A pyridazine derivative inhibitor, its preparation method and application

Abstract

This invention relates to a pyridazine derivative inhibitor, its preparation method, and its application. In particular, this invention relates to compounds represented by general formula (III), their preparation methods, pharmaceutical compositions containing such compounds, and their application in the preparation of TYK2 inhibitor drugs.

Description

[0001] This invention is a divisional application of a PCT patent application filed in China with Chinese patent application number 202080001485.X, entitled "A pyridazine derivative inhibitor, its preparation method and application", and international filing date of January 20, 2020. Technical Field

[0002] This invention belongs to the field of drug synthesis, specifically relating to a pyridazine derivative inhibitor, its preparation method, and its application. Background Technology

[0003] Janus kinases (JAKs) are intracellular non-receptor tyrosine kinases that mediate the signal transduction and activation of various cytokines. The JAK kinase family is divided into four subtypes: JAK1, JAK2, JAK3, and TYK2. Each subtype mediates different types of cytokine signaling pathways. JAK-1, JAK-2, and TYK-2 are expressed in all human tissues and cells, while JAK-3 is mainly expressed in hematopoietic cells. A common characteristic of cytokine receptors is that the receptors themselves do not possess kinase activity, but their intracellular domains contain binding sites for tyrosine kinases (JAKs). When a cytokine receptor binds to its ligand, it activates receptor-coupled JAKs, leading to receptor phosphorylation. The phosphorylated tyrosine residues can bind to STAT proteins containing SH2 domains, thereby recruiting STAT to the receptor and phosphorylating it through JAKs. Subsequently, phosphotyrosine mediates STAT dimerization. The activated STAT dimer translocates to the nucleus and activates the transcription of its target genes, thereby regulating various cellular functions such as growth, activation, and differentiation.

[0004] TYK2 is the earliest discovered subtype of the JAK family, mediating the function of cytokines such as IFN-α, IL-6, IL-10, IL-12, and IL-23. Studies have shown that TYK2 deletion mutations can effectively inhibit the occurrence of immune diseases such as allergies, autoimmune diseases, and inflammation. IL-23 plays a crucial role in the development and progression of psoriasis. Recent research indicates that the pathogenesis of psoriasis involves endogenous unknown antigens activating antigen-presenting cells (APCs) to secrete IL-23. IL-23 then activates Th17 cells to secrete cytokines such as IL-17, inducing keratinocyte differentiation and proliferation and IL-23 secretion, further stimulating inflammation and keratinocyte proliferation to produce psoriasis. TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23. Inhibiting JAK2 can lead to anemia and other blood-related side effects; therefore, targeting TYK2 to inhibit the IL-23 signaling pathway is a good strategy for treating psoriasis.

[0005] Early TYK2 inhibitors, such as tofacitinib, were non-selective JAK inhibitors and were the first oral JAK inhibitors, exhibiting significant inhibitory activity against JAK1, 2, and 3 subtypes. Inhibition of other subtypes, such as JAK1, JAK2, and JAK3, increased the efficacy of tofacitinib but also brought more serious side effects, including infection, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. Since JAK2 activity is related to erythroid cell differentiation and lipid metabolism, some of the aforementioned adverse reactions, such as anemia, are thought to be related to the insufficient selectivity of tofacitinib for JAK-2, caused by the drug's non-selective inhibition. Currently, there are no selective TYK2 inhibitors on the market. Early JAK inhibitors mainly exerted their effects by competitively binding the kinase domain to ATP, thus generally suffering from low selectivity.

[0006] Given the good efficacy and severe side effects associated with multiple target-related factors of non-selective JAK inhibitors, developing a safer TYK2 selective inhibitor for the treatment of inflammatory diseases such as psoriasis has great clinical application potential. BMS's international patent applications WO2015069310A1 and WO2018081488A1 report a TYK2 selective inhibitor. Their developed drug, BMS-986165, has achieved good efficacy in Phase II clinical trials and has entered Phase III clinical trials, demonstrating the advantages of TYK2 selective inhibitors and possessing significant clinical application value. Summary of the Invention

[0007] The object of this invention is to provide a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound of general formula (I) has the following structure:

[0008]

[0009] R is selected from: hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -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 ;

[0010] R1 is selected from cycloalkyl, heterocyclic, aryl, heteroaryl, and -R groups. 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 -(CH2) n1 NR aa C(O)C(O)R aa Or -(CH2) n1 NR aa S(O) m1 R bb The cycloalkyl, heterocyclic, aryl, and heteroaryl groups thereon may be further substituted with one or more substituents selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl groups.

[0011] R2 is selected from cycloalkyl, heterocyclic, aryl, heteroaryl, and -R groups. 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 bb The cycloalkyl, heterocyclic, aryl, and heteroaryl groups thereon may be further substituted with one or more substituents selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl groups.

[0012] R3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkenyl, or alkynyl.

[0013] R4, R5, R6, and R7 may or may not be present; if present, they are selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(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 ;

[0014] Alternatively, R4 and R6 or R6 and R7 are linked to form a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally further substituted by one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0015] R aa R bb R cc and R dd Each of the following is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl may optionally be further substituted by one or more substituents selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0016] Or, any two adjacent or non-adjacent R aa R bb R cc and R ddThe links form a cycloalkyl, heterocyclic, aryl, and heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl group is optionally further substituted by one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0017] x is an integer of 0, 1, 2 or 3;

[0018] m1 is an integer of 0, 1, or 2; and

[0019] n1 is an integer of 0, 1, 2, 3, 4 or 5.

[0020] The preferred option is: R is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogen, amino, thiol, -OR aa -SR aa -S(O) m1 R aa or -NR aa R bb Preferred hydrogen and C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, fluorine, chlorine, bromine, -OR aa -SR aa -S(O) m1 R aa or -NR aa R bb More preferably hydrogen, methyl, ethyl, propyl, 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 Further preferred options include CH3O-, (CH3)2N-, CH3S-, F3CO-, F2HCO-, F-, or CH3S(O)2-.

[0021] Among them, R aa or R bb Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-7 membered heterocyclic groups, preferably hydrogen, hydroxyl, or C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, cyano, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD3, -CD2CD3, propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH2-, F2CH-, F3C-, cyano, cyclopropyl, cyclobutyl, cyclohexyl, epoxyethyl, epoxypropyl, epoxybutyl, epoxypentyl, tetrahydropyrrolyl or piperidinyl; further preferably hydrogen, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;

[0022] R1 is selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-12 Aryl, 3-7 heteroaryl, -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 R f C=ONR c R d C is preferred 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 3-6 aryl, -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 R f C=ONR c R d C is preferred 3-6 Cycloalkyl, 3-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, -NR c C(O)R d -NR c C(O)NR d R e -NR cS(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 R f C=ONR c R d Further optimization

[0023]

[0024] R c R d R e R f or R g Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, cyano groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-12 Aryl and 3-7-membered heteroaryl groups, preferably hydrogen and C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, fluorine, chlorine, bromine, cyano, C 2-5 alkenyl, 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 Aryl and 3-6 heteroaryl groups containing 1-3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD3, -CD2CD3, propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH2-, F2CH-, F3C-, cyano, fluorine, chlorine, CH3O-, CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0025] Further preferred groups include hydrogen, methyl, ethyl, -CD3, -CD2CD3, propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH2-, F2CH-, F3C-, cyano, fluorine, chlorine, CH3O-, CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0026] Or, any two adjacent or non-adjacent R c R d R e or R f Links form a C 3-7 Cycloalkyl, 3-7 membered heterocyclic, aryl, and 3-7 membered heteroaryl, preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-12 Aryl and 3-6 quinone heteroaryl, more preferably C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl groups and 3-6 membered heteroaryl groups containing 1-2 N, O, or S atoms, with cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups being further preferred.

[0027] Further preferred formulations include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0028]

[0029]

[0030] R2 is selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C6-12 Aryl, 3-7 aryl, C 1-6 Hydroxyalkyl, -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 The C mentioned therein 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-12 Aryl or 3-7 heteroaryl groups, optionally topped with hydrogen, deuterium, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 One or more substituents in the cycloalkyl group are substituted; preferably C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic groups, C 6-10 aryl, substituted or unsubstituted 3-6 heteroaryl, C 1-3 Hydroxyalkyl, -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 The C mentioned therein 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-12 Aryl or 3-7 heteroaryl, optionally topped with hydrogen, deuterium, fluorine, chlorine, bromine, or C. 1-3 Alkyl or C 3-5 One or more substituents in the cycloalkyl group are substituted; more preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups containing 1-3 N, O, or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl groups containing 1-3 N, O, or S atoms, C 1-3 Hydroxyalkyl, -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) n1S(O) m1 R hh Or -(CH2) n1 NR hh S(O) m1 R ii The C mentioned therein 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-12 The aryl or 3-7 heteroaryl group is optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl, or cyclohexyl; more preferably HOCH2-, HOCH2CH2-, HOCH2C(O)-, CH3NHC(O)-, D3CNHC(O)-, CH3NHS(O)2-, D3CNHS(O)2-.

[0031] R hh R ii R jj or R kk Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, cyano groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, preferably hydrogen, deuterium, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, fluorine, chlorine, bromine, cyano, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, -CD3, -CD2CD3, propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH2-, F2CH-, F3C-, cyano, fluorine, chlorine, CH3O-, CH3CH2O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrole or piperidinyl;

[0032] R3 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl, or cyano groups, preferably hydrogen, deuterium, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, hydroxyl or cyano;

[0033] R4, R5, R6, and R7 may or may not be present; if present, they are selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl, cyano, oxo, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic, aryl, 3-7 membered heteroaryl, -(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 Hydrogen, deuterium, and C are preferred. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl, cyano, oxo, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12Aryl, 3-6 membered heteroaryl 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, and C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl, cyano, oxo, C 2-5 alkenyl, 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 Aryl, 3-6 membered heteroaryl containing 1-3 N, O or S atoms, -(CH2) n1 R ll -(CH2) n1 OR ll or -NR ll R mm Further preferred groups include hydrogen, methyl, ethyl, propyl, isopropyl, butyl, (CH3)3C-, CF3CH2-, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, vinyl, CH2=CHCH2-, ethynyl. Cyano, CNCH2-, CNCH2CH2-, CH3OCH2-, CH3OCH2CH2-, CF3C(CH3)2-

[0034] R ll or R mm Each is independently selected from hydrogen, deuterium, hydroxyl, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, halogens, cyano groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, preferably hydrogen, deuterium, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, fluorine, chlorine, bromine, cyano, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, -CD3, -CD2CD3, propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH2-, F2CH-, F3C-, cyano, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, glycidyl, glycidyl, glycidyl, glycidyl, tetrahydropyrrole or piperidinyl;

[0035] Alternatively, R4 and R6 or R6 and R7 are linked to form a heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group is optionally influenced by hydrogen, deuterium, halogen, or C. 1-6 Alkyl or C 3-6 One or more substituents in the cycloalkyl group are substituted; preferably 3-6 membered heterocyclic groups or 3-7 membered heteroaryl groups, wherein the heterocyclic group or heteroaryl group is optionally replaced by hydrogen, deuterium, fluorine, chlorine, bromine, or C. 1-3 Alkyl or C 3-5 One or more substituents are selected from the cycloalkyl group; more preferably, a 3-6 membered heterocyclic group containing 1-3 N, O, or S atoms or a 3-7 membered heteroaryl group containing 1-3 N, O, or S atoms, wherein the heterocyclic group or heteroaryl group is optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl, or cyclohexyl; further preferably...

[0036]

[0037] An optional condition is that the compound of formula I is not

[0038]

[0039] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, further comprises general formula (II):

[0040]

[0041] in

[0042] R to R6 and x are as described in general formula (I).

[0043] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, further comprises general formula (III):

[0044]

[0045] in:

[0046] R, R1, R3 to R6 and x are as described in general formula (I).

[0047] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, further wherein general formula (I) is shown as general formula (V):

[0048]

[0049] in:

[0050] R9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -(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 The alkyl, haloalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups thereon may be further substituted by one or more substituents selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, hydroxyl, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups.

[0051] R, R3~R6, Raa R bb And x is as described in general formula (I).

[0052] The preferred option is: R9 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-6 Halogenated alkyl, hydroxyl, amino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-12 Aryl or 3-7 membered heteroaryl, -(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 Hydrogen, deuterium, and C are preferred. 1-3 Alkyl, C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Halogenated alkyl, hydroxyl, amino, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 3-6 heteroaryl, -(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)Rbb or -NR aa S(O) m1 R bb More preferably, C substituted with hydrogen, deuterium, or hydroxyl groups. 1-3 Alkyl, C 1-3 Cycloalkyl-substituted C 1-3 Alkyl, hydroxyl substituted C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Halogenated alkyl, hydroxyl, C 3-6 Cycloalkyl-substituted amino groups, halogen-substituted C groups 2-5 Alkenyl, halogen-substituted C 2-5 Alkyne- and halogen-substituted C 3-6 cycloalkyl, C 1-3 Alkyl-substituted C 3-6 Cycloalkyl and cyano-substituted C 3-6 cycloalkyl, C 1-3 alkoxy-substituted C 3-6 cycloalkyl, C 1-3 Halogenated alkyl-substituted C 3-6 Cycloalkyl, 3-7 membered heterocyclic groups containing 1-3 N, O or S atoms, phenyl, naphthyl or 3-7 membered heteroaryl groups 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 Further optimization

[0053]

[0054] R aa or R bb Independently selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, halogen, cyano, nitro, C 1-6 Halogenated alkyl, hydroxyl, amino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, 3-7 membered heterocyclic groups, C 6-12 Aryl or 3-7 heteroaryl, preferably hydrogen, deuterium, or C 1-3 Alkyl, C 1-3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 Halogenated alkyl, hydroxyl, amino, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6Cycloalkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 Aryl or 3-7 heteroaryl containing 1-3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or biphenyl;

[0055] m1 can be 0, 1, 2, or 3;

[0056] n1 can be 0, 1, 2 or 3.

[0057] The present invention also provides a preferred embodiment, wherein the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, is further represented as shown in general formula (VIII):

[0058]

[0059] in:

[0060] R3 to R6 and x are as described in general formula (I).

[0061] The preferred solution is that the

[0062] R3 is selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine;

[0063] R4 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally further substituted with one or more substituents selected from methyl, ethyl, fluorine or chlorine; preferably C 1-3 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl, 3-5 membered heterocyclic groups, more preferably C 1-3 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-5 Cycloalkyl groups, 3-5 membered heterocyclic groups containing 1-3 N, O, or S atoms, further preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, propargyl, etc.

[0064] R5 or R6 are each independently hydrogen or deuterium;

[0065] x is 0, 1, 2 or 3.

[0066] The present invention also provides a preferred embodiment, wherein each of the general formulas, their stereoisomers, or their pharmaceutically acceptable salts, as described in any one of the claims, wherein,

[0067] R is selected from hydrogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR aa -SR aa or -NR aa R bb ;

[0068] R1 is selected from 3-8 membered heterocyclic groups, 5-8 membered heteroaryl groups, and -(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 3-8-membered heterocyclic group and the 5-8-membered heteroaryl group are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, halogen, hydroxyl, amino, cyano, oxo, and C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0069] R2 is selected from 3-8 membered heterocyclic groups, 5-8 membered heteroaryl groups, and -C(O)R groups. aa -(CH2) n1 OR aa -C(O)NR aa R bb or -S(O) m1 NR aa R bbThe 3-8-membered heterocyclic group and the 5-8-membered heteroaryl group are optionally further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, halogen, hydroxyl, amino, cyano and C 3-8 One or more substituents in the cycloalkyl group are substituted;

[0070] R3 is selected from hydrogen, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0071] R5 is selected from hydrogen, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0072] R4 and R6 are each independently selected from hydrogen, halogen, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, or -(CH2) n1 R aa Preferred compounds include hydrogen, cyclopropyl, or...

[0073] Or R4 and R6 can be linked to form a C 3-8 Cycloalkyl; preferably cyclopentyl;

[0074] R7 is selected from non-existent, hydrogen, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0075] Or R6 and R7 can be linked to form a C 3-8 Cycloalkyl; preferably cyclopentyl;

[0076] R9 is selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 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 The C mentioned therein 1-6 Alkyl, C 3-8 Cycloalkyl groups and 3-8-membered heterocyclic groups may be further selected from hydrogen, deuterium, C1-6 Alkyl, C 1-6 Halogenated alkyl, halogen, hydroxyl, amino, oxo, nitro, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0077] R aa R bb R cc and R dd Each is independently selected from hydrogen, deuterium, cyano, halogen, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8-membered heterocyclic and 5-8-membered heteroaryl groups may be further selected from hydrogen, deuterium, C 1-6 Alkyl, halogen, hydroxyl, amino, oxo, cyano, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 The aryl group and one or more substituents in the 5-8 membered heteroaryl group are substituted;

[0078] Or, R cc and R dd Links form a C 3-8 cycloalkyl, wherein the C 3-8 The cycloalkyl group may optionally be further selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, halogen, amino, oxo, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 It is substituted by one or more substituents in the hydroxyalkyl group.

[0079] This invention also relates to a technical solution that provides a compound of general formula (XI), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0080]

[0081] in:

[0082] R 18 Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, or -(CH2) n1 R aa Hydrogen, deuterium, and C are preferred. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, fluorine, chlorine, bromine, hydroxyl, cyano, C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, or -(CH2) n1 R aa More preferably hydrogen, methyl, cyclopropyl,

[0083] R 19 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, amino, hydroxyl or cyano groups, preferably hydrogen, deuterium, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 The halogenated alkoxy group, fluorine, chlorine, bromine, amino, hydroxyl or cyano group, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, hydroxyl or cyano group;

[0084] R aa Selected from hydrogen, deuterium, cyano, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, preferably hydrogen, deuterium, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, fluorine, chlorine, bromine, cyano, C 2-5 alkenyl, C 2-5 alkynyl or C 3-6 Cycloalkyl, more preferably hydrogen, methyl, ethynyl or cyclopropyl;

[0085] n1 is 0, 1, or 2;

[0086] r can be 0, 1, 2 or 3.

[0087] This invention also relates to a technical solution, a method for preparing compounds of general formula (V) or their stereoisomers and pharmaceutically acceptable salts, comprising the following steps:

[0088]

[0089] The reaction of general formula (V-1) with general formula (V-2) yields general formula (V-3), and the further reaction of general formula (V-3) yields the compound shown in general formula (V) or its stereoisomers and pharmaceutically acceptable salts thereof.

[0090] in:

[0091] X is selected from halogens;

[0092] R3 to R6, R9 and x are as described in general formula (V).

[0093] The present invention also relates to a technical solution, a method for preparing the compound represented by the general formula (V) or its stereoisomers and pharmaceutically acceptable salts, characterized by comprising the following steps:

[0094]

[0095] The reaction of general formula (V-4) with general formula (V-5) yields general formula (V-6), which in turn reacts with general formula (V-2) to yield the compound shown in general formula (V) or its stereoisomers and pharmaceutically acceptable salts thereof.

[0096] in:

[0097] X is selected from halogens;

[0098] R3 to R6, R9 and x are as described in general formula (V).

[0099] The present invention also relates to a technical solution, a pharmaceutical composition comprising a therapeutically effective dose of a compound of general formula (I), a compound of general formula (IX), and a compound of general formula (X), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0100] The present invention also relates to a technical solution, the use of any of the general formula (I), any of the general formula (IX), and any of the general formula (X) compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof in the preparation of a TYK2 inhibitor drug.

[0101] The present invention also relates to a technical solution, the use of any of the general formula (I), any of the general formula (IX), and any of the general formula (X) compounds, their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof in the preparation of a treatment for inflammatory diseases and autoimmune diseases; wherein the inflammatory diseases and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease).

[0102] The present invention further relates to compounds of general formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of methods for treating inflammatory diseases.

[0103] Detailed description of the invention

[0104] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0105] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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, 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. 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, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0106] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" 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, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0107] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 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, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0108] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, they are 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl groups.

[0109] It also includes spirocyclic alkyl groups that share a spiro atom with heterocyclic alkyl groups.

[0110] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.

[0111] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic.

[0112] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0113] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxobutyl, thiobutyl, pyrrolyl, pyrrolidone, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxobutyl, pyrrolidone, tetrahydrofuranyl, pyrrolidone, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved may optionally be connected to other groups by single bonds, or may be further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0114] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 3 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). mThe rings consist of heteroatoms (where m is an integer from 0 to 2), with the remaining ring atoms being carbon. They may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, they are 6 to 14 ternary, more preferably 7 to 10 ternary. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, they are 3 / 5, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups.

[0115] 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 the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of 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.

[0116] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic.

[0117] The heterocyclic ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0118] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0119] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.

[0120] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0121] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, and thiazolyl; more preferably triazolyl, pyrroleyl, thiophene, thiazolyl, pyridinyl, and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring.

[0122] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0123] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0124] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0125] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0126] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0127] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0128] "Alkyne" refers to (CH≡C-), wherein the alkynyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0129] The different terms such as "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 express the same meaning, that is, X can be any one or more of A, B, and C.

[0130] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0131] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be 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.

[0132] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0133] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0134] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity. Attached Figure Description

[0135] Figure 1 PASI scores for different compounds in an imiquimod-induced mouse psoriasis model. Detailed Implementation

[0136] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0137] Example

[0138] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0139] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0140] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0141] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0142] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0143] Example 1

[0144] Preparation of 6-(bicyclo[1.1.1]pentane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0145]

[0146] Step 1: Preparation of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)aniline

[0147]

[0148] 3-Bromo-2-methoxyaniline (2.02 g, 10 mmol), bis-pinacolyl diborane (3.05 g, 12 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (816.6 mg, 1 mmol), and potassium acetate (2.45 g, 25 mmol) were mixed in dioxane (20 mL). The reaction system was purged with nitrogen three times and reacted overnight at 100 °C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was separated by water and CH2Cl2. The organic phase was separated and washed with saturated sodium chloride aqueous solution. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography yielded the title compound 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)aniline (2.0 g, 80%).

[0149] 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);

[0150] MS m / z (ESI): 250.1 [M+H] + .

[0151] Step 2: Preparation of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

[0152]

[0153] 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-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), and tetra(triphenylphosphine)palladium (924.5 mg, 0.8 mmol) were mixed in 1,4-dioxane (40 mL) and water (5 mL). The reaction system was purged with nitrogen three times and reacted overnight at 100 °C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was separated by water and CH₂Cl₂. The organic phase was separated and washed with saturated sodium chloride aqueous solution. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography yielded the title compound 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.14 g, 70%).

[0154] 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);

[0155] MS m / z(ESI): 205.1 [M+H] + .

[0156] Step 3: Preparation of lithium 4,6-dichloropyridazine-3-carboxylate

[0157]

[0158] Methyl 4,6-dichloropyridazine-3-carboxylic acid ester (2.07 g, 10 mmol) and lithium bromide (2.6 g, 30 mmol) were dissolved in acetonitrile (20 mL) and water (2 mL). The mixture was cooled to 0 °C, and DIPEA (5.2 mL, 30 mmol) was added dropwise. The mixture was allowed to rise naturally to room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (2 mL × 4). The filter cake was collected and dried to give the title compound, lithium 4,6-dichloropyridazine-3-carboxylic acid (1.73 g, 87%).

[0159] MS m / z (ESI): 193.1 [M+H] + .

[0160] 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

[0161]

[0162] 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 mixture was cooled to room temperature, and water (6 mL) was added. The mixture was stirred for 1 h. The reaction solution was filtered, and the filter cake was washed with water (6 mL × 2) and THF (6 mL). The filter cake was collected and dried to give 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%).

[0163] MS m / z(ESI): 361.1 [M+H] + .

[0164] Step 5: Preparation of ((6-(bicyclo[1.1.1]pentane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc)

[0165]

[0166] ((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-carboxamide (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), and palladium acetate (4.5 mg, 0.02 mmol) and (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (22 mg, 0.04 mmol) were added. The reaction system was purged with nitrogen three times and reacted overnight at 75 °C. The reaction was cooled to room temperature, and water (4 mL) and acetic acid (2 mL) were added. The mixture was washed with petroleum ether (6 mL × 2), and then the aqueous phase was separated. Water (2 mL) was added to the aqueous phase, and the mixture was extracted with CH2Cl2 (5 mL × 3). The organic phases were combined and washed with saturated NaCl aqueous solution. The organic phase was separated and dried with anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure to give the title compound ((6-(bicyclo[1.1.1]pentane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc (122 mg, 65.2%).

[0167] MS m / z (ESI): 436.2 [M+H] + .

[0168] Step 6: Preparation of 6-(bicyclo[1.1.1]pentane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0169]

[0170] ((6-(bicyclo[1.1.1]pentane-1-carbamate)-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), DIPEA (258 mg, 2.0 mmol) were mixed in DMF (1 mL), and HATU (380 mg, 1.0 mmol) was added. The mixture was reacted overnight at 40 °C. The reaction was cooled to room temperature, separated by saturated sodium bicarbonate aqueous solution and CH2Cl2, the organic phase was washed with saturated NaCl aqueous solution, dried with anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure before column chromatography to obtain the title compound 6-(bicyclo[1.1.1]pentane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (41 mg, 45%).

[0171] 1 H NMR (400MHz, CDCl3) 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= 7.9,1.3Hz,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);

[0172] MS m / z (ESI): 452.2 [M+H] + .

[0173] Example 2

[0174] Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(oxobutylcyclo-3-carbamate)pyridazine-3-carboxamide

[0175]

[0176] The preparation method of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(oxobutylcyclo-3-carbamate)pyridazine-3-carboxamide is as described in Example 1.

[0177] MS m / z(ESI): 442.2 [M+H] + .

[0178] Example 3

[0179] Preparation of 6-(cyclobutyramido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0180]

[0181] The preparation method of 6-(cyclobutyramido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0182] 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);

[0183] MS m / z (ESI): 440.2 [M+H] + .

[0184] Example 4

[0185] Preparation of 6-((1R,2R)-2-fluorocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0186]

[0187] The preparation method of 6-((1R,2R)-2-fluorocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0188] 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);

[0189] MS m / z (ESI): 444.2 [M+H] + .

[0190] Example 5

[0191] 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-carbamate)pyridazine-3-carboxamide

[0192]

[0193] The preparation method 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-carbamate)pyridazine-3-carboxamide is as described in Example 1.

[0194] MS m / z (ESI): 440.2 [M+H] + .

[0195] Example 6

[0196] Preparation of 6-((3-cyclopropyloxobutylcyclo-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0197]

[0198] The preparation method of 6-((3-cyclopropyloxobutylcyclo-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0199] MS m / z (ESI): 454.2 [M+H] + .

[0200] Example 7

[0201] Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-methyloxobutylcyclo-3-yl)amino)pyridazine-3-carboxamide

[0202]

[0203] The preparation method of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-methyloxobutylcyclo-3-yl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0204] MS m / z (ESI): 428.2 [M+H] + .

[0205] Example 8

[0206] 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

[0207]

[0208] The preparation method 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 is as described in Example 1.

[0209] MS m / z (ESI): 480.2 [M+H] + .

[0210] Example 9

[0211] 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

[0212]

[0213] The preparation method 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 is as described in Example 1.

[0214] MS m / z (ESI): 480.2 [M+H] + .

[0215] Example 10

[0216] 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

[0217]

[0218] The preparation method 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 is as described in Example 1.

[0219] MS m / z (ESI): 480.2 [M+H] + .

[0220] Example 11

[0221] Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropane-2-yl)amino)pyridazine-3-carboxamide

[0222]

[0223] The preparation method of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropane-2-yl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0224] MS m / z (ESI): 454.2 [M+H] + .

[0225] Example 12

[0226] 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-trifluoropropane-2-yl)amino)pyridazine-3-carboxamide

[0227]

[0228] The preparation method of (R)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropane-2-yl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0229] MS m / z (ESI): 454.2 [M+H] + .

[0230] Example 13

[0231] 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-trifluoropropane-2-yl)amino)pyridazine-3-carboxamide

[0232]

[0233] The preparation method of (S)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1,1,1-trifluoropropane-2-yl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0234] MS m / z (ESI): 454.2 [M+H] + .

[0235] Example 14

[0236] Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(1-methylcyclopropane-1-carbamate)pyridazine-3-carboxamide

[0237]

[0238] The preparation method of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(1-methylcyclopropane-1-carbamate)pyridazine-3-carboxamide is as described in Example 1.

[0239] 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);

[0240] MS m / z (ESI): 440.2 [M+H] + .

[0241] Example 15

[0242] Preparation of 6-(1-cyanocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0243]

[0244] The preparation method of 6-(1-cyanocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0245] 1 H 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);

[0246] MS m / z (ESI): 451.2 [M+H] + .

[0247] Example 16

[0248] 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-carbamate)pyridazine-3-carboxamide

[0249]

[0250] The preparation method of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(1-(trifluoromethyl)cyclopropane-1-carbamate)pyridazine-3-carboxamide is as described in Example 1.

[0251] 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);

[0252] MS m / z(ESI): 494.2 [M+H] + .

[0253] Example 17

[0254] Preparation of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1-methoxycyclopropane-1-carbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0255]

[0256] The preparation method of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1-methoxycyclopropane-1-carbamate)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0257] MS m / z (ESI): 456.2 [M+H] + .

[0258] Example 18

[0259] Preparation of (S)-6-(2,2-dimethylcyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0260]

[0261] The preparation method of (S)-6-(2,2-dimethylcyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0262] MS m / z (ESI): 454.2 [M+H] + .

[0263] Example 19

[0264] Preparation of (R)-6-(2,2-dimethylcyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0265]

[0266] The preparation method of (R)-6-(2,2-dimethylcyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0267] MS m / z (ESI): 454.2 [M+H] + .

[0268] Example 20

[0269] Preparation of (R)-6-(2,2-difluorocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0270]

[0271] The preparation method of (R)-6-(2,2-difluorocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0272] MS m / z(ESI): 462.2 [M+H] + .

[0273] Example 21

[0274] Preparation of (S)-6-(2,2-difluorocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0275]

[0276] The preparation method of (S)-6-(2,2-difluorocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0277] MS m / z(ESI): 462.2 [M+H] + .

[0278] Example 22

[0279] Preparation of 6-(cyclopropanesulfonamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0280]

[0281] The preparation method of 6-(cyclopropanesulfonamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0282] 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);

[0283] MS m / z(ESI): 462.2 [M+H] + .

[0284] Example 23

[0285] 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

[0286]

[0287] The preparation method 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 is as described in Example 1.

[0288] MS m / z (ESI): 471.2 [M+H] + .

[0289] Example 24

[0290] Preparation of 6-(3-cyclopropylurea)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0291]

[0292] The preparation method of 6-(3-cyclopropylurea)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0293] 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);

[0294] MS m / z (ESI): 441.2 [M+H] + .

[0295] Example 25

[0296] Preparation of cyclopropyl (5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazine-3-yl)carbamate

[0297]

[0298] The preparation method of cyclopropyl (5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d3)carbamoyl)pyridazine-3-yl)carbamate is as described in Example 1.

[0299] MS m / z(ESI): 442.2 [M+H] + .

[0300] Example 26

[0301] 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

[0302]

[0303] The preparation method 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 is as described in Example 1.

[0304] 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);

[0305] MS m / z (ESI): 440.2 [M+H] + .

[0306] Example 27

[0307] Preparation of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxycyclopropionimide amide)-N-(methyl-d3)pyridazine-3-carboxamide

[0308]

[0309] The preparation method of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxycyclopropionimino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0310] MS m / z (ESI): 455.2 [M+H] + .

[0311] Example 28

[0312] Preparation of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyacetyliminoamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0313]

[0314] The preparation method of (E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyacetyliminoamide)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0315] MS m / z(ESI): 429.2 [M+H] + .

[0316] Example 29

[0317] Preparation of (Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxycyclopropionimide amide)-N-(methyl-d3)pyridazine-3-carboxamide

[0318]

[0319] The preparation method of (Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxycyclopropionimide amide)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0320] MS m / z (ESI): 455.2 [M+H] + .

[0321] Example 30

[0322] Preparation of (Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyacetyliminoamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0323]

[0324] The preparation method of (Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyacetyliminoamide)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0325] MS m / z(ESI): 429.2 [M+H] + .

[0326] Example 31

[0327] Preparation of (E)-6-(N'-cyanocyclopropionimide amide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0328]

[0329] The preparation method of (E)-6-(N'-cyanocyclopropionimino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0330] MS m / z (ESI): 450.2 [M+H] + .

[0331] Example 32

[0332] Preparation of (E)-6-(N'-cyanoacetyliminoamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0333]

[0334] The preparation method of (E)-6-(N'-cyanoacetyliminoamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0335] MS m / z (ESI): 424.2 [M+H] + .

[0336] Example 33

[0337] Preparation of (Z)-6-(N'-cyanocyclopropionimide amide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0338]

[0339] The preparation method of (Z)-6-(N'-cyanocyclopropionimide amide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0340] MS m / z (ESI): 450.2 [M+H] + .

[0341] Example 34

[0342] Preparation of (Z)-6-(N'-cyanoacetyliminoamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0343]

[0344] The preparation method of (Z)-6-(N'-cyanoacetyliminoamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0345] MS m / z (ESI): 424.2 [M+H] + .

[0346] Example 35

[0347] Preparation of 6-((cyclopropylidene fluoromethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0348]

[0349] The preparation method of 6-((cyclopropylfluoromethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0350] MS m / z (ESI): 428.2 [M+H] + .

[0351] Example 36

[0352] 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

[0353]

[0354] The preparation method 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 is as described in Example 1.

[0355] MS m / z (ESI): 416.2 [M+H] + .

[0356] Example 37

[0357] Preparation of 6-((1-cyclopropylidene-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

[0358]

[0359] The preparation method of 6-((1-cyclopropylidene-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 is as described in Example 1.

[0360] MS m / z (ESI): 478.2 [M+H] + .

[0361] Example 38

[0362] 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

[0363]

[0364] The preparation method 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 is as described in Example 1.

[0365] MS m / z (ESI): 466.2 [M+H] + .

[0366] Example 39

[0367] Preparation of 6-((1-cyclopropylidene-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

[0368]

[0369] The preparation method of 6-((1-cyclopropylidene-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 is as described in Example 1.

[0370] MS m / z (ESI): 460.2 [M+H] + .

[0371] Example 40

[0372] 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

[0373]

[0374] The preparation method 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 is as described in Example 1.

[0375] MS m / z (ESI): 448.2 [M+H] + .

[0376] Example 41

[0377] 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

[0378]

[0379] The preparation method 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 is as described in Example 1.

[0380] MS m / z(ESI): 412.2 [M+H] + .

[0381] Example 42

[0382] 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

[0383]

[0384] The preparation method 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 is as described in Example 1.

[0385] MS m / z (ESI): 450.2 [M+H] + .

[0386] Example 43

[0387] 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

[0388]

[0389] The preparation method 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 is as described in Example 1.

[0390] MS m / z (ESI): 424.2 [M+H] + .

[0391] Example 44

[0392] 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

[0393]

[0394] The preparation method 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 is as described in Example 1.

[0395] MS m / z (ESI): 449.2 [M+H] + .

[0396] Example 45

[0397] 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

[0398]

[0399] The preparation method 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 is as described in Example 1.

[0400] MS m / z(ESI): 423.2 [M+H]+ .

[0401] Example 46

[0402] 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

[0403]

[0404] The preparation method 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 is as described in Example 1.

[0405] MS m / z (ESI): 499.2 [M+H] + .

[0406] Example 47

[0407] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((1-methyl-1H-pyrazole)-3-sulfonylamino)pyridazine-3-carboxamide

[0408]

[0409] The preparation method 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-sulfonamide)pyridazine-3-carboxamide is as described in Example 1.

[0410] MS m / z (ESI): 502.2 [M+H] + .

[0411] Example 48

[0412] 6-(cyclopropylcarbamoyl)-4-((2-(dimethylamino)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0413]

[0414] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-(dimethylamino)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0415] MS m / z(ESI): 439.2 [M+H] + .

[0416] Example 49

[0417] 6-(cyclopropylcarbamoyl)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methylthio)phenyl)amino)pyridazine-3-carboxamide

[0418]

[0419] The preparation method of 6-(cyclopropylcarbamoyl)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methylthio)phenyl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0420] 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);

[0421] MS m / z(ESI): 442.2 [M+H] + .

[0422] Example 50

[0423] 6-(cyclopropylcarbamate)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide

[0424]

[0425] The preparation method of 6-(cyclopropylcarbamoyl)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0426] MS m / z (ESI): 480.2 [M+H] + .

[0427] Example 51

[0428] 6-(cyclopropylcarbamate)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0429]

[0430] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0431] 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);

[0432] MS m / z(ESI): 462.2 [M+H] + .

[0433] Example 52

[0434] 6-(cyclopropylcarbamate)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0435]

[0436] The preparation method of 6-(cyclopropylcarbamoyl)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0437] 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);

[0438] MS m / z (ESI): 444.2 [M+H] + .

[0439] Example 53

[0440] 6-(cyclopropylcarbamate)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0441]

[0442] The preparation method of 6-(cyclopropylcarbamoyl)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0443] 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);

[0444] MS m / z (ESI): 444.2 [M+H] + .

[0445] Example 54

[0446] 6-(cyclopropylcarbamate)-4-((4-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0447]

[0448] The preparation method of 6-(cyclopropylcarbamoyl)-4-((4-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0449] MS m / z (ESI): 444.2 [M+H] + .

[0450] Example 55

[0451] 4-((6-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0452]

[0453] The preparation method of 4-((6-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylcarbamoyl)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0454] MS m / z (ESI): 451.2 [M+H] + .

[0455] Example 56

[0456] 4-((5-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0457]

[0458] The preparation method of 4-((5-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylcarbamoyl)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0459] MS m / z (ESI): 451.2 [M+H] + .

[0460] Example 57

[0461] 4-((4-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0462]

[0463] The preparation method of 4-((4-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylcarbamoyl)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0464] MS m / z (ESI): 451.2 [M+H] + .

[0465] Example 58

[0466] 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0467]

[0468] Step 1: Preparation of 2-methoxy-3-nitrobenzamide

[0469]

[0470] At room temperature, methyl 2-methoxy-3-nitrobenzoic acid ester (5 g, 23.7 mmol) was dissolved in ammonia-methanol solution (100 mL, 7 M), and ammonia water (28 wt%, 50 mL) was added. The mixture was stirred overnight at room temperature, diluted with ethyl acetate (300 mL), and then the organic phase was washed successively with saturated NaHCO3 aqueous solution (300 mL × 2) and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate. After concentrating the organic solvent under reduced pressure, column chromatography was used to obtain the title compound 2-methoxy-3-nitrobenzoamide (4.3 g, 92%).

[0471] MS m / z (ESI): 197.1 [M+H] + .

[0472] Step 2: Preparation of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0473]

[0474] 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. After concentration under reduced pressure, crude DMF-DMA addition product was obtained and dissolved in ethanol (20 mL) for later use. In an ice bath, ethanol (70 mL) and acetic acid (21 mL) were added to a reaction flask. After stirring for 5 minutes, hydrazine hydrate (80 wt.%, 10.5 mL) was slowly added dropwise while stirring for another 15 minutes. Then, the ethanol solution of the crude DMF-DMA addition product was added dropwise. The mixture was slowly brought to room temperature and stirred for another 4 hours at room temperature. After the reaction solution was concentrated under reduced pressure, it was diluted with ethyl acetate (300 mL). The organic phase was washed successively with saturated NaHCO3 aqueous solution (300 mL × 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%).

[0475] MS m / z(ESI): 221.1 [M+H] + .

[0476] Step 3: Preparation of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0477]

[0478] 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (200 mg, 0.91 mmol), copper acetate (198 mg, 1.1 mmol), 2,2'-bipyridine (170 mg, 1.1 mmol), and sodium carbonate (192 mg, 1.8 mmol) were mixed in 1,2-dichloroethane (5 mL). Cyclopropylboronic acid (234 mg, 2.72 mmol) was added at room temperature, and the mixture was heated to 85 °C and stirred overnight. After cooling the reaction solution to room temperature, it was diluted with a large amount of ethyl acetate. The organic phase was washed several times with saturated brine, then separated and dried over anhydrous sodium sulfate. After concentrating the organic solvent under reduced pressure, column chromatography was used to obtain the title compound 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (125 mg, 53%).

[0479] 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);

[0480] MS m / z(ESI): 261.1 [M+H] + .

[0481] Step 4: Preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline

[0482]

[0483] Palladium / carbon (30 mg) was added to a methanol (5 mL) solution of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (120 mg, 0.46 mmol). After reacting for 12 hours under a hydrogen atmosphere at ambient temperature and pressure, the catalyst was removed by filtration with diatomaceous earth. 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.

[0484] MS m / z(ESI): 231.1 [M+H] + .

[0485] Step 5: Preparation of zinc 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate

[0486]

[0487] 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 mixture was cooled to room temperature, and water (3 mL) was added. The mixture was stirred for 1 h. The reaction solution was filtered, and the filter cake was washed with water (3 mL × 2) and THF (2 mL). The filter cake was collected and dried to give 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%).

[0488] MS m / z (ESI): 387.1 [M+H] + .

[0489] Step 6: Preparation of zinc 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate

[0490]

[0491] 6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylic acid zinc (130 mg, 0.31 mmol), cyclopropionamide (86 mg, 1.0 mmol), DBU (61 mg, 0.4 mmol), and 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-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (22 mg, 0.04 mmol) were added. The reaction system was purged with nitrogen three times and heated to 75 °C overnight. The reaction was cooled to room temperature, and water (4 mL) and acetic acid (2 mL) were added. The mixture was washed with petroleum ether (6 mL × 2), and then the aqueous phase was separated. Water (2 mL) was added to the aqueous phase, and the mixture was extracted with CH2Cl2 (5 mL × 3). The organic phases were combined, washed with saturated NaCl aqueous solution, and the organic phase was dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure to give the title compound 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylic acid zinc (109 mg, 75%).

[0492] MS m / z (ESI): 436.1 [M+H] + .

[0493] Step 7: Preparation of 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0494]

[0495] 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylic acid zinc (90 mg, 0.19 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. The mixture was reacted overnight at 50 °C. The reaction was cooled to room temperature, separated by saturated sodium bicarbonate aqueous solution and CH2Cl2, the organic phase was washed with saturated NaCl aqueous solution, dried with anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure before column chromatography to give the title compound 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (35 mg, 38%).

[0496] 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);

[0497] MS m / z (ESI): 452.2 [M+H] + .

[0498] Example 59

[0499] 6-(cyclopropylcarbamate)-4-((3-(1-isopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0500]

[0501] The preparation method of 6-(cyclopropylcarbamoyl)-4-((3-(1-isopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 58.

[0502] MS m / z (ESI): 454.2 [M+H] + .

[0503] Example 60

[0504] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(oxobutylcyclo-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0505]

[0506] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(oxobutylcyclo-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 58.

[0507] 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);

[0508] MS m / z (ESI): 468.2 [M+H] + .

[0509] Example 61

[0510] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0511]

[0512] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 58.

[0513] 1H 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);

[0514] MS m / z (ESI): 470.2 [M+H] + .

[0515] Example 62

[0516] 4-((3-(1-(2-cyanoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0517]

[0518] The preparation method of 4-((3-(1-(2-cyanoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 58.

[0519] 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);

[0520] MS m / z (ESI): 465.2 [M+H] + .

[0521] Example 63

[0522] 6-(cyclopropylcarbamate)-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

[0523]

[0524] The preparation method of 6-(cyclopropylcarbamoyl)-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 is as described in Example 1.

[0525] 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);

[0526] MS m / z (ESI): 452.2 [M+H] + .

[0527] Example 64

[0528] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0529]

[0530] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0531] 1H 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);

[0532] MS m / z(ESI): 426.2 [M+H] + .

[0533] Example 65

[0534] 6-(cyclopropylcarbamoyl)-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

[0535]

[0536] The preparation method of 6-(cyclopropylcarbamoyl)-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 is as described in Example 1.

[0537] 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);

[0538] MS m / z (ESI): 452.2 [M+H] + .

[0539] Example 66

[0540] 6-(cyclopropylcarbamate)-4-((3-(5-fluoro-1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0541]

[0542] The preparation method of 6-(cyclopropylcarbamoyl)-4-((3-(5-fluoro-1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0543] MS m / z (ESI): 444.2 [M+H] + .

[0544] Example 67

[0545] 6-(cyclopropylcarbamate)-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0546]

[0547] The preparation method of 6-(cyclopropylcarbamoyl)-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0548] MS m / z (ESI): 444.2 [M+H] + .

[0549] Example 68

[0550] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-methyl-N-(methyl-d3)pyridazine-3-carboxamide

[0551]

[0552] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-methyl-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0553] MS m / z (ESI): 440.2 [M+H] + .

[0554] Example 69

[0555] 5-Cyano-6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0556]

[0557] The preparation method of 5-cyano-6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0558] MS m / z (ESI): 451.2 [M+H] + .

[0559] Example 70

[0560] N-(6-(1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropylformamide

[0561]

[0562] The preparation method 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)cyclopropanediamide is as described in Example 1.

[0563] MS m / z(ESI): 432.2 [M+H] + .

[0564] Example 71

[0565] 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)cyclopropylformamide

[0566]

[0567] The preparation method 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)cyclopropanediamide is as described in Example 1.

[0568] MS m / z(ESI): 433.2 [M+H] + .

[0569] Example 72

[0570] N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1H-tetrazol-5-yl)pyridazin-3-yl)cyclopropylformamide

[0571]

[0572] The preparation method 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)cyclopropanediamide is as described in Example 1.

[0573] MS m / z(ESI): 434.2 [M+H] + .

[0574] Example 73

[0575] 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)cyclopropylformamide

[0576]

[0577] The preparation method 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)cyclopropanediamide is as described in Example 1.

[0578] MS m / z (ESI): 446.2 [M+H] + .

[0579] Example 74

[0580] 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)cyclopropylformamide

[0581]

[0582] The preparation method 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)cyclopropanediamide is as described in Example 1.

[0583] MS m / z (ESI): 447.2 [M+H] + .

[0584] Example 75

[0585] 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)cyclopropylformamide

[0586]

[0587] The preparation method 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)cyclopropylformamide is as described in Example 1.

[0588] MS m / z (ESI): 472.2 [M+H] + .

[0589] Example 76

[0590] 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)cyclopropylformamide

[0591]

[0592] The preparation method 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)cyclopropylformamide is as described in Example 1.

[0593] MS m / z(ESI): 473.2 [M+H] + .

[0594] Example 77

[0595] 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-dicarboxamide

[0596]

[0597] N 6 -Cyclopropyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N 3The preparation method of -(methyl-d3)pyridazine-3,6-dicarboxamide is as described in Example 1.

[0598] 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);

[0599] MS m / z(ESI): 426.2 [M+H] + .

[0600] Example 78

[0601] N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N-(methyl-d3)aminosulfonyl)pyridazine-3-yl)cyclopropionamide

[0602]

[0603] The preparation method of N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N-(methyl-d3)aminosulfonyl)pyridazine-3-yl)cyclopropanediamide is as described in Example 1.

[0604] MS m / z(ESI): 462.2 [M+H] + .

[0605] Example 79

[0606] N-(6-(hydroxymethyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropylformamide

[0607]

[0608] The preparation method of N-(6-(hydroxymethyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanediamide is as described in Example 1.

[0609] MS m / z(ESI): 396.2 [M+H] + .

[0610] Example 80

[0611] N-(6-(2-hydroxyacetyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-yl)cyclopropylformamide

[0612]

[0613] The preparation method of N-(6-(2-hydroxyacetyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanediamide is as described in Example 1.

[0614] MS m / z (ESI): 424.2 [M+H] + .

[0615] Example 81

[0616] 2-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyrimidin-5-carboxamide

[0617]

[0618] The preparation method of 2-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide is as described in Example 1.

[0619] MS m / z(ESI): 426.2 [M+H] + .

[0620] Example 82

[0621] 3-(cyclopropylcarbamate)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-1,2,4-triazine-6-carboxamide

[0622]

[0623] The preparation method of 3-(cyclopropylcarbamoyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-1,2,4-triazine-6-carboxamide is as described in Example 1.

[0624] MS m / z (ESI): 427.2 [M+H] + .

[0625] Example 83

[0626] 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)pyrimidin-2,4-diamine

[0627]

[0628] 6-Methoxy-N 2 -(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N 4 The preparation method of -(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine is as described in Example 1.

[0629] MS m / z (ESI): 408.2 [M+H] + .

[0630] Example 84

[0631] 2-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyrimidin-5-carboxamide

[0632]

[0633] The preparation method of 2-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyrimidine-5-carboxamide is as described in Example 1.

[0634] 1 H 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);

[0635] MS m / z(ESI): 423.2 [M+H] + .

[0636] Example 85

[0637] N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(N-methylaminosulfonyl)pyridin-2-yl)cyclopropionamide

[0638]

[0639] The preparation method of N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(N-methylaminosulfonyl)pyridin-2-yl)cyclopropanediamide is as described in Example 1.

[0640] MS m / z (ESI): 458.2 [M+H] + .

[0641] Example 86

[0642] 3-(cyclopropylcarbamate)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-1,2,4-triazine-6-carboxamide

[0643]

[0644] The preparation method of 3-(cyclopropylcarbamoyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-1,2,4-triazine-6-carboxamide is as described in Example 1.

[0645] MS m / z (ESI): 424.2 [M+H] + .

[0646] Example 87

[0647] 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

[0648]

[0649] The preparation method 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 is as described in Example 1.

[0650] MS m / z (ESI): 454.2 [M+H] + .

[0651] Example 88

[0652] 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0653]

[0654] Preparation of 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (Step 1)

[0655]

[0656] 5-Fluoro-2-methoxybenzamide (3.5 g, 20.7 mmol) was dissolved in DMF-DMA (25 mL), heated to 95 °C and reacted for 1 hour. After concentration under reduced pressure, crude DMF-DMA addition product was obtained and dissolved in ethanol (20 mL) for later use. In an ice bath, ethanol (56 mL) and acetic acid (17 mL) were added to a reaction flask. After stirring for 5 minutes, hydrazine hydrate (80 wt.%, 8.4 mL) was added dropwise, and stirring continued for 15 minutes. Then, the ethanol solution of the crude DMF-DMA addition product was added dropwise, the mixture was slowly heated to room temperature, and stirring continued at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, it was diluted with ethyl acetate (300 mL), washed with saturated NaHCO3 aqueous solution (300 mL × 2), the organic phase was separated and washed with saturated brine, dried with 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%).

[0657] MS m / z (ESI): 194.2 [M+H] + .

[0658] Step 2: Preparation of 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0659]

[0660] 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (1.1 g, 5.69 mmol) was dissolved in concentrated sulfuric acid (10 mL). Nitric acid (68 wt.%, 1.05 g, 11.39 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred under ice bath conditions for 2 hours. The reaction solution was poured into ice water, and ammonia was slowly added dropwise to adjust the pH to approximately 9. The mixture was extracted with ethyl acetate, and the organic phase was separated and dried. After concentrating the organic solvent under reduced pressure, crude 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.26 g) was obtained and used directly in the next reaction step.

[0661] MS m / z(ESI): 239.2 [M+H] + .

[0662] Step 3: Preparation of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0663]

[0664] 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), and 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 cooling the reaction solution to room temperature, it was diluted with a large amount of ethyl acetate. The organic phase was washed several times with saturated brine, then dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. Column chromatography was then used to obtain the title compound 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 38%).

[0665] 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);

[0666] MS m / z(ESI): 279.0 [M+H] + .

[0667] Step 4: Preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline

[0668]

[0669] Palladium / carbon (60 mg) was added to a methanol (5 mL) solution of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 0.93 mmol). After reacting for 8 hours under a hydrogen atmosphere at ambient temperature and pressure, the catalyst was removed by filtration with diatomaceous earth. 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.

[0670] MS m / z(ESI): 249.2 [M+H] + .

[0671] 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

[0672]

[0673] At room temperature, a tetrahydrofuran solution of LiHMDS (1M, 2.78mL, 2.78mmol) was added dropwise to a tetrahydrofuran solution of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (230mg, 0.93mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (194mg, 0.93mmol). After stirring the reaction solution at room temperature for 2 hours, it was quenched with a saturated ammonium chloride aqueous solution. The reaction solution was diluted with dichloromethane, the organic phase was washed several times with saturated brine, and then the organic phase was separated, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and 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%).

[0674] MS m / z(ESI): 421.2 [M+H] + .

[0675] Step 6: Preparation of 6-(cyclopropylcarbamate)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0676]

[0677] 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), and cesium carbonate (360 mg, 1.1 mmol) were mixed in dioxane (5 mL), and tris(dibenzylideneacetone)dipalladium (101 mg, 0.11 mmol) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (127 mg, 0.22 mmol) were added. The mixture was deoxygenated under nitrogen for 5 minutes and then microwaved at 145 °C for 2 hours. The reaction solution was diluted with dichloromethane, the organic phase was washed several times with saturated brine, and then the organic phase was separated, dried with anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-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%).

[0678] 1 H 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);

[0679] MS m / z (ESI): 470.2 [M+H] + .

[0680] Example 89

[0681] 6-(cyclopropylcarbamate)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0682]

[0683] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0684] MS m / z (ESI): 440.2 [M+H]+ .

[0685] Example 90

[0686] 6-(cyclopropylcarbamate)-4-((2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0687]

[0688] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0689] 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);

[0690] MS m / z (ESI): 414.2 [M+H] + .

[0691] Example 91

[0692] 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0693]

[0694] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole

[0695]

[0696] At -20°C, a 10 mL solution of SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane was slowly added dropwise to a 20 mL solution of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00 g, 4.54 mmol), DMAP (55.0 mg, 0.454 mmol), and DIPEA (1.05 mL, 6.36 mmol). After the addition was complete, the temperature was slowly raised to -10°C and stirred overnight at this temperature. The reaction solution was washed with saturated brine, the organic phase was separated and dried, filtered, and the organic solvent was concentrated under reduced pressure. The crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next step of the reaction.

[0697] MS m / z (ESI): 351.2 [M+H] + .

[0698] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

[0699]

[0700] 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 sequentially. The mixture was stirred at 50 °C for 2 hours, and then the reaction system was cooled. The insoluble matter was removed by diatomaceous earth filtration. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. After separating the organic phase, the mixture was dried with a drying agent, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography was used to separate the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, two-step yield: 45%).

[0701] MS m / z(ESI): 321.2 [M+H] + .

[0702] 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

[0703]

[0704] 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). After the addition was complete, the temperature was slowly raised to room temperature and stirred at room temperature for 2 hours. The solution was quenched with saturated brine, then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The solution was then separated by column chromatography to obtain 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%).

[0705] MS m / z(ESI): 493.2 [M+H] + .

[0706] Step 4: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0707]

[0708] 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), cyclopropionamide (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 to remove oxygen for 5 minutes. Then Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added in sequence. Under nitrogen protection, the reaction was heated at 130°C in the microwave for 90 minutes, cooled to room temperature, and the organic solvent was concentrated under reduced pressure before column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-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%).

[0709] MS m / z (ESI): 542.3 [M+H]+ .

[0710] Step 5: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0711]

[0712] At 0 °C, TFA (6.0 mL) was added to a DCM solution of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol), and the mixture was stirred overnight at room temperature. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and then washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. After drying the organic phase, it was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (270 mg, 57%).

[0713] 1H 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);

[0714] MS m / z(ESI): 412.2 [M+H] + .

[0715] Step 6: Preparation of 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0716]

[0717] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-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 mixture 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-(cyclopropylcarbamate)-N-(methyl-d3)pyridazin-3-carboxamide (12 mg, 39%).

[0718] 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);

[0719] MS m / z (ESI): 452.2 [M+H] + .

[0720] Example 92

[0721] 6-(cyclopropylcarbamate)-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

[0722]

[0723] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole

[0724]

[0725] At -20°C, a 10 mL solution of SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane was slowly added dropwise to a 20 mL solution of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00 g, 4.54 mmol), DMAP (55.0 mg, 0.454 mmol), and DIPEA (1.05 mL, 6.36 mmol). After the addition was complete, the temperature was slowly raised to -10°C and stirred overnight at this temperature. The reaction solution was washed with saturated brine, the organic phase was separated and dried, filtered, and the organic solvent was concentrated under reduced pressure. The crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next step of the reaction.

[0726] MS m / z (ESI): 351.2 [M+H] + .

[0727] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

[0728]

[0729] 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 sequentially. The mixture was stirred at 50 °C for 2 hours, and then the reaction system was cooled. The insoluble matter was removed by diatomaceous earth filtration. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. After separating the organic phase, the mixture was dried with a drying agent, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography was used to separate the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, two-step yield: 45%).

[0730] MS m / z(ESI): 321.2 [M+H] + .

[0731] 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

[0732]

[0733] 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). After the addition was complete, the temperature was slowly raised to room temperature and stirred at room temperature for 2 hours. The solution was quenched with saturated brine, then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The solution was then separated by column chromatography to obtain 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%).

[0734] MS m / z(ESI): 493.2 [M+H] + .

[0735] Step 4: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0736]

[0737] 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), cyclopropionamide (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 to remove oxygen for 5 minutes. Then Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added in sequence. Under nitrogen protection, the reaction was heated at 130°C in the microwave for 90 minutes, cooled to room temperature, and the organic solvent was concentrated under reduced pressure before column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-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%).

[0738] MS m / z (ESI): 542.3 [M+H]+ .

[0739] Step 5: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0740]

[0741] At 0 °C, TFA (6.0 mL) was added to a 20 mL solution of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol) in DCM, and the mixture was stirred overnight at room temperature. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and then washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. After drying the organic phase, it was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (270 mg, 57%).

[0742] 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);

[0743] MS m / z(ESI): 412.2 [M+H] + .

[0744] Step 6: Preparation of 6-(cyclopropylcarbamate)-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

[0745]

[0746] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (30 mg, 0.073 mmol), bromopropyne (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 mixture was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (10 mg, 31%).

[0747] 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);

[0748] MS m / z (ESI): 450.2 [M+H] + .

[0749] Example 93

[0750] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0751]

[0752] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0753] MS m / z(ESI): 494.2 [M+H] + .

[0754] Example 94

[0755] 4-((3-(1-(tert-butyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0756]

[0757] The preparation method of 4-((3-(1-(tert-butyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0758] MS m / z (ESI): 468.2 [M+H] + .

[0759] Example 95

[0760] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0761]

[0762] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(1,1,1-trifluoro-2-methylpropane-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0763] MS m / z(ESI): 522.2 [M+H] + .

[0764] Example 96

[0765] 4-((3-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0766]

[0767] The preparation method of 4-((3-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0768] MS m / z (ESI): 478.2 [M+H] + .

[0769] Example 97

[0770] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-(thiobutan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0771]

[0772] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(thiobutyron-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0773] MS m / z (ESI): 484.2 [M+H] + .

[0774] Example 98

[0775] 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(3-methyloxobutylcyclo-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0776]

[0777] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(3-methyloxobutylcyclo-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0778] 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);

[0779] MS m / z(ESI): 482.2 [M+H] +.

[0780] Example 99

[0781] 6-(Cyclopropylthiolamino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0782]

[0783] The preparation method of 6-(cyclopropylmethylthioamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0784] MS m / z(ESI): 442.2 [M+H] + .

[0785] Example 100

[0786] 6-(cyclopropylcarbamoyl)-4-((2-(dimethylphospho)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0787]

[0788] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-(dimethylphospho)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0789] MS m / z (ESI): 472.2 [M+H] + .

[0790] Example 101

[0791] 6-(cyclopropylcarbamate)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methanesulfonyl)phenyl)amino)pyridazine-3-carboxamide

[0792]

[0793] The preparation method of 6-(cyclopropylcarbamoyl)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methanesulfonyl)phenyl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0794] MS m / z(ESI): 474.2 [M+H] + .

[0795] Example 102

[0796] 4-((3-(1-(cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0797]

[0798] The preparation method of 4-((3-(1-(cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamoyl)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0799] MS m / z (ESI): 451.2 [M+H] + .

[0800] Example 103

[0801] 4-((3-(1-(bicyclo[1.1.1]pentane-1-ylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide

[0802]

[0803] The preparation method of 4-((3-(1-(bicyclo[1.1.1]pentane-1-ylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarbamate)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0804] MS m / z(ESI): 492.2 [M+H] + .

[0805] Example 104

[0806] 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(oxobutylcyclo-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0807]

[0808] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(oxobutylcyclo-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 92.

[0809] 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);

[0810] MS m / z(ESI): 482.2 [M+H] + .

[0811] Example 105

[0812] 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]heptane-5-yl)pyridazine-3-carboxamide

[0813]

[0814] The preparation method 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]heptane-5-yl)pyridazine-3-carboxamide is as described in Example 1.

[0815] MS m / z (ESI): 452.2 [M+H] + .

[0816] Example 106

[0817] 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

[0818]

[0819] The preparation method 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 is as described in Example 1.

[0820] MS m / z (ESI): 437.2 [M+H] + .

[0821] Example 107

[0822] (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

[0823]

[0824] The preparation method 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 is as described in Example 1.

[0825] MS m / z (ESI): 437.2 [M+H] + .

[0826] Example 108

[0827] (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

[0828]

[0829] The preparation method 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 is as described in Example 1.

[0830] MS m / z (ESI): 437.2 [M+H] + .

[0831] Example 109

[0832] 6-(1-Fluorocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0833]

[0834] The preparation method of 6-(1-fluorocyclopropane-1-carbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0835] 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);

[0836] MS m / z (ESI): 444.2 [M+H] + .

[0837] Example 110

[0838] 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-vinyloxobutylcyclo-3-yl)amino)pyridazine-3-carboxamide

[0839]

[0840] The preparation method of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-vinyloxobutylcyclo-3-yl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0841] MS m / z (ESI): 440.2 [M+H] + .

[0842] Example 111

[0843] 6-((3-ethynyloxadiazine-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0844]

[0845] The preparation method of 6-((3-ethynyloxadiazine-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0846] MS m / z (ESI): 438.2 [M+H] + .

[0847] Example 112

[0848] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0849]

[0850] Step 1: Preparation of 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole

[0851]

[0852] At -20°C, a 10 mL solution of SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane was slowly added dropwise to a 20 mL solution of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00 g, 4.54 mmol), DMAP (55.0 mg, 0.454 mmol), and DIPEA (1.05 mL, 6.36 mmol). After the addition was complete, the temperature was slowly raised to -10°C and stirred overnight at this temperature. The reaction solution was washed with saturated brine, the organic phase was separated and dried, filtered, and the organic solvent was concentrated under reduced pressure. The crude product 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was used directly in the next step of the reaction.

[0853] MS m / z (ESI): 351.2 [M+H] + .

[0854] Step 2: Preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

[0855]

[0856] 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 sequentially. The mixture was stirred at 50 °C for 2 hours, and then the reaction system was cooled. The insoluble matter was removed by diatomaceous earth filtration. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. After separating the organic phase, the mixture was dried with a drying agent, filtered, and the organic solvent was concentrated under reduced pressure. Column chromatography was used to separate the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline (650 mg, two-step yield: 45%).

[0857] MS m / z(ESI): 321.2 [M+H] + .

[0858] 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

[0859]

[0860] 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). After the addition was complete, the temperature was slowly raised to room temperature and stirred at room temperature for 2 hours. The solution was quenched with saturated brine, then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The solution was then separated by column chromatography to obtain 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%).

[0861] MS m / z(ESI): 493.2 [M+H] + .

[0862] Step 4: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0863]

[0864] 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), cyclopropionamide (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 to remove oxygen for 5 minutes. Then Pd2(dba)3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added in sequence. Under nitrogen protection, the reaction was carried out at 130°C in a microwave oven for 90 minutes. After cooling to room temperature and concentrating the organic solvent under reduced pressure, column chromatography was used to separate the title compound 6-(cyclopropylcarbamate)-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%).

[0865] MS m / z (ESI): 542.3 [M+H] + .

[0866] Step 5: Preparation of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0867]

[0868] At 0 °C, TFA (6.0 mL) was added to a DCM solution of 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol), and the mixture was stirred overnight at room temperature. The next day, the organic solvent was concentrated under reduced pressure, the residue was dissolved in DCM, and then washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. After drying the organic phase, it was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (270 mg, 57%).

[0869] 1H 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);

[0870] MS m / z(ESI): 412.2 [M+H] + .

[0871] Example 113

[0872] 6-(cyclopropylcarbamate)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide

[0873]

[0874] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide is as described in Example 1.

[0875] 1 H 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);

[0876] MS m / z (ESI): 409.2 [M+H] + .

[0877] Example 114

[0878] 6-(cyclopropylcarbamate)-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-carboxamide

[0879]

[0880] The preparation method of 6-(cyclopropylcarbamoyl)-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-carboxamide is as described in Example 92.

[0881] 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);

[0882] MS m / z (ESI): 468.2 [M+H] + .

[0883] Example 115

[0884] 6-(cyclopropylcarbamoyl)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0885]

[0886] The preparation method of 6-(cyclopropylcarbamoyl)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0887] 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);

[0888] MS m / z (ESI): 466.2 [M+H] + .

[0889] Example 116

[0890] 6-(cyclopropylcarbamate)-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

[0891]

[0892] The preparation method of 6-(cyclopropylcarbamoyl)-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 is as described in Example 92. Example 116 is one of the products of the sixth step reaction.

[0893] 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);

[0894] MS m / z (ESI): 450.2 [M+H] + .

[0895] Example 117

[0896] 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0897]

[0898] The preparation method of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is as described in Example 1.

[0899] 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);

[0900] MS m / z (ESI): 470.1 [M+H] + .

[0901] Example 118

[0902] 6-(cyclopropylcarbamate)-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

[0903]

[0904] The preparation method of 6-(cyclopropylcarbamoyl)-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 is as described in Example 92. Example 118 is one of the products of the sixth step reaction.

[0905] 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);

[0906] MS m / z (ESI): 450.2 [M+H] + .

[0907] Example 119

[0908] 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide

[0909]

[0910] The preparation method of 6-(cyclopropylcarbamoyl)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)nicotinamide is as described in Example 92.

[0911] 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(brs,1H),10.63(br s,1H);

[0912] MS m / z (ESI): 449.2 [M+H] + .

[0913] Example 120

[0914] 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide

[0915]

[0916] The preparation method of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide is as described in Example 1.

[0917] 1 H 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);

[0918] MS m / z (ESI): 451.1 [M+H] + .

[0919] Example 121

[0920] 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide

[0921]

[0922] The preparation method of 6-(cyclopropylcarbamoyl)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide is as described in Example 1.

[0923] 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);

[0924] MS m / z (ESI): 469.2 [M+H] + .

[0925] Biological test evaluation

[0926] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0927] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on the TYK2 signaling pathway in cells.

[0928] Experimental objective: The purpose of this test case is to test the inhibitory activity of the compound on the TYK2 signaling pathway in cells.

[0929] Experimental apparatus:

[0930] The centrifuge (5702R) was purchased from Eppendorf.

[0931] The pipette was purchased from Eppendorf.

[0932] The microplate reader was purchased from BioTek Inc. in the United States, model SynergyH1 full-function microplate reader.

[0933] Experimental Methods: This experiment used the U266 cell line expressing TYK2. The TYK2 signaling pathway was activated by INF-α stimulation. The inhibitory activity of the compound on the phosphorylation of downstream STAT3 was detected, and the half-maximal inhibitory concentration (IC50) of the compound on the activity of the TYK2 signaling pathway was determined. 50 .

[0934] The specific experimental procedure is as follows:

[0935] 3-12 μL of U266 cells were seeded into each well of a 384-well plate (100-300 cells per well). 2 μL of a serially diluted compound solution was added, and the plate was incubated in a CO2 incubator for 2 hours. After 2 hours, 2 μL of INF-α was added, bringing the final INF-α concentration to 1000 U / mL, and the plate was shaken at room temperature for 20 minutes. 2-5 μL of (5X) LANCE Ultra Lysis Buffer 2 solution was added, and the plate was shaken at room temperature for 2 hours. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT5 (Y694 / Y699) Antibody (PerkinElmer) at a final concentration of 2 nM and LANCE Ultra U Light-labeled Anti-STAT5 Antibody (PerkinElmer) at a final concentration of 20 nM were added, and the plate was incubated overnight at room temperature. The fluorescence signal value at 665 nm was measured using a microplate reader. The inhibition rate was calculated based on the fluorescence signal value, and the IC50 of the compound was obtained by curve fitting based on the inhibition rate at different concentrations. 50 .

[0936] Experimental data processing methods:

[0937] The percentage inhibition data for the wells treated with the compound were calculated using positive control wells (DMSO control wells) and negative control wells (no cells) on a plate: {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[0938] Experimental conclusion:

[0939] The experimental data on the inhibitory activity of the compound of this invention on the TYK2 signaling pathway in cells, obtained through the above methods, are shown in the table below:

[0940] Compound numbering Cell viability U266 pSTAT3 (nM) Example 3 4.36 Example 4 4.22 Example 53 2.43 Example 58 1.41 Example 60 6.01 Example 88 0.83 Example 89 4.95 Example 91 0.34 Example 92 0.13 Example 98 0.90 Example 104 1.88 Example 112 4.6 Example 114 2.10 Example 115 3.43 Example 118 1.27 Example 119 4.22 Example 120 1.65 Example 121 3.01

[0941] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on the JAK2 signaling pathway in cells.

[0942] Experimental objective: The purpose of this test case is to test the activity of the compound in inhibiting the JAK2 signaling pathway in cells.

[0943] Experimental apparatus:

[0944] The centrifuge (5702R) was purchased from Eppendorf.

[0945] The pipette was purchased from Eppendorf.

[0946] The microplate reader was purchased from BioTek Inc. in the United States, model SynergyH1 full-function microplate reader.

[0947] Experimental Methods: This experiment used the TF-1 cell line. The JAK2 signaling pathway was activated by IL-6 stimulation. The inhibitory activity of the compound on downstream STAT3 phosphorylation was detected, and the half-maximal inhibitory concentration (IC50) of the compound on the JAK2 signaling pathway activity was determined. 50 .

[0948] The specific experimental procedure is as follows:

[0949] 3-12 μL of TF-1 cells were seeded into each well of a 384-well plate (100-300 cells per well). 2 μL of a serially diluted compound solution was added, and the plate was incubated in a CO2 incubator for 2 hours. After 2 hours, 2 μL of IL-6 (30 ng / mL) was added, and the plate was shaken at room temperature for 20 minutes. 2-5 μL of (5X) LANCE Ultra Lysis Buffer 2 solution was added, and the plate was shaken at 4°C for 2 hours. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT3 (Tyr705) Antibody (PerkinElmer) solution (final concentration 2 nM) and LANCE Ultra U Light-labeled Anti-STAT3 Antibody (PerkinElmer) solution (final concentration 20 nM) were added, and the plate was incubated overnight at room temperature. The fluorescence signal value at 665 nm was measured using a microplate reader. The inhibition rate was calculated from the fluorescence signal value, and the IC50 of the compound was obtained by curve fitting based on the inhibition rate at different concentrations. 50 .

[0950] Experimental data processing methods:

[0951] The percentage inhibition data for the wells treated with the compound were calculated using positive control wells (DMSO control wells) and negative control wells (no cells) on a plate: {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[0952] Experimental conclusion:

[0953] The experimental data on the inhibitory activity of the compound of this invention on the JAK2 signaling pathway in cells, obtained through the above methods, are shown in the table below:

[0954]

[0955] Experimental conclusion: As can be seen from the data in the table, the compounds in the examples showed higher selectivity for JAK2 cell activity compared to TYK2 cell activity.

[0956] Test Example 3: Plasma Protein Binding Rate Test in Mice

[0957] 1. Research Objective:

[0958] The purpose of this experiment was to evaluate the protein binding rates of Examples 58, 88, and 92 (5 μM) in mouse plasma using the balanced dialysis method.

[0959] 2. Compounds and experimental materials:

[0960] 1) Prepare a 10 mM stock solution of the test compound using DMSO and store it at -20°C until use.

[0961] 2) Frozen plasma and dialysate of the required species (100mM phosphate buffer (Lot#SLBS7904 and Lot#SLBR3106V), pH 7.4).

[0962] 3. Experimental Apparatus

[0963] 96-well plate (Lot#07917415), detection membrane device (Lot#SD2369421), liquid chromatography-tandem mass spectrometry (LC-MS / MS) (LC-20AD, API4000), centrifuge (Eppendorf 5804R / 5424R), vortex apparatus (IKA VORTEXGENIUS 3), pipettes (Eppendorf 10~100μL (PIP-100-002), Eppendorf 100~1000μL (PIP-1000-002), RAININ 0.5~10μL (PIP-10-002), water bath (Shanghai Hengke).

[0964] 4. Experimental Procedure

[0965] 4.1 Preparation of dialysis solution

[0966] Take 4.01 mL of 1M K2HPO4 (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade), dilute with ultrapure water to 50 mL, and prepare 100 mM phosphate buffer (pH = 7.4) as dialysate.

[0967] 4.2 Preparation of plasma

[0968] Thaw the frozen plasma at room temperature or in a 37°C water bath, centrifuge at 3500 rpm for 5 min, and collect the supernatant.

[0969] 4.3 Preparation of the reaction termination solution

[0970] Use acetonitrile (or other suitable solution) containing an internal standard as the stop solution and store it in a refrigerator at 2-8°C. The specific concentration of the internal standard can be found in the final report.

[0971] 4.4 Preparation of compound working solutions

[0972] Preparation of working solution for compound: Dilute stock solution with DMSO to a final concentration of 1 mM.

[0973] 4.5 Preparation of plasma solution

[0974] Add 4 μL of the compound working solution to 796 μL of blank plasma to a final concentration of 5 μM, and vortex to mix.

[0975] 4.6 Balanced Dialysis

[0976] 1) Prepare the equilibrium dialysis apparatus and place the detection membrane device into the equilibrium dialysis 96-well plate;

[0977] 2) Add 200 μL of the prepared plasma solution to the membrane, n = 2;

[0978] 3). Take another 4 μL of plasma solution, dilute it 10-fold with 36 μL of blank plasma of the same species, add 160 μL of acetonitrile termination solution containing internal standard, and store it in a -20°C refrigerator to obtain the T0 (Total) sample;

[0979] 4). Add 350 μL of dialysis solution (100 mM phosphate buffer) outside the membrane;

[0980] 5). Seal the dialysis plate and place it in a 37°C water bath for incubation for 6 hours;

[0981] 6). After dialysis, take out 4 μL from the sample wells inside the membrane respectively, and dilute it 10-fold with 36 μL of blank plasma of the same species; take out 40 μL of dialysis solution from the sample wells outside the membrane respectively, and add 160 μL of acetonitrile termination solution containing internal standard to obtain the T6 (Total) sample and the F6 (Total) sample;

[0982] 7). After centrifugation of the T0 (Total) and T6 (Total) samples, take the supernatant;

[0983] 8). LC-MS analysis.

[0984] 5. Experimental Results

[0985]

[0986] Test Example 4. Pharmacokinetic Determination in Balb / C Mice

[0987] 1. Research Purpose:

[0988] Using Balb / C mice as test animals, study the pharmacokinetic behavior of the plasma of compound Examples 58, 88 and 92 after oral administration at a dose of 5 mg / kg in mice.

[0989] 2. Test Scheme

[0990] 2.1 Test Drugs:

[0991] Compound Examples 58, 88 and 92 of the present invention, self-made.

[0992] 2.2 Test Animals:

[0993] 18 Balb / C mice (6 mice per example), male, Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License Number (SCXK (Hu) 2013 - 0006 N0.311620400001794).

[0994] 2.3 Administration:

[0995] Eighteen male Balb / C mice were administered oral medication (PO) at a dose of 5 mg / kg and a volume of 10 mL / kg after fasting overnight.

[0996] 2.4 Sample Collection:

[0997] Before and after drug administration, 0.1 mL of blood was collected from the orbital cavity of mice at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours. The blood was placed in EDTA-K2 tubes, centrifuged at 6000 rpm for 6 min at 4℃ to separate the plasma, and stored at -80℃.

[0998] 2.5 Sample preparation:

[0999] 1) Add 40uL of plasma sample to 160uL of acetonitrile to precipitate, mix, and centrifuge at 3500×g for 5-20 minutes.

[1000] 2) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the analyte by LC / MS / MS.

[1001] 2.6 Liquid Chromatography Analysis

[1002] • Liquid phase conditions: Shimadzu LC-20AD pump

[1003] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[1004] • Column: phenomenex Gemiu 5um C18 50×4.6mm

[1005] • Mobile phase: Solution A is a 0.1% formic acid aqueous solution, and solution B is acetonitrile.

[1006] • Flow rate: 0.8 mL / min

[1007] Elution time: 0-4.0 minutes, eluent as follows:

[1008]

[1009] 3. Experimental Results and Analysis

[1010] The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the mouse pharmacokinetic experiment are shown in the table below:

[1011] compound <![CDATA[t max (h)]]> <![CDATA[C max (ng / mL)]]> <![CDATA[AUC 0-t (ng / mL*h)]]> <![CDATA[AUC 0-∞ (ng / mL*h)]]> <![CDATA[t 1 / 2 (h)]]> <![CDATA[MRT 0-∞ (h)]]> BMS-986165 1.0 696 1987 2038 1.4 2.3 Example 53 0.5 2043 6250 6348 1.3 2.3 Example 58 0.5 3930 13590 14473 1.9 3.0 Example 88 1.0 2190 20991 21001 2.1 5.6 Example 92 1.0 939 2466 2637 2.0 2.8 Example 118 0.5 1927 3391 3719 2.7 2.5

[1012] Experimental conclusion: The data in the table show the AUC of the compound in the examples in mice. 0-tThe pharmacokinetic exposure (ng / mL*h) was superior to that of the reference compound BMS-986165, especially in Examples 58 and 88, where the pharmacokinetic exposure was significantly better than that of the reference compound BMS-986165, exceeding the difference by 6 times and 10 times respectively.

[1013] Test Example 5: Determination of the efficacy of the compound of the present invention in an imiquimod-induced mouse psoriasis-like model.

[1014] 1. Experimental objective:

[1015] To evaluate the efficacy of the compound in an imiquimod-induced mouse psoriasis-like model.

[1016] 2. Main instruments and reagents for the experiment

[1017] 2.1 Instruments

[1018] Instrument and equipment name model factory Electronic balance SQP type SECURA225D-1CN Sartorius Electronic balance MP5002 Shanghai Sunny Hengping

[1019] 2.2 Reagents

[1020]

[1021]

[1022] 3. Experimental Procedure

[1023] 3.1 Modeling

[1024] Day 0: Shave the test area on the animal's back. Days 1-6: Apply 62.5 mg imiquimod to the test area on the animal's back once daily.

[1025] 3.2 Administration

[1026] From Day 1 to Day 7, animals in each group were administered drugs according to the experimental protocol. The experimental design for the imiquimod-induced mouse psoriasis-like model is shown in the table below:

[1027]

[1028] 3.3 Severity Index Score for Dermatitis Skin Damage

[1029] From Day 1 to Day 7, the redness, scaling, and thickening of the test area on the animal's back were scored from 0 to 4. 0: No damage; 1: Slight; 2: Moderate; 3: Obvious; 4: Very obvious.

[1030] The total score indicates the severity of the injury.

[1031] 4. Experimental Data

[1032] 4.1 The comparison results of PASI scores of different compounds in an imiquimod-induced mouse psoriasis model are shown in the table below:

[1033]

[1034] 4.2 PASI score results of different compounds in an imiquimod-induced mouse psoriasis model are as follows: Figure 1 As shown, the data points represent the mean PASI scores within the group, N=8. The One-way ANOVA was used to compare the vehicle group, and ***p<0.001.

[1035] 5. Experimental Results

[1036] As can be seen from the above results, Examples 58, 88 and 92 of this patent can effectively improve psoriasis symptoms in the imiquimod-induced mouse psoriasis-like model, showing a highly significant difference compared with the Vehicle group (P<0.001), and are superior to the reference compound BMS-986165 (P<0.01).

Claims

1. A compound of general formula (V), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: R is selected from C 1-6 Alkoxy; R3 is selected from hydrogen or halogen; R5 is selected from hydrogen; R4 is selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, Or -(CH2) n1 R aa ; R6 is selected from hydrogen; R9 is selected from ; R aa Selected from C 3-8 cycloalkyl or 3-8 membered heterocyclic groups; x is 0, 1, 2, or 3; n1 is 1.

2. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the compound further represents the general formula (VIII): in: R3~R6 and x are as described in claim 1.

3. The compound according to claim 2, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, The R3 is selected from hydrogen, fluorine, chlorine, or bromine; R4 is selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl or .

4. The compound according to claim 2, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, The R3 is selected from hydrogen or fluorine; R4 is selected from cyclopropyl, cyclobutyl, cyclopentyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, or propargyl. .

5. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from the following compounds: and 。 6. A compound of general formula (XI), its stereoisomer or a pharmaceutically acceptable salt thereof: in: R 18 Selected from C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, oxetyl, or -(CH2) n1 R aa ; R 19 Selected from hydrogen or halogen; R aa Selected from C 3-8 cycloalkyl or 3-8 membered heterocyclic groups; n1 is 1; r can be 0, 1, 2 or 3.

7. The compound according to claim 6, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R 18 Selected from C 2-5 alkenyl, C 2-5 alkynyl group, C 3-6 Cycloalkyl, oxetyl, or -(CH2) n1 R aa ; R 19 Selected from hydrogen, fluorine, or chlorine; R aa Selected from C 3-6 Cycloalkyl.

8. The compound according to claim 6, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R 18 Selected from cyclopropyl or ; R 19 Selected from hydrogen or fluorine.

9. The compound according to claim 6, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Selected from the following compounds: or 。 10. A method for preparing the compound of general formula (V) according to claim 1, or its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that... Includes the following steps, The reaction of general formula (V-1) with general formula (V-2) yields general formula (V-3), and the further reaction of general formula (V-3) yields the compound shown in general formula (V) or its stereoisomers and pharmaceutically acceptable salts thereof; in: X is selected from halogens; R, R3~R6, R9 and x are as described in claim 1.

11. A method for preparing the compound of general formula (V) according to claim 1, or its stereoisomers and pharmaceutically acceptable salts thereof, characterized in that... Includes the following steps, The reaction of general formula (V-4) with general formula (V-5) yields general formula (V-6), which in turn reacts with general formula (V-2) to yield the compound shown in general formula (V) or its stereoisomers and pharmaceutically acceptable salts thereof. in: X is selected from halogens; R, R3~R6, R9 and x are as described in claim 1.

12. A pharmaceutical composition comprising a therapeutically effective dose of the compound shown in any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

13. The use of the compound, stereoisomer, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, in the preparation of a TYK2 inhibitor drug.

14. The use of the compound according to any one of claims 1 to 9, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 12 in the preparation of a treatment for inflammatory diseases and autoimmune diseases; wherein the inflammatory diseases and autoimmune diseases are selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.

Images