Pyrimido pyrazole compound, pharmaceutical composition thereof and application of pyrimido pyrazole compound

Abstract

The invention belongs to the field of medicines, and particularly relates to a pyrimido pyrazole compound as well as a pharmaceutical composition and application thereof. Specifically, the invention relates to a compound shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I), and each variable has the meaning described in the invention. As a TYK2 inhibitor, the compound and the pharmaceutical composition thereof can be used for preparing drugs for preventing or treating TYK2 related diseases. # imgabs0 #

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals. Specifically, this invention relates to a pyrimidinepyrazole compound as a TYK2 inhibitor, pharmaceutical compositions thereof, and the use of such compounds and pharmaceutical compositions thereof in the preparation of medicaments for the prevention or treatment of TYK2-related diseases. Background Art

[0002] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that regulate important events such as cell proliferation, differentiation, apoptosis, and immune responses through activation via the JAK-STAT pathway. The four members of the JAK family are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). Studies have found that TYK2 is closely related to the development of various inflammatory diseases such as inflammatory bowel disease, psoriasis, dermatitis, and rheumatoid arthritis. TYK2 deletion mutations can inhibit the occurrence of autoimmune diseases and inflammation related to the IL-12 and IL-23 pathways. Currently, Ventyx Biosciences' TAK-279 exhibits good TYK2 inhibitory activity but is still in clinical development. Further development of TYK2 inhibitors for therapeutic use is needed. Summary of the Invention

[0003] This invention provides a compound, or a pharmaceutical composition thereof, which can act as an inhibitor of TYK2. The invention further relates to the use of said compound or pharmaceutical composition thereof in the preparation of a medicament that treats related diseases and / or conditions by inhibiting TYK2 activity. The diseases or conditions include those described in this invention.

[0004] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I).

[0005]

[0006] in,

[0007] R 1 and R 2 Each independently represents H and C. 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 aryl or 5-10 heteroaryl, wherein the R 1 and R 2 Each of the following is independently and optionally selected by 1, 2, 3, or 4 factors chosen from D, F, Cl, Br, I, CN, OH, NH2, COOH, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Substituted with hydroxyalkyl groups and -C(=O)NH2 substituents;

[0008] R 3 For OH, NH2, NHOH, -NHOC 1-6 Alkyl, -NR 5 R 6 -NHR 5 or -NH(CR) 7 R 8 ) m R 6 ;

[0009] R 5 and R 6 Each independently is C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 aryl or 5-10 heteroaryl, wherein the R 5 and R 6 Each of the following is independently and optionally selected by 1, 2, 3, or 4 factors chosen from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 alkyl)2、-NH(C 1-6 alkyl) and -N(C) 1-6 Substituents of alkyl group 2;

[0010] R 7 and R 8 Each can be independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, or C. 1-6 Alkyl; or, R 7 、R 8 Together with the carbon atom attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0011] A 1 C 6-10aryl, 5-10 quinone heteroaryl, C 3-6 Cycloalkylene or 5-7 membered heterocyclic alkylene, wherein the A 1 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 9 Replaced; of which each R 9 Independently, it is H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2;

[0012] A 2 C 1-6 Alkylene, C 6-10 aryl, 5-10 quinone heteroaryl, C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; wherein the A 2 The earth may be optionally coated with 1, 2, 3 or 4 elements selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) and -N(C) 1-6 Substituents of alkyl group 2;

[0013] L is a covalent bond, C 1-6 Alkylene, -OC 1-6 alkylene-, -C 1-6 Alkylene -O- or -NH-C 1-6 Alkylene, wherein the L is optionally replaced by 1, 2, 3 or 4 derivatives selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl) and -N(C) 1-6 Substituents of alkyl group 2;

[0014] R 4 For H, D, C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10Aryl, 5-10 heteroaryl, -C(=O)OC 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl, -C(=O)NH2, -C(=O)-(C 3-6 cycloalkyl), -C(=O)-(3-6 membered heterocyclic group), -C(=O)NHC 1-6 Alkyl or -C(=O)N(C 1-6 alkyl)2; wherein the R 4 The earth may be optionally coated with 1, 2, 3 or 4 elements selected from F, Cl, Br, I, CN, OH, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-S(=O)2C 1-6 Alkyl groups and -S(=O)C 1-6 Substituents of alkyl groups; and

[0015] m can be 0, 1, 2, 3, 4, 5, or 6.

[0016] In some implementation schemes, R 1 and R 2 Each independently represents H and C. 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl, wherein the R 1 and R 2 Each of the following is independently and optionally selected by 1, 2, 3, or 4 factors chosen from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 It is substituted by hydroxyalkyl groups and -C(=O)NH2 substituents.

[0017] In some implementation schemes, R 1 and R 2Each of the following is independently H, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, aziridine, oxacyclobutyl, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein R 1 and R 2 Each can be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH and -C(=O)NH2.

[0018] In some implementation schemes, R 3 For OH, NH2, NHOH, -NHOC 1-4 Alkyl, -NR 5 R 6 -NHR 5 or -NH(CR) 7 R 8 ) m R 6 , or R 3 For OH, NH2, NHOH, -NHOCH3, -NHOCH2CH3, -NHO(CH2)2CH3, -NHOCH(CH3)2, -NHOC(CH3)3, -NHO(CH2)3CH3, -NR 5 R 6 -NHR 5 or -NH(CR) 7 R 8 ) m R 6 Among them, R 5 、R 6 、R 7 、R 8 Both m and m have the definitions described in this invention.

[0019] In some implementation schemes, R5 and R 6 Each independently is C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 aryl or 5-6 heteroaryl, wherein the R 5 and R 6 Each of the following is independently and optionally selected by 1, 2, 3, or 4 factors chosen from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyalkyl, -C(=O)OC 1-4 Alkyl group, -C(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 alkyl)2、-NH(C 1-4 alkyl) and -N(C) 1-4 Substituents of alkyl group 2;

[0020] R 7 and R 8 Each can be independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, or C. 1-4 Alkyl; or, R 7 、R 8 Together with the carbon atom attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0021] In some implementation schemes, R 5 and R 6 Each of the following is independently -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, 3-oxabicyclo[3.1.0]hexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, aziridine, oxabicyclo, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein R 5 and R 6Each of the following can be independently and optionally selected from 1, 2, 3, or 4 elements: D, F, Cl, Br, I, CN, OH, NH2, COOH, -CD3, -CH3, -CH2CH3, -CD2CD3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH 3) Substituents of 2OH, -(CH2)3CH2OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NHCH3, -NHCH2CH3, -N(CH3)2 and -N(CH2CH3)2;

[0022] R 7 and R 8 Each can be independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2 or -CH2C(CH3)3; or, R 7 、R 8 Together with the carbon atom attached thereto, it forms cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, aziridine, oxaziridine, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, or hexahydropyrimidinyl.

[0023] In some embodiments,

[0024] A 1 for

[0025] The A mentioned therein 1 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 9 Replaced; of which each R 9 Independently, it is H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4Halogenated alkyl, C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2; or

[0026] A 1 for

[0027] Where "*" indicates connection with -NH-, and "**" indicates connection with -A 2 - Connection, wherein A is described 1 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 9 Replaced; of which each R 9 Independently, it can be H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, - OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(C H3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) or -N(CH3)2.

[0028] In some implementation schemes, A 2 C 1-4 Alkylene

[0029] The A mentioned therein 2 The earth may be optionally coated with 1, 2, 3 or 4 elements selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl) and -N(C) 1-4 Substituents of alkyl group 2; or

[0030] A2 -CH2-, -(CH2)2-, -(CH3)2-, -CH(CH3)-,

[0031]

[0032] Where, "**" indicates the relationship with -A 1 - connection, "***" indicates a connection with -L-, where A 2 The radical can be optionally selected from 1, 2, 3, or 4 of the following: D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3. The substituents are substituted by -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) and -N(CH3)2.

[0033] In some implementations, L is a covalent bond, C 1-4 Alkylene, -OC 1-4 alkylene-, -C 1-4 Alkylene -O- or -NH-C 1-4 Alkylene, wherein the L is optionally replaced by 1, 2, 3 or 4 derivatives selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkyl groups, -NH(C 1-4 alkyl) and -N(C) 1-4 Substituents of alkyl group 2; or

[0034] L is a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -OCH2-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -CH2O-, -(CH2)2O-, -(CH2)3O-, -(CH2)4O-, -NHCH2-, -NH(CH2)2-, -NH(CH2)3-, or -NH(CH2)4-, wherein L is optionally composed of 1, 2, 3, or 4 atoms selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, -CH3, ... The substituents of -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -NH(CH2CH3), -N(CH3)(CH2CH3) and -N(CH3)2 are substituted.

[0035] In some implementation schemes, R 4 For H, D, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -C(=O)OC 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-4 Alkyl, -C(=O)NH2, -C(=O)-(C 3-6 cycloalkyl), -C(=O)-(3-6 membered heterocyclic group), -C(=O)NH(C 1-4 Alkyl) or -C(=O)N(C 1-4 Alkyl)2,; wherein the R 4 The earth may be optionally coated with 1, 2, 3 or 4 elements selected from F, Cl, Br, I, CN, OH, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2、-S(=O)2C 1-4 Alkyl groups and -S(=O)C 1-4 Alkyl groups are substituted.

[0036] In some implementation schemes, R 4 The following are not part of the given name: H, D, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecycloalkyl, aziridine, oxacyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidine alkyl, phenyl, pyrrolyl, pyrazolyl, imidazoleyl, furanyl, thiaranyl, pyridyl, pyrimidinyl, pyrazinyl, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH2CH3, -S(=O)2(CH 2) 2CH3, -S(=O)2CH(CH3)2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH3, -S(=O)(CH2)2CH3, -C(=O)NH2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-azacyclobutyl, -C(=O)-oxacyclobutyl, -C(=O)-pyrroleyl -C(=O)-pyrazolyl, -C(=O)-imidazolyl, -C(=O)-tetrahydrofuranyl, -C(=O)-tetrahydrothiaranyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-morpholinyl, -C(=O)-hexahydropyrimidinyl, -C(=O)NHCH3, -C(=O)NH(CH2CH3), -C(=O)N(CH3)(CH2CH3) or -C(=O)N(CH3)2; wherein R 4The radical is optionally selected from 1, 2, 3, or 4 of the following: F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCH2OCH3, -O(CH2)2OCH3, -O(CH2)2OCH2CH3, -OCH2OCH2CH3, -C(= The substituents of -O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)O(CH2)3CH3, -C(=O)OCH(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)N(CH3)2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH2CH3, -S(=O)2(CH2)2CH3, -S(=O)2CH(CH3)2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH3, -S(=O)(CH2)2CH3 and -S(=O)CH(CH3)2 are substituted.

[0037] In some embodiments, it is the compound shown in (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound shown in (II).

[0038]

[0039] Among them, R 1 、R 3 、A 2 L, R 9 and R 4 Each has the definition as described in this invention.

[0040] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds described herein.

[0041] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0042] In some embodiments, the excipients described in this invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0043] On the other hand, the present invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of TYK2-related diseases.

[0044] In some implementations, the TYK2-related diseases described in this invention are autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases.

[0045] In some embodiments, the TYK2-mediated diseases described in this invention are rheumatoid arthritis, psoriasis, diabetes, ankylosing spondylitis, vitiligo, atopic dermatitis, lupus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, cancer, transplant rejection, or neurological disorders.

[0046] On the other hand, the present invention also provides a method for preventing or treating TYK2-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention.

[0047] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds of formula (I) or (II).

[0048] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of this invention.

[0049] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically suitable in relation to the other components of the formulation and the mammal intended for treatment.

[0050] The salts of the compounds of the present invention also include salts for the preparation or purification of intermediates of the compounds of formula (I) or (II) or for the isolation of enantiomers of the compounds of formula (I) or (II), but are not necessarily pharmaceutically acceptable salts.

[0051] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0052] Detailed Description of the Invention

[0053] Definitions and general terms

[0054] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0055] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0056] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0057] As used in this invention, the term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0058] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0059] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0060] "Stereoisomers" refer to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans isomers), trans-blocking isomers, and so on. Unless otherwise stated, all stereoisomers or mixtures of stereoisomers of the structures described in this invention are within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms.

[0061] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0062] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0063] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0064] As described in this invention, the compounds of this invention can be independently and optionally substituted by one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the terms "independently and optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0065] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0066] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0067] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0068] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, denoted as C1. 1-6 Alkyl group; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, denoted as C1 1-4 Alkyl group; in another embodiment, the alkyl group contains 1-3 carbon atoms, denoted as C1 1-3Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-B) u、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1 -Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0069] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon. In some embodiments, the alkylene group contains 1-6 carbon atoms, denoted as C1. 1-6 Alkylene; in other embodiments, the alkylene group contains 1-4 carbon atoms, denoted as C1. 1-4 Alkylene; in other embodiments, the alkylene group contains 1-3 carbon atoms, denoted as C1. 1-3 Alkylene group; in other embodiments, the alkylene group contains 1-2 carbon atoms, denoted as C2. 1-2 Alkylene groups. Examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, etc.

[0070] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl and hydroxyl groups have the definitions as described in this invention. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C14-C ... 1-6 Hydroxyalkyl, i.e., C 1-6 Alkyl groups are substituted with one or more hydroxyl groups, preferably C 1-6 Hydroxyalkyl indicates C 1-6 An alkyl group is an alkyl group substituted with a hydroxyl group. In some embodiments, hydroxyalkyl represents C10. 1-4 Hydroxyalkyl. In some embodiments, hydroxyalkyl means C 1-3 Hydroxyalkyl groups. Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, -CH2CH(OH)CH2CH(CH3)OH, etc.

[0071] The term "haloalkyl" indicates that an alkyl group is replaced by one or more halogen atoms, wherein the alkyl group and the halogen atom have the definitions described herein. In some embodiments, the haloalkyl group is C10. 1-6 Haloalkyl, indicating C 1-6 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-4 Haloalkyl, indicating C 1-4 The alkyl group is replaced by one or more halogen atoms; in other embodiments, the haloalkyl group is C10. 1-3 Haloalkyl, indicating C 1-3 The alkyl group is replaced by one or more halogen atoms. Examples of such groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and so on.

[0072] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing C0. 1-6 Alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4 Alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C1-3 Alkoxy group. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0073] The term "alkoxyalkoxy" refers to an alkoxy group substituted with one or more alkoxy groups, wherein the alkoxy group has the definition as defined in this invention. In some embodiments, alkoxyalkoxy means an alkoxy group substituted with one alkoxy group. Examples of alkoxy groups include, but are not limited to, -OCH2OCH3, -O(CH2)2OCH3, -O(CH2)2OCH2CH3, or -OCH2OCH2CH3, etc.

[0074] The term “deuterated alkoxy” refers to an alkoxy group substituted with deuterium (D), wherein the alkoxy group has the definition as described in this invention.

[0075] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group and the halogen have the definitions as defined in this invention. In some embodiments, a haloalkoxy group refers to a haloalkoxy group containing 1-6 carbon atoms, i.e., C6. 1-6 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-4 carbon atoms, i.e., C646-C ... 1-4 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-3 carbon atoms, i.e., C646-C ... 1-3Halogenated alkoxy groups. Examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy (-OCF3), monofluoromethoxy (-OCH2F), 2-fluoroethoxy (-OCH2CH2F), etc.

[0076] The term "carbocyclic" or "carbocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbocyclic system comprising 3 to 12 ring atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (or -(CO)-). In one embodiment, the carbocyclic group comprises 3 to 6 ring carbon atoms, denoted as C. 3-6 Carbocyclic group; in other embodiments, the carbocyclic group is a saturated ring comprising 3-6 ring carbon atoms, denoted as C 3-6 cycloalkyl; in other embodiments, the C 3-6 The cycloalkyl group is a saturated monocyclic ring. In one embodiment, the carbocyclic group comprises 7-12 cyclic carbon atoms, denoted as C1. 7-12 Carbocyclic group; in other embodiments, the carbocyclic group is a saturated ring comprising 7-12 ring carbon atoms, denoted as C 7-12 Cycloalkyl groups. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-1H-indenyl, octahydrocyclopentadienyl, etc. Examples of carbocyclic groups in which the -CH2- group can be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc.

[0077] The term "cycloalkyl" refers to a monocyclic or bicyclic carbocyclic system with 3-12 carbon atoms, wherein the -CH2- group in the carbocyclic ring may optionally be replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl group comprises 3-10 ring carbon atoms, i.e., C 3-10 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-6 cyclic carbon atoms, i.e., C1 3-6 Cycloalkyl; in another embodiment, the cycloalkyl group comprises 3-5 cyclic carbon atoms, i.e., C1 3-5 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydrocyclopentadienyl, etc. Examples of carbocyclic groups in which the -CH2- group can be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, etc.

[0078] The terms "heterocycle" and "heterocyclic group" refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system comprising 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein the heterocycle or heterocyclic group is non-aromatic and does not contain any aromatic ring. When a heterocycle is attached to other parts of a molecule through a linking site, the heterocycle is represented as a monovalent heterocyclic group. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclic group consists of 3-10 atoms and is represented as a 3-10 membered heterocycle or a 3-10 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-9 atoms and is represented as a 3-9 membered heterocycle or a 3-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-9 atoms and is represented as a 5-9 membered heterocycle or a 5-9 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 3-6 atoms and is represented as a 3-6 membered heterocycle or a 3-6 membered heterocyclic group; in other embodiments, the heterocycle or heterocyclic group consists of 5-6 atoms and is represented as a 5-6 membered heterocycle or a 5-6 membered heterocyclic group. Examples of the heterocycles include, but are not limited to, ethylene oxide, aziridine, aziridine, oxacyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazoline, pyrazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazoline, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, and 2,5-diazabicyclo[2.2.2]octane. The heterocyclic groups include, but are not limited to, ethylene oxide, aziridine, aziridine, oxazolidine, pyrrolidine, tetrahydrofuranyl, tetrahydrothiopheneyl, thiazoline, pyrazolidine, pyrazolidine, pyrazolidine, oxazolidine, imidazoline, piperidinyl, piperazinyl, or morpholinyl.

[0079] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms. In some embodiments, the aryl group contains 6-12 ring atoms, denoted as C 6-12 Aryl or 6-12-membered aryl. In some embodiments, the aryl group contains 6-10 ring atoms, denoted as C. 6-10 Aryl or 6-10-membered aryl. Examples of aryl groups can include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracene. When the aryl group is used as a linking group, the term "aryl" is used to indicate an arylene, for example, A in general formula (I). 2 As a linking group, it can be C 6-10 Alpha-aryl.

[0080] The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic, or tricyclic system containing 5-14, 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is typically, but not necessarily, linked to the parent molecule via its aromatic ring. When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-. Unless otherwise stated, the heteroaryl group may be linked to the remainder of the molecule (e.g., the main structure in the general formula) through any reasonable site (which may be C or N). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, denoted as a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, denoted as a 5-10-membered heteroaryl group; in still other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, denoted as a 5-6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrroleyl, benzopyrazoleyl, benzopyrrolealkyl, etc.

[0081] In this invention, the terms "arylene," "heteroarylene," "cycloalkylene," or "heterocyclic" refer to divalent groups formed when an aryl, heteroaryl, cycloalkyl, or heterocyclic group acts as a linking group connecting two groups on its left and right. For example, when group A in the compound of general formula (I) of this invention is a 5-10-membered heteroarylene, it means that the 5-10-membered heteroarylene is a divalent group formed when a 5-10-membered heteroarylene is connected to L and A1.

[0082] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0083] The term "oxo" means =O.

[0084] The term "cyano" means -CN or -C≡N.

[0085] The term "hydroxyl group" represents -OH.

[0086] The term "carboxyl group" represents -C(=O)OH.

[0087] The term "amino" represents -NH2.

[0088] The term "composed of jk atoms" or "of jk elements" means that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k and any natural number between them. For example, "composed of 3-8 atoms" or "3-8 elements", "composed of 3-6 atoms" or "3-6 elements", "composed of 5-10 atoms" or "5-10 elements", or "composed of 5-6 atoms" or "5-6 elements" indicates that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10), or 5-6 (i.e., 5 or 6) ring atoms, wherein the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, P, etc.

[0089] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I) or (I-1) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group.

[0090] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0091] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or these salts obtained by other methods described in the literature, such as ion exchange. This invention also contemplates the formation of quaternary ammonium salts from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained through quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates, and aromatic sulfonates.

[0092] In this invention, "solvent" refers to an association formed by one or more solvent molecules and a compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0093] When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; and in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound.

[0094] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0095] The term “prevention” or “avoidance” refers to the reduction of the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but has not yet experienced or exhibited symptoms of the disease).

[0096] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0097] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are included within the scope of this invention.

[0098] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0099] The nitrogen oxides of the compounds of this invention are also included within the scope of this invention. The nitrogen oxides of the compounds of this invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances in the presence of an acid, such as acetic acid, using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature, or by reacting with a peracid in a suitable solvent, such as with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0100] The compounds shown in formula (I) or (II) can exist in the form of salts.

[0101] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I.

[0102] Description of the compounds of the present invention

[0103] This invention provides a compound, or a pharmaceutical composition thereof, which can act as an inhibitor of TYK2. The invention further relates to the use of said compound or pharmaceutical composition thereof in the preparation of a medicament that treats related diseases and / or conditions by inhibiting TYK2 activity. The diseases or conditions include those described in this invention.

[0104] The excellent properties of certain parameters of the compounds of this invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, and solubility, can promote the reduction of side effects, the expansion of the therapeutic index, or the improvement of tolerability.

[0105] On the one hand, the present invention provides compounds of formula (I), or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds of formula (I).

[0106]

[0107] Among them, each R 1 、R 2 、R 3 、R 4 、A 1 、A 2 L and L each have the definitions described in this invention.

[0108] In some implementation schemes, R 1 and R 2 Each independently represents H and C. 1-6 Alkyl, C3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 aryl or 5-10 heteroaryl, wherein the R 1 and R 2 Each of the following is independently and optionally selected by 1, 2, 3, or 4 factors chosen from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 It is substituted by hydroxyalkyl groups and -C(=O)NH2 substituents.

[0109] In some implementation schemes, R 1 and R 2 Each independently represents H and C. 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl, wherein the R 1 and R 2 Each of the following is independently and optionally selected by 1, 2, 3, or 4 factors chosen from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 It is substituted by hydroxyalkyl groups and -C(=O)NH2 substituents.

[0110] In some implementation schemes, R 1 and R 2 Each of the following is independently H, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, aziridine, oxacyclobutyl, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein R 1 and R 2Each can be independently and optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH and -C(=O)NH2.

[0111] In some implementation schemes, R 3 For OH, NH2, NHOH, -NHOC 1-6 Alkyl, -NR 5 R 6 -NHR 5 or -NH(CR) 7 R 8 ) m R 6 , where R 5 、R 6 、R 7 、R 8 Both m and m have the definitions described in this invention.

[0112] In some implementation schemes, R 3 For OH, NH2, NHOH, -NHOC 1-4 Alkyl, -NR 5 R 6 -NHR 5 or -NH(CR) 7 R 8 ) m R 6 , where R 5 、R 6 、R 7 、R 8 Both m and m have the definitions described in this invention.

[0113] In some implementation schemes, R 3 For OH, NH2, NHOH, -NHOCH3, -NHOCH2CH3, -NHO(CH2)2CH3, -NHOCH(CH3)2, -NHOC(CH3)3, -NHO(CH2)3CH3, -NR 5 R 6 -NHR 5 or -NH(CR) 7 R 8 )m R 6 Among them, R 5 、R 6 、R 7 、R 8 Both m and m have the definitions described in this invention.

[0114] In some implementations, m is 0, 1, 2, 3, 4, 5, or 6.

[0115] In some implementation schemes, R 5 and R 6 Each independently is C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 aryl or 5-10 heteroaryl, wherein the R 5 and R 6 Each of the following is independently and optionally selected by 1, 2, 3, or 4 factors chosen from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 alkyl)2、-NH(C 1-6 alkyl) and -N(C) 1-6 It is replaced by a substituent of alkyl)2.

[0116] In some implementation schemes, R 5 and R 6 Each independently is C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 aryl or 5-6 heteroaryl, wherein the R 5 and R 6 Each of the following is independently and optionally selected by 1, 2, 3, or 4 factors chosen from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyalkyl, -C(=O)OC 1-4 Alkyl group, -C(=O)C 1-4Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 alkyl)2、-NH(C 1-4 alkyl) and -N(C) 1-4 It is replaced by a substituent of alkyl)2.

[0117] In some implementation schemes, R 5 and R 6 Each of the following is independently -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, 3-oxabicyclo[3.1.0]hexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, aziridine, oxabicyclo, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiaranyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein R 5 and R 6 Each of the following can be independently and optionally selected from 1, 2, 3, or 4 elements: D, F, Cl, Br, I, CN, OH, NH2, COOH, -CD3, -CH3, -CH2CH3, -CD2CD3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH 3) Substituents of 2OH, -(CH2)3CH2OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NHCH3, -NHCH2CH3, -N(CH3)2 and -N(CH2CH3)2.

[0118] In some implementation schemes, R 7 and R 8Each can be independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, or C. 1-6 Alkyl; or, R 7 、R 8 Together with the carbon atom attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0119] In some implementation schemes, R 7 and R 8 Each can be independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, or C. 1-4 Alkyl; or, R 7 、R 8 Together with the carbon atom attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0120] In some implementation schemes, R 7 and R 8 Each can be independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2 or -CH2C(CH3)3; or, R 7 、R 8 Together with the carbon atom attached thereto, it forms cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecyclo, aziridine, oxaziridine, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, or hexahydropyrimidinyl.

[0121] In some implementation schemes, A 1 C 6-10 aryl, 5-10 quinone heteroaryl, C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene, wherein the A 1 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 9 Replaced; of which each R 9 Independently, it is H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2.

[0122] In some implementation schemes, A 1 for

[0123]

[0124] The A mentioned therein 1 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 9 Replaced; of which each R 9 Independently, it is H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl) or -N(C) 1-4 Alkyl)2.

[0125] In some implementation schemes, A 1 for

[0126] Where "*" indicates connection with -NH-, and "**" indicates connection with -A 2 - Connection, wherein A is described 1 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 9 Replaced; of which each R 9 Independently, it can be H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3. -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH( CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) or N(CH3)2.

[0127] In some implementation schemes, A 2 C 1-6 Alkylene, C 6-10aryl, 5-10 quinone heteroaryl, C 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; wherein the A 2 The earth may be optionally coated with 1, 2, 3 or 4 elements selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) and -N(C) 1-6 It is replaced by a substituent of alkyl)2.

[0128] In some implementation schemes, A 2 C 1-4 Alkylene

[0129] The A mentioned therein 2 The earth may be optionally coated with 1, 2, 3 or 4 elements selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, -C(=O)C 1-4 Alkyl, -NH(C) 1-4 alkyl) and -N(C) 1-4 It is replaced by a substituent of alkyl)2.

[0130] In some implementation schemes, A 2 -CH2-, -(CH2)2-, -(CH3)2-, -CH(CH3)-,

[0131]

[0132] Where, "**" indicates the relationship with -A 1 - connection, "***" indicates a connection with -L-, where A 2The radical can be optionally selected from 1, 2, 3, or 4 of the following: D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3. The substituents are substituted by -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) and -N(CH3)2.

[0133] In some implementations, L is a covalent bond, C 1-6 Alkylene, -OC 1-6 alkylene-, -C 1-6 Alkylene -O- or -NH-C 1-6 Alkylene, wherein the L is optionally replaced by 1, 2, 3 or 4 derivatives selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl) and -N(C) 1-6 It is replaced by a substituent of alkyl)2.

[0134] In some implementations, L is a covalent bond, C 1-4 Alkylene, -OC 1-4 alkylene-, -C 1-4 Alkylene -O- or -NH-C 1-4 Alkylene, wherein the L is optionally replaced by 1, 2, 3 or 4 derivatives selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkyl groups, -NH(C 1-4 alkyl) and -N(C) 1-4 It is replaced by a substituent of alkyl)2.

[0135] In some embodiments, L is a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -OCH2-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -CH2O-, -(CH2)2O-, -(CH2)3O-, -(CH2)4O-, -NHCH2-, -NH(CH2)2-, -NH(CH2)3-, or -NH(CH2)4-, wherein L is optionally composed of 1, 2, 3, or 4 atoms selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, The substituents of -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -NH(CH2CH3), -N(CH3)(CH2CH3) and -N(CH3)2 are substituted.

[0136] In some implementation schemes, R 4 For H, D, C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, -C(=O)OC 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-6 Alkyl, -C(=O)NH2, -C(=O)-(C 3-6 cycloalkyl), -C(=O)-(3-6 membered heterocyclic group), -C(=O)NH(C 1-6 Alkyl) or -C(=O)N(C 1-6 alkyl)2; wherein the R 4 The earth may be optionally coated with 1, 2, 3 or 4 elements selected from F, Cl, Br, I, CN, OH, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-6 Alkyl), -C(=O)N(C 1-6 Alkyl)2、-S(=O)2C 1-6 Alkyl groups and -S(=O)C1-6 Alkyl groups are substituted.

[0137] In some implementation schemes, R 4 For H, D, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -C(=O)OC 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)C 1-4 Alkyl, -C(=O)NH2, -C(=O)-(C 3-6 cycloalkyl), -C(=O)-(3-6 membered heterocyclic group), -C(=O)NH(C 1-4 Alkyl) or -C(=O)N(C 1-4 Alkyl)2,; wherein the R 4 The earth may be optionally coated with 1, 2, 3 or 4 elements selected from F, Cl, Br, I, CN, OH, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, -C(=O)NH2, -C(=O)NH(C 1-4 Alkyl), -C(=O)N(C 1-4 Alkyl)2、-S(=O)2C 1-4 Alkyl groups and -S(=O)C 1-4 Alkyl groups are substituted.

[0138] In some implementation schemes, R 4The following are not part of the given name: H, D, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-epoxyethylene, 1,4-dioxanecycloalkyl, aziridine, oxacyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidine alkyl, phenyl, pyrrolyl, pyrazolyl, imidazoleyl, furanyl, thiaranyl, pyridyl, pyrimidinyl, pyrazinyl, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH2CH3, -S(=O)2(CH 2) 2CH3, -S(=O)2CH(CH3)2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH3, -S(=O)(CH2)2CH3, -C(=O)NH2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-azacyclobutyl, -C(=O)-oxacyclobutyl, -C(=O)-pyrroleyl -C(=O)-pyrazolyl, -C(=O)-imidazolyl, -C(=O)-tetrahydrofuranyl, -C(=O)-tetrahydrothiaranyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-morpholinyl, -C(=O)-hexahydropyrimidinyl, -C(=O)NHCH3, -C(=O)NH(CH2CH3), -C(=O)N(CH3)(CH2CH3) or -C(=O)N(CH3)2; wherein R 4The radical is optionally selected from 1, 2, 3, or 4 of the following: F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCH2OCH3, -O(CH2)2OCH3, -O(CH2)2OCH2CH3, -OCH2OCH2CH3, -C(= The substituents of -O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)O(CH2)3CH3, -C(=O)OCH(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)N(CH3)2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH2CH3, -S(=O)2(CH2)2CH3, -S(=O)2CH(CH3)2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH3, -S(=O)(CH2)2CH3 and -S(=O)CH(CH3)2 are substituted.

[0139] In some embodiments, it is the compound shown in (II), or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound shown in (II).

[0140]

[0141] Among them, R 1 、R 3 、A 2 L, R 9 and R 4 Each has the definition as described in this invention.

[0142] In some embodiments, the compounds of this invention are compounds having the following structures, or stereoisomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof.

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds described herein.

[0160] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0161] In some embodiments, the excipients described in this invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0162] On the other hand, the present invention provides the use of the pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of TYK2-related diseases.

[0163] In some implementations, the TYK2-related diseases described in this invention are autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases.

[0164] In some embodiments, the TYK2-mediated diseases described in this invention are rheumatoid arthritis, psoriasis, diabetes, ankylosing spondylitis, vitiligo, atopic dermatitis, lupus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, cancer, transplant rejection, or neurological disorders.

[0165] In some implementations, the inflammatory condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0166] In some implementations, the proliferative condition is cancer.

[0167] In some implementations, the proliferative condition is a blood cancer.

[0168] In some implementation schemes, the endocrine disorder is polycystic ovary syndrome, Kruzon syndrome, or type 1 diabetes.

[0169] In some implementations, the neurological condition is Alzheimer's disease.

[0170] On the other hand, the present invention also provides a method for preventing or treating TYK2-related diseases, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention.

[0171] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds of formula (I) or (II).

[0172] Unless otherwise indicated, all stereoisomers, tautomers, nitrides, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of this invention are within the scope of this invention.

[0173] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically suitable in relation to the other components of the formulation and the mammal intended for treatment.

[0174] The salts of the compounds of the present invention also include salts for the preparation or purification of intermediates of the compounds of formula (I) or (II) or for the isolation of enantiomers of the compounds of formula (I) or (II), but are not necessarily pharmaceutically acceptable salts.

[0175] Formulation, administration and use of pharmaceutical compositions of the compounds of the present invention

[0176] The pharmaceutical compositions of the present invention are characterized by comprising compounds of formula (I) or (II), compounds listed in the present invention, or compounds of the embodiments, and pharmaceutically acceptable carriers. The amounts of compounds in the pharmaceutical compositions of the present invention are effective in treating or alleviating TYK2-mediated diseases in patients.

[0177] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0178] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of this literature demonstrate that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. The use of any conventional adjuvants that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition in a harmful manner, is also within the scope of this invention.

[0179] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0180] In preparing the pharmaceutical compositions provided by this invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or packaged in a carrier, such as a capsule, sachet, paper, or other container. If the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material, serving as a carrier, container, or medium for the active ingredient. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), such as ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterilely packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.

[0181] The compounds or pharmaceutical compositions of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0182] The compounds or pharmaceutical compositions of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0183] The compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0184] The compounds or pharmaceutical compositions of the present invention are also coupled with soluble polymers that act as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0185] The dosing regimen of the compounds or pharmaceutical compositions of this invention will vary depending on a variety of known factors, such as the pharmacokinetic characteristics and patterns of administration of the specific agent; the recipient's race, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. A physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, counteract, or halt the development of cancer.

[0186] According to general guidelines, in order to achieve the specified effect, the dosage of each active ingredient used is in the range of approximately 0.001 to 1000 mg / kg body weight per day, preferably between approximately 0.01 and 100 mg / kg body weight. The compounds of the present invention can be administered once daily, or can be administered in two, three, or four divided doses daily.

[0187] Each unit dose of a suitable dosage form (pharmaceutical composition) may contain from about 1 mg to about 100 mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally account for about 0.5-95% of the total weight of the composition.

[0188] The compounds and compositions described in this invention can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of this invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of this invention can be included in a single formulation along with other therapeutic agents or in a separate formulation.

[0189] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0190] The compounds, pharmaceutical salts, hydrates, or pharmaceutical compositions thereof involved in this invention are effective in preventing, treating, or alleviating TYK2-mediated diseases in patients.

[0191] In some implementations, TYK2-mediated diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases.

[0192] In some implementations, TYK2-mediated diseases include rheumatoid arthritis, psoriasis, diabetes, ankylosing spondylitis, vitiligo, atopic dermatitis, lupus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, cancer, transplant rejection, or neurological disorders.

[0193] In some implementations, the inflammatory condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0194] In some implementations, the proliferative condition is cancer.

[0195] In some implementations, the proliferative condition is a blood cancer.

[0196] In some implementation schemes, the endocrine disorder is polycystic ovary syndrome, Kruzon syndrome, or type 1 diabetes.

[0197] In some implementations, the neurological condition is Alzheimer's disease.

[0198] General Synthesis Process

[0199] To describe this invention, the following embodiments will be used to further illustrate the technical solution of this invention. These embodiments are only used to illustrate specific implementation methods of this invention so that those skilled in the art can understand it, but are not intended to limit the scope of protection of this invention. In the specific implementation methods of this invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0200] Unless otherwise specified, the substituents are defined as described in this invention. The following reaction schemes and examples are provided to further illustrate the content of this invention.

[0201] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0202] In the examples described below, unless otherwise specified, all temperatures are in degrees Celsius (°C). Room temperature in the examples represents 15°C–30°C; in some examples, room temperature is 20°C–30°C. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification. Unless otherwise specified, general reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0203] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0204] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0205] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0206] 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. 1 ¹H NMR spectra are performed using CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0207] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min; mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, detection by UV.

[0208] Pure compounds were detected using UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0209] The following English or abbreviation terms are used throughout this invention:

[0237] Synthetic scheme 1 for intermediate compound (III-1)

[0238]

[0239] The intermediate compound (III-1) can be prepared by the above synthetic scheme, wherein R 4 Having the definition as described in this invention, Hal 1 For F, Cl, Br, or I; Q is N or CH; R a For H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2. Compound (III-1-1) reacts with compound 3-amino-1,2-dihydropyridin-2-one under the action of a base (such as cesium carbonate) to give intermediate compound (III-1).

[0240] Synthetic scheme 2 for intermediate compound (III-1)

[0241]

[0242] The intermediate compound (III-1) can be prepared by the above synthetic scheme, wherein Hal 1 and Hal 3 Each can be F, Cl, Br, or I independently; Q can be N or CH; R a For H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) and -N(C) 1-6Alkyl)2. Compound (III-4-1) reacts with compound 3-amino-1,2-dihydropyridin-2-one in the presence of a base (such as cesium carbonate) to give intermediate compound (III-4-2); compound (III-4-2) undergoes a coupling reaction with compound (III-1-2) to give compound (III-1).

[0243] Synthetic scheme for intermediate compound (III-2)

[0244]

[0245] The intermediate compound (III-2) can be prepared by the above synthetic scheme, wherein R 5 Having the definition as described in this invention, R 1a C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 membered heteroaryl. Compound (III-2-1) and compound R 1a NH2 or compound R 1a The hydrochloride salt of NH2 reacts with a base (such as triethylamine) to give compound (III-2-1); compound (III-2-1) reacts with compound PMBCl to give compound (III-2-2); compound (III-2-2) undergoes hydrolysis to give compound (III-2-3); compound (III-2-3) reacts with compound R... 5 The NH2 coupling reaction yielded the intermediate compound (III-2).

[0246] Synthetic scheme for intermediate compound (III-4)

[0247]

[0248] The intermediate compound (III-4) can be prepared by the above synthetic scheme, wherein Hal 1 and Hal 3 Each can be F, Cl, Br, or I independently; Q can be N or CH; R a For H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) and -N(C) 1-6Alkyl)2. Compound (III-4-1) reacts with compound 3-amino-1,2-dihydropyridin-2-one under the action of a base (such as cesium carbonate) to give intermediate compound (III-4-2); compound (III-4-2) undergoes a coupling reaction with compound triisopropylsilylacetylene to give compound (III-4).

[0249] Synthetic scheme for intermediate compound (III-5)

[0250]

[0251] The intermediate compound (III-5) can be prepared by the above synthetic scheme, wherein Hal 1 and Hal 3 Each is independently F, Cl, Br, or I; A 2 and R 4 Each has the definition as described in this invention. Compound (III-5-1) reacts with compound 3-amino-1,2-dihydropyridin-2-one under the action of a base (such as cesium carbonate) to give intermediate compound (III-5-2); compound (III-5-2) undergoes a coupling reaction with compound (III-5-3) to give compound (III-5).

[0252] Synthesis of compound (III)

[0253]

[0254] Compound (III) can be prepared by the above synthetic scheme, wherein R 5 and R 4 Each has the definition as described in this invention, R 1a C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; Q is N or CH; R a For H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl group 2. Compounds (III-1) and (III-2) were coupled to give compound (III-3); compound (III-3) was deactivated under acidic conditions to give compound (III).

[0255] Synthesis of compound (IV)

[0256]

[0257] Compound (IV) can be prepared by the above synthetic scheme, wherein R 5 Having the definition as described in this invention; R 1a C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; Q is N or CH; R a For H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)C 1-6 Alkyl, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl group 2. Compounds (III-4) and (III-2) were coupled to give compound (IV-1); compound (IV-1) was deactivated under acidic conditions to give compound (IV-2); compound (IV-2) was reacted with TABF to form compound (IV).

[0258] Synthesis of compound (V)

[0259]

[0260] Compound (V) can be prepared by the above synthetic scheme, wherein R 5 、R 4 A and R each have the definitions described in this invention; 1a C 1-6 Alkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl. Compounds (III-4) and (III-2) are coupled to give compound (V-1); compound (V-1) is de-PMB grouped under acidic conditions to give compound (V).

[0261] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention. Example

[0262] Example 1: Synthesis of Compound 1

[0263]

[0264] Step 1: Synthesis of Compound 1-1

[0265] 5-Bromo-2-fluoropyridine (0.20 g, 1.14 mmol), triisopropylsilylacetylene (0.31 g, 1.71 mmol), cuprous iodide (0.011 g, 0.057 mmol), and bis(triphenylphosphine)palladium dichloride (0.04 g, 0.057 mmol) were added to a 50 mL two-necked flask. Nitrogen was introduced, followed by the addition of diisopropylamine (5 mL). The mixture was heated to 100 °C. After 3 h, TLC analysis showed complete reaction of the starting material. The reaction was then stopped by cooling. The mixture was dissolved in 40 mL of ethyl acetate, washed with water (10 mL × 2), dried over an evaporative dryness, and purified by column chromatography (PE as eluent) to give 0.32 g of a pale yellow oily liquid, 100% yield. MS (ESI, pos.ion) m / z: 278.2 [M+H] + .

[0266] Step 2: Synthesis of Compounds 1-2

[0267] Compound 1-1 (0.40 g, 1.44 mmol), 3-amino-1,2-dihydropyridin-2-one (0.19 g, 1.73 mmol), and cesium carbonate (1.17 g, 3.60 mmol) were added to a 25 mL double-necked flask under nitrogen protection. N,N-dimethylacetamide (6 mL) was added, and the mixture was heated to 95 °C. After 4.5 h, TLC analysis showed that the starting material had reacted completely. The reaction was stopped, cooled to room temperature, and 50 mL of water was added. The mixture was then extracted with ethyl acetate (70 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 3), concentrated, and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-3 / 1) to give 0.13 g of a yellow solid, yield 43.02%. MS (ESI, pos.ion) m / z: 212.15 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.68(d,J=1.5Hz,1H),8.01(d,J=8.4Hz,1H),7.92(dd,J=8.4,2.1Hz,1H) ,7.36(dd,J=7.2,1.5Hz,1H),6.60(dd,J=7.1,1.5Hz,1H),6.23(t,J=7.1Hz,1H),3.28(s,1H).

[0268] Step 3: Synthesis of compounds 1-3

[0269] Ethyl 3-amino-1H-pyrazole-4-carboxylate (10.30 g, 66.39 mmol) and diethyl malonate (12.76 g, 79.67 mmol) were added to a single-necked flask, followed by 120 mL of anhydrous ethanol. Sodium ethoxide (9.04 g, 132.78 mmol) was slowly added at room temperature. The mixture was heated to 80 °C and reacted for 7 h. TLC analysis showed complete reaction. The mixture was evaporated to dryness, and 70 mL of water was added. After stirring to dissolve the product, the pH was adjusted to 3-4 with concentrated hydrochloric acid to obtain a solid product. The solid product was filtered, dried at 60 °C, and yielded 10.89 g of a yellow solid, with a yield of 73.46%. MS (ESI, pos.ion) m / z: 224.3 [M+H] + .

[0270] Step 4: Synthesis of compounds 1-4

[0271] Compounds 1-3 (5.00 g, 22.40 mmol) and phosphorus oxychloride (30 mL) were added to a single-necked flask, followed by the slow addition of N,N-dimethylaniline (4.61 g, 38.08 mmol). The mixture was heated to 90 °C and reacted for 7 h. TLC analysis showed the reaction was complete. The mixture was cooled to room temperature, concentrated, and slowly transferred to 100 mL of sodium hydroxide ice water (1 mol / L). Extraction was performed with dichloromethane (100 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 1 / 0-30 / 1) to give 2.18 g of a yellow solid, with a yield of 37.39%. MS (ESI, pos.ion) m / z: 260.0 [M+H] + .

[0272] Step 5: Synthesis of compounds 1-5

[0273] Compounds 1-4 (2.00 g, 7.69 mmol), methylamine hydrochloride (0.67 g, 10.00 mmol), and acetonitrile (20 mL) were added to a 100 mL single-necked flask, followed by N,N-diisopropylethylamine (2.98 g, 23.07 mmol). The mixture was heated to 80 °C and reacted for 4.5 h. TLC analysis showed that the reaction proceeded completely. The mixture was concentrated under reduced pressure, and water (50 mL) was added. The mixture was stirred for 10 min, filtered, and the resulting solid was dried under blast heat at 60 °C for 11 h to give 1.88 g of a pale yellow solid, with a yield of 95.74%. MS (ESI, pos.ion) m / z: 255.3 [M+H] + .

[0274] Step 6: Synthesis of compounds 1-6

[0275] Compounds 1-5 (2.00 g, 7.85 mmol), cesium carbonate (5.12 g, 15.7 mmol), and DMF (18 mL) were added to a 100 mL single-necked flask. The mixture was cooled to -5 °C, and 4-methoxybenzyl chloride (1.84 g, 11.77 mmol) was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature for 10 min, then allowed to react at room temperature for 4 h. TLC analysis showed that the starting material had reacted completely. The mixture was cooled to 0 °C, and the reaction was quenched with ice water (60 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM / EA (v / v) = 1 / 0-40 / 1) to give 1.88 g of a yellow solid, with a yield of 63.72%.

[0276] Step 7: Synthesis of compounds 1-7

[0277] Compounds 1-6 (1.80 g, 4.80 mmol), tributyltin oxide (8.58 g, 14.40 mmol), and toluene (18 mL) were added to a 100 mL single-necked flask. The mixture was refluxed at 120 °C for 10 h. TLC analysis showed that the reaction proceeded completely. The solution was concentrated, and 50 mL of ethyl acetate was added. The pH was adjusted to ≤3 with hydrochloric acid. Water was added to create a soluble liquid. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 1.65 g of a pale yellow solid, with a yield of 99.15%. MS (ESI, pos.ion) m / z: 347.2 [M+H] + .

[0278] Step 8: Synthesis of compounds 1-8

[0279] Compound 1-7 (0.60 g, 1.73 mmol) and dichloromethane (8 mL) were added to a 100 mL single-necked flask, followed by cyclobutylamine (0.18 g, 2.59 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.50 g, 2.59 mmol). The reaction was carried out at room temperature. After 11.5 h, TLC analysis showed that the reaction proceeded completely. 50 mL of dichloromethane was added, and the organic phase was washed with water (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA(v / v) = 1 / 0-10 / 1-3 / 1) to give 0.52 g of off-white solid, yield 74.61%.

[0280] Step 9: Synthesis of compounds 1-9

[0281] Starting materials 1-8 (100 mg, 0.25 mmol), compounds 1-2 (52.80 mg, 0.25 mmol), BrettPhos Pd G3 (23 mg, 0.025 mmol), BrettPhos (27 mg, 0.050 mmol), and cesium carbonate (160 mg, 0.50 mmol) were added to a 25 mL double-necked flask. The flask was purged with nitrogen, and 1,4-dioxane (5 mL) was added. The mixture was heated to 110 °C. After 2 h, TLC analysis showed that the reaction was complete. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was then washed with water (4 mL). The organic phase was purified by silica gel column chromatography (eluent: DCM / EA (v / v) = 15 / 1–5 / 1) to give 25 mg of a yellow solid, yield 17.40%. MS (ESI, pos.ion) m / z: 575.50 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.69(s,1H),8.43(d,J=4.4Hz,2H),8.08–8.01(m,2H),8.00–7.92 (m,2H),7.63(d,J=6.0Hz,1H),7.16(d,J=8.5Hz,2H),6.85(d,J=8.5Hz,2H),6.45(t,J= 7.3Hz,1H),5.52(s,1H),5.13(s,2H),4.72(dd,J=16.4,8.2Hz,1H),3.79(s,3H),3.30( s,1H),3.05(s,3H),2.51(d,J=3.4Hz,2H),2.01(d,J=8.9Hz,2H),1.80(d,J=5.2Hz,2H).

[0282] Step 10: Synthesis of Compound 1

[0283] Add starting materials 1-9 (25 mg, 0.044 mmol) to a 5 mL single-necked flask, then add dichloromethane (2 mL), and slowly add trifluoroacetic acid (300 mg, 2.64 mmol) at room temperature. The reaction is continued at room temperature. After 3.5 h, TLC analysis showed that the starting materials had largely reacted, and the reaction was stopped. The mixture was cooled to 0 °C, and the pH was adjusted to 9 with 20% potassium phosphate solution. 10 mL of dichloromethane was added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1-1 / 1) to obtain 12 mg of a yellow solid, yield 60.69%. MS (ESI, pos.ion) m / z: 455.20 [M+H] + ; 1H NMR(400MHz, CDCl3)δ8.72(s,1H),8.48(d,J=7.1Hz,1H),8.38(s,1H),8.08(s,1 H),8.01(t,J=8.7Hz,2H),7.98–7.91(m,1H),7.65(d,J=7.0Hz,1H),6.46(t,J=7. 2Hz,1H),6.31(d,J=4.9Hz,1H),5.48(s,1H),4.72(dd,J=16.0,8.1Hz,1H),3.33( s,1H),3.10(d,J=5.1Hz,3H),2.53(s,2H),2.07–2.01(m,2H),1.86–1.80(m,2H).

[0284] Example 2: Synthesis of Compound 2

[0285]

[0286] Step 1: Synthesis of Compound 2-1

[0287] In a 50 mL double-necked flask, 5-bromo-2-fluoropyridine (1.00 g, 5.68 mmol), 1-(trimethylsilyl)propyne (0.96 g, 8.52 mmol), copper iodide (0.22 g, 1.14 mmol), triethylamine (2.87 g, 28.4 mmol), palladium dichloride bis(triphenylphosphine) (0.80 g, 1.14 mmol), and tetrahydrofuran (10 mL) were added dropwise. Under nitrogen protection, tetrabutylammonium fluoride (2.23 g, 8.52 mmol) was added dropwise at room temperature. After approximately 4 hours, TLC analysis showed a small amount of reactants remaining. The reaction was stopped, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether) to give 0.41 g of a yellow liquid, with a yield of 53.52%. 1 H NMR (400MHz, CDCl3) δ8.22(d,J=2.3Hz,1H),7.73(td,J=8.2,2.3Hz,1H),6.84(dd,J=8.5,3.0Hz,1H),2.04(s,3H).

[0288] Step 2: Synthesis of compound 2-2

[0289] Compound 2-1 (0.40 g, 2.96 mmol), 3-amino-1,2-dihydropyridin-2-one (0.33 g, 2.96 mmol), and cesium carbonate (0.96 g, 2.96 mmol) were added to a 50 mL single-necked flask, followed by N,N-dimethylacetamide (8 mL). The reaction was carried out at 110 °C for 15.5 h. The reaction was then stopped, and the reaction mixture was extracted with water (30 mL) and dichloromethane (8 mL × 4). The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 5 / 1-2 / 1) to give 0.17 g of a yellow solid, yield 18.90%. MS (ESI, pos.ion) m / z: 226.2 [M+H] + .

[0290] Step 3: Synthesis of compounds 2-3

[0291] Compound 2-2 (19 mg, 0.084 mmol), compound 1-8 (40 mg, 0.10 mmol), BrettPhos Pd G3 (8 mg, 0.0084 mmol), BrettPhos (9 mg, 0.017 mmol), and cesium carbonate (55 mg, 0.17 mmol) were added to a 10 mL double-necked flask. The mixture was purged with nitrogen, and then 1,4-dioxane (5 mL) was added. The mixture was heated to 110 °C. After 2 h of reaction, TLC analysis showed that the reactants had reacted completely. The reaction was stopped, cooled to room temperature, and filtered. The filter cake was washed with ethyl acetate (20 mL), and the organic phase was washed with water (4 mL). The mixture was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM / EA (v / v) = 15 / 1–5 / 1) to give 24 mg of a green solid, with a yield of 48.33%. MS(ESI,pos.ion)m / z:589.50[M+H] + ; 1HNMR (400MHz, CDCl3) δ8.61 (s, 1H), 8.44 (d, J = 6.0Hz, 2H), 8.10–8.01 (m, 2H), 7.92 (d, J = 8.4Hz, 1H),7.86(dd,J=8.4,2.0Hz,1H),7.62(d,J=5.7Hz,1H),7.18(d,J=8.6Hz,2H),6.87(d,J=8.5Hz ,2H),6.45(t,J=7.3Hz,1H),5.54(s,1H),5.15(s,2H),4.74(dd,J=16.1,7.9Hz,1H),3.81(s,3H ),3.07(s,3H),2.53(d,J=3.0Hz,2H),2.13(s,3H),2.03(d,J=7.2Hz,2H),1.83(d,J=5.0Hz,2H).

[0292] Step 4: Synthesis of Compound 2

[0293] Dichloromethane (5 mL) was added to a 25 mL single-necked flask containing compound 2-3 (23 mg, 0.039 mmol). After stirring and dissolving at room temperature, trifluoroacetic acid (270 mg, 2.34 mmol) was added dropwise. The reaction was allowed to proceed at room temperature. After 4 hours of reaction, a sample was taken and the pH was adjusted to 8 with potassium phosphate solution. TLC analysis showed that the starting material had reacted completely. The reaction was stopped, and dichloromethane (20 mL) was added. The mixture was cooled to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, dried over anhydrous sodium sulfate, and evaporated to dryness. The purified solid was obtained by silica gel column chromatography (eluent: DCM / PE (v / v) = 10 / 1–2 / 1) to give 12 mg of green solid, with a yield of 65.55%. MS (ESI, pos.ion) m / z: 469.30 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.59 (s, 1H), 8.44 (d, J = 7.4Hz, 1H), 8.36 (s, 1H), 7.91 (d, J = 8.2Hz, 2H),7.84(dd,J=8.4,2.0Hz,1H),7.60(d,J=6.4Hz,1H),6.43(t,J=7.2Hz,1H),6.30(s,1H ),5.48(s,1H),5.34(t,J=4.9Hz,1H),4.69(dd,J=16.2,8.2Hz,1H),3.08(d,J=5.1Hz,3H ), 2.50 (d, J = 3.3Hz, 2H), 2.11 (s, 3H), 2.01 (d, J = 7.0Hz, 2H), 1.80 (dd, J = 9.2, 4.1Hz, 2H).

[0294] Example 3: Synthesis of Compound 3

[0295]

[0296]

[0297] Step 1: Synthesis of Compound 3-1

[0298] 5-Bromo-2-fluoropyridine (1.00 g, 5.68 mmol), cuprous iodide (0.056 g, 0.28 mmol), palladium dichloride (0.20 g, 0.28 mmol), and diisopropylamine (15 mL) were added to a 100 mL two-necked flask. The mixture was heated to 100 °C under nitrogen protection, and cyclopropylacetylene (0.56 g, 8.52 mmol) was slowly added. The reaction was carried out at 100 °C for approximately 5 h. TLC was performed; the reactants were almost completely reacted. The reaction was stopped, the reaction solution was filtered, and the filtrate was washed with water (30 mL), extracted with ethyl acetate (10 mL × 3), dried over the organic phase, concentrated, and purified by column chromatography (eluent PE) to obtain 1.05 g of a yellowish-brown liquid. MS (ESI, pos.ion) m / z: 162.5 [M+H] + .

[0299] Step 2: Synthesis of compound 3-2

[0300] Compound 3-1 (0.60 g, 3.72 mmol), 3-amino-1,2-dihydropyridin-2-one (0.49 g, 4.46 mmol), cesium carbonate (3.03 g, 9.30 mmol), and N,N-dimethylacetamide (10 mL) were added to a 50 mL single-necked flask and reacted at 110 °C for approximately 9 h. TLC was performed; a small amount of reactant remained, and the reaction was stopped. The reaction mixture was filtered, washed with ethyl acetate (35 mL), and the filtrate was washed with water (20 mL). The mixture was separated, dried over dry conditions, and concentrated. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 2 / 1) to give 0.20 g of a yellow solid, yield 21.38%. MS (ESI, pos.ion) m / z: 252.3 [M+H] + .

[0301] Step 3: Synthesis of compound 3-3

[0302] To a 50 mL two-necked flask were added compound 3-2 (60 mg, 0.15 mmol), compound 1-8 (38 mg, 0.15 mmol), BrettPhos Pd G3 (14 mg, 0.015 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (16 mg, 0.03 mmol), and cesium carbonate (98 mg, 0.3 mmol). Under nitrogen, 1,4-dioxane (8 mL) was added and the mixture was refluxed at 80°C for approximately 3 h. TLC indicated that the reaction was essentially complete. The product was filtered and the filter cake was rinsed with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 1 / 1) to obtain 64 mg of a solid with a yield of 67.22%. MS(ESI,pos.ion)m / z:615.3[M+H] + .

[0303] Step 4: Synthesis of Compound 3

[0304] Compound 3-3 (84 mg, 0.14 mmol), dichloromethane (6 mL), and trifluoroacetic acid (960 mg, 8.4 mmol) were added to a 25 mL single-necked flask and reacted at room temperature for approximately 3 h. TLC was performed; after complete reaction, dichloromethane (8 mL) was added, followed by adjustment of pH to 8 with 20% potassium phosphate aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: DCM / EA (v / v) = 8 / 1-5 / 1) to give 57 mg of solid, yield 72.56%. MS (ESI, pos.ion) m / z: 495.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.60–8.53(m,1H),8.47–8.40(m,1H),8.35(s,1H),8.11(s,1H),7.9 5–7.86(m,2H),7.82(dd,J=8.4,1.9Hz,1H),7.62–7.56(m,1H),6.42(t,J=7.3Hz,1H),6.3 1(d,J=4.7Hz,1H),5.45(s,1H),4.68(q,J=8.1Hz,1H),3.06(d,J=5.1Hz,3H),2.49(d,J=5 .7Hz,2H),2.04–1.98(m,2H),1.42(d,J=2.9Hz,2H),0.96–0.91(m,2H),0.88–0.85(m,2H).

[0305] Example 4: Synthesis of Compound 4

[0306]

[0307] Step 1: Synthesis of compound 4-1

[0308] 5-Bromo-2-fluoropyridine (1.00 g, 5.68 mmol), 3-amino-2-hydroxypyridine (0.63 g, 5.68 mmol), and cesium carbonate (4.63 g, 14.2 mmol) were added to a 25 mL two-necked flask under nitrogen protection. N,N-dimethylacetamide (13 mL) was added, and the mixture was heated to 95 °C. After 5 h of reaction, TLC analysis showed that the starting material had reacted completely. The mixture was cooled to room temperature, and water (50 mL) was added. The mixture was then extracted with EA (70 mL × 3). The organic phases were combined, concentrated, and subjected to column chromatography (eluent: PE / EA (v / v = 10 / 1-3 / 1)). The collected solid was evaporated to dryness to give 330 mg of a yellow solid, yield 21.83%. MS (ESI, pos.ion) m / z: 266.05 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.63 (d, J=1.8Hz, 1H), 7.96 (dd, J=8.6, 2.3Hz, 1H), 7.91 (d, J=8.6 Hz,1H),7.31(dd,J=7.2,1.4Hz,1H),6.60(dd,J=7.1,1.4Hz,1H),6.22(t,J=7.1Hz,1H).

[0309] Step 2: Synthesis of compound 4-2

[0310] Compound 4-1 (252 mg, 0.95 mmol), triisopropylsilyl acetylene (0.17 g, 0.95 mmol), cuprous iodide (9 mg, 0.048 mmol) and bistriphenylphosphine palladium dichloride (33 mg, 0.048 mmol) were added to a 10 mL two-necked flask, replaced with nitrogen, and then diisopropylamine (4 mL) was added. The atmosphere was replaced with nitrogen again for protection, and the temperature was raised to 100 ° C for reaction. After 3 h, TLC detection showed that the raw materials were completely reacted. The reaction solution was concentrated, and EA (10 mL) was added for dissolution. The mixture was filtered, and the filter cake was rinsed with EA (15 mL). The organic phases were combined and washed once with saturated sodium chloride solution (5 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography (eluent: PE / EA (v / v = 15 / 1-5 / 1). The mixture was collected and spin-dried to obtain 152 mg of a brown oil (yield 43.67%). MS (ESI, pos. ion) m / z: 368.30 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.63(d,J=1.2Hz,1H),7.95(d,J=8.4Hz,1H),7.88(dd,J=8.4,2.0Hz,1 H),7.36–7.31(m,1H),6.60(d,J=6.1Hz,1H),6.22(t,J=7.1Hz,1H),1.16(d,J=2.6Hz,21H).

[0311] Step 3: Synthesis of compound 4-3

[0312] Add starting materials 1-7 (0.7 g, 2.02 mmol) and DCM (10 mL) to the reaction flask, followed by cyclopropylamine (0.20 g, 2.77 mmol) and EDCI (0.62 g, 3.23 mmol). React at room temperature. After 4.5 h, TLC analysis showed complete reaction of the starting materials. Stop the reaction, add DCM (20 mL), wash once with saturated sodium chloride solution (8 mL), dry the organic phase with anhydrous sodium sulfate, evaporate to dryness, and perform column chromatography (eluent: PE / EA (v / v) = 10 / 1-3 / 1). Collect and evaporate to dryness to give 271 mg of a grayish-white solid, yield 34.66%. MS (ESI, pos.ion) m / z: 386.30 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.54(d,J=11.0Hz,1H),7.94(s,1H),7.16(d,J=8.6Hz,2H),6.86(d,J=8.6Hz,2H),6.02(s,1H),5. 27(d,J=19.1Hz,2H),3.79(s,3H),3.16(s,3H),2.92(dq,J=10.8,3.6Hz,1H),0.86(q,J=6.8Hz,2H),0.69–0.61(m,2H).

[0313] Step 4: Synthesis of compound 4-4

[0314] Add starting materials 4-3 (65 mg, 0.17 mmol), BrettPhos-G3-Pd (0.015 g, 0.017 mmol), Brettphos (0.018 g, 0.034 mmol), and cesium carbonate (0.11 g, 0.34 mmol) to a 10 mL double-necked flask, purge with nitrogen, dissolve compound 4-2 (0.062 g, 0.17 mmol) in 1,4-dioxane (3 mL), add it to the reaction flask, purge with nitrogen, and heat to 75 °C for reaction. After 1.5 hours, TLC analysis showed that the reaction of the starting material was complete. The mixture was cooled to room temperature, filtered, and the filter cake was washed with EA (20 mL). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. The mixture was then subjected to column chromatography with PE / EA (v / v = 10 / 1-3 / 1) as the eluent. The collected sample was evaporated to dryness to give 83 mg of yellow solid, with a yield of 68.72%. 1 H NMR (400MHz, CDCl3) δ8.68(s,1H),8.47(s,1H),8.27(d,J=6.0Hz,1H),8.02(s,2H ),7.94(s,2H),7.63(d,J=5.9Hz,1H),7.18(d,J=8.5Hz,2H),6.87(d,J=8.6Hz,2H) ,6.48(t,J=7.3Hz,1H),5.52(s,1H),5.15(s,2H),3.81(s,3H),3.07(s,3H),3.04( d,J=3.6Hz,1H),1.17(d,J=3.0Hz,21H),0.94–0.90(m,2H),0.68(t,J=7.8Hz,2H).

[0315] Step 5: Synthesis of compounds 4-5

[0316] The starting material 4-4 (78 mg, 0.11 mmol) and DCM (3 mL) were added to a 10 mL single-necked flask and stirred. Trifluoroacetic acid (0.75 g, 6.6 mmol) was then added, and the reaction was carried out at room temperature. After 4 hours, a sample was taken, and the pH was adjusted to 8 with potassium phosphate solution. TLC analysis showed that the reaction was complete. DCM (30 mL) was added, the mixture was cooled to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, the organic phase was evaporated to dryness, and then subjected to column chromatography with DCM / EA ((v / v) = 3 / 1) as the eluent. The collected sample was evaporated to dryness to give 55 mg of a yellow solid, with a yield of 84.71%. 1H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 8.37 (s, 1H), 8.29 (d, J = 6.8Hz, 1H), 8.0 4(s,1H),7.93(s,2H),7.87(s,1H),7.60(d,J=6.4Hz,1H),6.45(t,J=7.3Hz ,1H),6.28(d,J=4.8Hz,1H),5.44(s,1H),3.07(d,J=5.1Hz,3H),3.01(dd, J=7.0,3.6Hz,1H),1.15(d,J=2.8Hz,21H),0.90–0.86(m,2H),0.65(s,2H).

[0317] Step 6: Synthesis of compound 4

[0318] Add starting material 4-5 (55 mg, 0.092 mmol) and THF (3 mL) to a 10 mL single-necked flask, stir until dissolved, and add tetrabutylammonium fluoride (0.18 mL, 0.18 mmol) dropwise at room temperature. After 1.5 h, TLC analysis showed that the reaction was complete. Stop the reaction, add ethyl acetate (30 mL) and 5 mL water (5 mL), extract and separate the liquid. Dry the organic phase with anhydrous sodium sulfate, evaporate to dryness, and perform column chromatography using DCM / MeOH ((v / v) = 1 / 0-30 / 1) as eluent. Collect and evaporate to dryness to give 28 mg of yellow solid, yield 68.98%. MS (ESI, pos.ion) m / z: 441.20 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.40 (s, 1H), 8.32 (d, J = 6.1Hz, 1H), 8.06 (s,1H),7.99(dd,J=8.6,6.7Hz,2H),7.89(s,1H),7.65(d,J=5.8Hz,1H),6.4 9(t,J=7.3Hz,1H),6.30(d,J=4.9Hz,1H),5.47(s,1H),3.33(s,1H),3.10(d ,J=5.2Hz,3H),3.07–2.98(m,1H),0.91(d,J=7.0Hz,2H),0.69–0.66(m,2H).

[0319] Example 5: Synthesis of Compound 5

[0320]

[0321] Step 1: Synthesis of compound 5-1

[0322] Sodium methanesulfinate (3.88 g, 38.02 mmol), copper dichloride (0.39 g, 2.93 mmol), and N,N-dimethylformamide (20 mL) were added to a 50 mL double-necked flask under nitrogen protection. 3-chloro-3-methyl-1-butyne (3 g, 29.25 mmol) was added dropwise to the stirred suspension. After the addition was complete, the mixture was heated to 40 °C and reacted for 22.5 h. The reaction was then stopped, and EA (30 mL) was added to the reaction solution. The mixture was then washed once with water (15 mL) and once with saturated sodium chloride solution (15 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography using PE / EA (v / v = 1 / 0 - 10 / 1) as the eluent. The collected solution was evaporated to dryness, yielding 2.55 g of a colorless, transparent liquid, with a yield of 59.62%. MS (ESI, pos.ion) m / z: 147.20 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ2.67(s,1H),2.61(s,3H),1.68(s,3H),1.59(s,3H).

[0323] Step 2: Synthesis of compound 5-2

[0324] Starting materials 4-1 (514 mg, 1.93 mmol), 5-1 (0.34 g, 2.32 mmol), cuprous iodide (0.018 g, 0.097 mmol), and bis(triphenylphosphine)palladium dichloride (0.068 g, 0.097 mmol) were added to a 25 mL double-necked flask, purged with nitrogen, and then diisopropylamine (7 mL) was added. The mixture was purged with nitrogen again, and the temperature was raised to 100 °C. The reaction was allowed to proceed for 5.5 h, and TLC analysis confirmed the reaction was complete. The mixture was concentrated, and the residue was dissolved in EA (20 mL). The residue was washed twice with water (7 mL), and the organic phase was evaporated to dryness. The solution was then subjected to column chromatography using DCM / EA (v / v = 10 / 1-3 / 1) as the eluent. The collected solution was evaporated to dryness to give 106 mg of a yellow solid, with a yield of 16.56%. MS (ESI, pos.ion) m / z: 332.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.61(d,J=1.6Hz,1H),8.01(d,J=8.4Hz,1H),7.87(dd,J=8.5,2.1Hz,1H),7.33(dt,J=1 7.6,8.8Hz,1H),6.61–6.53(m,1H),6.21(t,J=7.1Hz,1H),5.30(s,2H),3.08(s,3H),1.76(d,J=17.2Hz,6H).

[0325] Step 3: Synthesis of compound 5-3

[0326] The starting materials 1-8 (120 mg, 0.30 mmol), 5-2 (99 mg, 0.30 mmol), BrettPhos-G3-Pd (27 mg, 0.030 mmol), Brettphos (32 mg, 0.060 mmol), and cesium carbonate (200 g, 0.60 mmol) were placed in a 10 mL two-necked flask. The atmosphere was purged with nitrogen, and 1,4-dioxane (3 mL) was added. The atmosphere was purged with nitrogen again, and the temperature was raised to 80°C for 1.6 h. After TLC, the reaction was complete. The mixture was filtered, and the filter cake was rinsed with EA (20 mL). The organic phase was washed once with water (5 mL), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was purified by column chromatography using DCM / EA (v / v = 15 / 1-3 / 1) as the eluent. The mixture was collected and dried by spin drying to give 136 mg of a yellow solid (yield 65.23%). MS(ESI,pos.ion)m / z:695.3[M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.65(s,1H),8.42(d,J=3.4Hz,2H),8.07–7.96(m,3H),7.92(dd,J =8.4,1.9Hz,1H),7.63(d,J=6.5Hz,1H),7.16(d,J=8.5Hz,2H),6.84(d,J=8.5Hz,2H),6. 44(t,J=7.3Hz,1H),5.52(s,1H),5.13(s,2H),4.78–4.63(m,1H),3.78(s,3H),3.09(s, 3H),3.05(s,3H),2.57–2.44(m,2H),2.03–1.93(m,2H),1.84–1.79(m,2H),1.79(s,6H).

[0327] Step 4: Synthesis of compound 5

[0328] Starting material 5-3 (132 mg, 0.19 mmol) and DCM (4 mL) were added to a 25 mL single-necked flask. After stirring, trifluoroacetic acid (1.30 g, 11.4 mmol) was added dropwise, and the reaction was carried out at room temperature. After about 1.5 h, a sample was taken, and the pH was adjusted to 8 with potassium phosphate solution. TLC was performed. After the starting material reaction was complete, DCM (15 mL) was added, and the pH was adjusted to 8 with potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography. DCM / MeOH (v / v = 1 / 0-30 / 1) was used as the eluent. The collected sample was evaporated to dryness to give 70 mg of a yellow solid, with a yield of 64.12%. MS (ESI, pos.ion) m / z: 575.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ8.65(s,1H),8.46(d,J=7.2Hz,1H),8.35(s,1H),8.07–7.9 9(m,2H),7.92(dd,J=11.5,4.7Hz,2H),7.62(d,J=7.1Hz,1H),6.44(t,J=7.3Hz,1 H),6.31(d,J=5.1Hz,1H),5.44(s,1H),4.68(dt,J=16.3,8.2Hz,1H),3.11–3.05( m,6H),2.50(d,J=3.6Hz,2H),2.04–1.98(m,2H),1.85–1.80(m,2H),1.79(s,6H).

[0329] Example 6: Synthesis of Compound 6

[0330]

[0331] Step 1: Synthesis of compound 6-1

[0332] Compounds 4-3 (150 mg, 0.39 mmol), 2-2 (88 mg, 0.39 mmol), BrettPhos-G3-Pd (35 mg, 0.039 mmol), BrettPhos (42 mg, 0.078 mmol), and cesium carbonate (0.25 g, 0.78 mmol) were added to a 50 mL double-necked flask under nitrogen protection. 1,4-Dioxane (8 mL) was added, and the reaction was carried out at 80 °C for 2 h. TLC analysis showed that the reaction proceeds were completely reacted. The reaction solution was filtered, washed with dichloromethane (10 mL), and the filtrate was concentrated and purified by column chromatography (eluent: DCM / EA (v / v) = 10 / 1) to give 208 mg of a yellow solid, yield 93.11%. MS (ESI, pos.ion) m / z: 575.5 [M+H] + .

[0333] Step 2: Synthesis of Compound 6

[0334] Compound 6-1 (201 mg, 0.35 mmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (2.39 g, 21 mmol). The reaction was carried out at room temperature for approximately 3 hours. TLC analysis showed that the starting material had reacted completely. The reaction was then stopped, and the pH was adjusted to approximately 7 with 20% potassium phosphate aqueous solution. The mixture was separated, and the aqueous phase was extracted with dichloromethane (8 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH (v / v) = 100 / 1-70 / 1) to give 64 mg of a blue solid, with a yield of 38.31%. MS (ESI, pos.ion) m / z: 456.4 [M+H] +; 1 H NMR (400MHz, CDCl3) δ8.61–8.56(m,1H),8.37(s,1H),8.30–8.24(m,1H),8.14–8.01(m,1H),7.92–7.81(m,3H),7.59(d,J=6.2Hz,1H),6.44(t, J=7.2Hz,1H),6.33–6.26(m,1H),5.44(s,1H),3.06(d,J=5.1Hz,3H),3. 05–3.01(m,1H),2.11(s,3H),0.90(d,J=5.7Hz,2H),0.69–0.62(m,2H).

[0335] Example 7: Synthesis of Compound 7

[0336]

[0337] Step 1: Synthesis of Compound 7-1

[0338] Compounds 4-3 (150 mg, 0.39 mmol), 3-2 (98 mg, 0.39 mmol), BrettPhos-G3-Pd (0.035 g, 0.039 mmol), BrettPhos (42 mg, 0.078 mmol), and cesium carbonate (0.25 g, 0.78 mmol) were added to a 50 mL double-necked flask under nitrogen protection. 1,4-Dioxane (8 mL) was added, and the mixture was reacted at 80 °C for 2 h. TLC analysis showed complete reaction of the starting material. The reaction solution was filtered, washed with 10 mL of dichloromethane, and the filtrate was concentrated and purified by column chromatography (DCM / EA(v / v) = 10 / 1) to obtain 213 mg of a green solid, yield 91.22%. MS (ESI, pos.ion) m / z: 601.5 [M+H] + .

[0339] Step 2: Synthesis of Compound 7

[0340] Compound 7-1 (200 mg, 0.33 mmol) and dichloromethane (8 mL) were added to a 25 mL single-necked flask, followed by the addition of trifluoroacetic acid (2.26 g, 19.8 mmol). The reaction was carried out at room temperature for approximately 3 hours. TLC analysis showed that the reaction proceeded completely. The pH was adjusted to approximately 7 with 20% potassium phosphate aqueous solution. The mixture was separated from the aqueous phase and extracted with 8 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by DCM / MeOH = 80 / 1 column chromatography to yield 70 mg of a yellow solid, with a yield of 40.95%. MS (ESI, pos.ion) m / z: 481.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.61–8.56(m,1H),8.39(s,1H),8.30(dd,J=7.3,1.4Hz,1H),8.06(s,1H), 7.93–7.87(m,2H),7.84(dd,J=8.4,2.1Hz,1H),7.61(dd,J=7.1,1.5Hz,1H),6.46(t,J=7.3Hz,1 H),6.33–6.25(m,1H),5.45(s,1H),3.09(d,J=5.2Hz,3H),1.57–1.48(m,1H),1.34–1.25(m,1H) ,0.96(dt,J=7.7,2.5Hz,2H),0.94–0.91(m,2H),0.89(dd,J=7.1,4.5Hz,2H),0.69–0.65(m,2H).

[0341] Example 8: Synthesis of Compound 8

[0342]

[0343]

[0344] Step 1: Synthesis of compound 8-1

[0345] Raw materials 4-3 (0.2 g, 0.52 mmol), 5-2 (0.17 g, 0.52 mmol), BrettPhos-G3-Pd (0.047 g, 0.052 mmol), BrettPhos (0.056 g, 0.10 mmol), and cesium carbonate (0.34 g, 1.04 mmol) were placed in a 10 mL two-necked flask. The atmosphere was purged with nitrogen, followed by the addition of 1,4-dioxane (5 mL). The atmosphere was purged with nitrogen again, and the reaction temperature was raised to 80°C for 2 h. TLC confirmed complete reaction. The mixture was filtered, and the filter cake was rinsed with EA (50 mL). The organic phase was washed once with water (8 mL), dried over anhydrous sodium sulfate, and spin-dried. The residue was passed through a chromatography column using DCM / EA (v / v = 15 / 1-3 / 1) as the eluent. The mixture was collected and spin-dried to yield 0.27 g of a yellow solid, a yield of 75.92%. MS(ESI,pos.ion)m / z:681.2[M+H] + .

[0346] Step 2: Synthesis of compound 8

[0347] Starting material 8-1 (0.26 g, 0.39 mmol) and DCM (5 mL) were added to a reaction flask and stirred. Trifluoroacetic acid (2.67 g, 23.40 mmol) was then added dropwise. The mixture was stirred at room temperature for 2.5 h, and TLC analysis showed that the starting material had reacted completely. DCM (20 mL) was added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was evaporated to dryness. The solution was then passed through a chromatography column. Using DCM / MeOH (v / v) = 1 / 0 - 40 / 1 as the eluent, 0.20 g of a yellow solid was obtained, with a yield of 84.48%. MS (ESI, pos.ion) m / z: 561.4 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.67 (s, 1H), 8.40 (s, 1H), 8.31 (d, J = 6.2Hz, 1H), 8.04 (d, J = 8. 5Hz,2H),7.94(dd,J=8.4,2.0Hz,1H),7.88(s,1H),7.65(d,J=6.0Hz,1H),6.48(t,J =7.3Hz,1H),6.32(d,J=5.0Hz,1H),5.46(s,1H),3.12(s,3H),3.09(d,J=5.1Hz,3H) ,3.04(td,J=7.1,3.6Hz,1H),1.81(s,6H),0.91(d,J=6.7Hz,2H),0.70–0.64(m,2H).

[0348] Example 9: Synthesis of Compound 9

[0349]

[0350] Step 1: Synthesis of compound 9-1

[0351] The starting materials 5-bromo-2-fluoropyridine (1 g, 5.68 mmol), triethylamine (1.72 g, 17.04 mmol), cuprous iodide (0.054 g, 0.28 mmol), and bis(triphenylphosphine)palladium dichloride (0.20 g, 0.28 mmol) were added to a 25 mL double-necked flask, purged with nitrogen, and then N,N-dimethylformamide (8 mL) was added. The temperature was raised to 60 °C, and methyl propynyl ether (0.80 g, 11.36 mmol) was slowly added dropwise over 4.5 h. After the addition was complete, TLC analysis showed that the reaction was complete, and the mixture was cooled to room temperature. Water (20 mL) was added, and the mixture was extracted with EA (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and then evaporated to dryness. The product was analyzed by column chromatography (eluent: PE-PE / EA (v / v = 50 / 1)), collected, evaporated to dryness, and weighed to obtain 0.29 g of a reddish-brown liquid, yield 30.90%. MS (ESI, pos.ion) m / z: 166.2 [M+H] + .

[0352] Step 2: Synthesis of Compound 9-2

[0353] Compound 9-1 (0.29 g, 1.76 mmol), 3-amino-2-hydroxypyridine (0.19 g, 1.76 mmol), and cesium carbonate (1.43 g, 4.4 mmol) were added to a 25 mL double-necked flask. Under nitrogen protection, N,N-dimethylacetamide (5 mL) was added, and the mixture was heated to 95 °C. After 17.5 h of reaction, TLC analysis showed that the starting material had reacted completely. The mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with EA (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 3), concentrated, and subjected to column chromatography (eluent: PE / EA (v / v = 50 / 1-2 / 1)) to give 0.17 g of a yellow solid, yield 37.93%. MS (ESI, pos.ion) m / z: 256.20 [M+H] + .

[0354] Step 3: Synthesis of compound 9-3

[0355] Starting materials 1-8 (0.2 g, 0.50 mmol), 9-2 (0.13 g, 0.50 mmol), BrettPhos-G3-Pd (0.045 g, 0.050 mmol), BrettPhos (0.054 g, 0.10 mmol), and cesium carbonate (0.33 g, 1 mmol) were added to a 10 mL reaction flask, purged with nitrogen, and 1,4-dioxane (5 mL) was added. The mixture was heated to 80 °C and reacted. After 1.5 h, TLC analysis showed that the reaction was complete. The mixture was cooled to room temperature, dissolved in EA (30 mL), washed twice with water (10 mL), dried over anhydrous sodium sulfate, and subjected to column chromatography with DCM / MeOH (v / v = 35 / 1) as eluent. The collected solid was evaporated to dryness, yielding 235 mg of a yellow solid. The yield was 75.94%. MS(ESI,pos.ion)m / z:619.3[M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.68(s,1H),8.45(s,2H),8.12–8.02(m,2H),7.96(dd,J=23.8 ,8.2Hz,2H),7.65(d,J=6.5Hz,1H),7.18(d,J=7.9Hz,2H),6.87(d,J=8.1Hz,2H),6.4 6(t,J=6.9Hz,1H),5.54(s,1H),5.15(s,2H),4.74(d,J=8.1Hz,1H),4.39(s,2H),3.8 1(s,3H),3.50(s,3H),3.07(s,3H),2.53(s,2H),2.03(d,J=7.9Hz,2H),1.83(s,2H).

[0356] Step 4: Synthesis of compound 9

[0357] Compound 9-3 (235 mg, 0.38 mmol), DCM (5 mL), and trifluoroacetic acid (2.60 g, 22.8 mmol) were added to a 25 mL single-necked flask and reacted at room temperature. After 1.5 h, TLC analysis showed the starting material had reacted completely. 30 mL of DCM was added, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / MeOH (v / v = 1 / 0 - 30 / 1) as the eluent. The collected solid was evaporated to dryness, yielding 120 mg of a grayish-white solid. Yield: 63.34%. MS (ESI, pos.ion) m / z: 499.25 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.64(s,1H),8.43(d,J=6.7Hz,1H),8.34(s,1H),8.07(s,1 H),7.97(d,J=8.4Hz,1H),7.90(d,J=7.5Hz,2H),7.60(d,J=6.5Hz,1H),6.47–6.3 0(m,2H),5.43(s,1H),4.68(dd,J=16.1,8.1Hz,1H),4.36(s,2H),3.47(s,3H),3. 04(d,J=5.0Hz,3H),2.49(d,J=3.1Hz,2H),2.05–1.92(m,2H),1.80–1.74(m,2H).

[0358] Example 10: Synthesis of Compound 10

[0359]

[0360] Step 1: Synthesis of compound 10-1

[0361] Compounds 1-7 (0.5 g, 1.44 mmol) and DCM (4 mL) were added to a reaction flask, followed by (1R,2S)-2-fluorocyclopropylamine p-toluenesulfonate (0.22 g, 2.88 mmol) and EDCI (0.41 g, 2.16 mmol). The reaction was carried out at room temperature for 10 h. TLC analysis showed that the starting material had reacted completely. DCM (100 mL) was added, and the mixture was washed once with water (60 mL). The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The solution was then passed through a chromatography column using PE / EA (v / v = 1 / 0 - 10 / 1 - 1 / 1) as the eluent. The eluents were combined to give 0.28 g of a white solid, with a yield of 48.09%.

[0362] Step 2: Synthesis of compound 10-2

[0363] Compounds 10-1 (0.2 g, 0.52 mmol), 5-2 (0.17 g, 0.50 mmol), BrettPhos-G3-Pd (0.045 g, 0.050 mmol), BrettPhos (0.054 g, 0.10 mmol), and cesium carbonate (0.33 g, 1 mmol) were added to a 10 mL double-necked flask, followed by 1,4-dioxane (6 mL). The mixture was purged with nitrogen and heated to 80 °C for 1 h. TLC analysis showed the reactants reacted completely. The mixture was filtered, and the filter cake was washed with EA (50 mL). The organic phase was washed once with water (8 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was passed through a chromatography column, with a DCM / EA ratio of (v / v = 15 / 1 - 3 / 1), and weighed to obtain 0.22 g, yielding 63.57%.

[0364] Step 3: Synthesis of Compound 10

[0365] 0.22 g (0.31 mmol) of starting material and 8 mL of DCM were added to a reaction flask and stirred. Trifluoroacetic acid (2.12 g, 18.6 mmol) was then added dropwise, and the mixture was stirred at room temperature for 2.5 h. TLC analysis confirmed the reaction was complete. 10 mL of DCM was added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was evaporated to dryness. The solution was then passed through a chromatography column (eluent: DCM / MeOH (v / v = 1 / 0-40 / 1)). The eluates were combined, evaporated to dryness, and weighed to obtain 0.12 g of a pale green solid, yield 65.87%. MS (ESI, pos.ion) m / z: 579.5 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.67(s,1H),8.42(s,1H),8.35(d,J=7.1Hz,1H),8.08–8.00( m,2H),7.94(dd,J=8.5,2.1Hz,1H),7.85(d,J=4.5Hz,1H),7.60(d,J=6.2Hz,1H),6 .49(t,J=7.3Hz,1H),6.29(d,J=5.4Hz,1H),5.46(s,1H),4.78–4.71(m,1H),3.22– 3.16(m,1H),3.13–3.08(m,6H),1.81(s,6H),1.14–1.08(m,1H),1.07–1.01(m,1H).

[0366] Example 11: Synthesis of Compound 11

[0367]

[0368] Step 1: Synthesis of compound 11-1

[0369] In a 50 mL two-necked flask, compound 10-1 (0.2 g, 0.50 mmol), 2-2 (0.11 g, 0.50 mmol), BrettPhos-G3-Pd (0.05 g, 0.045 mmol), BrettPhos (0.054 g, 0.1 mmol) and cesium carbonate (0.33 g, 1.00 mmol) were placed. Under nitrogen protection, 1,4-dioxane (8 mL) was added and the reaction was carried out at 80° C. for about 2 h. According to TLC detection, the raw material reaction was complete. The reaction solution was filtered, the filtrate was concentrated, and the product was purified by column chromatography (eluted with DCM / EA (v / v=10 / 1)) to give 196 mg of a light green solid with a yield of 66.78%.

[0370] Step 2: Synthesis of compound 11

[0371] Compound 11-1 (0.19 g, 0.32 mmol) was added to dichloromethane (8 mL), followed by trifluoroacetic acid (2.19 g, 19.2 mmol). The reaction was carried out at room temperature for approximately 3 hours. TLC analysis showed that the reaction proceeded completely. The pH was adjusted to approximately 7 with 20% potassium phosphate aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was concentrated and purified by column chromatography (eluent: DCM / EA (v / v = 5 / 1-3 / 1) to give 70 mg of a blue solid, yielding 48.23%. MS (ESI, pos.ion) m / z: 473.4 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.60(d,J=1.4Hz,1H),8.42(s,1H),8.34(d,J=7.2Hz,1H),8.0 8(s,1H),7.91(d,J=8.4Hz,1H),7.85(dd,J=8.3,2.0Hz,2H),7.57(dd,J=7.1,1.4Hz ,1H),6.46(t,J=7.2Hz,1H),6.29(d,J=5.2Hz,1H),5.45(s,1H),4.94–4.71(m,1H), 3.19(td,J=10.4,5.2Hz,1H),3.08(d,J=5.2Hz,3H),2.13(s,3H),1.17–0.97(m,2H).

[0372] Example 12: Synthesis of Compound 12

[0373]

[0374]

[0375] Step 1: Synthesis of compound 12-1

[0376] The starting materials 10-1 (0.2 g, 0.50 mmol), 9-2 (0.13 g, 0.50 mmol), BrettPhos-G3-Pd (0.045 g, 0.050 mmol), BrettPhos (0.054 g, 0.10 mmol), and cesium carbonate (0.33 g, 1 mmol) were placed in a two-necked flask, the atmosphere was purged with nitrogen, and 1,4-dioxane (6 mL) was added. The temperature was raised to 80°C and the reaction was allowed to react for 2 h. TLC confirmed complete reaction. The mixture was filtered, and the filter cake was rinsed with EA (50 mL). The organic phase was washed once with 8 mL of water (8 mL), dried over anhydrous sodium sulfate, and spin-dried. The mixture was then passed through a chromatography column using DCM / EA (v / v = 15 / 1 to 3 / 1) as the eluent to obtain 0.25 g of a yellow solid. The yield was 81.07%. MS(ESI,pos.ion)m / z:623.3[M+H] + .

[0377] Step 2: Synthesis of compound 12

[0378] Compound 12-1 (0.25 g, 0.40 mmol) and DCM (8 mL) were added to a reaction flask, stirred, and then trifluoroacetic acid (2.74 g, 24 mmol) was added dropwise. The mixture was stirred at room temperature for 2.5 h. TLC analysis showed that the starting material had reacted completely. The reaction was stopped, DCM (10 mL) was added, the temperature was lowered to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was evaporated to dryness. The solution was passed through a chromatography column, with DCM / MeOH = 1 / 0-40 / 1 as the eluent, yielding 0.04 g of a white solid, a yield of 19.83%. MS (ESI, pos.ion) m / z: 503.4 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ8.67(s,1H),8.42(s,1H),8.35(d,J=7.0Hz,1H),8.07(s,1H),7.99(d,J=8. 4Hz,1H),7.93(dd,J=8.4,2.0Hz,1H),7.85(d,J=4.3Hz,1H),7.59(d,J=7.2Hz,1H),6.48(t,J=7.2 Hz,1H),6.27(d,J=4.8Hz,1H),5.46(s,1H),4.83(dd,J=64.2,3.1Hz,1H),4.39(s,2H),3.51(s,3H ),3.24–3.16(m,1H),3.10(d,J=5.2Hz,3H),1.07(dd,J=14.1,11.2Hz,1H),0.89(d,J=7.4Hz,1H).

[0379] Example 13: Synthesis of Compound 13

[0380]

[0381]

[0382] Step 1: Synthesis of compound 13-1

[0383] The starting materials 10-1 (0.2 g, 0.52 mmol), 3-2 (0.13 g, 0.50 mmol), BrettPhos-G3-Pd (0.045 g, 0.050 mmol), BrettPhos (0.054 g, 0.10 mmol), and cesium carbonate (0.33 g, 1 mmol) were placed in a two-necked flask, the atmosphere was purged with nitrogen, and 1,4-dioxane (6 mL) was added. The temperature was raised to 80°C and the reaction was allowed to react for 2 h. TLC confirmed complete reaction. The mixture was filtered, and the filter cake was rinsed with EA (50 mL). The organic phase was washed once with water (8 mL), dried over anhydrous sodium sulfate, and spin-dried. The product was then passed through a chromatography column using DCM / EA (v / v = 15 / 1 to 3 / 1) as the eluent to obtain 0.24 g of a yellow solid in a yield of 78.33%.

[0384] Step 2: Synthesis of Compound 13

[0385] Add 8 mL of DCM to starting material 13-1 (0.24 g, 0.39 mmol), stir, and then add trifluoroacetic acid (2.67 g, 23.40 mmol) dropwise. Stir the reaction at room temperature for 2.5 h. TLC analysis showed the reaction was complete. Add 10 mL of DCM, cool to 0 °C, adjust pH to 8 with 20% potassium phosphate solution, separate the layers, and evaporate the organic phase to dryness. Pass through a chromatography column; DCM / MeOH = 1 / 0 - 40 / 1. Combine the eluents, evaporate to dryness, and weigh to obtain 0.132 g, yield 68.26%. MS (ESI, pos.ion) m / z: 499.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.58 (s, 1H), 8.42 (s, 1H), 8.34 (d, J = 7.1Hz, 1H), 8.08 (s, 1H), 7.91 –7.81(m,3H),7.57(d,J=7.0Hz,1H),6.47(t,J=7.3Hz,1H),6.26(d,J=5.3Hz,1H),5.45( s,1H),5.34(d,J=18.9Hz,1H),4.91(s,1H),4.75(d,J=2.5Hz,1H),3.18(d,J=5.1Hz,1H) ,3.10(d,J=5.1Hz,3H),1.08(d,J=25.3Hz,1H),0.99–0.94(m,2H),0.90(t,J=4.2Hz,2H).

[0386] Example 14: Synthesis of Compound 14

[0387]

[0388]

[0389] Step 1: Synthesis of Compound 14-1

[0390] 5-Bromo-2,3-difluoropyridine (1.0 g, 5.16 mmol), 3-amino-2-hydroxypyridine (0.57 g, 5.16 mmol), cesium carbonate (3.36 g, 10.32 mmol), and N,N-dimethylacetamide (10 mL) were added to a 25 mL reaction flask, and the mixture was heated to 95 °C. After 4 h, TLC analysis showed that the starting material had reacted completely. 40 mL of water was added, and the mixture was extracted with EA (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, and subjected to column chromatography with PE / EA (v / v = 3 / 1) as the eluent. The collected product was evaporated to dryness, yielding 0.87 g of an oily product, with a yield of 59.41%. MS (ESI, pos.ion) m / z: 284.0, 286.0 [M+H] + .

[0391] Step 2: Synthesis of compound 14-2

[0392] Starting material 14-1 (0.4 g, 1.41 mmol), triisopropylsilylacetylene (0.26 g, 1.41 mmol), cuprous iodide (0.013 g, 0.070 mmol), and bis(triphenylphosphine)palladium dichloride (0.049 g, 0.070 mmol) were added to a 25 mL double-necked flask, purged with nitrogen, and then diisopropylamine (12 mL) was added. The mixture was heated to 100 °C and reacted. After 3 h, TLC analysis showed that the reaction was complete. The reaction solution was concentrated, dissolved in EA (25 mL), washed once with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography using PE / EA (v / v = 15 / 1-5 / 1) as eluent to give 473 mg of a brown oil, with a yield of 87.15%. MS (ESI, pos.ion) m / z: 386.2 [M+H] + .

[0393] Step 3: Synthesis of compound 14-3

[0394] Starting materials 1-8 (0.30 g, 0.75 mmol), 14-2 (0.29 g, 0.75 mmol), BrettPhos-G3-Pd (0.068 g, 0.075 mmol), BrettPhos (0.081 g, 0.15 mmol), and cesium carbonate (0.49 g, 1.5 mmol) were added to a 25 mL double-necked flask under nitrogen protection. Then, 1,4-dioxane (5 mL) was added, and the mixture was heated to 80 °C. After 1.5 h, TLC analysis showed that the starting materials had largely reacted. DCM (50 mL) was added, and the mixture was washed with saturated ammonium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, and subjected to rotary evaporation. The solution was then subjected to column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent. The collected solution was evaporated to dryness, yielding 0.42 g of a yellow solid, with a yield of 74.75%.

[0395] Step 4: Synthesis of compound 14-4

[0396] Compound 14-3 (0.42 g, 0.56 mmol) and N,N-dimethylformamide (6 mL) were added to a 25 mL single-necked flask and stirred until dissolved. Cesium fluoride (0.17 g, 1.12 mmol) was then added, and the reaction was carried out at room temperature. TLC analysis after 3 h showed complete reaction of the starting material. The reaction was stopped, water (20 mL) was added, and the mixture was extracted with EA (25 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / EA (v / v = 1 / 0-5 / 1) as eluent. The collected solid was evaporated to dryness, yielding 0.29 g of a pale yellow solid, with a yield of 87.26%. MS (ESI, pos.ion) m / z: 593.3 [M+H] + .

[0397] Step 5: Synthesis of Compound 14

[0398] Starting material 14-4 (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (3.22 g, 28.2 mmol). The reaction was carried out at room temperature. After 1.8 h, TLC analysis showed that the reaction was complete. DCM (25 mL) was added, the mixture was cooled to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent to give 0.16 g of an off-white solid, yield 71.67%. MS (ESI, pos.ion) m / z: 473.20 [M+H] + ; 1HNMR(400MHz,DMSO-d6)δ9.06(s,1H),8.64(d,J=1.1Hz,1H),8.41(d,J=7.3Hz,1H ),8.30(dd,J=9.9,1.5Hz,1H),8.19(s,1H),7.95(dd,J=11.3,6.5Hz,2H),7.47(dd ,1H),6.48(t,J=7.2Hz,1H),6.22(s,1H),4.74(s,1H),4.54–4.40(m,1H),2.91(d, J=4.8Hz,3H),2.34(dd,J=16.0,7.6Hz,2H),2.01–1.86(m,2H),1.80–1.65(m,2H).

[0399] Example 15: Synthesis of Compound 15

[0400]

[0401] Step 1: Synthesis of Compound 15-1

[0402] The starting materials 4-3 (0.30 g, 0.78 mmol), 14-2 (0.30 g, 0.78 mmol), BrettPhos-G3-Pd (0.071 g, 0.078 mmol), BrettPhos (0.084 g, 0.16 mmol), and cesium carbonate (0.51 g, 1.56 mmol) were placed in a 25 mL two-necked flask under nitrogen. 1,4-dioxane (5 mL) was then added and the temperature was raised to 80°C. After 1.5 h, TLC indicated that the starting materials had essentially reacted. The reaction solution was concentrated, dissolved in DCM (50 mL), and washed with saturated ammonium chloride (10 mL). The organic phase was separated and dried over anhydrous sodium sulfate, spin-dried, and eluted with column chromatography using DCM / EA (v / v = 1 / 0-5 / 1). The resulting mixture was collected and spin-dried to yield 0.43 g, a yield of 75.25%.

[0403] Step 2: Synthesis of compound 15-2

[0404] Compound 15-2 (0.42 g, 0.57 mmol), cesium fluoride (0.17 g, 1.14 mmol), and DMF (6 mL) were added to a 25 mL single-necked flask and reacted at room temperature. After 2.5 h, TLC analysis showed the starting material had reacted completely. Water (20 mL) was added, and the mixture was extracted with EA (25 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / EA (v / v = 1 / 0-5 / 1) as eluent. The collected solid was evaporated to dryness, yielding 0.26 g of a pale yellow solid, with a yield of 78.63%. MS (ESI, pos.ion) m / z: 579.2 [M+H] + .

[0405] Step 3: Synthesis of compound 15

[0406] The starting material 15-2 (0.26 g, 0.45 mmol) and dichloromethane (6 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (3.08 g, 27 mmol). The reaction was carried out at room temperature. After 1 h, TLC analysis showed that the reaction was complete. DCM (25 mL) was added, the mixture was cooled to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness and subjected to column chromatography with DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent. The collected solution was evaporated to dryness to give 0.18 g of an off-white solid, with a yield of 87.38%. MS (ESI, pos.ion) m / z: 459.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.63(d,J=1.5Hz,1H),8.32–8.24(m,2H),8.21(s,1H),7.93(t,J=4.7Hz,1H),7.83(d,J=3.9Hz,1H),7.46(dd ,J=6.9,1.6Hz,1H),6.54–6.43(m,1H),6.19(s,1H),4.74(s,1H),2.90(d ,J=4.8Hz,3H),2.88–2.81(m,1H),0.84–0.71(m,2H),0.56–0.47(m,2H).

[0407] Example 16: Synthesis of Compound 16

[0408]

[0409] Step 1: Synthesis of compound 16-1

[0410] The starting materials 10-1 (0.28 g, 0.69 mmol), 14-2 (0.27 g, 0.69 mmol), BrettPhos-G3-Pd (0.063 g, 0.069 mmol), BrettPhos (0.074 g, 0.14 mmol), and cesium carbonate (0.45 g, 1.38 mmol) were placed in a 25 mL two-necked flask under nitrogen. 1,4-dioxane (5 mL) was then added and the temperature was raised to 80°C for reaction. After 1.5 h, TLC confirmed complete reaction. The reaction solution was concentrated, dissolved in DCM (50 mL), and washed with saturated ammonium chloride solution (10 mL). The organic phase was separated and dried over anhydrous sodium sulfate, spin-dried, and eluted with column chromatography using DCM / EA (v / v = 1 / 0-5 / 1). The mixture was collected and spin-dried to give 0.39 g of a yellow solid (yield 74.71%).

[0411] Step 2: Synthesis of Compound 16-2

[0412] Compound 16-1 (0.39 g, 0.52 mmol), cesium fluoride (0.16 g, 1.04 mmol), and DMF (6 mL) were added to a 25 mL single-necked flask and reacted at room temperature. After 1.0 h, TLC analysis showed the reactants had reacted completely. Water (20 mL) was added, and the mixture was extracted with EA (20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (15 mL × 3). The organic phases were dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / EA (v / v = 1 / 0-5 / 1) as eluent. The collected solid was evaporated to dryness, yielding 0.30 g of a pale yellow solid, with a yield of 97.08%. MS (ESI, pos.ion) m / z: 597.2 [M+H] + .

[0413] Step 3: Synthesis of Compound 16

[0414] The starting material 16-2 (0.30 g, 0.50 mmol) and dichloromethane (6 mL) were added to a 25 mL single-necked flask, followed by the addition of trifluoroacetic acid (3.42 g, 30 mmol). The reaction was carried out at room temperature. After 1.4 h, TLC analysis showed that the reaction was complete. DCM (30 mL) was added, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / MeOH (v / v = 30 / 1) as the eluent. The collected solid was evaporated to dryness, yielding 0.15 g of an off-white solid, with a yield of 62.61%. MS (ESI, pos.ion) m / z: 477.2 [M+H] + ; 1H NMR(400MHz, DMSO-d6)δ9.02(d,J=9.0Hz,1H),8.63(d,J=1.5Hz,1H),8.34–8. 21(m,3H),8.00–7.91(m,1H),7.82(d,J=4.6Hz,1H),7.41(dd,J=6.9,1.6Hz,1 H),6.49–6.38(m,1H),6.24(s,1H),4.90(dtd,J=65.0,5.7,3.0Hz,1H),4.73( s,1H),3.00(dq,J=9.3,4.7Hz,1H),2.91(t,J=7.7Hz,3H),1.27–1.20(m,2H).

[0415] Example 17: Synthesis of Compound 17

[0416]

[0417] Step 1: Synthesis of compound 17-1

[0418] Add 10⁻¹ (0.20 g, 0.50 mmol), 4⁻² (0.18 g, 0.50 mmol), BrettPhos-G3-Pd (0.045 g, 0.05 mmol), BrettPhos (0.054 g, 0.10 mmol), and cesium carbonate (0.33 g, 1.00 mmol) to a 50 mL two-necked flask. Purge with nitrogen, add anhydrous 1,4-dioxane (8 mL), purge with nitrogen again, and reflux at 80 °C for about 2 h. Spot by TLC. After the starting material has reacted completely, stop the reaction, filter, wash the filter cake with ethyl acetate (50 mL), wash the organic phase once with 8 mL of water, dry with anhydrous sodium sulfate, and evaporate to dryness. Purify by column chromatography (eluent DCM / EA = 20 / 1-10 / 1) to give 0.267 g of yellow solid, yield 73.36%. 1 HNMR(400MHz, CDCl3)δ8.67(s,1H),8.49(s,1H),8.31(d,J=7.1Hz,1H),8.04–7.96(m,2H ),7.93(s,2H),7.59(d,J=7.2Hz,1H),7.18(d,J=8.5Hz,2H),6.87(d,J=8.6Hz,2H),6.48( t,J=7.2Hz,1H),5.53(s,1H),5.14(s,2H),4.83(ddd,J=64.3,8.7,5.9Hz,1H),3.81(s,3 H),3.20(dt,J=10.6,5.4Hz,1H),3.06(s,3H),1.17(d,J=2.9Hz,21H),1.13–1.02(m,2H).

[0419] Step 2: Synthesis of Compound 17-2

[0420] Compound 17-1 (0.26 g, 0.35 mmol) and cesium fluoride (0.11 g, 0.70 mmol) were added to a 50 mL single-necked flask, followed by 8 mL of DMF. The reaction was allowed to proceed at room temperature. After 2.5 h, TLC analysis showed that the starting material had reacted completely. The reaction was then stopped, and 90 mL of saturated brine was added. The aqueous phase was extracted with 50 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The solution was purified by column chromatography (DCM / EA = 10 / 1-5 / 1) to give 0.216 g of a brown solid, in 100% yield. 1 H NMR (400MHz, CDCl3) δ8.68(d,J=2.0Hz,1H),8.47(s,1H),8.29(dd,J=7.3,1.7Hz,1H),7.98–7. 91(m,3H),7.59(dd,J=7.1,1.7Hz,1H),7.16(d,J=8.4Hz,2H),6.88–6.82(m,2H),6.46(t,J=7.2 Hz,1H),5.51(s,1H),5.12(s,2H),4.81(dtd,J=64.3,5.9,3.1Hz,1H),3.79(s,3H),3.30(s,1H) ,3.18(dd,J=8.9,5.0Hz,1H),3.03(s,3H),2.92(d,J=28.9Hz,1H),1.10(td,J=5.7,3.0Hz,2H).

[0421] Step 3: Synthesis of compound 17

[0422] Compound 17-2 (0.13 g, 0.22 mmol) and dichloromethane (5 mL) were added to a 50 mL single-necked flask. After stirring, trifluoroacetic acid (1.51 g, 13.2 mmol) was added dropwise, and the reaction was carried out at room temperature. After 2 h of reaction, TLC analysis showed that the starting material had reacted completely. The mixture was cooled to 0 °C, and the pH was adjusted to approximately 8 with a 20% potassium phosphate aqueous solution. The mixture was separated, and the aqueous phase was extracted again with dichloromethane (20 mL). The organic phases were combined, concentrated, and subjected to column chromatography (elution buffer: DCM / CH3OH (v / v = 1 / 0-40 / 1)). The collected solid was evaporated to dryness to give 0.08 g of off-white solid, yield 77.67%. MS (ESI, pos.ion) m / z: 578.22 [M+H] + ; 1H NMR(400MHz, CDCl3)δ8.69(d,J=2.0Hz,1H),8.40(s,1H),8.33(d,J=7.3Hz,1H),8 .05(s,1H),8.00–7.93(m,2H),7.83(d,J=4.7Hz,1H),7.58(dd,J=7.2,1.7Hz,1H) ,6.46(t,J=7.3Hz,1H),6.26(d,J=5.6Hz,1H),5.44(s,1H),4.95–4.68(m,1H),3. 30(s,1H),3.17(dq,J=9.8,5.3Hz,1H),3.08(d,J=5.2Hz,3H),1.14–0.79(m,2H).

[0423] Example 18: Synthesis of Compound 18

[0424]

[0425] Step 1: Synthesis of Compound 18-1

[0426] To starting material 1-7 (3.57 g, 10.30 mmol), DCM (30 mL) and N,N-diisopropylethylamine (5.32 g, 41.2 mmol) were added. EDCI (2.96 g, 15.45 mmol) and ethyl 2-oximecyanoacetate (0.29 g, 2.06 mmol) were then added at 0°C. Finally, (1R,2R)-2-methoxycyclobutylamine hydrochloride (2.13 g, 15.45 mmol) was added. The reaction was incubated for 5 minutes and then brought to room temperature. After 4.5 hours, TLC confirmed complete reaction. 20 mL of DCM was added, and the organic phase was washed with water (10 mL), dried over anhydrous sodium sulfate, and spin-dried. The product was then passed through a chromatography column with a PE / EA ratio of 1:0 to 1:1. The combined eluates were spin-dried to yield 0.9 g, a yield of 20.34%. MS(ESI,pos.ion)m / z:430.2[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.61(s,1H),8.28(s,1H),7.17(d,J=8.6Hz,2H),6.87(d,J=8.7Hz,2H),6.06(s,1H),5.30(s,2H),4.55–4.39(m,1H),3 .90(q,J=7.3Hz,1H),3.80(s,3H),3.38(s,3H),3.18(s,3H),2.26(dd,J=19.2,9.1Hz,1H),2.15(dd,J=17.8,8.8Hz,1H),1.73–1.62(m,2H).

[0427] Step 2: Synthesis of compound 18-2

[0428] To a 25 mL two-necked flask were added compound 18-1 (0.30 g, 0.70 mmol), 4-2 (0.26 g, 0.70 mmol), BrettPhos-G3-Pd (0.063 g, 0.070 mmol), BrettPhos (0.075 g, 0.14 mmol), cesium carbonate (0.46 g, 1.4 mmol), and 1,4-dioxane (5 mL). The mixture was heated to 80°C under nitrogen atmosphere. After 1.4 h, TLC confirmed complete reaction. The reaction mixture was concentrated, and the residue was dissolved in EA (40 mL) and washed with saturated sodium chloride solution (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, dried by spin-drying, and purified by column chromatography using PE / EA (v / v = 15 / 1-2 / 1) as the eluent. The mixture was collected and dried by spin-drying to afford 0.40 g of a yellow solid (75.32% yield). 1 H NMR (400MHz, DMSO-d6) δ9.21(s,1H),8.72(s,1H),8.33(d,J=7.3Hz,1H),8.28(s,1H),8.18(d,J=9.1Hz,1H),8.1 3(dd,J=8.4,2.0Hz,1H),7.91(d,J=8.4Hz,1H),7.66(d,J=7.0Hz,1H),7.16(d,J=8.5Hz,2H),6.88(d,J=8.5Hz,2 H),6.47(dd,J=13.8,6.6Hz,2H),5.12(s,2H),4.39–4.29(m,1H),3.77–3.68(m,4H),3.21(s,3H),2.99(s,3H),2 .08(dd,J=19.3,8.6Hz,2H),1.52(dd,J=19.0,9.2Hz,1H),1.39(dd,J=19.9,9.9Hz,1H),1.12(d,J=3.8Hz,21H).

[0429] Step 3: Synthesis of compound 18-3

[0430] Compound 18-2 (0.40 g, 0.53 mmol), cesium fluoride (0.16 g, 1.06 mmol), and N,N-dimethylformamide (5 mL) were added to a 25 mL single-necked flask and reacted at room temperature. TLC analysis after 45 min showed complete reaction of the starting material. The reaction was stopped, water (30 mL) was added, and the mixture was extracted with EA (40 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (15 mL × 3). The organic phases were dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / EA (v / v = 1 / 0-5 / 1) as eluent. The collected solid was evaporated to dryness, yielding 0.254 g of an off-white solid, with a yield of 79.92%. 1 H NMR(400MHz, DMSO-d6)δ9.20(s,1H),8.75(d,J=1.6Hz,1H),8.32(d,J=6.2Hz,1H),8.28(s,1H),8.16(dd, J=14.6,5.9Hz,2H),7.92(d,J=8.4Hz,1H),7.67(dd,J=5.8Hz,1H),7.16(d,J=8.5Hz,2H),6.88(d,J=8.6H z,2H),6.46(dd,J=14.0,6.7Hz,2H),5.13(s,2H),4.58(s,1H),4.37–4.29(m,1H),3.73(d,J=8.7Hz,4H), 3.21(s,3H),2.99(s,3H),2.11(dt,J=19.5,8.8Hz,2H),1.52(dd,J=19.4,9.1Hz,1H),1.45–1.36(m,1H).

[0431] Step 4: Synthesis of compound 18

[0432] Compound 18-3 (0.25 g, 0.41 mmol) and dichloromethane (5 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (2.80 g, 24.60 mmol). The reaction was carried out at room temperature. After 1 h, TLC analysis showed that the starting material had reacted completely. DCM (30 mL) was added, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness and subjected to column chromatography with DCM / MeOH (v / v = 1 / 0 - 30 / 1) as the eluent. The collected solution was evaporated to dryness to give 0.16 g of an off-white solid, with a yield of 79.87%. MS (ESI, pos.ion) m / z: 485.1 [M+H] + ; 1H NMR(400MHz, CDCl3)δ8.70(s,1H),8.43–8.34(m,2H),8.09–7.88(m,4H),7.63(d,J=6.1 Hz,1H),6.43(t,J=7.3Hz,1H),6.29(d,J=4.6Hz,1H),5.46(s,1H),4.64–4.51(m,1H),3 .83(dd,J=15.1,7.6Hz,1H),3.37(s,3H),3.31(s,1H),3.09(d,J=5.1Hz,3H),2.32(dd, J=19.1,9.4Hz,1H),2.14(dd,J=18.7,9.1Hz,1H),1.75–1.68(m,1H),1.54–1.46(m,1H).

[0433] Example 19: Synthesis of Compound 19

[0434]

[0435]

[0436] Step 1: Synthesis of Compound 19-1

[0437] Compounds 18-1 (185 mg, 0.43 mmol), 2-2 (0.097 g, 0.43 mmol), BrettPhos-G3-Pd (0.039 g, 0.043 mmol), BrettPhos (0.046 g, 0.086 mmol), and cesium carbonate (0.28 g, 0.86 mmol) were added to a 100 mL double-necked flask under nitrogen protection. 1,4-Dioxane (15 mL) was added, and the reaction was carried out at 80 °C for approximately 3 h. TLC analysis showed that the reaction proceeds were completely reacted. The reaction solution was filtered, the filtrate was concentrated, and purified by PE / EA = 1 / 1 column chromatography to give 113 mg of a blue-black solid, with a yield of 42.44%. MS (ESI, pos.ion) m / z: 618.9 [M+H] + .

[0438] Step 2: Synthesis of Compound 19

[0439] Compound 19-1 (0.11 g, 0.18 mmol) was added to dichloromethane (8 mL), followed by trifluoroacetic acid (1.23 g, 10.8 mmol). The reaction was carried out at room temperature for approximately 2 hours. TLC analysis showed that the starting material had reacted completely. The reaction was then stopped, and the pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The mixture was separated from the stock solution and extracted with dichloromethane (8 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / MeOH = 80 / 1, yielding 20 mg of a blue solid, 21.57% yield). MS (ESI, pos.ion) m / z: 499.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.64–8.51(m,1H),8.45–8.35(m,2H),8.08(dd,J=14.9,7.8Hz,2H),7.9 6–7.80(m,2H),7.66–7.56(m,1H),6.48–6.43(m,1H),6.31(s,1H),5.48(s,1H),4.59(dd,J=1 6.3,8.0Hz,1H),3.85(dd,J=7.2Hz,1H),3.40(s,3H),3.11(d,J=5.1Hz,3H),2.34(dd,J=19.2 ,9.5Hz,1H),2.21–2.15(m,1H),1.98(d,J=5.5Hz,3H),1.80–1.72(m,1H),1.57–1.50(m,1H).

[0440] Example 20: Synthesis of Compound 20

[0441]

[0442]

[0443] Step 1: Synthesis of compound 20-1

[0444] To a 100 mL two-necked flask were added 5-bromo-2-fluoropyridine (2 g, 11.36 mmol), 1-(trimethylsilyl)butyne (2.15 g, 17.04 mmol), copper iodide (0.43 g, 2.27 mmol), bistriphenylphosphine palladium dichloride (1.59 g, 2.27 mmol), and triethylamine (5.57 g, 56.8 mmol). The atmosphere was then replaced with nitrogen, followed by the addition of tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (17.04 mL, 17.04 mmol) was added dropwise at room temperature. After approximately 6 h of reaction at room temperature, TLC confirmed that the reaction was essentially complete. The reaction mixture was filtered, the filtrate concentrated, and purified by PE column chromatography to afford 0.178 g of a yellow liquid in a 46.49% yield.

[0445] Step 2: Synthesis of compound 20-2

[0446] In a 100 mL single-necked flask, 20-1 (0.76 g, 5.10 mmol), 3-amino-2-hydroxypyridine (0.56 g, 5.10 mmol), cesium carbonate (1.66 g, 5.10 mmol), and N,N-dimethylacetamide (15 mL) were added, and the reaction was carried out at 110 °C. After approximately 4.5 h, TLC analysis showed that the starting material had essentially reacted completely. The mixture was extracted with 30 mL of water using dichloromethane (20 mL × 4), and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography purification (PE / EA = 10 / 1-2 / 1) yielded 0.14 g of a yellow solid. The yield was 11.48%.

[0447] Step 3: Synthesis of compound 20-3

[0448] Compounds 1-8 (0.2 g, 0.50 mmol), 20-2 (0.12 g, 0.50 mmol), BrettPhos-G3-Pd (0.045 g, 0.05 mmol), BrettPhos (0.054 g, 0.10 mmol), cesium carbonate (0.33 g, 1.00 mmol), and anhydrous 1,4-dioxane (9 mL) were added to a 50 mL two-necked flask. The mixture was refluxed at 80 °C for approximately 3 h under nitrogen protection. The reaction was observed by TLC. After the reactants had reacted completely, the mixture was filtered. The filter cake was washed with ethyl acetate (50 mL), and the organic phase was washed once with water (8 mL). The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was purified by column chromatography (eluent: DCM / EA (v / v = 20 / 1--3 / 1)) to give 0.12 g of a green solid, with a yield of 39.81%. 1 HNMR(600MHz, CDCl3)δ8.45–8.37(m,4H),8.05(s,3H),7.93–7.82(m,4H),7.61(dd,J=7.2,1.8Hz,2H),7.18–7.14(m,4H), 6.87–6.83(m,4H),6.43(t,J=7.2Hz,2H),4.71(q,J=8.2Hz,2H),4.12(q,J=7.1Hz,1H),3.79(s,6H),1.11(t,J=7.5Hz,2H).

[0449] Step 4: Synthesis of Compound 20

[0450] Compound 20-3 (0.12 g, 0.20 mmol) and dichloromethane (5 mL) were added to a 50 mL single-necked flask. After stirring, trifluoroacetic acid (1.37 g, 12 mmol) was added dropwise. The reaction was allowed to proceed at room temperature. After 2 hours, TLC analysis showed that the reaction proceeded completely. The mixture was cooled to 0 °C, and the pH was adjusted to approximately 8 with a 20% potassium phosphate aqueous solution. The mixture was separated into aqueous and aqueous phases. The aqueous phase was extracted again with dichloromethane (20 mL). The organic phases were combined, concentrated, and subjected to column chromatography (eluent: DCM / CH3OH (v / v = 1 / 0-50 / 1)). The collected solid was evaporated to dryness to give 0.09 g of an off-white solid, with a yield of 93.67%. MS (ESI, pos.ion) m / z: 483.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.48(d,J=7.3Hz,1H),8.38(s,1H),8.10(s,1H),7.93(d ,J=8.3Hz,2H),7.87(d,J=6.3Hz,1H),7.62(d,J=5.9Hz,1H),6.45(t,J=7.2Hz,1H),6.29(d ,J=5.3Hz,1H),5.47(s,1H),4.72(dd,J=16.3,8.4Hz,1H),3.10(d,J=5.2Hz,3H),2.50(dd, J=14.9,7.4Hz,4H),2.09–1.95(m,2H),1.84(dt,J=14.4,4.9Hz,2H),1.31(d,J=7.4Hz,3H).

[0451] Example 21: Synthesis of Compound 21

[0452]

[0453] Step 1: Synthesis of Compound 21-1

[0454] The starting materials 18-1 (0.2 g, 0.52 mmol), 9-2 (0.17 g, 0.50 mmol), BrettPhos-G3-Pd (0.051 g, 0.056 mmol), BrettPhos (0.060 g, 0.11 mmol), and cesium carbonate (0.36 g, 1.12 mmol) were placed in a two-necked flask, the atmosphere was purged with nitrogen, and 1,4-dioxane (7.5 mL) was added. The temperature was raised to 80°C and the reaction mixture reacted for 2.5 h. TLC confirmed complete reaction. The mixture was filtered, and the filter cake was rinsed with EA (50 mL). The organic phase was washed once with water (8 mL), dried over anhydrous sodium sulfate, and spin-dried. The product was then passed through a chromatography column using DCM / EA (v / v = 15 / 1 to 3 / 1) as the eluent to obtain 0.24 g of a yellow solid, in a yield of 66.27%. MS(ESI,pos.ion)m / z:649.2[M+H] + .

[0455] Step 2: Synthesis of Compound 21

[0456] Add 8 mL of DCM to starting material 21-1 (0.24 g, 0.37 mmol), stir, and then add trifluoroacetic acid (3.37 g, 29.6 mmol) dropwise. Stir the reaction at room temperature for 5.5 h. TLC analysis showed the reaction was complete. Add 20 mL of DCM, cool to 0 °C, adjust pH to 8 with 20% potassium phosphate solution, separate the layers, and evaporate the organic phase to dryness. Filter the solution onto a chromatography column; using DCM / MeOH = 1 / 0-25 / 1 as the eluent, give 0.05 g of a pale yellow solid. Yield: 25.57%. MS (ESI, pos.ion) m / z: 529.2 [M+H] + ; 1 HNMR(599MHz,DMSO-d6)δ9.04(s,1H),8.75(s,1H),8.34(d,J=7.0Hz,1H),8.22(s,1H),8.1 2(dd,J=34.8,8.3Hz,2H),7.94(d,J=8.2Hz,2H),7.66(d,J=6.6Hz,1H),6.47(t,J=7.0Hz,1H ),6.23(s,1H),4.41(s,2H),4.38–4.29(m,1H),3.73(dd,J=14.8,7.5Hz,1H),3.44(s,3H),3 .21(s,3H),2.92(d,J=4.3Hz,3H),2.18–2.04(m,2H),1.58–1.50(m,1H),1.43–1.37(m,1H).

[0457] Example 22: Synthesis of Compound 22

[0458]

[0459] Step 1: Synthesis of compound 22-1

[0460] 4-Bromo-2-fluoropyridine (1.5 g, 8.52 mmol), 3-amino-2-hydroxypyridine (0.94 g, 8.52 mmol), cesium carbonate (11.83 g, 36.32 mmol), and N,N-dimethylacetamide (40 mL) were added to a 100 mL single-necked flask and reacted at 95 °C for 6.5 h. The reaction was monitored by TLC. After the reactants had completely reacted, 100 mL of water was added, followed by extraction with ethyl acetate (30 mL × 4). The organic phases were combined, concentrated, and then water (20 mL) was added with stirring. A large amount of solid precipitated. The solid was filtered, washed with water (30 mL), and dried under vacuum at 60 °C to give 2.07 g of a brownish-yellow solid, with a yield of 42.83%. MS (ESI, pos.ion) m / z: 267.9 [M+H] + .

[0461] Step 2: Synthesis of compound 22-2

[0462] Compound 22-1 (1 g, 3.76 mmol), cuprous iodide (0.036 g, 0.19 mmol), and bis(triphenylphosphine)palladium dichloride (0.13 g, 0.19 mmol) were added to a 50 mL double-necked flask. Diisopropylamine (15 mL) was added, and the mixture was kept under nitrogen protection. Triisopropylsilylacetylene (1.03 g, 5.64 mmol) was added, and the reaction was carried out at 100 °C for approximately 1.5 h. TLC analysis showed that the reaction proceeds were completely reacted. The reaction solution was filtered, washed with dichloromethane (20 mL), concentrated, and purified by PE / EA (v / v = 5 / 1) column chromatography to obtain 1.16 g of a brownish-red liquid, with a yield of 83.98%. MS (ESI, pos.ion) m / z: 368.2 [M+H] + .

[0463] Step 3: Synthesis of compound 22-3

[0464] Compounds 18-1 (200 mg, 0.47 mmol), 22-2 (0.17 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94 mmol), BrettPhos-G3-Pd (0.043 g, 0.047 mmol), and BrettPhos (0.050 g, 0.094 mmol) were added to a 50 mL double-necked flask under nitrogen protection. 1,4-Dioxane (15 mL) was added, and the reaction was carried out at 80 °C for approximately 4 h. TLC analysis showed that the reaction proceeds were completely reacted. The reaction solution was filtered, concentrated, and purified by PE / EA (v / v = 2 / 1) column chromatography to give 313 mg of an off-white solid, with a yield of 88.41%.

[0465] Step 4: Synthesis of compound 22-4

[0466] Compound 22-3 (0.39 g, 0.51 mmol) and cesium fluoride (0.15 g, 1.02 mmol) were added to a 100 mL single-necked flask, followed by 8 mL of N,N-dimethylformamide. The mixture was reacted at room temperature for 1 h. TLC analysis showed the reaction was complete. The sample was washed with 30 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phase was dried, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 4 / 1)) to give 308 mg of a yellowish-brown oily liquid, with a yield of 99.39%. MS (ESI, pos.ion) m / z: 605.2 [M+H] + .

[0467] Step 5: Synthesis of compound 22

[0468] In a 100 mL single-necked flask, 22-4 (308 mg, 0.51 mmol), DCM (10 mL), and trifluoroacetic acid (1.74 g, 15.3 mmol) were added. The reaction was carried out at room temperature for 2 h. TLC analysis showed that the starting material had reacted completely. The pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The mixture was separated into aqueous and organic phases. The aqueous phase was extracted with 10 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (elution: DCM / EA (v / v = 4 / 1-3 / 1)) to obtain 134 mg of a blue solid, yielding 54.30%. MS (ESI, pos.ion) m / z: 485.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.61(d,J=5.0Hz,1H),8.43(dd,J=7.3,1.4Hz,1H),8.39(s,1H),8.11(s, 1H),8.05(d,J=7.9Hz,2H),7.60(dd,J=7.1,1.5Hz,1H),7.47–7.43(m,1H),6.45(t,J=7.3Hz,1H ),6.33(q,J=4.7Hz,1H),5.49(s,1H),4.64–4.57(m,1H),3.87–3.82(m,1H),3.41(s,4H),3.10 (d,J=5.2Hz,3H),2.38–2.31(m,1H),2.17(d,J=9.3Hz,1H),1.76(s,1H),1.54(d,J=9.6Hz,1H).

[0469] Example 23: Synthesis of Compound 23

[0470]

[0471] Step 1: Synthesis of Compound 23-1

[0472] In a 100 mL three-necked flask, 5-bromo-2,3-difluoropyridine (3 g, 15.47 mmol), 1-(trimethylsilyl)propyne (2.60 g, 23.21 mmol), cuprous iodide (0.59 g, 3.09 mmol), palladium dichloride bis(triphenylphosphine) (2.17 g, 3.09 mmol), and triethylamine (7.83 g, 77.35 mmol) were added, followed by the addition of tetrahydrofuran (15 mL). Under nitrogen protection, tetrabutylammonium fluoride (23.2 mL, 23.21 mmol) was added dropwise at room temperature. After 3 h, TLC analysis showed that the reaction proceeds were complete. The reaction solution was filtered, concentrated, and purified by petroleum ether column chromatography to give 767 mg of a yellow liquid, with a yield of 89.52%. MS (ESI, pos.ion) m / z: 154.1 [M+H] + .

[0473] Step 2: Synthesis of compound 23-2

[0474] Compound 23-1 (750 mg, 4.90 mmol), 3-amino-2-hydroxypyridine (0.65 g, 5.88 mmol), and cesium carbonate (3.99 g, 12.25 mmol) were added to a 50 mL single-necked flask, followed by N,N-dimethylformamide (10 mL). The reaction was carried out at 95 °C. After 4 h, TLC analysis showed that the reaction mixture was essentially complete. The reaction solution was filtered, washed with water (40 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: PE / EA (v / v = 2 / 1)) to give 273 mg of green liquid, with a yield of 22.92%. MS (ESI, pos.ion) m / z: 244.1 [M+H] + .

[0475] Step 3: Synthesis of compound 23-3

[0476] Compounds 18-1 (100 mg, 0.23 mmol), 23-2 (56 mg, 0.23 mmol), BrettPhos-G3-Pd (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.046 mmol), and cesium carbonate (150 mg, 0.46 mmol) were added to a 50 mL double-necked flask. Under nitrogen protection, 1,4-dioxane (5 mL) was added, and the reaction was carried out at 80 °C for about 3 h. TLC analysis showed that the reaction proceeds were completely reacted. The reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (elution: DCM / EA (v / v = 10 / 1)) to give 117 mg of green solid, yield 79.00%. MS (ESI, pos.ion) m / z: 637.2 [M+H] + .

[0477] Step 4: Synthesis of compound 23

[0478] Compound 23-3 (176 mg, 0.28 mmol) was added to dichloromethane (8 mL), followed by trifluoroacetic acid (0.96 g, 8.4 mmol). The reaction was carried out at room temperature for approximately 7 hours. TLC analysis showed that the reactants had reacted completely. The reaction was then stopped, and the pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The mixture was separated from the stock solution. The extract was then drawn with 8 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH (v / v = 80 / 1-70 / 1)) to give 68 mg of a blue solid, yielding 43.20%. MS (ESI, pos.ion) m / z: 517.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.45(d,J=5.9Hz,2H),8.40(s,1H),8.04(d,J=6.3Hz,2H),7.64(dd, J=9.6,1.4Hz,1H),7.20(dd,J=6.9,1.4Hz,1H),6.45(t,J=7.2Hz,1H),6.32(dt,J=7.3,4.0 Hz,1H),5.48(s,1H),4.64–4.56(m,1H),3.85(q,J=7.6Hz,1H),3.40(s,3H),3.10(d,J=5.2 Hz,3H),2.34(d,J=9.5Hz,1H),2.15(s,4H),1.78(d,J=10.9Hz,1H),1.54(d,J=9.6Hz,1H).

[0479] Example 24: Synthesis of Compound 24

[0480]

[0481]

[0482] Step 1: Synthesis of Compound 24-1

[0483] The starting materials 2-bromo-5-iodopyrazine (0.30 g, 1.05 mmol), 3-amino-2-hydroxypyridine (0.12 g, 1.05 mmol), cesium carbonate (0.68 g, 2.1 mmol), and N,N-dimethylacetamide (5 mL) were added to a 25 mL single-necked flask and the mixture was heated to 100 °C. After 2 h, TLC analysis showed that the reaction was complete. 25 mL of water was added, and the mixture was extracted with EA (25 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 3), and the organic phase was evaporated to dryness. Column chromatography (eluent: PE / EA (v / v = 2 / 1)) was performed to give 0.13 g of a yellow solid. Yield: 46.22%. MS (ESI, pos.ion) m / z: 267.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ9.21(dd,J=7.4,1.2Hz,1H),8.67(dt,J=36.6,18.3Hz,1H),7.30–7.27(m,1H),6.60–6.55(m,1H),6.25(td,J=7.2,2.1Hz,1H).

[0484] Step 2: Synthesis of compound 24-2

[0485] Starting material 24-1 (0.22 g, 0.82 mmol), triisopropylsilylacetylene (0.15 g, 0.82 mmol), cuprous iodide (8 mg, 0.041 mmol), and bis(triphenylphosphine)palladium dichloride (29 mg, 0.041 mmol) were added to a 10 mL double-necked flask, purged with nitrogen, and then diisopropylamine (5 mL) was added. The mixture was heated to 100 °C and reacted. After 1.3 h, TLC analysis showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the residue was dissolved in EA (30 mL). The solution was then washed with saturated ammonium chloride solution (8 mL × 2). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using PE / EA (v / v = 5 / 1) as the eluent to give 0.25 g of a yellow solid, with a yield of 82.35%. MS (ESI, pos.ion) m / z: 369.2 [M+H] + ; 1 H NMR(400MHz, CDCl3) δ9.35(d,J=1.1Hz,1H),8.62(d,J=1.1Hz,1H),7.32(dd,J=7.2, 1.4Hz, 1H), 6.59 (dd, J=7.1, 1.4Hz, 1H), 6.26 (t, J=7.1Hz, 1H), 1.21–1.15 (m, 21H).

[0486] Step 3: Synthesis of compound 24-3

[0487] Starting materials 18-1 (0.27 g, 0.63 mmol), 24-2 (0.23 g, 0.63 mmol), BrettPhos-G3-Pd (0.057 g, 0.063 mmol), BrettPhos (0.068 g, 0.13 mmol), and cesium carbonate (0.41 g, 1.26 mmol) were added to a 10 mL double-necked flask, purged with nitrogen, and 1,4-dioxane (5 mL) was added. The mixture was heated to 80 °C and reacted. After 7 h, the reaction was completed by TLC, and the mixture was cooled to room temperature. The mixture was filtered, the filter cake was washed with EA (5 mL), evaporated to dryness, and then EA (5 mL) was added again. The mixture was stirred at room temperature for 30 min, filtered again, and the filter cake was evaporated to dryness to obtain 0.36 g of a yellow solid. The yield was 75.22%. 1 H NMR (400MHz, CDCl3) δ9.35(d,J=1.3Hz,1H),8.65(d,J=1.3Hz,1H),8.44(s,1H),8.38(dd,J=7.3,1.5Hz,1H),8.13(d ,J=8.8Hz,1H),7.99(s,1H),7.61(dd,J=7.2,1.5Hz,1H),7.16(d,J=8.6Hz,2H),6.85(d,J=8.6Hz,2H),6.47(t,J=7. 3Hz,1H),5.53(s,1H),5.15(s,2H),4.65–4.52(m,1H),3.87–3.81(m,1H),3.79(s,3H),3.38(s,3H),3.06(s,3H),2. 32(dd,J=19.4,9.7Hz,1H),2.15(dd,J=18.4,9.1Hz,1H),1.79–1.66(m,1H),1.56–1.43(m,1H),1.28–1.13(m,21H).

[0488] Step 4: Synthesis of compound 24-4

[0489] Compound 24-3 (0.36 g, 0.47 mmol), cesium fluoride (0.14 g, 0.94 mmol), and DMF (5 mL) were added to a reaction flask and reacted at room temperature. After 1.5 h, TLC analysis showed complete reaction of the starting material. The reaction was stopped, water (20 mL) was added, and the mixture was extracted with EA (30 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / MeOH (v / v = 1 / 0 - 30 / 1) as eluent to give 173 mg of a yellow solid, yield 60.46%. MS (ESI, pos.ion) m / z = 606.3 [M + H] + ; 1H NMR (400MHz, CDCl3) δ9.40(d,J=1.2Hz,1H),8.69(d,J=1.1Hz,1H),8.44(s,1H),8.38(dd,J=7.3,1.3Hz,1H),8.12(d,J= 8.7Hz,1H),7.98(s,1H),7.63(dd,J=7.2,1.4Hz,1H),7.16(d,J=8.6Hz,2H),6.85(d,J=8.6Hz,2H),6.48(t,J=7.3Hz,1H) ,5.54(s,1H),5.15(s,2H),4.64–4.53(m,1H),3.86–3.81(m,1H),3.79(s,3H),3.43(s,1H),3.38(s,3H),3.06(s,3H),2 .32(dd,J=19.0,9.4Hz,1H), 2.14(dd,J=18.3,9.1Hz,1H), 1.74(dd,J=19.7,10.6Hz,1H), 1.51(dd,J=19.7,10.2Hz,1H).

[0490] Step 5: Synthesis of Compound 24

[0491] Compound 24-4 (0.17 g, 0.28 mmol) and DCM (3 mL) were added to a reaction flask and stirred until dissolved. Trifluoroacetic acid (1.92 g, 16.8 mmol) was then added, and the reaction was carried out at room temperature. TLC analysis after 1.5 h showed that the starting material had completely reacted. DCM (30 mL) was added, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / MeOH (v / v = 30 / 1) as the eluent, yielding 80 mg of a yellow solid (58.70%). MS (ESI, pos.ion) m / z: 486.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ9.42(d,J=1.1Hz,1H),8.69(d,J=1.0Hz,1H),8.42(d,J=6.1Hz,1H),8.37(s,1H),8 .03(s,1H),7.96(d,J=8.6Hz,1H),7.63(d,J=5.9Hz,1H),6.48(t,J=7.3Hz,1H),6.31(d,J=5.2Hz,1H),5 .48(s,1H),4.65–4.50(m,1H),3.83(dd,J=15.1,7.7Hz,1H),3.43(s,1H),3.38(s,3H),3.09(d,J=5.2Hz ,3H),2.32(dd,J=19.3,9.6Hz,1H),2.14(dd,J=18.7,9.0Hz,1H),1.79–1.66(m,1H),1.54–1.45(m,1H).

[0492] Example 25: Synthesis of Compound 25

[0493]

[0494] Step 1: Synthesis of compound 25-1

[0495] Add trimethylsilylpropargyl alcohol (3 g, 23.39 mmol) and DCM (30 mL) to a 100 mL single-necked flask, cool to 0°C, add triethylamine (7.10 g, 70.17 mmol), and slowly add methylsulfonyl chloride (8.04 g, 70.17 mmol) dropwise. Stir for 20 minutes after completion of the addition, then warm to room temperature for reaction. After 11.5 hours, TLC analysis indicated that the starting material had essentially reacted. Stop the reaction, filter, and wash the filtrate once with water (10 mL), then spin dry. The yield is calculated based on the theoretical yield.

[0496] Step 2: Synthesis of compound 25-2

[0497] 3-Amino-2-hydroxypyridine (0.27 g, 2.42 mmol), DME (5 mL), and potassium tert-butoxide (0.27 g, 2.42 mmol) were added to a reaction flask and stirred at room temperature for 20 min. Then, a DME (3 mL) dilution solution of compound 25-1 (0.50 g, 2.42 mmol) and potassium carbonate (0.23 g, 1.69 mmol) were added, and the mixture was heated to 80 °C. After 2 h, TLC analysis showed that the starting material had reacted completely. The reaction solution was concentrated, dissolved in EA (30 mL), washed with water (10 mL × 3), dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / EA (v / v = 5 / 1) as the eluent to give 54 mg of a yellow solid, yield 15.04%. MS (ESI, pos.ion) m / z: 149.1 [M+H] + .

[0498] Step 3: Synthesis of Compound 25-3

[0499] Compounds 18-1 (0.30 g, 0.70 mmol), 25-2 (0.10 g, 0.70 mmol), BrettPhos-G3-Pd (0.063 g, 0.070 mmol), BrettPhos (0.075 g, 0.14 mmol), and cesium carbonate (0.46 g, 1.4 mmol) were added to a reaction flask under nitrogen protection. Then, 1,4-dioxane (5 mL) was added, and the mixture was heated to 80 °C. The reaction proceeds were completely reacted after 2 hours. The reaction solution was concentrated, and the residue was extracted with DCM (20 mL) and water (10 mL). The organic phase was evaporated to dryness and subjected to column chromatography using DCM / MeOH (v / v = 30 / 1) as the eluent. The collected sample was evaporated to dryness to give 175 mg of an off-white solid, yield 46.30%. MS (ESI, pos.ion) m / z: 542.0 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.45(s,1H),8.34(d,J=6.1Hz,1H),8.15(d,J=8.8Hz,1H),7.98(s,1H),7.34(d,J= 5.7Hz,1H),7.18(d,J=8.5Hz,2H),6.87(d,J=8.6Hz,2H),6.38(t,J=7.2Hz,1H),5.53(s,1H),5.15(s,2H) ,4.89(d,J=2.5Hz,2H),4.66–4.55(m,1H),3.88–3.80(m,4H),3.39(s,3H),3.07(s,3H),2.54(t,J=2.5H z,1H),2.33(dd,J=19.4,9.6Hz,1H),2.16(dd,J=18.5,9.1Hz,1H),1.80–1.69(m,1H),1.56–1.46(m,1H).

[0500] Step 4: Synthesis of compound 25

[0501] Compound 25-3 (0.17 g, 0.31 mmol), DCM (4 mL), and trifluoroacetic acid (2.12 g, 18.6 mmol) were added to a reaction flask, and the reaction was carried out at room temperature. After 2 hours, TLC analysis showed that the starting material had reacted completely. The reaction was stopped, and the mixture was diluted with DCM (30 mL). The temperature was lowered to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM / MeOH (v / v = 30 / 1) as the eluent. 113 mg of a white solid was obtained, with a yield of 85.42%. MS (ESI, pos.ion) m / z: 422.1 [M+H] + ; 1 H NMR(400MHz, CDCl3) δ8.35(d,J=4.8Hz,2H),8.04–7.94(m,2H),7.31(d,J=6.9Hz,1H),6. 35(t,J=7.2Hz,1H),6.28(dd,J=9.8,4.7Hz,1H),5.44(s,1H),4.87(d,J=2.3Hz,2H),4.6 2–4.51(m,1H),3.81(dd,J=15.4,7.8Hz,1H),3.36(s,3H),3.08(d,J=5.2Hz,3H),2.51(s ,1H),2.30(dd,J=19.1,9.6Hz,1H),2.12(dd,1H),1.77–1.65(m,1H),1.54–1.42(m,1H).

[0502] Example 26: Synthesis of Compound 26

[0503]

[0504]

[0505] Step 1: Synthesis of Compound 26-1

[0506] 3-Bromo-2-fluoropyridine (1.92 g, 10.90 mmol), 3-amino-2-hydroxypyridine (1 g, 9.08 mmol), cesium carbonate (5.92 g, 18.16 mmol), and N,N-dimethylacetamide (15 mL) were added to a 100 mL single-necked flask. The mixture was reacted overnight at 95 °C. TLC analysis showed that the reactants had reacted completely. The reaction was stopped, and the mixture was washed with water (80 mL). Extraction was performed with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by DCM / EA = 3 / 1 column chromatography to give 1.24 g of a green solid, yield 51.31%. MS (ESI, pos.ion) m / z: 265.9 [M+H] + .

[0507] Step 2: Synthesis of compound 26-2

[0508] Compound 26-1 (0.6 g, 2.25 mmol), cuprous iodide (0.021 g, 0.11 mmol), and bis(triphenylphosphine)palladium dichloride (0.079 g, 0.11 mmol) were added to a 50 mL double-necked flask, followed by diisopropylamine (8 mL). Under nitrogen protection, triisopropylsilylacetylene (0.62 g, 3.38 mmol) was added, and the reaction was carried out at 100 °C for approximately 1 h. TLC analysis showed complete reaction of the starting material. The reaction solution was filtered, washed with dichloromethane (10 mL), concentrated, and purified by DCM column chromatography to obtain 530 mg of a brownish-red oily liquid, with a yield of 63.95%. MS (ESI, pos.ion) m / z: 368.3 [M+H] + Step 3: Synthesis of compound 26-3

[0509] In a 50 mL double-necked flask, 18-1 (0.22 g, 0.51 mmol), 26-3 (0.17 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94 mmol), BrettPhos-G3-Pd (0.043 g, 0.047 mmol), and BrettPhos (0.050 g, 0.094 mmol) were added. Under nitrogen protection, 1,4-dioxane (10 mL) was added, and the reaction was carried out at 80 °C for about 2 h. The reaction mixture was detected by TLC, and the starting material was found to be completely reacted. The reaction solution was filtered, concentrated, and purified by column chromatography (elution buffer: DCM / EA (v / v = 8 / 1)) to give 275 mg of yellow solid, with a yield of 70.61%.

[0510] Step 4: Synthesis of compound 26-4

[0511] 26-3 (275 mg, 0.36 mmol), cesium fluoride (0.11 g, 0.72 mmol), and N,N-dimethylformamide (8 mL) were added to a 100 mL single-necked flask. The mixture was reacted at room temperature for 2.5 h. TLC analysis showed the reactants were completely reacted. The mixture was washed with 40 mL of water and extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: PE / EA (v / v) = 1 / 1) to give 168 mg of a yellow oily liquid, with a yield of 76.89%. MS (ESI, pos.ion) m / z: 605.1 [M+H] + .

[0512] Step 5: Synthesis of Compound 26

[0513] In a 100 mL single-necked flask, 26-4 (168 mg, 0.28 mmol), DCM (8 mL), and trifluoroacetic acid (0.96 g, 8.4 mmol) were added. The reaction was carried out at room temperature for about 5 h. TLC analysis showed that the starting material had reacted completely. The pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted separately with dichloromethane (8 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: DCM / MeOH (v / v = 100 / 1)) to give 54 mg of a blue solid, with a yield of 39.79%. MS (ESI, pos.ion) m / z: 485.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.63(d,J=6.1Hz,1H),8.44(d,J=7.3Hz,1H),8.37(s,1H),8.08(s,1H),8.06– 8.00(m,2H),7.47(dd,J=7.7,4.9Hz,1H),7.13–7.06(m,1H),6.40(t,J=7.2Hz,1H),6.32(d,J=5.1H z,1H),5.45(s,1H),4.58(p,J=8.8Hz,1H),3.84(q,J=7.7Hz,1H),3.38(s,3H),3.30(s,1H),3.06(d ,J=5.1Hz,3H),2.32(q,J=9.2Hz,1H),2.20–2.09(m,1H),1.68(d,J=10.4Hz,1H),1.57–1.47(m,1H).

[0514] Example 27: Synthesis of Compound 27

[0515]

[0516] Step 1: Synthesis of Compound 27-1

[0517] 2-Bromo-6-fluoropyridine (1.76 g, 9.99 mmol), 3-amino-2-hydroxypyridine (1 g, 9.08 mmol), cesium carbonate (5.92 g, 18.16 mmol), and N,N-dimethylacetamide (20 mL) were added to a 100 mL single-necked flask. The mixture was reacted at 95 °C for approximately 2.5 h. TLC analysis showed that the reactants were completely reacted. The mixture was washed with water (80 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was concentrated and purified by DCM / EA = 10 / 1 column chromatography to give 2.21 g of a yellow solid, yield 91.95%. MS (ESI, pos.ion) m / z: 266.0 [M+H] + .

[0518] Step 2: Synthesis of compound 27-2

[0519] Compound 27-1 (0.6 g, 2.25 mmol), cuprous iodide (0.021 g, 0.11 mmol), and bis(triphenylphosphine)palladium dichloride (0.079 g, 0.11 mmol) were added to a 50 mL double-necked flask. Diisopropylamine (8 mL) was added, and the mixture was kept under nitrogen protection. Triisopropylsilylacetylene (0.62 g, 3.38 mmol) was added, and the mixture was reacted at 100 °C for approximately 1 h. TLC analysis showed that the reactants had reacted completely. The reaction was stopped, the reaction solution was filtered, washed with dichloromethane (10 mL), concentrated, and purified by DCM column chromatography to obtain 493 mg of a brownish-red liquid, with a yield of 59.48%. MS (ESI, pos.ion) m / z: 368.0 [M+H] + Step 3: Synthesis of compound 27-3

[0520] In a 50 mL double-necked flask, 18-1 (0.2 g, 0.47 mmol), 27-2 (0.17 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94 mmol), BrettPhos-G3-Pd (0.043 g, 0.047 mmol), and BrettPhos (0.050 g, 0.094 mmol) were added. Under nitrogen protection, 1,4-dioxane (10 mL) was added, and the reaction was carried out at 80 °C for approximately 3.5 h. TLC analysis showed that the reactants had reacted completely, and the reaction was stopped. The reaction solution was filtered, concentrated, and purified by column chromatography (elution: PE / EA (v / v = 1 / 1)) to give 235 mg of a yellow solid, with a yield of 66.38%.

[0521] Step 4: Synthesis of compound 27-4

[0522] Compound 27-3 (235 mg, 0.31 mmol), cesium fluoride (0.094 g, 0.62 mmol), and N,N-dimethylformamide (8 mL) were added to a 100 mL single-necked flask. The mixture was reacted at room temperature for 3 h. TLC analysis showed that the reaction proceeded completely. The mixture was washed with water (30 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 3 / 1) to give 175 mg of white solid, yield 93.72%. MS (ESI, pos.ion) m / z: 605.8 [M+H] + .

[0523] Step 5: Synthesis of Compound 27

[0524] In a 100 mL single-necked flask, 27-4 (175 mg, 0.29 mmol) and DCM (8 mL) were added, followed by trifluoroacetic acid (0.99 g, 8.7 mmol). The reaction was carried out at room temperature for approximately 2 hours. TLC analysis showed that the starting material had reacted completely. The reaction was then stopped, and the pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The mixture was separated from the aqueous phase, and the organic phase was extracted with 8 mL of dichloromethane. The organic phase was dried and purified by column chromatography (elution: DCM / MeOH (v / v = 80 / 1)) to obtain 102 mg of a white solid, with a yield of 69.26%. MS (ESI, pos.ion) m / z: 485.0 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ8.39(dd,J=7.3,1.4Hz,1H),8.36(s,1H),8.07–7.99(m,2H),7.96(d,J=8.0Hz,1H) ,7.88(t,J=7.8Hz,1H),7.61(dd,J=7.1,1.4Hz,1H),7.56(d,J=7.4Hz,1H),6.41(t,J=7.3Hz,1H),6.31(q, J=4.6,4.1Hz,1H),5.45(s,1H),4.58(p,J=8.7Hz,1H),3.82(q,J=7.7Hz,1H),3.37(s,3H),3.25(s,1H),3 .07(d,J=5.2Hz,3H),2.31(q,J=9.5Hz,1H),2.18–2.11(m,1H),1.75(d,J=10.8Hz,1H),1.54–1.45(m,1H).

[0525] Example 28: Synthesis of Compound 28

[0526]

[0527] Step 1: Synthesis of Compound 28-1

[0528] In a 50 mL double-necked flask, 27-1 (0.5 g, 1.88 mmol), cuprous iodide (0.072 g, 0.38 mmol), palladium dichloride bis(triphenylphosphine) (0.26 g, 0.38 mmol), and 1-(trimethylsilyl)propyne (0.32 g, 2.82 mmol) were added, followed by triethylamine (0.95 g, 9.40 mmol). Under nitrogen protection, anhydrous THF (8 mL) was added, and tetrabutylammonium fluoride (2.8 mL, 2.82 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for approximately 3 h. TLC analysis showed complete reaction of the starting material. The reaction solution was filtered, concentrated, and purified by column chromatography (elution: DCM / EA (v / v = 4 / 1)) to obtain 412 mg of a brownish-yellow solid, with a yield of 97.34%. MS (ESI, pos.ion) m / z: 226.1.0 [M+H] + .

[0529] Step 2: Synthesis of compound 28-2

[0530] Compounds 18-1 (250 mg, 0.58 mmol), 28-1 (0.28 g, 1.28 mmol), cesium carbonate (0.38 g, 1.16 mmol), BrettPhos-G3-Pd (0.053 g, 0.058 mmol), and BrettPhos (0.062 g, 0.12 mmol) were added to a 50 mL double-necked flask under nitrogen protection. 1,4-Dioxane (10 mL) was added, and the reaction was carried out at 80 °C for approximately 15 h. TLC analysis indicated complete reaction of the starting material. The reaction solution was filtered, concentrated, and purified by column chromatography (PE / EA (v / v = 1 / 1)) to give 170 mg of a green solid, yielding 47.25%. MS (ESI, pos.ion) m / z: 619.3 [M+H] + .

[0531] Step 3: Synthesis of Compound 28

[0532] Compound 28-2 (170 mg, 0.27 mmol), DCM (8 mL), and trifluoroacetic acid (0.92 g, 8.10 mmol) were added to a 50 mL single-necked flask. The reaction was allowed to proceed at room temperature for approximately 3.5 h. TLC analysis showed that the starting material was completely reacted. The pH was adjusted to approximately 7 with saturated sodium bicarbonate solution, and the mixture was separated. The extract was further extracted with dichloromethane (8 mL), the organic phase was dried, concentrated, and purified by column chromatography (elution: DCM / MeOH (v / v = 80 / 1-60 / 1)) to give 107 mg of a yellow solid, with a yield of 73.44%. MS (ESI, pos.ion) m / z: 499.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ8.44–8.35(m,2H),8.06(d,J=9.2Hz,2H),7.87–7.80(m,2H), 7.61–7.56(m,1H),7.49–7.43(m,1H),6.42(t,J=7.3Hz,1H),6.32(q,J=4.9Hz,1H), 5.48(s,1H),4.63–4.56(m,1H),3.87–3.80(m,1H),3.40(s,3H),3.10(d,J=5.2Hz,3 H),2.37–2.30(m,1H),2.21–2.12(m,4H),1.74(d,J=9.2Hz,1H),1.54–1.48(m,1H).

[0533] Example 29: Synthesis of Compound 29

[0534]

[0535] Step 1: Synthesis of Compound 29-1

[0536] In a 100 mL three-necked flask, 3,6-dibromopyridazine (1.5 g, 6.31 mmol), 3-amino-2-hydroxypyridine (0.76 g, 6.94 mmol), cuprous iodide (0.24 g, 1.26 mmol), and potassium carbonate (0.87 g, 6.31 mmol) were added under nitrogen protection. Then, 1,4-dioxane (15 mL) and N,N'-dimethylethylenediamine (0.22 g, 2.52 mmol) were added. The mixture was reacted overnight at 110 °C. TLC analysis was performed. After the reactants had reacted completely, the reaction mixture was filtered, concentrated, and purified by PE / EA = 2 / 1-1 / 1 column chromatography to give 95 mg of a blue solid, yield 5.64%. MS (ESI, pos.ion) m / z: 266.95 [M+H] + .

[0537] Step 2: Synthesis of compound 29-2

[0538] Compound 29-1 (90 mg, 0.34 mmol), triisopropylsilylacetylene (93 mg, 0.51 mmol), cuprous iodide (3 mg, 0.017 mmol), and bis(triphenylphosphine)palladium dichloride (12 mg, 0.017 mmol) were added to a 50 mL double-necked flask. Under nitrogen protection, diisopropylamine (5 mL) was added, and the mixture was reacted at 100 °C for 1.5 h. TLC analysis showed that the reaction proceeds were complete. The reaction solution was filtered, concentrated, and purified by column chromatography (PE / EA (v / v = 5 / 1)) to obtain 97 mg of a yellow oily liquid, with a yield of 78.10%. MS (ESI, pos.ion) m / z: 369.1 [M+H] + .

[0539] Step 3: Synthesis of Compound 29-3

[0540] Compound 18-1 (0.11 g, 0.26 mmol), cesium carbonate (0.17 g, 0.52 mmol), BrettPhos-G3-Pd (0.024 g, 0.026 mmol), and BrettPhos (0.028 g, 0.052 mmol) were added to a 50 mL double-necked flask under nitrogen protection. Compound 29-2 (0.096 g, 0.26 mmol) was dissolved in 1,4-dioxane (8 mL) and added to the flask. The reaction was carried out at 80 °C for 1 h. The reaction proceeds were detected by TLC. The reaction mixture was filtered, and the filter cake was washed with 8 mL of dichloromethane. The solution was concentrated and purified by column chromatography (elution: PE / EA (v / v = 2 / 1-1 / 1)) to give 94 mg of yellow solid, with a yield of 48.21%. 1 H NMR (400MHz, CDCl3) δ8.47(s,1H),8.43(dd,J=7.4,1.4Hz,1H),8.23(d,J=9.0Hz,1H),8.14(d,J=8.7Hz,1H),7.95(s,1H ),7.81(dd,J=7.2,1.7Hz,1H),7.76(d,J=9.0Hz,1H),7.18(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),6.52(t,J=7.3Hz,1H) ,5.54(s,1H),5.17(s,2H),4.62(p,J=8.9Hz,1H),3.89–3.83(m,1H),3.81(s,3H),3.41(s,3H),3.08(s,3H),2.38–2.31( m,1H),2.18(q,J=8.8Hz,1H),1.80–1.72(m,1H),1.58–1.48(m,1H),1.27(dd,J=8.8,4.3Hz,3H),1.19(d,J=5.1Hz,18H).

[0541] Step 4: Synthesis of compound 29-4

[0542] Compound 29-3 (137 mg, 0.18 mmol), cesium fluoride (0.055 g, 0.36 mmol), and DMF (5 mL) were added to a 50 mL single-necked flask. The mixture was reacted at room temperature for about 3 h. TLC analysis showed that the starting material had reacted completely. The reaction was then stopped, and the mixture was washed with water (20 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 100 mg of a yellow liquid, with a yield of 91.83%.

[0543] Step 5: Synthesis of Compound 29

[0544] Compound 29-4 (100 mg, 0.17 mmol), DCM (8 mL), and trifluoroacetic acid (0.58 g, 5.10 mmol) were added to a 50 mL single-necked flask. The reaction was carried out at room temperature for 1.5 h. TLC analysis showed that the reaction proceeded completely. The pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The mixture was separated into aqueous and organic phases. The aqueous phase was extracted with dichloromethane (8 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: DCM / MeOH (v / v = 80 / 1)) to give 43 mg of an off-white solid, yielding 50.88%. MS (ESI, pos.ion) m / z: 486.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.91(d,J=5.7Hz,1H),8.42(dd,J=7.4,1.7Hz,1H),8.40(s,1H),8.32(d,J =5.6Hz,1H),8.03–7.96(m,2H),7.94(dd,J=7.3,1.7Hz,1H),6.49(d,J=7.3Hz,1H),6.35(d,J=5 .4Hz,1H),5.50(s,1H),4.62–4.57(m,1H),3.84(d,J=7.6Hz,1H),3.39(s,3H),3.25(s,1H),3.1 2(d,J=5.2Hz,3H),2.34(d,J=9.5Hz,1H),2.17(d,J=9.4Hz,1H),1.75(s,1H),1.55–1.51(m,1H).

[0545] Example 30: Synthesis of Compound 30

[0546]

[0547]

[0548] Step 1: Synthesis of Compound 30-1

[0549] Add 2,4-dibromothiazol (0.5 g, 2.06 mmol), 3-amino-2-hydroxypyridine (0.23 g, 2.06 mmol), cuprous iodide (0.078 g, 0.41 mmol), and potassium carbonate (0.85 g, 6.18 mmol) to a 10 mL reaction flask, purge with nitrogen, then add a mixture of N,N'-dimethylethylenediamine (0.073 g, 0.82 mmol) and 1,4-dioxane (5 mL), and heat to 75 °C. After 4 h, TLC analysis showed a small amount of starting material remaining. Dissolve in EA (30 mL), wash with 10 mL of water, separate, and evaporate the organic phase to dryness. Purify by column chromatography using PE / EA (v / v = 1 / 0-5 / 1) as eluent to give 80 mg of white solid. Yield: 14.28%. MS (ESI, pos.ion) m / z: 272 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.19 (d, J = 7.3Hz, 1H), 7.16 (s, 1H), 6.59 (d, J = 7.1Hz, 1H), 6.33 (t, J = 7.2Hz, 1H).

[0550] Step 2: Synthesis of compound 30-2

[0551] The starting material 30-1 (65 mg, 0.24 mmol), palladium dichloride bis(triphenylphosphine) (0.017 g, 0.024 mmol), and cuprous iodide (5 mg, 0.024 mmol) were added to a 10 mL double-necked flask, purged with nitrogen, and then diisopropylamine (3 mL) was added. The temperature was raised to 50 °C. Triisopropylsilylacetylene (0.044 g, 0.24 mmol) was dissolved in 1.5 mL of diisopropylamine and slowly added dropwise to the reaction solution. After 1 h, TLC analysis showed that the starting material had largely reacted. The reaction solution was concentrated, dissolved in DCM (30 mL), washed with ammonium chloride solution (10 mL), dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (PE / EA, v / v = 20 / 1-3 / 1) to give 75 mg of a yellow solid, yield 84.05%. MS (ESI, pos.ion) m / z: 374.2 [M+H] + Step 3: Synthesis of compound 30-3

[0552] Compound 18-1 (0.130 g, 0.30 mmol), BrettPhos-G3-Pd (0.027 g, 0.030 mmol), BrettPhos (0.032 g, 0.060 mmol), and cesium carbonate (0.20 g, 0.60 mmol) were added to a 10 mL double-necked flask, and the mixture was purged with nitrogen. Compound 30-2 (0.11 g, 0.30 mmol) was dissolved in 1,4-dioxane (4 mL) and added to the reaction flask. The mixture was heated to 80 °C and reacted. After 1.3 h, TLC analysis showed that the reaction proceeded completely. The reaction solution was directly concentrated and purified by column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent. The solution was collected and evaporated to dryness to give 170 mg of a yellow solid, with a yield of 73.29%. 1 H NMR (400MHz, CDCl3) δ8.61(d,J=7.3Hz,1H),8.47(s,1H),8.40(d,J=6.1Hz,1H),8.12(d,J=8.6Hz,1H),7.9 4(s,1H),7.49(s,1H),7.19(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),6.56(t,J=7.4Hz,1H),5.54(s,1H),5. 17(s,2H),4.66–4.55(m,1H),3.85(t,J=7.6Hz,1H),3.81(s,3H),3.40(s,3H),3.10(s,3H),2.34(dd,J=19 .1,9.9Hz,1H),2.17(dd,J=18.1,8.6Hz,1H),1.78–1.72(m,1H),1.54–1.48(m,1H),1.18(d,J=3.0Hz,21H).

[0553] Step 4: Synthesis of compound 30-4

[0554] Compound 30-3 (165 mg, 0.22 mmol), DMF (4 mL), and cesium fluoride (0.067 g, 0.44 mmol) were added to a 10 mL single-necked flask and reacted at room temperature. After 2 h, the starting material was completely reacted by TLC. 16 mL of water was added, and the mixture was extracted with EA (30 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (8 mL × 4). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (DCM:EA = 1:0-3:1) as the eluent to give 110 mg, with a yield of 83.73%. MS (ESI, pos.ion) m / z: 611.0 [M+H] + .

[0555] Step 5: Synthesis of Compound 30

[0556] Compound 30-4 (0.11 g, 0.18 mmol), DCM (3 mL), and trifluoroacetic acid (1.23 g, 10.80 mmol) were added to a 10 mL single-necked flask and reacted at room temperature. After 1.3 h, TLC analysis showed the starting material had reacted completely. DCM (30 mL) was added, the mixture was cooled to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Column chromatography was performed using DCM / MeOH (v / v = 1 / 0-25 / 1) as the eluent. The collected sample was evaporated to dryness, yielding 75 mg of an off-white solid. MS (ESI, pos.ion) m / z: 491.0 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ9.33(s,1H),8.47(dd,J=7.3,1.2Hz,1H),8.36(dd,J=7.3,1.1Hz, 1H),8.22(s,1H),8.06–7.96(m,3H),6.67(t,J=7.3Hz,1H),6.23(s,1H),4.37(s,1H),4.30 (dt,J=17.3,8.7Hz,1H),3.66(dd,J=15.0,7.6Hz,1H),3.19(s,3H),2.93(d,J=4.8Hz,3H) ,2.08(td,J=19.3,9.0Hz,2H), 1.50(dd,J=19.4,9.2Hz,1H), 1.35(dd,J=19.6,9.7Hz,1H).

[0557] Example 31: Synthesis of Compound 31

[0558]

[0559] Step 1: Synthesis of compound 31-1

[0560] THF (3.2 mL) and 1,3-dimethylpropaneurea (2.1 mL) were added to a 100 mL double-necked flask, followed by nitrogen purging. Then, 1,3-oxazole (0.5 g, 7.24 mmol) was added, and the reaction flask was cooled to -78 °C. Bis(trimethylsilyl)aminolithium (2.42 g, 14.48 mmol) was added dropwise over approximately 1.5 h. Iodine (3.68 g, 14.48 mmol) was dissolved in THF (10 mL) and added to the reaction flask. The reaction was continued at -78 °C for 1 h, then transferred to room temperature for 63 h. After the reactants were fully reacted (TLC), a saturated sodium thiosulfate solution (40 mL) was added, followed by extraction with EA (100 mL). The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and purified by concentrated column chromatography (PE) to obtain 1.34 g of a white solid (57.68%). MS(ESI,pos.ion)m / z:321.85[M+H] + .

[0561] Step 2: Synthesis of compound 31-2

[0562] Compound 31-1 (0.58 g, 1.82 mmol), 3-amino-2-hydroxypyridine (0.2 g, 1.82 mmol), potassium carbonate (0.75 g, 5.46 mmol), and cuprous iodide (69 mg, 0.36 mmol) were added to a 50 mL double-necked flask. The mixture was purged with nitrogen. Then, N,N'-dimethylethylenediamine (64 mg, 0.73 mmol) and 1,4-dioxane (8 mL) were added, and the mixture was purged with nitrogen again. The reaction was carried out at 70 °C for 21.5 h. The reaction proceeded to completion as monitored by TLC. Ice water (10 mL) was added, followed by extraction with EA (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was mixed and purified by column chromatography (PE / EA = 0.2:1) to obtain 33 mg of a yellow solid, with a yield of 5.99%. MS (ESI, pos.ion) m / z: 304.00 [M+H] + .

[0563] Step 3: Synthesis of compound 31-3

[0564] Compound 31-2 (70 mg, 0.23 mmol), cuprous iodide (2 mg, 0.012 mmol), and bis(triphenylphosphine)palladium dichloride (8 mg, 0.012 mmol) were added to a 50 mL double-necked flask. The mixture was purged with nitrogen, followed by the addition of triisopropylsilylacetylene (42 mg, 0.23 mmol), triethylamine (5 mL), and 1,4-dioxane (5 mL). The mixture was purged with nitrogen again, and the temperature was raised to 50 °C. After 2 hours, TLC monitoring showed complete reaction of the starting material. The reaction solution was concentrated, dissolved in DCM (20 mL), washed once with water (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: PE / EA (v / v = 4 / 1)) to obtain 49 mg of a yellow oily substance, with a yield of 59.34%. MS (ESI, pos.ion) m / z: 358.10 [M+H] + .

[0565] Step 4: Synthesis of compound 31-4

[0566] Compounds 18-1 (73 mg, 0.17 mmol), 31-3 (60 mg, 0.17 mmol), BrettPhos-G3-Pd (15 mg, 0.017 mmol), BrettPhos (18 mg, 0.34 mmol), and cesium carbonate (110 mg, 0.34 mmol) were added to a 25 mL double-necked flask, purged three times with nitrogen, and then 1,4-dioxane (5 mL) was added. The mixture was heated to 80 °C and reacted. After 1 h, TLC monitoring showed that the starting material had basically reacted. DCM (50 mL) was added to dissolve the reactants, and the mixture was washed with saturated ammonium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, and evaporated to dryness. The mixture was then purified by column chromatography (elution: PE / EA (v / v = 1 / 1)) to obtain 86 mg of a yellow solid, with a yield of 68.24%.

[0567] Step 5: Synthesis of compound 31-5

[0568] Compound 31-4 (82 mg, 0.11 mmol), cesium fluoride (33 mg, 0.22 mmol), and N,N-dimethylformamide (2 mL) were added to a 25 mL single-necked flask. The mixture was purged with nitrogen three times and stirred at 25 °C for 4 h. TLC monitoring showed that the reaction proceeded completely. The reaction was stopped, 10 mL of water was added, and the mixture was extracted with EA (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (eluent: PE / EA (v / v = 1 / 2)) to obtain 54 mg of a white solid, yield 83.17%. MS (ESI, pos.ion) m / z: 595.00 [M+H] + .

[0569] Step 6: Synthesis of Compound 31

[0570] Compound 31-5 (54 mg, 0.091 mmol) and dichloromethane (4 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (0.62 g, 5.46 mmol). The reaction was carried out at 25 °C for 1.5 h. TLC monitoring showed complete reaction of the starting material. 25 mL of DCM was added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness and subjected to column chromatography with DCM / MeOH (v / v = 1 / 0 - 40 / 1) as the eluent. The collected solution was evaporated to dryness to give 22 mg of a white solid, yielding 51.06%. MS (ESI, pos.ion) m / z: 475.00 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.73(s,1H),8.33(d,J=6.4Hz,1H),8.22(s,1H),8 .01(dd,J=15.7,7.0Hz,2H),7.54(d,J=5.8Hz,1H),6.47(t,J=7.2Hz,1H),6.19(s,1H),4 .58(s,1H),4.38–4.23(m,1H),3.70(dd,J=15.0,7.5Hz,1H),3.20(s,3H),2.91(d,J=4. 7Hz, 3H), 2.09 (td, J=19.2, 8.8Hz, 2H), 1.56-1.46 (m, 1H), 1.35 (dd, J=19.5, 9.9Hz, 1H).

[0571] Example 32: Synthesis of Compound 32

[0572]

[0573]

[0574] Step 1: Synthesis of Compound 32-1

[0575] In a 50 mL double-necked flask, 31-1 (0.92 g, 2.87 mmol), cuprous iodide (0.027 g, 0.14 mmol), and bis(triphenylphosphine)-palladium dichloride (0.10 g, 0.14 mmol) were added, purged with nitrogen, and then diisopropylamine (6 mL) was added. Triisopropylsilylacetylene (0.63 g, 3.44 mmol) was dissolved in diisopropylamine (5 mL), and then slowly added dropwise to the reaction flask. The temperature was raised to 45 °C. After approximately 2.5 h, TLC analysis showed that the reactants had reacted completely. The reaction solution was concentrated, dissolved in ethyl acetate (40 mL), filtered, and the filter cake was washed with ethyl acetate (15 mL). The organic phase was then washed once with 20 mL of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE) to obtain 0.5 g of a yellow transparent liquid, with a yield of 46.46%. MS(ESI,pos.ion)m / z:375.9[M+H] + .

[0576] Step 2: Synthesis of compound 32-2

[0577] Cuprous iodide (0.076 g, 0.40 mmol), potassium carbonate (0.55 g, 3.99 mmol), and 3-amino-2-hydroxypyridine (0.22 g, 2.00 mmol) were added to a 50 mL double-necked flask. Nitrogen was used to purge the solution. Compound 32-1 (0.5 g, 1.33 mmol) and N,N'-dimethylethylenediamine (0.059 g, 0.67 mmol) were dissolved in 1,4-dioxane (10 mL) and added to the reaction flask. The mixture was heated to 90 °C and reacted. After approximately 23 h, TLC monitoring showed a small amount of reactant remaining, at which point the reaction was stopped. The mixture was filtered, and the filter cake was washed with ethyl acetate (40 mL). The organic phase was collected, concentrated, and purified by column chromatography (elution: PE / EA (v / v = 1 / 0-10 / 1)) to give 0.08 g of a yellow liquid, with a yield of 16.8%.

[0578] Step 3: Synthesis of compound 32-3

[0579] Compound 18-1 (120 mg, 0.29 mmol), BrettPhos-G3-Pd (20 mg, 0.022 mmol), BrettPhos (24 mg, 0.044 mmol), and cesium carbonate (140 mg, 0.44 mmol) were added to a 50 mL double-necked flask, and the mixture was purged with nitrogen. Compound 32-2 (80 mg, 0.44 mmol) was then dissolved in 8 mL of 1,4-dioxane and added to the flask. The mixture was heated to 80 °C and reacted. After approximately 5 hours, TLC monitoring showed complete reaction of the starting material. 30 mL of dichloromethane was added, and the organic phase was washed with 20 mL of water and dried over anhydrous sodium sulfate. Column chromatography (elution: PE / EA (v / v = 1 / 1)) was used to separate and purify the mixture, yielding 153 mg of a yellow solid (91.05%). 1 H NMR (400MHz, CDCl3) δ8.64(s,1H),8.46(s,1H),8.35(d,J=7.3Hz,1H),8.20–8.12(m,2H),7.97( s,1H),7.18(d,J=8.3Hz,2H),6.87(d,J=8.4Hz,2H),6.49(t,J=7.4Hz,1H),5.55(s,1H),5.17(s, 2H),4.60(q,J=8.5Hz,2H),3.81(s,4H),3.40(s,3H),3.09(s,3H),2.39–2.29(m,2H),2.24(t,J =7.7Hz,1H),2.16(t,J=9.3Hz,1H),2.03(s,1H),1.75(t,J=10.0Hz,1H),1.18(d,J=5.4Hz,18H).

[0580] Step 4: Synthesis of compound 32-4

[0581] Add 32-3 (100 mg, 0.13 mmol) and tetrahydrofuran (8 mL) to a 50 mL double-necked flask, purge with nitrogen, and cool to 0 °C. Then dissolve tetrabutylammonium fluoride (0.26 mL, 0.26 mmol) in tetrahydrofuran (1 mL) and add it dropwise at 0 °C. After the addition is complete, react at 0 °C for about 10 minutes. TLC monitoring showed that the starting material was basically completely reacted. Quench the reaction with 20 mL of water, extract with dichloromethane (40 mL), dry the organic phase with anhydrous magnesium sulfate, concentrate, and purify by column chromatography (elution: DCM / EA (v / v = 1 / 1)) to obtain 50 mg of off-white solid, yield 56.83%. 1H NMR (400MHz, CDCl3) δ8.69 (s, 1H), 8.47 (s, 1H), 8.36 (d, J = 7.6Hz, 1H), 8.14 ( d,J=5.9Hz,2H),7.97(s,1H),7.19(d,J=8.4Hz,2H),6.88(d,J=8.5Hz,2H),6 .50(t,J=7.5Hz,1H),5.55(s,1H),5.17(s,2H),4.66–4.56(m,2H),3.88–3.8 0(m,4H),3.40(s,3H),3.09(s,3H),2.34(d,J=9.4Hz,2H),2.28–2.19(m,2H).

[0582] Step 5: Synthesis of Compound 32

[0583] Compound 32-4 (50 mg, 0.084 mmol) and dichloromethane (6 mL) were added to a 50 mL single-necked flask. After stirring, trifluoroacetic acid (570 mg, 5.04 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature. After 2 hours, TLC analysis showed that the starting material had reacted completely. The reaction was then stopped, and the temperature was lowered to 0 °C. The pH was adjusted to approximately 8 with a 20% potassium phosphate aqueous solution. The mixture was separated, and the aqueous phase was extracted again with dichloromethane (30 mL). The organic phases were combined, concentrated, and subjected to column chromatography (elution: DCM / CH3OH (v / v = 1 / 0-50 / 1)) to give 25 mg of white solid, with a yield of 62.66%. MS (ESI, pos.ion) m / z: 475.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.71(s,1H),8.40(d,J=5.9Hz,2H),8.13(d,J=6.7Hz,1H),8.03(s,1H),6.50(t,J=7.3Hz,2H),5.50(s,1H ), 4.60 (d, J = 7.3Hz, 2H), 3.84 (d, J = 7.5Hz, 2H), 3.39 (s, 3H), 3.12 (d, J = 5.2Hz, 3H), 2.34 (d, J = 10.7Hz, 2H), 2.27–2.21 (m, 2H).

[0584] Example 33: Synthesis of Compound 33

[0585]

[0586] Step 1: Synthesis of Compound 33-1

[0587] 5-Bromo-2-iodopyrimidine (0.5 g, 1.76 mmol), 3-amino-2-hydroxypyridine (0.19 g, 1.76 mmol), cesium carbonate (1.15 g, 3.52 mmol), and N,N-dimethylacetamide (10 mL) were added to a 50 mL two-necked flask. The mixture was reacted at 60 °C for 5 h. The reaction proceeded to completion by TLC. Water (40 mL) was added, followed by extraction with EA (40 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: PE / EA (v / v = 0 / 1-1 / 1) to obtain 0.12 g of a yellow solid, yield 25.60%. MS (ESI, pos.ion) m / z: 267.95 [M+H] + .

[0588] Step 2: Synthesis of compound 33-2

[0589] Compound 33-1 (0.12 g, 0.45 mmol), cuprous iodide (4 mg, 0.023 mmol), and bis(triphenylphosphine)palladium dichloride (16 mg, 0.023 mmol) were added to a 50 mL double-necked flask. The mixture was purged with nitrogen. Then, triisopropylsilylacetylene (82 mg, 0.45 mmol) and diisopropylamine (6 mL) were added, followed by another nitrogen purging. The reaction was carried out at 100 °C for 4.5 h. TLC monitoring showed complete reaction of the starting material. The reaction was stopped, and the reaction solution was concentrated. The solution was dissolved in EA (10 mL), filtered, and the filter cake was washed with EA (15 mL). The organic phases were combined and washed once with water (5 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (PE / EA (v / v) = 2 / 1) to give 113 mg of a yellow solid, yield 68.24%. MS (ESI, pos.ion) m / z: 369.20 [M+H] + Step 3: Synthesis of compound 33-3

[0590] Compounds 18-1 (0.13 g, 0.30 mmol), 33-2 (0.11 g, 0.30 mmol), BrettPhos-G3-Pd (27 mg, 0.030 mmol), BrettPhos (32 mg, 0.60 mmol), and cesium carbonate (0.2 g, 0.60 mmol) were added to a 25 mL double-necked flask, purged with nitrogen three times, and then 1,4-dioxane (5 mL) was added, purged with nitrogen three times. The mixture was heated to 80 °C and reacted. After 1 h, TLC monitoring showed that the starting materials had basically reacted completely, and the reaction was stopped. DCM (50 mL) was added to dissolve the reactants, and the mixture was washed with saturated ammonium chloride solution (10 mL). The mixture was separated, dried over anhydrous sodium sulfate, and evaporated to dryness. The solution was purified by column chromatography (PE:EA = 1:1) to obtain 154 mg of a yellow solid, with a yield of 67.71%.

[0591] Step 4: Synthesis of compound 33-4

[0592] Compound 33-3 (154 mg, 0.2 mmol), cesium fluoride (61 mg, 0.4 mmol), and N,N-dimethylformamide (2 mL) were added to a 25 mL single-necked flask. The mixture was purged with nitrogen three times and stirred at 25 °C for 15 h. TLC monitoring showed that the reaction proceeded completely. The reaction was stopped, 10 mL of water was added, and the mixture was extracted with EA (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (PE / EA (v / v) = 1 / 2) to obtain 72 mg of a yellow solid, yield 58.82%. MS (ESI, pos.ion) m / z: 606.05 [M+H] + .

[0593] Step 5: Synthesis of Compound 33

[0594] Compound 33-4 (72 mg, 0.12 mmol) and dichloromethane (4 mL) were added to a 25 mL single-necked flask, followed by the addition of trifluoroacetic acid (0.82 g, 7.2 mmol). The reaction was carried out at 25 °C for 2.5 h. TLC monitoring showed complete reaction of the starting material. DCM (25 mL) was added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness and subjected to column chromatography with DCM / MeOH (v / v = 1 / 0 - 40 / 1) as the eluent. The collected solution was evaporated to dryness, yielding 36 mg of a pale yellow solid, with a yield of 62.37%. MS (ESI, pos.ion) m / z: 486.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.19 (s, 2H), 9.04 (s, 1H), 8.33 (d, J = 6.4Hz, 1H), 8.21 (s, 1H), 8. 09(d,J=9.1Hz,1H),7.96(d,J=4.6Hz,1H),7.54(d,J=6.4Hz,1H),6.44(t,J=7.1Hz,1H), 6.19(s,1H),4.88(s,1H),4.40–4.23(m,1H),3.73(dd,J=15.0,7.4Hz,1H),3.21(s,3H), 2.91(d,J=4.6Hz,3H),2.10(dt,J=19.3,8.9Hz,2H),1.46(ddd,J=38.9,19.3,9.6Hz,2H)

[0595] Example 34: Synthesis of Compound 34

[0596]

[0597]

[0598] Step 1: Synthesis of Compound 34-1

[0599] In a 100 mL single-necked flask, 2-iodo-5-bromopyridine (1 g, 3.52 mmol), triisopropylsilylacetylene (0.96 g, 5.28 mmol), bis(triphenylphosphine)palladium dichloride (0.12 g, 0.18 mmol), and cuprous iodide (0.034 g, 0.18 mmol) were added under nitrogen protection. Triethylamine (1.78 g, 17.6 mmol) and anhydrous THF (12 mL) were added, and the mixture was heated to 45 °C and reacted for 2.5 h. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction solution was filtered, and the filter cake was washed with dichloromethane (10 mL). The filtrate was concentrated and purified by column chromatography with petroleum ether to give 1.0 g of a pale yellow liquid, with a yield of 83.90%. MS (ESI, pos.ion) m / z: 338.1 [M+H] + .

[0600] Step 2: Synthesis of compound 34-2

[0601] In a 50 mL double-necked flask, 34-1 (0.6 g, 1.77 mmol), 3-amino-2-hydroxypyridine (0.29 g, 2.66 mmol), cuprous iodide (0.067 g, 0.35 mmol), potassium carbonate (0.24 g, 1.77 mmol), and N,N'-dimethylethylenediamine (0.062 g, 0.71 mmol) were added. Under nitrogen protection, 1,4-dioxane (10 mL) was added, and the reaction was carried out at 110 °C for approximately 4.5 h. TLC analysis showed that the reactants had reacted completely. The reaction solution was filtered, washed with 20 mL of dichloromethane (20 mL), and washed with saturated ammonium chloride solution (10 mL). The organic phase was concentrated and purified by PE / EA = 2 / 1 column chromatography to give 366 mg of a yellow solid, with a yield of 56.15%. MS (ESI, pos.ion) m / z: 368.1 [M+H] + .

[0602] Step 3: Synthesis of compound 34-3

[0603] Compounds 18-1 (250 mg, 0.58 mmol), 34-2 (0.26 g, 0.70 mmol), cesium carbonate (0.38 g, 1.16 mmol), BrettPhos-G3-Pd (0.053 g, 0.058 mmol), and BrettPhos (0.062 g, 0.12 mmol) were added to a 50 mL double-necked flask under nitrogen protection. 1,4-Dioxane (10 mL) was added, and the reaction was carried out at 80 °C for approximately 1.5 h. TLC analysis showed that the starting material reacted completely. The reaction solution was filtered, washed with dichloromethane (8 mL), concentrated, and purified by column chromatography (elution buffer: PE / EA (v / v = 1 / 1)) to obtain 353 mg of a green solid, with a yield of 79.77%. 1 H NMR (400MHz, CDCl3) δ8.69(d,J=2.1Hz,1H),8.47(s,1H),8.44–8.39(m,1H),8.15(d,J=8.7Hz,1H),8.00(s ,1H),7.83(dd,J=8.4,2.5Hz,1H),7.66(d,J=8.3Hz,1H),7.18(d,J=8.5Hz,2H),7.08–7.03(m,1H),6.87(d, J=8.6Hz,2H),6.45(t,J=7.2Hz,1H),5.54(s,1H),5.16(s,2H),3.81(s,3H),3.41(s,3H),3.08(s,3H),2.3 3(dd,J=14.3,4.8Hz,1H),2.20–2.12(m,1H),1.80–1.71(m,1H),1.58–1.50(m,1H),1.18(d,J=4.0Hz,21H).

[0604] Step 4: Synthesis of compound 34-4

[0605] Compound 34-3 (0.35 g, 0.46 mmol), cesium fluoride (0.14 g, 0.92 mmol), and DMF (8 mL) were added to a 50 mL single-necked flask. The reaction was allowed to proceed at room temperature for approximately 2.5 h. TLC analysis showed the reactants were completely reacted. The mixture was washed with water (30 mL), extracted with ethyl acetate (15 mL × 3), dried over the organic phase, concentrated, and purified by column chromatography (DCM / EA (v / v = 3 / 1)) to give 275 mg of a green solid, with a yield of 98.89%. MS (ESI, pos.ion) m / z: 605.0 [M+H] + .

[0606] Step 5: Synthesis of Compound 34

[0607] Compound 34-4 (270 mg, 0.45 mmol), DCM (8 mL), and trifluoroacetic acid (1.54 g, 13.5 mmol) were added to a 50 mL single-necked flask and reacted at room temperature for 8 h. TLC analysis showed the reactants were completely reacted. The pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted with 8 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: DCM / MeOH (v / v = 80 / 1)) to give 43 mg of a blue solid, yielding 19.20%. MS (ESI, pos.ion) m / z: 485.0 [M+H]+; 1 H NMR (400MHz, CDCl3) δ8.73(d,J=2.0Hz,1H),8.47(d,J=6.6Hz,1H),8.40(s,1H),8.06(s,1H),8.01(d,J= 8.8Hz,1H),7.89(dd,J=8.3,2.5Hz,1H),7.69(d,J=8.3Hz,1H),7.07(d,J=6.0Hz,1H),6.46(t,J=7.2Hz, 1H),6.35(q,J=5.0Hz,1H),5.49(s,1H),4.62–4.57(m,1H),3.85(d,J=7.6Hz,1H),3.40(s,3H),3.30(s, 1H),3.11(d,J=5.2Hz,3H),2.35(d,J=9.9Hz,1H),2.20–2.13(m,1H),1.77(s,1H),1.53(d,J=9.7Hz,1H).

[0608] Example 35: Synthesis of Compound 35

[0609]

[0610] Step 1: Synthesis of Compound 35-1

[0611] 2-Bromo-5-iodopyrazine (1 g, 3.51 mmol), 3-amino-2-hydroxypyridine (0.39 g, 3.51 mmol), cesium carbonate (2.29 g, 7.02 mmol), and N,N-dimethylacetamide (15 mL) were added to a 50 mL single-necked flask, and the reaction was carried out at 100 °C. After about 3 h, TLC showed that the reactants had reacted completely. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography (PE / EA (v / v = 0 / 1-1 / 1)) to give 550 mg of a yellow solid product, yield 58.67%. MS (ESI, pos.ion) m / z: 267.0 [M+H] +; 1 H NMR (400MHz, CDCl3) δ9.21(d,J=5.3Hz,1H),8.78(s,1H),7.29(d,J=7.2Hz,1H),6.58(d,J=7.0Hz,1H),6.24(t,J=7.1Hz,1H),1.25(s,2H).

[0612] Step 2: Synthesis of compound 35-2

[0613] Compound 35-1 (0.50 g, 1.59 mmol), 1-(trimethylsilyl)-1-propyne (0.27 g, 2.39 mmol), cuprous iodide (0.061 g, 0.32 mmol), bis(triphenylphosphine)palladium dichloride (0.22 g, 0.32 mmol), and triethylamine (0.80 g, 7.95 mmol) were added to a 100 mL double-necked flask. The mixture was purged with nitrogen, and 5 mL of THF was added. The mixture was stirred at room temperature. Tetrabutylammonium fluoride (4.4 mL, 4.40 mmol) was dissolved and slowly added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 45 °C. The reaction was continued for 2 h, and TLC analysis showed that the starting material had completely reacted. Dissolve the sample in DCM (40 mL), wash with saturated sodium chloride solution (10 mL × 2), evaporate the organic phase to dryness, and purify by column chromatography using DCM / EA (v / v = 30 / 1-8 / 1) as the eluent to obtain 0.30 g of yellow solid, yield 83.30%.

[0614] Step 3: Synthesis of compound 35-3

[0615] Starting materials 18-1 (0.30 g, 0.70 mmol), 35-2 (0.16 g, 0.70 mmol), BrettPhos-G3-Pd (0.063 g, 0.070 mmol), BrettPhos (0.075 g, 0.14 mmol), and cesium carbonate (0.46 g, 1.4 mmol) were added to a 25 mL double-necked flask. The mixture was purged with nitrogen, and 1,4-dioxane (5 mL) was added. The mixture was then purged with nitrogen again, and the temperature was raised to 80 °C. After 1 h of reaction, TLC analysis showed that the starting materials had reacted completely. The reaction solution was concentrated, dissolved in DCM (40 mL), washed once with water (10 mL), and dried over anhydrous sodium sulfate. The organic phase was then evaporated to dryness and purified by column chromatography using DCM:EA = 30:1-4:1 as the eluent, yielding 0.28 g of a yellow solid (64.75% yield). MS(ESI,pos.ion)m / z:620.0[M+H] + ; 1H NMR (400MHz, CDCl3) δ9.29(s,1H),8.56(s,1H),8.43(s,1H),8.37(d,J=7.2Hz,1H),8.13(d,J=8.7Hz,1H ),7.99(s,1H),7.60(d,J=7.1Hz,1H),7.16(d,J=8.4Hz,2H),6.84(d,J=8.4Hz,2H),6.46(t,J=7.3Hz,1H ),5.53(s,1H),5.14(s,2H),4.66–4.50(m,1H),3.83(dd,J=15.3,7.8Hz,1H),3.78(s,3H),3.37(s,3H), 3.05(s,3H),2.31(q,J=9.6Hz,1H),2.19–2.09(m,4H),1.73–1.65(m,1H),1.51(dd,J=19.8,9.7Hz,1H).

[0616] Step 4: Synthesis of Compound 35

[0617] Compound 35-3 (0.28 g, 0.45 mmol) and dichloromethane (8 mL) were added to a reaction flask and stirred until dissolved. Trifluoroacetic acid (3.08 g, 27 mmol) was then added, and the reaction was carried out at room temperature. TLC analysis after 2 hours showed that the starting material had completely reacted. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the aqueous phase was back-extracted once with DCM (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-35 / 1) as the eluent. 95 mg of a yellow solid was obtained, with a yield of 42.09%. MS (ESI, pos.ion) m / z: 500.0 [M+H]+; 1 H NMR(400MHz, CDCl3)δ9.31(s,1H),8.57(s,1H),8.47–8.28(m,2H),8.15–7 .87(m,2H),7.59(d,J=6.1Hz,1H),6.45(t,J=6.8Hz,1H),6.34(s,1H),5.47 (s,1H),4.64–4.50(m,1H),3.82(d,J=6.6Hz,1H),3.37(s,3H),3.08(s,3H) ,2.32(d,J=9.0Hz,1H),2.23–2.07(m,4H),1.55–1.44(m,1H),1.25(s,1H).

[0618] Example 36: Synthesis of Compound 36

[0619]

[0620] Step 1: Synthesis of Compound 36-1

[0621] Compound 30-1 (184 mg, 0.68 mmol), 1-(trimethylsilyl)-1-propyne (0.11 g, 1.02 mmol), palladium dichloride bis(triphenylphosphine) (0.095 g, 0.14 mmol), cuprous iodide (0.026 g, 0.14 mmol), and triethylamine (0.34 g, 3.40 mmol) were added to the reaction flask, purged with nitrogen, and THF (3 mL) was added. Tetrabutylammonium fluoride (2 mL, 2.00 mmol) was slowly added dropwise to the reaction solution, and the mixture was heated to 40 °C and reacted for 12.5 h. TLC analysis showed that the starting material reacted completely. The reaction solution was concentrated, and DCM (50 mL) was added to dissolve the reactants. The organic phase was washed with saturated sodium chloride solution (10 mL × 2), evaporated to dryness, and purified by column chromatography using PE / EA (v / v = 10 / 1-3 / 1) as the eluent to give 101 mg of a yellow solid, with a yield of 64.59%. MS(ESI,pos.ion)m / z:232.1[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.27(d,J=7.3Hz,1H),7.27(s,1H),6.58(d,J=7.1Hz,1H),6.30(t,J=7.2Hz,1H),4.33(s,2H),2.09(s,3H).

[0622] Step 2: Synthesis of Compound 36-2

[0623] Add 36-1 (95 mg, 0.41 mmol), 18-1 (0.23 g, 0.53 mmol), BrettPhos-G3-Pd (0.037 g, 0.041 mmol), BrettPhos (0.044 g, 0.082 mmol), and cesium carbonate (0.27 g, 0.82 mmol) to the reaction flask, purge with nitrogen, then add 1,4-dioxane (4 mL), and heat to 80 °C. After 1 h, TLC analysis showed that the starting material had largely reacted. Concentrate the solution, dissolve the residue in DCM (30 mL), wash with water (5 mL × 2), dry the organic phase with anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as eluent to obtain 145 mg of yellow solid, yield 56.50%. 1H NMR (400MHz, CDCl3) δ8.54(dd,J=7.3,1.4Hz,1H),8.44(s,1H),8.35(dd,J=7.3,1.3Hz,1H),8.08(d,J=8 .5Hz,1H),7.93(s,1H),7.33(s,1H),7.16(d,J=8.6Hz,2H),6.85(d,J=8.6Hz,2H),6.51(t,J=7.4Hz,1H) ,5.52(s,1H),5.14(s,2H),4.63–4.52(m,1H),3.82(d,J=7.4Hz,1H),3.79(s,3H),3.37(s,3H),3.07(s, 3H),2.36–2.29(m,1H),2.19–2.13(m,1H),2.10(s,3H),1.74(dd,J=18.0,9.0Hz,1H),1.53–1.46(m,1H).

[0624] Step 3: Synthesis of Compound 36

[0625] Compound 36-2 (0.14 g, 0.22 mmol), DCM (4 mL), and trifluoroacetic acid (1.51 g, 13.2 mmol) were added to a reaction flask, and the reaction was carried out at room temperature. After 2.5 h, TLC analysis showed that the starting material had reacted completely. The reaction was stopped, and the mixture was diluted with DCM (30 mL). The temperature was lowered to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0 - 40 / 1) as the eluent. 100 mg of a yellow solid was obtained, with a yield of 88.44%. MS (ESI, pos.ion) m / z: 505.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.54(d,J=6.2Hz,1H),8.41–8.33(m,2H),7.99(s,1H),7.93(d,J=8.4Hz, 1H),7.33(s,1H),6.49(q,J=7.2Hz,1H),6.34(d,J=5.1Hz,1H),5.47(s,1H),4.61–4.49(m,1H) ,3.81(dd,J=13.7,6.1Hz,1H),3.36(s,3H),3.08(d,J=6.5Hz,3H),2.32(dd,J=19.1,9.4Hz,1H ),2.16(dd,J=11.7,7.0Hz,1H),2.10(s,3H),1.78–1.71(m,1H),1.49(dd,J=19.5,9.9Hz,1H).

[0626] Example 37: Synthesis of Compound 37

[0627]

[0628] Step 1: Synthesis of Compound 37-1

[0629] 1-Bromobut-2-yne (1.0 g, 7.52 mmol), 3-amino-2-hydroxypyridine (0.83 g, 7.52 mmol), potassium carbonate (2.08 g, 15.04 mmol), and 1,2-dichloroethane (15 mL) were added to a reaction flask, and the mixture was heated to 80 °C. After 1 h, TLC analysis showed that the starting material had largely reacted. DCM (50 mL) was added, followed by washing with water (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography. The DCM / EA ratio (v / v = 10 / 1 - 3 / 1) yielded 0.35 g of a brown solid. Yield: 28.70%. MS (ESI, pos.ion) m / z: 163.2 [M+H] + .

[0630] Step 2: Synthesis of compound 37-2

[0631] Compounds 18-1 (0.3 g, 0.70 mmol), 37-2 (0.11 g, 0.70 mmol), BrettPhos-G3-Pd (0.063 g, 0.070 mmol), BrettPhos (0.075 g, 0.14 mmol), and cesium carbonate (0.46 g, 1.4 mmol) were added to a reaction flask under nitrogen protection. Then, 1,4-dioxane (5 mL) was added, followed by nitrogen purging. The mixture was heated to 80 °C. After 1.5 h, TLC analysis showed that the starting material had reacted completely. The mixture was dissolved in DCM (40 mL), washed with saturated sodium chloride solution (10 mL), and the organic phase was evaporated to dryness. The solution was purified by column chromatography (eluent: DCM / MeOH (v / v = 1 / 0-65 / 1)) to give 0.38 g of a yellow solid, with a yield of 98.00%. MS(ESI,pos.ion)m / z:556.3[M+H] + ; 1H NMR (400MHz, CDCl3) δ8.42(s,1H),8.31(dd,J=7.3,1.3Hz,1H),8.15(d,J=8.8Hz,1H),7.97(s,1H),7.36(dd,J= 6.9,1.4Hz,1H),7.15(d,J=8.5Hz,2H),6.84(d,J=8.6Hz,2H),6.34(t,J=7.2Hz,1H),5.50(s,1H),5.12(s,2H),4 .80(d,J=2.4Hz,2H),4.64–4.53(m,1H),3.82(d,J=6.4Hz,1H),3.79(s,3H),3.37(s,3H),3.04(s,3H),2.30(dd ,J=19.2,9.5Hz,1H),2.13(dd,J=18.1,9.0Hz,1H),1.89(t,J=2.3Hz,3H),1.76–1.70(m,1H),1.53–1.46(m,1H).

[0632] Step 3: Synthesis of Compound 37

[0633] Compound 37-2 (0.37 g, 0.67 mmol) and dichloromethane (10 mL) were added to a reaction flask, followed by trifluoroacetic acid (4.58 g, 40.2 mmol). The reaction was carried out at room temperature. After 3 hours, TLC analysis showed that the starting material had reacted completely. The reaction was stopped, the temperature was lowered to 0 °C, and DCM (30 mL) was added. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0 - 65 / 1) as the eluent. 195 mg of a grayish-white solid was obtained, with a yield of 67.24%. MS (ESI, pos.ion) m / z: 436.2 [M+H] + ; 1HNMR(400MHz, CDCl3) δ8.36(d,J=6.8Hz,2H),8.03(d,J=12.1Hz,2H),7.38(d,J=6.9Hz,1H),6. 36(t,J=7.2Hz,1H),6.30(d,J=5.0Hz,1H),5.46(s,1H),4.83(d,J=2.2Hz,2H),4.64–4.51(m,1H ),3.83(dd,J=15.2,7.6Hz,1H),3.39(s,3H),3.10(d,J=5.2Hz,3H),2.32(dd,J=19.4,9.5Hz,1 H),2.15(dd,J=18.5,9.2Hz,1H),1.92(s,3H),1.77–1.70(m,1H),1.52(dd,J=19.8,9.5Hz,1H).

[0634] Example 40: Synthesis of Compound 40

[0635]

[0636] Step 1: Synthesis of Compound 40-1

[0637] In a 100 mL double-necked flask, 29-1 (970 mg, 3.63 mmol), cuprous iodide (0.14 g, 0.73 mmol), bis(triphenylphosphine)palladium dichloride (0.51 g, 0.73 mmol), and tetrahydrofuran (20 mL) were added. The mixture was purged with nitrogen three times, followed by the addition of triethylamine (1.84 g, 18.15 mmol) and 1-(trimethylsilyl)-1-propyne (0.61 g, 5.45 mmol). Tetrabutylammonium fluoride (5.45 mL, 5.45 mmol) was added dropwise, and the reaction was carried out at 25 °C. After 3 h, TLC showed complete reaction of the starting material. Water (20 mL) and dichloromethane (40 mL) were added, and the mixture was washed and separated. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (DCM / EA(v / v) = 0 / 1-4 / 1) to give 728 mg of a brown solid product. The yield was 88.60%. MS(ESI,pos.ion)m / z:227.1[M+H] + Step 2: Synthesis of compound 40-2

[0638] Compounds 40-1 (200 mg, 0.88 mmol), 18-1 (0.38 g, 0.88 mmol), BrettPhos-G3-Pd (0.080 g, 0.088 mmol), BrettPhos (0.094 g, 0.18 mmol), cesium carbonate (0.57 g, 1.76 mmol), and 1,4-dioxane (8 mL) were added to a 50 mL double-necked flask. The mixture was purged with nitrogen three times and reacted at 80 °C. After 4 hours of reaction, TLC showed that the starting material had reacted completely. 20 mL of saturated ammonium chloride solution (20 mL) and dichloromethane (40 mL) were added. The mixture was washed and separated. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography (DCM / EA (v / v = 0 / 1-2:1)) to give 212 mg of a yellow, bubbly product, yield 38.70%. MS (ESI, pos.ion) m / z: 620.3 [M+H] + .

[0639] Step 3: Synthesis of Compound 40

[0640] Compound 40-2 (212 mg, 0.34 mmol), dichloromethane (5 mL), and trifluoroacetic acid (2.33 g, 20.40 mmol) were added to a 25 mL single-necked flask and reacted at room temperature. After 1 h of reaction, TLC showed that the starting material had reacted completely. 30 mL of DCM was added, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography with DCM:MeOH = 30:1 as the eluent to give 60 mg of a yellow solid. Yield: 35.11%. MS (ESI, pos.ion) m / z: 500.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.44(d,J=7.2Hz,1H),8.37(s,1H),8.18(d,J=9.0Hz,1H),7.98(d,J=7.4Hz, 2H),7.78(d,J=7.0Hz,1H),7.66(d,J=9.0Hz,1H),6.48(t,J=7.3Hz,1H),6.31(d,J=4.8Hz,1H),5. 47(s,1H),4.62–4.53(m,1H),3.82(dd,J=15.5,7.9Hz,1H),3.37(s,3H),3.09(d,J=5.1Hz,3H),2. 32(dd,J=19.2,10.0Hz,1H),2.19(s,3H),2.17–2.12(m,1H),1.75–1.69(m,1H),1.53–1.47(m,1H).

[0641] Example 41: Synthesis of Compound 41

[0642]

[0643] Step 1: Synthesis of Compound 41-1

[0644] 2,4-Dibromothiazole (1.0 g, 4.12 mmol), palladium dichloride bis(triphenylphosphine) (0.58 g, 0.82 mmol), cuprous iodide (0.16 g, 0.82 mmol), triethylamine (2.08 g, 20.6 mmol), a THF solution of tetrabutylammonium fluoride (3.1 mL, 6.18 mmol), and THF (10 mL) were added to the reaction flask. The mixture was purged with nitrogen, heated to 30 °C, and 1-(trimethylsilyl)propyne (0.60 g, 5.36 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed for 1.5 h, and TLC analysis showed that the starting materials reacted completely. The residue was concentrated, dissolved in DCM (50 mL), and washed with saturated ammonium chloride solution (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using PE / DCM (v / v) = 20 / 1-6 / 1 as the eluent. The collected residue was evaporated to dryness to give 0.35 g, yield 42.08%. MS (ESI, pos.ion) m / z: 201.9 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.15 (s, 1H), 2.11 (s, 3H).

[0645] Step 2: Synthesis of compound 41-2

[0646] Compound 41-1 (0.50 g, 2.47 mmol), 3-amino-2-hydroxypyridine (0.33 g, 2.96 mmol), cuprous iodide (0.094 g, 0.49 mmol), and potassium carbonate (0.68 g, 4.94 mmol) were added to a reaction flask under nitrogen protection. Then, N,N'-dimethylethylenediamine (0.11 g, 1.24 mmol) and 1,4-Dioxane (5 mL) were added, and the mixture was heated to 90 °C. After 12.5 h, the reaction proceeded completely by TLC. The reaction was stopped, concentrated, and purified by column chromatography using DCM / EA (v / v = 1 / 0-15 / 1) as eluent, yielding 0.20 g of a brown solid. MS (ESI, pos.ion) m / z: 232.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.25 (s, 1H), 7.83 (d, J = 7.2Hz, 1H), 6.49 (t, J = 34.0Hz, 1H), 6.18 (t, J = 7.2Hz, 1H), 2.14 (s, 3H).

[0647] Step 3: Synthesis of compound 41-3

[0648] Compounds 18-1 (0.25 g, 0.58 mmol), 41-2 (0.13 g, 0.58 mmol), BrettPhos-G3-Pd (0.053 g, 0.058 mmol), BrettPhos (0.062 g, 0.12 mmol), and cesium carbonate (0.38 g, 1.16 mmol) were added to the reaction flask under nitrogen protection. Then, 1,4-dioxane (4 mL) was added, and the temperature was raised to 80 °C. After 2 hours, TLC analysis showed that the reactants had largely reacted. DCM (30 mL) was added to the reaction solution, followed by washing with water (6 mL × 2). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-50 / 1) as the eluent, yielding 0.32 g of a yellow solid in 88.08% yield. MS(ESI,pos.ion)m / z:625.3[M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.43(s,1H),8.30(d,J=6.5Hz,1H),8.23(s,1H),8.18–8.10(m,2H),8 .05(s,1H),7.16(d,J=8.5Hz,2H),6.84(d,J=8.5Hz,2H),6.39(t,J=7.3Hz,1H),5.53(s,1H ),5.13(s,2H),4.63–4.53(m,1H),3.84–3.77(m,4H),3.37(s,3H),3.05(s,3H),2.31(dd,J =19.3,9.7Hz,1H),2.18–2.09(m,4H),1.68(d,J=11.1Hz,1H),1.48(dd,J=19.0,9.4Hz,1H).

[0649] Step 4: Synthesis of Compound 41

[0650] Compound 41-3 (0.30 g, 0.48 mmol), DCM (5 mL), and trifluoroacetic acid (3.28 g, 28.80 mmol) were added to a reaction flask and reacted at room temperature. TLC analysis after 1 h showed the starting material had reacted completely. DCM (30 mL) was added, the mixture was cooled to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-50 / 1) as the eluent, yielding 134 mg of a yellow solid, with a yield of 51.07%. MS (ESI, pos.ion) m / z: 504.9 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.36–8.31(m,2H),8.25(s,1H),8.11(d,J=10.5Hz,2H ),8.00(d,J=8.6Hz,1H),6.41–6.28(m,2H),5.46(s,1H),4.63–4.49(m,1H), 3.82(dd,J=15.3,7.7Hz,1H),3.36(s,3H),3.07(d,J=5.1Hz,3H),2.31(dd,J =19.4,9.6Hz,1H),2.20–2.09(m,4H),1.71–1.64(m,1H),1.55–1.43(m,1H).

[0651] Example 42: Synthesis of Compound 42

[0652]

[0653]

[0654] Step 1: Synthesis of Compound 42-1

[0655] 2,4-Dibromothiazole (2.0 g, 8.23 ​​mmol), cuprous iodide (78 mg, 0.41 mmol), palladium dichloride (0.29 g, 0.41 mmol), triisopropylsilylacetylene (1.5 g, 8.23 ​​mmol), triethylamine (4.16 g, 41.15 mmol), and 1,4-dioxane (30 mL) were added to a 50 mL two-necked flask. The mixture was purged with nitrogen and reacted at 90 °C. After 2 h, TLC monitoring showed complete reaction of the starting material. The reaction was stopped, the reaction solution was concentrated, dissolved in 50 mL of DCM, washed once with 20 mL of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: PE / EA (v / v = 100 / 1)) to obtain 1.75 g of a yellow oily substance, yield 61.72%. MS (ESI, pos.ion) m / z: 344.10 [M+H] + .

[0656] Step 2: Synthesis of compound 42-2

[0657] Compound 42-1 (1.75 g, 5.08 mmol), 3-amino-2-hydroxypyridine (0.56 g, 5.08 mmol), potassium carbonate (2.11 g, 15.24 mmol), and cuprous iodide (0.19 g, 1.02 mmol) were added to a 50 mL double-necked flask. The mixture was purged with nitrogen. Then, N,N'-dimethylethylenediamine (0.18 g, 2.03 mmol) and 1,4-dioxane (30 mL) were added, and the mixture was purged with nitrogen again. The reaction was carried out at 90 °C for 26 h. The reaction proceeds were monitored by TLC until complete. The mixture was concentrated, dissolved in 50 mL of DCM, and 20 mL of water was added. The mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA = 0-20:3) to obtain 0.98 g of a yellow oily substance, with a yield of 51.62%. MS (ESI, pos.ion) m / z: 374.20 [M+H] + .

[0658] Step 3: Synthesis of compound 42-3

[0659] Compounds 18-1 (0.23 g, 0.54 mmol), 42-2 (0.2 g, 0.54 mmol), BrettPhos-G3-Pd (49 mg, 0.054 mmol), BrettPhos (58 mg, 0.11 mmol), and cesium carbonate (0.35 g, 1.08 mmol) were added to a 25 mL double-necked flask, purged three times with nitrogen, and then 1,4-dioxane (8 mL) was added. The mixture was heated to 80 °C and reacted. After 20 h, the reaction was monitored by TLC. Once the starting material had completely reacted, it was dissolved in DCM (50 mL), washed with saturated ammonium chloride solution (10 mL), separated, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (elution: PE / EA (v / v = 2 / 1)) to obtain 292 mg of off-white solid, with a yield of 71.11%.

[0660] Step 4: Synthesis of compound 42-4

[0661] Compound 42-3 (240 mg, 0.31 mmol) was dissolved in THF (10 mL), and tetrabutylammonium fluoride (0.37 mL, 0.37 mmol) was added at 0 °C. The mixture was stirred for 20 min, and TLC monitoring showed that the reaction proceeded completely. The reaction was quenched with saturated ammonium chloride solution (5 mL), extracted with DCM (20 mL), concentrated the organic phase, and purified by column chromatography (elution: DCM / EA (v / v = 1 / 1)) to obtain 158 mg of an off-white solid, with a yield of 82.69%. MS (ESI, pos.ion) m / z: 611.20 [M+H] + .

[0662] Step 5: Synthesis of Compound 42

[0663] Compound 42-4 (0.15 g, 0.25 mmol) and dichloromethane (10 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (1.71 g, 15 mmol). The reaction was carried out at 25 °C for 4.5 h. TLC monitoring showed complete reaction of the starting material. DCM (25 mL) was added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness and subjected to column chromatography with DCM / MeOH (v / v = 1 / 0 - 40 / 1) as the eluent. The collected solution was evaporated to dryness to give 78 mg of a white solid, yielding 64.74%. MS (ESI, pos.ion) m / z: 491.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.42 (s, 1H), 8.29 (d, J = 6.9Hz, 1H), 8.21 (s, 1H), 8. 07(d,J=9.0Hz,1H),7.95(d,J=6.7Hz,2H),6.47(t,J=7.1Hz,1H),6.22(s,1H),5.11(s,1H ),4.41-4.22(m,1H),3.69(dd,J=14.8,7.3Hz,1H),3.20(s,3H),2.92(d,J=4.4Hz,3H),2. 09(dd,J=18.9,10.0Hz,2H), 1.50(dd,J=18.6,9.2Hz,1H), 1.38(dd,J=19.8,10.2Hz,1H).

[0664] Example 43: Synthesis of Compound 43

[0665]

[0666] Step 1: Synthesis of Compound 43-1

[0667] 3-Bromo-5-iodopyridine (1 g, 3.52 mmol), 3-amino-2-hydroxypyridine (0.58 g, 5.28 mmol), cuprous iodide (0.13 g, 0.70 mmol), potassium carbonate (0.49 g, 3.52 mmol), N,N'-dimethylethylenediamine (0.12 g, 1.41 mmol), and 1,4-dioxane (10 mL) were added to a two-necked flask. The mixture was reacted at 100 °C for 18 h, and the reaction mixture was monitored by TLC. After the reactants had reacted completely, the reaction solution was concentrated to dryness, dissolved in dichloromethane (20 mL), and the organic phase was washed successively with water (5 mL) and saturated brine (5 mL). The solution was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (dichloromethane / ethyl acetate (v / v) = 1 / 0-3 / 1) to give 0.2 g of a pale yellow solid, yield: 18.13%. MS (ESI, pos.ion) m / z: 314.00 [M+H] + .

[0668] Step 2: Synthesis of compound 43-2

[0669] Compound 43-1 (0.2 g, 0.64 mmol), triisopropylsilylacetylene (0.12 g, 0.64 mmol), cuprous iodide (0.0061 g, 0.032 mmol), bis(triphenylphosphine)palladium dichloride (0.022 g, 0.032 mmol), diisopropylamine (6 mL), and 1,4-dioxane (6 mL) were added to a two-necked flask. The mixture was purged with nitrogen and reacted at 100 °C for 4 h. TLC analysis showed complete reaction of the starting materials. The reaction solution was concentrated, dissolved in 20 mL of ethyl acetate, washed once with 5 mL of water, dried over anhydrous sodium sulfate, and concentrated. The solution was purified by column chromatography (eluent: DCM / EA (v / v) = 1 / 0 - 10 / 1) to give 0.22 g of a brown solid, yield: 93.70%. MS (ESI, pos.ion) m / z: 368.25 [M+H] + .

[0670] Step 3: Synthesis of compound 43-3

[0671] Compounds 43-2 (0.22 g, 0.60 mmol), 18-1 (0.26 g, 0.60 mmol), BrettPhos-G3-Pd (0.054 g, 0.060 mmol), BrettPhos (0.064 g, 0.12 mmol), cesium carbonate (0.39 g, 1.2 mmol), and anhydrous 1,4-dioxane (5 mL) were added to a two-necked flask. The mixture was purged with nitrogen and reacted at 80 °C for 3 h. The reaction proceeds were detected by TLC. The starting materials were completely reacted. The reaction solution was concentrated to dryness, dissolved in dichloromethane (30 mL), washed with saturated ammonium chloride solution (10 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. Column chromatography (dichloromethane / ethyl acetate (v / v = 1 / 0-4 / 1) yielded 0.34 g of a light green solid, yield: 91.82%.

[0672] Step 4: Synthesis of compound 43-4

[0673] Compound 43-3 (0.34 g, 0.45 mmol), cesium fluoride (0.14 g, 0.90 mmol), and N,N-dimethylformamide (3.5 mL) were added to a flask and reacted at room temperature for 3 h. TLC analysis showed the reactants had reacted completely. The reaction was stopped, and water (15 mL) was added. Extraction was performed with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (elution: DCM / MeOH (v / v = 1 / 0 - 100 / 3)) to give 0.25 g of a pale green solid, yield: 92.54%. MS (ESI, pos.ion) m / z: 605.30 [M+H] + .

[0674] Step 5: Synthesis of Compound 43

[0675] Compound 43-4 (0.25 g, 0.41 mmol), dichloromethane (5 mL), and trifluoroacetic acid (2.80 g, 24.60 mmol) were added to a reaction flask. The reaction was carried out at room temperature for 2 h. TLC analysis showed that the reactants had reacted completely, and the reaction was stopped. 20 mL of dichloromethane was added to the reaction solution, and the mixture was cooled to 0 °C. A 20% potassium phosphate aqueous solution was added to adjust the pH to 8. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (DCM / MeOH (v / v = 1 / 0 ~ 20 / 1)) was used to purify the solution, yielding 0.17 g of a pale yellow solid (yield: 84.86%). MS (ESI, pos.ion) m / z: 485.10 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.79(d,J=1.5Hz,1H),8.69(d,J=2.3Hz,1H),8.44(dd,J=7.4,1.3Hz,1H),8.37( s,1H),8.04(s,1H),7.98(d,J=8.7Hz,1H),7.94(d,J=1.9Hz,1H),7.03(dd,J=6.9,1.4Hz,1H),6.43(t, J=7.2Hz,1H),6.35(d,J=5.1Hz,1H),5.47(s,1H),4.65–4.50(m,1H),3.83(dd,J=15.3,7.7Hz,1H),3. 38(s,3H),3.32(s,1H),3.07(d,J=5.2Hz,3H),2.23(ddd,J=27.5,18.9,9.3Hz,2H),1.60–1.16(m,2H).

[0676] Example 44: Synthesis of Compound 44

[0677]

[0678] Step 1: Synthesis of Compound 44-1

[0679] Compound 43-1 (0.69 g, 2.20 mmol), 1-(trimethylsilyl)-1-propyne (0.49 g, 4.4 mmol), cuprous iodide (0.084 g, 0.44 mmol), bis(triphenylphosphine)palladium dichloride (0.15 g, 0.22 mmol), tetrahydrofuran (7 mL), and triethylamine (1.11 g, 11 mmol) were added to a reaction flask. The mixture was purged with nitrogen, and tetrabutylammonium fluoride (4.4 mL, 4.4 mmol) was added dropwise. The reaction was carried out at room temperature for 2 h, and the reaction mixture was monitored by TLC. After the starting materials had reacted completely, the reaction solution was concentrated, dissolved in ethyl acetate (20 mL), washed with 10 mL of water, and the organic phase was purified by anhydrous sodium sulfate and concentrated. The solution was purified by column chromatography (elution: petroleum ether / ethyl acetate (v / v = 1 / 0 - 1 / 1)) to give 0.49 g of brown solid, yield: 98.71%. MS(ESI,pos.ion)m / z:226.10[M+H] + .

[0680] Step 2: Synthesis of compound 44-2

[0681] Compounds 44-1 (0.3 g, 1.33 mmol), 18-1 (0.57 g, 1.33 mmol), BrettPhos-G3-Pd (0.12 g, 0.13 mmol), BrettPhos (0.14 g, 0.27 mmol), cesium carbonate (0.87 g, 2.66 mmol), and 1,4-dioxane (6 mL) were added to a two-necked flask, purged with nitrogen, and reacted at 80 °C for 3.5 h. TLC analysis showed that the reactants reacted completely. The reaction solution was concentrated to dryness, dissolved in dichloromethane (30 mL), washed with 10 mL of saturated ammonium chloride solution (10 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. Column chromatography (elution: DCM / EA (v / v = 1 / 0 to 4 / 1) yielded 0.35 g of a light green solid, yield: 42.48%. MS (ESI, pos.ion) m / z: 619.30 [M+H] + .

[0682] Step 3: Synthesis of Compound 44

[0683] Compound 44-2 (0.35 g, 0.57 mmol), dichloromethane (7 mL), and trifluoroacetic acid (3.90 g, 34.20 mmol) were added to a flask and reacted at room temperature for 1 h. TLC analysis showed the reactants had reacted completely, so the reaction was stopped. Dichloromethane (20 mL) was added to the reaction mixture, and the temperature was lowered to 0 °C. The pH was adjusted to 8 by adding 20% ​​potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography was used for purification (elution: DCM, MeOH (v / v = 1 / 0-30 / 1)) to give 0.18 g of a pale yellow solid, yield: 63.82%. MS (ESI, pos.ion) m / z: 499.25 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.69 (s, 1H), 8.61 (s, 1H), 8.43 (d, J = 7.3Hz, 1H), 8.37 (s, 1H), 8 .07(s,1H),7.98(d,J=8.7Hz,1H),7.82(s,1H),7.02(d,J=5.8Hz,1H),6.41(t,J=7.2H z,1H),6.35(d,J=5.1Hz,1H),5.47(s,1H),4.64–4.51(m,1H),3.83(q,J=7.6Hz,1H),3 .37(s,3H),3.07(d,J=5.1Hz,3H),2.38–2.12(m,2H),2.09(s,3H),1.56–1.20(m,2H).

[0684] Example 45: Synthesis of Compound 45

[0685]

[0686] Step 1: Synthesis of Compound 45-1

[0687] Compound 33-1 (0.24 g, 0.90 mmol), 1-(trimethylsilyl)-1-propyne (0.20 g, 1.8 mmol), cuprous iodide (0.034 g, 0.18 mmol), bis(triphenylphosphine)palladium dichloride (0.063 g, 0.090 mmol), tetrahydrofuran (7 mL), and triethylamine (0.46 g, 4.5 mmol) were added to a flask. The mixture was purged with nitrogen, and tetrabutylammonium fluoride (1.8 mL, 1.8 mmol) was added dropwise. The reaction was carried out at room temperature for 2 h, and the reaction mixture was monitored by TLC. After the starting material had reacted completely, the reaction solution was concentrated, dissolved in ethyl acetate (20 mL), washed with 10 mL of water, separated, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (elution: dichloromethane / ethyl acetate (v / v = 1 / 0-4 / 1)) yielded 0.15 g of a brownish-red solid, yield: 73.79%.

[0688] Step 2: Synthesis of compound 45-2

[0689] Compounds 45-1 (0.15 g, 0.66 mmol), 18-1 (0.28 g, 0.66 mmol), BrettPhos-G3-Pd (0.060 g, 0.066 mmol), BrettPhos (0.071 g, 0.13 mmol), cesium carbonate (0.43 g, 1.32 mmol), and 1,4-dioxane (6 mL) were added to a two-necked flask, purged with nitrogen, and reacted at 80 °C for 2.5 h. TLC analysis showed that the reactants reacted almost completely. The reaction solution was concentrated to dryness, dissolved in dichloromethane (30 mL), washed with saturated ammonium chloride solution (10 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then concentrated and purified by column chromatography (elution: DCM / EA (v / v = 1 / 0 to 4 / 1) to obtain 0.3 g of a pale yellow solid, yield: 73.02%. MS (ESI, pos.ion) m / z: 620.30 [M+H] + .

[0690] Step 3: Synthesis of Compound 45

[0691] 45-2 (0.3 g, 0.48 mmol), dichloromethane (6 mL), and trifluoroacetic acid (3.28 g, 28.80 mmol) were added to a reaction flask and stirred at room temperature for 3 h. TLC analysis showed the reactants had reacted completely. Dichloromethane (20 mL) was added to the reaction mixture, and the mixture was cooled to 0 °C. A 20% potassium phosphate aqueous solution was added to adjust the pH to 8. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (elution: dichloromethane / methanol (v / v = 1 / 0-20 / 1)) yielded 0.14 g of a yellow solid, yield: 57.89%. MS (ESI, pos.ion) m / z: 500.30 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.85 (s, 2H), 8.38 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 8. 8Hz,1H),7.42–7.33(m,1H),6.39(t,J=7.3Hz,1H),6.34(d,J=4.3Hz,1H),5.45(s,1H),4 .64–4.49(m,1H),3.82(q,J=7.6Hz,1H),3.37(s,3H),3.08(d,J=5.2Hz,3H),2.31(dd,J= 19.3,9.6Hz,1H),2.15(s,3H),2.13–2.05(m,1H),1.71–1.62(m,1H),1.56–1.43(m,1H).

[0692] Example 46: Synthesis of Compound 46

[0693]

[0694]

[0695] Step 1: Synthesis of Compound 46-1

[0696] 3-Amino-2-hydroxypyridine (1.6 g, 14.53 mmol), 2,4-diiodopyrimidine (5.30 g, 15.98 mmol), and cesium carbonate (4.73 g, 14.53 mmol) were added to a 100 mL single-necked flask, followed by N,N-dimethylacetamide (35 mL). The reaction was carried out at 95 °C. After 14 h, the reaction proceeded to completion by TLC. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by DCM column chromatography to give 1.21 g of a yellow solid, with a yield of 26.51%. MS (ESI, pos.ion) m / z: 315.0 [M+H] + .

[0697] Step 2: Synthesis of Compound 46-2

[0698] Compound 46-1 (0.50 g, 1.59 mmol), palladium dichloride bis(triphenylphosphine) (0.22 g, 0.32 mmol), cuprous iodide (0.061 g, 0.32 mmol), triethylamine (0.80 g, 7.95 mmol), tetrabutylammonium fluoride (2.39 mL, 2.39 mmol), and THF (6 mL) were added to a reaction flask under nitrogen protection. 1-(trimethylsilyl)propyne (0.23 g, 2.07 mmol) was slowly added dropwise. After 1 h, TLC analysis showed the reaction was complete. The reaction was quenched with water (20 mL), and then extracted with DCM (100 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-50 / 1) as the eluent, yielding 89 mg of a yellow solid, with a yield of 24.71%. MS(ESI,pos.ion)m / z:227.1[M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.75(d,J=5.6Hz,1H),8.18(d,J=5.6Hz,1H),7.58(dt,J=25.5,1 2.8Hz,1H),6.56(dd,J=7.1,1.3Hz,1H),6.31–6.14(m,1H),4.27(s,2H),2.13(s,3H).

[0699] Step 3: Synthesis of Compound 46-3

[0700] Compounds 46-2 (89 mg, 0.39 mmol), 18-1 (0.17 g, 0.39 mmol), BrettPhos-G3-Pd (0.035 g, 0.039 mmol), BrettPhos (0.042 g, 0.078 mmol), and cesium carbonate (0.25 g, 0.78 mmol) were added to a reaction flask under nitrogen protection. 1,4-Dioxane (4 mL) was added, and the mixture was heated to 80 °C. After 5 h, the reaction was stopped, the reaction solution was concentrated, dissolved in DCM (50 mL), and washed with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent, yielding 160 mg of a yellow solid. MS (ESI, pos.ion) m / z: 620.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.85(d,J=5.6Hz,1H),8.46(s,1H),8.38(d,J=5.9Hz,1H),8.15(dd,J=13.3,7.1 Hz,2H),7.97(s,1H),7.90(dd,J=7.3,1.4Hz,1H),7.18(d,J=8.5Hz,2H),6.87(d,J=8.6Hz,2H),6.47(t ,J=7.3Hz,1H),5.55(s,1H),5.17(s,2H),4.67–4.55(m,1H),3.87–3.78(m,4H),3.40(s,3H),3.09(s, 3H),2.34(dd,J=19.1,9.4Hz,1H),2.23–2.12(m,4H),1.73(dd,J=18.4,7.9Hz,1H),1.57–1.44(m,1H).

[0701] Step 4: Synthesis of Compound 46

[0702] Compound 46-3 (155 mg, 0.25 mmol), dichloromethane (4 mL), and trifluoroacetic acid (1.71 g, 15 mmol) were added to the reaction flask and stirred at room temperature. After 2 hours, TLC analysis showed the reaction was complete. The mixture was cooled to 0 °C, the pH was adjusted to 8 with 20% potassium phosphate solution, and DCM (30 mL) was added for extraction and separation. The organic phase was evaporated to dryness and purified by column chromatography using DCM / MeOH (v / v = 1 / 0 - 40 / 1) as the eluent, yielding 69 mg of a yellow solid (55.22% yield). MS (ESI, pos.ion) m / z: 500.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.83(d,J=5.6Hz,1H),8.41–8.35(m,2H),8.17(d,J=5.6Hz,1H) ,8.02–7.93(m,2H),7.87(dd,J=7.3,1.5Hz,1H),6.44(t,J=7.3Hz,1H),6.32(d,J=5.2 Hz,1H),5.47(s,1H),4.61–4.50(m,1H),3.84–3.78(m,1H),3.37(s,3H),3.09(d,J=5. 2Hz,3H),2.34–2.28(m,1H),2.17–2.09(m,4H),1.75–1.70(m,1H),1.51–1.45(m,1H).

[0703] Example 47: Synthesis of Compound 47

[0704]

[0705] Step 1: Synthesis of Compound 47-1

[0706] Compound 46-1 (400 mg, 1.27 mmol), triisopropylsilylacetylene (0.35 g, 1.91 mmol), cuprous iodide (0.012 g, 0.064 mmol), bis(triphenylphosphine)palladium dichloride (0.045 g, 0.064 mmol), and triethylamine (0.64 g, 6.35 mmol) were added to a 50 mL double-necked flask under nitrogen protection. THF (8 mL) was added, and the mixture was reacted at 50 °C for 4.5 h. TLC analysis showed a small amount of starting material remaining. The reaction was stopped, and dichloromethane (15 mL) and water (5 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: PE / EA (v / v = 4 / 1-3 / 1)) to obtain 146 mg of a yellow oily liquid, yielding 31.11%. MS (ESI, pos.ion) m / z: 369.2 [M+H] + .

[0707] Step 2: Synthesis of Compound 47-2

[0708] Compounds 18-1 (210 mg, 0.49 mmol), 47-1 (0.18 g, 0.49 mmol), cesium carbonate (0.32 g, 0.98 mmol), BrettPhos-G3-Pd (0.044 g, 0.049 mmol), and BrettPhos (0.053 g, 0.098 mmol) were added to a 50 mL double-necked flask under nitrogen protection. 1,4-Dioxane (8 mL) was added, and the mixture was reacted at 80 °C for approximately 3 h. TLC analysis showed that the reaction proceeds were completely reacted. The reaction solution was filtered, washed with dichloromethane (10 mL), concentrated, and purified by column chromatography (elution buffer: PE / EA (v / v = 1 / 1)) to obtain 285 mg of a yellow solid, with a yield of 76.57%. 1H NMR (400MHz, CDCl3) δ8.87(d,J=5.6Hz,1H),8.47(s,1H),8.41–8.37(m,1H),8.21(d,J=5.6Hz,1H),8.14(d,J=8 .7Hz,1H),7.98(s,1H),7.96(dd,J=7.4,1.7Hz,1H),7.18(d,J=8.5Hz,2H),6.87(d,J=8.5Hz,2H),6.50(t,J=7.4 Hz,1H),5.55(s,1H),5.17(s,2H),4.63(q,J=8.5Hz,1H),3.88–3.83(m,1H),3.81(s,3H),3.40(s,3H),3.09(s, 3H),2.34(d,J=8.8Hz,1H),2.20–2.13(m,1H),1.76(d,J=9.0Hz,1H),1.57–1.50(m,1H),1.19(d,J=5.1Hz,21H).

[0709] Step 3: Synthesis of Compound 47-3

[0710] Compound 47-2 (285 mg, 0.37 mmol) was added to a 50 mL double-necked flask under nitrogen protection. THF (8 mL) was added, followed by dropwise addition of tetrabutylammonium fluoride (0.74 mL, 0.74 mmol) at 0 °C. The reaction was maintained at this temperature for 0.5 h. TLC analysis showed complete reaction of the starting material. The reaction was stopped, the reaction solution was concentrated, and purified by column chromatography (elution: DCM / EA (v / v = 4 / 1)) to give 45 mg of a yellow solid, yield 19.87%. MS (ESI, pos.ion) m / z: 606.3 [M+H] + .

[0711] Step 4: Synthesis of Compound 47

[0712] In a 50 mL single-necked flask, 47-3 (100 mg, 0.17 mmol), trifluoroacetic acid (0.58 g, 5.10 mmol), and DCM (8 mL) were added. The mixture was reacted at room temperature for 2 h. TLC analysis showed that the starting material had reacted completely. The reaction was stopped, and saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The mixture was separated into aqueous and organic phases. The aqueous phase was extracted with 8 mL of dichloromethane, and the organic phase was dried, concentrated, and purified by column chromatography (elution: DCM / MeOH (v / v = 50 / 1)) to obtain 40 mg of white solid, yield 48.20%. MS (ESI, pos.ion) m / z: 486.2 [M+H]+; 1HNMR(400MHz, CDCl3)δ8.91(d,J=5.6Hz,1H),8.45–8.42(m,1H),8.40(s,1H),8.32(d,J=5.6H z,1H),8.03–7.97(m,2H),7.94(dd,J=7.4,1.7Hz,1H),6.48(d,J=7.3Hz,1H),6.34(d,J=5.5H z,1H),5.50(s,1H),4.58(d,J=8.3Hz,1H),3.84(d,J=7.8Hz,1H),3.40(s,3H),3.26(s,1H),3 .13(d,J=5.2Hz,3H),2.34(d,J=9.7Hz,1H),2.17(d,J=9.7Hz,1H),1.75(s,1H),1.51(s,1H).

[0713] Example 48: Synthesis of Compound 48

[0714]

[0715] Step 1: Synthesis of Compound 48-1

[0716] Compound 31-1 (1.4 g, 4.36 mmol), cuprous iodide (0.17 g, 0.87 mmol), palladium dichloride bis(triphenylphosphine) (0.61 g, 0.87 mmol), 1-(trimethylsilyl)propyne (0.98 g, 8.72 mmol), triethylamine (2.21 g, 21.8 mmol), and tetrahydrofuran (12 mL) were added to a 100 mL double-necked flask. Under nitrogen protection, tetrabutylammonium fluoride (1.71 g, 6.54 mmol) was added dropwise. After reacting at room temperature for about 3 h, the reaction proceeds were monitored by TLC until complete. The reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (elution: PE / DCM (v / v = 1 / 0-9 / 1)) to give 0.35 g of yellow solid, yield 34.43%. MS (ESI, pos.ion) m / z: 234.0 [M+H] + .

[0717] Step 2: Synthesis of Compound 48-2

[0718] Compound 48-1 (0.35 g, 1.50 mmol), cuprous iodide (0.086 g, 0.45 mmol), potassium carbonate (0.62 g, 4.50 mmol), and 3-amino-2-hydroxypyridine (0.25 g, 2.25 mmol) were added to a 50 mL double-necked flask, purged with nitrogen, and then N,N'-dimethyl-ethylenediamine (0.066 g, 0.75 mmol) was dissolved in 1,4-dioxane (1... Add the reactants to the flask, then heat to 85℃ and react for about 15 hours. TLC monitoring showed a small amount of reactants remaining. Filter the mixture, wash the filter cake with dichloromethane (50 mL), collect the organic phase, wash once with water (30 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography (elution buffer: PE / EA (v / v = 1 / 0-50 / 1-5 / 1)) to obtain 0.085 g of pale yellow solid, yield 26.29%. MS (ESI, pos.ion) m / z: 216.1 [M+H] + .

[0719] Step 3: Synthesis of Compound 48-3

[0720] Compounds 18-1 (260 mg, 0.60 mmol), 48-2 (100 mg, 0.46 mmol), BrettPhos-G3-Pd (42 mg, 0.046 mmol), BrettPhos (49 mg, 0.092 mmol), and cesium carbonate (300 mg, 0.92 mmol) were added to a 50 mL double-necked flask. The flask was purged with nitrogen, and then 1,4-dioxane (8 mL) was added to the flask. The temperature was raised to 80 °C, and the reaction was monitored by TLC after approximately 5.5 h. Once the reactants had reacted completely, the mixture was filtered. The filter cake was washed with 30 mL of dichloromethane (30 mL), and the organic phase was washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate. Column chromatography (DCM / EA = 1 / 0-7 / 3) was used to separate and purify the mixture, yielding 210 mg of a yellow solid (74.25%). MS(ESI,pos.ion)m / z:609.3[M+H] + ; 1HNMR(400MHz, CDCl3)δ8.62(s,1H),8.46(s,1H),8.35(d,J=7.4Hz,1H),8.18–8.12( m,2H),7.98(s,1H),7.18(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),6.49(t,J=7.4Hz, 1H),5.55(s,1H),5.17(s,2H),4.67–4.54(m,2H),4.14(dd,J=14.3,7.1Hz,1H),3.8 8–3.80(m,4H),3.40(s,3H),3.08(s,3H),2.34(dd,J=19.3,9.2Hz,2H),2.18(s,3H).

[0721] Step 4: Synthesis of Compound 48

[0722] Compound 48-3 (0.21 g, 0.35 mmol) and dichloromethane (11 mL) were added to a 100 mL single-necked flask. After dissolving by stirring at room temperature, trifluoroacetic acid (2.39 g, 21 mmol) was added dropwise. The reaction was allowed to proceed at room temperature. After approximately 2 hours of reaction, a sample was taken and the pH was adjusted to 8 with potassium phosphate solution. TLC analysis showed that the starting material had reacted completely. The mixture was cooled to 0 °C, and the pH was adjusted to approximately 8 with a 20% potassium phosphate aqueous solution. The mixture was separated from the aqueous phase, and the aqueous phase was extracted with 20 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution: DCM / CH3OH (v / v = 1 / 0-50 / 1)) to obtain 110 mg of a green solid, with a yield of 65.26%. MS (ESI, pos.ion) m / z: 489.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.64(s,1H),8.38(d,J=7.4Hz,2H),8.14(d,J=5.8Hz,1H),8.05–7.98(m,2H),6.48(t,J=7.4Hz,1H),6.31(d,J=5.4Hz,1H) ,5.50(s,1H),4.65–4.53(m,2H),3.84(dd,J=15.3,7.8Hz,2H),3.39(s,3H),3.12(d,J=5.2Hz,3H),2.34(dd,J=19.5,10.0Hz,2H),2.18(s,3H).

[0723] Example 49: Synthesis of Compound 49

[0724]

[0725]

[0726] Step 1: Synthesis of Compound 49-1

[0727] Compound 2,4-diiodopyrimidine (1.0 g, 3.01 mmol), bis(triphenylphosphine)palladium dichloride (0.42 g, 0.60 mmol), cuprous iodide (0.11 g, 0.60 mmol), triethylamine (1.52 g, 15.05 mmol), tetrabutylammonium fluoride (3.61 mL, 3.61 mmol), and THF (10 mL) were added to the reaction flask under nitrogen protection and cooled to 0 °C. 1-(trimethylsilyl)propyne (0.34 g, 3.01 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature. The reaction was continued for 5 h. TLC analysis showed a small amount of starting material remaining. Extraction was performed with DCM (100 mL) and water (15 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using PE / DCM (v / v = 1 / 0-3 / 1) as the eluent to give 0.32 g of a yellowish-brown solid, with a yield of 43.52%. MS(ESI,pos.ion)m / z:245.0[M+H] + ; 1 HNMR (400MHz, CDCl3) δ8.36 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 2.11 (s, 3H).

[0728] Step 2: Synthesis of Compound 49-2

[0729] Compound 49-1 (0.32 g, 1.31 mmol), 3-amino-2-hydroxypyridine (0.17 g, 1.57 mmol), cuprous iodide (0.050 g, 0.26 mmol), and potassium carbonate (0.36 g, 2.62 mmol) were added to a reaction flask under nitrogen protection. N,N'-dimethylethylenediamine (0.046 g, 0.52 mmol) and 1,4-dioxane (3 mL) were added, and the mixture was heated to 70 °C. After 5 h, TLC analysis showed that the reaction proceeds were completely reacted. DCM (40 mL) was added to the reaction solution. The organic phase was washed with ammonium chloride solution (15 mL), dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (DCM:EA = 15:1-3:1) to give 52 mg of a yellow solid, yield 17.53%. MS (ESI, pos.ion) m / z: 227.1 [M+H] + .

[0730] Step 3: Synthesis of Compound 49-3

[0731] Compounds 49-2 (70 mg, 0.31 mmol), 18-1 (0.13 g, 0.31 mmol), BrettPhos-G3-Pd (0.028 g, 0.031 mmol), BrettPhos (0.033 g, 0.062 mmol), and cesium carbonate (0.20 g, 0.62 mmol) were added to a reaction flask under nitrogen protection. Then, 1,4-dioxane (4 mL) was added, and the mixture was heated to 80 °C. After 4.5 h, TLC analysis showed that the reaction was complete. DCM (60 mL) was added, followed by washing with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0 - 40 / 1) as the eluent, yielding 132 mg of a yellow solid. Yield: 68.84%. MS (ESI, pos.ion) m / z: 620.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.83(d,J=5.1Hz,1H),8.44(s,1H),8.33(d,J=6.3Hz,1H),8.17(d,J=8.7Hz,1H) ,8.00(s,1H),7.39(d,J=5.1Hz,1H),7.35(d,J=5.9Hz,1H),7.16(d,J=8.5Hz,2H),6.85(d,J=8.5Hz,2 H),6.38(t,J=7.2Hz,1H),5.50(s,1H),5.12(s,2H),4.65–4.53(m,1H),3.85–3.77(m,4H),3.38(s,3H ),3.05(s,3H),2.31(dd,J=19.3,9.6Hz,1H),2.17–2.09(m,4H),1.75–1.67(m,1H),1.54–1.46(m,1H).

[0732] Step 4: Synthesis of Compound 49

[0733] Compound 49-3 (0.16 g, 0.26 mmol), DCM (10 mL), and trifluoroacetic acid (0.89 g, 7.80 mmol) were added to the reaction flask. After 1.5 h, TLC analysis indicated the reaction was complete. DCM (30 mL) was added, the mixture was cooled to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-35 / 1) as the eluent. 89 mg of a white solid was obtained, with a yield of 69.00%. MS (ESI, pos.ion) m / z: 500.3 [M+H] + ; 1H NMR(400MHz, CDCl3) δ8.85(d,J=4.8Hz,1H),8.39(d,J=5.3Hz,2H),8.13–8.01(m,2 H),7.39(dd,J=21.3,5.6Hz,2H),6.42–6.32(m,2H),5.45(s,1H),4.65–4.52(m,1H ),3.84(dd,J=15.0,7.5Hz,1H),3.39(s,3H),3.09(d,J=4.8Hz,3H),2.33(dd,J=18 .1,8.9Hz,1H),2.20–2.11(m,4H),1.71(dd,J=19.6,9.9Hz,1H),1.56–1.47(m,1H).

[0734] Example 50: Synthesis of Compound 50

[0735]

[0736] Step 1: Synthesis of Compound 50-1

[0737] 4-Bromo-2-fluoropyridine (1 g, 5.68 mmol), 3-amino-2-hydroxypyridine (0.63 g, 5.68 mmol), cesium carbonate (3.70 g, 11.36 mmol), and N,N-dimethylacetamide (10 mL) were added to a flask and reacted at 90 °C for 2 h. TLC analysis showed the reactants reacted completely. Water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (eluent: PE / EA (v / v = 1 / 0 - 1 / 1)) to give 0.8 g of a yellowish-brown solid, yield 52.91%. MS (ESI, pos.ion) m / z: 266.0 [M+H] + .

[0738] Step 2: Synthesis of Compound 50-2

[0739] Compound 50-1 (0.8 g, 3.01 mmol), 1-(trimethylsilyl)-1-propyne (0.68 g, 6.02 mmol), cuprous iodide (0.11 g, 0.60 mmol), bis(triphenylphosphine)palladium dichloride (0.21 g, 0.30 mmol), and triethylamine (1.52 g, 15.05 mmol) were added to a two-necked flask. The mixture was purged with nitrogen, and then tetrabutylammonium fluoride (6.0 mL, 6.02 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. The reaction proceeded to complete reaction by TLC. The reaction solution was concentrated to dryness, dissolved in dichloromethane (20 mL), and water (10 mL) was added. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (elution: PE:EA (v / v = 1 / 0-1 / 1)) yielded 0.67 g of a light yellow solid, yield 98.93%. MS(ESI,pos.ion)m / z:226.15[M+H] + .

[0740] Step 3: Synthesis of Compound 50-3

[0741] Compounds 50-2 (0.25 g, 1.11 mmol), 18-1 (0.48 g, 1.11 mmol), BrettPhos-G3-Pd (0.10 g, 0.11 mmol), BrettPhos (0.12 g, 0.22 mmol), cesium carbonate (0.72 g, 2.22 mmol), and 1,4-dioxane (10 mL) were added to a two-necked flask. Nitrogen gas was purged, and the mixture was reacted at 80 °C for 3.5 h. TLC analysis showed complete reaction of the starting materials. The reaction solution was concentrated, dissolved in 30 mL of dichloromethane, washed with 10 mL of saturated ammonium chloride solution, separated, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (elution: DCM / EA (v / v = 1 / 0 to 4 / 1)) to give 0.53 g of a yellow solid. MS (ESI, pos.ion) m / z: 619.30 [M+H] + .

[0742] Step 4: Synthesis of Compound 50

[0743] Compound 50-3 (0.53 g, 0.86 mmol), dichloromethane (10 mL), and trifluoroacetic acid (5.88 g, 51.6 mmol) were added to a reaction flask and reacted at room temperature for 2 h. TLC analysis showed the reactants had reacted completely. Dichloromethane (20 mL) was added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 by adding 20% ​​potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (elution: DCM / MeOH (v / v = 1 / 0 ~ 30 / 1) yielded 0.26 g of a pale yellow solid. MS (ESI, pos.ion) m / z: 499.30 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.51(d,J=5.1Hz,1H),8.39(d,J=7.3Hz,1H),8.36(s,1H),8.12(s,1H),8.03(d,J= 8.8Hz,1H),7.88(s,1H),7.58–7.52(m,1H),7.31(d,J=5.1Hz,1H),6.41(t,J=7.2Hz,1H),6.30(d,J=5.2H z,1H),5.46(s,1H),4.64–4.48(m,1H),3.83(q,J=7.6Hz,1H),3.37(s,3H),3.06(d,J=5.2Hz,3H),2.31( dd,J=19.1,9.5Hz,1H),2.14(dd,J=18.5,8.9Hz,1H),1.78–1.70(m,1H),1.69(s,3H),1.57–1.42(m,1H).

[0744] Example 51: Synthesis of Compound 51

[0745]

[0746] Step 1: Synthesis of Compound 51-1

[0747] Compound 31-2 (120 mg, 0.4 mmol), cuprous iodide (15 mg, 0.08 mmol), and bis(triphenylphosphine)palladium dichloride (56 mg, 0.08 mmol) were added to a 50 mL double-necked flask. The mixture was purged with nitrogen, and then 1-(trimethylsilyl)-1-propyne (90 mg, 0.8 mmol), triethylamine (0.2 g, 2 mmol), and tetrahydrofuran (6 mL) were added. Tetrabutylammonium fluoride (0.8 mL, 0.8 mmol) was added dropwise at room temperature. After 3.5 h, the reaction was monitored by TLC. The reaction mixture was concentrated, dissolved in DCM (20 mL), washed once with water (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 40 / 1)) to obtain 42 mg of a yellow oily substance, with a yield of 49.29%. MS(ESI,pos.ion)m / z:216.20[M+H] + .

[0748] Step 2: Synthesis of compound 51-2

[0749] Compounds 18-1 (130 mg, 0.3 mmol), 51-1 (64 mg, 0.3 mmol), BrettPhos-G3-Pd (27 mg, 0.03 mmol), BrettPhos (32 mg, 0.06 mmol), and cesium carbonate (200 mg, 0.6 mmol) were added to a 25 mL double-necked flask. The mixture was purged with nitrogen three times, and then 1,4-dioxane (5 mL) was added. The mixture was heated to 80 °C and reacted. After 13.5 h, TLC monitoring showed that the reactants had largely reacted. 50 mL of DCM was added, and the mixture was washed with 10 mL of saturated ammonium chloride solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness and purified by column chromatography (eluent: DCM / EA (v / v = 10 / 1)) to obtain 73 mg of a yellow solid, with a yield of 40.33%. MS (ESI, pos.ion) m / z: 609.30 [M+H] + .

[0750] Step 3: Synthesis of Compound 51

[0751] Compound 51-2 (73 mg, 0.12 mmol) and dichloromethane (4 mL) were added to a 25 mL single-necked flask, followed by the addition of trifluoroacetic acid (0.82 g, 7.2 mmol). The reaction was carried out at 25 °C for 2 h. TLC monitoring showed complete reaction of the starting material. 25 mL of DCM was added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness and subjected to column chromatography with DCM / EA (v / v = 2 / 3) as the eluent. The collected solution was evaporated to dryness to give 25 mg of an off-white solid, yielding 46.27%. MS (ESI, pos.ion) m / z: 489.25 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.56 (s, 1H), 8.33 (d, J = 7.1Hz, 1H), 8.22 (s, 1H) ),8.01(dd,J=16.4,6.9Hz,2H),7.53(d,J=6.4Hz,1H),6.46(t,J=7.2Hz,1H),6.19(s ,1H),4.38-4.24(m,1H),3.71(dd,J=14.8,7.4Hz,1H),3.21(s,3H),2.91(d,J=4.6Hz ,3H),2.18-2.01(m,5H),1.51(td,J=19.2,9.7Hz,1H),1.36(dd,J=15.5,6.4Hz,1H).

[0752] Example 52: Synthesis of Compound 52

[0753]

[0754] Step 1: Synthesis of Compound 52-1

[0755] 5-Bromo-2-iodopyrimidine (0.60 g, 2.11 mmol), bis(triphenylphosphine)palladium dichloride (0.30 g, 0.42 mmol), cuprous iodide (0.080 g, 0.42 mmol), triethylamine (1.07 g, 10.55 mmol), tetrabutylammonium fluoride (2.11 mL, 2.11 mmol), and THF (10 mL) were added dropwise under nitrogen protection. Then, 1-(trimethylsilyl)-1-propyne (0.24 g, 2.11 mmol) was slowly added dropwise. After reacting at room temperature for 12.5 h, TLC analysis showed a small amount of starting material remaining. Extraction was performed with DCM (50 mL) and ammonium chloride solution (20 mL). The organic phase was evaporated to dryness and purified by column chromatography using PE / DCM (v / v = 1 / 0-2 / 1) as eluent, yielding 0.18 g of a yellow solid. The yield was 42.65%. MS(ESI,pos.ion)m / z:197.1[M+H] + Step 2: Synthesis of compound 52-2

[0756] Compound 52-1 (0.23 g, 1.17 mmol), 3-amino-2-hydroxypyridine (0.15 g, 1.40 mmol), cuprous iodide (0.045 g, 0.23 mmol), and potassium carbonate (0.32 g, 2.34 mmol) were added to a reaction flask under nitrogen protection. N,N'-dimethylethylenediamine (0.041 g, 0.47 mmol) and 1,4-dioxane (5 mL) were added, and the mixture was heated to 85 °C and reacted for 3.5 h. TLC analysis showed a small amount of starting material remaining, at which point the reaction was stopped. The mixture was cooled to room temperature. The reaction solution was concentrated, and DCM (40 mL) was added to dissolve the reactants. The organic phase was washed with ammonium chloride solution (15 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: DCM / EA (v / v = 15 / 1-3 / 1)) to give 0.15 g of a yellow solid, yield 56.80%. MS(ESI,pos.ion)m / z:227.1[M+H] + .

[0757] Step 3: Synthesis of compound 52-3

[0758] Compounds 52-2 (0.15 g, 0.66 mmol), 18-1 (0.28 g, 0.66 mmol), BrettPhos-G3-Pd (0.060 g, 0.066 mmol), BrettPhos (0.071 g, 0.13 mmol), and cesium carbonate (0.43 g, 1.32 mmol) were added to a reaction flask under nitrogen protection. 1,4-dioxane (5 mL) was added, and the mixture was heated to 80 °C. After 1.5 h, TLC analysis indicated complete reaction of the starting material. DCM (30 mL) was added, and the mixture was washed twice with water (6 mL). The organic phase was evaporated to dryness and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-28 / 1) as the eluent, yielding 0.38 g of a yellow solid (92.49% yield). MS (ESI, pos.ion) m / z: 620.3 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ8.86 (s, 2H), 8.47–8.36 (m, 2H), 8.09 (d, J = 8.6Hz, 1H), 7.94 (s, 1H), 7.16(d,J=8.6Hz,2H),7.03(dd,J=7.0,1.5Hz,1H),6.84(d,J=8.6Hz,2H),6.47(t,J=7.2Hz, 1H),5.52(s,1H),5.15(s,2H),4.64–4.52(m,1H),3.85–3.77(m,4H),3.38(s,3H),3.06(s, 3H), 2.32 (dd, J=19.3, 9.6Hz, 1H), 2.18–2.10 (m, 4H), 1.77–1.69 (m, 1H), 1.54–1.45 (m, 1H).

[0759] Step 4: Synthesis of Compound 52

[0760] Compound 52-3 (0.38 g, 0.61 mmol), dichloromethane (10 mL), and trifluoroacetic acid (4.17 g, 36.6 mmol) were added to a reaction flask, and the reaction was carried out at room temperature. After 2 hours, TLC analysis showed that the starting material had reacted completely, and the reaction was stopped. 30 mL of DCM was added to dilute the reaction solution, and the mixture was cooled to 0 °C. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0 - 30 / 1) as the eluent. 165 mg of a yellow solid was obtained, with a yield of 53.87%. MS (ESI, pos.ion) m / z: 500.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.87 (s, 2H), 8.44 (d, J = 6.6Hz, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7.94 (d ,J=8.6Hz,1H),7.02(d,J=6.0Hz,1H),6.46(t,J=7.2Hz,1H),6.38(d,J=5.0Hz,1H),5.47(s ,1H),4.65–4.49(m,1H),3.82(dd,J=15.2,7.7Hz,1H),3.37(s,3H),3.08(d,J=5.1Hz,3H), 2.32(dd,J=19.2,9.6Hz,1H),2.18–2.08(m,4H),1.68(d,J=10.8Hz,1H),1.53–1.45(m,1H).

[0761] Example 53: Synthesis of Compound 53

[0762]

[0763] Step 1: Synthesis of Compound 53-1

[0764] 2,6-Dibromopyrazine (0.50 g, 2.10 mmol), 3-amino-2-hydroxypyridine (0.23 g, 2.1 mmol), cesium carbonate (1.37 g, 4.2 mmol), and N,N-dimethylacetamide (10 mL) were added to a reaction flask, and the mixture was heated to 70 °C. After 12.5 h, TLC analysis showed that the starting material had completely reacted. The reaction was quenched with water (30 mL), and then extracted with EA (50 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (15 mL × 4). The organic phases were dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography with DCM / EA (v / v) = 30 / 1-10 / 1 as the eluent, yielding 305 mg of a yellow solid, with a yield of 54.33%.

[0765] Step 2: Synthesis of compound 53-2

[0766] Compound 53-1 (0.10 g, 0.37 mmol), bis(triphenylphosphine)palladium dichloride (0.052 g, 0.074 mmol), cuprous iodide (0.014 g, 0.074 mmol), triethylamine (0.19 g, 1.85 mmol), and tetrabutylammonium fluoride (0.55 mL, 0.55 mmol) were added to the reaction flask under nitrogen protection. Then, 4 mL of THF was added, followed by the slow dropwise addition of 1-(trimethylsilyl)propyne (0.054 g, 0.48 mmol) at room temperature. After 1 h, TLC analysis indicated the reaction was complete. DCM (50 mL) was added, followed by washing with saturated ammonium chloride solution (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / EA (v / v = 20 / 1–5 / 1) as the eluent, yielding 66 mg of a yellow solid in 77.92% yield. MS(ESI,pos.ion)m / z:227.1[M+H] + ; 1 H NMR (400MHz, CDCl3) δ9.20(s,1H),8.57(s,1H),7.54(d,J=7.0Hz,1H),6.57(d,J=6.8Hz,1H),6.22(t,J=7.0Hz,1H),4.30(s,2H),2.14(s,3H).

[0767] Step 3: Synthesis of compound 53-3

[0768] Compounds 53-2 (66 mg, 0.29 mmol), 18-1 (0.12 g, 0.29 mmol), BrettPhos-G3-Pd (0.026 g, 0.029 mmol), BrettPhos (0.031 g, 0.058 mmol), and cesium carbonate (0.19 g, 0.58 mmol) were added to a reaction flask under nitrogen protection. Then, 1,4-dioxane (4 mL) was added, and the mixture was heated to 80 °C. After 2.3 h, TLC analysis showed that the starting material had completely reacted. DCM (30 mL) was added, followed by washing with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-50 / 1) as the eluent, yielding 130 mg of a yellow solid, with a yield of 71.91%. MS (ESI, pos.ion) m / z: 620.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.66(s,1H),8.47(s,1H),8.40(dd,J=7.3,1.5Hz,1H),8.16(d,J=8.8Hz,1H),7.99(s, 1H),7.62(dd,J=7.2,1.5Hz,1H),7.56(dd,J=7.3,1.3Hz,1H),7.18(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),6 .47(t,J=7.3Hz,1H),5.56(s,1H),5.17(s,2H),4.68–4.55(m,1H),3.84(d,J=6.3Hz,1H),3.81(s,3H),3.40 (s,3H),3.08(s,3H),2.34(dd,J=19.5,9.8Hz,1H),2.20–2.12(m,4H),1.78–1.72(m,1H),1.55–1.50(m,1H).

[0769] Step 4: Synthesis of Compound 53

[0770] Add 0.12 g (0.19 mmol) of 53-3, 3 mL of dichloromethane, and 1.30 g (11.4 mmol) of trifluoroacetic acid to the reaction flask and stir at room temperature. After 1.5 h, TLC analysis showed that the reaction proceeded completely. Cool to 0 °C, adjust pH to 8 with 20% potassium phosphate solution, add 30 mL of DCM for extraction and separation, evaporate the organic phase to dryness, and purify by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as eluent to give 35 mg of a yellow solid, yield 36.18%. MS (ESI, pos.ion) m / z: 500.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ9.25(s,1H),8.66(s,1H),8.44(dd,1H),8.39(s,1H),8.07–7.99( m,2H),7.61(d,J=7.2Hz,1H),6.47(t,J=7.2Hz,1H),6.34(d,J=5.2Hz,1H),5.50(s,1H) ,4.55-4.63(m,1H),3.84(d,J=9.3Hz,1H),3.40(s,3H),3.11(d,J=5.1Hz,3H),2.34(dd ,J=19.2,8.8Hz,1H),2.21–2.14(m,4H),1.75(d,J=9.4Hz,1H),1.52(d,J=10.3Hz,1H).

[0771] Example 54: Synthesis of Compound 54

[0772]

[0773] Step 1: Synthesis of Compound 54-1

[0774] Compound 53-1 (0.30 g, 1.12 mmol), bis(triphenylphosphine)palladium dichloride (0.16 g, 0.22 mmol), cuprous iodide (0.043 g, 0.22 mmol), and triethylamine (0.57 g, 5.60 mmol) were added to the reaction flask under nitrogen protection. THF (5 mL) was added, and the mixture was heated to 50 °C. Triisopropylsilylacetylene (0.25 g, 1.34 mmol) was slowly added dropwise. After 2.5 h, TLC analysis showed that the reaction was complete. DCM (50 mL) was added, followed by washing with saturated ammonium chloride solution (15 mL × 2). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using DCM / EA (v / v = 20 / 1-5 / 1) as eluent, yielding 0.38 g of a yellow solid, with a yield of 91.79%. MS (ESI, pos.ion) m / z: 369.3 [M+H] + .

[0775] Step 2: Synthesis of Compound 54-2

[0776] Compounds 54-1 (0.20 g, 0.54 mmol), 18-1 (0.23 g, 0.54 mmol), BrettPhos-G3-Pd (0.049 g, 0.054 mmol), BrettPhos (0.058 g, 0.11 mmol), and cesium carbonate (0.35 g, 1.08 mmol) were added to a reaction flask under nitrogen protection. Then, 1,4-dioxane (5 mL) was added, and the mixture was heated to 80 °C. After 2.3 h, TLC analysis showed that the starting material had reacted completely. DCM (30 mL) was added, and the mixture was washed once with water (8 mL). The organic phase was evaporated to dryness and purified by column chromatography using DCM / EA (v / v = 15 / 1-3 / 1) as the eluent, yielding 0.28 g of a yellow solid, with a yield of 67.71%. MS (ESI, pos.ion) m / z: 762.4 [M+H] + ; 1HNMR (400MHz, CDCl3) δ9.26(s,1H),8.73(s,1H),8.47(s,1H),8.41(dd,J=7.3,1.6Hz,1H),8.16(d,J=8.7Hz,1H ),8.00(s,1H),7.66(dd,J=7.2,1.6Hz,1H),7.18(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),6.50(t,J=7.3Hz,1H) ,5.56(s,1H),5.17(s,2H),4.67–4.55(m,1H),3.87–3.84(m,1H),3.81(s,3H),3.41(s,3H),3.08(s,3H),2.34( dd,J=19.4,9.8Hz,1H),2.17(dd,J=18.0,9.0Hz,1H),1.81–1.75(m,1H),1.56–1.48(m,1H),1.20–1.16(m,21H).

[0777] Step 3: Synthesis of Compound 54-3

[0778] Compound 54-2 (0.27 g, 0.35 mmol), dichloromethane (5 mL), and trifluoroacetic acid (2.39 g, 21 mmol) were added to the reaction flask and stirred at room temperature. After 2 hours, TLC analysis indicated complete reaction of the starting material. The mixture was cooled to 0 °C, and the pH was adjusted to 8 with pre-cooled 20% potassium phosphate solution. 50 mL of DCM was added for extraction and separation. The organic phase was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0 - 50 / 1) as the eluent, yielding 215 mg of a yellow solid (94.54% yield). MS (ESI, pos.ion) m / z: 642.3 [M+H] + .

[0779] Step 4: Synthesis of Compound 54

[0780] Compound 54-3 (195 mg, 0.30 mmol) and tetrahydrofuran (3 mL) were added to the reaction flask, and the mixture was cooled to 0 °C. Tetrabutylammonium fluoride (0.36 mL, 0.36 mmol) was then added dropwise. TLC analysis after 27 min showed that the reaction proceeded completely. The reaction was quenched with ice water (10 mL), and then extracted with DCM (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to give 90 mg of a pale yellow solid, with a yield of 61.49%. MS (ESI, pos.ion) m / z: 486.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 9.09 (s, 1H), 8.91 (s, 1H), 8.37 (dd, J = 7.3, 1.3Hz, 1H), 8.22 (s ,1H),8.07(d,J=9.1Hz,1H),7.95(q,J=4.2Hz,1H),7.64(dd,J=7.0,1.4Hz,1H),6.52(t,J=7.2Hz,1 6.24 (s, 1H), 4.84 (s, 1H), 4.38–4.25 (m, 1H), 3.73 (dd, J = 15.1, 7.5 Hz, 1H), 3.22 (s, 3H), 2.92 (d, J = 4.8 Hz, 3H), 2.18–2.03 (m, 2H), 1.55–1.47 (m, 1H), 1.41 (dd, J = 19.3, 9.6 Hz, 1H). Example 55: Synthesis of compound 55

[0781]

[0782] Step 1: Synthesis of Compound 55-1

[0783] 5-Bromo-2-iodopyridine (1 g, 3.52 mmol), bis(triphenylphosphine)palladium dichloride (0.49 g, 0.70 mmol), cuprous iodide (0.13 g, 0.70 mmol), triethylamine (1.78 g, 17.6 mmol), tetrabutylammonium fluoride (3.5 mL, 3.52 mmol), and tetrahydrofuran (13 mL) were added to a reaction flask under nitrogen protection. Then, 1-(trimethylsilyl)-1-propyne (0.40 g, 3.52 mmol) was slowly added dropwise. The reaction was carried out at room temperature for 4 h, and TLC showed that the starting material reacted completely. Extraction was performed with DCM (50 mL) and ammonium chloride solution (20 mL). The organic phase was evaporated to dryness, and column chromatography was performed using PE / EA (v / v = 10 / 1). The eluent was collected and evaporated to dryness, yielding 0.3 g of a pale yellow viscous solid, with a yield of 43.44%.

[0784] Step 2: Synthesis of compound 55-2

[0785] Compound 55-1 (0.2 g, 1.02 mmol), 3-amino-2-hydroxypyridine (0.17 g, 1.53 mmol), cuprous iodide (0.039 g, 0.20 mmol), potassium carbonate (0.14 g, 1.02 mmol), and N,N'-dimethylethylenediamine (0.090 g, 1.02 mmol) were added to a 50 mL single-necked flask under nitrogen protection. 1,4-dioxane (10 mL) was added, and the mixture was reacted at 110 °C for 16 h. TLC analysis revealed a small amount of reactant remaining. The reaction mixture was filtered, and 15 mL of saturated ammonium chloride solution was added. Extraction was performed with 30 mL of ethyl acetate. The organic phase was dried, concentrated, and purified by DCM / EA (v / v) = 3 / 1 column chromatography (215 mg) to give a yellow solid, yielding 93.56%. MS (ESI, pos.ion) m / z: 226.1 [M+H] + .

[0786] Step 3: Synthesis of Compound 55-3

[0787] Compounds 18-1 (0.3 g, 0.70 mmol), 55-2 (0.16 g, 0.70 mmol), cesium carbonate (0.46 g, 1.4 mmol), BrettPhos-G3-Pd (0.063 g, 0.070 mmol), and BrettPhos (0.075 g, 0.14 mmol) were added to a 50 mL double-necked flask. Under nitrogen protection, 1,4-dioxane (18 mL) was added, and the reaction was carried out at 80 °C for about 4 h. TLC analysis showed that the reaction proceeds were completely reacted. The reaction solution was filtered, the filtrate was concentrated, and purified by DCM / EA (v / v) = 4 / 1 column chromatography to obtain 365 mg of green solid, with a yield of 84.54%. MS (ESI, pos.ion) m / z: 619.3 [M+H] + .

[0788] Step 4: Synthesis of Compound 55

[0789] Compound 55-3 (365 mg, 0.59 mmol), DCM (15 mL), and trifluoroacetic acid (2.02 g, 17.7 mmol) were added to a 50 mL single-necked flask and reacted at room temperature for 2 h. TLC analysis showed the reactants were completely reacted. The pH was adjusted to approximately 7 with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by DCM / MeOH (v / v = 70 / 1) column chromatography to give 145 mg of a blue solid, yielding 48.06%. MS (ESI, pos.ion) m / z: 499.1 [M+H] + ; 1H NMR(400MHz, CDCl3)δ8.66(d,J=2.6Hz,1H),8.44(dd,J=7.4,1.8Hz,1H),8.38(s,1H),8.07(s,1H),8.00 (d,J=8.7Hz,1H),7.82(dd,J=8.4,2.6Hz,1H),7.54(d,J=8.4Hz,1H),7.06(dd,J=7.0,1.7Hz,1H),6.46– 6.35(m,2H),5.48(s,1H),4.58(q,J=8.5Hz,1H),3.88–3.82(m,1H),3.39(s,3H),3.09(d,J=5.2Hz,3H), 2.38–2.30(m,1H),2.18(d,J=9.2Hz,1H),2.14(s,3H),1.72(dd,J=11.1,9.0Hz,1H),1.57–1.48(m,1H).

[0790] Example 56: Synthesis of Compound 56

[0791]

[0792] Step 1: Synthesis of Compound 56-1

[0793] 3-Methyl-1-butyne (2.0 g, 29.36 mmol) was dissolved in tetrahydrofuran (20 mL), and n-butyllithium (2.26 g, 35.23 mmol) was added dropwise at -78 °C over a period of 2 h. After the addition was complete, the mixture was stirred for 30 min, and paraformaldehyde (1.06 g, 35.23 mmol) was added. The mixture was then allowed to react at room temperature for 16 h. The reaction was quenched with 50 mL of saturated ammonium chloride, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA (v / v = 10 / 1) to give 1.78 g of a pale yellow oil, with a yield of 61.78%. Step 2: Synthesis of compound 56-2

[0794] Compound 56-1 (0.5 g, 5.09 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (0.52 g, 5.09 mmol) was added. Methanesulfonyl chloride (0.58 g, 5.09 mmol) was added dropwise at 0 °C. The mixture was then stirred at 25 °C for 18 h. TLC monitoring showed that the reaction proceeded completely. The reaction was quenched with hydrochloric acid (1 mol / L, 2 mL), washed with saturated sodium bicarbonate (10 mL), and the organic phase was washed with saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated to give 0.72 g of a pale yellow oil, with a yield of 80.19%.

[0795] Step 3: Synthesis of Compound 56-3

[0796] Compound 56-2 (0.70 g, 3.94 mmol), 3-amino-2-hydroxypyridine (0.29 g, 2.63 mmol), potassium carbonate (0.80 g, 5.79 mmol), and DMF (4 mL) were added to a 50 mL single-necked flask. The reaction was carried out at 60 °C for 12.5 h. The reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), extracted with diethyl ether (50 mL), washed with water (3 × 25 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:1) to obtain 118 mg of a yellow oil, with a yield of 23.55%. MS (ESI, pos.ion) m / z: 191.20 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.11 (dd, J=6.9, 1.4Hz, 1H), 6.59-6.48 (m, 1H), 6.13 (t, J=7.0Hz,1H),4.77(d,J=2.0Hz,2H),2.69-2.51(m,3H),1.18(d,J=6.9Hz,6H).

[0797] Step 4: Synthesis of compound 56-4

[0798] Compounds 18-1 (270 mg, 0.62 mmol), 56-3 (118 mg, 0.62 mmol), BrettPhos-G3-Pd (56 mg, 0.062 mmol), BrettPhos (67 mg, 0.12 mmol), and cesium carbonate (400 mg, 1.24 mmol) were added to a 25 mL double-necked flask, purged three times with nitrogen, and then 1,4-dioxane (5 mL) was added, purged three times with nitrogen. The mixture was heated to 80 °C and reacted. After 13.5 h, TLC monitoring showed that the starting materials had basically reacted completely. The reaction solution was concentrated, dissolved in DCM (50 mL), washed with saturated ammonium chloride solution (10 mL), separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was then evaporated to dryness and purified by column chromatography (DCM / EA(v / v) = 20 / 1) to obtain 276 mg of a pale yellow solid, with a yield of 76.23%. MS(ESI,pos.ion)m / z:584.35[M+H] + .

[0799] Step 5: Synthesis of Compound 56

[0800] Compound 56-4 (276 mg, 0.47 mmol) and dichloromethane (4 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (3.22 g, 28.2 mmol). The reaction was carried out at 25 °C for 2 h. TLC monitoring showed complete reaction of the starting material. DCM (25 mL) was added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the aqueous phase was extracted once more with DCM (25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / EA (v / v) = 3 / 2) to give 156 mg of a light green solid, yield 71.17%. MS (ESI, pos.ion) m / z: 464.25 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ8.98(s,1H),8.24(dd,J=7.4,1.5Hz,1H),8.20(s,1H),8.06(d,J=9.1Hz,1H),7.9 3(d,J=4.9Hz,1H),7.49(dd,J=6.9,1.6Hz,1H),6.35(t,J=7.1Hz,1H),6.21(s,1H),4.83(d,J=1.8Hz,2H) ,4.37-4.24(m,1H),3.69(q,J=7.6Hz,1H),3.20(s,3H),2.91(d,J=4.8Hz,3H),2.61(dt,J=13.7,6.9Hz,1 H),2.18–2.02(m,2H),1.51(dd,J=19.2,9.0Hz,1H),1.37(dd,J=19.2,9.6Hz,1H),1.11(d,J=6.9Hz,6H).

[0801] Example 57: Synthesis of Compound 57

[0802]

[0803]

[0804] Step 1: Synthesis of Compound 57-1

[0805] 3-Amino-2-hydroxypyridine (1 g, 9.08 mmol), 4-dimethylaminopyridine (0.055 g, 0.45 mmol), and DCM (15 mL) were added to a 50 mL single-necked flask, followed by triethylamine (1.38 g, 13.62 mmol), and then Boc anhydride (2.18 g, 9.99 mmol). The reaction was carried out at room temperature. After 3.5 h, TLC analysis showed that the starting material had completely reacted. The reaction solution was washed with water (5 mL × 2), and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The solution was purified by column chromatography (DCM / EA (v / v) = 5 / 1) to give 0.32 g of an off-white solid. Yield: 16.76%. MS (ESI, pos.ion) m / z: 233.1 [M + Na] + ; 1 HNMR (400MHz, CDCl3) δ12.65(s,1H),8.12(d,J=6.6Hz,1H),7.58(s,1H),7.02(dd,J=6.6,1.7Hz,1H),6.34(t,J=7.0Hz,1H),1.54(s,9H).

[0806] Step 2: Synthesis of Compound 57-2

[0807] The starting materials 3-butyn-2-ol (1.0 g, 14.27 mmol), DCM (10 mL), and triethylamine (1.44 g, 14.27 mmol) were added to a reaction flask, cooled to 0 °C, and methanesulfonyl chloride (1.63 g, 14.27 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature. TLC analysis after 3 h showed that the starting materials had largely reacted. DCM (30 mL) was added, followed by washing with saturated sodium chloride solution (10 mL × 2). The organic phase was evaporated to dryness to give 2.42 g of an oily liquid, with a yield of 100%.

[0808] Step 3: Synthesis of Compound 57-3

[0809] Compound 57-1 (0.16 g, 0.74 mmol), potassium tert-butoxide (0.083 g, 0.74 mmol), and DME (3 mL) were added to a reaction flask and stirred at room temperature for 20 min. Then, a 1 mL dilution of DME in the form of compound 57-2 (0.11 g, 0.74 mmol) was added, followed by potassium carbonate (0.072 g, 0.52 mmol). The mixture was heated to 60 °C. After 2 h, TLC analysis showed that the reaction proceeded completely. The mixture was concentrated, dissolved in 40 mL of DCM, washed once with 8 mL of water and once with saturated sodium chloride solution, and the organic phase was evaporated to dryness. The solution was purified by column chromatography (PE / DCM (v / v) = 10 / 1 - 1 / 1) to give 137.8 mg of a pale yellow oil, yield 70.77%. MS (ESI, pos.ion) m / z: 263.2 [M+H]+ .

[0810] Step 4: Synthesis of compound 57-4

[0811] Compound 57-3 (237 mg, 0.90 mmol), DCM (5 mL), and trifluoroacetic acid (1.03 g, 9 mmol) were added to the reaction flask and stirred at room temperature. After 2 hours, TLC analysis showed that the starting material had largely reacted. The pH was adjusted to 8 with 20% potassium phosphate solution, and DCM (30 mL) was added for extraction and separation. The organic phase was evaporated to dryness and purified by column chromatography using DCM as the eluent, yielding 104 mg of a red oily substance. Yield: 70.97%. MS (ESI, pos.ion) m / z: 163.1 [M+H] + ; 1 H NMR(400MHz, CDCl3) δ7.19(dd,J=7.0,1.6Hz,1H),6.54(dd,J=7.1,1.6Hz,1H),6.17(t,J =7.1Hz, 1H), 6.00 (qd, J = 6.9, 2.4Hz, 1H), 2.46 (t, J = 12.5Hz, 1H), 1.58 (d, J = 6.9Hz, 3H).

[0812] Step 5: Synthesis of compound 57-5

[0813] Compound 18-1 (0.27 g, 0.62 mmol), BrettPhos-G3-Pd (0.056 g, 0.062 mmol), BrettPhos (0.067 g, 0.12 mmol), and cesium carbonate (0.40 g, 1.24 mmol) were added to the reaction flask under nitrogen protection. Compound 57-4 (0.10 g, 0.62 mmol) was dissolved in 1,4-dioxane (5 mL) and added to the reaction flask. The mixture was then purged with nitrogen again, and the temperature was raised to 80 °C. TLC analysis after 1 h showed complete reaction of the starting material. The mixture was filtered, the filtrate was evaporated to dryness, and purified by column chromatography (DCM / EA(v / v) = 20 / 1-5 / 1) to give 0.16 g of a yellow solid, yield 46.70%. MS (ESI, pos.ion) m / z: 556.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.45(s,1H),8.32(d,J=6.5Hz,1H),8.16(d,J=8.8Hz,1H),7.98(s,1H),7.50(dd,J=7.0,1.6Hz, 1H),7.18(d,J=8.6Hz,2H),6.87(d,J=8.7Hz,2H),6.40(t,J=7.2Hz,1H),6.00(qd,J=6.8,2.4Hz,1H),5.53(s,1H),5.1 5(s,2H),4.66–4.53(m,1H),3.88–3.76(m,4H),3.39(s,3H),3.07(s,3H),2.58(dd,J=2.4,1.2Hz,1H),2.33(dd,J=19. 4,9.5Hz,1H),2.16(dd,J=18.4,9.0Hz,1H),1.75(dd,J=19.1,10.0Hz,1H),1.64(s,3H),1.53(dd,J=20.0,9.4Hz,1H).

[0814] Step 6: Synthesis of Compound 57

[0815] Compound 57-5 (0.16 g, 0.29 mmol), DCM (3 mL), and trifluoroacetic acid (1.98 g, 17.4 mmol) were added to the reaction flask and stirred at room temperature. After 2 hours, TLC analysis showed the reaction was complete. The mixture was cooled to 0 °C, and the pH was adjusted to 8 with pre-cooled 20% potassium phosphate solution. DCM (30 mL) was added for extraction and separation. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Column chromatography (DCM / MeOH (v / v) = 1 / 0-50 / 1) was used for purification, yielding 98 mg of a yellow solid. Yield: 78.15%. MS (ESI, pos.ion) m / z: 436.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.41–8.29(m,2H),8.10–7.95(m,2H),7.49(d,J=6.6Hz,1H),6.39(t,J=7.2 Hz,2H),6.01(dt,J=6.7,4.5Hz,1H),5.46(s,1H),4.68–4.51(m,1H),3.83(dd,J=15.0,7.4Hz,1H ),3.38(s,3H),3.08(d,J=5.1Hz,3H),2.58(s,1H),2.31(dd,J=19.0,9.4Hz,1H),2.15(dd,J=18. 1,8.8Hz,1H),1.73(dd,J=19.7,10.3Hz,1H),1.65(d,J=6.7Hz,3H),1.51(dd,J=19.7,9.9Hz,1H).

[0816] Example 58: Synthesis of Compound 58

[0817]

[0818] Step 1: Synthesis of Compound 58-1

[0819] 5-Bromo-2,3-difluoropyridine (4 g, 20.62 mmol), 3-amino-2-hydroxypyridine (2.27 g, 20.62 mmol), cesium carbonate (13.44 g, 41.24 mmol), and N,N-dimethylacetamide (40 mL) were added to a 100 mL reaction flask, and the mixture was heated to 95 °C and reacted for 8 h. TLC analysis showed that the reactants were completely reacted. Water (160 mL) was added, and the mixture was extracted with EA (160 mL × 3). The organic phases were combined, washed with sodium chloride solution (120 mL × 3), dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography (PE / EA (v / v) = 3 / 1) was used to purify the solid, yielding 4.56 g of a green solid. Yield: 77.84%. MS (ESI, pos.ion) m / z: 284.0 [M+H] + .

[0820] Step 2: Synthesis of Compound 58-2

[0821] Compound 58-1 (0.2 g, 0.70 mmol), triisopropylsilylacetylene (0.13 g, 0.70 mmol), cuprous iodide (0.0067 g, 0.035 mmol), and bis(triphenylphosphine)palladium dichloride (0.025 g, 0.035 mmol) were added to a 50 mL double-necked flask under nitrogen protection. Then, diisopropylamine (6 mL) was added, and the mixture was purged with nitrogen. The temperature was raised to 100 °C and reacted for 3.5 h. TLC analysis showed that the starting material reacted completely. The reaction solution was concentrated, dissolved in EA (10 mL), filtered, and the filter cake was washed with EA (40 mL). The combined organic phases were washed once with water (10 mL) and once with saturated sodium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography (PE / EA (v / v) = 15 / 1-5 / 1 as eluent). The collected sample was evaporated to dryness and weighed to obtain 0.2 g of a brown oily substance. The yield was 73.68%. MS(ESI,pos.ion)m / z: 386.1 [M+H] + .

[0822] Step 3: Synthesis of Compound 58-3

[0823] The starting materials 18-1 (0.2 g, 0.52 mmol), 58-2 (0.17 g, 0.50 mmol), BrettPhos-G3-Pd (0.063 g, 0.070 mmol), BrettPhos (0.075 g, 0.14 mmol), and cesium carbonate (0.46 g, 1.4 mmol) were placed in a double-necked flask, purged with nitrogen, and then 1,4-dioxane (15 mL) was added. The mixture was then purged with nitrogen again, and the temperature was raised to 80 °C for 1.5 h. TLC analysis showed that the reaction was complete. The mixture was filtered, and the filter cake was washed with EA (50 mL). The organic phase was washed once with water (8 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by column chromatography (DCM / EA (v / v) = 15 / 1-3 / 1) to obtain 0.41 g, a yield of 75.42%. MS(ESI,pos.ion)m / z:779.4[M+H] + .

[0824] Step 5: Synthesis of compound 58-4

[0825] 0.4 g (0.51 mmol) of 58-4 and 6 mL of DMF were added to a 2 mL flask, followed by 0.15 g (1.02 mmol) of cesium fluoride. The reaction was carried out at room temperature for 2 h. TLC analysis showed that the starting material was completely reacted. 20 mL of water was added, and the mixture was extracted with EA (25 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography (DCM / EA (v / v) = 1 / 0-5 / 1). 0.27 g of a brown oily substance was obtained, with a yield of 84.45%. MS (ESI, pos.ion) m / z: 623.2 [M+H] + .

[0826] Step 6: Synthesis of Compound 58

[0827] The starting material 58-5 (0.27 g, 0.43 mmol) was added to DCM (10 mL), stirred until dissolved, and then trifluoroacetic acid (3.92 g, 34.4 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 4.5 h. TLC analysis showed that the reaction was complete. The reaction was stopped, DCM (10 mL) was added, the temperature was lowered to 0 °C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The mixture was separated, and the organic phase was evaporated to dryness. Column chromatography (DCM / MeOH (v / v) = 1 / 0-25 / 1) was used to purify the product, yielding 0.18 g of a white solid (82.61% yield). MS (ESI, pos.ion) m / z: 503.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.55(s,1H),8.45(d,J=7.3Hz,1H),8.40(s,1H),8.03(d,J=10.4Hz,2H),7. 77(d,J=8.1Hz,1H),7.21(d,J=6.9Hz,1H),6.46(t,J=7.2Hz,1H),6.31(d,J=5.2Hz,1H),5.48(s,1 H),4.66–4.52(m,1H),3.86(dd,J=15.2,7.6Hz,1H),3.41(d,J=4.4Hz,4H),3.11(d,J=5.2Hz,3H), 2.34(dd,J=19.5,9.6Hz,1H),2.17(dd,J=18.3,9.7Hz,1H),1.78–1.71(m,1H),1.56–1.50(m,1H).

[0828] Example 59: Synthesis of Compound 59

[0829]

[0830]

[0831] Step 1: Synthesis of Compound 59-1

[0832] Add cuprous iodide (0.34 g, 1.77 mmol), potassium carbonate (2.44 g, 17.67 mmol), 3-amino-2-hydroxypyridine (0.78 g, 7.07 mmol), and 2,6-dibromo-4-fluoropyridine (1.5 g, 5.89 mmol) to a 100 mL double-necked flask, purge with nitrogen, and then dissolve N,N'-dimethylethylenediamine (0.26 g, 2.94 mmol) in 1,4-dioxane (11... The reactants were added to the flask and reacted at room temperature. After about 17 hours, TLC monitoring showed that the reactants had basically reacted completely. The mixture was filtered, and the filter cake was washed with 50 mL of dichloromethane. The organic phase was collected, washed once with 20 mL of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA (v / v = 5 / 1) to give 0.4 g of white solid, yield 23.93%. MS (ESI, pos.ion) m / z: 284.0 [M+H] + .

[0833] Step 2: Synthesis of Compound 59-2

[0834] Compound 59-1 (0.15 g, 0.53 mmol), cuprous iodide (0.02 g, 0.11 mmol), and palladium dichloride (0.074 g, 0.11 mmol) were added to a 50 mL double-necked flask and purged with nitrogen. Then, 1-(trimethylsilyl)propyne (0.071 g, 0.64 mmol), triethylamine (0.27 g, 2.65 mmol), and tetrahydrofuran (5 mL) were added to the flask. Tetrabutylammonium fluoride (0.80 mL, 0.80 mmol) was then added dropwise at room temperature. After reacting at room temperature for approximately 1.5 h, TLC monitoring showed that the reactants had essentially completed the reaction. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 mL). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. Purified by column chromatography (PE / EA (v / v) = 5 / 1-4 / 1) to give 0.1 g of pale yellow solid, yield 77.86%. MS (ESI, pos.ion) m / z: 242.3 [M+H] + .

[0835] Step 3: Synthesis of Compound 59-3

[0836] Compound 18-1 (210 mg, 0.49 mmol), BrettPhos-G3-Pd (37 mg, 0.041 mmol), BrettPhos (44 mg, 0.082 mmol), cesium carbonate (270 mg, 0.82 mmol), and compound 59-2 (100 mg, 0.41 mmol) were added to a 50 mL double-necked flask. The flask was purged with nitrogen, and then 1,4-dioxane (5 mL) was added to the flask. The temperature was raised to 80 °C, and the reaction was monitored by TLC after approximately 2 hours. Once the reactants had largely reacted, the mixture was filtered. The filter cake was washed with dichloromethane (20 mL), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solution was purified by column chromatography (DCM / EA(v / v) = 1 / 0-9 / 1) to give 160 mg of a yellow solid, with a yield of 61.13%. 1 H NMR(400MHz, CDCl3) δ8.46(s,1H),8.38(dd,J=7.3,1.6Hz,1H),8.17(d,J=8.5Hz,1H),7.99(s,1H),7 .74(dd,J=9.3,2.0Hz,1H),7.68(dd,J=7.2,1.6Hz,1H),7.21–7.15(m,3H),6.87(d,J=8.6Hz,2H),6. 43(t,J=7.3Hz,1H),5.54(s,1H),5.17(s,2H),4.65–4.58(m,1H),3.86(t,J=7.6Hz,1H),3.81(s,3H) ,3.40(s,3H),3.09(s,3H),2.34(dd,J=18.9,9.1Hz,2H),2.14(s,3H),1.76(dd,J=19.0,9.9Hz,2H).

[0837] Step 4: Synthesis of Compound 59

[0838] Compound 59-3 (0.21 g, 0.35 mmol) and dichloromethane (11 mL) were added to a 100 mL single-necked flask. After stirring and dissolving at room temperature, trifluoroacetic acid (2.39 g, 21 mmol) was added dropwise. The reaction was allowed to proceed at room temperature. After approximately 2 hours, TLC analysis showed t...

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), in, R 1 and R 2 Each independently is H, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein said R 1 and R 2 Each independently optionally substituted by 1, 2, 3 or 4 selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Substituted with hydroxyalkyl and -C(=O)NH2 substituents; R 3 OH, NH2, NHOH, -NHOC 1-6 Alkyl, -NR 5 R 6 、-NHR 5 or -NH(CR 7 R 8 ) m R 6 ; R 5 and R 6 Each independently is C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein said R 5 and R 6 Each independently optionally substituted by 1, 2, 3 or 4 selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Hydroxyalkyl, -C(=O)OC 1-6 Alkyl, -C(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)C 1-6 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 Alkyl)2, -NH(C 1-6 Alkyl) and -N(C 1-6 alkyl)2 is substituted by a substituent; R 7 and R 8 Each independently is H, D, F, Cl, Br, I, OH, CN, NH2, COOH or C 1-6 Alkyl; or, R 7 , R 8 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; A 1 C 6-10 Arylene, 5-10 membered heteroarylene, C 3-6 Cycloalkylene or 5-7 membered heterocyclylene, wherein the A 1 Optionally 1, 2, 3 or 4 R 9 replaced; wherein each R 9 are independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C(=O)OC 1-6 Alkyl, -C(=O)C 1-6 Alkyl, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)2; A 2 C 1-6 Alkylene, C 6-10 Arylene, 5-10 membered heteroarylene, C 3-6 Cycloalkylene or 3-6 membered heterocyclylene; wherein A 2 Optionally, 1, 2, 3 or 4 selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C(=O)OC 1-6 Alkyl, -C(=O)C 1-6 Alkyl, -NH(C 1-6 Alkyl) and -N(C 1-6 alkyl)2 is substituted by a substituent; L is a covalent bond, C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O- or -NH-C 1-6 Alkylene, wherein said L is optionally substituted by 1, 2, 3 or 4 groups selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl) and -N(C 1-6 alkyl)2 is substituted by a substituent; R 4 H, D, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(=O)OC 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)C 1-6 Alkyl, -C(=O)NH2, -C(=O)-(C 3-6 Cycloalkyl), -C(=O)-(3-6 membered heterocyclyl), -C(=O)NH(C 1-6 alkyl) or -C(=O)N(C 1-6 Alkyl)2; wherein R 4 Optionally, 1, 2, 3 or 4 selected from F, Cl, Br, I, CN, OH, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, -C(=O)OC 1-6 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 Alkyl)2, -S(=O)2C 1-6 Alkyl and -S(=O)C 1-6 substituted with an alkyl substituent; and m is 0, 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1, wherein R 1 and R 2 Each independently is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said R 1 and R 2 Each independently optionally substituted by 1, 2, 3 or 4 selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 The group may be substituted with hydroxyalkyl and -C(=O)NH2.

3. The compound according to claim 1 or 2, wherein R 1 and R 2 Each is independently H, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-oxirane, 1,4-dioxanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiopyranyl, pyridinyl, pyrimidinyl or pyrazinyl, wherein R 1 and R 2 Each is independently optionally substituted by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH3)2OH, -(CH2)3CH2OH and -C(=O)NH2.

4. The compound according to any one of claims 1 to 3, wherein R 3 OH, NH2, NHOH, -NHOC 1-4 Alkyl, -NR 5 R 6 、-NHR 5 or -NH(CR 7 R 8 ) m R 6 , or R 3 For OH, NH2, NHOH, -NHOCH3, -NHOCH2CH3, -NHO(CH2)2CH3, -NHOCH(CH3)2, -NHOC(CH3)3, -NHO(CH2)3CH3, -NR 5 R 6 、-NHR 5 or -NH(CR 7 R 8 ) m R 6 .

5. The compound according to any one of claims 1 to 4, wherein R 5 and R 6 Each independently is C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, wherein the R 5 and R 6 Each independently optionally substituted by 1, 2, 3 or 4 selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyalkyl, -C(=O)OC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -S(=O)C 1-4 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 Alkyl)2, -NH(C 1-4 Alkyl) and -N(C 1-4 alkyl)2 is substituted by a substituent; R 7 and R 8 Each independently is H, D, F, Cl, Br, I, OH, CN, NH2, COOH or C 1-4 Alkyl; or, R 7 , R 8 Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group.

6. The compound according to any one of claims 1 to 5, wherein R 5 and R 6 Each is independently -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 1,2-oxirane, 1,4-dioxanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiopyranyl, pyridinyl, pyrimidinyl or pyrazinyl, wherein R 5 and R 6 each independently optionally represented by 1, 2, 3 or 4 selected from D, F, Cl, Br, I, CN, OH, NH2, COOH, -CD3, -CH3, -CH2CH3, -CD2CD3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -CH2OH, -CH2CH2OH, -(CH2)2CH2OH, -CH(CH 3) substituted by a substituent selected from the group consisting of -2OH, -(CH2)3CH2OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NHCH3, -NHCH2CH3, -N(CH3)2 and -N(CH2CH3); R 7 and R 8 each independently represents H, D, F, Cl, Br, I, OH, CN, NH2, COOH, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, or -CH2C(CH3)3; or, R 7 , R 8 Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-oxiranyl, 1,4-dioxanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl or hexahydropyrimidinyl group.

7. The compound according to any one of claims 1 to 6, wherein A 1 for The A 1 Optionally 1, 2, 3 or 4 R 9 replaced; wherein each R 9 are independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -C(=O)OC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -NH(C 1-4 Alkyl) or -N(C 1-4 alkyl)2; or A 1 for Among them, "*" indicates connection with -NH-, and "**" indicates connection with -A 2 - connection, where the A 1 Optionally 1, 2, 3 or 4 R 9 replaced; wherein each R 9 are independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, - OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(C H3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) or -N(CH3)2.

8. The compound according to any one of claims 1 to 7, wherein A 2 C 1-4 Alkylene, The A 2 Optionally, 1, 2, 3 or 4 selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -C(=O)OC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -NH(C 1-4 Alkyl) and -N(C 1-4 alkyl)2; or A 2 -CH2-, -(CH2)2-, -(CH3)2-, -CH(CH3)-, Among them, "**" indicates the same as -A 1 - connection, "***" indicates connection with -L-, wherein the A 2 optionally substituted by 1, 2, 3 or 4 selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) and -N(CH3)2 substituents.

9. The compound according to any one of claims 1 to 8, wherein L is a covalent bond, C 1-4 Alkylene, -OC 1-4 Alkylene-, -C 1-4 Alkylene-O- or -NH-C 1-4 Alkylene, wherein said L is optionally substituted by 1, 2, 3 or 4 groups selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -NH(C 1-4 Alkyl) and -N(C 1-4 alkyl)2; or L is a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -OCH2-, -O(CH2)2-, -O(CH2)3-, -O(CH2)4-, -CH2O-, -(CH2)2O-, -(CH2)3O-, -(CH2)4O-, -NHCH2-, -NH(CH2)2-, -NH(CH2)3- or -NH(CH2)4-, wherein said L is optionally substituted by 1, 2, 3 or 4 moieties selected from D, F, Cl, Br, I, CN, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -NH(CH2CH3), -N(CH3)(CH2CH3) and -N(CH3)2 substituents.

10. The compound according to any one of claims 1 to 9, wherein R 4 H, D, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -C(=O)OC 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -S(=O)C 1-4 Alkyl, -C(=O)NH2, -C(=O)-(C 3-6 Cycloalkyl), -C(=O)-(3-6 membered heterocyclyl), -C(=O)NHC 1-4 Alkyl or -C(=O)N(C 1-4 Alkyl)2; wherein R 4 Optionally, 1, 2, 3 or 4 selected from F, Cl, Br, I, CN, OH, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkoxy, -C(=O)OC 1-4 Alkyl, -C(=O)NH2, -C(=O)NH(C 1-4 alkyl), -C(=O)N(C 1-4 Alkyl)2, -S(=O)2C 1-4 Alkyl and -S(=O)C 1-4 The alkyl group is substituted with an alkyl substituent.

11. The compound according to any one of claims 1 to 10, wherein R 4 H, D, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2-oxirane, 1,4-dioxanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidine phenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiopyranyl, pyridyl, pyrimidinyl, pyrazinyl, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH2CH3, -S(=O)2(CH 2)2CH3, -S(=O)2CH(CH3)2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH3, -S(=O)(CH2)2CH3, -C(=O)NH2, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-azetidinyl, -C(=O)-oxetanyl, -C(=O)-pyrrolidinyl , -C(=O)-pyrazolidinyl, -C(=O)-imidazolidinyl, -C(=O)-tetrahydrofuranyl, -C(=O)-tetrahydrothiopyranyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-morpholinyl, -C(=O)-hexahydropyrimidinyl, -C(=O)NHCH3, -C(=O)NH(CH2CH3), -C(=O)N(CH3)(CH2CH3) or -C(=O)N(CH3)2; wherein R 4 optionally substituted by 1, 2, 3 or 4 selected from F, Cl, Br, I, CN, OH, NH2, COOH, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2CH(CH3)2, -CH2C(CH3)3, -CF3, -CHF2, -CH2F, -CH2CF3, -CCl3, -CH2Cl3, -CH2CH2F, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH(CH3)2, -OC(CH2)3CH3, -OCH2OCH3, -O(CH2)2OCH3, -O(CH2)2OCH2CH3, -OCH2OCH2CH3, -C(= -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)O(CH2)3CH3, -C(=O)OCH(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)N(CH3)2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH2CH3, -S(=O)2(CH2)2CH3, -S(=O)2CH(CH3)2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH3, -S(=O)CH2CH3, -S(=O)(CH2)2CH3 and -S(=O)CH(CH3)2 are substituted by substituents selected from the group consisting of: -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -S(=O)CH2CH3, -S(=O)(CH2)2CH3 and -S(=O)CH(CH3)2.

12. A compound according to any one of claims 1 to 11, which is a compound represented by formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound represented by formula (II), in, R 1 , R 3 , A 2 , L, R 9 and R 4 Each has the definition as described in any one of claims 1 to 11.

13. The compound according to any one of claims 1 to 12, which is a compound of the following structure, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, 14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.

15. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing, treating or alleviating TYK2-related diseases.

16. The use according to claim 15, wherein The TYK2-mediated disease is rheumatoid arthritis, psoriasis, diabetes, ankylosing spondylitis, vitiligo, atopic dermatitis, lupus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, cancer, transplant rejection or a neurological disorder.

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