Nitrogen-containing heterocyclic pyridine compound

Abstract

To provide a TYK2 inhibitor having better drug-like properties.SOLUTION: Provided are a nitrogen-containing heterocyclic protein inhibitor compound having the following structure, and a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. Also provided are a preparation method for the nitrogen-containing heterocyclic compound, and a use thereof. A drug prepared from such a compound is widely used for treating diseases, the diseases comprising multiple types of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, dry syndrome, and scleroderma.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention aims to control various cytokine signaling pathways by inhibiting TYK2. The present invention also relates to methods for preparing such compounds and Use in the treatment of disease. [Background technology]

[0002] Nitrogen-containing heterocycles are a type of nitrogen-containing heterocyclic compound with unique structures and a wide range of biological activities. Since the successful development of nitrogen-containing heterocyclic herbicides, research on nitrogen-containing heterocyclic compounds has rapidly progressed. For example, the nitrogen-containing heterocyclic mycins were the first nitrogen-containing compounds with natural fungicidal activity. Research has shown that nitrogen-containing heterocyclic compounds are useful as herbicides, insecticides, and antibacterial agents. , antiviral agents, antihypertensive drugs, and other agricultural and pharmaceutical products, and have superior biological activity. It has been revealed that:

[0003] [ka]

[0004] The cytokines interleukin IL-12 and IL-23 activate antigen-presenting cells. These cytokines play an important role in the differentiation and proliferation of T cells, and contribute to the development of rheumatoid arthritis. Intermediate in various autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, inflammatory bowel disease, and lupus erythematosus is involved in mediation.

[0005] Tyrosine kinase 2 (TYK2) is a JAK phagocytosis inhibitor. She is a member of Millie (other members include JAK1, JAK2, and JAK3). , involved in IFN-α, IL-6, IL-10 and IL-12 signaling, TYK2 IL-12, IL-23, and type I interferon receptor downstream STAT proteins By inhibiting TYK2 activity, it is thought to be effective in treating multiple sclerosis and rheumatoid arthritis. inflammatory bowel disease, lupus erythematosus, neurodermatitis, dermatitis, psoriasis, psoriatic arthritis It can effectively treat various autoimmune diseases such as Crohn's disease, sicca syndrome and scleroderma. This can be done.

[0006] TYK2 inhibitors with superior efficacy, pharmacokinetic properties, and better drug-like properties The design of TYK2 inhibitors is a major challenge for medicinal chemists. In recent years, a series of TYK2 inhibitors have been disclosed. Although it is widely used, it has better efficacy, pharmacokinetic properties and better physicochemical properties. There remains a need to discover and develop new compounds that exhibit the same structure as those of general formula (I). and designing compounds having excellent TYK2 inhibitory effects and comprehensive properties. It was found that Summary of the Invention

[0007] The present invention relates to compounds of formula (I), their stereoisomers, tautomers or pharmaceutically acceptable salts thereof. Provide salt, [ka] L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkyl alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino can be, Ring B is aryl, heteroaryl, or heterocyclyl, and Ring B is selected from the following groups: Been: [ka] where T, G, Y, Z, and M are each independently an oxygen atom, CR A1 , C.R. A2 , Nitrogen atom or NR B is selected from E is a nitrogen atom or a carbon atom, R A1 , R A2 are hydrogen, deuterium, and C 1-6 Alkyl, halogen, and the following structure Selected from: [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 Alkyl-S(O)2-, alkenyl, deuterated alkenyl and is selected from alkynyl, alkynyl, deuterated alkynyl, and the following structures: [ka] Q is a chemical bond or -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -C(N -R 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, or heterocyclyl, and Ring A is selected from the following groups: Been: [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 are hydrogen, deuterium, halogens, and Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkenyl carbamate Alkenyl, deuterated alkenylcarbonyl, alkyl, deuterated alkyl, alkylcarbonyl and deuterated alkylcarbonyl, wherein alkynyl, alkenyl, deuterated alkylcarbonyl are selected from the group consisting of alkynyl, alkenyl, deuterated alkylcarbonyl, and deuterated alkylcarbonyl. Alkenyl, deuterated alkenyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, optionally substituted with 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: do. [ka]

[0009] The present invention relates to compounds of formula (I-1), their stereoisomers, tautomers, and pharmaceutically acceptable salts thereof. Provide salt, [ka] where L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, Deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkyl It is an amino 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 are hydrogen, deuterium, and halogens. alkynyl, amino, alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl wherein alkynyl, alkenyl, alkyl and deuteroalkyl are selected from halo alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl are optionally substituted, R 9 is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl, alkoxy, halo Alkoxy, 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) n 1S(O) m1 R aa , -(CD2) n1 S(O) m1 R aa , -NR aa R bb , -C(O)N R 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 hydrogen, deuterium, alkyl, deuterium alkyl, halo, alkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, thiazolinone, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl aryl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are selected from the group consisting of 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 hydroxy alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted and one or more of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. optionally substituted with substituents, 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: do. [ka]

[0011] The present invention relates to compounds of formula (II-1), their stereoisomers, tautomers, and pharmaceutically acceptable salts thereof. providing salt that [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 alkyl alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino can be, 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)-, or -S(O)2-, all of which Nawachi: [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 hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R 9 is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl, alkoxy, halo Alkoxy, 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 ORaa , -SR aa , -(CD2) n1 C(O)R aa , -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH2) n 1S(O) m1 R aa , -(CD2) n1 S(O) m1 R aa , -NR aa R bb , -C(O)N R 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 hydrogen, deuterium, alkyl, deuterium alkyl, halo, alkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, thiazolinone, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl aryl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are selected from the group consisting of 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 hydroxy alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted and one or more of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. optionally substituted with substituents, n=1, 2, 3, 4, n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4.

[0012] The present invention relates to compounds of formula (II-1A), their stereoisomers, tautomers, pharmaceutically acceptable salts thereof, providing salt that can be used in the manufacture of food, [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 alkyl alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino can be, 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 hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R 9 is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl, alkoxy, halo Alkoxy, 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) n 1S(O) m1 R aa , -(CD2) n1 S(O) m1 R aa , -NR aa R bb , -C(O)N R 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 hydrogen, deuterium, alkyl, deuterium alkyl, halo, alkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, thiazolinone, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl aryl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are selected from the group consisting of 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 hydroxy alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted and one or more of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. optionally substituted with substituents, 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: do. [ka]

[0014] The present invention relates to compounds of formula (II-1B), their stereoisomers, tautomers, pharmaceutically acceptable salts thereof, providing salt that can be used in the manufacture of food, [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 alkyl alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino can be, 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 hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R 9a , R 9b , R 9c is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl , 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: do. [ka]

[0016] The present invention relates to the compound of formula (II-2), its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof. providing salt that [ka] where L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, Deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkyl It is an amino R 10 , R 11 , R D1 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen the law of nature, 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 hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R 9a , R 9b , R 9c is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl , 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 relates to compounds of formula (II-2-1), their stereoisomers, tautomers, pharmaceutically acceptable salts thereof, providing salt to be [ka] where R 12 is deuterium, hydrogen, alkyl, deuterium alkyl, haloalkyl, amino , alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated hydrogen cycloalkylamino, R 10 , R 11 , R D1 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen the law of nature, 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 7is hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R 9a , R 9b , R 9c is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl , or R 9a and R 9b together with the carbon atom to which it is attached form a cycloalkyl, n=1, 2, 3.

[0018] The present invention relates to compounds of formula (II-2-2), their stereoisomers, tautomers, pharmaceutically acceptable salts thereof, providing salt to be [ka] where R 12 is deuterium, hydrogen, alkyl, deuterium alkyl, haloalkyl, amino , alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated hydrogen cycloalkylamino, R 10 , R 11 , R D1 is hydrogen, deuterium, alkyl, deuterium alkyl, halogen the law of nature, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; where R 1 , R 2 , R 3 , R 4 , R 5 , R 7is hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R 9a , R 9b , R 9c is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl , 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: do. [ka]

[0020] The present invention relates to one or more of the compounds according to any one of the invention and their pharmaceutical use. Pharmaceutical compositions containing a possible carrier or diluent are provided.

[0021] A use of a compound according to any one of the present invention in the preparation of a medicament for the treatment of a disease, comprising The diseases are multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, and neurodermatitis. dermatitis, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, sicca syndrome or TYK2 kinase-mediated inflammatory or autoimmune diseases, including scleroderma, and tumors. It is a use.

[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. It has.

[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 having 1 to 10 carbon atoms. The term refers to a group, which includes both straight chain and branched hydrocarbon groups. Suitable examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Examples include sec-butyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl. The alkyl groups described herein are optionally fluoro, chloro, bromo, iodo, cyclohexane ... Ano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, acyl hydroxy, oxo, amide, ester, amine, cycloalkyl, cycloalkenyl, cycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, Heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl or The heteroaryl may be substituted with one or more substituents.

[0034] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic carbonyl group. The cycloalkyl ring is a cycloalkyl group having 3 to 20 carbon atoms, preferably It consists of 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms. Non-limiting examples of alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl ... clopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclohexyl butenyl, cycloheptatrienyl, cyclooctyl, etc., and polycyclic cycloalkenyl The alkyl groups include spirocyclohexyl, thickening cyclohexenyl, bridged cyclohexenyl, Examples include:

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

[0036] The term "heteroaryl" as used herein refers to a heteroaryl group consisting of 5 to 10 atoms, including N, O, or or S. This term refers to an aromatic group containing at least one heteroatom selected from Single rings (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyrazole, lysine, pyrazine, oxazole, thiazole, etc.) or multiple thickening rings ( Non-limiting examples include benzothiophene, benzofuran, indole, and isoindole. and the like), wherein the thickening ring is an aromatic heteroaryl group. Assuming that the aromatic moiety is an aromatic moiety containing a heteroatom, The heteroaryl groups described herein may optionally be substituted with fluoro, chloro, bromo, or methyl. Bromo, iodo, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, Acyloxy, amide, ester, amine, sulfonyl, sulfenyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy may be substituted with one or more substituents.

[0037] The term "alkenyl" as used herein refers to an alkyl group having 2 to 8 carbon atoms and at least one Non-limiting examples of alkenyl include: Examples include vinyl, propenyl, allyl, isopropenyl, butenyl, and isobutenyl. The alkenyl groups described herein may contain any of deuterium, fluorine, chlorine, bromine, iodine, chlorine, and methyl. Ano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, Amides, esters, amines, sulfonyls, sulfenyls, cycloalkyls, cycloalkanes cycloalkyl, cycloalkoxy, mercapto, alkylmercapto, heavy Alkylmercapto, sulfonyl, sulfoxylidene, amide, silyl, phosphono alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, The aryl may be substituted with one or more alkyl, ester, or other substituents.

[0038] The term "alkynyl" as used herein refers to two adjacent alkyl groups joined by a triple bond. and the alkyl group is an alkyl group containing carbon atoms as defined herein. Alkynyl includes ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or at least two carbon atoms and at least one carbon-carbon triple bond, such as 3-butynyl Alkynyl refers to an unsaturated alkyl group as defined above, which may be substituted or unsubstituted. If substituted, the substituents are preferably 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 alkyl mercapto, alkyl mercaptide, sulfone, sulfenyl, amine, alkyl, phosphonoalkyl, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl independently selected from aryl, alkyne, alkenyl, arylalkyl, and ester groups. It is one or more groups. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention will be further explained below with reference to examples, but the present invention is not limited to these examples. Throughout this application, the present specification provides multiple examples of the compounds and methods of the present invention. The present invention is not limited to these examples, and the following examples are merely examples of the present invention. It is intended to provide a method for the preparation of a medicament ...

[0040] The compounds provided by this invention can be prepared by standard synthetic methods well known in the art. and the present 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, and then 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, and then Reaction with SM-3 gives IM-2A, and removal of the protecting group gives IM-3A, Further reaction gives compound IA.

[0043] The compounds of the present invention and the corresponding preparation methods are further described below by way of examples and preparations. Typical or preferred reaction conditions are described and listed in specific examples. However, one skilled in the art will appreciate that other reaction conditions may be used. The conditions may vary depending on the particular reaction substrates or solvents used, but the conditions are well within the skill of those in the art. The individual can be determined by routine optimization.

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

[0045] [ka] Preparation scheme in the literature (Journal of the Chinese Chemica l Society (Taipei) (1998), 45(2), 307-312) and Refer to the deuterated reagent (deuterated water) in the reaction and prepare it to obtain deuterated propargyl bromide. do.

[0046] [ka] Preparation scheme in the literature (Bioorganic & Medicinal Chemist ry (2013), 21(21), 6634-6641) and the corresponding deuteration reagent (heuterium oxide Deuterated propargyl bromide was prepared by following the procedure described in (2) and (3). obtain.

[0047] [ka]

[0048] Step 1: 2.4 g of lithium aluminum deuteride was dispersed in 150 ml of diethyl ether. Cool to -50°C and add 150 ml of distilled water containing 6.0 g of methyl propargylate. Slowly add dropwise to the ethyl ether solution, and after the addition is complete, continue stirring at -30°C until the temperature reaches room temperature. The temperature was raised and the mixture was stirred overnight. The reaction mixture was added with 3 ml of heavy water and sodium hydroxide (0.22 g in 1.5 mL). The solution was dissolved in 2 ml of heavy water, and 2 ml of heavy water was added dropwise. The mixture was filtered under suction, and the filter cake was collected in 30 ml of diethyl ether. The mixture was washed twice with ether, and the filtrate was collected and concentrated under reduced pressure to give a dark yellow oily product, 13 Distillation under reduced pressure at 0° C. gave 2.3 g of a colorless oil.

[0049] Step 2: 1.2 g of deuterated propargyl alcohol was dissolved in 15 ml of dichloromethane and Under nitrogen protection, the mixture was cooled to -5°C, and 6.0 g of phosphorus tribromide was slowly added dropwise. 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. The organic layer was separated and washed successively with 25 ml of saturated sodium bicarbonate solution and 25 ml of water. After washing and drying with anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure to give 1.6 g of A pale yellow oily liquid was obtained.

[0050] Or prepared according to the following scheme: [ka] In a 50 ml single-neck flask, add (3-bromoprop-1-yn-1-yl-3,3-d2 ) trimethylsilane (300 mg, 1.55 mmol), potassium carbonate (644 mg, 4 0.7 mmol) and methanol-OD (3 ml) were added, and the mixture was stirred at room temperature for 30 min. The insoluble matter in the reaction mixture was removed by filtration, and 50 ml of heavy water was added to the filtrate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was obtained.

[0051] Preparation scheme 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(1) 6), 2981-2984, Bulletin of the Chemical Soc. iety of Japan(2003), 76(2), 347-353, Angewandt. e Chemie,International Edition(2016),55(9), 3171-3175) to prepare the following deuterated intermediates: [ka] Cyanocyclopropane is added dropwise to a deuterated methanol solution containing sodium The mixture was refluxed for 16 hours, concentrated under reduced pressure to remove deuterated methanol, and concentrated to give a yellow solution. A mixed solution of deuterated methanol and deuterated water was then obtained (GC-MS: 69.1). The mixture was refluxed for 8 h and concentrated under reduced pressure to remove the solvent to give the target product.

[0052] [ka] SMD1 (50 g) and heavy water (35 ml) were added to a 500 ml three-neck flask and the mixture was stirred under nitrogen protection. Then, heat it to 100°C to dissolve and clear it, and remove most of the water (about 25ml to 30ml) under reduced pressure. The system was refilled with heavy water (25 ml) and the water was again distilled off under reduced pressure. Repeat this process three times to allow sufficient exchange of carboxy hydrogen with deuterium in heavy water. The mixture was heated to 60°C, water was removed by distillation under reduced pressure, and the mixture was heated to 200°C and distilled under reduced pressure. The distillation was completed in 5 to 10 minutes, and 22 g of a colorless oily fraction was obtained. I got my minutes.

[0053] In a 250 ml three-neck flask, add SMD2 (6.5 g), dichloromethane (30 ml), Add DMF (0.5 ml), cool to 0 to -10°C under nitrogen protection, and add oxalyl chloride ( 9.5g) was added dropwise and the internal temperature was maintained below 0°C. After the addition was completed, the reaction was continued at 0°C for 2-3 hours. After detecting the reaction by TLC, the mixture was concentrated under reduced pressure to remove dichloromethane. A reaction flask was charged with 150 ml of THF, and cooled to 0°C under nitrogen protection. The concentrated solution of chlorine chloride was added to the THF solution all at once, and the temperature was returned to 20°C. After stirring for min, the filtrate was filtered and concentrated to give 1.6 g of the target product.

[0054] [ka]

[0055] Step 1 In a 250 ml three-neck flask, add trimethylsilylene (10.0 g) and dry tetrahydrofuran. Add 100 ml of fluorofuran, cool to -80°C, and add 40 ml of n-butyllithium. After that, the mixture was allowed to react at -80°C for 30 minutes, and then methyl chloroformate (10.6 g) was added dropwise. The reaction mixture was then allowed to warm naturally to about -50°C and reacted for 30 minutes while keeping the temperature. ammonium chloride solution and quenched with 200 ml of diethyl ether. The crude product was extracted with HCl, partitioned, dried and concentrated, and purified by silica gel column chromatography. The residue was purified by filtration to give 8.0 g of a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3): δ 3.79(s,3H),0.26(s,9H).

[0056] Step 2 In a 500 ml single-neck flask, the product of the previous step (7.0 g) and diethyl ether were added. (300 ml), cooled to 0°C, added LiAlD4 (1.5 g) in one portion, and After that, the reaction was allowed to proceed for 1 hour while keeping the temperature. An appropriate amount of water was slowly added dropwise to the reaction mixture to quench the reaction. After that, an appropriate amount of anhydrous sodium sulfate was added to dry it, filtered, and the filtrate was concentrated to obtain the crude product. The product was purified by column chromatography to give 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 of the previous step (4.0 g) was added to a 250 ml single-neck flask, and triphenylphosphite was added. Add fin (8.1 g) and dichloromethane (100 ml), cool to 0°C, and add NBS (5.5 g, 30.9 mmol) was added all at once, and the reaction mixture was stirred for 30 minutes. The solution was concentrated under reduced pressure at 0°C to remove most of the dichloromethane solvent, and the residue was dissolved in 100 ml of n- Add to hexane, filter while stirring, and then directly apply the filtrate to column chromatography. The eluate was concentrated under reduced pressure at 10°C to give about 3.0 g of a colorless liquid.

[0058] Step 4 In a 50 ml single-neck flask, add the product from the previous step (2.0 g), acetone (40 ml), Add water (1 ml) and silver trifluoromethanesulfonate (270 mg), then add the mixture at room temperature for 1 The reaction mixture was added to 200 ml of saturated aqueous ammonium chloride solution and Extract with ethyl ether, partition, dry, and concentrate 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), N,N-dimethylformamide Add sodium hydroxide (50 ml), cool to 0°C, add sodium hydride (1.5 g) in one portion, The reaction mixture was then stirred for 20 minutes, slowly warmed to room temperature, and stirred for 30 minutes. Cool to °C and add 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide ( Add dropwise a solution of 3.9 g of the solution in tetrahydrofuran (40 ml) slowly, and keep the temperature below 5°C. After the dropwise addition, the mixture was stirred overnight. (40 ml) was added, stirred for 30 minutes, and then filtered with suction. The filter cake was washed twice with water. After drying, 3.95 g of an off-white solid was obtained. 1 H NMR (400 MHz, CDCl 3): δ 12.53(s,1H),9.39(s,1H),8.38(s,1H),8.34(s,1 H),8.22(d,J=5.2 Hz,1H),7.65(d,J=5.2 Hz,1H),5.6 2(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 In a reaction flask, the product of the previous step (2.4 g), DCPF (1.1 g), paradiacetic acid Add cesium (111 mg), cesium carbonate (8 g), and DME (90 ml) in order, and then evaporate under nitrogen. After the substitution, the mixture was heated to 90°C and reacted for 1 hour. The reaction mixture was cooled to room temperature, filtered by suction, and The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 2.76 g of a pale yellow solid. The compound was obtained. MS: m / z 543.3 [M+H] + .

[0063] Step 3 In a reaction flask, add the product from the previous step (2.7 g) and trifluoroacetic acid (60 ml). The mixture was stirred at 70°C overnight, concentrated to dryness under reduced pressure, and toluene (100 ml) was added. Tetrahydrofuran (100 ml) was added to the concentrate, and the mixture was soaked in carbonated water at room temperature. Slowly add sodium chloride to adjust the pH to 7-8, suction filter to remove solids, and The solution was concentrated and used directly in the next step.

[0064] Step 4 The product of the previous step was treated with N,N-dimethylformamide (50 ml), bromopropylene ( Add potassium carbonate (2.8 g) in one portion and stir at room temperature for 30 minutes. The reaction mixture was then stirred at room temperature for 2 hours. The mixture was extracted three times with ether, and the organic phases were combined, concentrated to dryness, and purified by silica gel column chromatography. The residue was purified by chromatography to give 450 mg of compound 7 as a pale yellow solid. 1 H NMR(4 00 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: In a 50 ml single-neck flask, add the triazole compound (310 mg), N,N-dimethylformamide (N,N-dimethylformamide), and methylamide (45 ml) and 3-bromoprop-1-yne-3,3-d2 (1.2 g) ) and add potassium carbonate (310 mg) all at once while stirring. The reaction mixture was stirred and reacted for 1 hour. The reaction mixture was poured into 400 ml of water to quench the reaction. Extract with ethyl acetate, separate, wash the organic phase with 200 ml of water three times, and add anhydrous sodium sulfate. The mixture was dried over ice, filtered, concentrated, and purified by silica gel column chromatography to give a 120 ml g of a pale yellow solid was obtained. 1 H NMR(400 MHz,DMSO-d6): δ 12.4 7(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: In a 25 ml single-neck flask, add the triazole compound (200 mg), N,N-dimethylformamide (N,N-dimethylformamide), and methylamide (15 ml) and 3-bromoprop-1-yn-1,3,3-d3 (1.0 g), and then add potassium carbonate (210 mg) all at once while stirring. The reaction was stirred for 1 hour, and the reaction mixture was poured into 200 ml of water to quench the reaction. The mixture was extracted with 100 ml of ethyl acetate, partitioned, and the organic phase was washed three times with 100 ml of water and washed with anhydrous sodium sulfate. The extract was dried over HCl, filtered, concentrated, and purified by silica gel column chromatography to give an 80 ml solution. g of a pale yellow solid was obtained. 1 H NMR(400 MHz,CDCl3): δ 12.47( s,1H),11.37(s,1H),9.90(s,1H),9.26(s,1H),8.80(s,1 H),8.16(d,J=5.2 Hz,1H),7.51(d,J=5.2 Hz,1H),3.9 0(s,3H),2.15-2.12(m,1H),0.95-0.82(m,4H).HR-M S: 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 45 3.4 [M+H] + .

[0071] Example 5: [ka]

[0072] Compound 11 was prepared according to the preparation scheme in Example 1. MS: m / z 45 2.3 [M+H] + The specific preparation method is as follows: [ka]

[0073] Step 1 In a reaction flask, triazole compound (1.20 g), cyclopropane-1-d-1- Carboxamide (0.42g), Xanthops (0.28g), Cs2CO3 (1. 58 g), Pd2(dba)3 (0.22 g) and 1,4-dioxane (30 ml) in this order. Then, under nitrogen protection, the mixture was heated to 100°C and stirred to react. After the reaction was completed, the mixture was cooled. Water was added, extracted with ethyl acetate, the organic layers were combined and concentrated under reduced pressure to give an oil, and silica Purification by gel column chromatography gave 0.74 g of a yellow solid. MS: m / z 544.3 [M+H] + .

[0074] Step 2 In a reaction flask, add the product of the previous step (0.72 g), dichloromethane (2.2 ml) and Add tetraethylammonium fluoride (2.16 g) in that order, and add trifluoroacetate (1.0 g) with stirring. After the addition of oroacetic acid (5.04 ml) was completed, the mixture was stirred at room temperature to react. After completion, the mixture was concentrated, water was added, impurities were extracted with methyl tert-butyl ether, and the aqueous phase was The solid was collected, the pH adjusted with saturated sodium bicarbonate, filtered, and dried to 0. Obtained 0.44g of a pale yellow solid. MS: m / z 414.2 [M+H] + .

[0075] Step 3 In a reaction flask, the product of the previous step (0.43 g), N,N-dimethylacetamide ( Add 20 ml of bromopropargyl (0.99 g) and stir to dissolve and clarify. , potassium carbonate (1.01 g) was added all at once, and the mixture was allowed to react at room temperature. After the reaction was complete, 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. A yellow oil was obtained, which was purified by silica gel column chromatography to give 81 mg of a white solid obtained. 1 H NMR(400 MHz,DMSO-d6): δ 12.47(s,1H),1 1.37(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, triazolates can be obtained in the final stage of the preparation of structures such as those in Examples 1 and 5. The chemoselectivity of the propargylation of zoles is superior to that of substituents such as methyl. and "Ring A" in general formula (I) connects the nitrogen atom of a triazole having a similar structure to another ring system. The chemoselectivity is superior to that of the corresponding reaction, and the resulting compound product is easily crystallized. Due to the above characteristics, post-treatment and purification are easy.

[0077] Example 6: [ka]

[0078] Step 1 In a 500 ml single-neck flask, add 4,6-dichloro-N-(methyl-d3)pyridazine-3 - Carboxamide (9.66 g), triazole compound (10.0 g) and ethylene glycol Add 200 ml of ethanol dimethyl ether, stir to dissolve and clear the solution. Cool to 20°C, add LiHMDS (1M in THF, 110 ml) dropwise, and then The reaction mixture was stirred at room temperature for 2 hours. When the completion of the reaction was monitored by TLC, the reaction mixture was diluted with 300 ml of saturated chloride solution. The mixture was poured into an aqueous ammonium chloride solution, extracted with ethyl acetate, separated, and dried over anhydrous sodium sulfate. The residue was added with 500 ml of methyl tert-butyl ether. The solid was precipitated and filtered, and the filtrate was concentrated to dryness. Add 500 ml of a solvent containing ethyl acetate (4:1), leave overnight for crystallization, and obtain 5.3 g of a pale yellow solid. I got a body.

[0079] Step 2 In a 250 ml single-neck flask, the product of the previous step (4.0 g), cyclopropanamide (1.4g), potassium phosphate (5.16g), BINAP (2.0g), palladium acetate Aluminum trifluoromethanesulfonate (192 mg) and Add ethylene glycol dimethyl ether (150 ml) and purge with nitrogen. The reaction mixture was heated to 0°C and reacted overnight. The reaction mixture was cooled to room temperature and poured into 500 ml of water. Chill, extract, partition, dry, and concentrate to give 6.5 g of crude product, which was carried on directly to the next step. Used for the pool.

[0080] Step 3 In a 250 ml single-neck flask, the crude product (6.5 g) from the previous step and dichloromethane (7 0 ml) and tetraethylammonium fluoride (4.2 g) were added and stirred for 10 minutes. Then, trifluoroacetic acid (60 ml) was added and the mixture was stirred at room temperature overnight. The residue was added to 100 ml of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and The mixture was dried over sodium sulfate, filtered, concentrated to dryness under reduced pressure, and then paraffinized with 50 ml of ethyl acetate. The product was purified to give 3.5 g of a yellow solid. 1H NMR (400 MHz, DMSO-d): 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=7.9,1.5Hz,1H),7.55(d d,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=174.2,167.0,156.3,154.5,1 50.9, 148.6, 145.2, 135.5, 132.6, 126.4, 125.1, 12 4.7, 124.0, 97.2, 61.6, 14.9, 8.6.

[0081] Step 4 In a 50 ml single-neck flask, the product of the previous step (1.3 g), 2-chloroethylmethyl Sulfide (1.4 g), N,N-dimethylacetamide (30 ml), potassium carbonate ( Add 1.1g of sodium iodide (100mg) and heat to 100°C. The reaction mixture was poured into 500 ml of water, extracted with ethyl acetate, and the organic phases were combined. Washed three times with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and then filtered onto silica gel. The solid was purified by column chromatography to give 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 (100 MHz, DMSO-d): δ = 17 4.2, 167.0, 159.4, 156.3, 151.0, 145.6, 145.2, 135 .5,133.0,126.6,126.5,124.8,123.2,97.2,61.6,4 8.6,33.4,14.8,8.6. MS: m / z 486.2 [M+H] + .

[0082] Step 5 In a 50 ml single-neck flask, add the product from the previous step (360 mg), acetic acid (10 ml), N aIO4 (500 mg) and 2 drops of water were added, and the mixture was then heated to 50°C and reacted for 2 hours. The reaction solution was added to 100 ml of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and The extract was dried over sodium hydroxide, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. This was purified by HPLC to give 250 mg of a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6): 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(d d,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(100 MHz,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 2000 ml single-neck flask, add methyl 2-methoxy-3-nitrobenzoate (55 g ), ammonia methanol solution (7M, 1200 ml) and ammonia water (500 ml ) was added, and the mixture was stirred at room temperature for 17 hours. After the reaction was completed, the mixture was concentrated to dryness and added to 1000 ml of water. The mixture was added and pulped for 10 minutes, filtered, and the filter cake was washed twice with water. The filter cake was then collected. After drying, 50 g of a yellow solid was obtained. 1 H NMR (400 MHz, CDCl): 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 In a 3000 ml single-neck flask, add 2-methoxy-3-nitro-benzamide (50 g). and N,N-dimethylformamide dimethyl acetal (DMF-DMA, 300 ml) After stirring at 95°C for 1 hour, the mixture was concentrated to dryness and then washed twice with 1,2-dichloroethane. Absolute ethanol (2000 ml) and acetic acid (250 ml) were added to the concentrate, and the mixture was placed in an ice bath. Hydrazine hydrate (120 ml) was slowly added dropwise under the conditions below, and the mixture was then stirred at room temperature for 6 hours. After the reaction was completed, the mixture was concentrated to dryness, 1000 ml of water was added, and the mixture was stirred for 10 minutes, filtered, and The filter cake was washed with water and the filter cake was collected and dried to give 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 In a 500 ml single-neck flask, the product of the previous step (10 g), N,N-diisopropyl Ethylamine (8.2 g), 4-dimethylaminopyridine (55.5 mg) and dichloromethane Add 150 ml of fluoromethane and add 2-(trimethylsilyl)ethoxymethyl chloride at room temperature. (9.1 g) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until approximately 50% reaction was achieved. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was dissolved in 200 ml of ethyl acetate and water was added. The organic phase was washed three times (200 ml each time), dried over anhydrous sodium sulfate, filtered, and reduced. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 5.3 g of a yellow oil. The product was a mixture of isomers in a ratio of about 62:38, with the hydrogen sulfide of the isomer with the higher content being The spectrum is as follows: 1 H NMR (400 MHz, CDCl): δ 8.3 6(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),3.9 6(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 In a 500 ml single-neck flask, the product of the previous step (5.3 g), ethanol (150 ml) l), 5% palladium carbon (530 mg) was added, and then the mixture was completely replaced with hydrogen gas. After the reaction was complete, the reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated to give 4 Obtained 0.8 g of yellow oil. MS: m / z 321.2 [M+H] + .

[0088] Step 5 In a 250 ml single-neck flask, add the product of the previous step (4.8 g), 4,6-dichloro-N -(methyl-d3)pyridazine-3-carboxamide (2.97 g) and tetrahydrofuran Add 20 ml of ethanol, flush with nitrogen, and add bis(trimethylsilyl)aminolithium in an ice bath. After the reaction was completed, the reaction mixture was stirred for 0.5 hours. The reaction mixture was added to 50 ml of ammonium chloride solution, and then mixed with 200 ml of water and 200 ml of vinegar. Ethyl acetate was added, stirred, allowed to settle, partitioned, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 5 g of a yellow oil. MS: m / z 493.2 [M+H] + .

[0089] Step 6 In a 500 ml single-neck flask, the product of the previous step (5 g), cyclopropanamide (1 0.2g), cesium carbonate (19g), BINAP (1.6g), toluene (150ml) , and palladium acetate (262 mg) were added, and then the mixture was completely replaced with nitrogen and heated at 90°C for 1. The reaction was allowed to proceed for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and 200 ml of water was added. Dilute and extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and filter. The mixture was 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 In a 100 ml single-neck flask, add 6-(cyclopropylamido)-4-((2-methoxy-3 -(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3 Pyridazine-3-carboxamide (3g), 2-(Boc-amino)-ethyl bromide (4.8 g), potassium carbonate (2.18 g), sodium iodide (200 mg) and DMSO ( 70 ml) was added, and then the mixture was heated to 100°C and stirred for 2 hours. The mixture was cooled, quenched by adding water, extracted with ethyl acetate, and the organic layers were combined and washed three times with water. The mixture was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography. Purification by chromatography gave 800 mg of a pale yellow solid, a yield of 19%. MS: m / z 555.3 [M+H] + .

[0092] Step 2 In a 100 ml single-neck flask, add the product from the previous step (800 mg) and dichloromethane. (20 ml) was added, and TFA (10 ml) was slowly added dropwise, followed by stirring at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the concentrate, and ethyl acetate was added. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate). 00 mg of off-white solid product was obtained.

[0093] Step 3 In a 100 ml single-neck flask, add carbon disulfide (0.5 g) and tetrahydrofuran (5 0 ml), purged with nitrogen, and slowly added dropwise methylmagnesium bromide (1 M) at room temperature. After the dropwise addition was completed, the mixture was heated to 65°C and stirred for 1 hour. -Chlorobenzotriazole (1 g) was added and the mixture was stirred at room temperature for 20 minutes.

[0094] In a 50 ml single-neck flask, add the product from the previous step (350 mg) and DMF (35 ml ) was added, and the above preliminary reagent (9 ml) was slowly added dropwise at room temperature, followed by stirring for 30 minutes. After completion, the reaction mixture was slowly poured into water to quench the reaction, extracted with ethyl acetate, and the organic layers were combined. Wash once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by gel column chromatography gave 180 mg of a reddish brown solid. 1 HNM R(400 MHz,CDCl3): δ 10.99(s,1H),9.86(s,1H),8.7 0(s,1H),8.17-8.10(m,3H),7.83(dd,J=7.9,1.5 Hz,1 H),7.52(dd,J=7.9,1.4 Hz,1H),7.29(t,J=7.9 Hz,1 H),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). 13 C NMR (100 MHz, 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-necked flask and placed in an ice bath. Slowly add 20 ml of sodium nitrite (2.1 g, 30.4 mmol) in water below Stannous chloride (17.1 g, 90.2 mmol) was added dropwise and stirred at 0-5°C for 1 hour. A concentrated hydrochloric acid solution (20 ml) was slowly added dropwise, and the mixture was stirred at 0 to 5°C for 2 hours. The mixture was filtered through a pad of diatomaceous earth, and the pH of the filtrate was adjusted to approximately 8 with saturated aqueous sodium hydroxide. Extraction was performed with ethyl acetate, and the organic layers were combined, washed once with saturated brine, and then washed with anhydrous sodium sulfate. The mixture was dried, filtered, and the filtrate was concentrated to dryness, and methyl tert-butyl ether (30 ml) was added. The mixture was stirred at room temperature for 20 minutes, filtered, and the filter cake was dried to obtain 2.4 g of a yellow solid. MS: m / z 184.1 [M+H] + .

[0097] Step 2 In a 100 ml single-neck flask, add the product of the previous step (2.4 g), 1,1,3,3-tetrachloroethylene, Add 2.6 g of methoxypropane and 60 ml of absolute ethanol and heat to 80°C. The mixture was heated 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 completed, the mixture was cooled to room temperature, concentrated to dryness, and saturated aqueous NaHCO3 solution was added slowly. The pH of the aqueous phase was adjusted to 7-8, and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The mixture was washed once with HCl, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and passed through a silica gel column. Purification by chromatography gave 2.8 g of a pink solid. MS: m / z 22 0.1 [M+H] + .

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

[0099] Step 4 In a 250 ml three-neck flask, add the product of 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 and the mixture was placed under nitrogen. The mixture was cooled to 10-15°C and LiHMDS (1M in THF, 38.4 ml) was added. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added. The mixture was quenched with ethyl acetate, extracted with ethyl acetate, washed once with saturated brine, and then washed with anhydrous sodium sulfate. The mixture was dried over sodium, filtered, and the filtrate was concentrated to dryness and purified with methyl tert-butyl ether (60 ml). l) was added, stirred at room temperature for 20 minutes, filtered, and the filter cake was dried to obtain 2.8 g of a pale yellow solid. The compound was obtained. MS: m / z 362.1 [M+H] + .

[0100] Step 5 In a 100 ml single-neck flask, the product of the previous step (1.5 g), cyclopropanamide (530 mg), cesium carbonate (6.8 g), ethylene glycol dimethyl ether (6 0 ml), 1,1'-bis(dicyclohexylphosphine)-ferrocene (961 mg) and The mixture was heated to 90°C and stirred for 2 hours. The mixture was cooled to room temperature, water was added, extracted with ethyl acetate, washed once with saturated brine, and then extracted with anhydrous sodium sulfate. The mixture was dried over sodium hydroxide, filtered, and the filtrate was concentrated to dryness and purified by methyl tert-butyl ether (60 ml) was added, stirred at room temperature for 20 minutes, filtered, and the filter cake was diluted with dichloromethane (20 ml ), slowly add methyl tert-butyl ether (80 ml), and let stand at room temperature for 2 The mixture was stirred for 10 minutes, filtered, and the filter cake was dried to give 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 CNM R(100 MHz,DMSO-d6): δ 174.2,167.0,156.4,145 .2,144.9,141.1,135.5,134.8,133.1,131.9,125. 2,121.6,121.3,107.8,97.5,61.2,14.9,8.6.MS: m / z 411.2 [M+H] + .

[0101] Example 10: [ka]

[0102] Step 1 In a 250 ml three-neck flask, add 80% hydrazine hydrate (32.8 g) and water (60 ml) was added, and p-methylbenzenesulfonyl chloride (10.0 g) was added in an ice bath. A solution of 30 ml of dihydrofuran was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. After completion, tetrahydrofuran is concentrated, cooled to room temperature, filtered, and the filter cake is dried to obtain 8. 3 g of a white solid was obtained. MS: m / z 187.1 [M+H] + .

[0103] Step 2 In a 100 ml single-neck flask, the product of the previous step (4.8 g), 2,2-dimethoxyaniline Add acetaldehyde (3.6 g) and methanol (60 ml), replace with nitrogen, and keep at room temperature. Acetic acid (1.3 g) and 2-methoxy-3-nitroaniline (3 g) were added to the flask and stirred at rt for 3 hours. The mixture was heated to 75°C and stirred for 16 hours. After the reaction was completed, the mixture was concentrated to dryness and saturated NaHCO The aqueous solution (3) was slowly added to adjust the pH of the aqueous phase to 7-8, and the organic layer was extracted with ethyl acetate. The combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 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 In a 100 ml single-neck flask, add the product from the previous step (3.7 g), 5% Pd / C (2 g), The mixture was purged with hydrogen gas and stirred at room temperature for 5 hours. Upon completion, it 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 In a 250 ml three-neck flask, the product of the previous step (3.0 g), 4,6-dichloro-N -(methyl-d3)pyridazine-3-carboxamide (5.0 g) and ethylene glycol Add dimethyl ether (80 ml), flush with nitrogen, cool to 10-15°C, and add LiH MDS (1M in THF) was slowly added dropwise and the reaction was allowed to proceed at room temperature for 30 minutes. After completion, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and The mixture was washed once with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Add 100 ml of ethyl tert-butyl ether, stir at room temperature for 20 minutes, and filter. The filter cake was dried to give 4.6 g of a yellow solid. MS: m / z 363.1 [M+H] + .

[0106] Step 5 In a 100 ml single-neck flask, the product of the previous step (1.5 g), cyclopropanamide (529 mg), cesium carbonate (6.8 g), ethylene glycol dimethyl ether (6 0 ml), 1,1'-bis(dicyclohexylphosphine)-ferrocene (961 mg) and The mixture was heated to 90°C and stirred for 2 hours. The mixture was cooled to room temperature, water was added, extracted with ethyl acetate, washed once with saturated brine, and then extracted with sodium sulfate anhydride. The mixture was dried over sodium, filtered, and the filtrate was concentrated and purified by silica gel column chromatography. This gave 230 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d ): δ 11.41(s,1H),11.09(s,1H),9.20(s,1H),8.56(s,1 H),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,3 H),2.14-2.05(m,1H),0.90-0.78(m,4H). 13C NMR(1 00 MHz,DMSO-d6): δ 174.3,167.0,156.4,146.0, 144.8,135.5,134.3,133.3,131.8,127.1,125.5,1 23.6,122.4,97.5,61.7,14.9,8.7. MS: m / z 412. 2 [M+H] + .

[0107] Example 11: [ka]

[0108] Step 1 In a 500 ml single-neck flask, add 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) were added, and then the mixture was purged with nitrogen and heated in an ice bath. The mixture was cooled to 0°C, and bis(trimethylsilyl)aminolithium (150 ml) was added. The reaction mixture was then allowed to warm to room temperature and react for 2 hours. The solution was poured into a broth, extracted with ethyl acetate (500 ml), dried over anhydrous sodium sulfate, and filtered. The concentrate was added to 200 ml of dichloromethane to dissolve and clarify the residue. Add ethylamine (3 g) and triphenylmethane (8 g), and stir at room temperature for 30 minutes. After the reaction was completed, the reaction solution was diluted with 200 ml of water. The organic phase was washed with sodium sulfate, partitioned, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography gave 19.0 g of a pale yellow oil.

[0109] Step 2 In a 500 ml single-neck flask, the product of the previous step (19 g), cyclopropanamide ( 6.6g), BINAP (9.6g), cesium carbonate (62.8g) and toluene ( After that, the mixture was completely replaced with nitrogen, heated to 60°C, and palladium acetate (8 The reaction mixture was heated to 90°C and reacted for 5 hours, and the remaining raw material was monitored by TLC. The solution was poured into 500 ml of water, extracted with ethyl acetate (300 ml), and the organic phase was concentrated and Purification by gel column chromatography gave 10 g of a yellow solid.

[0110] Step 3 In a 250 ml single-neck flask, add tetraethylammonium fluoride dihydrate (100 g) Add the above product (10 g) and keep warm for 3 hours. The reaction mixture was poured into 500 ml of water and stirred for 20 minutes. The mixture was stirred to precipitate a large amount of solid, filtered, and the filter cake was washed with 200 ml of water. The mixture was transferred to a 250 ml single-neck flask, 100 ml of ethyl acetate was added, and the mixture was left to stand at room temperature for 30 min. The mixture was stirred, filtered, and the filter cake was dried to give 5 g of a pale yellow solid.

[0111] Step 4 In a 100 ml single-neck flask, add the product of the previous step (2.5 g), N,N-dimethylacetone Add 50 ml of bromopropylene (5.7 g) and then add ... add After stirring for 3 min, potassium carbonate (5.9 g) was added in one portion, and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into 500 ml of ice water, and 200 ml of The organic phase was washed three times with 300 ml of water and added to anhydrous sodium sulfate. The crude product was dried at 77°C, filtered, and concentrated under reduced pressure to give 1.5 g of crude product. Purified by column chromatography and pulped with ethyl acetate (50 ml) to obtain 650 mg of off-white solid was obtained. 1 H NMR (400 MHz, DMSO-d): 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 (100 MHz, DMSO-d): δ 17 4.2, 167.0, 162.5, 156.3, 151.2, 145.0, 135.5, 133 .3,126.3,125.5,125.0,122.4,97.3,78.8,76.0,61 .9,43.2,14.9,8.6. MS: m / z 451.2 [M+H] + .

[0112] Example 12: [ka]

[0113] Step 1 In a reaction flask, 5-hydroxyl-3-(methylthio)-1,2,4-triazine-6- Add ethyl carboxylate (4 g) and tetrahydrofuran (70 ml) and cool to 0°C. Then, DIPEA (6.5 ml) and NMM (94 mg) were added slowly in that order, and the temperature was raised to 3°C. The reaction mixture was then controlled to a temperature of less than 100°C, and triclosan rin (2.6 ml) was added dropwise, followed by reaction for 1 hour. Add n-hexane to the reaction mixture, stir for 10 minutes, and then suction filter through a pad of diatomaceous earth. The residue was washed once with n-hexane, and the filtrate was concentrated to give 3.13 g of a pale yellow solid.

[0114] To the concentrate was added NMP (30 ml) and triazole-SEM compound (4.7 g), The reaction was allowed to proceed at room temperature for 1 hour. Saturated ammonium chloride (10 ml) and water (20 ml) were added to the reaction mixture. The mixture was stirred in an ice bath for 30 minutes, filtered by suction, and the filter cake was washed twice with water and dried. Obtained 0.9g of a pale yellow solid. MS: m / z 518.2 [M+H] + .

[0115] Step 2 In a reaction flask, the product of the previous step (6.9 g), deuterated methylamine hydrochloride (1.3 2g, 18.7mmol), lithium bromide (4.6g), acetonitrile (120ml) and DIPEA (12 ml) were added successively, and the atmosphere was replaced with nitrogen, followed by stirring 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 4.6 Obtained 5 g of a pale yellow solid. MS: m / z 506.2 [M+H] + .

[0116] Step 3 In a reaction flask, the product of the previous step (4.5 g), ammonia in methanol (7 M) Add 70 ml of ammonia water, then slowly heat to 110°C and cook for 6 hours. The reaction mixture was concentrated to a small volume, filtered under suction, and the filtrate was extracted twice with dichloromethane. The filter cake solids were combined and dissolved in dichloromethane, and the dichloromethane solution was 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 A reaction flask was charged with the product of the previous step (4.2 g), dichloromethane (80 ml) and 2,6-dimethylpyridine (5.7 g) was added sequentially, the atmosphere was replaced with nitrogen, and the mixture was cooled to 0°C. Cyclopropanoyl chloride (2.3 g) was slowly added dropwise, and then the reaction was continued for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride, extracted three times with MTBE, and the active The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The solid was solidified and purified by silica gel column chromatography to give 4.2 g of a pale yellow solid. S: m / z 543.3 [M+H] + .

[0118] Step 5 A reaction flask was charged with the product of the previous step (4.2 g), dichloromethane (4 ml) and T FA (80 ml) was added, and the mixture was heated to 40°C and reacted for 30 minutes. The mixture was concentrated to dryness under reduced pressure. Add THF (80 ml) and sodium bicarbonate (20 g) and stir until no bubbles remain. The mixture was filtered by suction, and the filtrate was dried and concentrated to dryness, and then used directly in the next step.

[0119] Step 6 In a reaction flask, add the product from the previous step, DMF (40 ml), and potassium carbonate (2.1 g). Then, bromopropylene (7.4 g) was added dropwise at room temperature, and the mixture was allowed to react at room temperature for 1 hour. The reaction was quenched by adding water, extracted three times with MTBE, and the organic phases were combined and saturated. Wash once with brine, dry over anhydrous sodium sulfate, filter, concentrate to dryness, and then load onto silica gel column. The solid was purified by column chromatography and then purified by liquid phase purification to give 134 mg of a pale yellow solid. Ta. 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 In a 1000 ml three-neck flask, add 2-hydroxyl-3-nitroacetophenone (30 g), potassium carbonate (46 g) and N,N-dimethylformamide (300 ml) in this order. Then, iodomethane (38.4 g) was slowly added dropwise, and the mixture was stirred at room temperature. After that, the reaction was carried out at room temperature for 20 minutes, and then the mixture was heated to 50°C and stirred overnight. The mixture was cooled to room temperature, saturated saline (500 ml) was added, and the mixture was diluted with methyl tert-butyl ether. Extract three times, combine the organic phases, wash three times with saturated brine, dry over anhydrous sodium sulfate, Filtration and concentration of the filtrate gave 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 In a 500 ml three-neck flask, the product of the previous step (32 g), DMF-DMA (39 g ) and toluene (200 ml) were added successively, and the mixture was purged under nitrogen protection and then heated at 110°C for 6 hours. The reaction mixture was refluxed, concentrated under reduced pressure to remove most of the solvent, and the concentrate was added with 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 to react. After the reaction was completed, the mixture was concentrated to remove most of the solvent. After removing the solvent, ethyl acetate (1000 ml) was added, and the mixture was washed three times with water (300 ml). The mixture was dried over sodium, filtered, and the filtrate was concentrated to remove most of the solvent, followed by addition of petroleum ether ( 600 ml) was added, and the mixture was pulped at room temperature for 30 minutes, filtered, and dried to obtain 32.5 g of yellow pulp. A solid was obtained. 1 H 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 In a 1000 ml three-neck flask, the product of the previous step (21 g), diisopropyl ethyl Amine (18.6 g), DMAP (1.17 g) and dichloromethane (210 ml) were added After adding the solution, the mixture was stirred for 10 minutes. 50 ml) solution was slowly added dropwise, and then the reaction was allowed to proceed at room temperature. The reaction was quenched by the addition of ammonium chloride solution (400 ml), partitioned, and the organic phase was diluted with NH₄Cl The mixture was washed twice with 400 ml of the solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The extract was purified by silica gel column chromatography to give 38 g of a yellow oil (a small amount of SE (Contains M-Cl). MS: m / z 372.1 [M+Na] + .

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

[0125] Step 5 In a 3 L three-neck flask, the product of 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) was added, and the mixture was cooled to 0°C and LiH MDS (194 ml) was slowly added dropwise, and the mixture was then allowed to warm to room temperature and react for 1 hour. TLC showed that a small amount of the starting material had not reacted completely. Add ammonium solution (400 ml), extract with ethyl acetate (400 ml), and the organic phase The mixture 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 After that, the mixture was stirred at room temperature to remove the unreacted raw material, aniline compound. The organic phase was washed three times with ammonium solution (400 ml), dried over anhydrous sodium sulfate, and The mixture was dried, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give 26.3% g of a yellow solid was obtained. MS: m / z 492.2 [M+H] + .

[0126] Step 6 In a 250 ml single-neck flask, the product of the previous step (14.3 g), cyclopropaneamine Benzene (4.76g), BINAP (7.15g), palladium acetate (0.66g), cerium carbonate Add sodium (47.6 g) and toluene (200 ml), then replace the entire atmosphere with nitrogen, The reaction was heated to 0°C for 8 hours and monitored by TLC. After the reaction was completed, water (400 ml) was added to the reaction mixture. The organic phases were combined and the mixture was washed with saturated saline (300 ml). l), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and applied to a silica gel column. Purification by column chromatography gave 10.8 g of a pale yellow solid. MS: m / z 5 41.3 [M+H] + .

[0127] Step 7 In a 250 ml single-neck flask, add the product from the previous step (5.4 g) and tetraethyl fluoride. Ammonium trihydrate (25 g) was added and the reaction was allowed to proceed at 85° C. overnight and monitored by TLC. After the reaction was completed, a large amount of water was added and the mixture was stirred for 30 minutes to precipitate a white solid. The mixture was dissolved in ethyl acetate (200 ml), washed three times with water (200 ml), and the organic phase was The solution was dried over sodium sulfate, filtered, and the filtrate was concentrated and mixed with an appropriate amount of ethyl acetate and methanol. A solvent (80:1) was added and the mixture was pulped for 30 minutes, and then filtered to obtain a white solid. Add 20 ml of ethyl acetate to a 50 ml single-neck flask, pulp for 1 hour, and then filter under suction. Filtration and drying gave 1.7 g of an off-white solid. MS: m / z 411.2 [M+ H] + .

[0128] Step 8 In a 50 ml single-neck flask, add N,N-dimethylacetamide (15 ml), Add the product (2.0 g) and 3-bromopropylene (5.2 g) and stir to dissolve. Potassium carbonate (5.4 g) was added all at once, and the reaction was carried out at room temperature for 24 hours. After completion, water (300 ml) was added, extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed three times with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was The mixture was concentrated and purified by silica gel column chromatography to give 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=7.7H z,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 2-chloro-3-methoxypyridine (250.0 g) and tetrahydrofuran. Add 2.5 L of toluene and cool to -75±5°C under nitrogen protection. 13L) and control the temperature at -75±5℃. After dripping, The reaction was continued for 2.5 to 3 hours. Iodine (274.5 g) in tetrahydrofuran (5 00ml) solution, and control the temperature at -75±5℃. After the dropwise addition, let it naturally return to 20-30℃. The temperature was gradually raised and the reaction was carried out for 2 to 3 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride (4.0 Successively add dropwise saturated sodium thiosulfate solution (4.0 L) and the temperature is kept at 20±5°C. The temperature was controlled to 100°C, and the mixture was added dropwise and stirred. The mixture was extracted twice with n-hexane, and the organic layers were combined and added with brine. The resulting mixture was washed with HCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil-solid mixture 42 0.0 g was obtained, 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 In a reaction flask, 2-chloro-4-iodo-3-methoxypyridine (100 g), N- Methylpyrrolidone (500 ml) and cuprous cyanide (66.3 g, 0.74 mol) The mixture was heated to 120±5°C and stirred for 4 to 6 hours. After the reaction was completed, the mixture was cooled to room temperature. 500 ml of ammonia water was added dropwise, and the temperature was controlled at 20±5°C. After the addition, ethyl acetate was added. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solid was concentrated under reduced pressure to give 54.3 g of a brown solid, which was purified by silica gel column chromatography. Purification gave 32.1 g of a white solid. MS: m / z 169.0, [M+H] + . 1 H NMR(400MHz,DMSO-d6): δ 8.35(d,J=5.0 Hz,1H), 7.90(d,J=4.9Hz,1H),4.09(s,3H).

[0132] Step 3 In a reaction flask, 2-chloro-3-methoxyisonicotinonitrile (3.0 g), methyl Add 3.9 g of methylformylhydrazine and 80 ml of tetrahydrofuran in that order. Cool to 0°C and add potassium tert-butoxide (4.4 g) to a tetrahydrofuran solution ( 50ml) slowly dripped in, and the temperature was controlled at 0±5℃. After dripping, the temperature was kept at 0±5℃. The reaction was continued for 0.5 to 1 hour while maintaining the temperature at this temperature. After the reaction was completed, a saturated aqueous solution of ammonium chloride (13 0 ml), extracted with ethyl acetate, combined, washed with brine, and added with anhydrous sodium sulfate. Drying, filtration, and concentration under reduced pressure gave 3.5 g, which was purified by column chromatography. Obtained 1.1 g of a white solid. MS: m / z 225.1, [M+H] + . 1 H NMR( 400MHz, DMSO-d6): δ 8.68(s,1H),8.25(d,J=5.0H z,1H),7.90(d,J=5.0 Hz,1H),3.99(s,3H),3.87(s,3H) .

[0133] Step 4 In a reaction flask, the product of the previous step (1.0 g), 4-methoxybenzylamine (10 0.8g), tris(dibenzylideneacetone)dipalladium-chloroform adduct (0.4 6g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.1g), carbonate Sodium (4.35 g) and 1,4-dioxane (30 ml) were added successively, and the mixture was stirred under the protection of nitrogen. The mixture was heated to 90±5°C and kept at this temperature for 14 to 16 hours. After the reaction was completed, the mixture was cooled to 20 to 30°C. The mixture was cooled to rt, water was added, extracted with ethyl acetate and concentrated to give 4.5 g of an oily crude product. MS: m / z 326.2 [M+H] + .

[0134] Step 5 In a reaction flask, the crude product (4.5 g) from the previous step, trifluoroacetic acid (45 m l) was added in order, and the mixture was heated to 90±5°C and kept at that temperature for 1 to 2 hours. After the reaction was completed, the mixture was concentrated. Dry the mixture, add methanol (110 ml) to dissolve it, and add sodium bicarbonate to adjust the pH. The mixture was adjusted to 7-8°C, stirred for 30 minutes, filtered, and concentrated to give 2.51 g of a brown oil. The solid was purified by gel column chromatography to give 2.1 g of a yellow oily solid mixture. MS: m / z 206.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d): 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 In a reaction flask, 3-methoxy-4-(1-methyl-1H-1,2,4-triazole- 3-yl)pyridin-2-amine (1.2 g, 5.85 mmol), 4,6-dibromo-N -(Methyl-d3)pyridazine-3-carboxamide (2.27g), N,N-dimethylformamide Add 24 ml of methyl methyl acrylate (24 ml) and, under the protection of nitrogen, cool to 0±5°C and add sodium hydride (24 ml). Add 0.94g of sodium hydroxide, stir at 0±5°C for 0.5 to 1 hour, and then let the temperature rise naturally to 20±5°C. After the reaction was completed, the reaction mixture was added dropwise to a saturated aqueous solution of ammonium chloride. After the dropwise addition, the mixture is stirred for 1-2 hours, filtered, and the solid is dissolved in water. After washing twice and drying, 0.84 g of a brown solid was obtained. 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 In a reaction flask, the product of the previous step (400 mg), N-methylpyrrolidone (16 ml ), cyclopropanethiocarboxamide (288.3 mg, 2.85 mmol), trichloroethylene Dicyclohexylphosphine (106.6 mg), N-methyldicyclohexylamine (55 6.7 mg) and bis(tri-tert-butylphosphine)palladium (97.5 mg ) were added in order, and the mixture was heated to 110±5°C under nitrogen protection and kept at that temperature for 1 to 2 hours to react. After the reaction was completed, the mixture was cooled to 20±5°C, and the reaction mixture was added dropwise to an aqueous solution of glacial acetic acid and diluted with dichloromethane. Extract three times, combine the organic layers, wash with brine, dry over anhydrous sodium sulfate, filter, Concentration under reduced pressure gave 1.2 g of a brown oil, which was purified by silica gel column chromatography. The resulting product was a yellow solid (30.0 mg). MS m / z 443.2 [M+H] + .

[0137] Example 15: [ka]

[0138] Step 1 In a 250 ml single-neck flask, add 4,6-dihydroxypyridazine-3-carboxylic acid ester Add ethyl acetate (8.5 g) and acetonitrile (100 ml) and cool to 0°C under nitrogen protection. A solution of phosphoryl bromide (39.7 g) in acetonitrile was added dropwise, and the mixture was then allowed to cool to room temperature. The temperature was gradually increased, and the mixture was stirred at 25°C, 55°C, 75°C, and 95°C for 40 minutes. The reaction was monitored by the officials. 50 ml of ethyl acetate was added to the system, filtered, and the filtrate was concentrated to dryness. The concentrate was dissolved in 100 ml of dichloromethane and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was adjusted to 8°C, partitioned, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then evaporated to silica. Purification by gel column chromatography gave 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 gL) and potassium carbonate (4.9 g) were added, and the After that, the mixture was stirred at room temperature overnight. 200 ml of water was added to the mixture, and it was extracted with ethyl acetate. The organic phase was The concentrate was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Pulping with a mixed solvent of ether and n-hexane gave 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 In a 250 ml single-neck flask, add the product from the previous step (4.86 g), acetonitrile (1 Add 100 ml of the solution and lithium bromide (5.15 g) and stir at room temperature for 30 min under nitrogen protection. The mixture was stirred, cooled to -26°C, diisopropylethylamine (9.58 g) was added, and the mixture was stirred for 10 min. Stir and add deuterated methylamine hydrochloride (1.04 g) in one portion at -30°C, then The reaction was continued at -25°C for 2 hours, and TLC showed that the reaction was nearly complete. 1 of ice water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, Concentration under reduced pressure and pulping of the concentrate with petroleum ether gave 2.93 g of an off-white solid. Got it.

[0141] Step 4 In a 100 ml single-neck flask, the product of the previous step (2.22 g), arylamine compound (1.5 g), lithium bromide (814 mg) and 2-methyltetrahydrofuran (3 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, after which 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 The extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. The residue was purified by filtration to give 2.1 g of a pale yellow solid. 1 H 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).M S: m / z 537.2 [M+H] + .

[0142] Step 5 In a 100 ml single-neck flask, the product of the previous step (1.42 g), cyclopropanethiol Carboxamide (400 mg), tricyclohexylphosphine (222 mg), N,N -Dicyclohexylmethylamine (1.55g), bis(tert-butyltriphosphine ) Palladium (200 mg) and N-methylpyrrolidone (14 ml) were added and the mixture was placed under nitrogen. The mixture was cooled, water was added, and the mixture was stirred with ethyl acetate. The organic phase was extracted, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then loaded onto a silica gel column. Purification by column chromatography gave 1.0 g of a yellow oily product. MS: m / z 558.1 [M+H] + .

[0143] Step 6 In a 100 ml single-neck flask, add the product from the previous step (900 mg), dichloromethane (1 6 ml), tetraethylammonium fluoride (2.7 g) and trifluoroacetic acid (40 The mixture was then stirred at room temperature for 2 hours. Ethyl acetate was added to the condensate to dissolve and clarify it, and the organic phase was washed three times with water and then extracted with anhydrous sodium sulfate. The mixture was dried at 77°C, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 3 00mg of a pale yellow solid was obtained. 1 H NMR (400 MHz, DMSO-d): δ 1 4.13(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,2) H). MS: m / z 428.2 [M+H] + .

[0144] Step 7 In a 100 ml single-neck flask, add the product from the previous step (270 mg), DMA (5 ml), Bromopropylene (600 mg) was added, and then the temperature was raised to 50°C. 0 mg) was added in one portion, and then stirring was continued for 3 h. Water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was 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] In a clean 25 ml single-neck flask, add the triazole compound (100 mg), N,N-dimethylformamide (100 mg), Dimethylformamide (10 ml), methyl 2,4-dibromobutyrate (70 mg) and cetethoxycarbonyl After that, the atmosphere was replaced with nitrogen, and the reaction was carried out at 45°C. The reaction was monitored for completion and the reaction was added to 50 ml of saturated ammonium chloride solution. Extract with ethyl acetate (30 ml), combine the organic phases, wash with saturated brine (30 ml), Drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure gave approximately 200 mg of crude product. Purification by silica gel column chromatography gave 80 mg of product. 1 H 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 Hz,1H),3.81(s,3H),3.73(s,3H),1.99-1.92(m,2H),1. 87-1.78(m,1H),1.78-1.71(m,2H),1.16-1.08(m,2H), 0.95-0.87(m,2H).MS: m / z 510.2 [M+H] + .

[0147] Example 17: [ka]

[0148] In a 100 ml single-neck flask, add 6-chloro-4-((2-methoxy-3-(1-methyl- 1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyri Dazin-3-carboxamide (500 mg, 1.33 mmol), cyclopropanesulfonate amide (322 mg), potassium phosphate (560 mg), 1,1'-bis(diphenylphosphine) Sphino)ferrocene (150 mg), tris(dibenzylideneacetone)dipalladium ( 119 mg) and 1,4-dioxane (15 ml) were added, and then the mixture was completely purged with nitrogen. The mixture was stirred at 0°C for 24 hours. The reaction mixture was concentrated to dryness, and 20 ml of water was added. After extraction, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and then passed through a silica gel column. Purification by chromatography gave 330 mg of a yellow solid. 1 H NMR (400 M Hz, 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(d d,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, CDCl): δ 164.7, 160.0, 155.9, 151.8, 146.9, 144.0, 131.3, 1 31.0,128.2,126.2,124.6,124.3,98.5,61.8,36.5, 31.7,5.47.MS: m / z 462.2,[M+H] + .

[0149] Example 18: [ka]

[0150] Step 1: In a 250 ml single-neck flask, add the raw material (1 g), benzophenone imine (3.0 g), and vinegar. Palladium carbonate (185 mg), cesium carbonate (13.4 g), 1,1'-bis(dicyclohexane) (xylphosphine)-ferrocene (1.9g), aluminum trifluoromethanesulfonate Add 195 mg of ammonium hydroxide and 120 ml of dioxane, protect with nitrogen, and heat to 100°C. After cooling the system, it was poured into 300 ml of water to wash it, and then 300 ml of Extraction with ethyl acetate, partitioning, concentration, and column chromatography yielded 2 g of a pale yellow solid. The product was obtained. MS: m / z 522.24, [M+H] + ,

[0151] Step 2: In a 100 ml one-neck flask, add the raw material (2.2 g) and 80 ml of THF, and let it cool at room temperature for 1 6 ml of 2 M / L HClaq was slowly added, and then the mixture was stirred at room temperature for 2 hours. The system was washed by pouring it into 200 ml of saturated sodium bicarbonate solution and then rinsing it with 200 ml of acetic acid ethanol. Extraction with chilling, partitioning, drying, concentration, and column chromatography yielded 1.1 g of reddish-brown A solid product was obtained. MS: m / z 358.18,[M+H] + ,

[0152] Step 3: In a 250 ml single-neck flask, add the raw material (500 mg) and 80 ml of distilled water for dissolution clarification. Add chloromethane and DIPEA (180 mg), cool to 0°C in an ice bath, and add allyl chloride (1 20 ml of a dichloromethane solution of 30 mg of benzophenone was added dropwise, and the mixture was then stirred at room temperature to react. The system was washed with 100 ml of water, partitioned, dried, concentrated, and purified by column chromatography. gave 150 mg of yellow solid product. 1 H NMR (400 MHz, CDCl): 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 Hz,1H),7.32(t,J=7.9 Hz,1H),6.69-6.62(m ,1H),6.33(dd,J=1.7,17.0 Hz,1H),5.84(dd,J=1.6,1 0.1 Hz,1H),3.95(s,3H),3.73(s,3H),MS: m / z 412. 19, [M+H] + .

[0153] Example 19: [ka]

[0154] In a 250 ml single-neck flask, add 6-chloro-4-((2-methoxy-3-(1-methyl- 1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyri Dazine-3-carboxamide (1.5 g), cesium carbonate (5.2 g), cyclobutyl carboxylate Ruboxamidine hydrochloride (962 mg), palladium acetate (89 mg), 1,1'-bis(di Cyclohexylphosphine)-ferrocene (884 mg) and ethylene glycol dimethicone Diethyl ether (100 ml) was added, and the mixture was purged with nitrogen, and then the temperature was raised to 90°C to carry out the reaction. The reaction mixture was cooled and poured into 200 ml of water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The extract was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give an 800 ml g of a pale yellow solid was obtained. 1 H NMR(400 MHz,DMSO-d6): δ=10.7 0(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 (100 MHz, DMSO-d): δ=167.4,167.0,166.5,159.4,150.9,145.6,144.9 ,134.3,133.3,126.7,126.2,124.8,123.7,102.9,6 1.6,36.5,16.0,8.4.MS: m / z 425.2,[M+H] + .

[0155] Example 20: [ka]

[0156] Step 1 In a reaction flask, 3-methoxy-4-(1-methyl-1H-1,2,4-triazole- 3-yl)pyridin-2-amine (1.4 g), N,N-dimethylformamide (50 ml ) was added, cooled to 0°C, sodium hydride (1.1 g) was added in one portion, and then 20 min The reaction mixture was stirred for 1 min, then slowly warmed to room temperature and stirred for 30 min. The reaction mixture was cooled to 0°C and 4,6-Dichloro-N-(methyl-d3)pyridazine-3-carboxamide (4.3g) The tetrahydrofuran solution (40 ml) was slowly added dropwise, and the temperature was controlled to less than 5°C. The reaction mixture was added dropwise over 2 hours and stirred overnight. After stirring for 30 minutes, the mixture was filtered under suction. The filter cake was washed twice with water and then filtered. The filter cake was dried to give 1.82 g of an off-white solid. MS: m / z 378.1 [M+H] + .

[0157] Step 2 A reaction flask was charged with the product of the previous step (1.82 g, 4.8 mmol), DCPF (1. 1g), palladium acetate (108mg), cesium carbonate (7.9g) and DME (60 After replacing with nitrogen, the temperature was raised to 90°C and the reaction was carried out for 1 hour. The mixture was cooled to rt, filtered by suction, and the filtrate was concentrated and purified by silica gel column chromatography. 430 mg of a pale yellow solid compound was obtained. 1 H NMR (400 MHz, DMSO-d): 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-d): δ 173.8,167.0,157.6,156.6,150.1,146.2,142.6,1 42.5, 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 In a reaction flask, 5-hydroxyl-3-methylthio-1,2,4-triazine-6-carboxylate was added. Add ethyl carboxylate (4.62 g) and acetonitrile (50 ml), cool to 0°C, and IPEA (5.17 g) and N-methylmorpholine (101 mg) were added, and then triclosan was added. Add 4.6g of thiamin monophosphate slowly, then warm to room temperature and let it react for 1 hour. After the reaction is complete, the reaction mixture is cooled to 0°C and adjusted to a pH of about 7-8 with DIPEA. 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline A solution (10 ml) of (3.27 g) in tetrahydrofuran was added dropwise, and the temperature was then raised to 30°C. The mixture was washed with saturated aqueous ammonium chloride solution and The organic phase was dried and concentrated, and purified by silica gel column chromatography. 5.0 g was obtained.

[0160] Step 2 A reaction flask was charged with the product of the previous step (5.0 g), deuterated methylamine hydrochloride (1. 02g) and acetonitrile (50ml), cooled to 0°C, and DIPEA (4.6 Add lithium bromide (2.08 g) and then slowly warm to room temperature and let it sit for 1 hour. A saturated aqueous solution of ammonium chloride was added to the system, and the system was extracted with dichloromethane. The phase was dried and concentrated, and purified by silica gel column chromatography to give 4.18 g Ta.

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

[0162] Step 4 In a 50 ml single-neck flask, the product of the previous step (100 mg), cyclopropanamide (50 mg), potassium tert-butoxide (150 mg), toluene (10 ml) The mixture was heated to 80°C under nitrogen protection and reacted for 3 hours. The mixture was poured into a liquid, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was concentrated with ethyl acetate and purified by silica gel column chromatography to give 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,1 H),7.78(dd,J=7.9,1.5 Hz,1H),7.31(t,J=8.1 Hz,1 H),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] In a 50 ml single-neck flask, add 6-(cyclopropylamido)-4-((2-methoxy-3- (1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyri Dazin-3-carboxamide (500 mg, 1.2 mmol), N,N-dimethylacetamide amide (20 ml), propargyl bromide (1.3 g, 10.9 mmol) and carbonate Potassium (1.3 g, 9.4 mmol) was added, and the reaction was then carried out at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 400 ml of water to quench the reaction, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then passed through a silica gel column. Purification by column chromatography gave 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=7.9,1.6H z,1H),7.55(dd,J=8.0,1.5 Hz,1H),7.28(t,J=7.9H z,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),0.9 4-0.87(m,2H). 13 C NMR (100 MHz, CDCl3): δ 173 .2,166.7,160.6,155.7,151.5,146.1,143.0,135. 0, 132.4, 127.1, 125.7, 124.6, 123.6, 97.8, 76.1, 75 .1,61.6,39.7,16.0,8.8, 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" refers to the compound of Example 146 in the reference document WO2014074661. The compound was prepared with reference to this literature method. Dosage and method: 20 mg / kg, BID, orally administered Experimental procedure: On Day 0, the test areas on the backs of the animals were shaved and divided into groups. One hour after the first morning administration, 40 mg of 5% imiquimodol was administered to the test site on the back of the mice. The psoriasis area and severity index (PA) was calculated based on the smearing of the psoriasis area and severity index (PA). The symptoms of psoriasis lesions and the effectiveness of medication are assessed by the SI score (degree of erythema, scaling, and thickening) The higher the score, the more severe the 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 are imines. It can improve the symptoms of psoriatic lesions in a quimod-induced psoriasis-like mouse model, 146 The compound improved the symptoms of psoriatic lesions in an imiquimod-induced mouse psoriasis-like model. The effects of Compounds 7, 8, 9, and 10 are greater than those of Compound 146. is also excellent.

[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. As shown in the data, compound 11 has an anti-psoriasis effect in an imiquimod-induced mouse psoriasis-like model. Compound 11 is more effective than Compound 146 in improving the symptoms of psoriasis. is also excellent.

[0171] Here, "Compound No. 146" refers to Compound No. 146 in Example 146 of Reference WO2014074661. and was prepared with reference to this literature method.

[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. The mixture was then added to the Echo plate with a gradient of different concentrations of the compound, each concentration being 200 times the final concentration. The instrument transferred 75 nL of compound from the Echo plate to the 384 experimental plate. Transfer 5 μl of K2-JH2 kinase to a 384-well plate. Add 3x the final concentration of Tb antibody 5 5 μl of Tracer at 3x the final concentration was added to the 384-well plate. The plate was centrifuged for 30 seconds and incubated at room temperature for 60 minutes. sion Enzyme Labeler (PerkinElmer) 495nm / 520nm fluorescence signal The ratio is read. The data is analyzed using XL-Fit software to calculate the compound IC50. I put it out.

[0175] Here, "A" means that the TYK2-JH2 binding inhibitory activity (IC50 value) is less than 0.10 nM. Show that "B" has a TYK2-JH2 binding inhibitory activity (IC50 value) range of 0.10nM to 0. 50nM, "C" indicates that the range of TYK2-JH2 binding inhibitory activity (IC50 value) is 0.50nM to 1nM. Indicates that it is M, "D" indicates that the TYK2-JH2 binding inhibitory activity (IC50 value) is greater than 1 nM .

[0176] [Table 3]

[0177] As can be seen from the above data, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11. Compound 2-1B-1, Compound 2-1B-2, Compound 2-1B-7, and Compound X-1 Some of these compounds have significant effects. showed.

[0178] Biological test example 4: Detection by flow cytometry fluorescence sorting technology (FACS) Inhibitory effect of selected compounds on pSTAT5 expression in CD3+ cells Compound dilution preparation: Compounds were prepared as 10 mM solutions in DMSO and the final concentration was adjusted to 10 mM in DMSO. The compound was diluted to a gradient solution of 500-fold different concentrations. 5 μL of the diluted compound was added to 0.1% BS A positive and negative control set was set up, and the positive and negative controls were The control group contained 0.2% DMSO at the end.

[0179] Testing Procedure: 1) In a 96-well cell culture plate, 0.5 million ions were added to each well, with a volume of 67.5 uL. Human PBMC cells are added. 2) Add 3.5 μl of diluted compound and mix evenly. 3) Incubate in a 37°C incubator for 60 minutes. 4) IFN-alpha was diluted to 600ng / mL in DPBS containing 0.1% BSA. After the 60-minute incubation, add PE-anti-hCD3 antibody to one well. Add 5uL 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 pre-warmed Add the Lyse / fix buffer. 7) Incubate at 37°C for 10 minutes away from light. 8) Centrifuge at 600g for 5 minutes, discard the supernatant, add 1 mL of PBS, wash twice, and centrifuge. Separation of the heart. 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 600 g for 5 minutes, discard the supernatant, and wash twice with 1 mL of PBS. , and centrifuge. 12) APC anti-human pSTAT5 antibody was used in staining buffer. Dilute 200-fold with fer and add 100 μL per well to the cell wells and mix evenly. do. 13) Incubate at room temperature for 40 minutes. 14) Wash twice with staining buffer, then add 1 mL of 600 ml of Centrifuge at 47°C for 5 min. 15) Discard the supernatant and resuspend the cell pellet in 300 μL of staining buffer. do. 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. the law of nature, "C" indicates that the inhibitory activity (IC50 value) of p-STAT5 expression ranges from 5 nM to 10 nM. can be, "D" indicates that the inhibitory activity (IC50 value) of p-STAT5 expression is greater than 10 nM. vinegar.

[0181] [Table 4]

[0182] As can be seen from the above data, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, compound 2-1A-1, compound 2-1B-1, compound 2-1B-2, compound 2-1B -7, Compound X-1 has an inhibitory effect on p-STAT5 expression. 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: Mixed solution (ethanol + TPGS + PEG300 = 5:5:90) was used as the administration solvent. It was used as. Injection: A mixed solution (PEG400 + ddH2O = 80:20) is used as the administration vehicle. did. 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. Ta. Administration route and dosage: 1 mg / kg for the intravenous group and 1 mg / kg for the oral group. It was administered at 10 mg / kg. 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 and the mixture was vortexed for 1 minute. The mixture was then centrifuged at 10,000 rpm for 5 minutes to remove the supernatant. The samples were sent to a laboratory and analyzed for drug content.

[0184] The test results are summarized as follows: [Table 5] Here, "Compound No. 146" refers to Compound No. 146 of Example 146 in Reference WO2014074661. It is a compound prepared with reference to this literature method.

[0185] As can be seen from the results of the pharmacokinetic study of compound 11 and compound X-1, compound 11 The absolute bioavailability of compound 146 is greater than that of compound 146.

[0186] Biological Test Example 6: Measurement of pharmacological effects in an imiquimod-induced 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 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, "+++" is a score of 4 tones or less, "++++" indicates a score of 4 or less.

[0187] [Table 6]

[0188] As can be seen from the above data, the above compounds have the potential to inhibit the imiquimod-induced psoriasis-like disease in mice. In this study, psoriasis lesion symptoms could be improved, and some compounds have a significant effect.

[0189] Application Example 7: Ointment Preparation The compound of the present invention has the following action route: and other diseases, some of which include skin-related diseases, and Developing it into a drug may be more convenient and directly usable in certain situations.

[0190] Ointment composition: [Table 7]

[0191] Ointment preparation: Homogenization: Put the specified amount of Vaseline into the main pot and melt it completely at 70-90°C. The temperature was controlled at 75±5°C, and the compound 7 or compound X-1, antioxidant, The inhibitor BHA (butylated hydroxyanisole) and benzylmethanol were mixed in a volume of about half. Add to heavy liquid paraffin and disperse evenly by mechanical stirring to obtain mixture 1. Mixture 1 and the remaining Add the light liquid paraffin and melted Vaseline solution to the main pot and mix at 30-60 rpm. Stir with a scraper and homogenize at a stirring speed of 1000 to 2800 rpm, and then use a vacuum of -50 to - Homogenize at 100Kpa, 70±5℃ for 20-30 minutes, then slowly cool to below 35℃. As a result, a paste was obtained.

[0192] Filling: The prepared plaster is filled into a filling machine according to the specified filling specifications. The temperature of the bag was controlled at 25 to 30°C, and the seal end temperature was controlled at 450±20°C. According to the synthesis and ointment preparation scheme, Compound 7 ointment and Compound X-1 ointment were obtained.

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

[0194] When the stability of a 5% ointment of Compound 7 was compared with that of a 5% ointment of Compound X-1, The 5% ointment prepared by preparing 1 showed visible granular particles in the ointment after 20 days of standing. This is thought to be the result of the product being precipitated after Compound X-1 was left standing for a long period of time. The 5% ointment containing Compound 7 was prepared and left for 30 days, after which visible granules appeared. The paste was uniform without any blemishes.

[0195] The above phenomenon indicates that the 5% ointment prepared using Compound 7 is suitable for storage and use. Indicates that it is suitable.

[0196] Biological Test Example 8: Rat model of imiquimod-induced IL-17 elevation by oral administration Measurement of pharmacological effects in Diseases controlled by IL-17 include, for example, ankylosing spondylitis, rheumatoid arthritis, These include autoimmune diseases such as atopic dermatitis and enteritis, and the compounds of the present invention inhibit IL-17 Modulating levels has potential therapeutic effects in autoimmune diseases. 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: 40 mg of imiquimod ointment was applied to the dorsal skin of SD rats once a day. We constructed a NET model. 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] As can be seen from the study of the imiquimod-induced rat model with different compounds, compound 7 The effect is superior to that of Compound X-1. Here, Compound 7 or Compound 11 was orally administered. When treated with IL-17F, the inflammatory factor in the experimental animals increased to levels close to those of normal animals. In some cases, oral administration of Compound 7 or Compound 11 significantly improved the skin lesion phenomenon in rats. The rat skin lesion area and severity index scores were significantly reduced compared to the compound X-1 treatment group. Further testing showed that the compound exhibited a higher activity than other compounds with similar structures. It was good.

[0200] Biological Test Example 9: In a rat model of elevated IL-17 induced by oral administration of imiquimod Measurement of pharmacological effects Biological Test The pharmacological effects of the compounds of the present invention were evaluated using the same scheme as in Example 8. Obtain test results.

[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] As can be seen from the treatment study of the imiquimod-induced rat model with different compounds, The therapeutic effect of 2-1A-1 is superior to that of Compound 1-1-1 and Compound X-1. Oral administration of compound 2-1A-1 reduced the inflammatory factor IL-17F in experimental animals. At the same time, oral administration of compound 2-1A-1 resulted in a decrease in the IL-12 level, which was close to that of normal animals. The skin lesion phenomenon in rats was significantly reduced, and the area and severity index scores of the skin lesions in rats were significantly reduced. 1-1-1, compound X-1 treatment group.

[0204] Biological Test Example 10: Imiquimod-induced IL-17 elevation in a rat model using smear administration Measurement of pharmacological effects in Experimental animals: 8-10 week old SD rats, half male and half female Model construction: 40 mg of imiquimod ointment was applied to the dorsal skin of SD rats once a day. A psoriasis-like rat model was established. Experimental procedure: The back skin of SD rats was depilated 3 days before the experiment. First, 40 mg of imiquimod was administered. The ointment was then applied at a dose of 1 g / day / animal (application area 5 x 15 cm), and 1 The test was performed once a day for 5 consecutive days, and the control group was not smeared. Before smearing, the skin was wiped clean. Ku. Test detection: On the 6th day, the rat skin was wiped clean, the skin was collected, and mixed with the cell lysis solution. The animals were 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] As shown by the treatment study of imiquimod-induced rat model with different compound ointments, The therapeutic effect of Compound 7 ointment is superior to that of Compound X-1 ointment. Oral administration of the ointment resulted in normal functioning of the inflammatory factor IL-17F in the skin of experimental animals. At the same time, compound 7 ointment or compound 11 ointment was orally administered to treat As a result, the skin lesion phenomenon in rats was significantly reduced, and the area and severity index score of the skin lesion in rats were , compound X-1 ointment treatment group, and further testing showed that It is superior to other compounds.

[0208] Biological Test Example 11: Imiquimod-induced IL-17 elevation in rat model by smear administration method Measurement of pharmacological effects in Biological Test The pharmacological effects of the compounds of the present invention were evaluated using the same scheme as in Example 10. The test results below are 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] As shown by the treatment study of imiquimod-induced rat model with different compound ointments, The therapeutic effect of Compound 2-1A-1 ointment was greater than that of Compound 1-1-1 ointment and Compound X-1 ointment. Oral administration of Compound 2-1A-1 ointment for treatment reduced inflammation in the skin of experimental animals. The level of IL-17F approached that of normal animals. Oral administration of the drug significantly reduced the incidence of skin lesions in rats, and the area and severity of skin lesions in rats were significantly reduced. The symptom index score was superior to that 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: Mixture: weighed amount of Compound 2-1A-1, starch, microcrystalline cellulose, carboxymethyl The starch is added to the wet mixer granulator and mixed. Binder solution preparation: Weigh out purified water and slowly add an appropriate amount of Polyvidone K3 while stirring. 0 and disperse uniformly while stirring to prepare an aqueous solution of adhesive-Polyvidone K30. Soft material preparation: Using a wet mixer granulator, control the stirring speed and shear rate to mix the soft material. The polyvidone K30 aqueous solution is slowly added, and the mixture is stirred and sheared to prepare a mixture material. Granulation: The prepared mixture was granulated in a swing granulator equipped with a 24-mesh sieve, and the wet 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: Put the sized particles into a three-dimensional multi-directional mixer, wait for the mixing to finish, and add stearin. Add magnesium sulfate and continue mixing for about 3 minutes to obtain a fully mixed particle. Tablet compression: Compress the tablets using a tablet press to prepare the tablets: perfect and polished appearance, Tablets of uniform color and suitable hardness and abrasion resistance are obtained.

[0213] The compounds prepared according to the present invention inhibit tyrosine kinase 2 (Tyrosine kinase 2). se 2, TYK2 inhibitory activity, and has a wide range of applications in the treatment of autoimmune diseases and tumors. There is potential for use.

[0214] The compounds of the present invention have excellent characteristics in terms of activity and drug-like properties and are of different structural types. The compounds have different absorption, metabolism, and distribution characteristics, which may affect enteritis, ankylosing spinal cord, In different parts of the body, such as spondylitis, and inflammation involving the skin, and other related diseases To provide more effective, convenient, and diverse options for the treatment of autoimmune diseases It also has an overall positive effect on raw material and formulation preparation, as well as product stability. .

Claims

1. A compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkyl, alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino can be, Ring B is aryl, heteroaryl, or heterocyclyl, and Ring B is selected from the following groups: Is: 【Chemistry 2】 where T, G, Y, Z, and M each independently represent an oxygen atom, CR Ａ１ , C.R. Ａ２ , Nitrogen atom or NR Ｂ is selected from E is a nitrogen atom or a carbon atom; R Ａ１ , R Ａ２ is hydrogen, deuterium, C １－６ Alkyl, halogen, and the following structure Selected from: 【Transformation 3】 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 Alkyl-S(O) ２ -, alkenyl, deuterated alkenyl and is selected from alkynyl, alkynyl, deuterated alkynyl, and the following structures: 【Chemistry 4】 Q is a chemical bond or -C(O)-, -C(S)-, -S(O)-, -S(O) ２ -, -C(N -R ８ )-, i.e.: 【Transformation 5】 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, or heterocyclyl, and Ring A is selected from the following groups: Is: 【Transformation 6】 C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and C is selected from the following groups: 【Transformation 7】 Here, R １ , R ２ , R ３ , R ４ , R ５ , R ７ , R ８ are hydrogen, deuterium, halogens, and Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkenyl carbamate Alkenyl, deuterated alkenylcarbonyl, alkyl, deuterated alkyl, alkylcarbonyl and deuterated alkylcarbonyl, wherein alkynyl, alkenyl, deuterated alkylcarbonyl are selected from the group consisting of alkynyl, alkenyl, deuterated alkylcarbonyl, and deuterated alkylcarbonyl. Alkenyl, deuterated alkenyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, optionally substituted with hydroxyl, amino, cycloalkyl, aryl, heteroaryl; n=1, 2, 3, 4, 5, 6. )

2. The following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: 【Transformation 8】

3. A compound of formula (I-1), its stereoisomers, tautomers and pharmaceutically acceptable salts. 【Chemistry 9】 (wherein L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, Deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkyl It is an amino 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: 【Chemistry 10】 Here, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ are hydrogen, deuterium, and halogens. alkynyl, amino, alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl wherein alkynyl, alkenyl, alkyl and deuteroalkyl are selected from halo alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl are optionally substituted, R ９ is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl, alkoxy, halo Alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH ２ ) ｎ１ R ａａ 、-(CH ２ ) ｎ１ OR ａａ 、-SR ａａ 、-(CH ２ ) ｎ１ C(O) R ａａ 、-(CD ２ ) ｎ１ R ａａ 、-(CD ２ ) ｎ１ OR ａａ 、-SR ａａ 、-(CD ２ ) ｎ１ C(O)R ａａ 、-C(O)OR ａａ 、-C(O)R ａａ 、-S(O) ｍ１ R ａａ 、-(CH ２ ) ｎ １ S(O) ｍ１ R ａａ ,-(CD ２ ) ｎ１ S(O) ｍ１ R ａａ 、-NR ａａ R ｂｂ 、-C(O)N R 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 hydrogen, deuterium, alkyl, deuterium alkyl, halo, alkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, thiazolinone, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl aryl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are selected from the group consisting of 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 hydroxy alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted and one or more of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. optionally substituted with substituents, n=1, 2, 3, 4, n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4. )

4. The following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: 【Chemistry 11】

5. Compounds of formula (II-1), stereoisomers, tautomers and pharmaceutically acceptable salts thereof. 【Chemistry 12】 wherein Ring B is aryl, heteroaryl, or heterocyclyl; X １ , E is a nitrogen atom or a carbon atom; L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkyl, alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino can be, 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 - and Nawachi: 【Chemistry 13】 C is alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, heterocyclyl, and C is selected from the following groups: 【Chemistry 14】 Here, R １ , R ２ , R ３ , R ４ , R ５ , R ７ is hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R ９ is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl, alkoxy, halo Alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH ２ ) ｎ１ R ａａ 、-(CH ２ ) ｎ１ OR ａａ 、-SR ａａ 、-(CH ２ ) ｎ１ C(O) R ａａ 、-(CD ２ ) ｎ１ R ａａ 、-(CD ２ ) ｎ１ OR ａａ 、-SR ａａ 、-(CD ２ ) ｎ１ C(O)R ａａ 、-C(O)OR ａａ 、-C(O)R ａａ 、-S(O) ｍ１ R ａａ 、-(CH ２ ) ｎ １ S(O) ｍ１ R ａａ ,-(CD ２ ) ｎ１ S(O) ｍ１ R ａａ 、-NR ａａ R ｂｂ 、-C(O)N R 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 hydrogen, deuterium, alkyl, deuterium alkyl, halo, alkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, thiazolinone, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl aryl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally , hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydride hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkoxyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyl, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl , substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; optionally substituted with multiple substituents; n=1, 2, 3, 4, n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4. )

6. A compound of formula (II-1A), its stereoisomers, tautomers and pharmaceutically acceptable salts. 【Chemistry 15】 wherein Ring B is aryl, heteroaryl, or heterocyclyl; X １ , E is a nitrogen atom or a carbon atom; L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkyl, alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino can be, 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: 【Chemistry 16】 Here, R １ , R ２ , R ３ , R ４ , R ５ , R ７ is hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R ９ is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl, alkoxy, halo Alkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-(CH ２ ) ｎ１ R ａａ 、-(CH ２ ) ｎ１ OR ａａ 、-SR ａａ 、-(CH ２ ) ｎ１ C(O) R ａａ 、-(CD ２ ) ｎ１ R ａａ 、-(CD ２ ) ｎ１ OR ａａ 、-SR ａａ 、-(CD ２ ) ｎ１ C(O)R ａａ 、-C(O)OR ａａ 、-C(O)R ａａ 、-S(O) ｍ１ R ａａ 、-(CH ２ ) ｎ １ S(O) ｍ１ R ａａ ,-(CD ２ ) ｎ１ S(O) ｍ１ R ａａ 、-NR ａａ R ｂｂ 、-C(O)N R 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 hydrogen, deuterium, alkyl, deuterium alkyl, halo, alkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, thiazolinone, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl aryl, aryl, and heteroaryl, wherein said alkyl, deuterated alkyl, alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally , hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydride hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkoxyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyl, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl , substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; optionally substituted with multiple substituents; n=1, 2, 3, 4, n1=0, 1, 2, 3, 4, m1=0, 1, 2, 3, 4. )

7. The following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: 【Chemistry 17】

8. A compound of formula (II-1B), its stereoisomers, tautomers and pharmaceutically acceptable salts. [Chemistry 18] wherein Ring B is aryl, heteroaryl, or heterocyclyl; X １ , E is a nitrogen atom or a carbon atom; L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkyl, alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino can be, 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: 【Chemistry 19】 Here, R １ , R ２ , R ３ , R ４ , R ５ , R ７ is hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R ９ａ , R ９ｂ , R ９ｃ is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl , or R ９ａ and R ９ｂ together with the carbon atom to which it is attached form a cycloalkyl, n = 1, 2, 3.)

9. The following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: 【Chemistry 20】

10. A compound of formula (II-2), its stereoisomers, tautomers and pharmaceutically acceptable salts. 【Chemistry 21】 (wherein L is alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, Deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkyl It is an amino R １０ , R １１ , R Ｄ１ is hydrogen, deuterium, alkyl, deuterium alkyl, halogen the law of nature, 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: 【Chemistry 22】 Here, R １ , R ２ , R ３ , R ４ , R ５ , R ７ is hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R ９ａ , R ９ｂ , R ９ｃ is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl , or R ９ａ and R ９ｂ together with the carbon atom to which it is attached form a cycloalkyl, n = 1, 2, 3.)

11. A compound of formula (II-2-1), its stereoisomers, tautomers and pharmaceutically acceptable salts. 【Chemistry 23】 (where R １２ is deuterium, hydrogen, alkyl, deuterium alkyl, haloalkyl, amino , alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated hydrogen cycloalkylamino, R １０ , R １１ , R Ｄ１ is hydrogen, deuterium, alkyl, deuterium alkyl, halogen the law of nature, 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: 【Chemistry 24】 Here, R １ , R ２ , R ３ , R ４ , R ５ , R ７ is hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R ９ａ , R ９ｂ , R ９ｃ is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl , or R ９ａ and R ９ｂ together with the carbon atom to which it is attached form a cycloalkyl, n = 1, 2, 3.)

12. A compound of formula (II-2-2), its stereoisomers, tautomers and pharmaceutically acceptable salts. 【Chemistry 25】 (where R １２ is deuterium, hydrogen, alkyl, deuterium alkyl, haloalkyl, amino , alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated hydrogen cycloalkylamino, R １０ , R １１ , R Ｄ１ is hydrogen, deuterium, alkyl, deuterium alkyl, halogen the law of nature, E1 is hydrogen, deuterium, alkyl, or deuterium alkyl; Here, R １ , R ２ , R ３ , R ４ , R ５ , R ７ is hydrogen, deuterium, halogen, amino, Alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkenyl and wherein the alkyl is selected from alkynyl, alkenyl, deuterated alkynyl, deuterated alkene, Nyl, alkyl and deuterated alkyl are substituted with halogen, alkyl, hydroxyl, amino, optionally substituted with cycloalkyl, aryl, heteroaryl; R ９ａ , R ９ｂ , R ９ｃ is hydrogen, deuterium, alkyl, deuterium alkyl, haloalkyl cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl , 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. )

13. The following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts: 【Chemistry 26】

14. One or more compounds according to any one of claims 1 to 13 and pharmaceutical uses A pharmaceutical composition including a possible carrier or diluent.

15. Use of a compound according to any one of claims 1 to 13 in the preparation of a medicament for the treatment of a disease. The disease is multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus Neurodermatitis, dermatitis, atopic dermatitis, psoriasis, psoriatic arthritis, Crohn's disease, xerosis inflammatory or autoimmune diseases mediated by the kinase TYK2, including inflammatory syndromes or scleroderma, tumors, Tumor, use.

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