RU2807611C2 - Pyridazine derivative inhibitor, method of its preparation and its use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to an inhibitor that is a pyridazine derivative, namely a compound of formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof, where R₉ is C_3-6 cycloalkyl, R is C_1-6 alkoxy, R₃ is selected from a group consisting of hydrogen and halogen, R₄ is cyclopropyl, R₅ and R₆ are hydrogen, x is either 0 or 1. The invention also relates to a method of producing a compound of formula (V), to a pharmaceutical composition containing it and to its use for the production of a TYK2 inhibitory medicinal product for the treatment of an inflammatory disease and an autoimmune disease, wherein the inflammatory disease and the autoimmune disease are selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel disease.

EFFECT: development of a safer selective TYK2 inhibitor for the treatment of inflammatory and autoimmune diseases.

10 cl, 1 dwg, 121 ex, 5 tbl

Description

TECHNICAL FIELD

The present invention relates to the field of drug synthesis and, in particular, relates to a pyridazine derivative inhibitor, a method for its preparation and its use.

BACKGROUND OF THE ART

Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates 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 cells of all tissues of the human body, and JAK-3 is mainly expressed in various cells of hematopoietic tissue. A common feature of cytokine receptors is that the receptor itself does not have kinase activity, while the intracellular segment of the receptor contains a binding site for the JAK tyrosine kinase. When a cytokine receptor binds to its ligand, JAKs bound to the receptor are activated, thereby causing phosphorylation of the receptor. The phosphorylated tyrosine site can bind to the SH2 domain-containing STAT protein, so that STAT is recruited to the receptor and phosphorylated by JAK. Phosphotyrosine mediates STAT dimerization. The activated STAT dimer translocates into the nucleus and activates the transcription of its target genes, thereby regulating the growth, activation, differentiation, and other functions of various cells.

TYK2 is the first subtype discovered in the JAK family, which mediates the functions of cytokines such as IFN-α, IL-6, IL-10, IL-12 and IL-23. Research has shown that TYK2 deletion mutation can effectively suppress the occurrence of immune diseases such as allergies, autoimmunity and inflammation. IL-23 plays a key role in the occurrence and development of psoriasis. Recent studies indicate that the pathogenesis of psoriasis is that an unknown endogenous antigen activates the secretion of IL-23, IL-23 by the antigen presenting cell (APC), activates the secretion of cytokines such as IL-17 by Th 17 cells, thereby causing the division of keratinocytes and their secretion of IL-23, as well as additionally stimulating inflammation and proliferation of keratinocytes, causing psoriasis. TYK2 and JAK2 jointly mediate the downstream IL-23 signaling pathway. Inhibition of JAK2 may cause anemia and other blood-related side effects. Therefore, targeting TYK2 to inhibit the IL-23 signaling pathway is a good strategy for the treatment of psoriasis.

All early TYK2 inhibitors are non-selective JAK inhibitors, such as tofacitinib, which is the first oral JAK inhibitor and has significant inhibitory activity against JAK1, 2 and 3 subtypes. Inhibition of the activity of other subtypes, such as JAK1, JAK2 and JAK3, increases the effectiveness of tofacitinib , but causes serious side effects. Adverse reactions include infection, tuberculosis, tumor, anemia, liver damage, increased cholesterol and the like. Because JAK2 activity is associated with erythroid cell differentiation and lipid metabolism, some of the above-mentioned adverse reactions (eg, anemia) are believed to be due to the lack of selectivity of tofacitinib for JAK-2 and are caused by a non-selective inhibitory effect of this drug. There is currently no selective TYK2 inhibitor on the market. Early JAK inhibitors act primarily by competing for kinase domain and ATP binding, so there is a general problem of low selectivity.

Due to the fact that non-selective JAK inhibitors have good efficacy and serious side effects associated with multiple targets, the development of a safer selective TYK2 inhibitor for the treatment of inflammatory diseases such as psoriasis has great potential for clinical application. International applications WO 2015069310 A1 and WO 2018081488 A1 filed by BMS describe selective TYK2 inhibitors. BMS-986165, developed by BMS, showed good results in phase II clinical studies and has entered phase III clinical studies. This demonstrates the advantage and significant clinical value of a selective TYK2 inhibitor.

BRIEF DESCRIPTION OF THE INVENTION

An object of the present invention is to provide a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (I) is as follows:

Where:

R is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, 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 and -NR _aa S(O) _m1 R _bb ;

R ₁ is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, -R _aa , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _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 , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n1 S (O) _m1 R _aa , -(CH ₂ ) _n1 NR _aa C(O)C(O)R _aa and -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , where each is cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

R ₂ is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, -R _aa , -C(O)R _aa , -(CH ₂ ) _n1 OR _bb , -(CH ₂ ) _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 , -(CH ₂ ) _n1 S(O) _m1 NR _aa R _bb , -(CH ₂ ) _n1 C(O)R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n1 S(O) _m1 R _aa and -(CH ₂ ) _n1 NR _aa S(O) _m1 R _bb , wherein each of cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thioxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

R ₃ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl and alkynyl;

each of R ₄ , R ₅ , R ₆ and R ₇ is present or absent, and each of them, if present, is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino , thiol, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -SR _aa , -(CH ₂ ) _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 and -NR _aa S(O) _m1 R _bb ;

or R ₄ and R ₆ or R ₆ and R ₇ are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium , alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R _aa , R _bb , R _cc and R _dd are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted ring oalkyl substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

or any two adjacent or non-adjacent of R _aa , R _bb , R _cc and R _dd are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

x is an integer equal to 0, 1, 2 or 3;

m1 is an integer equal to 0, 1 or 2; And

n1 is an integer equal to 0, 1, 2, 3, 4 or 5.

In a preferred embodiment: R is selected from the group consisting of hydrogen, deuterium, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _haloC1-6 alkoxy, halogen, amino, thiol, -OR _aa . -SR _aa , -S(O) _m1 R _aa and -NR _aa R _bb , preferably hydrogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, halogenC _1-3 alkoxy, fluorine, chlorine, bromine, -OR _aa , -SR _aa , -S(O) _m1 R _aa and -NR _aa R _bb , more preferably hydrogen, methyl, ethyl, propyl, FCH ₂ -, F ₂ CH-, F ₃ C-, ClCH ₂ -, Cl ₂ CH-, Cl ₃ C-, CH ₃ O-, CH ₃ CH ₂ O-, CH ₃ CH ₂ CH ₂ O-, FCH ₂ O-, F ₂ CHO-, F ₃ CO-, fluorine , chlorine, -OR _aa , -SR _aa , -S(O) _m1 R _aa and -NR _aa R _bb , and even more preferably CH ₃ O-, (CH ₃ ) ₂ N-, CH ₃ S-, F ₃ CO-, F ₂ HCO-, F- and CH ₃ S(O) ₂ -;

wherein each of R _aa and R _bb is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, cyano, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl and 3-7 membered heterocyclyl, preferably hydrogen, hydroxy, 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, C _3-6 cycloalkyl and 3-6 membered heterocyclyl containing 1-3 atoms N, O or S, more preferably hydrogen, methyl, ethyl, - CD ₃ , -CD ₂ CD ₃ , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH ₂ -, F ₂ CH-, F ₃ C-, cyano, cyclopropyl, cyclobutyl, cyclohexyl, epoxyethyl, epoxypropyl, epoxybutyl , epoxypentyl, tetrahydropyrrolyl and piperidinyl, and even more preferably hydrogen, methyl, ethyl, propyl, cyclopropyl and cyclobutyl;

R ₁ is selected from the group consisting of C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl, 3-7 member 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 , -(CH ₂ ) _n1 S(O) _m1 R _c , -(CH ₂ ) _n1 NR _c C(O)C(O)R ₈ , -(CH ₂ ) _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 and -CR _e R _f C=ONR _c R _d , preferably C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl, 3-6-membered 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 , -(CH ₂ ) _n1 S(O) _m1 R _c , -(CH ₂ ) _n1 NR _c C( O)C(O)R _g , -(CH ₂ ) _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 and -CR _e R _f C=ONR _c R _d , more preferably C _3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3 atoms N, O or S, -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 , -(CH ₂ ) _n1 S(O) _m1 R _c , -(CH ₂ ) _n1 NR _c C( O)C(O)R _g , -(CH ₂ ) _n1 NR _c S(O)m ₁ R _d , -NR _c CR _d R _e R _f , -NR _c C(S)R _d , -OC=ONR _c R _d and -CR _e R _f C=ONR _c R _d , and even more preferably

each of R _c , R _d , R _e , R _f and R _g is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1 -6} hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, C _6-12 aryl and 3-7 membered heteroaryl, preferably hydrogen, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, fluorine, chlorine, bromine, cyano, C _2-5 alkenyl, C _2-5 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl containing 1-3 N, O or S atoms, C _6-10 aryl and 3- 6-membered heteroaryl containing 1-3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, -CD ₃ , -CD ₂ CD ₃ , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH ₂ -, F ₂ CH-, F ₃ C-, cyano, fluorine, chlorine, CH ₃ O-, CH ₃ CH ₂ O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and even more preferably hydrogen, methyl, ethyl, -CD ₃ , -CD ₂ CD ₃ , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH ₂ -, F ₂ CH-, F ₃ C-, cyano, fluorine, chlorine, CH ₃ O-, CH ₃ CH ₂ O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

or any two adjacent or non-adjacent of _Rc , _Rd , _Rc and _Rf are linked to form a _C3-7 cycloalkyl, 3-7 membered heterocyclyl, aryl or 3-7 membered heteroaryl, preferably _C3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-12 aryl or 3-6 membered heteroaryl, more preferably C _3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, C _6-10 aryl or 3-6 membered heteroaryl containing 1-2 N, O or S atoms, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and even more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

R ₂ is selected from the group consisting of C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl, 3-7 member heteroaryl, C _1-6 hydroxyalkyl, -C(O)R _hh , -( CH ₂ ) _n1 OR _ii , -(CH ₂ ) _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 , -(CH ₂ ) _n1 S(O) _m1 NR _hh R _ii , -(CH ₂ ) _n1 C(O)R _hh , -NR _hh C(O)OR _ii , -(CH ₂ ) _n1 S(O) _m1 R _hh and -(CH ₂ ) _n1 NR _hh S(O) _m1 R _ii , where each of C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl and 3-7 member heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl, C _1-6 alkoxy and C _3-6 cycloalkyl; preferably C _3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, C _6-10 aryl, substituted or unsubstituted 3-6 membered heteroaryl, C _1-3 hydroxyalkyl, -C(O)R _hh , -(CH ₂ ) _n1 OR _ii , -(CH ₂ ) _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 , -(CH ₂ ) _n1 S(O) _m1 NR _hh R _ii , -(CH ₂ ) _n1 C(O)R _hh , -NR _hh C(O)OR _ii -(CH ₂ ) _n1 S(O) _m1 R _hh and -(CH ₂ ) _n1 NR _hh S(O) _m1 R _ii , where each of C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl and 3-7 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, C _1-3 alkyl and C _3-5 cycloalkyl; more preferably C _3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3 N, O or S atoms, C _{1 -3} hydroxyalkyl, -C(O)R _hh , -(CH ₂ ) _n1 OR _ii , -(CH ₂ ) _n1 NR _hh R _ii , -C(O)NR _hh R _ii , -(CH ₂ ) _n1 S( O) _m1 NR _hh R _ii , -(CH ₂ ) _n1 C(O)R _hh , -(CH ₂ ) _n1 S(O) _m1 R _hh and -(CH ₂ ) _n1 NR _hh S(O) _m1 R _ii wherein each of C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl and 3-7 member heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl and cyclohexyl; and even more preferably HOCH ₂ -, HOCH ₂ CH ₂ -, HOCH ₂ C(O)-, CH ₃ NHC(O)-, D ₃ CNHC(O)-, CH ₃ NHS(O) ₂ -, D ₃ CNHS (O) ₂ -,

R _hh , R _ii , R _jj and R _kk are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl , C _1-6 alkoxy, C _1-6 haloalkoxy, halogen, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, preferably hydrogen, deuterium, C _{1- 3} alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, fluorine, chlorine, bromine, cyano, C _2-5 alkenyl, C _{2 -5} alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, and more preferably hydrogen, deuterium, methyl, ethyl, -CD ₃ , -CD ₂ CD ₃ , propyl , hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH ₂ -, F ₂ CH-, F ₃ C-, cyano, fluorine, chlorine, CH ₃ O-, CH ₃ CH ₂ O-, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrolyl and piperidinyl;

R ₃ is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, fluorine, chlorine, bromine, amino , thiol, nitro, hydroxy and cyano, preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, fluorine, chlorine, bromine , amino, thiol, nitro, hydroxy and cyano, and more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, hydroxy and cyano;

each of R ₄ , R ₅ , R ₆ and R ₇ is present or absent, and each of them, if present, is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, fluorine, chlorine, bromine, amino, thiol, nitro, hydroxy, cyano, oxo, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 7} cycloalkyl, 3-7-membered heterocyclyl, aryl, 3-7-membered heteroaryl, -(CH ₂ ) _n1 R _ll , -(CH ₂ ) _n1 OR _ll , -SR _ll , -(CH ₂ ) _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 and -NR _ll S (O) _m1 R _mm , preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, fluorine, chlorine, bromine, amino , thiol, nitro, hydroxy, cyano, oxo, C _2-5 alkenyl, C _2-5 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl containing 1-3 atoms N, O or S, C _{6- 12} aryl, 3-6-membered heteroaryl containing 1-3 atoms N, O or S, -(CH ₂ ) _n1 R _ll , -(CH ₂ ) _n1 OR _ll , -SR _ll , -(CH ₂ ) _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 and - NR _ll S(O) _m1 R _mm , more preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, fluorine, chlorine, bromine, amino, thiol, nitro, hydroxy, cyano, oxo, C _2-5 alkenyl, C _2-5 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl containing 1-3 N, O or S atoms, C _6-10 aryl, 3-6-membered heteroaryl containing 1-3 atoms N, O or S, -(CH ₂ ) _n1 R _ll , -(CH ₂ ) _n1 OR _ll and -NR _ll R _mm , and even more preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, (CH ₃ ) ₃ C-, CF ₃ CH ₂ -, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, vinyl, CH ₂ =CHCH ₂ -, ethynyl, cyano, CNCH ₂ -, CNCH ₂ CH ₂ -, CH ₃ OCH ₂ -, CH ₃ OCH ₂ CH ₂ -, CF ₃ C(CH ₃ ) ₂ -,

each of R _ll and R _mm is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 haloalkoxy, halogen, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, preferably hydrogen, deuterium, C _1-3 alkyl, C _{1- 3} deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, fluorine, chlorine, bromine, cyano, C _2-5 alkenyl, C _2-5 alkynyl, C _{3 -6} cycloalkyl and 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, and more preferably hydrogen, deuterium, methyl, ethyl, -CD ₃ , -CD ₂ CD ₃ , propyl, hydroxymethyl, hydroxyethyl, vinyl , propenyl, ethynyl, propynyl, FCH ₂ -, F ₂ CH-, F ₃ C-, cyano, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrolyl and piperidinyl;

or R ₄ and R ₆ or R ₆ and R ₇ are linked to form a heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl and C _{3 -6} cycloalkyl; preferably to form a 3-6 membered heterocyclyl or 3-7 membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, C _1-3 alkyl and C _3-5 cycloalkyl; more preferably to form a 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, or a 3-7 membered heteroaryl containing 1-3 N, O or S atoms, where the heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl and cyclohexyl; and even more preferably with education

optionally provided that the compound of formula I is not

The present invention also provides a preferred embodiment of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (I) is additionally as represented by formula (II):

Where:

RR ₆ and x are as defined in formula (I).

The present invention also provides a preferred embodiment of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (I) is additionally as represented by formula (III):

Where:

R, R ₁ , R ₃ -R ₆ and x are as defined in formula (I).

The present invention also provides a preferred embodiment of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (I) is additionally as represented by formula (IV):

Where:

ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, and preferably heteroaryl;

R ₈ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl , heterocyclyl, aryl and heteroaryl; and preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl and cycloalkyl;

y is 0, 1, 2 or 3; And

R, R ₁ , R ₃ -R ₆ and x are as defined in formula (I). In a preferred embodiment, ring A is selected from the group consisting of C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl and 3-7 membered heteroaryl, preferably C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl and 3-6 membered heteroaryl, more preferably C _3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, phenyl, naphthyl and 3-6 membered heteroaryl containing 1-3 N, O or S atoms, even more preferably

and most preferably

R ₈ is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C _1-6 haloalkyl, hydroxy, amino, C _2-6 alkenyl , C _2-6 alkynyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl , fluorine, chlorine, bromine, cyano, nitro, C _1-3 haloalkyl, hydroxy, amino, C _2-5 alkenyl, C _2-5 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl containing 1-3 N, O or S atom, C _6-10 aryl and 3-6 membered heteroaryl containing 1-3 N, O or S atoms, and more preferably hydrogen, deuterium, methyl, ethyl, propyl, methyl chlorine, ethyl chlorine, fluorinated methyl, fluorinated ethyl, fluorine, chlorine, bromine, cyano, nitro, hydroxy, amino, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

The present invention also provides a preferred embodiment of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (I) is further as represented in formula (V):

Where:

R ₉ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -SR _aa , -(CH ₂ ) _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 and -NR _aa S(O) _m1 R _bb , where each is alkyl, haloalkyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; And

R, R ₃ -R ₆ , R _aa , R _bb and x are as defined in formula (I).

In a preferred embodiment: R ₉ is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C _1-6 haloalkyl, hydroxy, amino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, 3-7-membered heterocyclyl, C _6-12 aryl, 3-7-membered heteroaryl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -SR _aa , -(CH ₂ ) _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 and -NR _aa S(O) _m1 R _bb , preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, fluorine, chlorine, bromine , cyano, nitro, C _1-3 haloalkyl, hydroxy, amino, C _2-5 alkenyl, C _2-5 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, C _6-10 aryl, 3-6- member heteroaryl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -SR _aa , -(CH ₂ ) _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 and -NR _aa S(O) _m1 R _bb , more preferably hydrogen, deuterium, hydroxy-substituted C _1-3 alkyl, C _1-3 cycloalkyl-substituted C _1-3 alkyl, hydroxy-substituted C _1-3 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C _1-3 haloalkyl, hydroxy, C _3-6 cycloalkyl- substituted amino, halogen-substituted C _2-5 alkenyl, halogen-substituted C _2-5 alkynyl, halogen-substituted C _3-6 cycloalkyl, C _1-3 alkyl-substituted C _3-6 cycloalkyl, cyano-substituted C _3-6 cycloalkyl, C _1-3 alkoxy- substituted C _3-6 cycloalkyl, C _1-3 haloalkyl-substituted C _3-6 cycloalkyl, 3-7 membered heterocyclyl containing 1-3 N, O or S atoms, phenyl, naphthyl, 3-7 membered heteroaryl containing 1-3 atoms N, O or S, -(CH ₂ ) _n1 R _aa , -(CH ₂ )n ₁ OR _aa , -(CH ₂ ) _n1 C(O)R _aa and -NR _aa R _bb , and more more preferable

each of R _aa and R _bb is independently selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, halogen, cyano, nitro, C _1-6 haloalkyl, hydroxy, amino, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C _1-3 haloalkyl, hydroxy, amino, C _2-5 alkenyl, C _2-5 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl containing 1 -3 atoms N, O or S, C _6-10 aryl and 3-7 membered heteroaryl containing 1-3 atoms N, O or S, and more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and biphenyl;

m1 is 0, 1, 2 or 3; And

n1 is 0, 1, 2 or 3.

The present invention also provides a preferred embodiment of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (I) is further as represented in formula (VI):

Where:

ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, and preferably heteroaryl;

R ₁₀ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, where each of alkyl, deuterated alkyl, haloalkyl , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl and cycloalkyl;

z is 0, 1, 2 or 3;

R, R ₃ -R ₆ and x are as defined in formula (I). In a preferred embodiment, ring B is selected from the group consisting of C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl and 3-7 membered heteroaryl, preferably C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl and 3-6 membered heteroaryl, more preferably C _3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, phenyl, naphthyl and 3-6 membered heteroaryl containing 1-3 N, O or S atoms, even more preferably most preferable And And

R ₁₀ is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C _1-6 haloalkyl, hydroxy, amino, alkenyl, alkynyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-12 aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, fluorine, chlorine, bromine, cyano , nitro, C _1-3 haloalkyl, hydroxy, amino, alkenyl, alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl containing 1-3 N, O or S atoms, C _6-10 aryl and 3-6 -membered heteroaryl containing 1-3 N, O or S atoms, and more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, hydroxy, amino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The present invention also provides a preferred embodiment of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (I) is further as represented in formula (VII):

Where:

M represents S, NR _cc or CR _cc R _dd ;

R ₁₁ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterated alkyl, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl and cycloalkyl;

R _cc and R _dd are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R _cc and R _dd are linked to form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of deuterated alkyl, deuterium, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; And

R, R ₃ -R ₆ and x are as defined in formula (I).

In a preferred embodiment: M is S, NR _cc or CR _cc R _dd , and preferably S, NCH ₃ , NOCH ₃ , NCN, CH ₂ , CHCH ₃ or

R ₁₁ is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, halogen, cyano, nitro, C _1-6 haloalkyl, hydroxy, amino, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-12 aryl and 3-8 membered heteroaryl, preferably hydrogen, C _1-3 alkyl, C _1-3 deuterated alkyl, halogen, amino, cyano , alkyl, C _1-3 haloalkyl and C _3-5 cycloalkyl, and more preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl; And

R _cc and R _dd are each independently selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, fluorine, chlorine, bromine, cyano, nitro, hydroxy, amino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-12 aryl and 3-6 membered heteroaryl, preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 haloalkoxy, fluorine , chlorine, bromine, cyano, nitro, hydroxy, amino, C _2-5 alkenyl, C _2-5 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl containing 1-3 atoms N, O or S, C _6-10 aryl and 3-6 membered heteroaryl containing 1-3 atoms N, O or S, and more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, hydroxy and cyano;

or R _cc and R _dd are linked to form a C _3-6 cycloalkyl or 3-6 membered heterocyclyl, preferably a C _3-6 cycloalkyl or 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, and more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

The present invention also provides a preferred embodiment of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, further as represented by formula (VII):

Where:

R ₃ -R ₆ and x are as defined in formula (I).

In a preferred embodiment:

R ₃ is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine and bromine, preferably hydrogen, deuterium and fluorine, and more preferably hydrogen and fluorine;

R ₄ is selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, where each of C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of methyl, ethyl, fluorine and chlorine; preferably C _1-3 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _3-5 cycloalkyl and 3-5 membered heterocyclyl, more preferably C _1-3 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _3-5 cycloalkyl and 3-5 membered heterocyclyl containing 1-3 N, O or S atoms, and even more preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, vinyl, propenyl, allyl, ethynyl, pierced, pierced,

R ₅ and R ₆ are each independently hydrogen or deuterium; and x is 0, 1, 2 or 3.

The present invention also provides a preferred embodiment of a compound of each formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

ring A and ring B are selected from the group consisting of:

The present invention also provides a preferred embodiment of a compound of each formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of hydrogen, C _1-6 alkoxy, C _1-6 haloalkoxy, -OR _aa , -SR _aa , and -NR _aa R _bb ;

R ₁ is selected from the group consisting of 3-8 membered heterocyclyl, 5-8 membered heteroaryl, -(CH ₂ ) _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 , -(CH ₂ ) _n1 NR _aa C(O)C(O)R _aa , -NR _aa CR _bb =NR _cc and -NR _aa CR _bb =CR _cc R _dd , where each is a 3-8-membered heterocyclyl and a 5-8- the heteroaryl member is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, halogen, hydroxy, amino, cyano, oxo and C _3-8 cycloalkyl;

R ₂ is selected from the group consisting of 3-8 membered heterocyclyl, 5-8 membered heteroaryl, -C(O)R _aa , -(CH ₂ )n ₁ OR _aa , -C(O)NR _aa R _bb and -S(O) _m1 NR _aa R _bb wherein each of the 3-8 membered heterocyclyl and the 5-8 membered heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl , C _1-6 haloalkyl, halogen, hydroxy, amino, cyano and C _3-8 cycloalkyl;

R ₃ is selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 haloalkyl;

R ₅ is selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 haloalkyl;

each of R ₄ and R ₆ is independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and -(CH ₂ ) _n1 R _aa , and preferably hydrogen, cyclopropyl and

or R ₄ and R ₆ are linked to form C _3-8 cycloalkyl and preferably cyclopentanyl;

R ₇ is absent or selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 haloalkyl;

or R ₆ and R ₇ are linked to form C _3-8 cycloalkyl and preferably cyclopentanyl;

each of R ₈ and R ₁₀ is independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl and C _3-8 cycloalkyl;

R ₉ is selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n1 R _aa , -(CH ₂ ) _n1 OR _aa , -(CH ₂ ) _n1 C(O)R _aa , -C(O)OR _aa , -NR _aa R _bb and -C(O)NR _aa R _bb , where each of C _1-6 alkyl, C _3-8 cycloalkyl and 3 The -8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, halogen, hydroxy, amino, oxo, nitro, cyano, C _{2- 6} alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-8 membered heteroaryl;

R ₁₁ is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, halogen, cyano, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _{6 -10} aryl and 5-8 membered heteroaryl; And

R _aa , R _bb , R _cc and R _dd are each independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, 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 heterocyclyl and 5-8 membered heteroaryl, where each is 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 heterocyclyl and 5-8 membered heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, halogen, hydroxy, amino, oxo, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8- membered heterocyclyl, C _6-10 aryl and 5-8 membered heteroaryl;

or R _cc and R _dd are linked to form a C _3-8 cycloalkyl, wherein the C _3-8 cycloalkyl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkyl , halogen, amino, oxo, cyano, hydroxy, C _1-6 alkoxy, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl.

The present invention also relates to a technical solution providing a compound of formula (IX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Where:

ring C is selected from the group consisting of:

R ₁₂ is independently selected from the group consisting of -OR _ee , -C(O)NR _ee R _ff , -(CH ₂ ) _n1 NR _ee R _ff and -S(O) _m2 NR _ee R _ff ;

R ₁₇ is selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and -(CH ₂ ) _n1 R _aa ;

R _ee and R _ff are each independently selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl, wherein each of C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl is optionally additional substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, halogen, hydroxy, amino, oxo, cyano, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-8 membered heteroaryl;

n1 is 0, 1 or 2;

m2 is 0, 1 or 2; And

q is 0, 1, 2 or 3.

In a preferred embodiment:

R ₁₂ is selected from the group consisting of CD ₃ NHC(O)-, CH ₃ NHC(O)-, CH ₃ NHS(O) ₂ -, CH ₃ O-, D ₃ CNHS(O) ₂ -,

R ₁₇ is selected from the group consisting of hydrogen, halogen, cyano, C _1-3 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and -(CH ₂ ) _n1 R _aa , preferably hydrogen, halogen, cyano, C _1-3 alkyl, C _2-5 alkenyl, C _2-5 alkynyl, C _1-3 alkyl, substituted with 1-3 fluorine, chlorine or bromine, C _3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-3 atoms N, O or S, and -(CH ₂ ) _n1 R _aa , and more preferably hydrogen, methyl, ethyl, propyl, isopropyl, n -butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, thiocyclobutyl, thiocyclopentyl, thiocyclohexyl, allyl, propargyl, CF ₃ CH ₂ -, ( CH ₃ ) ₂ CF ₃ C-, CN-, CNCH ₂ -, CNCH ₂ CH ₂ -,

R _aa is selected from the group consisting of alkoxy, hydroxyalkyl, haloalkoxy, nitro, hydroxy, cyano, amino, aryl and heteroaryl, preferably C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy, nitro, hydroxy, cyano , amino, C _6-12 aryl and 3-12 membered heteroaryl, more preferably C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _1-3 haloalkoxy, nitro, hydroxy, cyano, amino, C _6-10 aryl and 5-8 membered heteroaryl, and even more preferably methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, C _1-3 alkoxy substituted with 1-3 fluorine, chlorine or bromine atoms, nitro, hydroxy, cyano, amino, aryl and 3-6-membered heteroaryl containing 1-3 N, O or S atoms; And

n1 is equal to 1 or 2.

The present invention also relates to a technical solution providing a compound of formula (X), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Where

each of R ₁₃ and R ₁₄ is independently selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl;

R ₁₅ is selected from the group consisting of 3-8 membered heterocyclyl, 5-8 membered heteroaryl, -(CH ₂ ) _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 , -(CH ₂ ) _n1 NR _aa C(O)C(O)R _aa , -NR _aa CR _bb =NR _cc and -NR _aa CR _bb =CR _cc R _dd , where each is a 3-8-membered heterocyclyl and a 5-8- the heteroaryl member is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, halogen, hydroxy, amino, cyano and C _3-8 cycloalkyl;

R ₁₆ is selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and -(CH ₂ ) _n1 R _aa ;

R _aa , R _bb , R _cc and R _dd are each independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, 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 heterocyclyl and 5-8 membered heteroaryl, where each is 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 heterocyclyl and 5-8 membered heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl, halogen, hydroxy, amino, oxo, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8- membered heterocyclyl, C _6-10 aryl and 5-8 membered heteroaryl;

n1 is 0, 1 or 2; And

m1 is 0, 1 or 2.

The present invention also relates to a technical solution providing a compound of formula (XI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Where:

R ₁₈ is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1 -6} haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and -(CH ₂ ) _n1 R _aa , preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, fluorine, chlorine, bromine, hydroxy, cyano, C _2-5 alkenyl, C _2-5 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and -(CH ₂ ) _n1 R _aa , and more preferably hydrogen, methyl, cyclopropyl,

R ₁₉ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, amino, hydroxy and cyano, preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, fluorine, chlorine, bromine, amino, hydroxy and cyano, and more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, hydroxy and cyano;

R _aa is selected from the group consisting of hydrogen, deuterium, cyano, hydroxy, halogen, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl, preferably hydrogen, deuterium, 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 and C _3-6 cycloalkyl, and more preferably hydrogen, methyl, ethynyl and cyclopropyl;

n1 is 0, 1 or 2; And

r is 0, 1, 2 or 3.

The present invention also relates to a technical solution relating to a method for producing a compound of formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

subjecting a compound of formula (V-1) to a compound of formula (V-2) to yield a compound of formula (V-3), then reacting a compound of formula (V-3) to yield a compound of formula (V), a stereoisomer thereof, or a pharmaceutical thereof acceptable salt;

Where:

X represents halogen; And

R ₃ -R ₆ , R ₉ and x are as defined in formula (V).

The present invention also relates to a technical solution relating to a method for producing a compound of formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

subjecting a compound of formula (V-4) to a compound of formula (V-5) to produce a compound of formula (V-6), then reacting a compound of formula (V-6) with a compound of formula (V-2) to yield a compound of formula ( V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof;

Where:

X represents halogen; And

R ₃ -R ₆ , R ₉ and x are as defined in formula (V).

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

The present invention also relates to a technical solution relating to the use of a compound of formula (I), a compound of formula (IX), a compound of formula (X), a stereoisomer thereof or a pharmaceutically acceptable salt thereof described above, or a pharmaceutical composition described above, for the preparation of a medicinal product. TYK2 inhibitory agent.

The present invention also relates to a technical solution relating to the use of a compound of formula (I), a compound of formula (IX), a compound of formula (X), a stereoisomer thereof or a pharmaceutically acceptable salt thereof described above, or a pharmaceutical composition described above, for the preparation of a medicinal product. agents for treating an inflammatory disease and an autoimmune disease, wherein the inflammatory disease and the autoimmune disease are selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel disease (ulcerative colitis and Crohn's disease).

The present invention also relates to a method of treating an inflammatory disease using a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present invention also relates to a method of preventing and/or treating an autoimmune disease, comprising the step of administering to a patient a therapeutically effective dose of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present invention also provides a method of treating a condition with a compound or pharmaceutical composition of the present invention, wherein the condition includes, but is not limited to, a condition associated with TYK2 kinase dysfunction.

The present invention also provides a method of treating a hyperproliferative disorder in a mammal, comprising the step of administering to said mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof according to the present invention.

In some embodiments, the method includes treating conditions such as cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disorder, respiratory disease, and heart disease.

In some embodiments, the method includes an inflammatory disease and an autoimmune disease selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease (ulcerative colitis and Crohn's disease).

A method of treatment provided herein includes the step of administering to a subject a therapeutically effective amount of a compound of the present invention. In one embodiment, the present invention provides a method for treating an inflammatory condition, including an autoimmune disease, in a mammal. The method includes the step of administering to said mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof of the present invention.

DEFINITIONS

Unless otherwise specified, terms used in the specification and claims have the meanings described below.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group that is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably alkyl containing from 1 to 8 carbon atoms, more preferably alkyl containing from 1 to 6 carbon atoms carbon, and most preferably alkyl containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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-methyl pentyl, 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. More preferably, the alkyl group is lower alkyl having from 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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. The alkyl group may be substituted or unsubstituted. In substitution, the substituent group(s) can be attached at any available connection point. The substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "alkylene" refers to an alkyl in which the hydrogen atom is additionally substituted, for example, "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ -, etc. The term "alkenyl" refers to an alkyl, as defined above, which consists of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl 1-, 2- or 3 -butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocyclylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group having from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms . Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. Polycyclic cycloalkyl includes cycloalkyl having a spiro ring, a fused ring or a bridged ring. Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term "spirocycloalkyl" refers to a 5-20 membered polycyclic group with individual rings connected via a single common carbon atom (called a spiroatom), where the rings may contain one or more double bonds, but none of the rings has a fully conjugated π electron systems. Spirocycloalkyl is preferably a 6-14 membered spirocycloalkyl and more preferably a 7-10 membered spirocycloalkyl. Depending on the number of spiroatoms common to the rings, spirocycloalkyl can be divided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, and spirocycloalkyl is preferably monospirocycloalkyl or dispirocycloalkyl, and more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

and also include spirocycloalkyl, in which the cycloalkyl and heterocyclyl are linked through a single spiroatom, non-limiting examples thereof include:

The term "fused cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring, one or more rings may contain one or more double bonds, but none of the rings does not have a fully coupled l-electronic system. The fused cycloalkyl is preferably a 6-14 membered fused cycloalkyl and more preferably a 7-10 membered fused cycloalkyl. Depending on the number of rings in its composition, the fused cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and the fused cycloalkyl is preferably a bicyclic or tricyclic fused cycloalkyl, and more preferably 5-membered/5-membered or 5-membered/ 6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl include:

The term "bridged cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group in which each two rings in the system share two unbonded carbon atoms, the rings may have one or more double bonds, but none of the rings have a fully conjugated π -electronic system. The bridged cycloalkyl is preferably a 6-14 membered bridged cycloalkyl and more preferably a 7-10 membered bridged cycloalkyl. Depending on the number of rings therein, the bridged cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and the bridged cycloalkyl is preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably a bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, where the ring associated with the parent structure is a cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like. Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

The term "heterocyclyl" refers to a 3-20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, where one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen or S(O) _m (where m represents is an integer from 0 to 2), but excluding -O-O-, -OS- or -SS- in the ring, and the remaining ring atoms are carbon atoms. Preferably, the heterocyclyl has from 3 to 12 ring atoms, where from 1 to 4 atoms are heteroatoms; more preferably 3 to 8 ring atoms; and most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl include oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopi perazinil, pyranyl and the like, and preferably oxacyclobutyl, pyrrolidonyl, tetrahydrofuranyl, pyrazolidinil, morpholinyl, piperazinil and pyranil. Polycyclic heterocyclyl includes heterocyclyl having a spiro ring, a fused ring or a bridged ring. A heterocyclyl having a spiro ring, fused ring or bridged ring is optionally linked to another group by a single bond, or is further linked to other cycloalkyl, heterocyclyl, aryl and heteroaryl via any two or more ring atoms.

The term "spiroheterocyclyl" refers to a 3-20 membered polycyclic heterocyclyl group with individual rings connected through a single common atom (called a spiroatom), where one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen or S( O) _m (where m is an integer between 0 and 2) and the remaining ring atoms are carbon atoms, and the rings may contain one or more double bonds, but none of the rings have a fully conjugated π electron system. The spiroheterocyclyl is preferably a 6-14 membered spiroheterocyclyl and more preferably a 7-10 membered spiroheterocyclyl. Depending on the number of spiroatoms common to the rings, spiroheterocyclyl can be divided into monospiroheterocyclyl, dispyroheterocyclyl or polyspyroheterocyclyl, and spiroheterocyclyl is preferably monospiroheterocyclyl or dispyroheterocyclyl, and more preferably 3-membered/5-membered, 4-membered/5-membered, 4-membered membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms with another ring, wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π electron system, and one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms represent carbon atoms. The fused heterocyclyl is preferably a 6-14 membered fused heterocyclyl, and more preferably a 7-10 membered fused heterocyclyl. Depending on the number of rings in its composition, the fused heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, and preferably it is a bicyclic or tricyclic fused heterocyclyl, and more preferably 3-membered/5-membered, 4-membered/5 -membered or 5-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include:

The term "bridged heterocyclyl" refers to a 5-14 membered polycyclic heterocyclyl group in which each two rings in the system share two unbonded atoms, where the rings may have one or more double bonds but none of the rings have a fully conjugated π- electronic system, and one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon atoms. The bridged heterocyclyl is preferably a 6-14 membered bridged heterocyclyl, and more preferably a 7-10 membered bridged heterocyclyl. Depending on the number of rings therein, the bridged heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and the bridged heterocyclyl is preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably a bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of heter cyclyl bridges include:

And .

The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring associated with the parent structure is a heterocyclyl. Non-limiting examples include:

etc.

The heterocyclyl may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

The term "aryl" refers to a 6-14 membered all-carbon monocyclic ring or polycyclic fused ring (that is, each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) having a conjugated π electron system, preferably 6-10 -membered aryl, for example, phenyl and naphthyl. Aryl is more preferably phenyl. An aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring associated with the parent structure is an aryl ring. Non-limiting examples include:

And

Aryl may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "heteroaryl" refers to a 5-14 membered heteroaromatic system having from 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryl is preferably a 5-10 membered heteroaryl and more preferably a 5- or 6-membered heteroaryl, for example imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc. etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and thiazolyl, and more preferably triazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl and pyrimidinyl. A heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring associated with the parent structure is a heteroaryl ring. Non-limiting examples include:

And .

Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "alkoxy" refers to an -O-(alkyl) or -O-(unsubstituted cycloalkyl) group, where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with hydroxyl(s), where alkyl is as defined above.

"Alkenyl" refers to a chain alkenyl group also known as an alkene group. Alkenyl may be further substituted with another related group, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthiothio, heterocyclylthio, carboxy or alkoxycarbonyl.

“Alkynyl” refers to (CH≡C-). Alkynyl may be further substituted with another related group, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthiothio, heterocyclylthio, carboxy or alkoxycarbonyl.

“Hydroxy” refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to the -NH ₂ group.

"Cyano" belongs to the -CN group.

"Nitro" refers to the -NO ₂ group.

“Carboxy” refers to the group -C(O)OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N,N-dimethylacetamide.

"Et ₂ O" refers to diethyl ether.

"DCE" refers to 1,2-dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone)dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bis(trimethylsilyl)amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

"DMAP" refers to 4-dimethylaminopyridine.

"SEM-Cl" refers to 2-chloromethyl-2-(trimethylsilyl)ethyl ether.

"Xantphos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

"DCM" refers to dichloromethane.

Various expressions such as "X is selected from the group consisting of A, B or C", "X is selected from the group consisting of A, B and C", "X is A, B or C", "X is A, B and C”, etc. express the same meaning, that is, X can represent any one or more of A, B, and C.

The hydrogen atom according to the present invention may be replaced by its isotope deuterium. Any of the hydrogen atoms in the compounds of the examples of the present invention may also be replaced by a deuterium atom.

“Optional” or “optional” means that the event or circumstance described below may, but does not necessarily have to, occur, and such description includes a situation in which the event or circumstance does or does not occur. For example, “heterocyclyl optionally substituted with alkyl” means that an alkyl group may, but need not, be present, and such description includes the situation where the heterocyclyl is substituted with alkyl and the heterocyclyl is not substituted with alkyl.

"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, and more preferably 1 to 3 hydrogen atoms, independently substituted with an appropriate number of substituents. It goes without saying that substituents exist only in their possible chemical positions. One skilled in the art can determine, without undue effort, whether replacement is possible, either experimentally or theoretically. For example, the combination of an amino or hydroxy having a free hydrogen and carbon atoms having unsaturated bonds (eg, olefinic) may be unstable.

"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components and other components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound into the body that promotes absorption of the active ingredient so that it exhibits biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective in mammals and has the desired biological activity.

DESCRIPTION OF GRAPHIC MATERIALS

In fig. Figure 1 shows the results of the PASI (Psoriasis Prevalence and Severity Index) assessment of various compounds in a mouse model of imiquimod-induced psoriasis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be further described with reference to the following examples, but the examples should not be construed as limiting the scope of the present invention.

EXAMPLES

The structures of the compounds of the present invention were identified using nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR shifts (δ) are given in parts per million (ppm). NMR was determined on a Bruker AVANCE-400 apparatus. Determination solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethylsilane (TMS).

Liquid chromatography with mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. High-performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C _18,150 ×4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C _18,150 ×4.6 mm chromatography column).

Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as a silica gel thin layer chromatography (TLC) plate. The size of the silica gel plate used in TLC ranged from 0.15 mm to 0.2 mm, and the size of the silica gel plate used in product purification ranged from 0.4 mm to 0.5 mm. Yantai Huanghai 200-300 mesh was used as the column chromatography carrier.

The starting materials used in the examples of the present invention are known and commercially available, or can be synthesized by or in accordance with methods known in the art.

Unless otherwise specified, all reactions according to the present invention were carried out under continuous magnetic stirring under an atmosphere of dry nitrogen or argon, the solvent was dry, and the reaction temperature was expressed in degrees Celsius.

Example 1

Receipt

6-(bicyclo[1.1.1]pentan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d ₃ )pyridazine-3-carboxamide

Step 1: Preparation of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

3-bromo-2-methoxyaniline (2.02 g, 10 mmol), bis(pinacolato)diboron (3.05 g, 12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (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 at 100°C overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and CH ₂ Cl ₂ . The organic phase was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then purified by column chromatography to obtain the title compound 2-methoxy-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (2.0 g, 80%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.36 (s, 12H), 3.83 (s, 3H), 6.92-6.99 (m, 2H), 7.16-7.20 ( m, 2H);

MS m/z (ESI): 250.1 [M+H] ⁺ .

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

2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 8 mmol), 3-bromo-1-methyl-1H- 1,2,4-triazole (1.61 g, 10 mmol), Cs ₂ CO ₃ (7.6 g, 20 mmol), tetrakis(triphenylphosphine) palladium (924.5 mg, 0.8 mmol) were mixed with 1 ,4-dioxane (40 ml) and water (5 ml). The reaction system was purged with nitrogen three times and reacted at 100°C overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and CH ₂ Cl ₂ . The organic phase was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then purified by column chromatography to obtain the title compound 2-methoxy-3-(1-methyl-1H-1,2,4 -triazol-3-yl)aniline (1.14 g, 70%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.77 (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);

MS m/z (ESI): 205.1 [M+H] ⁺ .

Step 3: preparation of lithium 4,6-dichloropyridazine-3-carboxylate

Methyl 4,6-dichloropyridazine-3-carboxylate (2.07 g, 10 mmol) and lithium bromide (2.6 g, 30 mmol) were dissolved in acetonitrile (20 ml) and water (2 ml). The resulting solution was cooled to 0°C and DIPEA (5.2 ml, 30 mmol) was added dropwise. The reaction solution was naturally warmed to room temperature and reacted for 1 hour. The reaction solution was filtered, the filter cake was washed with acetonitrile (2 ml×4), collected and dried to obtain the title compound lithium 4,6-dichloropyridazine-3-carboxylate (1.73 g, 87%).

MS m/z (ESI): 193.1 [M+H] ⁺ .

Stage 4: receiving

((6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-carbonyl)oxy)zinc

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 at 65°C overnight. The reaction solution was cooled to room temperature, then water (6 ml) was added and stirred for 1 hour. The reaction solution was filtered, the filter cake was washed with water (6 ml×2) and THF (6 ml), collected and dried to obtain the title compound ((6-chloro-4-((2-methoxy-3-(1-methyl -1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-carbonyl)oxy)zinc (1.44 g, 73%).

MS m/z (ESI): 361.1 [M+H] ⁺ .

Step 5: preparation of ((6-(bicyclo[1.1.1]pentan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl )phenyl)amino)pyridazine-3-carbonyl)oxy)zinc

((6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-carbonyl)oxy)zinc (157 mg, 0.4 mmol), bicyclo[1.1.1]pentane-1-carboxamide (111 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) followed by the addition of palladium acetate (4.5 mg, 0.02 mmol) and (R)-(-)-1-[(S)- 2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (22 mg, 0.04 mmol). The reaction system was purged with nitrogen three times and reacted at 75°C overnight. The reaction solution was cooled to room temperature, then water (4 ml) and acetic acid (2 ml) were added and washed with petroleum ether (6 ml×2). The aqueous phase was separated, then water (2 ml) was added and extracted with CH ₂ Cl ₂ (5 ml×3). The organic phases were combined and washed with saturated aqueous NaCl. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent to obtain the title compound ((6-(bicyclo[1.1.1]pentane-1-carboxamido)-4-((2-methoxy- 3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxy)zinc (122 mg, 65.2%). MS m/z (ESI): 436.2 [M+H] ⁺ .

Step 6: Preparation of 6-(bicyclo[1.1.1]pentan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl )amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

((6-(bicyclo[1.1.1]pentan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )pyridazine-3-carbonyl)oxy)zinc (94 mg, 0.2 mmol), deuterated methylamine hydrochloride (71 mg, 1.0 mmol) and DIPEA (258 mg, 2.0 mmol) were mixed in DMF (1 ml) followed by the addition of HATU (380 mg, 1.0 mmol), and the reaction solution was reacted at 40°C overnight. The reaction solution was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and CH ₂ Cl ₂ . The organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to obtain the title compound 6-(bicyclo[1.1.1]pentane-1-carboxamido)- 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide (41 mg , 45%).

^1H NMR (400 MHz, CDCl ₃ ) δ 2.17 (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, 1.3 Hz, 1H), 7.81 (dd, J=7.9, 1.4 Hz, 1H), 8.09-8.14 (m, 2H), 8.21 (s, 1H), 8.39 (s, 1H), 11.03 (s, 1H);

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 2 Receipt

4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(oxetane-3- carboxamido)pyridazine-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(oxetane-3- Carboxamido)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 442.2 [M+H] ⁺ .

Example 3 Receipt

6-(cyclobutanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazin- 3-carboxamide

6-(Cyclobutanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazin- 3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.85-2.05 (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), 7.26-7.33 (m, 1H), 7.55 (dd, J=7.0 Hz, 1H), 7.83 (dd, J=7.8, 1.1 Hz, 1H), 8.03-8.15 (m, 2H), 8.29 (s, 1H ), 9.18 (s, 1H), 11.06 (s, 1H);

MS m/z (ESI): 440.2 [M+H] ⁺ .

Example 4

Receipt

6-((1R,2R)-2-fluorocyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-((1R,2R)-2-Fluorocyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.18-1.28 (m, 1H), 1.88-2.06 (m, 2H), 3.81 (s, 3H), 4.01 ( s, 10 3H), 4.65-4.95 (m, 1H), 7.24-7.30 (m, 1H), 7.53 (dd, J=7.9, 1.3 Hz, 1H ), 7.81 (dd, J=7.9, 1.4 Hz, 1H), 8.02 (s, 1H), 8.11 (s, 1H), 8.27 (s, 1H), 9 .82 (s, 1H), 11.07 (s, 1H);

MS m/z (ESI): 444.2 [M+H] ⁺ .

Example 5 Receipt

4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((1S,2R )-2-ethylcyclopropane-1-carboxamido)pyridazine-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((1S,2R )-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 440.2 [M+H] ⁺ .

Example 6

Receipt

6-((3-cyclopropyloxetan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -(methyl-d ₃ )pyridazine-3-carboxamide

6-((3-Cyclopropyloxetan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 7

Receipt

4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((3-methyloxetane -3-yl)amino)pyridazin-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((3-methyloxetane -3-yl)amino)pyridazin-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 428.2 [M+H] ⁺ .

Example 8

Receipt

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-d ₃ )pyridazine-3-carboxamide

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-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 480.2 [M+H] ⁺ .

Example 9

Receipt

(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-d ₃ )pyridazine-3-carboxamide

(R)-6-((1-Cyutopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3- yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 480.2 [M+H] ⁺ .

Example 10

Receipt

(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-d ₃ )pyridazine-3-carboxamide

(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-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 480.2 [M+H] ⁺ .

Example 11

Receipt

4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((1,1 ,1-trifluoropropan-2-yl)amino)pyridazin-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((1,1 ,1-trifluoropropan-2-yl)amino)pyridazin-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 12 Preparation of (R)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )- 6-((1,1,1-trifluoropropan-2-yl)amino)pyridazin-3-carboxamide

(R)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-( (1,1,1-trifluoropropan-2-yl)amino)pyridazin-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 13

Receipt

(S)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-( (1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide

(S)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-( (1,1,1-trifluoropropan-2-yl)amino)pyridazin-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 14

Receipt

4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(1-methylcyclopropane- 1-carboxamido)pyridazine-3-carboxamide

Example 16

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(1-methylcyclopropane- 1-Carboxamido)pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 0.77-0.78 (m, 2H), 1.23-1.25 (m, 2H), 1.48 (s, 3H), 3.73 (s, 3H), 4.01 (s, 3H), 7.32 (t, J=8.0 Hz, 1H), 7.58 (dd, J=8.0, 1.2 Hz, 1H) , 7.68 (dd, J=8.0, 1.2 Hz, 1H), 8.18 (s, 1H), 8.47 (s, 1H);

MS m/z (ESI): 440.2 [M+H] ⁺ .

Example 15

Receipt

6-(1-cyanocyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d ₃ )pyridazine-3-carboxamide

6-(1-Cyanocyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d ₃ )pyridazine-3-carboxamide was prepared according to the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.20-1.31 (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, 1.2 Hz, 1H), 7.80 (dd, J=8.0, 1.2 Hz, 1H), 7.96 (s, 1H), 8.11 (s, 1H), 8.16 (br s, 1H), 9.00 (br s, 1H), 10.99 ( br s, 1H);

MS m/z (ESI): 451.2 [M+H] ⁺ .

Receipt

4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(1-(trifluoromethyl )cyclopropane-1-carboxamido)pyridazine-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-H-(methyl-d ₃ )-6-(1-(trifluoromethyl )cyclopropane-1-carboxamido)pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 1.28-1.38 (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, 1.2 Hz, 1H), 7.70 (dd, J=8.0 , 1.2 Hz, 1H), 8.12 (s, 1H), 8.48 (s, 1H);

MS m/z (ESI): 494.2 [M+H] ⁺ .

Example 17

Receipt

4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1-methoxycyclopropane-1-carboxamido)-N-(methyl -d ₃ )pyridazine-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1-methoxycyclopropane-1-carboxamido)-N-(methyl -d ₃ )pyridazine-3-carboxamide was prepared according to the method described in example 1.

MS m/z (ESI): 456.2 [M+H] ⁺ .

Example 18

Receipt

(S)-6-(2,2-dimethylcyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide

(S)-6-(2,2-Dimethylcyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 19

Receipt

(R)-6-(2,2-dimethylcyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide

(R)-6-(2,2-Dimethylcyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 20

Receipt

(R)-6-(2,2-difluoriotopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide

(R)-6-(2,2-Difluorotopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 462.2 [M+H] ⁺ .

Example 21

Receipt

(S)-6-(2,2-difluorocyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide

(S)-6-(2,2-Difluorotopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 462.2 [M+H] ⁺ .

Example 22

Receipt

6-(cyclopropanesulfonamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazin- 3-carboxamide

6-(Cyclopropanesulfonamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazin- 3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CD ₃ OD) δ 0.80-0.87 (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=8.20 Hz, 1H), 7.48 (dd, J=8.0, 1.2 Hz, 1H), 7.62 (dd, J=8.0, 1.2 Hz, 1H), 8.38 (s, 1H);

MS m/z (ESI): 462.2 [M+H] ⁺ .

Example 23

Receipt

N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d ₃ )carbamoyl)pyridazin- 3-yl)morpholine-4-carboxamide

N-(5-((2-Methoxy-3-(1-methyl-1H-l,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d ₃ )carbamoyl)pyridazin- 3-yl)morpholine-4-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 471.2 [M+H] ⁺ .

Example 24

Receipt

6-(3-cyclopropylureido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ ) pyridazine-3-carboxamide

6-(3-Cyclopropylureido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ ) Pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.64-0.66 (m, 2H), 0.82-0.87 (m, 2H), 2.71-2.73 (m, 1H), 3.79 (s, 3H), 4.01 (s, 3H), 7.23-7.27 (m, 1H), 7.45 (dd, J=8.0, 1.2 Hz, 1H) , 7.84 (dd, J=8.0, 1.2 Hz, 1H), 8.11 (s, 1H), 11.01 (brs, 1H);

MS m/z (ESI): 441.2 [M+H] ⁺ .

Example 25

Receipt

cyclopropyl-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d ₃ )carbamoyl)pyridazin- 3-yl)carbamate

Cyclopropyl-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d ₃ )carbamoyl)pyridazin- 3-yl)carbamate was prepared by the method described in example 1.

MS m/z (ESI): 442.2 [M+H] ⁺ .

Example 26

Receipt

6-(2-cyclopropylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ ) pyridazine-3-carboxamide

6-(2-Cyclopropylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ ) Pyridazine-3-carboxamide was prepared by the method described in example 1.

^1H NMR (400 MHz, CD ₃ OD) δ 0.24-0.28 (m, 2H), 0.57-0.61 (m, 2H), 1.12-1.15 (m, 1H) , 2.37 (d, J=8.0 Hz, 2H), 3.76 (s, 3H), 4.04 (s, 3H), 7.32 (t, J=8.0 Hz, 1H) , 7.64 (dd, J=8.0, 1.2 Hz, 1H), 7.70 (dd, J=8.0, 1.2 Hz, 1H), 8.20 (s, 1H), 8.50(s, 1H);

MS m/z (ESI): 440.2 [M+H] ⁺ .

Example 27

Receipt

(E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxycyclopropanecarboximidamido)-N-( methyl-d ₃ )pyridazine-3-carboxamide

(E)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxycyclopropanecarboximidamido)-N-( Methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 455.2 [M+H] ⁺ .

Example 28

Receipt

(E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyacetimidamido)-N-( methyl-d ₃ )pyridazine-3-carboxamide

(E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyace thymidamido)-N- (methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 429.2 [M+H] ⁺ .

Example 29

Receipt

(Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyciutopropanecarboximidamido)-N-( methyl-d ₃ )pyridazine-3-carboxamide

(Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxycyclopropanecarboximidamido)-N-( Methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 455.2 [M+H] ⁺ .

Example 30

Receipt

(Z)-4-((2-methoxy-3-(1-methyl-1H-l,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyacetimidamido)-N-( methyl-d ₃ )pyridazine-3-carboxamide

(Z)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methoxyacetimidamido)-N-( Methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 429.2 [M+H] ⁺ .

Example 31

Receipt

(E)-6-(N'-cyanocyclopropanecarboximimido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( methyl-d ₃ )pyridazine-3-carboxamide

(E)-6-(N'-Cyanocyclopropanecarboximimido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 32

Receipt

(E)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( methyl-d ₃ )pyridazine-3-carboxamide

(E)-6-(N'-Cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 424.2 [M+H] ⁺ .

Example 33

Receipt

(Z)-6-(N'-cyanocyclopropanecarboximimido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( methyl-d ₃ )pyridazine-3-carboxamide

(Z)-6-(N'-Cyanocyclopropanecarboximimido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 34

Receipt

(Z)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( methyl-d ₃ )pyridazine-3-carboxamide

(Z)-6-(N'-Cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 424.2 [M+H] ⁺ .

Example 35

Receipt

6-((cyclopropylidenefluoromethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-((Cyclopropylidenefluoromethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 428.2 [M+H] ⁺ .

Example 36

Receipt

(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-d ₃ )pyridazine-3-carboxamide

(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-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 416.2 [M+H] ⁺ .

Example 37

Receipt

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-d ₃ )pyridazine-3-carboxamide

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-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 478.2 [M+H] ⁺ .

Example 38

Receipt

(E)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-( (1,1,1-trifluorobut-2-en-2-yl)amino)pyridazine-3-carboxamide

(E)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-( (1,1,1-trifluorobut-2-en-2-yl)amino)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 466.2 [M+H] ⁺ .

Example 39

Receipt

6-((1-cyclopropylidene-2,2-difluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d ₃ )pyridazine-3-carboxamide

6-((1-Cyclopropylidene-2,2-difluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 460.2 [M+H] ⁺ .

Example 40

Receipt

(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-d ₃ )pyridazine-3-carboxamide

(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-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 448.2 [M+H] ⁺ .

Example 41

Receipt

4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((1-methylcyclopropyl )amino)pyridazine-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((1-methylcyclopropyl )Amino)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 412.2 [M+H] ⁺ .

Example 42

6-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl )phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

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-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 43

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(5-methyl- 4H-1,2,4-triazol-3-yl)pyridazin-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(5-methyl- 4H-1,2,4-triazol-3-yl)pyridazin-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 424.2 [M+H] ⁺ .

Example 44

6-(5-Cyclopropyl-1H-imidazol-2-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(5-Cyclopropyl-1H-imidazol-2-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 449.2 [M+H] ⁺ .

Example 45

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(5-methyl- 1H-imidazol-2-yl)pyridazin-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(5-methyl- 1H-imidazol-2-yl)pyridazin-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 423.2 [M+H] ⁺ .

Example 46

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(pyridin-2- sulfonamido)pyridazine-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-(pyridin-2- Sulfonamido)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 499.2 [M+H] ⁺ .

Example 47

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((1-methyl -1H-pyrazole)-3-sulfonamido)pyridazine-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-6-((1-methyl -1H-pyrazole)-3-sulfonamido)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 502.2 [M+H] ⁺ .

Example 48

6-(Cyclopropanecarboxamido)-4-((2-(dimethylamino)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ ) pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-(dimethylamino)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-(d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 439.2 [M+H] ⁺ .

Example 49

6-(Cyclopropanecarboxamido)-N-(methyl-(d ₃ )-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methylthio)phenyl)amino )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-N-(methyl-(d ₃ )-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methylthio)phenyl)amino )pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.87-0.92 (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);

MS m/z (ESI): 442.2 [M+H] ⁺ .

Example 50

6-(Cyclopropanecarboxamido)-N-(methyl-(d ₃ )-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-N-(methyl-(d ₃ )-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 480.2 [M+H] ⁺ .

Example 51

6-(Cyclopropanecarboxamido)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ ) pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-(difluoromethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-(d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

^1H NMR (400 MHz, CDCl ₃ ) δ 0.85-0.99 (m, 2H), 1.03-1.12 (m, 2H), 1.73-1.81 (m, 1H), 4.00 (s, 3H), 6.63-7.01 (m, 1H), 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);

MS m/z (ESI): 462.2 [M+H] ⁺ .

Example 52

6-(Cyclopropanecarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.84-0.95 (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) ;

MS m/z (ESI): 444.2 [M+H] ⁺ .

Example 53

6-(Cyclopropanecarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.94 (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);

MS m/z (ESI): 444.2 [M+H] ⁺ .

Example 54

6-(Cyclopropanecarboxamido)-4-((4-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((4-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 444.2 [M+H] ⁺ .

Example 55

4-((6-Cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3-carboxamide

4-((6-Cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 451.2 [M+H] ⁺ .

Example 56

4-((5-Cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3-carboxamide

4-((5-Cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 451.2 [M+H] ⁺ .

Example 57

4-((4-Cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3-carboxamide

4-((4-Cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 451.2 [M+H] ⁺ .

Example 58

6-(Cyclopropanecarboxamido)-4-((3-(1-ciu1opropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazin-3 -carboxamide

Step 1: Preparation of 2-methoxy-3-nitrobenzamide

Methyl 2-methoxy-3-nitrobenzoate (5 g, 23.7 mmol) was dissolved in a solution of ammonia in methanol (100 ml, 7 M) at room temperature, followed by the addition of aqueous ammonia solution (28 wt.%, 50 ml). The resulting mixture was stirred overnight at room temperature, diluted with ethyl acetate (300 ml), and then the organic phase was washed successively with saturated aqueous NaHCO ₃ (300 ml x 2) and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to obtain the title compound 2-methoxy-3-nitrobenzamide (4.3 g, 92%).

MS m/z (ESI): 197.1 [M+H] ⁺ .

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

2-Methoxy-3-nitrobenzamide (4.2 g, 21.4 mmol) was dissolved in DMF-DMA (28.6 ml) and the resulting solution was heated to 95°C for 1 hour and concentrated under reduced pressure to give the crude DMF-DMA adduct, which was dissolved in ethanol (20 ml) for further use. Ethanol (70 mL) and acetic acid (21 mL) were added to the reaction flask in an ice bath, and the resulting solution was stirred for 5 minutes. Hydrazine hydrate (80 wt %, 10.5 ml) was slowly added dropwise and the resulting solution was stirred for 15 minutes, followed by the dropwise addition of a solution of the above crude DMF-DMA adduct in ethanol. The reaction solution was slowly warmed to room temperature and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (300 ml). The organic phase was washed successively with saturated aqueous NaHCO ₃ (300 ml×2) and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then purified by column chromatography to obtain the title compound 3-(2-methoxy-3-nitrophenyl )-1H-1,2,4-triazole (4.5 g, 95%).

MS m/z (ESI): 221.1 [M+H] ⁺ .

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

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) followed by the addition of cyclopropylboronic acid (234 mg, 2.72 mmol) at room temperature. The reaction solution was heated to 85°C and stirred overnight. The reaction solution was cooled to room temperature and diluted with more ethyl acetate. The organic phase was washed several times with saturated brine, separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to give the title compound 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl )-1H-1,2,4-triazole (125 mg, 53%).

^1H NMR (400 MHz, CDCl ₃ ) δ 1.15-1.21 (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);

MS m/z (ESI): 261.1 [M+H] ⁺ .

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

Pd/C (30 mg) was added to the solution

1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (120 mg, 0.46 mmol) in methanol (5 ml). The reaction solution was reacted under a hydrogen atmosphere at normal temperature and normal pressure for 12 hours, and then filtered through diatomaceous earth to remove the catalyst. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the title compound 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (102 mg), which was immediately used for next stage.

MS m/z (ESI): 231.1 [M+H] ⁺ .

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

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 solution was cooled to room temperature, then water (3 ml) was added and stirred for 1 hour. The reaction solution was filtered, the filter cake was washed with water (3 ml×2) and THF (2 ml), collected and dried to obtain the title compound 6-chloro-4-((3-(1-cyclopropyl-1H-1,2 Zinc ,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate (130 mg, 78%).

MS m/z (ESI): 387.1 [M+H] ⁺ .

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

Zinc 6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate (130 mg, 0.31 mmol ), cyclopropanamide (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) followed by the addition of palladium acetate (4.5 mg, 0.02 mmol) and (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (22 mg, 0.04 mmol). The reaction system was purged with nitrogen three times and heated to 75°C overnight. The reaction solution was cooled to room temperature, then water (4 ml) and acetic acid (2 ml) were added and washed with petroleum ether (6 ml×2). The aqueous phase was separated, then water (2 ml) was added and extracted with CH ₂ Cl ₂ (5 ml×3). The organic phases were combined and washed with saturated aqueous NaCl. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent to obtain the title compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazole Zinc -3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate (109 mg, 75%).

MS m/z (ESI): 436.1 [M+H] ⁺ .

Step 7: Preparation of 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

Zinc 6-(Cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate (90 mg, 0. 19 mmol), declared methylamine hydrochloride (71 mg, 1.0 mmol) and DIPEA (258 mg, 2.0 mmol) were mixed in DMF (1 ml) followed by the addition of HATU (380 mg, 1.0 mmol), and the reaction the solution was reacted at 50°C overnight. The reaction solution was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and CH ₂ Cl ₂ . The organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to obtain the title compound 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl -1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide (35 mg, 38%).

^1H NMR (400 MHz, CDCl ₃ ) δ 0.86-0.99 (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);

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 59

6-(Cyclopropanecarboxamido)-4-((3-(1-isopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazin-3 -carboxamide

6-(Cyclopropanecarboxamido)-4-((3-(1-isopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazin-3 -carboxamide was prepared by the method described in example 58.

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 60

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(oxetan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(oxetan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -(d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 58.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90-0.96 (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);

MS m/z (ESI): 468.2 [M+H] ⁺ .

Example 61

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-( d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 58.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.80-0.95 (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=7.6 Hz, 1H), 7.82 (dd, J=7.7 Hz, 1H), 8.02 (s, 1H), 8.17-8.30 (m, 2H ), 10.14 (s, 1H), 11.06 (s, 1H);

MS m/z (ESI): 470.2 [M+H] ⁺ .

Example 62

4-((3-(1-(2-Cyanoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3-carboxamide

4-((3-(1-(2-Cyanoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 58.

^1H NMR (400 MHz, CDCl ₃ ) δ 0.86-0.94 (m, 2H), 1.07-1.12 (m, 2H), 1.22-1.26 (m, 2H), 1.74-1.80 (m, 1H), 3.08 (t, J=8.0 Hz, 2H), 3.81 (s, 3H), 4.53 (t, J=8.0 Hz , 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);

MS m/z (ESI): 465.2 [M+H] ⁺ .

Example 63

6-(Cyclopropanecarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methoxyphenyl)amino)- N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)-2-methoxyphenyl)amino)- N-(methyl-(d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90-0.95 (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);

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 64

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazin- 3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazin- 3-carboxamide was prepared by the method described in example 1.

^1H NMR (400 MHz, CDCl ₃ ) δ 0.94-1.02 (m, 2H), 1.07-1.11 (m, 2H), 1.76-1.84 (m, 1H), 3.48 (s, 3H), 3.83 (s, 3H), 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);

MS m/z (ESI): 426.2 [M+H] ⁺ .

Example 65

6-(Cyclopropanecarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methoxyphenyl)amino)- N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methoxyphenyl)amino)- N-(methyl-(d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91-0.97 (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, 2H), 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);

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 66

6-(Cyclopropanecarboxamido)-4-((3-(5-fluoro-1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((3-(5-fluoro-1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 444.2 [M+H] ⁺ .

Example 67

6-(Cyclopropanecarboxamido)-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 444.2 [M+H] ⁺ .

Example 68

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-methyl-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-methyl-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 440.2 [M+H] ⁺ .

Example 69

5-Cyano-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

5-Cyano-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-( d ₃ )pyridazine-3-carboxamide was prepared according to the method described in example 1.

MS m/z (ESI): 451.2 [M+H] ⁺ .

Example 70

N-(6-(1H-Imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin- 3-yl)cyclopropanecarboxamide

N-(6-(1H-Imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin- 3-yl)cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 432.2 [M+H] ⁺ .

Example 71

N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(4H-1,2,4-triazol- 3-yl)pyridazin-3-yl)cyclopropanecarboxamide

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)cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 433.2 [M+H] ⁺ .

Example 72

N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1H-tetrazol-5-yl)pyridazin- 3-yl)cyclopropanecarboxamide

N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1H-tetrazol-5-yl)pyridazin- 3-yl)cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 434.2 [M+H] ⁺ .

Example 73

N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl-1H-imidazol-2- yl)pyridazin-3-yl)cyclopropanecarboxamide

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)cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 446.2 [M+H] ⁺ .

Example 74

N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl-4H-1,2, 4-triazol-3-yl)pyridazin-3-yl)cyclopropanecarboxamide

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)cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 447.2 [M+H] ⁺ .

Example 75

N-(6-(5-Cyclopropyl-1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) amino)pyridazin-3-yl)cyclopropanecarboxamide

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)cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 472.2 [M+H] ⁺ .

Example 76

N-(6-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol- 3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanecarboxamide

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)cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 473.2 [M+H] ⁺ .

Example 77

N ⁶ -Cyclopropyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N ³ -(methyl-d ₃ )pyridazin- 3,6-dicarboxamide

N ⁶ -Cyclopropyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N ³ -(methyl-d ₃ )pyridazin- 3,6-dicarboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.67-0.72 (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);

MS m/z (ESI): 426.2 [M+H] ⁺ .

Example 78

N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N-(methyl-(d ₃ )sulfamoyl )pyridazin-3-yl)cyclopropanecarboxamide

N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(H-(methyl-(d ₃ )sulfamoyl )pyridazin-3-yl)cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 462.2 [M+H] ⁺ .

Example 79

N-(6-(Hydroxymethyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanecarboxamide

N-(6-(Hydroxymethyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanecarboxamide was prepared in the manner described in example 1.

MS m/z (ESI): 396.2 [M+H] ⁺ .

Example 80

N-(6-(2-Hydroxyacetyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl) cyclopropanecarboxamide

N-(6-(2-Hydroxyacetyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl) Cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 424.2 [M+H] ⁺ .

Example 81

2-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyrimidin- 5-carboxamide

2-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyrimidin- 5-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 426.2 [M+H] ⁺ .

Example 82

3-(Cyclopropanecarboxamido)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-1 ,2,4-triazine-6-carboxamide

3-(Cyclopropanecarboxamido)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )-1 ,2,4-triazine-6-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 427.2 [M+H] ⁺ .

Example 83

6-Methoxy-N ² -(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N ⁴ -(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

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 was prepared by the method described in example 1.

MS m/z (ESI): 408.2 [M+H] ⁺ .

Example 84

2-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyrimidine-5-carboxamide

2-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyrimidine-5-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.76-0.95 (m, 4H), 2.09-2.21 (m, 1H), 2.82 (d, J=4.4 Hz, 3H), 3.80 (s, 3H), 3.95 (s, 3H), 7.15 (t, J=8.1 Hz, 1H), 7.49 (dd, J=7.8 , 1.6 Hz, 1H), 8.55 (s, 1H), 8.67 (d, J=4.7 Hz, 1H), 8.75 (s, 1H), 10.92 (s, 1H ), 11.90 (s, 1H);

MS m/z (ESI): 423.2 [M+H] ⁺ .

Example 85

N-(4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(N-methylsulfamoyl)pyridin-2-yl) cyclopropanecarboxamide

N-(4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(N-methylsulfamoyl)pyridin-2-yl) Cyclopropanecarboxamide was prepared by the method described in example 1.

MS m/z (ESI): 458.2 [M+H] ⁺ .

Example 86

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

3-(Cyclopropanecarboxamido)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methyl-1,2,4- triazine-6-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 424.2 [M+H] ⁺ .

Example 87

6-(2-Cyclopropyl-2-oxoacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d ₃ )pyridazine-3-carboxamide

6-(2-Cyclopropyl-2-oxoacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d ₃ )pyridazine-3-carboxamide was prepared according to the method described in example 1.

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 88

6-(Cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

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

5-Fluoro-2-methoxybenzamide (3.5 g, 20.7 mmol) was dissolved in DMF-DMA (25 ml) and the resulting solution was heated to 95°C for 1 hour and concentrated under reduced pressure to give the crude addition product DMF-DMA, which was dissolved in ethanol (20 ml) for further use. Ethanol (56 mL) and acetic acid (17 mL) were added to the reaction flask in an ice bath, and the resulting solution was stirred for 5 minutes. Hydrazine hydrate (80 wt.%, 8.4 ml) was added dropwise and the resulting solution was stirred for 15 minutes, followed by the dropwise addition of a solution of the above crude DMF-DMA adduct in ethanol. The reaction solution was slowly warmed to room temperature and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (300 ml) and washed with saturated aqueous NaHCO ₃ solution (300 ml×2). The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then purified by column chromatography to obtain the title compound 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (3.1 g, 77%).

MS m/z (ESI): 194.2 [M+H] ⁺ .

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

3-(5-Fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (1.1 g, 5.69 mmol) was dissolved in concentrated sulfuric acid (10 ml) followed by dropwise addition of nitric acid (68 wt.%, 1.05 g, 11.39 mmol) in an ice bath. After addition was completed, the reaction solution was stirred for 2 hours in an ice bath. The reaction solution was poured into ice water, and an aqueous ammonia solution was slowly added dropwise to adjust the pH to approximately 9. The reaction solution was extracted with ethyl acetate, and the organic phase was separated, dried, concentrated under reduced pressure to remove the organic solvent, and then the crude title compound was obtained. 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.26 g), which was immediately used in the next step.

MS m/z (ESI): 239.2 [M+H] ⁺ .

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

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) followed by the addition of cyclopropylboronic acid (865 mg, 10.0 mmol) at room temperature. The reaction solution was heated to 85°C and stirred overnight. The reaction solution was cooled to room temperature and diluted with more ethyl acetate. The organic phase was washed several times with saturated brine, separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to give the title compound 1-cyclopropyl-3-(5-fluoro-2-methoxy -3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 38%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.16-1.20 (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, W);

MS m/z (ESI): 279.0 [M+H] ⁺ .

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

Pd/C (60 mg) was added to a solution of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 0.93 mmol) in methanol (5 ml). The reaction solution was reacted under a hydrogen atmosphere at normal temperature and normal pressure for 8 hours, and then filtered through diatomaceous earth to remove the catalyst. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the title compound 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (230 mg), which immediately used in the next step.

MS m/z (ESI): 249.2 [M+H] ⁺ .

Step 5: Preparation of 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl- d ₃ )pyridazine-3-carboxamide

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

MS m/z (ESI): 421.2 [M+H] ⁺ .

Step 6: Preparation of 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-( methyl-d ₃ )pyridazine-3-carboxamide

6-Chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d ₃ )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) followed by the addition of tris(dibenzylideneacetone) dipalladium (101 mg, 0.11 mmol) and 4,5-(bisdiphenylphosphino)-9,9-dimethylxanthene (127 mg, 0.22 mmol). The reaction solution was purged with nitrogen for 5 minutes and reacted in a microwave oven at 145°C for 2 hours. The reaction solution was diluted with dichloromethane. The organic phase was washed several times with saturated brine, separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to give the title compound 6-(cyclopropanecarboxamido)-4-((3-(1 -cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide (116 mg, 67%).

^1H NMR (400 MHz, CDCl ₃ ) δ 0.90-0.95 (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);

MS m/z (ESI): 470.2 [M+H] ⁺ .

Example 89

6-(Cyclopropanecarboxamido)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 440.2 [M+H] ⁺ .

Example 90

6-(Cyclopropanecarboxamido)-4-((2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazin- 3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d ₃ )pyridazin- 3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.86-0.93 (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);

MS m/z (ESI): 414.2 [M+H] ⁺ .

Example 91

4-((3-(1-Allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d ₃ )pyridazine-3 -carboxamide

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

A solution of SEM-Cl (0.964 ml, 5.45 mmol) in dichloromethane (10 ml) was slowly added dropwise to a 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) in dichloromethane (20 ml) at -20°C. After addition was complete, the reaction solution was slowly warmed to -10°C and stirred at this temperature overnight. The reaction solution was washed with saturated brine. The organic phase was separated, dried, filtered and then concentrated under reduced pressure to remove the organic solvent and obtain the crude product, 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- 1,2,4-triazole, which was immediately used in the next step.

MS m/z (ESI): 351.2 [M+H] ⁺ .

Stage 2: receiving

2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

The above crude product was dissolved in a mixture of ethanol (30 ml) and water (5 ml). Solid ammonium chloride (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added sequentially. The reaction solution was stirred at 50°C for 2 hours, then cooled and filtered through diatomaceous earth to remove insoluble matter. The filtrate was concentrated, the residue was dissolved in dichloromethane, and the resulting solution was washed with saturated brine. The organic phase was separated, dried over drying agent, filtered, concentrated under reduced pressure to remove the organic solvent and purified by column chromatography to give the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -1,2,4-triazol-3-yl)aniline (650 mg, yield for two steps: 45%).

MS m/z (ESI): 321.2 [M+H] ⁺ .

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-d ₃ )pyridazine-3-carboxamide

LiHMDS (1 M in THF, 5.00 ml) was added dropwise to a solution of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3- yl)aniline (640 mg, 2.00 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417 mg, 2.00 mmol) in THF (20 ml) at 0°C . After addition was completed, the reaction solution was slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction in the solution was stopped with saturated brine and the solution was extracted twice with DCM. The organic phases were combined, dried, concentrated under reduced pressure to remove the organic solvent and purified by column chromatography to give the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy) methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

MS m/z (ESI): 493.2 [M+H] ⁺ .

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

6-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), cyclopropanamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4- dioxane (20 ml). The reaction solution was purged with nitrogen for 5 minutes. Pd ₂ (dba) ₃ (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. The reaction solution was heated to 130°C in a microwave oven for 90 minutes under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to give the title compound 6-(cyclopropanecarboxamido)-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%).

MS m/z (ESI): 542.3 [M+H] ⁺ .

Step 5: Preparation of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3 -carboxamide

TFA (6.0 ml) was added to a solution of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole -3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol) in DCM at 0°C. The reaction solution was stirred at room temperature overnight. The next day, the reaction solution was concentrated under reduced pressure to remove the organic solvent. The residue was dissolved in DCM and the resulting solution was washed successively with saturated aqueous sodium bicarbonate and saturated brine. The organic phase was dried, concentrated under reduced pressure and purified by column chromatography to give the title compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl )amino)-N-(methyl-d3)pyridazine-3-carboxamide (270 mg, 57%).

^1H NMR (400 MHz, CDCl ₃ ) δ 0.99-1.03 (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);

MS m/z (ESI): 412.2 [M+H] ⁺ .

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

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

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.92 (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=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 8.03 (s, 1H ), 8.15 (s, 1H), 8.24 (s, 1H), 9.88 (br s, 1H), 11.05 (s, 1H);

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 92

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-in-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide

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

A solution of SEM-Cl (0.964 ml, 5.45 mmol) in dichloromethane (10 ml) was slowly added dropwise to a 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) in dichloromethane (20 ml) at -20°C. After addition was complete, the reaction solution was slowly warmed to -10°C and stirred at this temperature overnight. The reaction solution was washed with saturated brine. The organic phase was separated, dried, filtered and then concentrated under reduced pressure to remove the organic solvent and obtain the crude product, 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- 1,2,4-triazole, which was immediately used in the next step.

MS m/z (ESI): 351.2 [M+H] ⁺ .

Step 2: preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

The above crude product was dissolved in a mixture of ethanol (30 ml) and water (5 ml). Solid ammonium chloride (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added sequentially. The reaction solution was stirred at 50°C for 2 hours, then cooled and filtered through diatomaceous earth to remove insoluble matter. The filtrate was concentrated, the residue was dissolved in dichloromethane, and the resulting solution was washed with saturated brine. The organic phase was separated, dried over drying agent, filtered, concentrated under reduced pressure to remove the organic solvent and purified by column chromatography to give the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -1,2,4-triazol-3-yl)aniline (650 mg, yield for two steps: 45%).

MS m/z (ESI): 321.2 [M+H] ⁺ .

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

LiHMDS (1 M in TTP, 5.00 ml) was added dropwise to a solution of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3- yl)aniline (640 mg, 2.00 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417 mg, 2.00 mmol) in THF (20 ml) at 0°C . After addition was completed, the reaction solution was slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction in the solution was stopped with saturated brine and the solution was extracted twice with DCM. The organic phases were combined, dried, concentrated under reduced pressure to remove the organic solvent and purified by column chromatography to give the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy) methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

MS m/z (ESI): 493.2 [M+H] ⁺ .

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

6-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), cyclopropanamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4- dioxane (20 ml). The reaction solution was purged with nitrogen for 5 minutes. Pd ₂ (dba) ₃ (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. The reaction solution was heated to 130°C under microwave irradiation for 90 minutes under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography to give the title compound 6-(cyclopropanecarboxamido)-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%).

MS m/z (ESI): 542.3 [M+H] ⁺ .

Step 5: Preparation of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3 -carboxamide

TFA (6.0 ml) was added to a solution of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole -3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol) in DCM (20 ml) at 0°C. The reaction solution was stirred at room temperature overnight. The next day, the reaction solution was concentrated under reduced pressure to remove the organic solvent. The residue was dissolved in DCM and the resulting solution was washed successively with saturated aqueous sodium bicarbonate and saturated brine. The organic phase was dried, concentrated under reduced pressure and purified by column chromatography to give the title compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl )amino)-N-(methyl-d3)pyridazine-3-carboxamide (270 mg, 57%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.99-1.03 (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);

MS m/z (ESI): 412.2 [M+H] ⁺ .

Step 6: Preparation of 6-(cyclopropanecarboxamido)-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

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (30 mg, 0.073 mmol), bromopropine (8.7 mg, 0.073 mmol) and potassium carbonate (20 mg, 0.15 mmol) were mixed in MeCN (3 ml). The reaction solution was stirred at 0°C for 2 days. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain the title compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1 ,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (10 mg, 31%).

^1H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.93 (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, 2H), 7.26-7.30 (m, 1H), 7.52 (d, J=8, 0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 8.23 (s, 1H), 8.38 (s, 1H), 9 .88 (br s, 1H), 11.13 (s, 1H);

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 93

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

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1 -(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N- (methyl-d3)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 494.2 [M+H] ⁺ .

Example 94

4-((3-(1-(Tret-butyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3) pyridazine-3-carboxamide

4-((3-(1-(Tret-butyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3) Pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 468.2 [M+H] ⁺ .

Example 95

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-3-yl ))phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1,2,4-triazol-3-yl ))phenyl)amino)-N-(methyl-(d3)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 522.2 [M+H] ⁺ .

Example 96

4-((3-(1-(Bicyclo[1.1.1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido) -H-(methyl-d3)pyridazine-3-carboxamide

4-((3-(1-(Bicyuto[1.1.1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido) -N-(methyl-d3)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 478.2 [M+H] ⁺ .

Example 97

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(thietan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d3)pyridazine-3-carboxamide

6-(Cyyutopropanecarboxamido)-4-((2-methoxy-3-(1-(thietan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d3)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 484.2 [M+H] ⁺ .

Example 98

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(3-methyloxetan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N- (methyl-d3)pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(3-methyloxetan-3-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N- (methyl-(d3)pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91-0.93 (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=6.6 Hz, 2H), 5.25 (d, J=6.4 Hz, 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);

MS m/z (ESI): 482.2 [M+H] ⁺ .

Example 99

6-(Cyclopropanecarbothioamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3 -carboxamide

6-(Cyclopropanecarbothioamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3 -carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 442.2 [M+H] ⁺ .

Example 100

6-(Cyclopropanecarboxamido)-4-((2-(dimethylphosphoryl)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine -3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-(dimethylphosphoryl)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine -3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 472.2 [M+H] ⁺ .

Example 101

6-(Cyclopropanecarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methylsulfonyl)phenyl)amino)pyridazine -3-carboxamide

6-(Cyclopropanecarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(methylsulfonyl)phenyl)amino)pyridazine -3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 474.2 [M+H] ⁺ .

Example 102

4-((3-(1-(Cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazin- 3-carboxamide

4-((3-(1-(Cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazin- 3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 451.2 [M+H] ⁺ .

Example 103

4-((3-(1-(Bicyclo[1.1.1]pentan-1-ylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido) -N-(methyl-d3)pyridazine-3-carboxamide

4-((3-(1-(Bicyclo[1.1.1]pentan-1-ylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido) -N-(methyl-d3)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 492.2 [M+H] ⁺ .

Example 104

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(oxetan-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d3)pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(oxetan-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d3)pyridazine-3-carboxamide was prepared by the method described in example 92.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91-0.94 (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, 2H), 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);

MS m/z (ESI): 482.2 [M+H] ⁺ .

Example 105

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(4-oxo-5 -azaspiro[2.4]heptan-5-yl)pyridazin-3-carboxamide

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(4-oxo-5 -azaspiro[2.4]heptan-5-yl)pyridazin-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 106

6-((Cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( methyl-d3)pyridazine-3-carboxamide

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 was prepared by the method described in example 1.

MS m/z (ESI): 437.2 [M+H] ⁺ .

Example 107

(R)-6-((Cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d3)pyridazine-3-carboxamide

(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 was prepared by the method described in example 1.

MS m/z (ESI): 437.2 [M+H] ⁺ .

Example 108

(S)-6-((Cyano(ciutopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d3)pyridazine-3-carboxamide

(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 was prepared by the method described in example 1.

MS m/z (ESI): 437.2 [M+H] ⁺ .

Example 109

6-(1-Fluorocyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d3)pyridazine-3-carboxamide

6-(1-Fluorocyclopropan-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl -d3)pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38-1.50 (m, 4H), 3.81 (s, 3H), 4.00 (s, 3H), 7.23-7.29 ( m, 1H), 7.49 (dd, J=7.9, 1.4 Hz, 1H), 7.81 (dd, J=7.9, 1.5 Hz, 1H), 8.09-8 .22 (m, 3H), 9.09 (s, 1H), 11.00 (s, 1H);

MS m/z (ESI): 444.2 [M+H] ⁺ .

Example 110

4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-((3-vinyloxetane- 3-yl)amino)pyridazine-3-carboxamide

4-((2-Methoxy-3-(1-methyl-2,4-triazol-3-yl)phenyl)amino)-M-(methyl-d3)-6-((3-vinyloxetan-3-yl) amino)pyridazine-3-carboxamide was prepared by the method described in example 1.

MS m/z (ESI): 440.2 [M+H] ⁺ .

Example 111

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

6-((3-Ethynoxetan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -(methyl-d3)pyridazine-3-carboxamide was prepared as described in example 1.

MS m/z (ESI): 438.2 [M+H] ⁺ .

Example 112

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

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

A solution of SEM-Cl (0.964 ml, 5.45 mmol) in dichloromethane (10 ml) was slowly added dropwise to a 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) in dichloromethane (20 ml) at -20°C. After addition was complete, the reaction solution was slowly warmed to -10°C and stirred at this temperature overnight. The reaction solution was washed with saturated brine. The organic phase was separated, dried, filtered and then concentrated under reduced pressure to remove the organic solvent and obtain the crude product, 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- 1,2,4-triazole, which was immediately used in the next step.

MS m/z (ESI): 351.2 [M+H] ⁺ .

Step 2: preparation of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline

The above crude product was dissolved in a mixture of ethanol (30 ml) and water (5 ml). Solid ammonium chloride (1.60 g, 30.0 mmol) and reduced iron powder (1.67 g, 30.0 mmol) were added sequentially. The reaction solution was stirred at 50°C for 2 hours, then cooled and filtered through diatomaceous earth to remove insoluble matter. The filtrate was concentrated, the residue was dissolved in dichloromethane, and the resulting solution was washed with saturated brine. The organic phase was separated, dried over drying agent, filtered, concentrated under reduced pressure to remove the organic solvent and purified by column chromatography to give the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H -1,2,4-triazol-3-yl)aniline (650 mg, yield for two steps: 45%).

MS m/z (ESI): 321.2 [M+H] ⁺ .

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

LiHMDS (1 M in THF, 5.00 ml) was added dropwise to a solution of 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3- yl)aniline (640 mg, 2.00 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417 mg, 2.00 mmol) in THF (20 ml) at 0°C . After addition was completed, the reaction solution was slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction in solution was stopped with saturated brine and extracted twice with DCM. The organic phases were combined, dried, concentrated under reduced pressure to remove the organic solvent and purified by column chromatography to give the title compound 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy) methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (780 mg, 79%).

MS m/z (ESI): 493.2 [M+H] ⁺ .

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

6-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), cyclopropanamide (372 mg, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were mixed in 1,4- dioxane (20 ml). The reaction solution was purged with nitrogen for 5 minutes. Pd ₂ (dba) ₃ (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. The reaction solution was reacted at 130°C under microwave irradiation for 90 minutes under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to obtain the title compound 6-(cyclopropanecarboxamido)-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%).

MS m/z (ESI): 542.3 [M+H] ⁺ .

Step 5: Preparation of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3 -carboxamide

TFA (6.0 ml) was added to a solution of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole -3-yl)phenyl)amino)-N-(methyl-d3)pyridazin-3-carboxamide (630 mg, 1.16 mmol) in DCM at 0°C. The reaction solution was stirred at room temperature overnight. The next day, the reaction solution was concentrated under reduced pressure to remove the organic solvent. The residue was dissolved in DCM and the resulting solution was washed successively with saturated aqueous sodium bicarbonate and saturated brine. The organic phase was dried, concentrated under reduced pressure and purified by column chromatography to give the title compound 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl )amino)-N-(methyl-d3)pyridazine-3-carboxamide (270 mg, 57%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.99-1.03 (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);

MS m/z (ESI): 412.2 [M+H] ⁺ .

Example 113

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazin-3-carboxamide was prepared by the method described in the example 1.

^1H NMR (400 MHz, DMSO) δ 0.79-0.86 (m, 4H), 2.04-2.12 (m, 1H), 3.71 (s, 3H), 3.95 (s , 3H), 7.24-7.25 (m, 1H), 7.49-7.52 (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);

MS m/z (ESI): 409.2 [M+H] ⁺ .

Example 114

6-(Cyclopropanecarboxamido)-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

6-(Cyclopropanecarboxamido)-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 was prepared by the method described in example 92.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.84-0.87 (m, 2H), 1.23-1.34 (m, 2H), 2.09-2.12 (m, 1H ), 3.60 (s, 1H), 3.75 (s, 3H), 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);

MS m/z (ESI): 468.2 [M+H] ⁺ .

Example 115

6-(Cyclopropanecarboxamido)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazin- 3-carboxamide

6-(Cyclopropanecarboxamido)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazin- 3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.44-0.48 (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=7.2 Hz, 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);

MS m/z (ESI): 466.2 [M+H] ⁺ .

Example 116

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-in-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-in-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide was prepared in the manner described in Example 92, and Example 116 was one of the products of Step 6.

^1H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.93 (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=6.4 Hz, 2H), 7.26-7.36 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 8.12 (s, 1H), 9.64 (br s, 1H), 11.07 (s, 1H);

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 117

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

6-(Cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3) Pyridazine-3-carboxamide was prepared by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) 5 0.93-1.02 (m, 4H), 1.05-1.11 (m, 4H), 1.75-1.82 (m, 1H), 3.48 (s, 3H), 3.61-3.70 (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);

MS m/z (ESI): 470.1 [M+H] ⁺ .

Example 118

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(4-(prop-2-in-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(4-(prop-2-in-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide was prepared by the method described in Example 92, and Example 118 was one of the products of Step 6.

^1H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.93 (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=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 8.20 (s, 1H), 8.29 (s, 1H), 9.10 (br s, 1H), 11.07 (s, 1H);

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 119

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-in-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d3)nicotinamide

6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(prop-2-in-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)- N-(methyl-d3)nicotinamide was prepared by the method described in example 92.

^1H NMR (400 MHz, DMSO- _d6 ) δ 0.88-0.91 (m, 2H), 1.03-1.09 (m, 2H), 1.55-1.65 (m, 1H ), 3.81 (s, 3H), 5.06 (s, 2H), 6.79 (s, 1H), 7.26-7.77 (m, 2H), 8.06-8.37 ( m, 3H), 9.01 (br s, 1H), 10.63 (br s, 1H);

MS m/z (ESI): 449.2 [M+H] ⁺ .

Example 120

6-(Cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide

6-(Cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)nicotinamide was prepared by the method described in example 1.

^1H NMR (400 MHz, CDCl ₃ ) δ 0.84-0.89 (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);

MS m/z (ESI): 451.1 [M+H] ⁺ .

Example 121

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

6-(Cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3) nicotinamide was obtained by the method described in example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.87-0.94 (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);

MS m/z (ESI): 469.2 [M+H] ⁺ .

Biological analysis and evaluation

The present invention is further described below in conjunction with the following test examples, which do not limit the scope of the present invention.

Test Example 1 Determination of the inhibitory effect of the compounds of the present invention on the TYK2 cell signaling pathway

Purpose of the Experiment: The purpose of this test case is to determine the inhibitory effect of the compounds on the TYK2 cell signaling pathway.

Equipment for the experiment:

Centrifuge (5702R), purchased from Eppendorf,

Pipette purchased from Eppendorf

Microplate reader (Model: SynergyH1 full microplate reader) purchased from BioTek, USA.

Experimental procedure:

The U266 cell line expressing TYK2 was used in the experiment. The TYK2 signaling pathway was activated by INF-α stimulation, the inhibitory activity of the compound on subsequent STAT3 phosphorylation was determined, and the half-maximal inhibition concentration IC ₅₀ of the compound on TYK2 signaling pathway activity was obtained.

The specific process of the experiment is as follows:

3-12 μl of U266 cells were seeded into a 384-well detection plate (100-300 thousand cells per well). 2 μl of compound solution (serial dilution) was added. The plate was incubated in a carbon dioxide incubator for 2 hours. After 2 hours, 2 μl of INF-α was added (final concentration of FNF-α was 1000 U/ml) and the plate was shaken at room temperature for 20 minutes. Add 2-5 µl (5X) of LANCE Ultra Lysis Buffer 2 solution and shake the plate at room temperature for 2 hours. After 2 hours, 5 μl of a solution of LANCE Ultra Eu labeled anti-STAT5(Y694/Y699) antibody (PerkinElmer) (final concentration was 2 nM) and LANCE Ultra ULight labeled anti-STAT5 antibody (PerkinElmer) (final concentration 20 nM) was added and the plate was incubated at room temperature overnight. The fluorescence signal value of each well at 665 nm was determined using a microplate reader. The degree of inhibition was calculated from the fluorescence signal value. The IC ₅₀ of the compounds was obtained by curve fitting based on the degrees of inhibition of various concentrations. Methodology for processing experimental data:

The percent inhibition data for a compound-treated well was calculated from the positive control well (control well with DMSS and the negative control wells (no cells added) on the plate {% inhibition rate=100 - [(test compound value - negative control value )] / (positive control value - negative control value) × 100} The IC ₅₀ value was calculated by fitting the different concentration data and corresponding percentage inhibition rates to a four-parameter nonlinear logic formula using GraphPad prism.

Conclusion of the experiment:

Experimental data on the activity of the compounds of the present invention in inhibiting the TYK2 cell signaling pathway obtained using the above scheme are shown in the following table:

Test Example 2 Determination of the inhibitory effect of the compounds of the present invention on the JAK2 cell signaling pathway

Purpose of the Experiment: The purpose of this test case is to determine the inhibitory effect of the compounds on the JAK2 cellular signaling pathway.

Equipment for the experiment:

Centrifuge (5702R), purchased from Eppendorf,

Pipette purchased from Eppendorf

Microplate reader (Model: SynergyH1 full microplate reader) purchased from BioTek, USA.

Experimental procedure: The TF-1 cell line was used in the experiment. The JAK2 signaling pathway was activated by IL6 stimulation, the inhibitory activity of the compound on subsequent STAT3 phosphorylation was determined, and the half-maximal inhibition concentration IC ₅₀ of the compound on JAK2 signaling pathway activity was obtained.

The specific process of the experiment is as follows:

3-12 μl of TF-1 cells were seeded into a 384-well plate for detection (100-300 thousand cells per well). 2 μl of compound solution (serial dilution) was added. The plate was incubated in a carbon dioxide incubator for 2 hours. After 2 hours, 2 μl of IL6 was added (final IL6 concentration was 30 ng/ml) and the plate was shaken at room temperature for 20 minutes. Add 2-5 µl (5X) of LANCE Ultra Lysis Buffer 2 solution and shake the plate at 4°C for 2 hours. After 2 hours, 5 μl of a solution of LANCE Ultra Eu labeled anti-STAT3 antibody (Tyr705) (PerkinElmer) (final concentration was 2 nM) and LANCE Ultra ULight labeled anti-STAT3 antibody (PerkinElmer) (final concentration 20 nM) were added and the plate was incubated at room temperature. temperature overnight. The fluorescence signal value of each well at 665 nm was determined using a microplate reader. The degree of inhibition was calculated from the fluorescence signal value. The IC ₅₀ of the compounds was obtained by curve fitting based on the degrees of inhibition of various concentrations.

Methodology for processing experimental data:

The percentage inhibition data for a compound treated well was calculated from the positive control well (DMSO control well) and the negative control well (no added cells) on the plate {% inhibition rate=100 - [(test compound value - negative value control)] / (positive control value - negative control value) × 100}. The IC ₅₀ value was calculated by fitting the various concentration data and corresponding percentage inhibition rates to a four-parameter nonlinear logic formula using GraphPad prism. Conclusion of the experiment:

Experimental data on the activity of the compounds of the present invention in inhibiting the JAK2 cellular signaling pathway obtained using the above scheme are shown in the following table:

Conclusion of the experiment:

From the data shown in the table, it can be seen that the compounds of the examples have high selectivity for JAK2 cellular activity compared to TYK2 cellular activity.

Test Case 3: Plasma Protein Binding Test in Mice

1. Purpose of the study:

The purpose of this test is to evaluate the extent of protein binding of Example 58, Example 88 and Example 92 (5 μM) in mouse plasma by equilibrium dialysis.

2. Compounds and materials tested:

1) prepare a 10 mM stock solution of the test compound in DMSO and store it in a refrigerator at -20°C for later use;

2) frozen plasma of the required types, dialysate (100 mM phosphate buffer (serial no. SLBS7904 and serial no. SLBR3106V), pH 7.4).

3. Equipment for the experiment:

96-well plate (serial no. 07917415), membrane detection device (serial no. SD2369421), liquid chromatography with mass spectrometry/mass spectrometry (LC-MS/MS) (LC-20AD, ARG4000), centrifuge (Eppendorf 5804R/ 5424R), vortex mixer (IKA VORTEX GENIUS 3), pipette (Eppendorf 10-100 µl (PIP-100-002), Eppendorf 100-1000 µl (PIP-1000-002), RAIN IN 0.5-10 µl (PIP -10-002)), water bath (Shanghai Hengke).

4. Experimental procedure

4.1 Preparation of dialysate

4.01 ml of 1 M K ₂ HPO ₄ (analytical grade) and 0.99 ml of 1 M K ₂ HPO ₄ (analytical grade) were diluted to 50 ml with ultrapure water to obtain 100 mM phosphate buffer ( pH=7.4) as a dialysate.

4.2 Plasma preparation

Frozen plasma was thawed at room temperature or in a water bath at 37°C and centrifuged at 3500 rpm for 5 minutes. The supernatant was collected.

4.3 Preparation of stop solution

Acetonitrile (or other suitable solution) containing the internal standard was used as a stop solution and stored in a refrigerator at 2-8°C. The specific concentration of the internal standard can be found in the final report.

4.4 Preparation of working solution of the compound

Preparation of a working solution of the compound: the stock solution was diluted with DMSO to a final concentration of 1 mM.

4.5 Preparation of plasma solution

4 μl of the working solution of the compound was added to 796 μl of blank plasma (final concentration was 5 μM), and the resulting solution was shaken well.

4.6 Equilibrium dialysis

1) the device was set up for equilibrium dialysis, the membrane detection device was placed in a 96-well plate for equilibrium dialysis;

2) 200 μl of the prepared plasma solution was added to the membrane, n=2;

3) another 4 µl plasma solution was diluted 10-fold with 36 µl blank plasma from the same species and added 160 µl acetonitrile stop solution containing internal standard to obtain a T0 (total) sample, which was stored in a refrigerator at -20 °C;

4) 350 μl of dialysate (100 mM phosphate buffer) was added to the outside of the membrane;

5) the dialysis plate was well sealed and incubated in a water bath at 37°C for 6 hours;

6) after completion of dialysis, 4 μL of solution was taken from the sample well inside the membrane and diluted 10-fold with 36 μL of blank plasma from the same species; 40 μl of dialysate was taken from the sample well on the outside of the membrane, followed by the addition of 160 μl of acetonitrile stop solution containing the internal standard; thus, sample T6 (total) and sample F6 (total) were obtained;

7) samples T0 (total) and T6 (total) were centrifuged and the supernatant was collected;

8). LC-MS analysis.

5. Experimental results

Test Case 4: Pharmacokinetic Analysis in Balb/c Mice

1. Purpose of the study:

Balb/c mice were used as experimental animals. The pharmacokinetic behavior in mouse plasma of the compounds Example 58, Example 88 and Example 92 administered orally at a dose of 5 mg/kg was studied.

2. Test report

2.1 Test connections

Compounds of Example 58, Example 88 and Example 92 of the present invention prepared by the Applicant.

2.2 Experimental animals

18 male Balb/c mice (6 mice/example) purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, with Certificate No.: SCXK (Shanghai) 2013-0006 N0.311620400001794.

2.3 Introduction

After an overnight fast, 18 male Balb/c mice were orally administered the test compound at an administration dose of 5 mg/kg and an administration volume of 10 ml/kg.

2.4 Sample collection:

0.1 ml of blood was collected from the mouse orbit before administration and 0, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. Samples were stored in EDTA-K ₂ tubes and centrifuged for 6 minutes at 4°C, 6000 rpm to separate plasma. Plasma samples were stored at -80°C.

2.5 Sample processing:

1) 160 μL of acetonitrile was added to 40 μL of plasma sample to precipitate, and then the mixture was centrifuged for 5-20 minutes at 3500 × g.

2) 100 μl of the treated supernatant was taken for analysis of the concentration of the test compound using LC/MS/MS.

2.6 Liquid chromatography analysis

- Liquid chromatography conditions: Shimadzu LC-20AD pump

- Conditions for mass spectrometry: mass spectrometer AB Sciex API 4000

- Chromatographic column: Gemiu 5 µm C18 50 × 4.6 mm from phenomenex

- Mobile phase: eluent A was 0.1% formic acid in water, and eluent B was acetonitrile.

- Flow rate: 0.8 ml/min

- Elution time: 0-4.0 min, the eluent was as follows:

3. Test results and analysis

Main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the pharmacokinetic test in mice are shown in the following table:

Conclusion of the experiment: From the data shown in the table, it can be seen that the pharmacokinetic exposure AUC _0-t (ng/ml*h) of the compounds according to the examples in mice was better than that of the control compound BMS-986165. In particular, the pharmacokinetic exposure of compounds of Examples 58 and 88 was much higher than that of the control compound BMS-986165 (more than 6 and 10 times better than the control compound).

Test Example 5: Determination of the effectiveness of the compounds of the present invention in a mouse model of imiquimod-induced psoriasis-like condition.

1. Purpose of the experiment:

To evaluate the effectiveness of the compounds in a mouse model of imiquimod-induced psoriasis-like condition.

2. Basic equipment and reagents for the experiment

2.1 Equipment

2.2 Reagents

3. Experimental technique

3.1 Simulation

On day 0, the test area on the animal's back was shaved. From days 1 to 6, 62.5 mg of imiquimod was applied to the test site on the animal's back once daily.

3.2 Introduction

From days 1 to 7, administration was carried out in each group of animals in accordance with the experimental protocol. The experimental design of the mouse model of imiquimod-induced psoriasis-like condition is shown in the following table:

3.3 Index of severity of skin lesions by dermatitis

From days 1 to 7, the degree of redness, peeling and thickening of the test area on the animal’s back was assessed on a scale from 0 to 4. 0 - no lesion; 1 - weak; 2 - moderate; 3 - pronounced; 4 - very pronounced. The overall score indicates the severity of the lesion.

4. Test data

4.1 The results of the comparison of the PASI (Psoriasis Prevalence and Severity Index) scores of various compounds in a mouse model of imiquimod-induced psoriasis are shown in the following table:

4.2 The PASI results of various compounds in a mouse model of imiquimod-induced psoriasis are shown in FIG. 1, where data values represent the mean PASI scores of the group, N=8, compared with the vehicle group by one-way ANOVA, ***p < 0.001.

5. Experimental results

From the above results, it can be seen that in the mouse model of imiquimod-induced psoriasis, the compounds of Examples 58, 88 and 92 of the present application can effectively improve the symptom of psoriasis and have a very significant difference compared with the vehicle group (P<0.001) and show better results than control compound BMS-986165 (P < 0.01).

Claims (36)

1. A compound of formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: Where: R ₉ – C _3-6 cycloalkyl; R – C _1-6 alkoxy; R ₃ is selected from the group consisting of hydrogen and halogen; R ₄ – cyclopropyl; R ₅ and R ₆ – hydrogen; x is 0 or 1. 2. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that R ₉ selected from the group consisting of 3. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein formula (V) is further as represented in formula (VIII): Where: R ₃ -R ₆ and x are as defined in paragraph 1. 4. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 3, characterized in that R ₃ is selected from the group consisting of hydrogen and fluorine; R ₅ and R ₆ – hydrogen; And x is 0 or 1. 5. The compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (V) is selected from the group consisting of: 6. A method for producing a compound of formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it includes the following steps: subjecting a compound of formula (V-1) to a compound of formula (V-2) to yield a compound of formula (V-3), then reacting a compound of formula (V-3) with deuterated methylamine hydrochloride to yield a compound of formula (V), its a stereoisomer or a pharmaceutically acceptable salt thereof; Where: X represents halogen; And R ₃ -R ₆ , R ₉ and x are as defined in paragraph 1. 7. A method for producing a compound of formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it includes the following steps: subjecting a compound of formula (V-4) to a compound of formula (V-5) to produce a compound of formula (V-6), then reacting a compound of formula (V-6) with a compound of formula (V-2) to yield a compound of formula ( V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; Where: X represents halogen; And R ₃ -R ₆ , R ₉ and x are as defined in paragraph 1. 8. A pharmaceutical composition for the production of a medicinal product that inhibits TYK2, containing a therapeutically effective dose of a compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims. 1-5 and one or more pharmaceutically acceptable carriers, diluents or excipients. 9. Use of a compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-5 or the pharmaceutical composition according to claim 8 for obtaining a drug that inhibits TYK2. 10. Use of a compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims. 1-5 or a pharmaceutical composition according to claim 8 for producing a TYK2 inhibitory drug for treating an inflammatory disease and an autoimmune disease, wherein the inflammatory disease and the autoimmune disease are selected from the group consisting of rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel disease.