m,1H),3.60(s,1H),3.75(s,3 H),5.24(s,2H),7.39-7.47(m,2H),8.26(s,1H),8.72(s,1H),9.19(s,1H),11.20(s,1H),11.41(s,1H).

[0436] MS m / z(ESI):468.2[M+H] + .

[0437] Example 115 6-(cyclopropylcarboxamido)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0438] 1 H NMR(400MHz,CDCl3)δ0.44-0.48(m,2H),0.70-0.76(m,2H),0.86-0.93(m,2H),1.08-1.11(m,2H),1.33-1.40(m,1H),1.82-1.89(m,1H),3.82(s, 3H),4.10(d,J=7.2Hz,2H),7.25-7.30(m,1H),7.50-7.54(m,1H),7.80- 7.83(m,1H),8.02(s,1H),8.23-8.25(m,2H),9.98(s,1H),11.04(s,1H).

[0439] MS m / z(ESI):466.2[M+H] + .

[0440] Example 116 6-(Cyclopropanamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 92, and Example 116 is one of the products from the reaction of Step 6.

[0441] 1 H NMR(400MHz,CDCl3)δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.39(s,1H),3.48(s,3H),4.94(d, J=6.4Hz,2H),7.26-7.36(m,1H),7.43(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),8.07(s,1H),8.12(s,1H),9.64(br s,1H),11.07(s,1H).

[0442] MS m / z(ESI):450.2[M+H] + .

[0443] Example 117 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropylcarboxamide)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 1.

[0444] 1H NMR(400MHz,CDCl3)δ0.93-1.02(m,4H),1.05-1.11(m,4H),1.75-1.82(m,1H),3.48(s,3H),3.61-3.7 0(m,1H),7.13-7.17(m,1H),7.29-7.33(m,1H),7.93(s,2H),8.18(s,1H),10.61(s,1H),11.59(s,1H).

[0445] MS m / z(ESI):470.1[M+H] + .

[0446] Example 118

[0447] 6-(Cyclopropanamido)-4-((2-methoxy-3-(4-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka] For the preparation of 6-(cyclopropanamido)-4-((2-methoxy-3-(4-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, see Example 92, and Example 118 is one of the products from the reaction of step 6.

[0448] 1 H NMR(400MHz,CDCl3)δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),1.71(s,1H),3.81(s,3H),5.71(d,J=6.4 Hz,2H),7.22-7.30(m,1H),7.52(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),8.07(s,1H),8.20(s,1H),8.29(s,1H),9.10(br s,1H),11.07(s,1H).

[0449] MS m / z(ESI):450.2[M+H] + .

[0450] Example 119 6-(cyclopropanamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide [ka] For the preparation of 6-(cyclopropanamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide, see Example 92.

[0451] 1 H NMR(400MHz,DMSO-d6)δ0.88-0.91(m,2H),1.03-1.09(m,2H),1.55-1.65(m,1H),3. 81(s,3H),5.06(s,2H),6.79(s,1H),7.26-7.77(m,2H),8.06-8.37(m,3H),9.01(br s,1H),10.63(br s,1H).

[0452] MS m / z(ESI):449.2[M+H] + .

[0453] Example 120 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide, see Example 1.

[0454] 1H NMR(400MHz,CDCl3)δ0.84-0.89(m,2H),1.03-1.08(m,2H),1.11-1.14(m,2H),1.21-1.25(m,2H),1.51-1.57(m,1H),3.63-3.70(m,1H),3.81(s ,3H),6.46(s,1H),7.19-7.24(m,1H),7.51-7.54(m,1H),7.68-7.70(m, 1H), 8.06 (s, 1H), 8.17 (s, 1H), 8.30 (s, 1H), 8.60 (s, 1H), 10.41 (s, 1H).

[0455] MS m / z(ESI):451.1[M+H] + .

[0456] Example 121 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide [ka] For the preparation of 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide, see Example 1.

[0457] 1 H NMR(400MHz,CDCl3)δ0.87-0.94(m,2H),1.06-1.16(m,4H),1.20-1.25(m,2H),1.56-1.66(m,1H),3.65-3.69(m ,1H),3.81(s,3H),6.84(s,1H),7.44-7.50(m,1H),8.13-8.17(m,2H),8.47(s,1H),9.12(s,1H),10.77(s,1H).

[0458] MS m / z(ESI):469.2[M+H] + .

[0459] Biological Test Evaluation The present invention will be further explained and explained by the following test examples, but these examples are not intended to limit the scope of the present invention.

[0460] Test Example 1: Measurement of the inhibitory effect of the compound of the present invention on the cellular TYK2 signal transduction pathway Experimental Objective: The objective of this experiment is to test the inhibitory activity of compounds on the cellular TYK2 signaling pathway.

[0461] Experimental equipment: A centrifuge (5702R) purchased from Eppendorf; Pipettes purchased from Eppendorf, A full-featured microplate reader was purchased from BioTek, USA, with model number SynergyH1.

[0462] Experimental method: This experiment used U266 cell line expressing TYK2, activated the TYK2 signaling pathway by IFN-α stimulation, detected the inhibitory activity of compounds on downstream STAT3 phosphorylation, and determined the half inhibitory concentration (IC) of compounds on the activity of the TYK2 signaling pathway. 50 obtained.

[0463] The specific experimental procedures are as follows: 3-12 μL of U266 cells were spread on a 384-well detection plate, with the cell number of each well being 100-300K, and 2 μL of gradient diluted compound solution was added and incubated for 2 hours in an incubator containing carbon dioxide. After 2 hours, 2 μL of INF-α with a final concentration of 1000 U / mL was added and shaken at room temperature for 20 min. 2-5 μL of (5X) LANCE Ultra Lysis Buffer 2 solution was added and shaken at room temperature for 2 h. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT5 (Y694 / Y699) Antibody (PerkinElmer) with a final concentration of 2 nM and LANCE Ultra ULight-labeled Anti-STAT5 Antibody (PerkinElmer) with a final concentration of 20 nM were added and incubated overnight at room temperature. The microplate reader measured the 665 nm fluorescence signal value of each plate well, calculated the inhibition rate according to the fluorescence signal value, and determined the IC value of the compound by curve fitting based on the inhibition rate at different concentrations. 50 obtained.

[0464] Experimental data processing method: The percent inhibition data {% inhibition = 100-[(test compound value-negative control value)] / (positive control value-negative control value) x 100} of the compound-treated wells with positive control wells (DMSO control wells) and negative control wells (no cells added) on the plate were calculated. The IC was calculated by fitting the different concentrations and the corresponding percent inhibition data to a four-parameter nonlinear logistic equation using GraphPad prism. 50 values ​​were calculated.

[0465] Test conclusion: The test data of the inhibitory activity of the compounds of the present invention against the cellular TYK2 signaling pathway obtained by the above scheme are shown in the following table: [Table 1]

[0466] Test Example 2: Measurement of the inhibitory effect of the compounds of the present invention on the cellular JAK2 signaling pathway

[0467] Experimental Objective: The objective of this experiment is to test the inhibitory activity of compounds on the cellular JAK2 signaling pathway.

[0468] Experimental equipment: A centrifuge (5702R) purchased from Eppendorf; Pipettes purchased from Eppendorf, A full-featured microplate reader was purchased from BioTek, USA, with model number SynergyH1.

[0469] Experimental method: This experiment used TF-1 cell line, stimulated with IL6 to activate the JAK2 signaling pathway, detected the inhibitory activity of compounds on downstream STAT3 phosphorylation, and determined the half inhibitory concentration (IC) of compounds on the activity of the JAK2 signaling pathway. 50 obtained.

[0470] The specific experimental procedures are as follows: 3-12 μL of TF-1 cells were spread on a 384-well detection plate, and the number of cells in each well was 100-300K. 2 μL of gradient diluted compound solution was added and incubated for 2 hours in an incubator containing carbon dioxide. After 2 hours, 2 μL of IL6 with a final concentration of 30 ng / mL was added and shaken at room temperature for 20 min. 2-5 μL of (5X) LANCE Ultra Lysis Buffer 2 solution was added and shaken at 4 °C for 2 h. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT3 (Tyr705) Antibody (PerkinElmer) with a final concentration of 2 nM and LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 20 nM were added and incubated overnight at room temperature. The microplate reader measured the 665 nm fluorescence signal value of each plate well, calculated the inhibition rate according to the fluorescence signal value, and determined the IC value of the compound by curve fitting based on the inhibition rate at different concentrations. 50 obtained.

[0471] Experimental data processing method: The percent inhibition data {% inhibition = 100-[(test compound value-negative control value)] / (positive control value-negative control value) x 100} of the compound-treated wells with positive control wells (DMSO control wells) and negative control wells (no cells added) on the plate were calculated. The IC was calculated by fitting the different concentrations and the corresponding percent inhibition data to a four-parameter nonlinear logistic equation using GraphPad prism. 50 values ​​were calculated.

[0472] Test conclusion: The test data of the inhibitory activity of the compounds of the present invention against the cellular JAK2 signaling pathway obtained by the above scheme are shown in the following table: [Table 2]

[0473] Experimental Conclusion: As can be seen from the data in the table, the example compounds have higher selectivity for JAK2 cellular activity compared to TYK2 cellular activity.

[0474] Test Example 3: Plasma protein binding rate test in mice 1. Research purpose: The purpose of this study was to evaluate the protein binding profile of Example 58, Example 88 and Example 92 (5 μM) in mouse plasma using equilibrium dialysis.

[0475] 2. Compounds and test materials: 1) Test compounds were prepared in DMSO at 10 mM stock solution and stored in a refrigerator at -20°C for use. 2) Frozen plasma of the required species, dialysate (100 mM phosphate buffer (Lot#SLBS7904 and Lot#SLBR3106V), pH 7.4).

[0476] 3. Experimental equipment 96-well plate (Lot#07917415), detection membrane device (Lot#SD2369421), liquid chromatography-mass spectrometry combined (LC-MS / MS) (LC-20AD, API4000), centrifuge (Eppendorf 5804R / 5424R), vortex mixer (IKA VORTEX GENIUS 3), pipettes (Eppendorf 10-100 μL (PIP-100-002), Eppendorf 100-1000 μL (PIP-1000-002), RAININ 0.5-10 μL (PIP-10-002)), water bath (Shanghai Hengke).

[0477] 4. Experimental steps 4.1 Preparation of dialysis fluid 4.01 mL of 1 M K2HPO4 (AR grade) and 0.99 mL of 1 M KH2PO4 (AR grade) were diluted with ultrapure water to 50 mL, and 100 mM phosphate buffer (pH = 7.4) was prepared as a dialysis solution.

[0478] 4.2 Plasma preparation Frozen plasma was thawed at room temperature or in a water bath at 37°C, centrifuged at 3500 rpm for 5 minutes, and the supernatant was removed.

[0479] 4.3 Preparation of reaction solution The final solution is made with acetonitrile (or other appropriate solution) containing the internal standard and stored in a refrigerator at 2-8°C. For the specific concentration of the internal standard, refer to the final report.

[0480] 4.4 Preparation of compound working fluid Preparation of compound working solutions: Stock solutions were diluted in DMSO to a final concentration of 1 mM.

[0481] 4.5 Preparation of plasma solutions 4 μL of compound working solution was added to 796 μL of blank plasma to give a final concentration of 5 μM and shaken to mix uniformly.

[0482] 4.6 Equilibrium dialysis 1) Prepare an equilibrium dialysis apparatus and place the detection membrane device in a 96-well plate for equilibrium dialysis. 2) 200 μL of the prepared plasma solution was added to the membrane, n=2; 3) 4 μL of another plasma solution was diluted 10 times with 36 μL of the same type of blank plasma, and then 160 μL of acetonitrile ending solution containing an internal standard was added and stored in a refrigerator at -20°C to obtain a TO (Total) sample; 4) Add 350 μL of dialysis solution (100 mM phosphate buffer) to the outside of the membrane. 5) Seal the dialysis plate and incubate it in a 37°C water bath for 6 hours. 6) After the dialysis is completed, 4 μL of the dialysate from the sample hole in the membrane is diluted 10 times with 36 μL of the same type of blank plasma, and 160 μL of acetonitrile end solution containing an internal standard is added to 40 μL of the dialysate from the sample hole outside the membrane to obtain T6 (Total) sample and F6 (Total) sample. 7) After centrifuging the T0(Total) and T6(Total) samples, collect the supernatant. 8) LC-MS analysis was performed.

[0483] 5. Experimental results [Table 3]

[0484] Test Example 4: Pharmacokinetics measurement in Balb / C mice 1. Research purpose: Balb / C mice were used as test animals to study the pharmacokinetic behavior of the compounds of Example 58, Example 88 and Example 92 in mouse plasma when orally administered at a dose of 5 mg / kg.

[0485] 2. Experimental plan: 2.1 Test Drugs: Examples 58, 88 and 92 of the present invention prepared in the laboratory

[0486] 2.2 Test animals: 18 male Balb / C mice (6 mice / example) purchased from Shanghai Jieshijie Laboratory Animal Co., Ltd. with animal production permit number (SCXK (Shanghai) 2013-0006 No. 0.311620400001794)

[0487] 2.3 Administration: Each group consisted of 18 male Balb / C mice, which were administered po at a dose of 5 mg / kg in a volume of 10 mL / kg after an overnight fast.

[0488] 2.4 Sample Collection: 0.1 mL of blood was collected from the mouse orbit before administration and at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, placed in an EDTA-K2 test tube, centrifuged at 6000 rpm at 4°C for 6 minutes to separate plasma, and stored at -80°C.

[0489] 2.5 Sample Processing: 1) 160 μL of acetonitrile was added to 40 μL of plasma sample to precipitate, mixed, and then centrifuged at 3500 rpm for 5 to 20 minutes. 2) After treatment, 100 uL of the supernatant solution was subjected to LC / MS / MS to analyze the concentration of the test compound.

[0490] 2.6 Liquid phase analysis Liquid phase conditions: Shimadzu LC-20AD pump ·Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer Chromatography column: 50×4.6mm phenomenex Gemiu 5um C18 Mobile phase: Solution A is 0.1% formic acid in water, and solution B is acetonitrile. ·Flow rate: 0.8mL / min Elution time: 0-4.0 min, elution solution: [Table 4]

[0491] 3. Experimental results and analysis The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the pharmacokinetic experiments in mice are shown in the following table: [Table 5]

[0492] Experimental conclusion: As can be seen from the table, the pharmacokinetic exposure (AOC) of the compound in the example in mice was 0-t (ng / mL*h) is superior to the reference compound BMS-986165, and in particular the pharmacokinetic exposure of Example 58 and Example 88 is far superior to the reference compound BMS-986165, being 6-fold and 10-fold or more than that of the reference compound.

[0493] Test Example 5: Measurement of efficacy of the compound of the present invention in a mouse psoriasis model induced by imiquimod 1. Purpose of the experiment: The compounds are evaluated for efficacy in an imiquimod-induced psoriasis-like model in mice.

[0494] 2. Main experimental instruments and reagents 2.1 Equipment [Table 6]

[0495] 2.2 Reagents [Table 7]

[0496] 3. Experimental steps 3.1 Model Construction The animals were shaved at the test site on their backs on Day 0. On Days 1-6, 62.5 mg of imiquimod was applied daily to the test site on the animals' backs.

[0497] 3.2 Administration On days 1 to 7, animals in each group were administered according to the experimental plan. The experimental design of the imiquimod-induced mouse psoriasis-like model is shown in the table below: [Table 8]

[0498] 3.3 Severity index assessment of skin damage due to dermatitis On days 1 to 7, the redness, kogation, and thickening of the test site on the back of the animals were scored on a scale of 0 to 4, with 0 being no damage, 1 being slight, 2 being moderate, 3 being obvious, and 4 being very obvious. The total score indicates the severity of the damage.

[0499] 4. Test data 4.1 Comparative results of PASI assessment in imiquimod-induced mouse psoriasis model for different compounds are shown in the table below: [Table 9]

[0500] 4.2 The PASI assessment results in imiquimod-induced mouse psoriasis model of different compounds are shown in Figure 1, where the data points represent the mean PASI assessment score within the group, N=8, compared with the vehicle group using One-way ANOVA, ***p<0.001.

[0501] 5. Experimental results As can be seen from the above results, Examples 58, 88 and 92 of the present patent can effectively improve the symptoms of psoriasis in imiquimod-induced mouse psoriasis-like model, with a very significant difference compared with the vehicle group, P<0.001, and superior to the reference compound BMS-986165 (P<0.01).

Claims

1. A compound represented by general formula (V), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, R is C １-６ is an alkoxy group, R ３ is hydrogen, C １-６ selected from the group consisting of alkyl groups and halogens; R ４ is C ２-６ Alkenyl group, C ２-６ Alkynyl group, C ３-８ Cycloalkyl groups, 3- to 8-membered heterocyclic groups, and -(CH ２ ) ｎ１ R ａａ is selected from the group consisting of R ５ and R ６ is hydrogen, R ９ is C ３-６ Cycloalkyl groups and halogen-substituted C ３-６ cycloalkyl groups, R ａａ is C ３-８ cycloalkyl groups and 3- to 8-membered heterocyclic groups, ３-８ The cycloalkyl group and the 3- to 8-membered heterocyclic group each may further optionally be C １-６ may be substituted with an alkyl group, x is 0, 1, 2 or 3; n1 is 1.)

2. The R is CH ３ O-, CH ３ CH ２ O- and CH ３ CH ２ CH ２ 2. The compound of claim 1, its stereoisomer, or a pharma- ceutically acceptable salt thereof, which is selected from the group consisting of:

3. R ９ teeth 【Chemistry 2】 2. The compound according to claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof,

4. The general formula (V) is further represented by general formula (VIII): 【Chemistry 3】 During the ceremony, R ３ ~R ６ and x is as defined in claim 1, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

5. R ４ is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a vinyl group, CH ２ =CHCH ２ -, ethynyl group, 【Chemistry 4】 5. The compound according to claim 1 , its stereoisomer or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

6. R ３ The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1 to 4, wherein is selected from the group consisting of hydrogen, fluorine, chlorine and bromine.

7. R ３ is selected from the group consisting of hydrogen and fluorine. R ４ is a cyclopropyl group and 【Chemistry 5】 5. The compound according to claim 1 , its stereoisomer or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: 【Request 8】 【Chemical 6】 A compound, its stereoisomer or a pharma- ceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:

9. A method for producing a compound represented by general formula (V) or a stereoisomer thereof and a pharma- ceutically acceptable salt thereof according to claim 1, comprising the steps of reacting a compound represented by general formula (V-1) with a compound represented by general formula (V-2) to obtain a compound represented by general formula (V-3), and further reacting the compound represented by general formula (V-3) to obtain a compound represented by general formula (V) or a stereoisomer thereof and a pharma- ceutically acceptable salt thereof. 【Chemistry 7】 (In the formula, X is a halogen; R ３ ~R ６ , R ９ and x are as defined in claim 1.

10. A method for producing the compound represented by general formula (V) or its stereoisomer and its pharma- ceutically acceptable salt according to claim 1, comprising the steps of reacting a compound represented by general formula (V-4) with a compound represented by general formula (V-5) to obtain a compound represented by general formula (V-6), and further reacting the compound represented by general formula (V-6) with a compound represented by general formula (V-2) to obtain a compound represented by general formula (V) or its stereoisomer and its pharma- ceutically acceptable salt. 【Chemistry 8】 (In the formula, X is a halogen; R ３ ~R ６ , R ９ and x are as defined in claim 1.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, its stereoisomer or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents or excipients.

12. Use of the compound according to any one of claims 1 to 8, its stereoisomer or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the manufacture of a TYK2 inhibitor drug.

13. Use of the compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of an inflammatory disease and an autoimmune disease selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel disease.

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