Nitrogen-containing heterocyclic pyridine compounds

Abstract

The present invention provides nitrogen-containing heterocyclic protein inhibitor compounds, their stereoisomers, tautomers or pharma- ceutically acceptable salts, and further provides the preparation of nitrogen-containing heterocyclic compounds and their uses, and medicaments prepared using such compounds have a wide range of uses in the treatment of diseases, including multiple types of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, sicca syndrome and scleroderma.

Description

[Technical Field]

[0001] The present invention relates to nitrogen-containing heterocyclic compounds that can regulate various cytokine signaling pathways by inhibiting TYK2, and further relates to methods for preparing such compounds and their use in treating diseases. [Background technology]

[0002] Nitrogen-containing heterocycles are a type of nitrogen-containing heterocyclic compound with a unique structure and a wide range of biological activities. Since the successful development of nitrogen-containing heterocyclic herbicides, research on nitrogen-containing heterocyclic compounds has progressed rapidly. For example, nitrogen-containing heterocyclic mycin was the first nitrogen-containing heterocyclic compound with natural fungicidal activity. Research has shown that nitrogen-containing heterocyclic compounds have superior biological activity in pesticides and pharmaceuticals such as herbicides, insecticides, antibacterial agents, antivirals, and antihypertensives.

[0003] [ka]

[0004] The cytokines interleukin IL-12 and IL-23 activate antigen-presenting cells and play important roles in the differentiation and proliferation of T cells, and these cytokines have been implicated in mediating various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus erythematosus.

[0005] Tyrosine kinase 2 (TYK2), a member of the JAK family (other members include JAK1, JAK2, and JAK3), is involved in IFN-α, IL-6, IL-10, and IL-12 signaling. TYK2 promotes the phosphorylation of IL-12, IL-23, and STAT proteins downstream of the type I interferon receptor. Inhibition of TYK2 activity can effectively treat various autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, sicca syndrome, and scleroderma.

[0006] Designing TYK2 inhibitors with better efficacy, pharmacokinetic properties, and better drug-like properties is a major challenge for medicinal chemists. Although a series of TYK2 inhibitors have been disclosed in recent years, there is still a need to discover and develop new compounds with better efficacy, pharmacokinetic properties, and better physicochemical properties. The present invention has designed compounds having the structure of general formula (I) and found that such compounds exhibit excellent TYK2 inhibitory effects and comprehensive properties. Summary of the Invention

[0007] The present invention provides a compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, [ka] L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino; Ring B is aryl, heteroaryl, heterocyclyl, and Ring B is selected from the following groups: [ka] where T, G, Y, Z, and M are each independently an oxygen atom, CR A1 , C.R. A2 , nitrogen atom or NRB is selected from E is a nitrogen atom or a carbon atom, R A1 , R A2 are hydrogen, deuterium, and C 1-6 is selected from alkyl, halogen, and the following structure: [ka] R B is hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Haloalkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, substituted amino-C(O)-, C 1-6 is selected from alkyl-S(O)2-, alkenyl, deuterated alkenyl, alkynyl, deuterated alkynyl, and the following structure: [ka] Q is a chemical bond or -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -C(NR 8 )-, i.e.: [ka] P is an oxygen atom or a sulfur atom, X is a chemical bond, an oxygen atom, or an NH or NR A and R A is alkyl, deuteroalkyl, haloalkyl, U is a nitrogen atom or a carbon atom; Ring A is aryl, heteroaryl, heterocyclyl, and is selected from the following groups: [ka] C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and C is selected from the following groups: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 is selected from hydrogen, deuterium, halogen, amino, alkynyl, deuteroalkynyl, alkenyl, deuteroalkenyl, alkenylcarbonyl, deuteroalkenylcarbonyl, alkyl, deuteroalkyl, alkylcarbonyl, deuteroalkylcarbonyl, wherein alkynyl, alkenyl, deuteroalkynyl, deuteroalkenyl, alkyl and deuteroalkyl are optionally substituted with halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl; n=1, 2, 3, 4, 5, 6.

[0008] The present invention provides the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka]

[0009] The present invention provides compounds of formula (I-1), their stereoisomers, tautomers and pharmaceutically acceptable salts: [ka] wherein L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino; P is an oxygen atom or a sulfur atom, X is an oxygen atom, or NH or NR 9 and V, U, and W are nitrogen atoms, CR 6 and R D1 is hydrogen, C 1-6 alkyl, halogen, F1, F2 and F3 are a nitrogen atom and a carbon atom, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and ring C is selected from the following groups: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is selected from hydrogen, deuterium, halogen, amino, alkynyl, alkenyl, deuteroalkenyl, alkyl, deuteroalkyl, wherein alkynyl, alkenyl, alkyl, and deuteroalkyl are optionally substituted with halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl; R 9 is hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -(CD2) n1 R aa , -(CD2) n1 OR aa , -SR aa , -(CD2) n1 C(O)R aa , -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH2) n1 S(O) m1 R aa , -(CD2) n1 S(O) m1 Raa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb , -NR aa S(O) m1 R bb is selected from R aa , R bb are each independently selected from hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents: hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxyl, 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 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n=1, 2, 3, 4, n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4.

[0010] The present invention provides the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka]

[0011] The present invention provides a compound of formula (II-1), its stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka] wherein Ring B is aryl, heteroaryl, or heterocyclyl; X1 and E are nitrogen atoms or carbon atoms, L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino; R 10 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; Q is a chemical bond or -C(O)-, -C(S)-, -S(O)-, -S(O)2-, i.e.: [ka] C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and C is selected from the following groups: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 is selected from hydrogen, deuterium, halogen, amino, alkynyl, deuteroalkynyl, alkenyl, deuteroalkenyl, alkyl, deuteroalkyl, wherein alkynyl, alkenyl, deuteroalkynyl, deuteroalkenyl, alkyl and deuteroalkyl are optionally substituted with halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl; R 9 is hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1OR aa , -SR aa , -(CH2) n1 C(O)R aa , -(CD2) n1 R aa , -(CD2) n1 OR aa , -SR aa , -(CD2) n1 C(O)R aa , -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH2) n1 S(O) m1 R aa , -(CD2) n1 S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb , -NR aa S(O) m1 R bb is selected from R aa , R bbare each independently selected from hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents: hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxyl, 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 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n=1, 2, 3, 4, n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4.

[0012] The present invention provides a compound of formula (II-1A), its stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka] wherein Ring B is aryl, heteroaryl, or heterocyclyl; X1 and E are nitrogen atoms or carbon atoms, L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino; R 10 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and C is selected from the following groups: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 is selected from hydrogen, deuterium, halogen, amino, alkynyl, deuteroalkynyl, alkenyl, deuteroalkenyl, alkyl, deuteroalkyl, wherein alkynyl, alkenyl, deuteroalkynyl, deuteroalkenyl, alkyl and deuteroalkyl are optionally substituted with halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl; R 9 is hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 R aa , -(CH2) n1 OR aa , -SR aa , -(CH2) n1 C(O)R aa , -(CD2) n1 R aa , -(CD2) n1 OR aa , -SR aa , -(CD2) n1 C(O)R aa , -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH2) n1 S(O) m1 R aa , -(CD2) n1 S(O) m1 R aa , -NR aa R bb , -C(O)NRaa R bb , -NR aa C(O)R bb , -NR aa S(O) m1 R bb is selected from R aa , R bb are each independently selected from hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents: hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxyl, 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 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; n=1, 2, 3, 4, n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4.

[0013] The present invention provides the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka]

[0014] The present invention provides a compound of formula (II-1B), its stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka] wherein Ring B is aryl, heteroaryl, or heterocyclyl; X1 and E are nitrogen atoms or carbon atoms, L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino; R 10 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and C is selected from the following groups: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 is selected from hydrogen, deuterium, halogen, amino, alkynyl, deuteroalkynyl, alkenyl, deuteroalkenyl, alkyl, deuteroalkyl, wherein alkynyl, alkenyl, deuteroalkynyl, deuteroalkenyl, alkyl and deuteroalkyl are optionally substituted with halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl; R 9a , R 9b , R 9c is selected from hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, cycloalkyl, deuterocycloalkyl, alkynyl, deuteroalkynyl, or R 9a and R 9b together with the carbon atom to which it is attached form a cycloalkyl, n=1, 2, 3.

[0015] The present invention provides the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka]

[0016] The present invention provides a compound of formula (II-2), its stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka] wherein L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino; R 10 , R 11 , R D1 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; Q is a chemical bond, carbonyl, C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and C is selected from the following groups: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 is selected from hydrogen, deuterium, halogen, amino, alkynyl, deuteroalkynyl, alkenyl, deuteroalkenyl, alkyl, deuteroalkyl, wherein alkynyl, alkenyl, deuteroalkynyl, deuteroalkenyl, alkyl and deuteroalkyl are optionally substituted with halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl; R 9a , R 9b , R 9c is selected from hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, cycloalkyl, deuterocycloalkyl, alkynyl, deuteroalkynyl, or R 9a and R 9b together with the carbon atom to which it is attached form a cycloalkyl, n=1, 2, 3.

[0017] The present invention provides a compound of formula (II-2-1), its stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka] where R 12 is deuterium, hydrogen, alkyl, deuteroalkyl, haloalkyl, amino, alkylamino, deuteroalkylamino, cycloalkyl, cycloalkylamino, deuterocycloalkylamino, R 10 , R 11 , R D1 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; Q is a chemical bond, carbonyl; C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and C is selected from the following groups: [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 is selected from hydrogen, deuterium, halogen, amino, alkynyl, deuteroalkynyl, alkenyl, deuteroalkenyl, alkyl, deuteroalkyl, wherein alkynyl, alkenyl, deuteroalkynyl, deuteroalkenyl, alkyl and deuteroalkyl are optionally substituted with halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl; R 9a , R 9b , R 9c is selected from hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, cycloalkyl, deuterocycloalkyl, alkynyl, deuteroalkynyl, or R 9a and R 9btogether with the carbon atom to which it is attached form a cycloalkyl, n=1, 2, 3.

[0018] The present invention provides a compound of formula (II-2-2), its stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka] where R 12 is deuterium, hydrogen, alkyl, deuteroalkyl, haloalkyl, amino, alkylamino, deuteroalkylamino, cycloalkyl, cycloalkylamino, deuterocycloalkylamino, R 10 , R 11 , R D1 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; where R 1 , R 2 , R 3 , R 4 , R 5 , R 7 is selected from hydrogen, deuterium, halogen, amino, alkynyl, deuteroalkynyl, alkenyl, deuteroalkenyl, alkyl, deuteroalkyl, wherein alkynyl, alkenyl, deuteroalkynyl, deuteroalkenyl, alkyl and deuteroalkyl are optionally substituted with halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl; R 9a , R 9b , R 9c is selected from hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, cycloalkyl, deuterocycloalkyl, alkynyl, deuteroalkynyl, or R 9a and R 9b together with the carbon atom to which it is attached form a cycloalkyl, n1=1, 2, 3, n2=1, 2, 3.

[0019] The present invention provides the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: [ka]

[0020] The present invention provides pharmaceutical compositions comprising one or more of the compounds according to any one of the invention and a pharmaceutically acceptable carrier or diluent.

[0021] Use of a compound according to any one of the present invention in the preparation of a medicament for treating a disease, wherein the disease is an inflammatory or autoimmune disease mediated by the kinase TYK2, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, sicca syndrome or scleroderma, or a tumor.

[0022] Detailed Description of the Invention All technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art.

[0023] The term "hydrogen" as used herein means -H.

[0024] The term "deuterium" as used herein means -D.

[0025] The term "halogen" as used herein means -F, -Cl, -Br and -I.

[0026] The term "oxygen atom" means O herein.

[0027] The term "carbon atom" means C herein.

[0028] The term "nitrogen atom" means N herein.

[0029] The term "sulfur atom" means S herein.

[0030] The term "carbonyl" as used herein refers to -C(O)-.

[0031] The term "amino" as used herein refers to -NH2.

[0032] The term "hydroxyl" as used herein means --OH.

[0033] The term "alkyl," as used herein, refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and this term includes both straight-chain and branched hydrocarbon groups. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like. Alkyl groups described herein may be optionally substituted with one or more substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl, or heteroaryl.

[0034] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon. The base The cycloalkyl ring has 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, cyclooctyl, etc., and examples of polycyclic cycloalkyl groups include spirocyclohexyl, thickened cyclohexenyl, bridged cyclohexenyl, etc.

[0035] The term "aryl" is used herein to refer to a 6- to 10-membered all-carbon monocyclic or closely packed polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, or a polycyclic group having a conjugated π-electron system (i.e., rings having adjacent pairs of carbon atoms). An aryl group may be covalently attached to the defined chemical structure at any carbon atom that results in a stable structure. The aryl groups described herein may be optionally substituted with one or more substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxyl, amino, alkyl, alkoxy, acyl, amido, ester, amine, sulfonyl, sulfenyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0036] The term "heteroaryl," as used herein, refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. This term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple thickening rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), where the thickening ring may or may not be an aromatic moiety comprising a heteroatom, provided that the point of attachment is through an atom in the aromatic heteroaryl moiety. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, amido, ester, amine, sulfonyl, sulfenyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0037] The term "alkenyl," as used herein, refers to an alkenyl group having 2 to 8 carbon atoms and at least one site of alkenyl unsaturation. Non-limiting examples of alkenyl include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like. The alkenyl groups described herein may be substituted with one or more substituents including deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amido, ester, amine, sulfonyl, sulfenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, heavy alkylmercapto, sulfonyl, sulfoxylidene, amido, silyl, phosphono, heavy alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, and ester.

[0038] The term "alkynyl," as used herein, refers to an alkyl group comprising two adjacent carbon atoms connected by a triple bond, said alkyl group being as defined herein. Alkynyl refers to an unsaturated alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine group, sulfonyl, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, alkylmercaptide, sulfone, sulfenyl, amine, silyl, phosphonoalkyl, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkyne, alkenyl, arylalkyl, and ester groups. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention will be further described below by way of examples, but the present invention is not limited thereto. Throughout this application, the present specification refers to several examples of the compounds and methods of the present invention. The present invention is not limited to these examples, and the following examples merely provide methods for practicing the present invention and are not intended to limit the scope of the present invention in any way.

[0040] The compounds provided by this invention can be prepared by standard synthetic methods well known in the art, and this specification provides general methods for preparing the compounds of the invention. Starting materials are typically commercially available or prepared by methods well known to those skilled in the art.

[0041] Step 1 is as follows: [ka] First, SM-1 is used as the starting material and reacted with SM2 to give IM-1, which is then reacted with SM-3 to give compound I.

[0042] Step 2 is as follows: [ka] First, SM-1 is used as the starting material and reacted with SM-2A to give IM-1A, which is then reacted with SM-3 to give IM-2A, which is then deprotected to give IM-3A, which is then further reacted to give compound IA.

[0043] The compounds of the present invention and the corresponding preparation methods are further described and listed below through examples and preparations. Although typical or preferred reaction conditions are shown in specific examples, it should be understood that those skilled in the art may use other reaction conditions. The optimal reaction conditions may vary depending on the specific reaction substrates or solvents used, and the conditions can be determined by those skilled in the art through routine optimization.

[0044] Intermediate preparation Using 3-bromopropylene as the raw material, prepare deuterated propargyl bromide according to the preparation scheme in the literature (Journal of Medicinal Chemistry (2004), 47(2), 400-410). MS: m / z 262.1, [M+H] + .

[0045] [ka] The deuterated propargyl bromide is prepared according to the preparation scheme in the literature (Journal of the Chinese Chemical Society (Taipei) (1998), 45(2), 307-312) and the corresponding deuterated reagent (deuterated water).

[0046] [ka] The deuterated propargyl bromide is prepared by referring to the preparation scheme in the literature (Bioorganic & Medicinal Chemistry (2013), 21(21), 6634-6641) and the corresponding deuterated reagent (deuterated lithium aluminum hydroxide).

[0047] [ka]

[0048] Step 1: 2.4 g of lithium aluminum deuteride was dispersed in 150 ml of diethyl ether and cooled to -50°C. This was slowly added dropwise to 150 ml of diethyl ether solution containing 6.0 g of methyl propargylate. After the addition was completed, stirring was continued at -30°C, and the mixture was then warmed to room temperature and stirred overnight. 3 ml of deuterium oxide, sodium hydroxide (0.22 g dissolved in 1.5 ml of deuterium oxide), and 2 ml of deuterium oxide were added dropwise to the reaction mixture. The mixture was filtered under suction, and the filter cake was washed twice with 30 ml of diethyl ether. The filtrate was collected and concentrated under reduced pressure to give a dark yellow oily product, which was then distilled under reduced pressure at 130°C to give 2.3 g of a colorless oily product.

[0049] Step 2: 1.2 g of deuterated propargyl alcohol was dissolved in 15 ml of dichloromethane and cooled to -5°C under nitrogen protection. 6.0 g of phosphorus tribromide was slowly added dropwise. After the addition was complete, the mixture was stirred at -5°C for 1 hour, then warmed to room temperature and stirred. 15 ml of ice water was added to the reaction mixture, and the mixture was partitioned. The organic layer was washed successively with 25 ml of saturated sodium bicarbonate solution and 25 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding 1.6 g of a pale yellow oily liquid.

[0050] Or prepared according to the following scheme: [ka] A 50 ml single-neck flask was charged with (3-bromoprop-1-yn-1-yl-3,3-d2)trimethylsilane (300 mg, 1.55 mmol), potassium carbonate (644 mg, 4.7 mmol), and methanol-OD (3 ml), followed by stirring at room temperature for 30 min. The insoluble material in the reaction mixture was removed by filtration, and 50 ml of deuterium oxide was added to the filtrate. The mixture was extracted with diethyl ether, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the product.

[0051] The following deuterated intermediates were prepared according to the preparation schemes in the literature (WO2017181918, Journal of the American Chemical Society (1990), 112(8), 3156-3162, Journal of Organic Chemistry (1988), 53(20), 4748-4758, Organic Letters (2007), 9(16), 2981-2984, Bulletin of the Chemical Society of Japan (2003), 76(2), 347-353, Angewandte Chemie, International Edition (2016), 55(9), 3171-3175): [ka] Cyanocyclopropane was added dropwise to a deuterated methanol solution containing sodium chloride, refluxed for 16 h, concentrated under reduced pressure to remove the deuterated methanol, and concentrated to obtain a yellow solution (GC-MS: 69.1). Next, a mixture of deuterated methanol and deuterated water was added, refluxed for 8 h, and concentrated under reduced pressure to remove the solvent, yielding the target product.

[0052] [ka] A 500 ml three-neck flask was charged with SMD1 (50 g) and deuterium oxide (35 ml). Under nitrogen protection, the flask was heated to 100 °C to clear the solution. Most of the water (approximately 25 ml to 30 ml) was removed by distillation under reduced pressure. The system was then refilled with 25 ml of deuterium oxide and the water was removed by distillation under reduced pressure. This process was repeated three times to ensure sufficient exchange of the carboxyl groups with the deuterium in the deuterium oxide. The system was then heated to 160 °C and the water was removed by distillation under reduced pressure. The system was then heated to 200 °C and the distillation was continued under reduced pressure, collecting the fraction between 180 °C and 200 °C. The distillation was completed in 5 to 10 minutes, yielding 22 g of a colorless oily fraction.

[0053] A 250 ml three-neck flask was charged with SMD2 (6.5 g), dichloromethane (30 ml), and DMF (0.5 ml). The mixture was cooled to 0 to -10 °C under nitrogen protection, and oxalyl chloride (9.5 g) was added dropwise to maintain the internal temperature below 0 °C. After the addition, the mixture was reacted at 0 °C for 2 to 3 hours. After monitoring the reaction by TLC, the mixture was concentrated under reduced pressure to remove the dichloromethane. A separate reaction flask was charged with 150 ml of THF, cooled to 0 °C under nitrogen protection, and ammonia was added until saturated. The concentrated chlorine chloride solution was added all at once to the THF solution, returned to 20 °C, and stirred for 20 min. The filtrate was filtered and concentrated to obtain 1.6 g of the target product.

[0054] [ka]

[0055] Step 1 Trimethylsilylene (10.0 g) and dry tetrahydrofuran (100 ml) were placed in a 250 ml three-neck flask and cooled to -80°C. n-Butylithium (40 ml) was added and the mixture was reacted at -80°C for 30 minutes. Methyl chloroformate (10.6 g) was added dropwise and the mixture was allowed to warm naturally to around -50°C and kept at that temperature for 30 minutes. The reaction mixture was quenched by pouring it into 200 ml of aqueous ammonium chloride solution, extracted with 200 ml of diethyl ether, partitioned, dried, and concentrated to obtain a crude product. This was purified by silica gel column chromatography to obtain 8.0 g of a pale yellow liquid. 1 H NMR (400 MHz, CDCl3): δ 3.79(s,3H),0.26(s,9H).

[0056] Step 2 The product from the previous step (7.0 g) and diethyl ether (300 ml) were placed in a 500 ml single-neck flask, cooled to 0°C, and LiAlD4 (1.5 g) was added all at once. The mixture was then allowed to react for 1 hour while maintaining the temperature. An appropriate amount of water was slowly added dropwise to the reaction mixture to quench the reaction, after which an appropriate amount of anhydrous sodium sulfate was added to dry it, filtered, and the filtrate was concentrated to obtain a crude product, which was then purified by column chromatography to obtain 4.0 g of a colorless liquid.1 H NMR (400 MHz, CDCl3): δ 1.95(br s,1H),0.18(s,9H).

[0057] Step 3 The product (4.0 g) from the previous step was placed in a 250 ml single-neck flask, followed by triphenylphosphine (8.1 g) and dichloromethane (100 ml). The mixture was cooled to 0°C, and NBS (5.5 g, 30.9 mmol) was added all at once, followed by stirring for 30 minutes. The reaction mixture was concentrated under reduced pressure at 0°C to remove most of the dichloromethane solvent. The residue was added to 100 ml of n-hexane and filtered with stirring. The filtrate was directly subjected to column chromatography, and the eluate was concentrated under reduced pressure at 10°C to obtain approximately 3.0 g of a colorless liquid.

[0058] Step 4 The product from the previous step (2.0 g), acetone (40 ml), water (1 ml), and silver trifluoromethanesulfonate (270 mg) were added to a 50 ml single-neck flask and stirred at room temperature for 1 hour. The reaction mixture was added to 200 ml of saturated aqueous ammonium chloride solution, extracted with 200 ml of diethyl ether, partitioned, dried, and concentrated under reduced pressure at 0°C to give 2.0 g of a colorless liquid (containing a small amount of solvent), which was used as is.

[0059] Preparation of compounds

[0060] Example 1: [ka]

[0061] Step 1 A reaction flask was charged with 2-aminopyridine compound (3.0 g) and N,N-dimethylformamide (50 ml), cooled to 0°C, and sodium hydride (1.5 g) was added in one portion. The mixture was then stirred for 20 min, slowly warmed to room temperature, and stirred for 30 min. The reaction mixture was cooled to 0°C, and a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (3.9 g) in tetrahydrofuran (40 ml) was slowly added dropwise. The temperature was controlled below 5°C, and the mixture was stirred overnight. Aqueous ammonium chloride solution (20 ml) and water (40 ml) were added to the reaction mixture, which was stirred for 30 min. The mixture was then suction filtered. The filter cake was washed twice with water and dried to obtain 3.95 g of an off-white solid. 1 H NMR(400 MHz,CDCl3): δ 12.53(s,1H),9.39(s,1H),8.38(s,1H),8.34(s,1H),8.22(d,J=5.2 Hz,1H),7.65(d,J=5.2 Hz,1H),5.62(s,2H),4.04(s,3H),3.74(t,J=8.2 Hz,2H),0.98(t,J=8.2 Hz,2H),0.02(s,9H). MS: m / z 494.2 [M+H] + .

[0062] Step 2 The product from the previous step (2.4 g), DCPF (1.1 g), palladium acetate (111 mg), cesium carbonate (8 g), and DME (90 ml) were added sequentially to a reaction flask, and after purging with nitrogen, the mixture was heated to 90°C and reacted for 1 hour. The reaction mixture was cooled to room temperature, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.76 g of a pale yellow solid compound. MS: m / z 543.3 [M+H] + .

[0063] Step 3 The product (2.7 g) from the previous step and trifluoroacetic acid (60 ml) were added to a reaction flask, followed by stirring overnight at 70°C. The mixture was concentrated to dryness under reduced pressure, toluene (100 ml) was added, and the mixture was concentrated to dryness again. Tetrahydrofuran (100 ml) was added to the concentrate, and sodium bicarbonate was slowly added at room temperature to adjust the pH to 7-8. The mixture was then suction filtered to remove solids, and the filtrate was concentrated and used directly in the next step.

[0064] Step 4 To the product of the previous step, N,N-dimethylformamide (50 ml) and bromopropylene (3.6 g) were added and stirred at room temperature for 30 min. Potassium carbonate (2.8 g) was added all at once, and then the mixture was allowed to react at room temperature for 2 h. The reaction mixture was extracted three times with water (100 ml) and methyl tert-butyl ether. The organic phases were combined, concentrated to dryness, and purified by silica gel column chromatography to obtain 450 mg of compound 7 as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6): δ 12.46(s,1H),11.36(s,1H),9.89(s,1H),9.25(s,1H),8.79(s,1H),8.16(d,J=5.2 Hz,1H),7.50(d,J=5.2 Hz,1H),5.29(d,J=2.5 Hz,2H),3.91(s,3H),3.63(t,J=2.5 Hz,1H),2.19 - 2.08(m,1H),0.98 - 0.81(m,4H). MS: m / z 451.2 [M+H] + .

[0065] Example 2: [ka]

[0066] Compound 8 was prepared according to the preparation scheme in Example 1. MS: m / z 453.2, [M+H] + The specific preparation method is as follows: A 50 mL single-neck flask was charged with the triazole compound (310 mg), N,N-dimethylformamide (45 mL), and 3-bromoprop-1-yne-3,3-d2 (1.2 g). Potassium carbonate (310 mg) was added all at once with stirring, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was quenched by pouring into 400 mL of water, extracted with 200 mL of ethyl acetate, and partitioned. The organic phase was washed three times with 200 mL of water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to yield 120 mg of a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6): δ 12.47(s,1H),11.37(s,1H),9.90(s,1H),9.26(s,1H),8.80(s,1H),8.16(d,J=5.2 Hz,1H),7.51(d,J=5.2 Hz, 1H), 3.91 (s, 3H), 3.63 (s, 1H), 2.18-2.09 (m, 1H), 0.94-0.84 (m, 4H).

[0067] Example 3: [ka]

[0068] Compound 9 was prepared according to the preparation scheme in Example 1. MS: m / z 454.4, [M+H] + The specific preparation method is as follows: A 25 mL single-neck flask was charged with 200 mg of the triazole compound, 15 mL of N,N-dimethylformamide, and 1.0 g of 3-bromoprop-1-yne-1,3,3-d3. Potassium carbonate (210 mg) was added in one portion while stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by pouring into 200 mL of water, extracted with 100 mL of ethyl acetate, and partitioned. The organic phase was washed three times with 100 mL of water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to yield 80 mg of a pale yellow solid. 1H NMR(400 MHz,CDCl3): δ 12.47(s,1H),11.37(s,1H),9.90(s,1H),9.26(s,1H),8.80(s,1H),8.16(d,J=5.2 Hz,1H),7.51(d,J=5.2 Hz,1H),3.90(s,3H),2.15-2.12(m,1H),0.95-0.82(m,4H). HR-MS: m / z 454.2226 [M+H] + .

[0069] Example 4: [ka]

[0070] Compound 10 was prepared according to the preparation scheme in Example 1. MS: m / z 453.4 [M+H] + .

[0071] Example 5: [ka]

[0072] Compound 11 was prepared according to the preparation scheme in Example 1. MS: m / z 452.3 [M+H] + The specific preparation method is as follows: [ka]

[0073] Step 1 The triazole compound (1.20 g), cyclopropane-1-d-1-carboxamide (0.42 g), Xanthop (0.28 g), CsCO (1.58 g), Pd(dba) (0.22 g), and 1,4-dioxane (30 ml) were sequentially added to a reaction flask. The mixture was heated to 100 °C under nitrogen protection and stirred. After the reaction was completed, the mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography to give 0.74 g of a yellow solid. MS: m / z 544.3 [M+H] + .

[0074] Step 2 The product from the previous step (0.72 g), dichloromethane (2.2 ml), and tetraethylammonium fluoride (2.16 g) were added sequentially to a reaction flask, and trifluoroacetic acid (5.04 ml) was added dropwise with stirring. After the addition was complete, the mixture was allowed to react at room temperature with stirring. After the reaction was complete, the mixture was concentrated, water was added, and impurities were extracted with methyl tert-butyl ether. The aqueous phase was collected and the pH was adjusted with saturated sodium bicarbonate to precipitate a solid. The solid was filtered and dried to obtain 0.44 g of a pale yellow solid. MS: m / z 414.2 [M+H] + .

[0075] Step 3 The product (0.43 g) from the previous step, N,N-dimethylacetamide (20 ml), and bromopropargyl (0.99 g) were successively added to a reaction flask and stirred to dissolve and clarify the mixture. Potassium carbonate (1.01 g) was added all at once, and the mixture was allowed to react while maintaining the temperature at room temperature. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, dried, and concentrated under reduced pressure to obtain a yellow oily substance. This was purified by silica gel column chromatography to obtain 81 mg of a white solid. 1H NMR(400 MHz,DMSO-d6): δ 12.47(s,1H),11.37(s,1H),9.90(s,1H),9.26(s,1H),8.80(s,1H),8.16(d,J=5.2 Hz,1H),7.51(d,J=5.2 Hz,1H),5.29(d,J=2.6 Hz,2H),3.91(s,3H),3.64(t,J=2.5 Hz,1H),0.94-0.83(m,4H).

[0076] Under appropriate reaction conditions, during the preparation of structures such as those in Examples 1 and 5, the chemoselectivity of the final triazole propargylation step is superior to that of substituents such as methyl, and is superior to that of the corresponding reaction in which the "A ring" in general formula (I) connects the nitrogen atom of a triazole with a similar ring structure, and the resulting compound product is easy to crystallize. These characteristics make post-treatment and purification easy.

[0077] Example 6: [ka]

[0078] Step 1 4,6-Dichloro-N-(methyl-d3)pyridazine-3-carboxamide (9.66 g), triazole compound (10.0 g), and ethylene glycol dimethyl ether (200 ml) were sequentially added to a 500 ml single-neck flask and stirred to dissolve and clarify the mixture. The mixture was then cooled to 10-20°C, and LiHMDS (1 M in THF, 110 ml) was added dropwise. The mixture was then stirred at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the reaction mixture was poured into 300 ml of saturated aqueous ammonium chloride, extracted with ethyl acetate, partitioned, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 500 ml of methyl tert-butyl ether was added to the residue to precipitate the solid. The solid was filtered, and the filtrate was concentrated to dryness. 500 ml of a 4:1 mixture of n-hexane and ethyl acetate was added to the concentrate, and the mixture was left overnight to crystallize, yielding 5.3 g of a pale yellow solid.

[0079] Step 2 The product from the previous step (4.0 g), cyclopropanamide (1.4 g), potassium phosphate (5.16 g), BINAP (2.0 g), palladium acetate (182 mg), aluminum trifluoromethanesulfonate (192 mg), and ethylene glycol dimethyl ether (150 ml) were sequentially placed in a 250 ml single-neck flask, and after purging with nitrogen, the mixture was heated to 90°C and reacted overnight. The reaction mixture was cooled to room temperature, poured into 500 ml of water, extracted with ethyl acetate, partitioned, dried, and concentrated to give 6.5 g of crude product, which was used directly in the next step.

[0080] Step 3 The crude product (6.5 g), dichloromethane (70 ml), and tetraethylammonium fluoride (4.2 g) were added to a 250 ml single-neck flask and stirred for 10 minutes. After that, trifluoroacetic acid (60 ml) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was added to 100 ml of saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and pulped with 50 ml of ethyl acetate to obtain 3.5 g of a yellow solid. 1 H NMR(400 MHz,DMSO-d6): δ=11.36(br s,1H),11.00(s,1H),9.17(s,1H),8.32(s,1H),8.16(s,1H),7.76(dd,J=7.9,1.5 Hz,1H),7.55(dd,J=8.0,1.5 Hz,1H),7.31(t,J=7.9 Hz,1H),3.69(s,3H),2.14-2.02(m,1H),0.88-0.75(m,4H). 13 C NMR(100 MHz,DMSO-d6)δ=174.2,167.0,156.3,154.5,150.9,148.6,145.2,135.5,132.6,126.4,125.1,124.7,124.0,97.2,61.6,14.9,8.6.

[0081] Step 4 The product from the previous step (1.3 g), 2-chloroethyl methyl sulfide (1.4 g), N,N-dimethylacetamide (30 ml), potassium carbonate (1.1 g), and sodium iodide (100 mg) were added to a 50 ml single-neck flask, and then the mixture was heated to 100°C and reacted for 1 hour. The reaction solution was poured into 500 ml of water and extracted with ethyl acetate. The organic phases were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain 400 mg of a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6): δ=11.35(s,1H),11.01(s,1H),9.16(s,1H),8.66(s,1H),8.18(s,1H),7.67(dd,J=7.8,1.5 Hz,1H),7.53(dd,J=7.9,1.4 Hz,1H),7.30(t,J=7.9 Hz,1H),4.46(t,J=6.5 Hz,2H),3.72(s,3H),2.99(t,J=6.6 Hz,2H),2.13-2.06(m,1H),2.05(s,3H),0.87-0.79(m,4H). 13 C NMR(100MHz,DMSO-d6): δ=174.2,167.0,159.4,156.3,151.0,145.6,145.2,135.5,133.0,126.6,126.5,124.8,123.2,97.2,61.6,48.6,33.4,14.8,8.6. MS: m / z 486.2 [M+H] + .

[0082] Step 5 The product from the previous step (360 mg), acetic acid (10 ml), NaIO (500 mg), and two drops of water were added to a 50 ml single-neck flask, and the mixture was then heated to 50°C and reacted for 2 hours. The reaction mixture was added to 100 ml of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 250 mg of a pale yellow solid. 1H NMR(400 MHz,DMSO-d6): δ=11.35(s,1H),11.01(s,1H),9.16(s,1H),8.70(s,1H),8.17(s,1H),7.67(dd,J=7.9,1.6 Hz,1H),7.53(dd,J=8.0,1.5 Hz,1H),7.29(t,J=7.9 Hz,1H),4.68(t,J=6.6 Hz,2H),3.73(s,3H),3.38(t,J=6.6 Hz,2H),2.62(s,3H),2.13-2.03(m,1H),0.89-0.75(m,4H). 13 C NMR(100MHz,DMSO-d6): δ=174.2,167.0,159.6,156.3,151.0,145.6,145.2,135.5,133.0,126.51,126.48,124.8,123.3,97.2,61.6,52.6,43.2,38.6,14.9,8.6. MS: m / z 502.2 [M+H] + .

[0083] Example 7: [ka]

[0084] Step 1 In a 2000ml single-neck flask, methyl 2-methoxy-3-nitrobenzoate (55g), ammonia methanol solution (7M, 1200ml) and aqueous ammonia (500ml) were added, and then stirred at room temperature for 17 hours. After the reaction was completed, the mixture was concentrated to dryness, pulped with 1000ml of water for 10 minutes, filtered, and the filter cake was washed twice with water. The filter cake was collected and dried to obtain 50g of a yellow solid. 1 H NMR(400 MHz,CDCl3): δ 8.27(dd,J=7.9,1.8 Hz,1H),7.95(dd,J=8.1,1.8 Hz,1H),7.43(br s,1H),7.36(t,J=8.0 Hz,1H),6.85(br s,1H),4.01(s,3H).MS: m / z 197.1 [M+H] + .

[0085] Step 2 2-Methoxy-3-nitrobenzamide (50 g) and N,N-dimethylformamide dimethyl acetal (DMF-DMA, 300 ml) were added to a 3000 ml single-neck flask, followed by stirring at 95°C for 1 hour, concentrating to dryness, and azeotroping twice with 1,2-dichloroethane. To the concentrate, absolute ethanol (2000 ml) and acetic acid (250 ml) were added, and hydrazine hydrate (120 ml) was slowly added dropwise in an ice bath. The mixture was then stirred at room temperature for 6 hours. After the reaction was complete, the mixture was concentrated to dryness, 1000 ml of water was added, and the mixture was stirred for 10 minutes. The mixture was filtered, the filter cake was washed with water, and the filter cake was collected and dried to obtain 55 g of a yellow solid. 1 H NMR(400 MHz,DMSO-d6): δ 8.55(s,1H),8.22(dd,J=7.9,1.6 Hz,1H),7.99(dd,J=8.0,1.4 Hz,1H),7.46(t,J=8.0 Hz,1H),3.81(s,3H). MS: m / z 221.1 [M+H] + .

[0086] Step 3 The product from the previous step (10 g), N,N-diisopropylethylamine (8.2 g), 4-dimethylaminopyridine (55.5 mg), and dichloromethane (150 ml) were added to a 500 ml single-neck flask, and 2-(trimethylsilyl)ethoxymethyl chloride (9.1 g) was added dropwise at room temperature. The mixture was then stirred at room temperature for 3 hours, and the reaction was monitored by TLC until approximately 50% reaction had reached completion. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate and washed three times with water (200 ml each time). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to yield 5.3 g of a yellow oil. The product was an isomer mixture in a ratio of approximately 62:38. The hydrogen spectrum of the isomer with the higher content was as follows: 1H NMR(400 MHz,CDCl3): δ 8.36(s,1H),8.26(dd,J=7.8,1.7 Hz,1H),7.83(dd,J=8.1,1.7 Hz,1H),7.32(t,J=8.0 Hz,1H),5.60(s,2H),3.96(s,3H),3.73(t,J=8.2 Hz,2H),0.97(t,J=8.3 Hz,2H),0.01(s,9H). MS: m / z 351.2 [M+H] + .

[0087] Step 4 The product from the previous step (5.3 g), ethanol (150 ml), and 5% palladium on carbon (530 mg) were added to a 500 ml single-neck flask. The atmosphere was then completely purged with hydrogen gas, and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated to give 4.8 g of a yellow oil. MS: m / z 321.2 [M+H] + .

[0088] Step 5 The product from the previous step (4.8 g), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (2.97 g), and tetrahydrofuran (20 ml) were added to a 250 ml single-neck flask, purged with nitrogen, and bis(trimethylsilyl)aminolithium (35.7 ml) was slowly added dropwise in an ice bath. The reaction was then continued for 0.5 hours. After the reaction was complete, the reaction mixture was added to 50 ml of aqueous ammonium chloride, followed by 200 ml of water and 200 ml of ethyl acetate. The mixture was stirred, allowed to stand, partitioned, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 5 g of a yellow oil. MS: m / z 493.2 [M+H] + .

[0089] Step 6 The product from the previous step (5 g), cyclopropanamide (1.2 g), cesium carbonate (19 g), BINAP (1.6 g), toluene (150 ml), and palladium acetate (262 mg) were added to a 500 ml single-neck flask, which was then fully purged with nitrogen and reacted at 90°C for 1.5 hours. After analysis to confirm the complete reaction, the mixture was cooled to room temperature, diluted with 200 ml of water, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 3 g of a yellow oil. MS: m / z 542.3 [M+H] + .

[0090] Example 8: [ka]

[0091] Step 1 6-(cyclopropylamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (3 g), 2-(Boc-amino)-ethyl bromide (4.8 g), potassium carbonate (2.18 g), sodium iodide (200 mg), and DMSO (70 ml) were added to a 100 ml single-neck flask, and the mixture was then heated to 100 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched by adding water, and extracted with ethyl acetate. The organic layers were combined, washed three times with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 800 mg of a pale yellow solid in 19% yield. MS: m / z 555.3 [M+H] + .

[0092] Step 2 The product (800 mg) from the previous step and dichloromethane (20 ml) were added to a 100 ml single-neck flask, and TFA (10 ml) was slowly added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the concentrate, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate) to obtain 600 mg of an off-white solid product.

[0093] Step 3 Carbon disulfide (0.5 g) and tetrahydrofuran (50 ml) were added to a 100 ml single-neck flask, and the atmosphere was replaced with nitrogen. Methylmagnesium bromide (1 M) was slowly added dropwise at room temperature, and after the addition was complete, the mixture was heated to 65°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and 1-chlorobenzotriazole (1 g) was added. The mixture was then stirred at room temperature for 20 minutes to prepare the reaction mixture.

[0094] The product (350 mg) from the previous step and DMF (35 ml) were added to a 50 ml single-neck flask, and the above-mentioned preliminary reagent (9 ml) was slowly added dropwise at room temperature and stirred for 30 minutes. After the reaction was completed, the mixture was quenched by slowly pouring into water and extracted with ethyl acetate. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 180 mg of a reddish-brown solid. 1 H NMR (400 MHz, CDCl3): δ 10.99(s,1H),9.86(s,1H),8.70(s,1H),8.17-8.10(m,3H),7.83(dd,J=7.9,1.5 Hz,1H),7.52(dd,J=7.9,1.4 Hz,1H),7.29(t,J=7.9 Hz,1H),4.57-4.54(m,2H),4.22-4.18(m,2H),3.83(s,3H),2.55(s,3H),1.87-1.81(m,1H),1.09-1.05(m,2H),0.95-0.88(m,2H). 13C NMR(100MHz,CDCl3): δ 202.4,173.6,166.8,160.5,155.7,151.4,146.0,144.2,134.8,132.2 ,127.2,125.7,124.9,124.3,98.1,61.5,47.0,45.1,34.0,16.0,8.9. MS: m / z 513.2[M+H] + .

[0095] Example 9: [ka]

[0096] Step 1 Concentrated hydrochloric acid (40 ml) and water (40 ml) were added to a 500 ml three-neck flask. An aqueous solution (20 ml) of sodium nitrite (2.1 g, 30.4 mmol) was slowly added dropwise in an ice bath, and the mixture was stirred at 0-5°C for 1 hour. A solution (20 ml) of stannous chloride (17.1 g, 90.2 mmol) in concentrated hydrochloric acid was slowly added dropwise, and the mixture was stirred at 0-5°C for 2 hours. After the reaction was complete, the mixture was filtered through a pad of diatomaceous earth. The filtrate was adjusted to approximately pH 8 with saturated aqueous sodium hydroxide and extracted with ethyl acetate. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Methyl tert-butyl ether (30 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The filter cake was dried to obtain 2.4 g of a yellow solid. MS: m / z 184.1 [M+H] + .

[0097] Step 2 The product from the previous step (2.4 g), 1,1,3,3-tetramethoxypropane (2.6 g), and absolute ethanol (60 ml) were added to a 100 ml single-neck flask, heated to 80°C, and stirred for 2 hours. Concentrated hydrochloric acid (1.5 ml) was slowly added dropwise, and the mixture was stirred at 80°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated to dryness, and saturated aqueous NaHCO3 was slowly added to adjust the pH of the aqueous phase to 7-8. The mixture was extracted with ethyl acetate, and the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 2.8 g of a pink solid. MS: m / z 220.1 [M+H] + .

[0098] Step 3 The product from the previous step (2.8 g, 12.8 mmol), 5% Pd / C (1 g), and methanol (60 ml) were added to a 100 ml single-neck flask, purged with hydrogen gas, and stirred at room temperature for 5 hours. After completion of the reaction, the mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated to give 1.8 g of a pink solid. MS: m / z 190.1 [M+H] + .

[0099] Step 4 The product from the previous step (1.8 g, 9.6 mmol), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (3.0 g, 14.4 mmol), and ethylene glycol dimethyl ether (70 mL) were added to a 250 mL three-neck flask, purged with nitrogen, cooled to 10-15°C, and LiHMDS (1 M in THF, 38.4 mL) was slowly added dropwise and reacted at room temperature for 30 minutes. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Methyl tert-butyl ether (60 mL) was added, stirred at room temperature for 20 minutes, filtered, and the filter cake was dried to give 2.8 g of a pale yellow solid. MS: m / z 362.1 [M+H] + .

[0100] Step 5 The product from the previous step (1.5 g), cyclopropanamide (530 mg), cesium carbonate (6.8 g), ethylene glycol dimethyl ether (60 ml), 1,1'-bis(dicyclohexylphosphine)-ferrocene (961 mg), and palladium acetate (95 mg) were placed in a 100 ml single-neck flask, heated to 90°C, and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Methyl tert-butyl ether (60 ml) was added, and the mixture was stirred at room temperature for 20 minutes. After filtration, the filter cake was dissolved in dichloromethane (20 ml), methyl tert-butyl ether (80 ml) was slowly added, and the mixture was stirred at room temperature for 20 minutes. After filtration, the filter cake was dried to obtain 950 mg of an off-white solid. 1 H NMR(400 MHz,DMSO-d6): δ 11.38(s,1H),11.07(s,1H),9.18(s,1H),8.22(d,J=2.4 Hz,1H),8.21(s,1H),7.78(d,J=1.7 Hz,1H),7.47(td,J=8.5,1.6 Hz,2H),7.32(t,J=8.1 Hz,1H),6.57(t,J=2.1 Hz,1H),3.46(s,3H),2.14-2.04(m,1H),0.88-0.79(m,4H). 13 C NMR(100MHz,DMSO-d6): δ MS: m / z 411.2 [M+H] + .

[0101] Example 10: [ka]

[0102] Step 1 A 250 ml three-neck flask was charged with 80% hydrazine hydrate (32.8 g) and water (60 ml), and a solution of p-methylbenzenesulfonyl chloride (10.0 g) in tetrahydrofuran (30 ml) was slowly added dropwise in an ice bath. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the tetrahydrofuran was concentrated, cooled to room temperature, filtered, and the filter cake was dried to obtain 8.3 g of a white solid. MS: m / z 187.1 [M+H] + .

[0103] Step 2 The product from the previous step (4.8 g), 2,2-dimethoxyacetaldehyde (3.6 g), and methanol (60 ml) were placed in a 100 ml single-neck flask, purged with nitrogen, and stirred at room temperature for 3 hours. Acetic acid (1.3 g) and 2-methoxy-3-nitroaniline (3 g) were added, heated to 75°C, and stirred for 16 hours. After the reaction was complete, the mixture was concentrated to dryness, and saturated aqueous NaHCO3 was slowly added to adjust the pH of the aqueous phase to 7-8. The mixture was extracted with ethyl acetate. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to yield 3.8 g of an off-white solid. 1 H NMR(400 MHz,DMSO-d6): δ 8.63(d,J=1.2 Hz,1H),8.16(dd,J=8.2,1.6 Hz,1H),8.05(d,J=1.1 Hz,1H),8.03(dd,J=8.1,1.6 Hz,1H),7.57(t,J=8.2 Hz,1H),3.53(s,3H).MS: m / z 221.1 [M+H] + .

[0104] Step 3 The product from the previous step (3.7 g), 5% Pd / C (2 g), and methanol (70 ml) were added to a 100 ml single-neck flask, purged with hydrogen gas, and stirred at room temperature for 5 hours. After completion of the reaction, the mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated to give 3.0 g of an off-white solid. MS: m / z 191.1 [M+H] + .

[0105] Step 4 The product from the previous step (3.0 g), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (5.0 g), and ethylene glycol dimethyl ether (80 ml) were added to a 250 ml three-neck flask, purged with nitrogen, cooled to 10-15°C, and LiHMDS (1 M in THF) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 30 minutes. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Methyl tert-butyl ether (100 ml) was added, stirred at room temperature for 20 minutes, filtered, and the filter cake was dried to give 4.6 g of a yellow solid. MS: m / z 363.1 [M+H] + .

[0106] Step 5 The product of the previous step (1.5 g), cyclopropanamide (529 mg), cesium carbonate (6.8 g), ethylene glycol dimethyl ether (60 ml), 1,1'-bis(dicyclohexylphosphine)-ferrocene (961 mg), and palladium acetate (95 mg) were placed in a 100 ml single-neck flask, heated to 90°C, and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added, extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 230 mg of an off-white solid. 1 H NMR(400 MHz,DMSO-d6): δ 11.41(s,1H),11.09(s,1H),9.20(s,1H),8.56(s,1H),8.22(s,1H),8.01(s,1H),7.66(d,J=8.0 Hz,1H),7.49(d,J=8.1 Hz,1H),7.41(t,J=8.0 Hz,1H),3.47(s,3H),2.14-2.05(m,1H),0.90-0.78(m,4H). 13C NMR(100 MHz,DMSO-d6): δ 174.3,167.0,156.4,146.0,144.8,135.5,134.3,133.3,131.8,127.1,125.5,123.6,122.4,97.5,61.7,14.9,8.7. MS: m / z 412.2 [M+H] + .

[0107] Example 11: [ka]

[0108] Step 1 A 500 mL single-neck flask was charged with tetrazole compound (18 g), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (15 g), lithium chloride (5.8 g), and dry tetrahydrofuran (350 mL). The atmosphere was then purged with nitrogen and cooled to 0°C in an ice bath. Bis(trimethylsilyl)aminolithium (150 mL) was added, and the mixture was allowed to warm to room temperature and react for 2 hours. The reaction mixture was poured into 500 mL of saturated aqueous ammonium chloride, extracted with ethyl acetate (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was added to 200 mL of dichloromethane to dissolve and clarify the solution. Triethylamine (3 g) and triphenylmethane (8 g) were added, and the mixture was stirred at room temperature for 30 minutes to remove any unreacted tetrazole precursor. After the reaction was completed, the reaction mixture was washed with 200 ml of water and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 19.0 g of a pale yellow oil.

[0109] Step 2 The product from the previous step (19 g), cyclopropanamide (6.6 g), BINAP (9.6 g), cesium carbonate (62.8 g), and toluene (450 ml) were placed in a 500 ml single-neck flask, which was then fully purged with nitrogen. The mixture was heated to 60°C, followed by the addition of palladium acetate (865 mg). The mixture was then heated to 90°C and reacted for 5 hours, during which the remaining raw materials were monitored by TLC. The reaction mixture was poured into 500 ml of water, extracted with ethyl acetate (300 ml), and the organic phase was concentrated and purified by silica gel column chromatography to yield 10 g of a yellow solid.

[0110] Step 3 Tetraethylammonium fluoride dihydrate (100 g) was added to a 250 ml single-neck flask and heated to 85°C to melt. The product from the previous step (10 g) was added and the mixture was allowed to react for 3 hours while maintaining the temperature. The remaining raw material was monitored by TLC. The reaction mixture was poured into 500 ml of water and stirred for 20 minutes to precipitate a large amount of solid. The precipitate was filtered, and the filter cake was washed with 200 ml of water. The filter cake was transferred to a 250 ml single-neck flask, 100 ml of ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes. The filter cake was then dried to obtain 5 g of a pale yellow solid.

[0111] Step 4 The product from the previous step (2.5 g), N,N-dimethylacetamide (50 ml), and bromopropylene (5.7 g) were added to a 100 ml single-neck flask and stirred at room temperature for 20 min. Potassium carbonate (5.9 g) was added all at once, and the mixture was stirred at room temperature for 3 h. The reaction was monitored for completion by LTC. The reaction solution was poured into 500 ml of ice water and extracted twice with 200 ml of ethyl acetate. The organic phase was washed three times with 300 ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 1.5 g of crude product. The crude product was purified by silica gel column chromatography and pulped with ethyl acetate (50 ml) to yield 650 mg of an off-white solid. 1H NMR(400 MHz,DMSO-d6): δ 11.38(s,1H),11.06(s,1H),9.18(s,1H),8.18(s,1H),7.73(dd,J=7.8,1.5 Hz,1H),7.67(dd,J=8.0,1.4 Hz,1H),7.39(t,J=7.9 Hz,1H),5.83(d,J=2.6 Hz,2H),3.77(t,J=5.2 Hz,1H),3.75(s,3H),2.15-2.03(m,1H),0.90-0.75(m,4H). 13 C NMR(100MHz,DMSO-d6): δ MS: m / z 451.2 [M+H] + .

[0112] Example 12: [ka]

[0113] Step 1 Ethyl 5-hydroxyl-3-(methylthio)-1,2,4-triazine-6-carboxylate (4 g) and tetrahydrofuran (70 ml) were added to a reaction flask and cooled to 0°C. DIPEA (6.5 ml) and NMM (94 mg) were added slowly in that order, and triclosan rin (2.6 ml) was added dropwise while controlling the temperature below 3°C. The mixture was then reacted for 1 hour. n-Hexane was added to the reaction mixture, which was stirred for 10 minutes, suction filtered through a pad of diatomaceous earth, the filter cake was washed once with n-hexane, and the filtrate was concentrated to give 3.13 g of a pale yellow solid.

[0114] NMP (30 ml) and triazole-SEM compound (4.7 g) were added to the concentrate and reacted at room temperature for 1 hour. Saturated ammonium chloride (10 ml) and water (20 ml) were added to the reaction mixture, which was stirred in an ice bath for 30 minutes, filtered under suction, and the filter cake was washed twice with water and dried to obtain 6.9 g of a pale yellow solid. MS: m / z 518.2 [M+H] + .

[0115] Step 2 The product from the previous step (6.9 g), deuterated methylamine hydrochloride (1.32 g, 18.7 mmol), lithium bromide (4.6 g), acetonitrile (120 ml), and DIPEA (12 ml) were added sequentially to a reaction flask, and the atmosphere was purged with nitrogen. The mixture was then stirred at room temperature for 45 minutes. The reaction mixture was extracted with saturated ammonium chloride (50 ml) and ethyl acetate (30 ml x 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4.65 g of a pale yellow solid. MS: m / z 506.2 [M+H] + .

[0116] Step 3 The product from the previous step (4.5 g), ammonia methanol solution (7 M), and aqueous ammonia (70 ml) were added to a reaction flask, and then the mixture was slowly heated to 110°C and reacted for 6 hours. The reaction mixture was concentrated to a small volume, suction filtered, and the filtrate was extracted twice with dichloromethane. The filter cake solids were combined and dissolved in dichloromethane. The dichloromethane solutions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4.2 g of a yellow solid. MS: m / z 475.2 [M+H] + .

[0117] Step 4 The product from the previous step (4.2 g), dichloromethane (80 ml), and 2,6-dimethylpyridine (5.7 g) were added sequentially to a reaction flask, and the atmosphere was purged with nitrogen. The mixture was then cooled to 0°C, and cyclopropanoyl chloride (2.3 g) was slowly added dropwise. The reaction mixture was then allowed to react for 30 minutes. Saturated ammonium chloride quenching agent was added to the reaction mixture, which was then extracted three times with MTBE. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography to give 4.2 g of a pale yellow solid. MS: m / z 543.3 [M+H] + .

[0118] Step 5 The product from the previous step (4.2 g), dichloromethane (4 ml), and TFA (80 ml) were added to a reaction flask, and the mixture was heated to 40° C. and reacted for 30 minutes. The mixture was concentrated to dryness under reduced pressure, and THF (80 ml) and sodium bicarbonate (20 g) were added. The mixture was stirred until no bubbles remained, and then suction filtered. The filtrate was dried, concentrated to dryness, and used directly in the next step.

[0119] Step 6 The product from the previous step, DMF (40 ml), and potassium carbonate (2.1 g) were added to a reaction flask, followed by dropwise addition of bromopropylene (7.4 g) at room temperature. The reaction was then allowed to proceed for 1 hour. Water was added to quench the reaction, followed by extraction with MTBE three times. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography to obtain 134 mg of a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6): δ 12.15(s,1H),11.43(s,1H),9.29 - 9.18(m,2H),8.70(s,1H),7.60(dd,J=7.8,1.4 Hz,1H),7.23(t,J=8.1 Hz,1H),5.24(d,J=2.4 Hz,2H),3.84(s,3H),3.61(t,J=2.5 Hz,1H),2.25 - 2.14(m,1H),0.98 - 0.87(m,4H). MS: m / z 451.2 [M+H] + .

[0120] Example 13: [ka]

[0121] Step 1 2-Hydroxyl-3-nitroacetophenone (30 g), potassium carbonate (46 g), and N,N-dimethylformamide (300 ml) were added sequentially to a 1000 ml three-neck flask and then stirred at room temperature. Iodomethane (38.4 g) was slowly added dropwise, and the mixture was then reacted at room temperature for 20 minutes, heated to 50°C, and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, saturated brine (500 ml) was added, and the mixture was extracted three times with methyl tert-butyl ether. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield 34.9 g of a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ 7.94(dd,J=8.0,1.8 Hz,1H),7.82(dd,J=7.8,1.8 Hz,1H),7.30(t,J=7.9 Hz,1H),3.95(s,3H),2.67(s,3H).

[0122] Step 2 The product from the previous step (32 g), DMF-DMA (39 g), and toluene (200 ml) were sequentially added to a 500 ml three-neck flask. The mixture was purged under nitrogen protection and refluxed at 110 °C for 6 hours. The mixture was concentrated under reduced pressure to remove most of the solvent. To the concentrate was added acetic acid (20.8 g), 80% hydrazine hydrate (16.4 g), and tetrahydrofuran (300 ml). The mixture was heated to 65 °C and stirred overnight. After completion of the reaction, the mixture was concentrated to remove most of the solvent. Ethyl acetate (1000 ml) was added, washed three times with water (300 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove most of the solvent. Petroleum ether (600 ml) was added, and the mixture was pulped at room temperature for 30 minutes. It was then filtered and dried to yield 32.5 g of a yellow solid. 1H NMR(400 MHz,DMSO-d6): δ 13.20(s,1H),8.17(d,J=7.6 Hz,1H),7.90(s,1H),7.83(d,J=7.7 Hz,1H),7.38(t,J=7.9 Hz,1H),6.77(d,J=2.1 Hz,1H),3.71(s,3H).MS: m / z 242.1 [M+Na] + .

[0123] Step 3 The product from the previous step (21 g), diisopropylethylamine (18.6 g), DMAP (1.17 g), and dichloromethane (210 ml) were added to a 1000 ml three-neck flask and stirred for 10 minutes. A solution of SEM-Cl (38.4 g) in dichloromethane (50 ml) was slowly added dropwise, and the mixture was allowed to react at room temperature. The reaction was quenched by adding saturated ammonium chloride solution (400 ml) to the mixture, followed by partitioning. The organic phase was washed twice with NH4Cl solution (400 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 38 g of a yellow oil (containing a small amount of SEM-Cl). MS: m / z 372.1 [M+Na] + .

[0124] Step 4 The product from the previous step (38 g), 5% palladium on carbon (3.8 g), and ethanol (380 ml) were added to a 1000 ml single-neck flask, and the mixture was then completely purged with hydrogen gas and reacted overnight at room temperature. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 22 g of a dark red liquid. MS: m / z 320.2 [M+H] + .

[0125] Step 5 A 3-L three-neck flask was charged with the product from the previous step (22 g), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (18.9 g), lithium chloride (8 g), and 2-methyltetrahydrofuran (400 ml). The mixture was then cooled to 0°C, and LiHMDS (194 ml) was slowly added dropwise. The mixture was then allowed to warm to room temperature and react for 1 hour, during which TLC monitored for incomplete reaction of a small amount of the starting material. Saturated ammonium chloride solution (400 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (400 ml). The organic phase was washed twice with saturated brine (300 ml), dried over anhydrous sodium sulfate, and filtered. Triphenylmethane (19.2 g) and triethylamine (20 ml) were added to the filtrate, which was then stirred at room temperature to remove any unreacted starting material (aniline compound). The reaction mixture was washed three times with saturated ammonium chloride solution (400 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and purified by silica gel column chromatography to give 26.3 g of a yellow solid. MS: m / z 492.2 [M+H] + .

[0126] Step 6 The product from the previous step (14.3 g), cyclopropanamide (4.76 g), BINAP (7.15 g), palladium acetate (0.66 g), cesium carbonate (47.6 g), and toluene (200 ml) were added to a 250 ml single-neck flask. The mixture was then purged with nitrogen, heated to 90°C, and reacted for 8 hours. The reaction mixture was monitored by TLC. After completion of the reaction, water (400 ml) was added to the reaction mixture, extracted three times with ethyl acetate, and the combined organic phases were washed once with saturated brine (300 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 10.8 g of a pale yellow solid. MS: m / z 541.3 [M+H] + .

[0127] Step 7 The product from the previous step (5.4 g) and tetraethylammonium fluoride trihydrate (25 g) were added to a 250 ml single-neck flask and reacted at 85°C overnight. The reaction was monitored by TLC. After the reaction was complete, a large amount of water was added and the mixture was stirred for 30 minutes to precipitate a white solid. The precipitate was filtered. The filter cake was dissolved in ethyl acetate (200 ml) and washed three times with water (200 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. An appropriate amount of a mixed solvent of ethyl acetate and methanol (80:1) was added, and the mixture was pulped for 30 minutes. After filtration, a white solid was obtained. The white solid was added to a 50 ml single-neck flask, pulped with 20 ml of ethyl acetate for 1 hour, suction filtered, and dried to obtain 1.7 g of an off-white solid. MS: m / z 411.2 [M+H] + .

[0128] Step 8 N,N-dimethylacetamide (15 ml), the product from the previous step (2.0 g), and 3-bromopropylene (5.2 g) were added to a 50 ml single-neck flask and stirred to dissolve and clarify the mixture. Potassium carbonate (5.4 g) was added all at once, and the mixture was allowed to react at room temperature for 24 hours. After the reaction was complete, water (300 ml) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed three times with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 0.5 g of a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6): δ 11.34(s,1H),11.00(s,1H),9.16(s,1H),8.18(s,1H),7.90(s,1H),7.69(d,J=7.5 Hz,1H),7.41(d,J=7.3 Hz,1H),7.24(t,J=7.7 Hz,1H),6.79(s,1H),5.13(s,2H),3.61(s,3H),3.53(s,1H),2.19-1.99(m,1H),0.96-0.73(m,4H). MS: m / z 449.2126 [M+H] + .

[0129] Example 14: [ka]

[0130] Step 1 A reaction flask was charged with 250.0 g of 2-chloro-3-methoxypyridine and 2.5 L of tetrahydrofuran, and cooled to -75 ± 5 °C under nitrogen protection. LDA (1.13 L) was added dropwise, controlling the temperature at -75 ± 5 °C. After the dropwise addition, the mixture was allowed to react for 2.5 to 3 hours while maintaining the temperature at -75 ± 5 °C. A solution of 274.5 g of iodine in 500 ml of tetrahydrofuran was added dropwise, controlling the temperature at -75 ± 5 °C. After the dropwise addition, the mixture was allowed to naturally warm to 20 to 30 °C and reacted for 2 to 3 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (4.0 L) and saturated aqueous sodium thiosulfate solution (4.0 L) were added dropwise, successively, while controlling the temperature at 20 ± 5 °C. The mixture was then stirred. Extracted twice with n-hexane, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 420.0 g of a brown oily solid mixture, which was pulped and dried to give 274.0 g of a yellow solid. MS: m / z 269.9, [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.78 (d, J=5.0 Hz, 1H), 7.66 (d, J=5.0 Hz, 1H), 3.91 (s, 3H).

[0131] Step 2 2-Chloro-4-iodo-3-methoxypyridine (100 g), N-methylpyrrolidone (500 ml), and cuprous cyanide (66.3 g, 0.74 mol) were added sequentially to a reaction flask, heated to 120±5°C, and stirred for 4 to 6 hours. After the reaction was complete, the mixture was cooled to room temperature, and 500 ml of aqueous ammonia was added dropwise. The temperature was controlled at 20±5°C, and the mixture was then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 54.3 g of a brown solid. This was purified by silica gel column chromatography to give 32.1 g of a white solid. MS: m / z 169.0, [M+H] + . 1H NMR (400MHz, DMSO-d6): δ 8.35 (d, J=5.0 Hz, 1H), 7.90 (d, J=4.9 Hz, 1H), 4.09 (s, 3H).

[0132] Step 3 2-Chloro-3-methoxyisonicotinonitrile (3.0 g), methylformylhydrazine (3.9 g), and tetrahydrofuran (80 ml) were sequentially added to a reaction flask and cooled to 0°C. A solution of potassium tert-butoxide (4.4 g) in tetrahydrofuran (50 ml) was slowly added dropwise, controlling the temperature at 0±5°C. After the dropwise addition, the mixture was allowed to react for 0.5 to 1 hour while maintaining the temperature at 0±5°C. After the reaction was complete, the mixture was poured into saturated aqueous ammonium chloride (130 ml), extracted with ethyl acetate, combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3.5 g of a white solid. Purification by column chromatography yielded 1.1 g. MS: m / z 225.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ 8.68(s,1H),8.25(d,J=5.0 Hz,1H),7.90(d,J=5.0 Hz,1H),3.99(s,3H),3.87(s,3H).

[0133] Step 4 The product from the previous step (1.0 g), 4-methoxybenzylamine (10.8 g), tris(dibenzylideneacetone)dipalladium-chloroform adduct (0.46 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.1 g), cesium carbonate (4.35 g), and 1,4-dioxane (30 ml) were sequentially added to a reaction flask. Under nitrogen protection, the mixture was heated to 90±5°C and maintained at that temperature for 14-16 hours. After completion of the reaction, the mixture was cooled to 20-30°C, water was added, and the mixture was extracted with ethyl acetate and concentrated to obtain 4.5 g of an oily crude product. MS: m / z 326.2 [M+H] + .

[0134] Step 5 The crude product (4.5 g) from the previous step and trifluoroacetic acid (45 ml) were added sequentially to a reaction flask, heated to 90±5°C, and allowed to react for 1-2 hours. After the reaction was complete, the mixture was concentrated to dryness, dissolved in methanol (110 ml), and the pH was adjusted to 7-8 with sodium bicarbonate. The mixture was stirred for 30 minutes, filtered, and concentrated to give 2.51 g of a brown oily substance. This was purified by silica gel column chromatography to give 2.1 g of a yellow oily solid mixture. MS: m / z 206.1, [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ 8.62(s,1H),7.73(d,J=5.6 Hz,1H),7.05(d,J=5.8 Hz,1H),6.77(br s,2H),3.96(s,3H),3.73(s,3H).

[0135] Step 6 A reaction flask was charged with 3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-amine (1.2 g, 5.85 mmol), 4,6-dibromo-N-(methyl-d3)pyridazine-3-carboxamide (2.27 g), and N,N-dimethylformamide (24 mL), followed by cooling to 0±5°C under nitrogen protection. Sodium hydride (0.94 g) was added and the mixture was stirred at 0±5°C for 0.5-1 hour. The mixture was then allowed to warm to 20±5°C and allowed to react for 3-4 hours. After completion of the reaction, the reaction mixture was added dropwise to saturated aqueous ammonium chloride solution, the temperature was controlled at 10±5°C, and the mixture was stirred for 1-2 hours. The mixture was then filtered, and the solid was washed twice with water and dried to give 0.84 g of a brown solid. MS: m / z 424.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6): δ 12.56(s,1H),9.48(s,1H),9.37(s,1H),8.68(s,1H),8.22(d,J=5.3 Hz,1H),7.56(d,J=5.2 Hz,1H),3.99(s,3H),3.91(s,3H).

[0136] Step 7 The product from the previous step (400 mg), N-methylpyrrolidone (16 mL), cyclopropanethiocarboxamide (288.3 mg, 2.85 mmol), tricyclohexylphosphine (106.6 mg), N-methyldicyclohexylamine (556.7 mg), and bis(tri-tert-butylphosphine)palladium (97.5 mg) were sequentially added to a reaction flask. Under nitrogen protection, the mixture was heated to 110±5°C and allowed to react for 1-2 hours. After completion of the reaction, the mixture was cooled to 20±5°C, added dropwise to an aqueous solution of glacial acetic acid, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.2 g of a brown oil. This was purified by silica gel column chromatography to give 30.0 mg of a yellow solid. MS m / z 443.2 [M+H] + .

[0137] Example 15: [ka]

[0138] Step 1 Ethyl 4,6-dihydroxypyridazine-3-carboxylate (8.5 g) and acetonitrile (100 ml) were placed in a 250 ml single-neck flask and cooled to 0°C under nitrogen. A solution of phosphoryl bromide (39.7 g) in acetonitrile was added dropwise, then allowed to warm to room temperature and stirred at 25°C, 55°C, 75°C, and 95°C for 40 minutes. The reaction mixture was monitored by TLC. 50 ml of ethyl acetate was added to the mixture, filtered, and the filtrate was concentrated to dryness. The concentrate was dissolved in 100 ml of dichloromethane and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was partitioned and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to yield 9.36 g of a yellow solid product.

[0139] Step 2 In a 100 ml single-neck flask, add the product from the previous step (7.3 g), DMA (75 ml), trifluoroethanol (2.61 g)and potassium carbonate (4.9 g) were added, and the mixture was stirred at room temperature overnight. 200 ml of water was added to the mixture, which was then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The concentrate was pulped with a mixed solvent of methyl tert-butyl ether and n-hexane to obtain 4.86 g of a brown solid. 1 H NMR(400 MHz,CDCl3): δ 7.29(d,J=6.9 Hz,1H),4.62-4.45(m,4H),1.43(t,J=7.1 Hz,3H). MS: m / z 329.0 [M+H] + .

[0140] Step 3 The product from the previous step (4.86 g), acetonitrile (100 ml), and lithium bromide (5.15 g) were placed in a 250 ml single-neck flask and stirred under nitrogen at room temperature for 30 min. The mixture was then cooled to -26 °C, diisopropylethylamine (9.58 g) was added, and the mixture was stirred for 10 min. Deuterated methylamine hydrochloride (1.04 g) was added in one portion at -30 °C, and the reaction was continued for 2 h at -25 °C, after which TLC showed the reaction was nearly complete. 200 ml of ice water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was pulped with petroleum ether to give 2.93 g of an off-white solid.

[0141] Step 4 The product of the previous step (2.22 g), arylamine compound (1.5 g), lithium bromide (814 mg), and 2-methyltetrahydrofuran (30 ml) were added to a 100 ml single-neck flask. Under nitrogen protection, the mixture was cooled to 0°C, and LiHMDS (18.75 ml) was added dropwise. The mixture was then cooled to room temperature and reacted for 3 hours. TLC showed that the reaction was nearly complete. The reaction was quenched with 10% ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.1 g of a pale yellow solid. 1H NMR(400 MHz,DMSO-d6): δ 11.10(s,1H),9.38(s,1H),8.83(s,1H),7.74(dd,J=7.8,4.1 Hz,1H),7.62(dd,J=7.9,1.0 Hz,1H),7.34-7.31(m,2H),5.58(s,2H),3.71(s,3H),3.66(t,J=8.0 Hz,2H),0.87(t,J=8.0 Hz,2H),-0.06(s,9H). MS: m / z 537.2 [M+H] + .

[0142] Step 5 The product from the previous step (1.42 g), cyclopropanethiocarboxamide (400 mg), tricyclohexylphosphine (222 mg), N,N-dicyclohexylmethylamine (1.55 g), bis(tert-butyltriphosphine)palladium (200 mg), and N-methylpyrrolidone (14 ml) were placed in a 100 ml single-neck flask, purged with nitrogen, and heated to 110°C for 2 hours. After cooling, the mixture was added with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 1.0 g of a yellow oily product. MS: m / z 558.1 [M+H] + .

[0143] Step 6 The product from the previous step (900 mg), dichloromethane (16 ml), tetraethylammonium fluoride (2.7 g), and trifluoroacetic acid (40 ml) were added to a 100 ml single-neck flask and allowed to react for 2 hours with stirring at room temperature. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the concentrate to dissolve and clarify it. The concentrate was then washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 300 mg of a pale yellow solid. 1H NMR(400 MHz,DMSO-d6): δ 14.13(s,1H),12.76(s,1H),11.15(s,1H),9.29(s,1H),8.90(s,1H),8.16(brs,1H),7.74(d,J=6.7 Hz,1H),7.65(d,J=7.7 Hz,1H),7.32(t,J=7.6 Hz,1H),3.72(s,3H),2.80-2.62(m,1H),1.17-1.13(m,2H),1.05-1.01(m,2H). MS: m / z 428.2 [M+H] + .

[0144] Step 7 The product from the previous step (270 mg), DMA (5 ml), and bromopropylene (600 mg) were added to a 100 ml single-neck flask. The temperature was then raised to 50°C, and potassium carbonate (610 mg) was added all at once. Stirring was continued for 3 hours. Water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 30 mg of a yellow solid. MS: m / z 466.2, [M+H] + .

[0145] Example 16: [ka]

[0146] A 25 ml clean single-neck flask was charged with the triazole compound (100 mg), N,N-dimethylformamide (10 ml), methyl 2,4-dibromobutyrate (70 mg), and cesium carbonate (317 mg) in that order, then purged with nitrogen and reacted at 45°C. The reaction was monitored for completion by TLC. The reaction mixture was added to 50 ml of saturated ammonium chloride solution and extracted with ethyl acetate (30 ml). The combined organic phases were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give approximately 200 mg of crude product, which was then purified by silica gel column chromatography to give 80 mg of product. 1H NMR(400 MHz,CDCl3): δ 11.04(s,1H),9.63(s,1H),8.30(s,1H),8.25(s,1H),8.07(s,1H),7.80(dd,J=7.8,1.5 Hz,1H),7.55(dd,J=8.0,1.5 Hz,1H),7.28(t,J=7.9 MS: m / z 510.2 [M+H] + .

[0147] Example 17: [ka]

[0148] A 100 ml single-neck flask was charged with 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (500 mg, 1.33 mmol), cyclopropanesulfonamide (322 mg), potassium phosphate (560 mg), 1,1'-bis(diphenylphosphino)ferrocene (150 mg), tris(dibenzylideneacetone)dipalladium (119 mg), and 1,4-dioxane (15 ml). The atmosphere was then purged with nitrogen and the mixture was stirred at 100°C for 24 hours. The reaction mixture was concentrated to dryness, 20 ml of water was added, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by silica gel column chromatography to yield 330 mg of a yellow solid. 1H NMR (400 MHz, CDCl3): δ 12.61(br s,1H),11.08(s,1H),8.15(s,1H),7.88(dd,J=7.8,1.6 Hz,1H),7.66(s,1H),7.45(dd,J=8.0,1.5 Hz,1H),7.27(t,J=7.9 Hz,1H),4.03(s,3H),3.82(s,3H),2.65-2.52(m,1H),1.22-1.13(m,2H),0.99-0.90(m,2H). 13 C NMR(100 MHz,CDCl3): δ 164.7,160.0,155.9,151.8,146.9,144.0,131.3,131.0,128.2,126.2,124.6,124.3,98.5,61.8,36.5,31.7,5.47. MS: m / z 462.2,[M+H] + .

[0149] Example 18: [ka]

[0150] Step 1: A 250ml single-neck flask was charged with starting material (1g), benzophenone imine (3.0g), palladium acetate (185mg), cesium carbonate (13.4g), 1,1'-bis(dicyclohexylphosphine)-ferrocene (1.9g), aluminum trifluoromethanesulfonate (195mg), and 120ml of dioxane. The mixture was protected with nitrogen and heated to 100°C for 10 hours. After cooling, the mixture was poured into 300ml of water and washed. The mixture was extracted with 300ml of ethyl acetate, partitioned, concentrated, and purified by column chromatography to obtain 2g of a pale yellow solid product. MS: m / z 522.24 [M+H] + ,

[0151] Step 2: A 100ml single-neck flask was charged with the starting material (2.2g) and 80ml of THF, and 16ml of 2M / L HCl was slowly added at room temperature. The mixture was then stirred and reacted for 2 hours. The mixture was poured into 200ml of saturated sodium bicarbonate solution, washed, extracted with 200ml of ethyl acetate, partitioned, dried, concentrated, and purified by column chromatography to obtain 1.1g of a reddish-brown solid product. MS: m / z 358.18, [M+H] + ,

[0152] Step 3: A 250 ml single-neck flask was charged with the raw material (500 mg), 80 ml of dichloromethane for dissolution clarification, and DIPEA (180 mg). The mixture was cooled to 0°C in an ice bath, and 20 ml of a dichloromethane solution of allyl chloride (130 mg) was added dropwise. The mixture was then stirred at room temperature to allow the reaction to proceed. The mixture was washed with 100 ml of water, partitioned, dried, concentrated, and purified by column chromatography to obtain 150 mg of a yellow solid product. 1 H NMR (400 MHz, CDCl3): δ 11.26(s,1H),11.01(s,1H),9.17(s,1H),8.57(s,1H),8.28(s,1H),7.69(dd,J=1.5,7.8 Hz,1H),7.58(dd,J=1.4,7.9 MS: m / z 412.19,[M+H] + .

[0153] Example 19: [ka]

[0154] A 250 ml single-neck flask was charged with 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (1.5 g), cesium carbonate (5.2 g), cyclobutylcarboxamidine hydrochloride (962 mg), palladium acetate (89 mg), 1,1'-bis(dicyclohexylphosphine)-ferrocene (884 mg), and ethylene glycol dimethyl ether (100 ml). The atmosphere was purged with nitrogen, and the temperature was raised to 90°C to allow the reaction to proceed. The reaction mixture was cooled and poured into 200 ml of water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to yield 800 mg of a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6): δ=10.70(s,1H),9.44(br s,1H),9.12(s,1H),8.57(s,1H),8.28(br s,1H),7.64(dd,J=7.8,1.4 Hz,1H),7.51(d,J=7.9 Hz,1H),7.27(t,J=7.9 Hz,1H),6.50(s,1H),3.95(s,3H),3.72(s,3H),1.69-1.57(m,1H),0.98-0.89(m,2H),0.83-0.74(m,2H). 13 C NMR(100MHz,DMSO-d6): δ=167.4,167.0,166.5,159.4,150.9,145.6,144.9,134.3,133.3,126.7,126.2,124.8,123.7,102.9,61.6,36.5,16.0,8.4. MS: m / z 425.2,[M+H] + .

[0155] Example 20: [ka]

[0156] Step 1 A reaction flask was charged with 3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-amine (1.4 g) and N,N-dimethylformamide (50 ml), cooled to 0°C, and sodium hydride (1.1 g) was added in one portion. The mixture was then stirred for 20 min, slowly warmed to room temperature, and stirred for 30 min. The reaction mixture was cooled to 0°C, and a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (4.3 g) in tetrahydrofuran (40 ml) was slowly added dropwise over 3 hours while maintaining the temperature below 5°C. The mixture was then stirred overnight. Aqueous ammonium chloride solution (20 ml) and water (40 ml) were added to the reaction mixture, which was stirred for 30 min. The mixture was then suction filtered, the filter cake was washed twice with water, and the filter cake was dried to obtain 1.82 g of an off-white solid. MS: m / z 378.1 [M+H] + .

[0157] Step 2 The product from the previous step (1.82 g, 4.8 mmol), DCPF (1.1 g), palladium acetate (108 mg), cesium carbonate (7.9 g), and DME (60 ml) were added sequentially to a reaction flask, and after purging with nitrogen, the mixture was heated to 90°C and reacted for 1 hour. The reaction mixture was cooled to room temperature and subjected to suction filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain 430 mg of a pale yellow solid compound. 1 H NMR(400 MHz,DMSO-d6): δ 12.44(s,1H),11.36(s,1H),9.89(s,1H),9.25(s,1H),8.67(s,1H),8.14(d,J=5.2 Hz,1H),7.50(d,J=5.2 Hz,1H),4.00(s,3H),3.91(s,3H),2.20-2.09(m,1H),0.96-0.81(m,4H). 13 C NMR(100 MHz,DMSO-d6): δ 173.8,167.0,157.6,156.6,150.1,146.2,142.6,142.5,142.0,135.5,131.4,117.2,102.2,61.7,36.8,14.9,8.6. MS: m / z 427.2 [M+H] + .

[0158] Example 21: [ka]

[0159] Step 1 Ethyl 5-hydroxyl-3-methylthio-1,2,4-triazine-6-carboxylate (4.62 g) and acetonitrile (50 ml) were added to a reaction flask and cooled to 0 ° C. DIPEA (5.17 g) and N-methylmorpholine (101 mg) were added, followed by the slow dropwise addition of triclosan rin (4.6 g). The mixture was then slowly warmed to room temperature and reacted for 1 hour. After the reaction was complete, the reaction solution was cooled to 0 ° C. and the pH was adjusted to approximately 7-8 with DIPEA. A solution of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (3.27 g) in tetrahydrofuran (10 ml) was then added dropwise. The mixture was then warmed to 30 ° C. and reacted for 4 hours. The mixture was washed with saturated aqueous ammonium chloride, extracted with dichloromethane, and the organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 5.0 g of the product.

[0160] Step 2 The product (5.0 g), deuterated methylamine hydrochloride (1.02 g), and acetonitrile (50 ml) were added to a reaction flask and cooled to 0°C. DIPEA (4.65 g) and lithium bromide (2.08 g) were added, and the mixture was then slowly warmed to room temperature and reacted for 1 hour. A saturated aqueous solution of ammonium chloride was added to the mixture, which was then extracted with dichloromethane. The organic phase was dried and concentrated, and purified by silica gel column chromatography to obtain 4.18 g.

[0161] Step 3 A 50ml single-neck flask was charged with 600mg of methyl sulfide compound and 20ml of dichloromethane, protected with nitrogen, and 800mg of MCPBA was added in one portion. The mixture was stirred at room temperature for 3 hours. The mixture was poured into aqueous sodium bicarbonate, 1g of sodium thiosulfate was added, stirred for 10 minutes, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 200mg of a yellow solid. MS: m / z 422.1 [M+H] + .

[0162] Step 4 The product from the previous step (100 mg), cyclopropanamide (50 mg), potassium tert-butoxide (150 mg), and toluene (10 ml) were placed in a 50 ml single-neck flask, and the mixture was heated to 80°C under nitrogen protection and reacted for 3 hours. The mixture was poured into an aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 30 mg of a yellow solid. 1 H NMR(400 MHz,CDCl3): δ 12.10(s,1H),8.85(dd,J=8.2,1.2 Hz,1H),8.71(s,1H),8.14(s,1H),7.92(s,1H),7.78(dd,J=7.9,1.5 Hz,1H),7.31(t,J=8.1 Hz,1H),4.04(s,3H),3.93(s,3H),2.37-2.27(m,1H),1.26-1.21(m,2H),1.01-0.95(m,2H). MS: m / z 427.2 [M+H] + .

[0163] Example 22 [ka]

[0164] 6-(cyclopropylamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (500 mg, 1.2 mmol), N,N-dimethylacetamide (20 mL), propargyl bromide (1.3 g, 10.9 mmol), and potassium carbonate (1.3 g, 9.4 mmol) were added to a 50 mL single-neck flask and reacted at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched by pouring it into 400 mL of water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 250 mg of an off-white solid. 1 H NMR(400 MHz,CDCl3): δ 11.01(s,1H),9.81(s,1H),8.39(s,1H),8.25(s,1H),8.06(s,1H),7.82(dd,J=7.9,1.6 Hz,1H),7.55(dd,J=8.0,1.5 Hz,1H),7.28(t,J=7.9 Hz,1H),5.08(d,J=2.5 Hz,2H),3.83(s,3H),2.64(t,J=2.6 Hz,1H),1.91-1.82(m,1H),1.15-1.08(m,2H),0.94-0.87(m,2H). 13 C NMR(100MHz,CDCl3): δ MS: m / z 450.2102 [M+H] + .

[0165] Biological Testing and Other Application Examples

[0166] Biological test example 1: Measurement of pharmacological effects in a mouse psoriasis-like model Experimental animals: Balb / c mice, Animal Grouping: (1) Negative control group (Vaseline smear, oral administration of solvent), (2) Model control group [imiquimod (IMQ) smear], (3) Administration group (IMQ smear, oral administration of compounds 7, 8, 9, 10, and 146) Here, "Compound No. 146" is the compound of Example 146 in reference document WO2014074661, and was prepared by referring to the method in this document. Dosage and method: 20 mg / kg, BID, orally administered Experimental procedure: On Day 0, the test sites on the backs of the animals were shaved and divided into groups. From Day 1 to Day 7, 1 hour after the first administration, 40 mg of 5% imiquimod cream was applied to the test sites on the backs of the mice. A second administration was then administered on the same day. Psoriasis lesion symptoms and drug efficacy were assessed based on the Psoriasis Area and Severity Index (PASI) score (erythema, scaling, and thickening). A higher score indicated more severe symptoms.

[0167] The PASI score results on Day 7 are shown in the table below. "+" indicates score ≥ 6; "++" indicates a score greater than 5 but less than 6, "+++" indicates a score of more than 4 but less than 5, "++++" indicates a score of 4 or less.

[0168] [Table 1]

[0169] As can be seen from the above data, Compounds 7, 8, 9, and 10 can improve the symptoms of psoriasis lesions in an imiquimod-induced mouse psoriasis-like model, and Compound 146 can also improve the symptoms of psoriasis lesions in an imiquimod-induced mouse psoriasis-like model. The effects of Compounds 7, 8, 9, and 10 are superior to those of Compound 146.

[0170] Biological test example 2: Measurement of pharmacological effects in a mouse psoriasis-like model Using the same scheme as in Test Example 1, the pharmacological action in an imiquimod-induced mouse psoriasis-like model was investigated. The data showed that compound 11 could improve psoriasis lesion symptoms in an imiquimod-induced mouse psoriasis-like model, and the action effect of compound 11 was superior to that of compound No. 146.

[0171] Here, "Compound No. 146" is the compound of Example 146 in reference document WO2014074661, and was prepared by referring to the method in this document.

[0172] The PASI score results on Day 7 are shown in the table below. "+" indicates score ≥ 6; "++" indicates a score greater than 5 but less than 6, "+++" indicates a score of more than 4 but less than 5, "++++" indicates a score of 4 or less.

[0173] [Table 2]

[0174] Biological Test Example 3: In vitro Enzymology Experiment Experimental procedure: Compounds were dissolved in DMSO to a stock concentration of 10 mM. A compound dilution plate was prepared with a gradient of different concentrations, 200 times the final compound concentration, and transferred to an Echo plate. 75 nL of compound was transferred from the Echo plate to a 384-well experimental plate using an Echo instrument. 5 μl of TYK2-JH2 kinase at 3 times the final concentration was transferred to a 384-well experimental plate. 5 μl of Tb antibody at 3 times the final concentration was added to the 384-well experimental plate. 5 μl of Tracer at 3 times the final concentration was added to the 384-well experimental plate. Centrifuge for 30 seconds and incubate for 60 minutes at room temperature. The 495 nm / 520 nm fluorescence signal ratio was read using an Envision enzyme labeler (PerkinElmer). Data was analyzed using XL-Fit software, and compound IC50 values ​​were calculated.

[0175] Here, "A" indicates that the TYK2-JH2 binding inhibitory activity (IC50 value) is less than 0.10 nM, "B" indicates that the range of TYK2-JH2 binding inhibitory activity (IC50 value) is 0.10 nM to 0.50 nM, "C" indicates that the range of TYK2-JH2 binding inhibitory activity (IC50 value) is 0.50 nM to 1 nM, "D" indicates that the TYK2-JH2 binding inhibitory activity (IC50 value) exceeds 1 nM.

[0176] [Table 3]

[0177] As can be seen from the above data, Compounds 7, 8, 9, 10, 11, 2-1B-1, 2-1B-2, 2-1B-7, and X-1 inhibited the activity of TYK2-JH2, and some of these compounds showed significant effects.

[0178] Biological Test Example 4: Inhibitory effect of compounds on pSTAT5 expression in CD3+ cells detected by flow cytometry fluorescence sorting technology (FACS) Compound dilution preparation: Compounds were prepared as 10 mM solutions in DMSO and diluted with DMSO to form gradient solutions with different concentrations 500-fold higher than the final concentration. 5 μL of the diluted compound was transferred to 120 μL of PBS containing 0.1% BSA. Positive and negative control sets were set up, and the positive and negative control sets finally contained 0.2% DMSO.

[0179] Testing Procedure: 1) Add 0.5 million human PBMC cells to each well of a 96-well cell culture plate in a volume of 67.5 uL. 2) Add 3.5 μl of diluted compound and mix evenly. 3) Incubate in a 37°C incubator for 60 minutes. 4) Dilute IFN-alpha to 600ng / mL with DPBS containing 0.1% BSA. After the 60-minute incubation, add 5uL of PE-anti-hCD3 antibody per well and 4µL of diluted IFN-alpha per well. 5) Incubate in a 37°C incubator for 30 minutes. 6) Transfer all cells to a 96-well deep well plate and add 1 mL of 37°C preheated Lyse / fix buffer. 7) Incubate at 37°C for 10 minutes away from light. 8) Centrifuge at 600 g for 5 minutes, discard the supernatant, add 1 mL of PBS to wash twice, and centrifuge. 9) Add 1 mL of Perm buffer III to the cell pellet. 10) Incubate at 4°C, away from light, for 30 minutes. 11) Centrifuge at 600g for 5 minutes, discard the supernatant, add 1 mL of PBS to wash twice, and centrifuge. 12) Dilute the APC anti-human pSTAT5 antibody 200-fold with staining buffer, add 100 μL per well to the cell wells, and mix evenly. 13) Incubate at room temperature for 40 minutes. 14) Wash twice with staining buffer, add 1 mL per well, and centrifuge at 600 g for 5 minutes. 15) Discard the supernatant and resuspend the cell pellet in 300 μL of staining buffer. 16) Analyze samples on a Beckman CytoFlex flow cytometer.

[0180] The experimental results are summarized as follows: Here, "A" means that the inhibitory activity (IC50 value) of p-STAT5 expression is less than 1 nM, "B" has an inhibitory activity (IC50 value) of p-STAT5 expression in the range of 1 nM to 5 nM, "C" has an inhibitory activity (IC50 value) of p-STAT5 expression in the range of 5 nM to 10 nM, "D" indicates that the inhibitory activity (IC50 value) of p-STAT5 expression exceeds 10 nM.

[0181] [Table 4]

[0182] As can be seen from the above data, Compounds 7, 8, 9, 10, 11, 2-1A-1, 2-1B-1, 2-1B-2, 2-1B-7, and X-1 have inhibitory effects on p-STAT5 expression, and some compounds showed significant inhibitory activity.

[0183] Biological Test Example 5: Pharmacokinetic Study Test animals: 8-10 week old male SD rats, fasted for 12 hours before administration. Drug preparation method Oral administration: A mixed solution (ethanol + TPGS + PEG300 = 5:5:90) was used as the administration vehicle. Injection administration: A mixed solution (PEG400 + ddH20 = 80:20) was used as the administration vehicle. Dosage: 5ml / kg Animal grouping: The animals were divided into an intravenous group (IV group) and an oral group (PO group), with three male SD rats in each group. Administration route and dose: 1 mg / kg was administered in the IV group, and 10 mg / kg was administered orally in the PO group. Dosage: Single dose. sampling: IV blood sampling points: 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h after administration PO blood sampling points: 15, 30 min, 1, 2, 4, 6, 8, 24 h after administration Sample processing Rat whole blood was centrifuged at 10,000 rpm for 5 minutes to separate plasma, which was then stored at 4°C. 0.1 ml of plasma was collected, 0.2 ml of acetonitrile was added, the mixture was vortexed for 1 minute, and the supernatant was collected by centrifugation at 10,000 rpm for 5 minutes. After filtration through a 0.22 μm filter, the supernatant was analyzed for drug content.

[0184] The test results are summarized as follows: [Table 5] Here, "Compound No. 146" is the compound of Example 146 in reference document WO2014074661, and is prepared by referring to the method in this document.

[0185] Compound 11 and Compound No. 146 As shown by the results of the pharmacokinetic study, the absolute bioavailability of compound 11 was Compound No. 146 is greater than.

[0186] Biological Test Example 6: Measurement of pharmacological effects in an imiquimod-induced mouse psoriasis-like model The pharmacological action of imiquimod in a mouse psoriasis-like model was studied using the same scheme as in Test Example 1, and the PASI score results on the 7th day are shown in the table below. "+" indicates score ≥ 6; "++" indicates a score greater than 5 but less than 6, "+++" is a score of 4 tones or less than 5, "++++" indicates a score of 4 or less.

[0187] [Table 6]

[0188] As can be seen from the above data, the above compounds can improve the symptoms of psoriasis lesions in an imiquimod-induced mouse psoriasis-like model, and some compounds have significant effects.

[0189] Application Example 7: Ointment Preparation The action pathway of the compounds of the present invention is related to autoimmune diseases and other diseases, such as ankylosing spondylitis, atopic dermatitis, enteritis, etc., some of which include skin-related diseases. Therefore, developing the compounds of the present invention into topical preparations can be more convenient and directly used in certain situations.

[0190] Ointment composition: [Table 7]

[0191] Ointment preparation: Homogenization: A specified amount of petrolatum was placed in a main pot and heated at 70-90°C until completely melted. The temperature was controlled at 75±5°C. Compound 7 or Compound X-1, the antioxidant BHA (butylated hydroxyanisole), and benzylmethanol were added to approximately half of the light liquid paraffin, and the mixture was uniformly dispersed using mechanical stirring to obtain Mixture 1. Mixture 1, the remaining light liquid paraffin, and the melted petrolatum solution were added to the main pot, and the mixture was stirred with a scraper at 30-60 rpm. The mixture was then homogenized at a stirring speed of 1000-2800 rpm, under a vacuum of -50 to -100 Kpa at a temperature of 70±5°C for 20-30 minutes, and then slowly cooled to below 35°C to obtain a paste.

[0192] Filling: The prepared paste was filled in a filling machine according to the prescribed filling specifications, while controlling the temperature of the funnel jacket at 25-30°C and the seal end temperature at 450±20°C. Compound 7 ointment and Compound X-1 ointment were obtained according to the above formulation and ointment preparation scheme.

[0193] Summary of long-term stability observation results for the ointment: [Table 8]

[0194] Comparing the stability of a 5% ointment containing Compound 7 and a 5% ointment containing Compound X-1, the 5% ointment containing Compound X-1 showed visible granular particles after 20 days of storage, which is believed to be the result of precipitation of the product after long-term storage of Compound X-1. However, the 5% ointment containing Compound 7 showed no visible granular particles after 30 days of storage, and the ointment was uniform.

[0195] The above phenomena indicate that the 5% ointment prepared using Compound 7 is suitable for storage and use.

[0196] Biological Test Example 8: Measurement of pharmacological effects in a rat model of imiquimod-induced IL-17 elevation by oral administration Diseases controlled by IL-17 include autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis, atopic dermatitis, and enteritis, and the compounds of the present invention have potential therapeutic effects on autoimmune diseases by regulating IL-17 levels. Experimental animals: 8-10 week old SD rats, half male and half female. Experimental Grouping: (1) Negative control group (Vaseline smear, oral administration of solvent), (2) Model control group [imiquimod (IMQ) smear], (3) Administration group (IMQ smear, oral administration of the compound of the present invention), Dosage and method: 20 mg / kg, BID, orally administered Model construction: A rat model was constructed by applying 40 mg of imiquimod ointment to the dorsal skin of SD rats once a day. Test detection: On day 6, blood IL-17F cytokine content was measured.

[0197] Test results: where A indicates that the IL-17F content is less than 30 pg / mL, B indicates that the IL-17F content ranges from 30 to 100 pg / mL; C indicates that the IL-17F content ranges from 100 to 300 pg / mL. D indicates that the IL-17F content ranges from 300 to 400 pg / mL. E indicates IL-17F content greater than 400 pg / mL.

[0198] [Table 9]

[0199] The study of imiquimod-induced rat models using different compounds showed that the effect of compound 7 was superior to that of compound X-1. Here, oral administration of compound 7 or compound 11 resulted in the inflammatory factor IL-17F in experimental animals approaching the level of normal animals. At the same time, oral administration of compound 7 or compound 11 significantly reduced the skin lesion phenomenon in rats, and the skin lesion area and severity index scores of rats were better than those of compound X-1 treatment group, and further testing also showed that they were better than other compounds with similar structures.

[0200] Biological Test Example 9: Measurement of pharmacological effects in a rat model of elevated IL-17 induced by imiquimod via oral administration Biological Test The pharmacological effects of the compounds of the present invention were evaluated in the same manner as in Example 8, and the following test results were obtained.

[0201] Test results: where A is an IL-17F content of less than 30 pg / mL; B, the IL-17F content ranges from 30 to 100 pg / mL; C has an IL-17F content range of 100 to 300 pg / mL; D has an IL-17F content range of 300-400 pg / mL; E indicates IL-17F content greater than 400 pg / mL.

[0202] [Table 10]

[0203] The study of the treatment of imiquimod-induced rat models with different compounds shows that the therapeutic effect of compound 2-1A-1 is superior to that of compound 1-1-1 and compound X-1.In addition, oral administration of compound 2-1A-1 treatment brought the inflammatory factor IL-17F in the experimental animals to the level of normal animals.At the same time, oral administration of compound 2-1A-1 treatment significantly reduced the skin lesion phenomenon in rats, and the skin lesion area and severity index score of rats were superior to those treated with compound 1-1-1 and compound X-1.

[0204] Biological Test Example 10: Measurement of pharmacological effects in a rat model of imiquimod-induced IL-17 elevation using the smear administration method Experimental animals: 8-10 week old SD rats, half male and half female Model construction: A psoriasis-like rat model was constructed by applying 40 mg of imiquimod ointment to the dorsal skin of SD rats once a day. Experimental procedure: The dorsal skin of SD rats was depilated 3 days prior to the experiment. First, 40 mg of imiquimod was applied, followed by 1 g of ointment per rat per day (5 × 15 cm area). The application was once daily for 5 consecutive days. The control group was not smeared. The skin was wiped clean before application. Test detection: On the 6th day, the rat skin was wiped clean, the skin was collected, mixed with cell lysis solution and crushed, and the supernatant was collected at rest to measure the skin IL-17F cytokine content.

[0205] Test results: where A has an IL-17F content of less than 2000 pg / g, B has an IL-17F content range of 2000 to 5000 pg / g; C has an IL-17F content range of 5000 to 10000 pg / g; D has an IL-17F content range of 15,000-20,000 pg / g; E indicates an IL-17F content of more than 20,000 pg / g.

[0206] [Table 11]

[0207] The therapeutic effect of Compound 7 ointment was superior to that of Compound X-1 ointment in the treatment of imiquimod-induced rat models with different compound ointments. smear When administered, the inflammatory factor IL-17F in the skin of experimental animals approached the level of normal animals. smearWhen administered and treated, the skin lesion phenomenon in rats was significantly reduced, and the skin lesion area and severity index scores in rats were superior to those in the compound X-1 ointment treatment group, and further testing showed that it was superior to other compounds with similar structures.

[0208] Biological Test Example 11: Measurement of pharmacological effects in a rat model of imiquimod-induced IL-17 elevation using the smear administration method Biological Test The pharmacological effects of the compounds of the present invention were evaluated in the same manner as in Example 10, and the following test results were obtained. where A has an IL-17F content of less than 2000 pg / g, B has an IL-17F content range of 2000 to 5000 pg / g; C has an IL-17F content range of 5000 to 10000 pg / g; D has an IL-17F content range of 15,000-20,000 pg / g; E indicates an IL-17F content of more than 20,000 pg / g.

[0209] [Table 12]

[0210] The therapeutic effect of Compound 2-1A-1 ointment was superior to that of Compound 1-1-1 ointment and Compound X-1 ointment in the treatment of imiquimod-induced rat models using different compound ointments. smear When administered, the inflammatory factor IL-17F in the skin of experimental animals approached the level of normal animals. smear After administration and treatment, the skin lesion phenomenon of rats was significantly reduced, and the skin lesion area and severity index scores of rats were superior to those of the compound 1-1-1 ointment and compound X-1 ointment treatment groups.

[0211] Pharmaceutical Application Example 12: Preparation of tablets of compound 2-1A-1 Formula composition: [Table 13]

[0212] Tablet preparation method: Mixing: Weighed compound 2-1A-1, starch, microcrystalline cellulose, and carboxymethyl starch are added to a wet mixer granulator and mixed. Preparation of binder solution: Weigh out purified water, slowly add an appropriate amount of Polyvidone K30 while stirring, and disperse evenly while stirring to prepare an aqueous solution of adhesive-Polyvidone K30. Preparation of soft material: Using a wet mixer granulator, control the stirring speed and shear rate, slowly add the polyvidone K30 aqueous solution, and stir and shear to prepare a mixture material. Granulation: The prepared mixture material is granulated in a swing granulator equipped with a 24 mesh sieve to obtain wet particles. Drying: Wet particles are added to a fluidized bed and the particles are dried. Granulation: The dry particles are sieved through a swing granulator and the weight of the granules is measured. Mixing: The sized particles are placed in a three-dimensional multi-directional mixer, and after mixing is complete, magnesium stearate is added and mixing is continued for approximately 3 minutes to obtain all mixed particles. Tablet compression: Compress the tablets using a tablet press to prepare the tablets: obtain tablets with perfect and polished appearance, uniform color, and suitable hardness and abrasion resistance.

[0213] The compounds prepared according to the present invention have tyrosine kinase 2 (TYK2) inhibitory activity and are expected to be widely applied in the treatment of autoimmune diseases and tumors.

[0214] The compounds of the present invention have excellent characteristics in terms of activity and drug-like properties, and different structural types of the compounds have different characteristics in terms of absorption, metabolism, and distribution, which contributes to providing more effective, convenient, and diverse options for the treatment of autoimmune diseases in different parts of the body, such as enteritis, ankylosing spondylitis, and inflammation involving the skin, as well as other related diseases, and also has an overall positive effect on the preparation of raw materials and formulations, and the stability of the products.

Claims

1. A compound of formula (II-2-2), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: 【Chemical 1】 (where R １２ is a deuterated C1 alkyl; R １０ , R １１ , R Ｄ１ is hydrogen, E １ is C1 alkyl, R １ , R ２ , R ３ , R ４ , R5 is selected from hydrogen or deuterium; R 7 is hydrogen; R ９ａ , R ９ｂ , R ９ｃ is selected from hydrogen or deuterium; n1 is 1, and n2 is 1.)

2. A compound selected from the group consisting of: 【Chemistry 2】

3. A compound according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is any of the following: 【Chemistry 3】

4. The compound of claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is: 【Chemistry 4】

5. The compound of claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is: 【Chemistry 5】

6. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or diluent.

7. A pharmaceutical composition for treating a disease, comprising a compound according to any one of claims 1 to 5, wherein the disease is an inflammatory or autoimmune disease mediated by the kinase TYK2, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, sicca syndrome or scleroderma, or a tumor.

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