Pyrimidopyrazole compound, and pharmaceutical composition thereof and use thereof

Abstract

The present invention relates to the field of medicines. Specifically, the present invention relates to a pyrimidopyrazole compound, and a pharmaceutical composition thereof and a use thereof. Specifically, the present invention relates to a compound of formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), wherein each variable has the meaning as described in the present invention. The compound and the pharmaceutical composition thereof involved in the present invention, as TYK2 inhibitors, can be used in preparation of medicines for preventing or treating TYK2-related diseases.

Description

Pyrimidopyrazole compounds, pharmaceutical compositions and uses thereof Technical Field

[0001] The present invention belongs to the field of medicine. Specifically, the present invention relates to a pyrimidopyrazole compound as a TYK2 inhibitor, a pharmaceutical composition thereof, and the use of the compound and the pharmaceutical composition thereof in preparing a drug for preventing or treating TYK2-related diseases. Background Art

[0002] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that regulate key events such as cell proliferation, differentiation, apoptosis, and immune responses through activation of 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 shown that TYK2 is closely associated with the development of various inflammatory diseases, such as inflammatory bowel disease, psoriasis, dermatitis, and rheumatoid arthritis. TYK2 deletion mutations can inhibit the development of autoimmune diseases and inflammation associated with the IL-12 and IL-23 pathways. Currently, Ventyx Biosciences' TAK-279 exhibits promising TYK2 inhibitory activity and is still in clinical development. The development of TYK2 inhibitors that can be used as therapeutic agents remains a challenge.

[0003] Summary of the Invention

[0004] The present invention provides a compound, or a pharmaceutical composition thereof, that is useful as a TYK2 inhibitor. The present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by inhibiting TYK2 activity. The disease or condition includes those described herein.

[0005] In one aspect, the present invention provides 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),

[0006] in,

[0007] 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 2Each 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 by hydroxyalkyl and -C(=O)NH2;

[0008] R 3 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 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;

[0010] R 7 and R 8 Each independently represents 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;

[0011] A 1 C 6-10 Arylene, 5-10 membered heteroarylene, C 3-6 Cycloalkylene or 5-7 membered heterocyclylene, wherein said A 1 Optionally 1, 2, 3 or 4 R 9 Replaced by; wherein each R 9 are independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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;

[0012] 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 Halogenated alkyl, 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;

[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 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 Halogenated alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl) and -N(C 1-6 alkyl)2 is substituted by a substituent;

[0014] R 4 H, D, C 1-6 Alkyl, C3-7 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)NHC 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 Halogenated alkyl, 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

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

[0016] In some embodiments, R 1 and R 2 Each independently is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 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 is substituted with a hydroxyalkyl group and a -C(=O)NH2 substituent.

[0017] In some embodiments, R 1 and R 2Each 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 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.

[0018] In some embodiments, 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 ; Among them, R 5 、R 6 、R 7 、R 8 and m each have the meanings as described in the present invention.

[0019] In some embodiments, R5 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 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 1-4 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;

[0020] R 7 and R 8 Each independently represents 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.

[0021] In some embodiments, 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]hexane, 3-oxabicyclo[3.1.0]hexane, 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 6each independently optionally replaced 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)2;

[0022] 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.

[0023] In some embodiments,

[0024] A 1 for The A 1 Optionally 1, 2, 3 or 4 R 9 Replaced by; wherein each R 9 are independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4Alkoxy, -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

[0025] A 1 for

[0026] 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 by; 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.

[0027] In some embodiments, A 2 C 1-4 Alkylene,

[0028] 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 Halogenated alkyl, 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

[0029] A 2-CH2-, -(CH2)2-, -(CH3)2-, -CH(CH3)-, Among them, "**" means -A 1 - connection, "***" means connected with -L-, wherein the A 2 optionally substituted by 1, 2, 3 or 4 moieties 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.

[0030] In some embodiments, 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 Halogenated alkyl, C 1-4 Alkoxy, -NH(C 1-4 Alkyl) and -N(C 1-4 alkyl)2; or

[0031] 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 atoms 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.

[0032] In some embodiments, 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)NH(C 1-4 alkyl) or -C(=O)N(C 1-4 Alkyl) 2, wherein the 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 Halogenated alkyl, 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 substituted by an alkyl substituent.

[0033] In some embodiments, 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, furyl, 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 4Optionally, 1, 2, 3 or 4 of the following are 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(=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.

[0034] In some embodiments, it 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),

[0035] Among them, R 1 、R 3 、A 2 , L, R 9 and R 4 Each has the definition as described in the present invention.

[0036] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0037] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0038] In some embodiments, the adjuvants of the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition can be in liquid, solid, semi-solid, gel or spray form.

[0039] In another aspect, the present invention provides use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing, treating or alleviating TYK2-related diseases.

[0040] In some embodiments, the TYK2-related disease described herein is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplantation-related disorder.

[0041] In some embodiments, the TYK2-mediated disease of the present invention 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.

[0042] In another aspect, the present invention provides the compound or pharmaceutical composition of the present invention for use in preventing, treating or alleviating TYK2-related diseases.

[0043] In some embodiments, the TYK2-mediated disease of the present invention 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.

[0044] In another aspect, the present invention further provides a method for preventing, treating or alleviating TYK2-related diseases, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof to a patient.

[0045] In some embodiments, the TYK2-mediated disease of the present invention 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.

[0046] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds of formula (I) or (II).

[0047] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

[0048] In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically in relation to the other ingredients making up the formulation and the mammal to be treated.

[0049] The salts of the compounds of the present invention also include salts of intermediates used in the preparation or purification of the compounds represented by formula (I) or (II) or separated enantiomers of the compounds represented by formula (I) or (II), but are not necessarily pharmaceutically acceptable salts.

[0050] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0051] Detailed description of the present invention

[0052] Definitions and General Terms

[0053] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0054] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0055] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0056] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0057] The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0058] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0059] "Stereoisomers" refer to compounds with the same chemical structure but with different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formulas described herein are within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein may include enriched isotopes of one or more different atoms.

[0060] Stereochemical definitions and conventions used herein generally follow SP 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.

[0061] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0062] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0063] As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, as described above for the general formula compounds, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the terms "independently optionally substituted with" or "optionally substituted with" are used interchangeably with the term "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of one or more hydrogen atoms in a given structure with a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.

[0064] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0065] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0066] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a 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 the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0067] The term "alkyl" refers to a saturated, linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms and is represented by C 1-6 Alkyl; In another embodiment, the alkyl group contains 1-4 carbon atoms, represented by C 1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, represented by C 1-3Alkyl. 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-Bu, -CH(CH3)CH2CH3), 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, and the like.

[0068] The term "alkylene" refers to a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a saturated straight or branched hydrocarbon. In some embodiments, the alkylene group contains 1 to 6 carbon atoms and is represented by C 1-6 In other embodiments, the alkylene group contains 1-4 carbon atoms and is represented by C 1-4 In other embodiments, the alkylene group contains 1-3 carbon atoms and is represented by C 1-3 In other embodiments, the alkylene group contains 1-2 carbon atoms and is represented by C 1-2 Alkylene. Examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0069] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl and hydroxy groups have the definitions described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with 1, 2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxy groups. In some embodiments, hydroxyalkyl refers to a C 1-6 Hydroxyalkyl, i.e. C 1-6 The alkyl group is substituted with one or more hydroxyl groups, preferably C 1-6 Hydroxyalkyl represents C 1-6 In some embodiments, hydroxyalkyl represents a C 1-4 In some embodiments, hydroxyalkyl represents C 1-3 Examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, -CH2CH(OH)CH2CH(CH3)OH, and the like.

[0070] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions described herein. In some embodiments, the haloalkyl group is C 1-6 Halogenated alkyl, indicating C 1-6 The alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl group is C 1-4 Halogenated alkyl, indicating C 1-4 The alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl group is C 1-3 Halogenated alkyl, indicating C 1-3 The alkyl group is substituted with one or more halogen atoms. Examples 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 the like.

[0071] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, indicating C 1-6 Alkoxy; In another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4 Alkoxy; In another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C1-3 Alkoxy. The alkoxy group can be optionally substituted with one or more substituents described herein. 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-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-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), and the like.

[0072] The term "alkoxyalkoxy" refers to an alkoxy group substituted with one or more alkoxy groups, wherein alkoxy groups have the meaning herein. In some embodiments, alkoxyalkoxy refers to 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.

[0073] The term "deuterated alkoxy" refers to an alkoxy group substituted with deuterium (D), wherein alkoxy has the definition as described herein.

[0074] The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy and halogen have the same meanings as those defined herein. In some embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1-6 In other embodiments, haloalkoxy represents a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C 1-4 In other embodiments, haloalkoxy represents a haloalkoxy group containing 1 to 3 carbon atoms, i.e., C 1-3Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy (—OCF 3 ), monofluoromethoxy (—OCH 2 F), 2-fluoroethoxy (—OCH 2 CH 2 F), and the like.

[0075] The term "carbocycle" or "carbocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic carbon ring system containing 3 to 12 ring atoms, wherein the -CH2- group in the carbocycle may be optionally replaced by -C(=O)- (or -(CO)-). In one embodiment, the carbocyclyl contains 3 to 6 ring carbon atoms and is represented by C 3-6 In other embodiments, the carbocyclyl group is a saturated ring containing 3-6 ring carbon atoms, represented by C 3-6 Cycloalkyl; In other embodiments, the C 3-6 In one embodiment, the carbocyclyl group contains 7 to 12 ring carbon atoms and is represented by C 7-12 In other embodiments, the carbocyclyl group is a saturated ring containing 7-12 ring carbon atoms, represented by C 7-12 Cycloalkyl. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-1H-indenyl, octahydropentalenyl, and the like. Examples of carbocyclic rings in which the -CH2- group may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

[0076] The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic carbon ring system of 3 to 12 carbon atoms, in which the -CH2- group may be optionally replaced by -C(=O)- (or -(CO)-). In one embodiment, the cycloalkyl group contains 3 to 10 ring carbon atoms, i.e., C 3-10 In another embodiment, the cycloalkyl group contains 3-6 ring carbon atoms, i.e., C 3-6 In another embodiment, the cycloalkyl group contains 3-5 ring carbon atoms, i.e., C 3-5 Cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydropentalenyl, and the like. Examples of carbocyclic rings in which the -CH2- group may be replaced by -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

[0077] The terms "heterocycle" and "heterocyclyl" refer to saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring systems containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings. When the heterocycle is attached to the rest of the molecule through a single attachment point, the heterocycle represents a monovalent heterocyclyl. Unless otherwise specified, the heterocyclyl group can be carbon or nitrogen, and the -CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclyl consists of 3-10 atoms, representing a 3-10-membered heterocycle or a 3-10-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-9 atoms, representing a 3-9-membered heterocycle or a 3-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-9 atoms, representing a 5-9-membered heterocycle or a 5-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-6 atoms, representing a 3-6-membered heterocycle or a 3-6-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-6 atoms, representing a 5-6-membered heterocycle or a 5-6-membered heterocyclyl. Examples of the heterocycle include, but are not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.2]octane. The heterocyclic group includes, but is not limited to, oxirane, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl.

[0078] The term "aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, 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 and is represented by C 6-12 In some embodiments, the aryl group contains 6-10 ring atoms and is represented by C 6-10 Aryl or 6-10 membered aryl. Examples of aryl groups may include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and anthracene. When aryl is used as a linking group, the term "aryl" is represented by arylene, for example, A in formula (I) 2 As a linking group, it can be C 6-10 Arylene.

[0079] The term "heteroaryl" or "heteroaromatic ring" refers to a monovalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. When a -CH2- group is present in the heteroaryl group, the -CH2- group can be optionally replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be attached to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable position (which can be C or N). The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group containing 5-12 ring atoms, represented by a 5-12-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-10 ring atoms, represented by a 5-10-membered heteroaryl group; in other embodiments, the heteroaryl group is a heteroaryl group containing 5-6 ring atoms, represented by a 5-6-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolidinyl, and the like.

[0080] In the present invention, the term "arylene", "heteroarylene", "cycloalkylene" or "heterocyclylene" refers to a divalent group formed when "aryl", "heteroaryl", "cycloalkylene" or "heterocyclyl" is used as a linking group to connect two groups on its left and right sides. For example, when the group A in the compound of general formula (I) of the present 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 heteroaryl group is connected to L and A1.

[0081] The term "halogen" refers to F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).

[0082] The term "oxo" means =0.

[0083] The term "cyano" refers to -CN or -C≡N.

[0084] The term "hydroxy" refers to -OH.

[0085] The term "carboxyl" refers to -C(=O)OH.

[0086] The term "amino" refers to -NH2.

[0087] The term "composed of jk atoms" or "jk-membered" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P; j and k are each independently any non-zero natural number, and k>j; "jk" includes j, k and any natural number in between. For example, “consisting of 3-8 atoms” or “3-8-membered”, “consisting of 3-6 atoms” or “3-6-membered”, “consisting of 5-10 atoms” or “5-10-membered”, or “consisting of 5-6 atoms” or “5-6-membered” means 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, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P.

[0088] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (I-1) in vivo. Such conversion is affected by the prodrug being hydrolyzed in the blood or being converted into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention may be an ester. In the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound.

[0089] "Metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting the compound of the invention with a mammal for a sufficient period of time.

[0090] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., "Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19." Pharmaceutically acceptable salts formed with non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates formed by reaction with amino groups, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or such salts may be obtained by other methods described in the literature, such as ion exchange. The present invention also contemplates quaternary ammonium salts formed from any compound containing a nitrogen group. Water-soluble or oil-soluble or dispersible products may be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium and amine cations that counter-form counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates and aromatic sulfonates.

[0091] The term "solvate" as used herein refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form 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 molecule is water.

[0092] When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be associated with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one water molecule, such as a dihydrate; and in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

[0093] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0094] The terms "prevent" or "prevention" refer to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be at risk or predisposed to the disease but has not yet experienced or displayed symptoms of the disease).

[0095] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.

[0096] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof of the compounds of the present invention are encompassed within the scope of the invention.

[0097] In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated and included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, the stereoisomers of the structure are unambiguous and defined.

[0098] Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. Nitrogen oxides of the compounds of the present invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperatures, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0099] The compound represented by formula (I) or (II) may exist in the form of a salt.

[0100] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the present 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.

[0101] Description of the compounds of the present invention

[0102] The present invention provides a compound, or a pharmaceutical composition thereof, that is useful as a TYK2 inhibitor. The present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by inhibiting TYK2 activity. Such diseases or conditions include those described herein.

[0103] The excellent properties of certain parameters of the compounds of the present invention, such as half-life, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can lead to reduced side effects, expanded therapeutic index or improved tolerability.

[0104] In one aspect, the present invention provides 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),

[0105] Among them, each R 1 、R 2 、R 3 、R 4 、A 1 、A 2 and L each have the meanings as described in the present invention.

[0106] In some embodiments, R 1 and R 2 Each independently is H, C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C6-10 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 The group is substituted with a hydroxyalkyl group and a -C(=O)NH2 substituent.

[0107] In some embodiments, R 1 and R 2 Each independently is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 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 is substituted with a hydroxyalkyl group and a -C(=O)NH2 substituent.

[0108] In some embodiments, 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 2each 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.

[0109] In some embodiments, R 3 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 and m each have the meanings as described in the present invention.

[0110] In some embodiments, R 3 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 and m each have the meanings as described in the present invention.

[0111] In some embodiments, 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 and m each have the meanings as described in the present invention.

[0112] In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6.

[0113] In some embodiments, 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.

[0114] In some embodiments, 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 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 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyalkyl, -C(=O)OC 1-4 Alkyl, -C(=O)C 1-4Alkyl, -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.

[0115] In some embodiments, 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]hexane, 3-oxabicyclo[3.1.0]hexane, 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 replaced 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)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.

[0116] In some embodiments, R 7 and R 8Each independently represents 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.

[0117] In some embodiments, R 7 and R 8 Each independently represents 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.

[0118] In some embodiments, 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.

[0119] In some embodiments, A 1 C 6-10 Arylene, 5-10 membered heteroarylene, C 3-6 Cycloalkylene or 3-6 membered heterocyclylene, wherein said A 1 Optionally 1, 2, 3 or 4 R 9 Replaced by; wherein each R 9 are independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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.

[0120] In some embodiments, A 1 for

[0121] The A 1 Optionally 1, 2, 3 or 4 R 9 Replaced by; wherein each R 9 are independently H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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.

[0122] In some embodiments, 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 by; 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( CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)OCH(CH3)2, -NH(CH2CH3), -N(CH3)(CH2CH3) or N(CH3)2.

[0123] In some embodiments, 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 2Optionally, 1, 2, 3 or 4 selected from D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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.

[0124] In some embodiments, 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 Halogenated alkyl, 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 is substituted by a substituent.

[0125] In some embodiments, A 2 -CH2-, -(CH2)2-, -(CH3)2-, -CH(CH3)-, Among them, "**" means -A 1 - connection, "***" means connected with -L-, wherein the A 2optionally substituted by 1, 2, 3 or 4 moieties 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.

[0126] In some embodiments, 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 Halogenated alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl) and -N(C 1-6 alkyl)2 is substituted by a substituent.

[0127] In some embodiments, 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 Halogenated alkyl, C 1-4 Alkoxy, -NH(C 1-4 Alkyl) and -N(C 1-4 alkyl)2 is substituted by a substituent.

[0128] 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 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.

[0129] In some embodiments, 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 Halogenated alkyl, 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)C1-6 substituted by an alkyl substituent.

[0130] In some embodiments, 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)NH(C 1-4 alkyl) or -C(=O)N(C 1-4 Alkyl) 2, wherein the 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 Halogenated alkyl, 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 substituted by an alkyl substituent.

[0131] In some embodiments, R 4H, 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, furyl, 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 4optionally substituted by 1, 2, 3 or 4 moieties 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)(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 and -S(=O)CH(CH3)2.

[0132] In some embodiments, it 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),

[0133] Among them, R 1 、R 3 、A 2 , L, R 9 and R 4 Each has the definition as described in the present invention.

[0134] In some embodiments, the compound described herein is a compound of the following structure, or a stereoisomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

[0135] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0136] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0137] In some embodiments, the adjuvants of the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition can be in liquid, solid, semi-solid, gel or spray form.

[0138] In another aspect, the present invention provides use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing, treating or alleviating TYK2-related diseases.

[0139] In some embodiments, the TYK2-related disease described herein is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplantation-related disorder.

[0140] In some embodiments, the TYK2-mediated disease of the present invention 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.

[0141] In some embodiments, the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0142] In some embodiments, the proliferative disorder is cancer.

[0143] In some embodiments, the proliferative disorder is a hematological cancer.

[0144] In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0145] In some embodiments, the neurological disorder is Alzheimer's disease.

[0146] In another aspect, the present invention provides the compound or pharmaceutical composition of the present invention for use in preventing, treating or alleviating TYK2-related diseases.

[0147] In some embodiments, the TYK2-mediated disease of the present invention 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.

[0148] In another aspect, the present invention further provides a method for preventing, treating or alleviating TYK2-related diseases, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition thereof to a patient.

[0149] In some embodiments, the TYK2-mediated disease of the present invention 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.

[0150] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds of formula (I) or (II).

[0151] Unless otherwise indicated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.

[0152] In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically in relation to the other ingredients making up the formulation and the mammal to be treated.

[0153] The salts of the compounds of the present invention also include salts of intermediates used in the preparation or purification of the compounds represented by formula (I) or (II) or separated enantiomers of the compounds represented by formula (I) or (II), but are not necessarily pharmaceutically acceptable salts.

[0154] Preparation, administration and use of pharmaceutical compositions of the compounds of the present invention

[0155] The pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I) or (II), a compound listed in the present invention, or a compound of the Examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical composition of the present invention is effective to treat or alleviate a TYK2-mediated disease in a patient.

[0156] The compounds of the present invention exist in free form or, where appropriate, as 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 to a patient in need, the compounds described in other aspects of the present invention, their metabolites, or their residues.

[0157] As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, such as those used in the present 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 the specific 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 these literatures indicate that various adjuvants can be used in the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except to the extent that any conventional adjuvants are incompatible with the compounds of the present invention, for example by producing any adverse biological effects or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0158] 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, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, 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 sodium carboxymethylcellulose, ethylcellulose 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; glycol compounds 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 saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0159] When preparing pharmaceutical compositions provided by the invention, active ingredient is usually mixed with excipient, diluted by excipient or encapsulated in such carrier in the form of, for example, capsule, pouch, paper or other container. If excipient is used as diluent, it can be solid, semisolid or liquid material, which is used as carrier, carrier or medium of active ingredient. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter etc. Therefore, composition can be tablet, pill, powder, lozenge, capsule, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (solid form or in liquid medium), for example, ointment, soft and hard gelatin capsule, suppository, sterile injection solution and aseptically packaged powder containing up to 10% by weight of active compound. In one embodiment, composition is formulated for oral administration. In one embodiment, composition is formulated into tablet or capsule.

[0160] The compounds or pharmaceutical compositions of the present invention can be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, all of which are well known to those of ordinary skill in the pharmaceutical field. They can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected mode of administration and standard pharmaceutical practice.

[0161] The compounds or pharmaceutical compositions of the present invention can be administered intranasally via topical use of a suitable intranasal vehicle, or transdermally via the use of a transdermal patch. When administered in the form of a transdermal delivery system, the dosage administered is continuous rather than intermittent throughout the duration of administration.

[0162] The compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

[0163] The compounds of the present invention or pharmaceutical compositions are also coupled to soluble polymers as targeted drug carriers. Such polymers include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled to a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic blocking copolymers of hydrogels.

[0164] The dosage regimen of the compounds or pharmaceutical compositions of the present invention will vary depending on various known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect. A physician or veterinarian can determine and prescribe an effective amount of the drug to prevent, counteract or arrest the development of cancer.

[0165] According to general guidelines, in order to achieve the specified effect, the dosage of each active ingredient used is in the range of about 0.001 to 1000 mg / kg body weight in a daily oral dose, preferably, between about 0.01 to 100 mg / kg body weight. The compounds of the present invention can be administered once a day, or can be administered in two, three or four divided doses per day.

[0166] Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 100 mg of 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.

[0167] The compounds and compositions of the present invention can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents via the same or different routes of administration. The compounds of the present invention can be included in a single formulation or in a separate formulation together with other therapeutic agents.

[0168] When the compounds of the invention are administered 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, in view of the additive or synergistic effects of the therapeutic agents when administered in combination.

[0169] The compound or pharmaceutically acceptable salt or hydrate thereof or pharmaceutical composition thereof according to the present invention can be effectively used for preventing, treating or alleviating TYK2-mediated diseases in patients.

[0170] In some embodiments, TYK2-mediated diseases include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or transplantation-related disorders.

[0171] In some embodiments, 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.

[0172] In some embodiments, the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0173] In some embodiments, the proliferative disorder is cancer.

[0174] In some embodiments, the proliferative disorder is a hematological cancer.

[0175] In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0176] In some embodiments, the neurological disorder is Alzheimer's disease.

[0177] General synthesis process

[0178] To illustrate the present invention, the following examples are used to further illustrate the technical solutions of the present invention. The following examples are only used to illustrate the specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0179] Unless otherwise specified, the substituents are as defined herein. The following reaction schemes and examples are provided to further illustrate the present invention.

[0180] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0181] In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise indicated. Room temperature in the examples refers to 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 used without further purification. Unless otherwise indicated, common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0182] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0183] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0184] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0185] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were obtained using CDC13, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm) and referenced to TMS (0 ppm) or chloroform (7.26 ppm). When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0186] Low-resolution mass spectrometry (MS) data were collected using an 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% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), electrospray ionization (ESI), UV detection at 210 nm / 254 nm.

[0187] The pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC) at 210 nm / 254 nm with UV detection.

[0188] The following English or abbreviated terms are used throughout this invention:

[0189] Synthesis Scheme 1 of Intermediate Compound (III-1)

[0190] The synthesis of the intermediate compound (III-1) can be prepared by the above synthesis scheme, wherein R 4 With the definition as described in the present invention, Hal 1 is F, Cl, Br or I; Q is N or CH; R a H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C(=O)OC 1-6 Alkyl, -C(=O)C1-6 Alkyl, -NH(C 1-6 Alkyl) and -N(C 1-6 Compound (III-1-1) reacts with compound 3-amino-1,2-dihydropyridin-2-one in the presence of a base (such as cesium carbonate) to obtain an intermediate compound (III-1).

[0191] Synthesis Scheme 2 of Intermediate Compound (III-1)

[0192] The synthesis of the intermediate compound (III-1) can be prepared by the above synthesis scheme, wherein Hal 1 and Hal 3 are each independently F, Cl, Br or I; Q is N or CH; R a H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 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 obtain intermediate compound (III-4-2); compound (III-4-2) undergoes a coupling reaction with compound (III-1-2) to obtain compound (III-1).

[0193] Synthesis scheme of intermediate compound (III-2)

[0194] The synthesis of the intermediate compound (III-2) can be prepared by the above synthesis scheme, wherein R 5 Having the definition as described in the present invention, R 1a C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl. Compound (III-2-1) and compound R 1a NH2 or compound R 1a The hydrochloride of NH2 reacts with a base (such as triethylamine) to obtain compound (III-2-1); compound (III-2-1) reacts with compound PMBCl to obtain compound (III-2-2); compound (III-2-2) is hydrolyzed to obtain compound (III-2-3); compound (III-2-3) reacts with compound R5 NH2 coupling reaction gives the intermediate compound (III-2).

[0195] Synthesis scheme of intermediate compound (III-4)

[0196] The synthesis of the intermediate compound (III-4) can be prepared by the above synthesis scheme, wherein Hal 1 and Hal 3 are each independently F, Cl, Br or I; Q is N or CH; R a H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 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 obtain intermediate compound (III-4-2); compound (III-4-2) undergoes a coupling reaction with compound triisopropylsilyl acetylene to obtain compound (III-4).

[0197] Synthesis scheme of intermediate compound (III-5)

[0198] The synthesis of the intermediate compound (III-5) can be prepared by the above synthesis scheme, wherein Hal 1 and Hal 3 are each independently F, Cl, Br or I; A 2 and R 4 Each has the definition as described in the present invention. Compound (III-5-1) reacts with compound 3-amino-1,2-dihydropyridin-2-one in the presence of a base (such as cesium carbonate) to produce intermediate compound (III-5-2); compound (III-5-2) and compound (III-5-3) undergo a coupling reaction to produce compound (III-5).

[0199] Synthesis of compound (III)

[0200] The synthesis of compound (III) can be prepared by the above synthesis scheme, wherein R 5 and R 4 Each has the definition as described in the present invention, R 1a C 1-6Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Q is N or CH; R a H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Compound (III-1) and compound (III-2) are coupled to give compound (III-3); compound (III-3) is subjected to the removal of the PMB group under acidic conditions to give compound (III).

[0201] Synthesis of compound (IV)

[0202] The synthesis of compound (IV) can be prepared by the above synthesis scheme, wherein R 5 Has the definition as described in the present invention; R 1a C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Q is N or CH; R a H, D, F, Cl, Br, I, OH, CN, NH2, COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Compound (III-4) and compound (III-2) are coupled to give compound (IV-1); compound (IV-1) is subjected to the removal of the PMB group under acidic conditions to give compound (IV-2); compound (IV-2) is reacted with TABF to give compound (IV).

[0203] Synthesis of compound (V)

[0204] The synthesis of compound (V) can be prepared by the above synthesis scheme, wherein R 5 、R 4 and A each have the meanings as described in the present invention; R 1a C1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Compound (III-4) and compound (III-2) are coupled to give compound (V-1); compound (V-1) is subjected to acidic conditions to remove the PMB group to give compound (V).

[0205] The compounds, pharmaceutical compositions and applications of the present invention are further described below with reference to the examples. Example

[0206] Example 1: Synthesis of Compound 1

[0207] Step 1: Synthesis of compound 1-1

[0208] To a 50 mL two-necked flask, 5-bromo-2-fluoropyridine (0.20 g, 1.14 mmol), triisopropylsilyl acetylene (0.31 g, 1.71 mmol), cuprous iodide (0.011 g, 0.057 mmol), and bistriphenylphosphine palladium dichloride (0.04 g, 0.057 mmol) were added. The atmosphere was purged with nitrogen, and diisopropylamine (5 mL) was added. The temperature was raised to 100°C for reaction. After 3 h, TLC indicated complete reaction. The reaction was then cooled and stopped. Dissolved in 40 mL of ethyl acetate, the mixture was washed with water (10 mL x 2), and the organic phase was dried, spin-dried, and purified by column chromatography (PE as eluent) to yield 0.32 g of a light yellow oily liquid in a 100% yield. MS (ESI, pos. ion) m / z: 278.2 [M+H] + .

[0209] Step 2: Synthesis of compound 1-2

[0210] 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 two-necked flask under nitrogen. N,N-dimethylacetamide (6 mL) was added and the temperature was raised to 95°C. After 4.5 h, TLC indicated complete reaction. The reaction was stopped, the temperature was lowered to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (70 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL x 3), concentrated, and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 10 / 1 to 3 / 1) to obtain 0.13 g of a yellow solid in a yield of 43.02%. MS (ESI, pos. ion) m / z: 212.15 [M+H] + ; 1H 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).

[0211] Step 3: Synthesis of Compound 1-3

[0212] To a single-necked flask, ethyl 3-amino-1H-pyrazole-4-carboxylate (10.30 g, 66.39 mmol) and diethyl malonate (12.76 g, 79.67 mmol) were added, followed by anhydrous ethanol (120 mL). Sodium ethoxide (9.04 g, 132.78 mmol) was slowly added at room temperature. The temperature was raised to 80°C and the reaction was allowed to proceed for 7 h. TLC confirmed complete reaction. The mixture was then dried by rotary evaporation, and 70 mL of water was added. After stirring to dissolve, the pH was adjusted to 3-4 with concentrated hydrochloric acid to obtain a solid product. The product was filtered and dried at 60°C to obtain 10.89 g of a yellow solid, with a yield of 73.46%. MS (ESI, pos.ion) m / z: 224.3 [M+H] + .

[0213] Step 4: Synthesis of Compound 1-4

[0214] Compound 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 temperature was raised to 90°C and the reaction was allowed to proceed for 7 h. TLC confirmed complete reaction. The mixture was cooled to room temperature, concentrated, and slowly transferred to 100 mL of iced sodium hydroxide solution (1 mol / L). Extraction was performed with dichloromethane (100 mL x 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 yield 2.18 g of a yellow solid in a 37.39% yield. MS (ESI, pos. ion) m / z: 260.0 [M+H] + .

[0215] Step 5: Synthesis of Compound 1-5

[0216] Compound 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. N,N-diisopropylethylamine (2.98 g, 23.07 mmol) was then added. The temperature was raised to 80°C and the reaction was allowed to proceed for 4.5 hours. TLC confirmed complete reaction. The mixture was concentrated under reduced pressure, water (50 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered and dried under forced air at 60°C for 11 hours to obtain 1.88 g of a light yellow solid, with a yield of 95.74%. MS (ESI, pos. ion) m / z: 255.3 [M+H]. + .

[0217] Step 6: Synthesis of Compound 1-6

[0218] To a 100 mL single-necked flask, compound 1-5 (2.00 g, 7.85 mmol), cesium carbonate (5.12 g, 15.7 mmol), and DMF (18 mL) were added. The temperature was lowered to -5°C, and 4-methoxybenzyl chloride (1.84 g, 11.77 mmol) was slowly added dropwise. After completion of the addition, the mixture was kept warm for 10 minutes, then brought to room temperature for 4 hours. TLC confirmed complete reaction. The reaction was cooled to 0°C and quenched by the addition of ice water (60 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were 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 to 40 / 1) to obtain 1.88 g of a yellow solid, with a yield of 63.72%.

[0219] Step 7: Synthesis of Compound 1-7

[0220] Compound 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 and refluxed at 120°C for 10 h. TLC confirmed complete reaction. The mixture was concentrated, 50 mL of ethyl acetate was added, and the pH was adjusted to ≤ 3 with hydrochloric acid. Water was added to separate the mixture, and the organic phase was dried over anhydrous sodium sulfate and concentrated to yield 1.65 g of a light yellow solid (99.15% yield). MS (ESI, pos. ion) m / z: 347.2 [M+H] + .

[0221] Step 8: Synthesis of Compound 1-8

[0222] To a 100 mL single-necked flask, compound 1-7 (0.60 g, 1.73 mmol) and dichloromethane (8 mL) were added, followed by cyclobutylamine (0.18 g, 2.59 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.50 g, 2.59 mmol). The mixture was allowed to react at room temperature. After 11.5 h, TLC confirmed complete reaction. 50 mL of dichloromethane was added, and the organic phase was washed with water (20 mL x 2), 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 afford 0.52 g of an off-white solid in a yield of 74.61%.

[0223] Step 9: Synthesis of Compound 1-9

[0224] Starting material 1-8 (100 mg, 0.25 mmol), compound 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 two-necked flask. The atmosphere was purged with nitrogen, 1,4-dioxane (5 mL) was added, and the temperature was raised to 110°C for reaction. After 2 h, TLC indicated complete reaction. The mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate (20 mL), and the filtrate was 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 yield 25 mg of a yellow solid in a 17.40% yield. 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).

[0225] Step 10: Synthesis of Compound 1

[0226] Raw material 1-9 (25 mg, 0.044 mmol) was added to a 5 mL single-necked flask, followed by dichloromethane (2 mL). Trifluoroacetic acid (300 mg, 2.64 mmol) was slowly added dropwise at room temperature and allowed to react. After 3.5 h, TLC indicated that the raw material had essentially reacted, and the reaction was stopped. The temperature was lowered to 0°C, and the pH was adjusted to 9 with 20% potassium phosphate solution. 10 mL of dichloromethane was added, and the layers were 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 to 1 / 1) to afford 12 mg of a yellow solid in a 60.69% yield. MS (ESI, pos. ion) m / z: 455.20 [M+H] + ; 1 H 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).

[0227] Example 2: Synthesis of Compound 2

[0228] Step 1: Synthesis of compound 2-1

[0229] In a 50 mL two-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), bistriphenylphosphine palladium dichloride (0.80 g, 1.14 mmol), and tetrahydrofuran (10 mL) were placed. Under nitrogen, tetrabutylammonium fluoride (2.23 g, 8.52 mmol) was added dropwise at room temperature. After approximately 4 h, TLC analysis revealed a small amount of residual starting material. The reaction was stopped and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether) to obtain 0.41 g of a yellow liquid in a 53.52% yield. 1H 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).

[0230] Step 2: Synthesis of compound 2-2

[0231] 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. N,N-dimethylacetamide (8 mL) was then added and the mixture was allowed to react at 110°C. The reaction was continued for 15.5 h, then stopped. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (8 mL x 4). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 5 / 1-2 / 1) to obtain 0.17 g of a yellow solid in an 18.90% yield. MS (ESI, pos. ion) m / z: 226.2 [M+H] + .

[0232] Step 3: Synthesis of compound 2-3

[0233] To a 10 mL two-necked flask were added 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). The atmosphere was purged with nitrogen, and 1,4-dioxane (5 mL) was added. The reaction was heated to 110°C. After 2 h of reaction, TLC confirmed complete reaction of the starting material. The reaction was stopped, cooled to room temperature, and filtered. The filter cake was rinsed with ethyl acetate (20 mL). The organic phase was washed with water (4 mL), 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 afford 24 mg of a green solid in a yield of 48.33%. MS(ESI,pos.ion)m / z:589.50[M+H] + ; 1H NMR(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,1 H),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).

[0234] Step 4: Synthesis of Compound 2

[0235] Compound 2-3 (23 mg, 0.039 mmol) was added to a 25 mL single-necked vial of dichloromethane (5 mL). Stirring at room temperature allowed the solution to dissolve. Trifluoroacetic acid (270 mg, 2.34 mmol) was then added dropwise. The mixture was allowed to react at room temperature after complete addition. After 4 h of reaction, a sample was taken and the pH was adjusted to 8 with potassium phosphate solution. TLC confirmed complete reaction. The reaction was stopped, and dichloromethane (20 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, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography (eluent: DCM / PE (v / v) = 10 / 1–2 / 1) to afford 12 mg of a green solid in a 65.55% yield. 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).

[0236] Example 3: Synthesis of Compound 3

[0237] Step 1: Synthesis of compound 3-1

[0238] 5-Bromo-2-fluoropyridine (1.00 g, 5.68 mmol), cuprous iodide (0.056 g, 0.28 mmol), bis(triphenylphosphine) palladium dichloride (0.20 g, 0.28 mmol), and diisopropylamine (15 mL) were added to a 100 mL two-necked flask. The temperature was raised to 100°C under nitrogen, and cyclopropylacetylene (0.56 g, 8.52 mmol) was slowly added. The reaction was allowed to proceed at 100°C for approximately 5 h. TLC indicated that the starting material had essentially reacted, so the reaction was stopped. The reaction solution was filtered, the filtrate washed with water (30 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was dried, concentrated, and purified by column chromatography (eluent PE) to yield 1.05 g of a yellow-brown liquid. MS (ESI, pos. ion) m / z: 162.5 [M+H] + .

[0239] Step 2: Synthesis of compound 3-2

[0240] 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 analysis indicated a small amount of residual starting material, so the reaction was stopped. The reaction mixture was filtered, rinsed with ethyl acetate (35 mL), and the filtrate washed with water (20 mL). The layers were separated, and the organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 2 / 1) to obtain 0.20 g of a yellow solid in a 21.38% yield. MS (ESI, pos. ion) m / z: 252.3 [M+H] + .

[0241] Step 3: Synthesis of compound 3-3

[0242] 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] + .

[0243] Step 4: Synthesis of compound 3

[0244] 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 allowed to react at room temperature for approximately 3 h. TLC indicated complete reaction. Dichloromethane (8 mL) was added, followed by a 20% aqueous potassium phosphate solution to adjust the pH to 8. The layers were 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 yield 57 mg of a solid in a 72.56% yield. 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).

[0245] Example 4: Synthesis of Compound 4

[0246] Step 1: Synthesis of compound 4-1

[0247] To a 25 mL two-necked flask were added 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). N,N-dimethylacetamide (13 mL) was added under nitrogen and the temperature was raised to 95°C. After 5 h, TLC indicated complete reaction. The mixture was cooled to room temperature, and water (50 mL) was added. The mixture was then extracted with EA (70 mL x 3). The combined organic phases were concentrated and purified by column chromatography (eluent: PE / EA (v / v = 10 / 1-3 / 1)). The mixture was collected and dried 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).

[0248] Step 2: Synthesis of compound 4-2

[0249] 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 nitrogen was replaced again for protection, and the temperature was raised to 100 ° C for reaction. After 3 h, TLC detection showed that the raw materials reacted completely. The reaction solution was concentrated and EA (10 The mixture was dissolved in 1% paraformaldehyde (5 mL) and filtered. 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).

[0250] Step 3: Synthesis of compound 4-3

[0251] To a reaction flask, raw material 1-7 (0.7 g, 2.02 mmol) and DCM (10 mL) were added, followed by cyclopropylamine (0.20 g, 2.77 mmol) and EDCI (0.62 g, 3.23 mmol). The reaction was allowed to proceed at room temperature. After 4.5 h, TLC indicated that the raw material had reacted completely. The reaction was stopped, and DCM (20 mL) was added. The mixture was washed once with saturated sodium chloride solution (8 mL). The organic phase was dried over anhydrous sodium sulfate, dried by spin-drying, and purified by column chromatography (eluent: PE / EA (v / v) = 10 / 1-3 / 1). The mixture was collected and dried by spin-drying to afford 271 mg of an off-white solid, in a yield of 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).

[0252] Step 4: Synthesis of compound 4-4

[0253] The raw material 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) were added to a 10 mL two-necked flask and replaced with nitrogen. Compound 4-2 (0.062 g, 0.17 mmol) was dissolved in 1,4-dioxane (3 mL) and added to the reaction flask. The atmosphere was replaced with nitrogen and the temperature was raised to 75 °C for reaction. After 1.5 h, TLC detection showed that the raw material reaction was complete. The temperature was cooled to room temperature and filtered. The filter cake was rinsed with EA (20 mL). The organic phase was washed with saturated sodium chloride solution (5 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography with PE / EA (v / v = 10 / 1-3 / 1) as eluent. The mixture was collected and spin-dried to give 83 mg of a 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).

[0254] Step 5: Synthesis of compound 4-5

[0255] Raw material 4-4 (78 mg, 0.11 mmol) and DCM (3 mL) were added to a 10 mL single-necked flask with stirring. Trifluoroacetic acid (0.75 g, 6.6 mmol) was then added and allowed to react at room temperature. After 4 h, a sample was taken and the pH was adjusted to 8 with potassium phosphate solution. TLC confirmed complete reaction. DCM (30 mL) was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried by spin drying. The organic phase was then purified by column chromatography using DCM / EA (v / v = 3 / 1) as the eluent. The mixture was collected and dried 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).

[0256] Step 6: Synthesis of compound 4

[0257] Add raw material 4-5 (55 mg, 0.092 mmol) and THF (3 mL) to a 10 mL single-necked flask and stir to dissolve. Tetrabutylammonium fluoride (0.18 mL, 0.18 mmol) was then added dropwise at room temperature. After 1.5 h, TLC confirmed complete reaction. The reaction was stopped, and ethyl acetate (30 mL) and 5 mL of water (5 mL) were added. Extraction was performed, and the organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and subjected to column chromatography using DCM / MeOH (v / v = 1 / 0-30 / 1) as the eluent. The mixture was collected and dried by spin drying to afford 28 mg of a yellow solid in a 68.98% yield. 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),6.49(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).

[0258] Example 5: Synthesis of Compound 5

[0259] Step 1: Synthesis of compound 5-1

[0260] 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 two-necked flask. 3-Chloro-3-methyl-1-butyne (3 g, 29.25 mmol) was added dropwise to the stirred suspension under nitrogen. After completion of the addition, the temperature was raised to 40°C and the reaction was allowed to proceed for 22.5 h. The reaction was then terminated 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, dried by spin drying, and purified by column chromatography using PE / EA (v / v = 1 / 0-10 / 1) as the eluent. The mixture was collected and dried by spin drying to obtain 2.55 g of a colorless, transparent liquid in 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).

[0261] Step 2: Synthesis of compound 5-2

[0262] Raw 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 bistriphenylphosphine palladium dichloride (0.068 g, 0.097 mmol) were added to a 25 mL two-necked flask. The atmosphere was purged with nitrogen, followed by diisopropylamine (7 mL). The atmosphere was purged with nitrogen again, and the mixture was heated to 100°C for 5.5 h. After TLC analysis, the reaction was complete. The residue was concentrated, dissolved in EA (20 mL), and washed twice with water (7 mL). The organic phase was dried by spin-drying and eluted with DCM / EA (v / v = 10 / 1-3 / 1). The mixture was collected and dried to give 106 mg of a yellow solid (16.56% yield). 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).

[0263] Step 3: Synthesis of compound 5-3

[0264] 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).

[0265] Step 4: Synthesis of compound 5

[0266] Raw 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 allowed to react at room temperature. After approximately 1.5 h, a sample was taken and the pH was adjusted to 8 with potassium phosphate solution. TLC was performed. Once the raw material reacted completely, DCM (15 mL) was added and the pH was adjusted to 8 with potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and subjected to column chromatography using DCM / MeOH (v / v = 1 / 0-30 / 1) as the eluent. The mixture was collected and dried by spin drying to obtain 70 mg of a yellow solid in a 64.12% yield. 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).

[0267] Example 6: Synthesis of Compound 6

[0268] Step 1: Synthesis of compound 6-1

[0269] Compound 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 placed in a 50 mL two-necked flask. Under nitrogen, 1,4-dioxane (8 mL) was added and the mixture was allowed to react at 80°C for 2 h. TLC confirmed complete reaction. The reaction mixture was filtered, rinsed 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 in a 93.11% yield. MS (ESI, pos. ion) m / z: 575.5 [M+H] + .

[0270] Step 2: Synthesis of compound 6

[0271] Compound 6-1 (201 mg, 0.35 mmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (2.39 g, 21 mmol). The mixture was allowed to react at room temperature for approximately 3 h. TLC indicated that the starting material had reacted completely, and the reaction was stopped. A 20% aqueous potassium phosphate solution was added to adjust the pH to approximately 7. The layers were separated, and the aqueous phase was extracted with additional 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 to 70 / 1) to obtain 64 mg of a blue solid in a 38.31% yield. MS (ESI, pos. ion) m / z: 456.4 [M+H] + ; 1H 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).

[0272] Example 7: Synthesis of Compound 7

[0273] Step 1: Synthesis of compound 7-1

[0274] Compound 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 placed in a 50 mL two-necked flask. Under nitrogen, 1,4-dioxane (8 mL) was added and the mixture was allowed to react at 80°C for 2 h. TLC confirmed complete reaction. The reaction mixture was filtered, rinsed with 10 mL of dichloromethane, and the filtrate was concentrated and purified by column chromatography (DCM / EA (v / v) = 10 / 1) to give 213 mg of a green solid in a 91.22% yield. MS (ESI, pos. ion) m / z: 601.5 [M+H] + .

[0275] Step 2: Synthesis of compound 7

[0276] Compound 7-1 (200 mg, 0.33 mmol) and dichloromethane (8 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (2.26 g, 19.8 mmol). The reaction was allowed to proceed at room temperature for approximately 3 h. TLC confirmed complete reaction. A 20% aqueous potassium phosphate solution was added to adjust the pH to approximately 7. The layers were separated, and the aqueous phase was extracted with an additional 8 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / MeOH = 80 / 1 to obtain 70 mg of a yellow solid in a 40.95% yield. 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).

[0277] Example 8: Synthesis of Compound 8

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

[0279] 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] + .

[0280] Step 2: Synthesis of compound 8

[0281] Raw material 8-1 (0.26 g, 0.39 mmol) and DCM (5 mL) were added to a reaction flask. After stirring, trifluoroacetic acid (2.67 g, 23.40 mmol) was added dropwise. The reaction was stirred at room temperature for 2.5 h. TLC confirmed complete reaction. DCM (20 mL) was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried by spin drying. The mixture was purified by chromatography using a DCM / MeOH (v / v) ratio of 1 / 0 to 40 / 1 as the eluent to obtain 0.20 g of a yellow solid in 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).

[0282] Example 9: Synthesis of Compound 9

[0283] Step 1: Synthesis of compound 9-1

[0284] 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 bistriphenylphosphine palladium dichloride (0.20 g, 0.28 mmol) were added to a 25 mL two-necked flask. The atmosphere was purged with nitrogen, and N,N-dimethylformamide (8 mL) was added. The temperature was raised to 60°C, and methyl propargyl ether (0.80 g, 11.36 mmol) was slowly added dropwise over 4.5 hours. After completion of the addition, TLC confirmed complete reaction. The mixture was cooled to room temperature. Water (20 mL) was added, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (10 mL x 3). The organic phases were dried over anhydrous sodium sulfate and spin-dried. The product was collected by column chromatography (eluent: PE-PE / EA (v / v = 50 / 1)), dried and weighed to give 0.29 g of a reddish-brown liquid, with a yield of 30.90%. MS (ESI, pos.ion) m / z: 166.2 [M+H] + .

[0285] Step 2: Synthesis of compound 9-2

[0286] 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 two-necked flask under nitrogen. N,N-dimethylacetamide (5 mL) was added and the temperature was raised to 95°C. After 17.5 h of reaction, TLC confirmed complete reaction of the starting material. 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 purified by column chromatography (eluent: PE / EA (v / v = 50 / 1-2 / 1)) to obtain 0.17 g of a yellow solid in a yield of 37.93%. MS (ESI, pos. ion) m / z: 256.20 [M+H] + .

[0287] Step 3: Synthesis of compound 9-3

[0288] Raw 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. The atmosphere was purged with nitrogen, 1,4-dioxane (5 mL) was added, and the temperature was raised to 80°C for reaction. After 1.5 h, TLC indicated complete reaction. The mixture was cooled to room temperature, dissolved in EA (30 mL), and washed twice with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and eluted with column chromatography using DCM / MeOH (v / v = 35 / 1). The mixture was collected and spin-dried to give 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).

[0289] Step 4: Synthesis of compound 9

[0290] 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 allowed to react at room temperature. After 1.5 h, TLC indicated complete reaction. 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, spin-dried, and subjected to column chromatography using DCM / MeOH (v / v = 1 / 0-30 / 1) as the eluent. The mixture was collected and spin-dried to afford 120 mg of an off-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).

[0291] Example 10: Synthesis of Compound 10

[0292] Step 1: Synthesis of compound 10-1

[0293] Compound 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 allowed to proceed at room temperature for 10 h. TLC confirmed complete reaction. 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 spin-dried. The mixture was then passed through a chromatography column using PE / EA (v / v = 1 / 0-10 / 1-1 / 1) as the eluent. The combined eluents yielded 0.28 g of a white solid, a yield of 48.09%.

[0294] Step 2: Synthesis of compound 10-2

[0295] Compound 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 placed in a 10 mL two-necked flask. 1,4-dioxane (6 mL) was added, the atmosphere was purged with nitrogen, and the temperature was raised to 80°C for 1 h. TLC confirmed complete reaction. The filter cake was then filtered and 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), yielding 0.22 g (yield 63.57%).

[0296] Step 3: Synthesis of compound 10

[0297] Raw material 10-2 (0.22 g, 0.31 mmol) and DCM (8 mL) were added to a reaction flask. After stirring, trifluoroacetic acid (2.12 g, 18.6 mmol) was added dropwise and the reaction was stirred at room temperature for 2.5 h. TLC confirmed the complete reaction. 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 phases were separated and the organic phase was dried by spin drying. The product was passed through a chromatography column (eluent: DCM / MeOH (v / v = 1 / 0-40 / 1). The eluates were combined and dried by spin drying to obtain 0.12 g of a light green solid, with a yield of 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).

[0298] Example 11: Synthesis of Compound 11

[0299] Step 1: Synthesis of compound 11-1

[0300] 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%.

[0301] Step 2: Synthesis of compound 11

[0302] Compound 11-1 (0.19 g, 0.32 mmol) was added to dichloromethane (8 mL), and trifluoroacetic acid (2.19 g, 19.2 mmol) was added. The mixture was reacted at room temperature for about 3 h. TLC indicated that the reaction was complete. A 20% aqueous potassium phosphate solution was added to adjust the pH to about 7. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 5 / 1-3 / 1) to obtain 70 mg of a blue solid in a yield of 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).

[0303] Example 12: Synthesis of Compound 12

[0304] Step 1: Synthesis of compound 12-1

[0305] 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] + .

[0306] Step 2: Synthesis of compound 12

[0307] Compound 12-1 (0.25 g, 0.40 mmol) and DCM (8 mL) were added to a reaction flask. After stirring, trifluoroacetic acid (2.74 g, 24 mmol) was added dropwise and the reaction was stirred at room temperature for 2.5 h. TLC indicated complete reaction of the starting material. The reaction was stopped, and 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 layers were separated, and the organic phase was dried by spin drying. The mixture was purified by chromatography using DCM / MeOH (1 / 0-40 / 1) as the eluent to obtain 0.04 g of a white solid in a yield of 19.83%. MS (ESI, pos. ion) m / z: 503.4 [M+H] + ; 1 H NMR (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).

[0308] Example 13: Synthesis of Compound 13

[0309] Step 1: Synthesis of compound 13-1

[0310] 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%.

[0311] Step 2: Synthesis of compound 13

[0312] To raw material 13-1 (0.24 g, 0.39 mmol) was added DCM (8 mL), stirred, and trifluoroacetic acid (2.67 g, 23.40 mmol) was added dropwise. The reaction was stirred at room temperature for 2.5 h. TLC indicated complete reaction. 10 mL of DCM was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The phases were separated, and the organic phase was dried by spin drying. The product was then passed through a chromatography column with DCM / MeOH (1 / 0 to 40 / 1). The combined eluents were dried by spin drying to yield 0.132 g, a yield of 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).

[0313] Example 14: Synthesis of Compound 14

[0314] Step 1: Synthesis of compound 14-1

[0315] To a 25 mL reaction flask, 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 and the reaction was heated to 95°C. After 4 h, TLC confirmed complete reaction. 40 mL of water was added, followed by extraction with EA (40 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and subjected to column chromatography using PE / EA (v / v = 3 / 1) as the eluent. The product was collected and dried to give 0.87 g of an oily product (59.41% yield). MS (ESI, pos. ion) m / z: 284.0, 286.0 [M+H] + .

[0316] Step 2: Synthesis of compound 14-2

[0317] The starting material 14-1 (0.4 g, 1.41 mmol), triisopropylsilyl acetylene (0.26 g, 1.41 mmol), cuprous iodide (0.013 g, 0.070 mmol), and bistriphenylphosphine palladium dichloride (0.049 g, 0.070 mmol) were added to a 25 mL two-necked flask. The atmosphere was purged with nitrogen, and diisopropylamine (12 mL) was added. The temperature was raised to 100°C for reaction. After 3 h, TLC indicated complete reaction. The reaction solution was concentrated, dissolved in EA (25 mL), 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 using PE / EA (v / v = 15 / 1-5 / 1) as the eluent to obtain 473 mg of a brown oil in an 87.15% yield. MS (ESI, pos. ion) m / z: 386.2 [M+H] + .

[0318] Step 3: Synthesis of compound 14-3

[0319] Raw 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 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 indicated that the raw materials had essentially reacted. DCM (50 mL) was added, and the mixture was washed with saturated ammonium chloride solution (10 mL). The organic phase was separated and dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent. The mixture was collected and spin-dried to give 0.42 g of a yellow solid, a yield of 74.75%.

[0320] Step 4: Synthesis of compound 14-4

[0321] 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 allowed to react at room temperature. After 3 h, TLC indicated complete reaction. The reaction was stopped, and water (20 mL) was added. The product was extracted with EA (25 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and subjected to column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent. The product was collected and dried to dryness to afford 0.29 g of a pale yellow solid in an 87.26% yield. MS (ESI, pos. ion) m / z: 593.3 [M+H] + .

[0322] Step 5: Synthesis of compound 14

[0323] Raw 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) and allowed to react at room temperature. After 1.8 h, TLC confirmed complete reaction. DCM (25 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 dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent to afford 0.16 g of an off-white solid in a yield of 71.67%. MS (ESI, pos. ion) m / z: 473.20 [M+H] + ; 1 HNMR(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).

[0324] Example 15: Synthesis of Compound 15

[0325] Step 1: Synthesis of compound 15-1

[0326] 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%.

[0327] Step 2: Synthesis of compound 15-2

[0328] 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 confirmed complete reaction. Water (20 mL) 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), dried over anhydrous sodium sulfate, and subjected to column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent. The mixture was collected and dried to give 0.26 g of a light yellow solid in a yield of 78.63%. MS (ESI, pos. ion) m / z: 579.2 [M+H] + .

[0329] Step 3: Synthesis of compound 15

[0330] Raw 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) and allowed to react at room temperature. After 1 h, TLC confirmed complete reaction. DCM (25 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 dried over anhydrous sodium sulfate, dried by spin drying, and subjected to column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent. The mixture was collected and dried by spin drying to afford 0.18 g of an off-white solid in an 87.38% yield. MS (ESI, pos. ion) m / z: 459.10 [M+H] + ; 1H 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).

[0331] Example 16: Synthesis of Compound 16

[0332] Step 1: Synthesis of compound 16-1

[0333] 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%).

[0334] Step 2: Synthesis of compound 16-2

[0335] 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 confirmed complete reaction. Water (20 mL) was added, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, and subjected to column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent. The mixture was collected and dried to give 0.30 g of a pale yellow solid in a 97.08% yield. MS (ESI, pos. ion) m / z: 597.2 [M+H] + .

[0336] Step 3: Synthesis of compound 16

[0337] Raw material 16-2 (0.30 g, 0.50 mmol) and dichloromethane (6 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (3.42 g, 30 mmol) and allowed to react at room temperature. After 1.4 h, TLC indicated complete reaction. 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, dried by spin drying, and subjected to column chromatography using DCM / MeOH (v / v = 30 / 1) as the eluent. The mixture was collected and dried by spin drying to yield 0.15 g of an off-white solid in a 62.61% yield. MS (ESI, pos.ion) m / z: 477.2 [M+H] + ; 1 H 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).

[0338] Example 17: Synthesis of Compound 17

[0339] Step 1: Synthesis of compound 17-1

[0340] To a 50 mL two-necked flask were added 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). The atmosphere was purged with nitrogen, and anhydrous 1,4-dioxane (8 mL) was added. The atmosphere was purged with nitrogen again, and the reaction was refluxed at 80°C for approximately 2 h. TLC indicated complete reaction of the starting material. The reaction was stopped and filtered. The filter cake was rinsed with ethyl acetate (50 mL). The organic phase was washed once with 8 mL of water, dried over anhydrous sodium sulfate, and spin-dried. Purification by column chromatography (eluent: DCM / EA = 20 / 1 to 10 / 1) afforded 0.267 g of a yellow solid in a yield of 73.36%. 1H NMR(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).

[0341] Step 2: Synthesis of compound 17-2

[0342] To a 50 mL single-necked flask, compound 17-1 (0.26 g, 0.35 mmol) and cesium fluoride (0.11 g, 0.70 mmol) were added, followed by DMF (8 mL) and allowed to react at room temperature. After 2.5 h, TLC indicated complete reaction of the starting material. The reaction was stopped, and saturated brine (90 mL) was added. The aqueous phase was extracted with dichloromethane (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (DCM / EA = 10 / 1 to 5 / 1) afforded 0.216 g of a brown solid in a 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).

[0343] Step 3: Synthesis of compound 17

[0344] 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 allowed to react at room temperature. After 2 h of reaction, TLC confirmed complete reaction. The mixture was cooled to 0°C and the pH was adjusted to approximately 8 with 20% aqueous potassium phosphate. The layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were concentrated and purified by column chromatography (eluent: DCM / CH3OH (v / v = 1 / 0-40 / 1)). The mixture was collected and dried to give 0.08 g of an off-white solid, a yield of 77.67%. MS (ESI, pos. ion) m / z: 578.22 [M+H] + ; 1 H 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).

[0345] Example 18: Synthesis of Compound 18

[0346] Step 1: Synthesis of compound 18-1

[0347] 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] + ; 1H 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).

[0348] Step 2: Synthesis of compound 18-2

[0349] 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).

[0350] Step 3: Synthesis of compound 18-3

[0351] 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. After 45 min, TLC indicated complete reaction. The reaction was stopped, and water (30 mL) was added. The mixture was extracted with EA (40 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, and subjected to column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent. The mixture was collected and dried to give 0.254 g of an off-white solid in 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).

[0352] Step 4: Synthesis of compound 18

[0353] 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) and allowed to react at room temperature. After 1 h, TLC confirmed complete reaction. 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, dried by spin drying, and subjected to column chromatography using DCM / MeOH (v / v = 1 / 0-30 / 1) as the eluent. The mixture was collected and dried by spin drying to yield 0.16 g of an off-white solid in 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).

[0354] Example 19: Synthesis of Compound 19

[0355] Step 1: Synthesis of compound 19-1

[0356] In a 100 mL two-necked flask, compound 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 placed under nitrogen. 1,4-Dioxane (15 mL) was added and the mixture was allowed to react at 80°C for approximately 3 h. TLC analysis indicated complete reaction. The reaction mixture was filtered, the filtrate concentrated, and purified by PE / EA (1 / 1) column chromatography to afford 113 mg of a bluish-black solid in a 42.44% yield. MS (ESI, pos. ion) m / z: 618.9 [M+H] + .

[0357] Step 2: Synthesis of compound 19

[0358] Compound 19-1 (0.11 g, 0.18 mmol) was added to dichloromethane (8 mL), and trifluoroacetic acid (1.23 g, 10.8 mmol) was added. The reaction was allowed to proceed at room temperature for about 2 h. TLC indicated that the reaction of the starting material was complete. The reaction was stopped and saturated sodium bicarbonate solution was added to adjust the pH to about 7. The layers were separated 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) to obtain 20 mg of a blue solid in a yield of 21.57%. MS (ESI, pos. ion) m / z: 499.1 [M+H] + ; 1H 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).

[0359] Example 20: Synthesis of Compound 20

[0360] Step 1: Synthesis of compound 20-1

[0361] 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.

[0362] Step 2: Synthesis of compound 20-2

[0363] To 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 reacted at 110°C. After approximately 4.5 hours, TLC indicated that the starting materials were essentially reacted. 30 mL of water was added and extracted with dichloromethane (20 mL x 4). The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (PE / EA = 10 / 1 to 2 / 1) afforded 0.14 g of a yellow solid. Yield: 11.48%.

[0364] Step 3: Synthesis of compound 20-3

[0365] To a 50 mL two-necked flask were added compound 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). Under nitrogen, the mixture was refluxed at 80°C for approximately 3 h. After completion of the reaction, the starting material was filtered, and the filter cake was rinsed with ethyl acetate (50 mL). The organic phase was washed once with water (8 mL), dried over anhydrous sodium sulfate, and then spin-dried. Purification by column chromatography (eluent: DCM / EA (v / v = 20 / 1 to 3 / 1)) afforded 0.12 g of a green solid in a 39.81% yield. 1 H NMR (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).

[0366] Step 4: Synthesis of compound 20

[0367] 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 and allowed to react at room temperature. After 2 h, TLC confirmed complete reaction. The mixture was cooled to 0°C and the pH was adjusted to approximately 8 with 20% potassium phosphate aqueous solution. The layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were concentrated and purified by column chromatography (eluent: DCM / CH3OH (v / v = 1 / 0-50 / 1)). The mixture was collected and dried to give 0.09 g of an off-white solid in a 93.67% yield. MS (ESI, pos. ion) m / z: 483.1 [M+H] + ; 1H 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).

[0368] Example 21: Synthesis of Compound 21

[0369] Step 1: Synthesis of compound 21-1

[0370] 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] + .

[0371] Step 2: Synthesis of compound 21

[0372] DCM (8 mL) was added to starting material 21-1 (0.24 g, 0.37 mmol). After stirring, trifluoroacetic acid (3.37 g, 29.6 mmol) was added dropwise and the reaction was stirred at room temperature for 5.5 h. TLC indicated complete reaction. 20 mL of DCM was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The phases were separated, and the organic phase was dried by spin drying. The product was then purified by column chromatography using DCM / MeOH (1 / 0-25 / 1) as the eluent to obtain 0.05 g of a light 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).

[0373] Example 22: Synthesis of Compound 22

[0374] Step 1: Synthesis of compound 22-1

[0375] 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. TLC was used to monitor the reaction. After the reaction was complete, 100 mL of water was added and extracted with ethyl acetate (30 mL x 4). The organic phases were combined, concentrated, and stirred with water (20 mL). A large amount of solid precipitated. The solid was filtered, rinsed with water (30 mL), and dried under vacuum at 60°C to obtain 2.07 g of a tan solid with a yield of 42.83%. MS (ESI, pos. ion) m / z: 267.9 [M+H] + .

[0376] Step 2: Synthesis of compound 22-2

[0377] Compound 22-1 (1 g, 3.76 mmol), cuprous iodide (0.036 g, 0.19 mmol), and bistriphenylphosphine palladium dichloride (0.13 g, 0.19 mmol) were added to a 50 mL two-necked flask. Diisopropylamine (15 mL) was added under nitrogen protection. Triisopropylsilyl acetylene (1.03 g, 5.64 mmol) was added and the mixture was reacted at 100°C for approximately 1.5 h. TLC confirmed complete reaction. The reaction mixture was filtered, rinsed with dichloromethane (20 mL), concentrated, and purified by PE / EA (v / v = 5 / 1) column chromatography to obtain 1.16 g of a brown liquid in an 83.98% yield. MS (ESI, pos. ion) m / z: 368.2 [M+H] + .

[0378] Step 3: Synthesis of compound 22-3

[0379] Compound 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 two-necked flask. Under nitrogen protection, 1,4-dioxane (15 mL) was added and the reaction was carried out at 80 ° C for about 4 h. According to TLC detection, the raw material was completely reacted. The reaction solution was filtered, concentrated, and purified by PE / EA (v / v = 2 / 1) column chromatography to obtain 313 mg of an off-white solid with a yield of 88.41%.

[0380] Step 4: Synthesis of compound 22-4

[0381] 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 N,N-dimethylformamide (8 mL). The reaction was allowed to proceed at room temperature for 1 h. TLC confirmed complete reaction. The mixture 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 obtain 308 mg of a yellow-brown oily liquid in a 99.39% yield. MS (ESI, pos. ion) m / z: 605.2 [M+H] + .

[0382] Step 5: Synthesis of compound 22

[0383] To 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 and allowed to react at room temperature for 2 h. TLC confirmed complete reaction. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The layers were separated, and the aqueous phase was extracted with another 10 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 4 / 1-3 / 1)) to afford 134 mg of a blue solid in a 54.30% yield. 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).

[0384] Example 23: Synthesis of Compound 23

[0385] Step 1: Synthesis of compound 23-1

[0386] To 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), bistriphenylphosphine palladium dichloride (2.17 g, 3.09 mmol), and triethylamine (7.83 g, 77.35 mmol) were added. Tetrahydrofuran (15 mL) was then added. Under nitrogen, tetrabutylammonium fluoride (23.2 mL, 23.21 mmol) was added dropwise at room temperature. After 3 h, TLC confirmed complete reaction. The reaction mixture was filtered, concentrated, and purified by petroleum ether column chromatography to yield 767 mg of a yellow liquid in an 89.52% yield. MS (ESI, pos. ion) m / z: 154.1 [M+H] + .

[0387] Step 2: Synthesis of compound 23-2

[0388] 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. N,N-dimethylformamide (10 mL) was then added and the mixture was allowed to react at 95°C. After 4 h, TLC indicated that the starting material had reacted completely. The reaction mixture was filtered, washed with water (40 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 2 / 1)) to afford 273 mg of a green liquid in a 22.92% yield. MS (ESI, pos. ion) m / z: 244.1 [M+H] + .

[0389] Step 3: Synthesis of compound 23-3

[0390] In a 50 mL two-necked flask, compound 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 placed. Under nitrogen, 1,4-dioxane (5 mL) was added and the mixture was allowed to react at 80°C for approximately 3 h. TLC confirmed complete reaction. The reaction mixture was filtered, the filtrate concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 10 / 1)) to afford 117 mg of a green solid in a 79.00% yield. MS (ESI, pos. ion) m / z: 637.2 [M+H] + .

[0391] Step 4: Synthesis of compound 23

[0392] Compound 23-3 (176 mg, 0.28 mmol) was added to dichloromethane (8 mL), and trifluoroacetic acid (0.96 g, 8.4 mmol) was added. The reaction was allowed to proceed at room temperature for approximately 7 h. TLC indicated that the reaction of the starting material was complete. The reaction was stopped and saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The layers were separated. The mixture was extracted with 8 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / MeOH (v / v = 80 / 1-70 / 1) to obtain 68 mg of a blue solid with a yield of 43.20%. MS (ESI, pos. ion) m / z: 517.1 [M+H] + ; 1H 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).

[0393] Example 24: Synthesis of Compound 24

[0394] Step 1: Synthesis of compound 24-1

[0395] The raw 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 heated to 100°C for reaction. After 2 h, TLC confirmed complete reaction. 25 mL of water was added, followed by extraction with EA (25 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL x 3), dried by rotary evaporation, and purified by column chromatography (eluent: PE / EA (v / v = 2 / 1)) to afford 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).

[0396] Step 2: Synthesis of compound 24-2

[0397] Raw material 24-1 (0.22 g, 0.82 mmol), triisopropylsilyl acetylene (0.15 g, 0.82 mmol), cuprous iodide (8 mg, 0.041 mmol), and bistriphenylphosphine palladium dichloride (29 mg, 0.041 mmol) were added to a 10 mL two-necked flask. The atmosphere was purged with nitrogen, and diisopropylamine (5 mL) was added. The temperature was raised to 100°C for reaction. After 1.3 h, TLC indicated complete reaction. The mixture was concentrated under reduced pressure, and the residue was dissolved in EA (30 mL) and washed with saturated ammonium chloride solution (8 mL x 2). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using PE / EA (v / v = 5 / 1) as the eluent to obtain 0.25 g of a yellow solid in 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).

[0398] Step 3: Synthesis of compound 24-3

[0399] Raw 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 placed in a 10 mL two-necked flask. The atmosphere was purged with nitrogen, 1,4-dioxane (5 mL) was added, and the reaction was heated to 80°C. After 7 h, TLC indicated complete reaction, and the temperature was lowered to room temperature. The filter cake was rinsed with EA (5 mL) and dried by evaporation. EA (5 mL) was added and stirred at room temperature for 30 min. The mixture was then filtered and the filter cake dried by evaporation to afford 0.36 g of a yellow solid. The yield was 75.22%. 1H 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=7.3 Hz,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).

[0400] Step 4: Synthesis of compound 24-4

[0401] Compound 24-3 (0.36 g, 0.47 mmol), cesium fluoride (0.14 g, 0.94 mmol), and DMF (5 mL) were added to the reaction flask and allowed to react at room temperature. After 1.5 h, TLC indicated complete reaction of the starting material. The reaction was stopped, and water (20 mL) was added. The product was then extracted with EA (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and spun down to dryness. The organic phases were then purified by column chromatography using DCM / MeOH (v / v = 1 / 0-30 / 1) as the eluent to afford 173 mg of a yellow solid in a 60.46% yield. 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).

[0402] Step 5: Synthesis of compound 24

[0403] Compound 24-4 (0.17 g, 0.28 mmol) and DCM (3 mL) were added to a reaction flask and stirred to dissolve. Trifluoroacetic acid (1.92 g, 16.8 mmol) was then added and allowed to react at room temperature. After 1.5 h, TLC confirmed complete reaction. 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, spin-dried, and subjected to column chromatography using DCM / MeOH (v / v = 30 / 1) as the eluent to afford 80 mg of a yellow solid in a 58.70% yield. 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).

[0404] Example 25: Synthesis of Compound 25

[0405] Step 1: Synthesis of compound 25-1

[0406] 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.

[0407] Step 2: Synthesis of compound 25-2

[0408] 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. Compound 25-1 (0.50 g, 2.42 mmol) diluted in DME (3 mL) and potassium carbonate (0.23 g, 1.69 mmol) were then added. The reaction was heated to 80°C. After 2 h, TLC indicated complete reaction. The reaction mixture was concentrated, dissolved in EA (30 mL), and washed with water (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / EA (v / v = 5 / 1) as the eluent to obtain 54 mg of a yellow solid in a 15.04% yield. MS (ESI, pos. ion) m / z: 149.1 [M+H]+ .

[0409] Step 3: Synthesis of compound 25-3

[0410] Compound 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. 1,4-dioxane (5 mL) was added and the temperature was raised to 80°C. After 2 h, the starting materials reacted completely. The reaction solution was concentrated, and the residue was extracted with DCM (20 mL) and water (10 mL). The organic phase was dried by spin drying and purified by column chromatography using DCM / MeOH (v / v = 30 / 1) as the eluent. The mixture was collected and dried to give 175 mg of an off-white solid in a 46.30% yield. MS (ESI, pos. ion) m / z: 542.0 [M+H] + ; 1 H 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).

[0411] Step 4: Synthesis of compound 25

[0412] 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 allowed to react at room temperature. After 2 h, TLC indicated complete reaction. The reaction was stopped, diluted with DCM (30 mL), cooled to 0°C, and adjusted to pH 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography using DCM / MeOH (v / v = 30 / 1) as the eluent to afford 113 mg of an off-white solid in an 85.42% yield. 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).

[0413] Example 26: Synthesis of Compound 26

[0414] Step 1: Synthesis of compound 26-1

[0415] 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 bottle and reacted overnight at 95°C. TLC confirmed complete reaction of the starting material. The reaction was stopped, washed with water (80 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / EA = 3 / 1 to obtain 1.24 g of a green solid in a 51.31% yield. MS (ESI, pos. ion) m / z: 265.9 [M+H] + .

[0416] Step 2: Synthesis of compound 26-2

[0417] Compound 26-1 (0.6 g, 2.25 mmol), cuprous iodide (0.021 g, 0.11 mmol), and bistriphenylphosphine palladium dichloride (0.079 g, 0.11 mmol) were added to a 50 mL two-necked flask, along with diisopropylamine (8 mL). Under nitrogen, triisopropylsilyl acetylene (0.62 g, 3.38 mmol) was added and the mixture was allowed to react at 100°C for approximately 1 h. TLC confirmed complete reaction. The reaction mixture was filtered, rinsed with dichloromethane (10 mL), concentrated, and purified by DCM column chromatography to yield 530 mg of a brown oily liquid in a 63.95% yield. MS (ESI, pos. ion) m / z: 368.3 [M+H]. + Step 3: Synthesis of compound 26-3

[0418] 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 to a 50 ml two-necked flask under nitrogen protection. 1,4-dioxane (10 mL) was added and the mixture was reacted at 80° C. for about 2 h. According to TLC detection, the reaction of the raw material was complete. The reaction solution was filtered, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v=8 / 1)) to obtain 275 mg of a yellow solid with a yield of 70.61%.

[0419] Step 4: Synthesis of compound 26-4

[0420] To a 100 mL single-necked flask, 26-3 (275 mg, 0.36 mmol) and cesium fluoride (0.11 g, 0.72 mmol) were added, along with N,N-dimethylformamide (8 mL). The mixture was allowed to react at room temperature for 2.5 h. TLC confirmed complete reaction. The mixture was washed with 40 mL of water and extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE / EA (v / v) = 1 / 1) to obtain 168 mg of a yellow oily liquid in a yield of 76.89%. MS (ESI, pos. ion) m / z: 605.1 [M+H] + .

[0421] Step 5: Synthesis of compound 26

[0422] To 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 and allowed to react at room temperature for approximately 5 h. TLC confirmed complete reaction. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The layers were separated, and the aqueous phase was extracted with additional dichloromethane (8 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / MeOH (v / v = 100 / 1)) to afford 54 mg of a blue solid in a 39.79% yield. MS (ESI, pos. ion) m / z: 485.1 [M+H] + ; 1 H 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=5.1Hz,1H),5.45(s,1H),4.58(p,J=8.8Hz,1H),3.84(q,J=7.7 Hz,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).

[0423] Example 27: Synthesis of Compound 27

[0424] Step 1: Synthesis of compound 27-1

[0425] 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 and reacted at 95°C for approximately 2.5 h. TLC indicated complete reaction. The mixture was washed with water (80 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using DCM / EA = 10 / 1 to obtain 2.21 g of a yellow solid in a 91.95% yield. MS (ESI, pos. ion) m / z: 266.0 [M+H] + .

[0426] Step 2: Synthesis of compound 27-2

[0427] Compound 27-1 (0.6 g, 2.25 mmol), cuprous iodide (0.021 g, 0.11 mmol), and bistriphenylphosphine palladium dichloride (0.079 g, 0.11 mmol) were added to a 50 mL two-necked flask. Diisopropylamine (8 mL) was then added. Under nitrogen protection, triisopropylsilyl acetylene (0.62 g, 3.38 mmol) was added and the mixture was allowed to react at 100°C for approximately 1 h. TLC confirmed complete reaction of the starting material. The reaction was stopped, the reaction solution was filtered, rinsed with dichloromethane (10 mL), concentrated, and purified by DCM column chromatography to yield 493 mg of a brown liquid in a 59.48% yield. MS (ESI, pos. ion) m / z: 368.0 [M+H] + .

[0428] Step 3: Synthesis of compound 27-3

[0429] To a 50 mL two-necked flask were added 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). Under nitrogen, 1,4-dioxane (10 mL) was added and the mixture was allowed to react at 80°C for approximately 3.5 h. TLC confirmed complete reaction of the starting materials and the reaction was stopped. The reaction mixture was filtered, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 1 / 1)) to give 235 mg of a yellow solid in a 66.38% yield.

[0430] Step 4: Synthesis of compound 27-4

[0431] 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 bottle and reacted at room temperature for 3 h. TLC showed that the reaction of the starting material was complete. Water (30 mL) was added for washing and the mixture was 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 a white solid with a yield of 93.72%. MS (ESI, pos. ion) m / z: 605.8 [M+H] + .

[0432] Step 5: Synthesis of compound 27

[0433] To a 100 mL single-necked flask, 27-4 (175 mg, 0.29 mmol) and DCM (8 mL) were added, along with trifluoroacetic acid (0.99 g, 8.7 mmol). The reaction was allowed to proceed at room temperature for approximately 2 h. TLC confirmed that the starting material had reacted completely, and the reaction was stopped. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The layers were separated, and the aqueous phase was extracted with an additional 8 mL of dichloromethane. The organic phase was dried and purified by column chromatography (eluent: DCM / MeOH (v / v = 80 / 1)) to afford 102 mg of a white solid in a 69.26% yield. MS (ESI, pos. ion) m / z: 485.0 [M+H] + ; 1 H NMR(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).

[0434] Example 28: Synthesis of Compound 28

[0435] Step 1: Synthesis of compound 28-1

[0436] To a 50 mL two-necked flask were added 27-1 (0.5 g, 1.88 mmol), cuprous iodide (0.072 g, 0.38 mmol), bistriphenylphosphine palladium dichloride (0.26 g, 0.38 mmol), and 1-(trimethylsilyl)propyne (0.32 g, 2.82 mmol). Triethylamine (0.95 g, 9.40 mmol) was then added. Anhydrous THF (8 mL) was added under nitrogen, followed by the dropwise addition of tetrabutylammonium fluoride (2.8 mL, 2.82 mmol). The reaction was allowed to proceed at room temperature for approximately 3 h. TLC confirmed complete reaction. The reaction mixture was filtered, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 4 / 1)) to afford 412 mg of a tan solid in a 97.34% yield. MS (ESI, pos. ion) m / z: 226.1.0 [M+H].+ .

[0437] Step 2: Synthesis of compound 28-2

[0438] To a 50 mL two-necked flask were added compound 18-1 (250 mg, 0.58 mmol), compound 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). Under nitrogen, 1,4-dioxane (10 mL) was added and the mixture was allowed to react at 80°C for approximately 15 h. TLC confirmed complete reaction. The reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA (v / v = 1 / 1)) to afford 170 mg of a green solid in a 47.25% yield. MS (ESI, pos. ion) m / z: 619.3 [M+H] + .

[0439] Step 3: Synthesis of compound 28

[0440] 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 and allowed to react at room temperature for approximately 3.5 h. TLC confirmed complete reaction. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The mixture was separated and extracted with dichloromethane (8 mL). The organic phase was dried, concentrated, and purified by column chromatography (eluent: DCM / MeOH (v / v = 80 / 1 to 60 / 1)) to afford 107 mg of a yellow solid in a 73.44% yield. MS (ESI, pos. ion) m / z: 499.2 [M+H] + ; 1 H 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).

[0441] Example 29: Synthesis of Compound 29

[0442] Step 1: Synthesis of compound 29-1

[0443] To 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, 1,4-dioxane (15 mL) and N,N'-dimethylethylenediamine (0.22 g, 2.52 mmol) were added. The mixture was allowed to react overnight at 110°C. TLC was used for monitoring the reaction. After the reaction was complete, the reaction mixture was filtered, concentrated, and purified by column chromatography using a PE / EA (2 / 1-1 / 1) column to obtain 95 mg of a blue solid in a 5.64% yield. MS (ESI, pos. ion) m / z: 266.95 [M+H] + .

[0444] Step 2: Synthesis of compound 29-2

[0445] Compound 29-1 (90 mg, 0.34 mmol), triisopropylsilyl acetylene (93 mg, 0.51 mmol), cuprous iodide (3 mg, 0.017 mmol), and bistriphenylphosphine palladium dichloride (12 mg, 0.017 mmol) were added to a 50 mL two-necked flask. Under nitrogen, diisopropylamine (5 mL) was added and the mixture was allowed to react at 100°C for 1.5 h. TLC confirmed complete reaction. The reaction mixture was filtered, concentrated, and purified by column chromatography (PE / EA (v / v = 5 / 1)) to afford 97 mg of a yellow oily liquid in a 78.10% yield. MS (ESI, pos. ion) m / z: 369.1 [M+H] + .

[0446] Step 3: Synthesis of compound 29-3

[0447] 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 two-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. After TLC detection, the raw material reaction was complete. The reaction solution was filtered, and the filter cake was rinsed with 8 mL of dichloromethane, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 2 / 1-1 / 1)) to obtain 94 mg of yellow solid with a yield of 48.21%. 1H 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).

[0448] Step 4: Synthesis of compound 29-4

[0449] 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 and reacted at room temperature for about 3 h. TLC detection showed that the raw material reaction was complete, and the reaction was stopped. Water (20 mL) was added for washing and extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 100 mg of a yellow liquid with a yield of 91.83%.

[0450] Step 5: Synthesis of compound 29

[0451] 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 and reacted at room temperature for 1.5 h. TLC confirmed complete reaction. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The layers were separated, and the aqueous phase was extracted with additional dichloromethane (8 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / MeOH (v / v = 80 / 1)) to give 43 mg of an off-white solid in a 50.88% yield. MS (ESI, pos. ion) m / z: 486.2 [M+H] + ; 1H 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).

[0452] Example 30: Synthesis of Compound 30

[0453] Step 1: Synthesis of compound 30-1

[0454] To a 10 mL reaction flask, 2,4-dibromothiazole (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) were added. The atmosphere was purged with nitrogen, and a mixture of N,N'-dimethylethylenediamine (0.073 g, 0.82 mmol) and 1,4-dioxane (5 mL) was added. The reaction was heated to 75°C. After 4 h, TLC analysis revealed a small amount of starting material remaining. Dissolve the product in EA (30 mL), wash with 10 mL of water, separate the layers, and spin-dry the organic phase. Purify the product by column chromatography using PE / EA (v / v = 1 / 0-5 / 1) as the eluent to obtain 80 mg of a 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).

[0455] Step 2: Synthesis of compound 30-2

[0456] Raw material 30-1 (65 mg, 0.24 mmol), bistriphenylphosphine palladium dichloride (0.017 g, 0.024 mmol), and cuprous iodide (5 mg, 0.024 mmol) were added to a 10 mL two-necked flask. The atmosphere was purged with nitrogen, and diisopropylamine (3 mL) was added. The temperature was raised to 50°C. Triisopropylsilyl acetylene (0.044 g, 0.24 mmol) was dissolved in 1.5 mL of diisopropylamine and slowly added dropwise to the reaction mixture. After 1 h, TLC indicated that the raw material had essentially reacted. The reaction mixture was concentrated, dissolved in DCM (30 mL), and washed with ammonium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using PE / EA (v / v = 20 / 1-3 / 1) to obtain 75 mg of a yellow solid in an 84.05% yield. MS (ESI, pos. ion) m / z: 374.2 [M+H] + .

[0457] Step 3: Synthesis of compound 30-3

[0458] To a 10 mL two-necked flask, 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 and the atmosphere 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 temperature was raised to 80°C for reaction. After 1.3 h, TLC confirmed complete reaction. The reaction solution was directly concentrated and purified by column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent. The mixture was collected and dried to give 170 mg of a yellow solid in a 73.29% yield. 1H 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).

[0459] Step 4: Synthesis of compound 30-4

[0460] 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 vial and allowed to react at room temperature. After 2 h, TLC indicated complete reaction. 16 mL of water was added, followed by extraction with EA (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (8 mL x 4), dried over anhydrous sodium sulfate, and then purified by column chromatography using DCM:EA (1:0-3:1) as the eluent to obtain 110 mg (83.73% yield). MS (ESI, pos. ion) m / z: 611.0 [M+H] + .

[0461] Step 5: Synthesis of compound 30

[0462] 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 vial and allowed to react at room temperature. After 1.3 h, TLC confirmed complete reaction. DCM (30 mL) was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and spin-dried. The residue was purified by column chromatography using DCM / MeOH (v / v = 1 / 0-25 / 1) as the eluent. The mixture was collected and spin-dried to yield 75 mg of an off-white solid. MS (ESI, pos. ion) m / z: 491.0 [M+H] + ; 1H 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).

[0463] Example 31: Synthesis of Compound 31

[0464] Step 1: Synthesis of compound 31-1

[0465] To a 100mL two-necked flask, THF (3.2mL) and 1,3-dimethylpropyleneurea (2.1mL) were added, followed by nitrogen replacement and the addition of 1,3-oxazole (0.5g, 7.24mmol). The flask was then cooled to -78°C and lithium bis(trimethylsilyl)amide (2.42g, 14.48mmol) was added dropwise over a 1.5h period. Iodine (3.68g, 14.48mmol) was dissolved in THF (10mL) and added to the flask. The reaction was continued at -78°C for 1h, then transferred to room temperature for 63h. TLC confirmed the completion of the reaction, followed by the addition of saturated sodium thiosulfate solution (40mL) and extraction with EA (100mL). The organic phase was washed once with saturated brine (50mL), dried over anhydrous sodium sulfate, and purified by concentrated column chromatography (PE) to afford 1.34g of a white solid in a 57.68% yield. MS(ESI,pos.ion)m / z:321.85[M+H] + .

[0466] Step 2: Synthesis of compound 31-2

[0467] To a 50 mL two-necked flask were added 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). The atmosphere was purged with nitrogen. N,N'-dimethylethylenediamine (64 mg, 0.73 mmol) and 1,4-dioxane (8 mL) were then added. The reaction was continued at 70°C for 21.5 h. TLC confirmed the complete reaction of the starting materials. Ice water (10 mL) was added, and the mixture was extracted with EA (20 mL x 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 afford 33 mg of a yellow solid in a yield of 5.99%. MS (ESI, pos. ion) m / z: 304.00 [M+H]. + .

[0468] Step 3: Synthesis of compound 31-3

[0469] Compound 31-2 (70 mg, 0.23 mmol), cuprous iodide (2 mg, 0.012 mmol), and bistriphenylphosphine palladium dichloride (8 mg, 0.012 mmol) were added to a 50 mL two-necked flask. The atmosphere was purged with nitrogen, and triisopropylsilyl acetylene (42 mg, 0.23 mmol), triethylamine (5 mL), and 1,4-dioxane (5 mL) were added. The atmosphere was purged with nitrogen again, and the temperature was raised to 50°C for reaction. After 2 h, TLC confirmed complete reaction. The reaction solution was concentrated, dissolved in DCM (20 mL), and washed once with water (5 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 4 / 1)) to afford 49 mg of a yellow oil in a yield of 59.34%. MS (ESI, pos. ion) m / z: 358.10 [M+H] + .

[0470] Step 4: Synthesis of compound 31-4

[0471] Compound 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 two-necked flask, and the atmosphere was replaced with nitrogen three times. 1,4-dioxane (5 mL) was then added, and the temperature was raised to 80°C for reaction. After 1 h, TLC monitoring showed that the raw materials had essentially reacted. DCM (50 mL) was added to dissolve the mixture, and the mixture was washed with saturated ammonium chloride solution (10 mL). The liquids were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated and purified by column chromatography (eluent: PE / EA (v / v = 1 / 1)) to give 86 mg of a yellow solid in a yield of 68.24%.

[0472] Step 5: Synthesis of compound 31-5

[0473] 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 atmosphere was replaced with nitrogen three times and stirred at 25°C for 4 h. TLC monitoring indicated that the starting material had reacted completely, and the reaction was stopped. 10 mL of water was added and the mixture was extracted with EA (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and then spin-dried. The organic phases were isolated and purified by column chromatography (eluent: PE / EA (v / v = 1 / 2)) to give 54 mg of a white solid in a yield of 83.17%. MS (ESI, pos. ion) m / z: 595.00 [M+H] + .

[0474] Step 6: Synthesis of compound 31

[0475] 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 allowed to proceed at 25°C for 1.5 h. TLC monitoring indicated that the reaction was complete. 25 mL of DCM was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent. The mixture was collected and dried by spin drying to afford 22 mg of a white solid (51.06% yield). MS (ESI, pos. ion) m / z: 475.00 [M+H]. + ; 1H 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).

[0476] Example 32: Synthesis of Compound 32

[0477] Step 1: Synthesis of compound 32-1

[0478] To a 50 mL two-necked flask, 31-1 (0.92 g, 2.87 mmol), cuprous iodide (0.027 g, 0.14 mmol), and bistriphenylphosphine palladium dichloride (0.10 g, 0.14 mmol) were added. The atmosphere was purged with nitrogen, and diisopropylamine (6 mL) was added. Triisopropylsilyl acetylene (0.63 g, 3.44 mmol) was dissolved in diisopropylamine (5 mL) and slowly added dropwise to the reaction flask. The temperature was raised to 45°C for reaction. After approximately 2.5 h of reaction, TLC confirmed complete reaction of the starting materials. The reaction solution was concentrated, dissolved in ethyl acetate (40 mL), filtered, and the filter cake was rinsed with ethyl acetate (15 mL). The organic phase was 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 in a yield of 46.46%. MS (ESI, pos.ion) m / z: 375.9 [M+H] + .

[0479] Step 2: Synthesis of compound 32-2

[0480] To a 50 mL two-necked flask, 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. The atmosphere was purged with nitrogen. 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 temperature was then raised to 90°C. After approximately 23 h of reaction, TLC monitoring indicated a small amount of residual starting material, and the reaction was stopped. The mixture was filtered, and the filter cake was rinsed with ethyl acetate (40 mL). The organic phase was collected, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 1 / 0-10 / 1)) to afford 0.08 g of a yellow liquid in a 16.8% yield.

[0481] Step 3: Synthesis of compound 32-3

[0482] To a 50 mL two-necked flask, 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 and the atmosphere was purged with nitrogen. Compound 32-2 (80 mg, 0.44 mmol) was dissolved in 1,4-dioxane (8 mL) and added to the flask. The temperature was raised to 80°C for reaction. After approximately 5 hours, TLC monitoring indicated that the reaction was complete. 30 mL of dichloromethane was added, and the organic phase was washed with 20 mL of water and dried over anhydrous sodium sulfate. Purification by column chromatography (eluent: PE / EA (v / v = 1 / 1)) afforded 153 mg of a yellow solid in a 91.05% yield. 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).

[0483] Step 4: Synthesis of compound 32-4

[0484] To a 50 mL two-necked flask were added 32-3 (100 mg, 0.13 mmol) and tetrahydrofuran (8 mL), the atmosphere was replaced with nitrogen, and the mixture was cooled to 0°C. Tetrabutylammonium fluoride (0.26 mL, 0.26 mmol) was dissolved in tetrahydrofuran (1 mL) and added dropwise at 0°C. After the addition was complete, the mixture was reacted at 0°C for about 10 minutes. TLC monitoring showed that the raw material was almost completely reacted. The reaction was quenched with 20 mL of water and extracted with dichloromethane (40 mL). The organic phase was dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 1 / 1)) to give 50 mg of an off-white solid in a yield of 56.83%. 1 H 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),6.5 0(t,J=7.5Hz,1H),5.55(s,1H),5.17(s,2H),4.66–4.56(m,2H),3.88–3.80 (m,4H),3.40(s,3H),3.09(s,3H),2.34(d,J=9.4Hz,2H),2.28–2.19(m,2H).

[0485] Step 5: Synthesis of compound 32

[0486] 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 allowed to react at room temperature. After 2 h, TLC indicated complete reaction of the starting material. The reaction was stopped and the temperature was lowered to 0°C. The pH was adjusted to approximately 8 with aqueous potassium phosphate (20% by mass). The layers were separated, and the aqueous phase was extracted with dichloromethane (30 mL). The combined organic phases were concentrated and purified by column chromatography (eluent: DCM / CH3OH (v / v = 1 / 0-50 / 1)) to afford 25 mg of a white solid in a yield of 62.66%. MS (ESI, pos. ion) m / z: 475.2 [M+H] + ; 1H 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).

[0487] Example 33: Synthesis of Compound 33

[0488] Step 1: Synthesis of compound 33-1

[0489] 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 and reacted at 60°C for 5 h. TLC monitored the complete reaction of the starting materials. Water (40 mL) was added, and the mixture was extracted with EA (40 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (eluent: PE / EA (v / v = 0 / 1-1 / 1) to obtain 0.12 g of a yellow solid in a yield of 25.60%. MS (ESI, pos. ion) m / z: 267.95 [M+H] + .

[0490] Step 2: Synthesis of compound 33-2

[0491] Compound 33-1 (0.12 g, 0.45 mmol), cuprous iodide (4 mg, 0.023 mmol), and bistriphenylphosphine palladium dichloride (16 mg, 0.023 mmol) were added to a 50 mL two-necked flask. The atmosphere was purged with nitrogen, and triisopropylsilyl acetylene (82 mg, 0.45 mmol) and diisopropylamine (6 mL) were added. The atmosphere was purged with nitrogen again and the reaction was carried out at 100°C. After 4.5 h, TLC monitoring indicated that the starting material had reacted completely. The reaction was stopped, the reaction solution was concentrated, dissolved in EA (10 mL), and filtered. The filter cake was rinsed with EA (15 mL). The organic phases were combined and washed once with water (5 mL). The organic phases were dried over anhydrous sodium sulfate, dried by spin drying, and purified by column chromatography (PE / EA (v / v) = 2 / 1) to give 113 mg of a yellow solid in a yield of 68.24%. MS (ESI, pos. ion) m / z: 369.20 [M+H] + .

[0492] Step 3: Synthesis of compound 33-3

[0493] Compound 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 two-necked flask, and the atmosphere was replaced with nitrogen three times. 1,4-dioxane (5 mL) was then added, and the atmosphere was replaced with nitrogen three times. The temperature was raised to 80° C. for reaction. After 1 h, TLC monitoring showed that the raw materials had basically reacted. The reaction was stopped, DCM (50 mL) was added to dissolve the mixture, and the mixture was washed with saturated ammonium chloride solution (10 mL). The liquids were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated and purified by column chromatography (PE:EA=1:1) to obtain 154 mg of a yellow solid with a yield of 67.71%.

[0494] Step 4: Synthesis of compound 33-4

[0495] 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 atmosphere was replaced with nitrogen three times and stirred at 25°C for 15 h. TLC monitoring indicated that the starting material had reacted completely, and the reaction was stopped. 10 mL of water was added and the mixture was extracted with EA (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (PE / EA (v / v) = 1 / 2) to afford 72 mg of a yellow solid in a yield of 58.82%. MS (ESI, pos. ion) m / z: 606.05 [M+H] + .

[0496] Step 5: Synthesis of compound 33

[0497] Compound 33-4 (72 mg, 0.12 mmol) and dichloromethane (4 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (0.82 g, 7.2 mmol). The reaction was allowed to proceed at 25°C for 2.5 h. TLC monitoring indicated that the reaction was complete. DCM (25 mL) was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and subjected to column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent. The mixture was collected and dried by spin drying to afford 36 mg of a light yellow solid in a 62.37% yield. MS (ESI, pos. ion) m / z: 486.10 [M+H] + ; 1H 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)

[0498] Example 34: Synthesis of Compound 34

[0499] Step 1: Synthesis of compound 34-1

[0500] To a 100 mL single-necked flask, 2-iodo-5-bromopyridine (1 g, 3.52 mmol), triisopropylsilyl acetylene (0.96 g, 5.28 mmol), bistriphenylphosphine palladium dichloride (0.12 g, 0.18 mmol), and cuprous iodide (0.034 g, 0.18 mmol) were added. Under nitrogen, triethylamine (1.78 g, 17.6 mmol) and anhydrous THF (12 mL) were added. The mixture was heated to 45°C and allowed to react for 2.5 h. TLC confirmed complete reaction. The reaction mixture was filtered, and the filter cake was rinsed with dichloromethane (10 mL). The filtrate was concentrated and purified by petroleum ether column chromatography to yield 1.0 g of a light yellow liquid in 83.90% yield. MS (ESI, pos. ion) m / z: 338.1 [M+H]. + .

[0501] Step 2: Synthesis of compound 34-2

[0502] To a 50 mL two-necked flask were added 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). Under nitrogen, 1,4-dioxane (10 mL) was added and the mixture was allowed to react at 110°C for approximately 4.5 h. TLC confirmed complete reaction. The reaction mixture was filtered, rinsed with 20 mL of dichloromethane (20 mL), and then washed with saturated ammonium chloride solution (10 mL). The organic phase was concentrated and purified by column chromatography using a PE / EA = 2 / 1 column to obtain 366 mg of a yellow solid in a 56.15% yield. MS (ESI, pos. ion) m / z: 368.1 [M+H] + .

[0503] Step 3: Synthesis of compound 34-3

[0504] Compound 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 two-necked flask. Under nitrogen protection, 1,4-dioxane (10 mL) was added and the reaction was carried out at 80 ° C for about 1.5 h. According to TLC detection, the raw material reaction was complete. The reaction solution was filtered, rinsed with dichloromethane (8 mL), concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 1 / 1)) to obtain 353 mg of 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).

[0505] Step 4: Synthesis of compound 34-4

[0506] 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 and allowed to react at room temperature for approximately 2.5 h. TLC confirmed complete reaction. The mixture was washed with water (30 mL) and extracted with ethyl acetate (15 mL × 3). The organic phase was dried, concentrated, and purified by column chromatography (DCM / EA (v / v = 3 / 1)) to give 275 mg of a green solid in a 98.89% yield. MS (ESI, pos. ion) m / z: 605.0 [M+H] + .

[0507] Step 5: Synthesis of compound 34

[0508] 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 confirmed complete reaction. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The layers were separated, and the aqueous phase was extracted with an additional 8 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / MeOH (v / v = 80 / 1)) to give 43 mg of a blue solid in a 19.20% yield. 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).

[0509] Example 35: Synthesis of Compound 35

[0510] Step 1: Synthesis of compound 35-1

[0511] 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 reacted at 100°C. After approximately 3 h, TLC indicated complete reaction. The mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and spin-dried. The product was purified by column chromatography (PE / EA (v / v = 0 / 1-1 / 1)) to afford 550 mg of the product as a yellow solid in a yield of 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).

[0512] Step 2: Synthesis of compound 35-2

[0513] To a 100 mL two-necked flask, add 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), bistriphenylphosphine palladium dichloride (0.22 g, 0.32 mmol), and triethylamine (0.80 g, 7.95 mmol). The atmosphere was purged with nitrogen, and THF (5 mL) 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 mixture. After completion of the addition, the temperature was raised to 45°C. The reaction was continued for 2 h, and TLC confirmed the complete reaction of the starting materials. DCM (40 mL) was added to dissolve the mixture, and the mixture was washed with saturated sodium chloride solution (10 mL×2). The organic phase was dried by rotary evaporation and purified by column chromatography using DCM / EA (v / v=30 / 1-8 / 1) as eluent to obtain 0.30 g of a yellow solid with a yield of 83.30%.

[0514] Step 3: Synthesis of compound 35-3

[0515] The 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 placed in a 25 mL two-necked flask. The atmosphere was purged with nitrogen, and 1,4-dioxane (5 mL) was added. The atmosphere was purged with nitrogen again, and the temperature was raised to 80°C for reaction. After 1 h of reaction, TLC confirmed the complete reaction of the starting materials. The reaction solution was concentrated, dissolved in DCM (40 mL), and washed once with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM:EA = 30:1-4:1 as the eluent to obtain 0.28 g of a yellow solid in a yield of 64.75%. MS (ESI, pos.ion) m / z: 620.0 [M+H] + ; 1 H 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).

[0516] Step 4: Synthesis of compound 35

[0517] 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 allowed to react at room temperature. After 2 h, TLC confirmed complete reaction. 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, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-35 / 1) as the eluent to obtain 95 mg of a yellow solid in a yield of 42.09%. MS (ESI, pos. ion) m / z: 500.0 [M+H]+; 1H 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).

[0518] Example 36: Synthesis of Compound 36

[0519] Step 1: Synthesis of compound 36-1

[0520] To a reaction flask, compound 30-1 (184 mg, 0.68 mmol), 1-(trimethylsilyl)-1-propyne (0.11 g, 1.02 mmol), bistriphenylphosphine palladium dichloride (0.095 g, 0.14 mmol), cuprous iodide (0.026 g, 0.14 mmol), and triethylamine (0.34 g, 3.40 mmol) were added. The atmosphere was purged with nitrogen, and THF (3 mL) was added. Tetrabutylammonium fluoride (2 mL, 2.00 mmol) was slowly added dropwise to the reaction mixture. The temperature was raised to 40°C and the reaction was allowed to proceed for 12.5 h. TLC confirmed complete reaction. The reaction mixture was concentrated and dissolved in DCM (50 mL). The organic phase was washed with saturated sodium chloride solution (10 mL x 2), dried by spin drying, and purified by column chromatography using PE / EA (v / v = 10 / 1 to 3 / 1) as the eluent to obtain 101 mg of a yellow solid in a 64.59% yield. 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).

[0521] Step 2: Synthesis of compound 36-2

[0522] To a reaction flask were added 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). The atmosphere was purged with nitrogen, and 1,4-dioxane (4 mL) was added. The reaction was heated to 80°C. After 1 h, TLC indicated that the starting materials had essentially reacted. The mixture was concentrated, and the residue was dissolved in DCM (30 mL) and washed with water (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / EA (v / v = 1 / 0-5 / 1) as the eluent to afford 145 mg of a yellow solid in a 56.50% yield. 1 H 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).

[0523] Step 3: Synthesis of compound 36

[0524] 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 allowed to react at room temperature. After 2.5 h, TLC indicated complete reaction. The reaction was stopped, diluted with DCM (30 mL), cooled to 0°C, and adjusted to pH 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent to obtain 100 mg of a yellow solid in an 88.44% yield. MS (ESI, pos. ion) m / z: 505.3 [M+H] + ; 1H 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).

[0525] Example 37: Synthesis of Compound 37

[0526] Step 1: Synthesis of compound 37-1

[0527] 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 reaction temperature was raised to 80°C. After 1 h, TLC indicated that the starting materials had essentially reacted. DCM (50 mL) was added, and the mixture was washed with water (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / EA (v / v = 10 / 1 to 3 / 1) to afford 0.35 g of a brown solid. Yield: 28.70%. MS (ESI, pos. ion) m / z: 163.2 [M+H] + .

[0528] Step 2: Synthesis of compound 37-2

[0529] To a reaction flask were added compound 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). Under nitrogen, 1,4-dioxane (5 mL) was added, the atmosphere was replaced with nitrogen, and the temperature was raised to 80°C. After 1.5 h, TLC indicated complete reaction. DCM (40 mL) was added for dissolution, and the product was washed with saturated sodium chloride solution (10 mL). The organic phase was then dried and purified by column chromatography (eluent: DCM / MeOH (v / v = 1 / 0 to 65 / 1)) to afford 0.38 g of a yellow solid in a 98.00% yield. MS (ESI, pos.ion) m / z: 556.3 [M+H] + ; 1 H 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).

[0530] Step 3: Synthesis of compound 37

[0531] 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), and the reaction was allowed to proceed at room temperature. After 3 h, TLC indicated complete reaction. 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 layers were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-65 / 1) as the eluent to obtain 195 mg of an off-white solid in a 67.24% yield. MS (ESI, pos. ion) m / z: 436.2 [M+H] + ; 1 HNMR(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).

[0532] Example 40: Synthesis of Compound 40

[0533] Step 1: Synthesis of compound 40-1

[0534] To a 100 mL two-necked flask were added 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). The atmosphere was purged with nitrogen three times, and triethylamine (1.84 g, 18.15 mmol) and 1-(trimethylsilyl)-1-propyne (0.61 g, 5.45 mmol) were added. Tetrabutylammonium fluoride (5.45 mL, 5.45 mmol) was added dropwise and the mixture was allowed to react at 25°C. After 3 h, TLC indicated complete reaction. Water (20 mL) and dichloromethane (40 mL) were added, and the separated liquid was washed. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (DCM / EA (v / v) = 0 / 1-4 / 1) to afford 728 mg of the product as a brown solid, in an 88.60% yield. MS (ESI, pos.ion) m / z: 227.1 [M+H] + .

[0535] Step 2: Synthesis of compound 40-2

[0536] In a 50 mL two-necked flask were added compound 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). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 80°C. After 4 h of reaction, TLC showed that the reaction of the starting material was complete. 20 mL of saturated ammonium chloride solution (20 mL) and dichloromethane (40 mL) were added, and the separated liquid was washed. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (DCM / EA (v / v = 0 / 1-2:1) to give 212 mg of a yellow foamy product in a yield of 38.70%. MS (ESI, pos. ion) m / z: 620.3 [M+H] + .

[0537] Step 3: Synthesis of compound 40

[0538] 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 allowed to react at room temperature. After 1 h of reaction, TLC indicated complete reaction of the starting material. 30 mL of DCM was added, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography using DCM:MeOH = 30:1 as the eluent to afford 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).

[0539] Example 41: Synthesis of Compound 41

[0540] Step 1: Synthesis of compound 41-1

[0541] To a reaction flask, add 2,4-dibromothiazole (1.0 g, 4.12 mmol), bistriphenylphosphine palladium dichloride (0.58 g, 0.82 mmol), cuprous iodide (0.16 g, 0.82 mmol), triethylamine (2.08 g, 20.6 mmol), tetrabutylammonium fluoride in THF (3.1 mL, 6.18 mmol), and THF (10 mL). After nitrogen replacement, raise the temperature to 30°C, and slowly add 1-(trimethylsilyl)propyne (0.60 g, 5.36 mmol) dropwise. After completion of the addition, react for 1.5 hours. TLC analysis indicates complete reaction of the starting materials. The residue was concentrated, dissolved in DCM (50 mL), and washed with saturated ammonium 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 / DCM (v / v) = 20 / 1 to 6 / 1 as eluent. The product was collected and dried by spin-drying to yield 0.35 g, a yield of 42.08%. MS (ESI, pos. ion) m / z: 201.9 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 2.11 (s, 3H).

[0542] Step 2: Synthesis of compound 41-2

[0543] To a reaction flask were added 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). N,N'-dimethylethylenediamine (0.11 g, 1.24 mmol) and 1,4-Dioxane (5 mL) were then added under nitrogen. The temperature was raised to 90°C for reaction. After 12.5 h, TLC indicated that the reaction was complete. The reaction was terminated, concentrated, and purified by column chromatography using DCM / EA (v / v = 1 / 0 to 15 / 1) as the eluent to yield 0.20 g of a brown solid. MS (ESI, pos.ion) m / z: 232.1[M+H]+; 1H 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).

[0544] Step 3: Synthesis of compound 41-3

[0545] To a reaction flask were added compound 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). Under nitrogen, 1,4-dioxane (4 mL) was added and the temperature was raised to 80°C. After 2 h, TLC indicated that the starting materials were essentially reacted. The reaction mixture was added with DCM (30 mL) and washed with water (6 mL x 2). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0 to 50 / 1) as the eluent to obtain 0.32 g of a yellow solid in an 88.08% yield. MS(ESI,pos.ion)m / z:625.3[M+H]+; 1H 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).

[0546] Step 4: Synthesis of compound 41

[0547] 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 allowed to react at room temperature. After 1 h, TLC confirmed complete reaction. DCM (30 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 dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-50 / 1) as the eluent to obtain 134 mg of a yellow solid in a 51.07% yield. 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).

[0548] Example 42: Synthesis of Compound 42

[0549] Step 1: Synthesis of compound 42-1

[0550] To a 50 mL two-necked flask were added 2,4-dibromothiazole (2.0 g, 8.23 ​​mmol), cuprous iodide (78 mg, 0.41 mmol), bistriphenylphosphine palladium dichloride (0.29 g, 0.41 mmol), triisopropylsilyl acetylene (1.5 g, 8.23 ​​mmol), triethylamine (4.16 g, 41.15 mmol), and 1,4-dioxane (30 mL). The atmosphere was purged with nitrogen and the reaction was allowed to proceed at 90°C. After 2 h, TLC monitoring indicated that the starting material had reacted completely, and the reaction was stopped. The reaction solution was concentrated, dissolved in DCM (50 mL), and washed once with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 100 / 1)) to afford 1.75 g of a yellow oil in a yield of 61.72%. MS (ESI, pos. ion) m / z: 344.10 [M+H] + .

[0551] Step 2: Synthesis of compound 42-2

[0552] To a 50 mL two-necked flask were added 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). The atmosphere was purged with nitrogen. N,N'-dimethylethylenediamine (0.18 g, 2.03 mmol) and 1,4-dioxane (30 mL) were then added. The reaction was continued at 90°C for 26 h. TLC confirmed the complete reaction of the starting material. The mixture was concentrated, dissolved in 50 mL of DCM, and separated by extraction with 20 mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA = 0-20:3) to afford 0.98 g of a yellow oil in a yield of 51.62%. MS (ESI, pos. ion) m / z: 374.20 [M+H]. + .

[0553] Step 3: Synthesis of compound 42-3

[0554] Compound 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 two-necked flask, and the atmosphere was replaced with nitrogen three times. 1,4-dioxane (8 mL) was then added, and the temperature was raised to 80°C for reaction. After 20 h of TLC monitoring, the raw materials reacted completely, and DCM (50 mL) was added to dissolve the mixture, washed with saturated ammonium chloride solution (10 mL), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated and purified by column chromatography (eluent: PE / EA (v / v = 2 / 1)) to obtain 292 mg of an off-white solid with a yield of 71.11%.

[0555] Step 4: Synthesis of compound 42-4

[0556] Compound 42-3 (240 mg, 0.31 mmol) was dissolved in THF (10 mL). Tetrabutylammonium fluoride (0.37 mL, 0.37 mmol) was added at 0°C and stirred for 20 min. TLC monitoring indicated that the reaction was complete. Saturated ammonium chloride solution (5 mL) was added to quench the reaction, followed by extraction with DCM (20 mL). The organic phase was concentrated and purified by column chromatography (eluent: DCM / EA (v / v = 1 / 1)) to afford 158 mg of an off-white solid in a yield of 82.69%. MS (ESI, pos. ion) m / z: 611.20 [M+H] + .

[0557] Step 5: Synthesis of compound 42

[0558] 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 mixture was allowed to react at 25°C for 4.5 h. TLC monitoring indicated that the reaction was complete. DCM (25 mL) was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent. The product was collected and dried by spin drying to give 78 mg of a white solid in a 64.74% yield. 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).

[0559] Example 43: Synthesis of Compound 43

[0560] Step 1: Synthesis of compound 43-1

[0561] To a two-necked flask were added 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). The reaction was allowed to proceed at 100°C for 18 h. TLC confirmed the complete reaction. The reaction solution was concentrated to dryness and dissolved in dichloromethane (20 mL). The organic phase was washed sequentially with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / ethyl acetate (v / v) = 1 / 0-3 / 1) to afford 0.2 g of a light yellow solid in a yield of 18.13%. MS (ESI, pos. ion) m / z: 314.00 [M+H] + .

[0562] Step 2: Synthesis of compound 43-2

[0563] Compound 43-1 (0.2 g, 0.64 mmol), triisopropylsilyl acetylene (0.12 g, 0.64 mmol), cuprous iodide (0.0061 g, 0.032 mmol), bistriphenylphosphine 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 atmosphere was purged with nitrogen and the reaction was carried out at 100°C for 4 h. TLC confirmed complete reaction. The reaction solution was concentrated, dissolved in 20 mL of ethyl acetate, and washed once with water (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (eluent: DCM / EA (v / v) = 1 / 0-10 / 1) afforded 0.22 g of a brown solid in a yield of 93.70%. MS (ESI, pos. ion) m / z: 368.25 [M+H] + .

[0564] Step 3: Synthesis of compound 43-3

[0565] Compound 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 atmosphere was replaced with nitrogen, and the reaction was carried out at 80 ° C for 3 h. According to TLC detection, the starting material was completely reacted. The reaction solution was directly 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. 0.34 g of light green solid was obtained by column chromatography (dichloromethane / ethyl acetate (v / v = 1 / 0-4 / 1), with a yield of 91.82%.

[0566] Step 4: Synthesis of compound 43-4

[0567] 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 the vial and allowed to react at room temperature for 3 h. TLC analysis indicated complete reaction of the starting material. The reaction was stopped, and water (15 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: DCM / MeOH (v / v = 1 / 0-100 / 3)) to afford 0.25 g of a light green solid in a yield of 92.54%. MS (ESI, pos. ion) m / z: 605.30 [M+H] + .

[0568] Step 5: Synthesis of compound 43

[0569] 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 and allowed to react at room temperature for 2 h. TLC confirmed complete reaction of the starting materials, and the reaction was stopped. 20 mL of dichloromethane was added to the reaction solution, and the temperature was lowered to 0°C. A 20% (mass fraction) aqueous potassium phosphate solution was added to adjust the pH to 8. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (DCM / MeOH (v / v = 1 / 0 to 20 / 1)) afforded 0.17 g of a light yellow solid in a yield of 84.86%. MS (ESI, pos. ion) m / z: 485.10 [M+H] + ; 1 H 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).

[0570] Example 44: Synthesis of Compound 44

[0571] Step 1: Synthesis of compound 44-1

[0572] 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), bistriphenylphosphine palladium dichloride (0.15 g, 0.22 mmol), tetrahydrofuran (7 mL) and triethylamine (1.11 g, 11 mmol) were added to the reaction flask. The atmosphere was replaced 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. TLC was used for detection. After the reaction of the starting materials, the reaction solution was concentrated, dissolved in ethyl acetate (20 mL), washed with 10 mL of water, and the organic phase was washed with anhydrous sodium sulfate and concentrated. The product was purified by column chromatography (eluent: petroleum ether / ethyl acetate (v / v = 1 / 0-1 / 1)) to give 0.49 g of a tan solid in a yield of 98.71%. MS(ESI,pos.ion)m / z:226.10[M+H] + .

[0573] Step 2: Synthesis of compound 44-2

[0574] Compound 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, replaced with nitrogen, and reacted at 80°C for 3.5 h. TLC analysis showed that the starting material was completely reacted. The reaction solution was directly 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 (eluent: DCM / EA (v / v = 1 / 0 to 4 / 1) gave 0.35 g of a light green solid, yield: 42.48%. MS (ESI, pos. ion) m / z: 619.30 [M+H] + .

[0575] Step 3: Synthesis of compound 44

[0576] Compound 44-2 (0.35 g, 0.57 mmol), dichloromethane (7 mL), and trifluoroacetic acid (3.90 g, 34.20 mmol) were added to the vial and allowed to react at room temperature for 1 h. TLC confirmed complete reaction of the starting materials, and the reaction was stopped. Dichloromethane (20 mL) was added to the reaction solution, cooled to 0°C, and 20% potassium phosphate solution was added dropwise to adjust the pH to 8. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (eluent: DCM, MeOH (v / v = 1 / 0-30 / 1)) afforded 0.18 g of a light yellow solid in a yield of 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).

[0577] Example 45: Synthesis of Compound 45

[0578] Step 1: Synthesis of compound 45-1

[0579] 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), bistriphenylphosphine palladium dichloride (0.063 g, 0.090 mmol), tetrahydrofuran (7 mL) and triethylamine (0.46 g, 4.5 mmol) were added to the bottle, the atmosphere was replaced with nitrogen, tetrabutylammonium fluoride (1.8 mL, 1.8 mmol) was added dropwise, and the mixture was reacted at room temperature for 2 h. After TLC detection, the raw materials were completely reacted, the reaction solution was concentrated, dissolved in ethyl acetate (20 mL), washed with 10 ml of water, separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (eluent: dichloromethane / ethyl acetate (v / v = 1 / 0-4 / 1)) gave 0.15 g of a brown solid in a yield of 73.79%.

[0580] Step 2: Synthesis of compound 45-2

[0581] Compound 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, replaced with nitrogen, and reacted at 80°C for 2.5 h. TLC analysis showed that the raw material was almost completely reacted. The reaction solution was directly concentrated to dryness, dissolved in dichloromethane (30 mL), washed with saturated ammonium chloride solution (10 mL), and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 1 / 0 to 4 / 1) to obtain 0.3 g of a light yellow solid, yield: 73.02%. MS (ESI, pos. ion) m / z: 620.30 [M+H] + .

[0582] Step 3: Synthesis of compound 45

[0583] 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 confirmed complete reaction. Dichloromethane (20 mL) was added to the reaction solution, cooled to 0°C, and the pH was adjusted to 8 by adding 20% ​​(mass fraction) potassium phosphate aqueous solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (eluent: dichloromethane / methanol (v / v = 1 / 0-20 / 1)) afforded 0.14 g of a yellow solid in a yield of 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).

[0584] Example 46: Synthesis of Compound 46

[0585] Step 1: Synthesis of compound 46-1

[0586] To a 100 mL single-necked flask, 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, followed by N,N-dimethylacetamide (35 mL) and allowed to react at 95°C. After 14 h, TLC indicated complete reaction. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by DCM column chromatography to yield 1.21 g of a yellow solid in a 26.51% yield. MS (ESI, pos. ion) m / z: 315.0 [M+H] + .

[0587] Step 2: Synthesis of compound 46-2

[0588] To a reaction flask, compound 46-1 (0.50 g, 1.59 mmol), bistriphenylphosphine palladium dichloride (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. Under nitrogen, 1-(trimethylsilyl)propyne (0.23 g, 2.07 mmol) was slowly added dropwise. After 1 h, TLC confirmed complete reaction. The reaction was quenched by addition of water (20 mL) and extracted with DCM (100 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-50 / 1) as the eluent to afford 89 mg of a yellow solid in a 24.71% yield. 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).

[0589] Step 3: Synthesis of compound 46-3

[0590] Compound 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. 1,4-dioxane (4 mL) was added and the temperature was raised to 80°C. The reaction was stopped after 5 h. 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, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent to obtain 160 mg of a yellow solid. MS (ESI, pos. ion) m / z: 620.3 [M+H] + ; 1 H 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).

[0591] Step 4: Synthesis of compound 46

[0592] 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 h, TLC confirmed complete reaction. The mixture was cooled to 0°C and adjusted to pH 8 with 20% potassium phosphate solution. DCM (30 mL) was added for extraction and the organic phase was dried and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent to obtain 69 mg of a yellow solid in a yield of 55.22%. MS (ESI, pos. ion) m / z: 500.3 [M+H] + ; 1H 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).

[0593] Example 47: Synthesis of Compound 47

[0594] Step 1: Synthesis of compound 47-1

[0595] Compound 46-1 (400 mg, 1.27 mmol), triisopropylsilyl acetylene (0.35 g, 1.91 mmol), cuprous iodide (0.012 g, 0.064 mmol), bistriphenylphosphine palladium dichloride (0.045 g, 0.064 mmol), and triethylamine (0.64 g, 6.35 mmol) were added to a 50 mL two-necked flask. Under nitrogen, THF (8 mL) was added and the mixture was allowed to react at 50°C for 4.5 h. TLC indicated a small amount of starting material remaining, so the reaction was stopped. Dichloromethane (15 mL) was added and the mixture was washed with water (5 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 4 / 1-3 / 1)) to give 146 mg of a yellow oily liquid in a 31.11% yield. MS (ESI, pos. ion) m / z: 369.2 [M+H] + .

[0596] Step 2: Synthesis of compound 47-2

[0597] Compound 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 two-necked flask. Under nitrogen protection, 1,4-dioxane (8 mL) was added and the reaction was carried out at 80 ° C for about 3 h. TLC detection showed that the raw material was completely reacted. The reaction solution was filtered, rinsed with dichloromethane (10 mL), concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 1 / 1)) to obtain 285 mg of a yellow solid with a yield of 76.57%. 1 H 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 =7.4Hz,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=5.1 Hz,21H).

[0598] Step 3: Synthesis of compound 47-3

[0599] Compound 47-2 (285 mg, 0.37 mmol) was added to a 50 mL two-necked flask under nitrogen protection. THF (8 mL) was then added dropwise at 0°C. Tetrabutylammonium fluoride (0.74 mL, 0.74 mmol) was added dropwise and the mixture was incubated for 0.5 h. TLC confirmed complete reaction of the starting material. The reaction was stopped, the reaction solution concentrated, and purified by column chromatography (eluent: DCM / EA (v / v = 4 / 1)) to give 45 mg of a yellow solid in a 19.87% yield. MS (ESI, pos. ion) m / z: 606.3 [M+H] + .

[0600] Step 4: Synthesis of compound 47

[0601] To 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 and allowed to react at room temperature for 2 h. TLC confirmed complete reaction of the starting material. The reaction was stopped and the pH was adjusted to approximately 7 by adding saturated sodium bicarbonate solution. The layers were separated, and the aqueous phase was extracted with an additional 8 mL of dichloromethane. The organic phase was dried, concentrated, and purified by column chromatography (eluent: DCM / MeOH (v / v = 50 / 1)) to give 40 mg of a white solid in a 48.20% yield. MS (ESI, pos. ion) m / z: 486.2 [M+H]+; 1 H NMR(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).

[0602] Example 48: Synthesis of Compound 48

[0603] Step 1: Synthesis of compound 48-1

[0604] To a 100 mL two-necked flask were added compound 31-1 (1.4 g, 4.36 mmol), cuprous iodide (0.17 g, 0.87 mmol), bistriphenylphosphine palladium dichloride (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). Under nitrogen, tetrabutylammonium fluoride (1.71 g, 6.54 mmol) was added dropwise. The mixture reacted at room temperature for approximately 3 h, and TLC confirmed the complete reaction. The reaction mixture was filtered, the filtrate concentrated, and purified by column chromatography (eluent: PE / DCM (v / v = 1 / 0 to 9 / 1)) to afford 0.35 g of a yellow solid in a 34.43% yield. MS (ESI, pos. ion) m / z: 234.0 [M+H] + .

[0605] Step 2: Synthesis of compound 48-2

[0606] 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 two-necked flask, and the atmosphere was replaced with nitrogen. N, N'-dimethyl-ethylenediamine (0.066 g, 0.75 mmol) was dissolved in 1,4-dioxane (1 The mixture was then added to a flask and heated to 85°C for reaction. After about 15 hours of reaction, TLC monitoring indicated a small amount of residual starting material. The mixture was filtered and the filter cake was rinsed with dichloromethane (50 mL). The organic phase was collected and washed once with water (30 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 1 / 0-50 / 1-5 / 1)) to give 0.085 g of a light yellow solid in a yield of 26.29%. MS (ESI, pos. ion) m / z: 216.1 [M+H] + .

[0607] Step 3: Synthesis of compound 48-3

[0608] To a 50 mL two-necked flask were added compound 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). The atmosphere was purged with nitrogen, and 1,4-dioxane (8 mL) was added. The mixture was heated to 80°C and reacted for approximately 5.5 h, monitored by TLC. After complete reaction, the mixture was filtered, and the filter cake was rinsed with 30 mL of dichloromethane (30 mL). The organic phase was washed with water (20 mL) and dried over anhydrous sodium sulfate. Purification by column chromatography (DCM / EA = 1 / 0 to 7 / 3) afforded 210 mg of a yellow solid in a 74.25% yield. 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).

[0609] Step 4: Synthesis of compound 48

[0610] Compound 48-3 (0.21 g, 0.35 mmol) and dichloromethane (11 mL) were added to a 100 mL single-necked flask and stirred at room temperature until dissolved. Trifluoroacetic acid (2.39 g, 21 mmol) was then added dropwise and allowed to react at room temperature. After approximately 2 h of reaction, a sample was taken and the pH was adjusted to 8 with potassium phosphate solution. TLC confirmed complete reaction. The mixture was cooled to 0°C and the pH was adjusted to approximately 8 with 20% aqueous potassium phosphate solution. The layers were separated, 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 (eluent: DCM / CH3OH (v / v = 1 / 0-50 / 1)) to yield 110 mg of a green solid in a 65.26% yield. 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).

[0611] Example 49: Synthesis of Compound 49

[0612] Step 1: Synthesis of compound 49-1

[0613] To a reaction flask, add 2,4-diiodopyrimidine (1.0 g, 3.01 mmol), bistriphenylphosphine 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). Under nitrogen, cool to 0°C, and slowly add 1-(trimethylsilyl)propyne (0.34 g, 3.01 mmol) dropwise. After complete addition, warm to room temperature. Continue the reaction for 5 h. TLC analysis indicates a small amount of starting material remaining. DCM (100 mL) and water (15 mL) are added for extraction. The organic phase is dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using PE / DCM (v / v = 1 / 0-3 / 1) as the eluent to obtain 0.32 g of a yellow-brown solid in a yield of 43.52%. MS (ESI, pos.ion) m / z: 245.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.36 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 5.0 Hz, 1H), 2.11 (s, 3H).

[0614] Step 2: Synthesis of compound 49-2

[0615] 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. N,N'-dimethylethylenediamine (0.046 g, 0.52 mmol) and 1,4-dioxane (3 mL) were added, and the temperature was raised to 70°C. After 5 h, TLC confirmed complete reaction. DCM (40 mL) was added to the reaction solution, and the organic phase was washed with ammonium chloride solution (15 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM:EA = 15:1 to 3:1) to obtain 52 mg of a yellow solid in a 17.53% yield. MS (ESI, pos. ion) m / z: 227.1 [M+H] + .

[0616] Step 3: Synthesis of compound 49-3

[0617] Compound 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. 1,4-dioxane (4 mL) was added and the temperature was raised to 80°C. After 4.5 h, TLC confirmed the complete reaction. DCM (60 mL) was added, followed by washing with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent to obtain 132 mg of a yellow solid. The yield was 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).

[0618] Step 4: Synthesis of compound 49

[0619] 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 confirmed the complete reaction. DCM (30 mL) was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-35 / 1) as the eluent to obtain 89 mg of an off-white solid in a 69.00% yield. 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).

[0620] Example 50: Synthesis of Compound 50

[0621] Step 1: Synthesis of compound 50-1

[0622] 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 the vial and reacted at 90°C for 2 h. TLC confirmed complete reaction. Water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: PE / EA (v / v = 1 / 0 to 1 / 1)) to afford 0.8 g of a yellow-brown solid, in a yield of 52.91%. MS (ESI, pos. ion) m / z: 266.0 [M+H] + .

[0623] Step 2: Synthesis of compound 50-2

[0624] 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), bistriphenylphosphine palladium dichloride (0.21 g, 0.30 mmol) and triethylamine (1.52 g, 15.05 mmol) were added to a two-necked flask, the atmosphere was replaced with nitrogen, and tetrabutylammonium fluoride (6.0 mL, 6.02 mmol) was added dropwise. The reaction was carried out at room temperature for 2 h. TLC showed that the reaction of the raw materials was complete. The reaction solution was directly concentrated to dryness, dissolved in dichloromethane (20 mL), and water (10 mL) was added. The liquid was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (eluent: PE:EA (v / v=1 / 0-1 / 1)) gave 0.67 g of a khaki solid with a yield of 98.93%. MS(ESI,pos.ion)m / z:226.15[M+H] + .

[0625] Step 3: Synthesis of compound 50-3

[0626] Compound 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. The atmosphere was replaced with nitrogen and the reaction was carried out at 80°C for 3.5 h. TLC confirmed complete reaction of the starting materials. The reaction solution was concentrated, dissolved in 30 mL of dichloromethane, and washed with 10 mL of saturated ammonium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (eluent: DCM / EA (v / v = 1 / 0 to 4 / 1)) to afford 0.53 g of a yellow solid. MS (ESI, pos. ion) m / z: 619.30 [M+H] + .

[0627] Step 4: Synthesis of compound 50

[0628] Compound 50-3 (0.53 g, 0.86 mmol), dichloromethane (10 mL) and trifluoroacetic acid (5.88 g, 51.6 mmol) were added to the reaction flask and reacted at room temperature for 2 h. TLC confirmed that the reaction of the starting materials was complete. Dichloromethane (20 mL) was added, the temperature was lowered to 0°C, and 20% mass fraction potassium phosphate solution was added dropwise to adjust the pH to 8. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (eluent: DCM / MeOH (v / v = 1 / 0 to 30 / 1) gave 0.26 g of a light 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).

[0629] Example 51: Synthesis of Compound 51

[0630] Step 1: Synthesis of compound 51-1

[0631] To a 50 mL two-necked flask were added compound 31-2 (120 mg, 0.4 mmol), cuprous iodide (15 mg, 0.08 mmol) and bistriphenylphosphine palladium dichloride (56 mg, 0.08 mmol). The atmosphere was replaced with nitrogen, and 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, TLC monitoring showed that the reaction of the starting material was complete. The reaction solution was concentrated, dissolved in DCM (20 mL), washed once with water (5 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography (eluent: DCM / EA (v / v = 40 / 1)) to give 42 mg of a yellow oil in a yield of 49.29%. MS(ESI,pos.ion)m / z:216.20[M+H] + .

[0632] Step 2: Synthesis of compound 51-2

[0633] Compound 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 placed in a 25 mL two-necked flask. The atmosphere was purged with nitrogen three times, and 1,4-dioxane (5 mL) was added. The temperature was raised to 80°C for reaction. After 13.5 h, TLC analysis indicated that the starting materials had essentially reacted. 50 mL of DCM was added, and the mixture was washed with 10 mL of saturated ammonium chloride solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and dried by spin drying. Purification by column chromatography (eluent: DCM / EA (v / v = 10 / 1)) afforded 73 mg of a yellow solid in a 40.33% yield. MS (ESI, pos. ion) m / z: 609.30 [M+H]. + .

[0634] Step 3: Synthesis of compound 51

[0635] Compound 51-2 (73 mg, 0.12 mmol) and dichloromethane (4 mL) were added to a 25 mL single-necked flask, followed by trifluoroacetic acid (0.82 g, 7.2 mmol). The reaction was allowed to proceed at 25°C for 2 h. TLC monitoring indicated that the reaction was complete. 25 mL of DCM was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and subjected to column chromatography using DCM / EA (v / v = 2 / 3) as the eluent. The mixture was collected and dried by spin drying to afford 25 mg of an off-white solid in a yield of 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).

[0636] Example 52: Synthesis of Compound 52

[0637] Step 1: Synthesis of compound 52-1

[0638] To a reaction flask, 5-bromo-2-iodopyrimidine (0.60 g, 2.11 mmol), bistriphenylphosphine 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. Under nitrogen, 1-(trimethylsilyl)-1-propyne (0.24 g, 2.11 mmol) was slowly added dropwise. After 12.5 h of reaction at room temperature, TLC revealed a small amount of starting material remaining. DCM (50 mL) and ammonium chloride solution (20 mL) were added for extraction. The organic phase was then dried and purified by column chromatography using PE / DCM (v / v = 1 / 0 to 2 / 1) as the eluent to afford 0.18 g of a yellow solid. Yield: 42.65%. MS (ESI, pos.ion) m / z: 197.1 [M+H] + .

[0639] Step 2: Synthesis of compound 52-2

[0640] 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. N,N'-dimethylethylenediamine (0.041 g, 0.47 mmol) and 1,4-dioxane (5 mL) were added. The temperature was raised to 85°C for 3.5 h. TLC analysis indicated a small amount of residual starting material, and the reaction was stopped. The temperature was then lowered to room temperature. The reaction solution was concentrated and dissolved in DCM (40 mL). 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 to 3 / 1)) to obtain 0.15 g of a yellow solid in a yield of 56.80%. MS (ESI, pos.ion) m / z: 227.1 [M+H] + .

[0641] Step 3: Synthesis of compound 52-3

[0642] Compound 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. 1,4-dioxane (5 mL) was added and the temperature was raised to 80°C. After 1.5 h, TLC confirmed complete reaction. DCM (30 mL) was added and the product was washed twice with water (6 mL). The organic phase was dried and purified by column chromatography using DCM / MeOH (v / v = 1 / 0 to 28 / 1) as the eluent to obtain 0.38 g of a yellow solid in a 92.49% yield. MS (ESI, pos. ion) m / z: 620.3 [M+H] + ; 1 H NMR (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).

[0643] Step 4: Synthesis of compound 52

[0644] 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 allowed to react at room temperature. After 2 h, TLC indicated complete reaction of the starting material, and the reaction was stopped. The reaction solution was diluted with 30 mL of DCM, cooled to 0°C, and adjusted to pH 8 with 20% potassium phosphate solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-30 / 1) as the eluent to obtain 165 mg of a yellow solid in a 53.87% yield. 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).

[0645] Example 53: Synthesis of Compound 53

[0646] Step 1: Synthesis of compound 53-1

[0647] To a reaction flask, 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 and the reaction mixture was heated to 70°C. After 12.5 h, TLC confirmed complete reaction. The reaction was quenched by the addition of water (30 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL x 4), dried over anhydrous sodium sulfate, and then purified by column chromatography using DCM / EA (v / v) = 30 / 1 to 10 / 1 as the eluent to obtain 305 mg of a yellow solid in a 54.33% yield.

[0648] Step 2: Synthesis of compound 53-2

[0649] To a reaction flask, compound 53-1 (0.10 g, 0.37 mmol), bistriphenylphosphine 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. THF (4 mL) was then added under nitrogen, and 1-(trimethylsilyl)propyne (0.054 g, 0.48 mmol) was slowly added dropwise at room temperature. After 1 h, TLC confirmed the complete reaction. DCM (50 mL) was added, and the mixture was washed with saturated ammonium chloride solution (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / EA (v / v = 20 / 1 to 5 / 1) as the eluent to obtain 66 mg of a yellow solid in a yield of 77.92%. 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).

[0650] Step 3: Synthesis of compound 53-3

[0651] Compound 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. 1,4-dioxane (4 mL) was added and the temperature was raised to 80°C. After 2.3 h, TLC confirmed complete reaction. DCM (30 mL) was added, followed by washing with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-50 / 1) as the eluent to afford 130 mg of a yellow solid in a 71.91% yield. 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).

[0652] Step 4: Synthesis of compound 53

[0653] To the reaction flask were added 53-3 (0.12 g, 0.19 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1.30 g, 11.4 mmol) and stirred at room temperature. After 1.5 h, TLC indicated complete reaction. The mixture was cooled to 0°C and adjusted to pH 8 with 20% potassium phosphate solution. DCM (30 mL) was then added for extraction and separation. The organic phase was dried and purified by column chromatography using DCM / MeOH (v / v = 1 / 0-40 / 1) as the eluent to afford 35 mg of a yellow solid in a yield of 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).

[0654] Example 54: Synthesis of Compound 54

[0655] Step 1: Synthesis of compound 54-1

[0656] Compound 53-1 (0.30 g, 1.12 mmol), bistriphenylphosphine 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 a reaction flask under nitrogen. THF (5 mL) was added, the temperature was raised to 50°C, and triisopropylsilyl acetylene (0.25 g, 1.34 mmol) was slowly added dropwise. After 2.5 h, TLC confirmed the complete reaction. DCM (50 mL) was added, and the mixture was washed with saturated ammonium chloride solution (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography using DCM / EA (v / v = 20 / 1-5 / 1) as the eluent to obtain 0.38 g of a yellow solid in a 91.79% yield. MS (ESI, pos. ion) m / z: 369.3 [M+H] + .

[0657] Step 2: Synthesis of compound 54-2

[0658] Compound 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. 1,4-dioxane (5 mL) was added and the temperature was raised to 80°C. After 2.3 h, TLC indicated complete reaction. DCM (30 mL) was added and the product was washed once with water (8 mL). The organic phase was then dried and purified by column chromatography using DCM / EA (v / v = 15 / 1 to 3 / 1) as the eluent to obtain 0.28 g of a yellow solid in a 67.71% yield. MS (ESI, pos. ion) m / z: 762.4 [M+H] + ; 1H NMR (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(d d,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).

[0659] Step 3: Synthesis of compound 54-3

[0660] Compound 54-2 (0.27 g, 0.35 mmol), dichloromethane (5 mL), and trifluoroacetic acid (2.39 g, 21 mmol) were added to a reaction flask and stirred at room temperature. After 2 h, TLC confirmed complete reaction. The mixture was cooled to 0°C and adjusted to pH 8 with 20% pre-cooled potassium phosphate solution. Extraction was performed with 50 mL of DCM, and the organic phase was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then purified by column chromatography using DCM / MeOH (v / v = 1 / 0-50 / 1) as the eluent to obtain 215 mg of a yellow solid in a 94.54% yield. MS (ESI, pos. ion) m / z: 642.3 [M+H] + .

[0661] Step 4: Synthesis of compound 54

[0662] Compound 54-3 (195 mg, 0.30 mmol) and tetrahydrofuran (3 mL) were added to the reaction flask, cooled to 0°C, and tetrabutylammonium fluoride (0.36 mL, 0.36 mmol) was added dropwise. After 27 min, TLC confirmed complete reaction. The reaction was quenched by the addition of ice water (10 mL), followed by extraction with DCM (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to afford 90 mg of a pale yellow solid in a 61.49% yield. 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,1H),6.24(s,1H),4.84(s,1H),4.38–4.25(m,1H),3.73(dd,J=15.1,7.5Hz,1H),3.22(s, 3H),2.92(d,J=4.8Hz,3H),2.18–2.03(m,2H),1.55–1.47(m,1H),1.41(dd,J=19.3,9.6Hz,1H).

[0663] Example 55: Synthesis of Compound 55

[0664] Step 1: Synthesis of compound 55-1

[0665] To a reaction flask, 5-bromo-2-iodopyridine (1 g, 3.52 mmol), bistriphenylphosphine 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 dropwise under nitrogen. 1-(Trimethylsilyl)-1-propyne (0.40 g, 3.52 mmol) was slowly added dropwise. The mixture was allowed to react at room temperature for 4 h. TLC indicated complete reaction. DCM (50 mL) and ammonium chloride solution (20 mL) were added for extraction. The organic phase was then dried by spin-drying and subjected to column chromatography with PE / EA (v / v = 10 / 1). The eluate was collected and dried, yielding 0.3 g of a pale yellow, viscous solid (43.44% yield).

[0666] Step 2: Synthesis of compound 55-2

[0667] 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 bottle. Under nitrogen, 1,4-dioxane (10 mL) was added and the mixture was allowed to react at 110°C for 16 h. TLC analysis revealed a small amount of residual starting material. The reaction mixture was filtered, 15 mL of saturated ammonium chloride solution was added, and the mixture was extracted with 30 mL of ethyl acetate. The organic phase was dried and concentrated, and purified by column chromatography using a DCM / EA (v / v) mixture of 3 / 1 to afford 215 mg of a yellow solid in a 93.56% yield. MS (ESI, pos. ion) m / z: 226.1 [M+H] + .

[0668] Step 3: Synthesis of compound 55-3

[0669] Compound 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 two-necked flask. Under nitrogen, 1,4-dioxane (18 mL) was added and the mixture was allowed to react at 80°C for approximately 4 h. TLC confirmed complete reaction. The reaction mixture was filtered, the filtrate concentrated, and purified by column chromatography using a DCM / EA (v / v) mixture of 4 / 1 to afford 365 mg of a green solid in an 84.54% yield. MS (ESI, pos. ion) m / z: 619.3 [M+H]. + .

[0670] Step 4: Synthesis of compound 55

[0671] 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 vial and allowed to react at room temperature for 2 h. TLC confirmed complete reaction. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 7. The layers were separated, and the aqueous phase was extracted with additional dichloromethane (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with DCM / MeOH (v / v = 70 / 1) to yield 145 mg of a blue solid in a 48.06% yield. 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).

[0672] Example 56: Synthesis of Compound 56

[0673] Step 1: Synthesis of compound 56-1

[0674] 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 for 2 h. After the addition was completed, the mixture was stirred for 30 min, and paraformaldehyde (1.06 g, 35.23 mmol) was added. The mixture was warmed to room temperature and reacted for 16 h. The reaction was quenched with 50 mL of saturated ammonium chloride and 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 light yellow oil in a yield of 61.78%.

[0675] Step 2: Synthesis of compound 56-2

[0676] 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 dropwise. Methanesulfonyl chloride (0.58 g, 5.09 mmol) was added dropwise at 0°C. The mixture was heated to 25°C and stirred for 18 h. TLC monitoring showed that the starting material had reacted completely. The reaction was quenched by adding hydrochloric acid (1 mol / L, 2 mL), and the mixture was washed with saturated sodium bicarbonate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 0.72 g of a light yellow oil with a yield of 80.19%.

[0677] Step 3: Synthesis of compound 56-3

[0678] 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 and reacted at 60°C for 12.5 h. TLC confirmed the complete reaction of the starting materials. The reaction was quenched by adding saturated ammonium chloride solution (20 mL). The mixture was extracted with 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 in 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).

[0679] Step 4: Synthesis of compound 56-4

[0680] Compound 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 two-necked flask, the atmosphere was replaced with nitrogen three times, 1,4-dioxane (5 mL) was added, the atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C for reaction, and after 13.5 h, TLC monitoring showed that the raw materials were basically reacted. The reaction solution was concentrated and DCM (50 mL) was added for dissolution. The mixture was washed with saturated ammonium chloride solution (10 mL), the liquid was separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated and purified by column chromatography (DCM / EA (v / v) = 20 / 1)) to give 276 mg of a light yellow solid with a yield of 76.23%. MS(ESI,pos.ion)m / z:584.35[M+H] + .

[0681] Step 5: Synthesis of compound 56

[0682] 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 allowed to proceed at 25°C for 2 h. TLC monitoring indicated that the reaction was complete. DCM (25 mL) was added, the temperature was lowered to 0°C, and the pH was adjusted to 8 with 20% potassium phosphate solution. The layers were separated, and the aqueous phase was extracted once more with DCM (25 mL). The combined organic phases were dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (DCM / EA (v / v) = 3 / 2) to give 156 mg of a light green solid in a yield of 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).

[0683] Example 57: Synthesis of Compound 57

[0684] Step 1: Synthesis of compound 57-1

[0685] 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. Triethylamine (1.38 g, 13.62 mmol) was then added dropwise, followed by the addition of Boc anhydride (2.18 g, 9.99 mmol). The reaction was allowed to react at room temperature. After 3.5 h, TLC confirmed complete reaction. The reaction mixture was washed with water (5 mL x 2), and the organic phase was dried over anhydrous sodium sulfate and spin-dried. Purification by column chromatography (DCM / EA (v / v) = 5 / 1) afforded 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).

[0686] Step 2: Synthesis of compound 57-2

[0687] Add 3-butyn-2-ol (1.0 g, 14.27 mmol), DCM (10 mL), and triethylamine (1.44 g, 14.27 mmol) to a reaction flask. Cool to 0°C and slowly add methylsulfonyl chloride (1.63 g, 14.27 mmol) dropwise. After completion of the addition, bring the mixture to room temperature for reaction. After 3 hours, TLC analysis indicates that the reaction is essentially complete. Add DCM (30 mL) and wash with saturated sodium chloride solution (10 mL x 2). The organic phase is then spin-dried to dryness to yield 2.42 g of an oily liquid, a 100% yield.

[0688] Step 3: Synthesis of compound 57-3

[0689] 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. Compound 57-2 (0.11 g, 0.74 mmol) diluted in DME (1 mL) was then added, along with potassium carbonate (0.072 g, 0.52 mmol). The reaction was then heated to 60°C. After 2 h, TLC indicated complete reaction. The mixture was concentrated and dissolved in DCM (40 mL). The mixture was washed once with water (8 mL) and once with saturated sodium chloride solution (8 mL). The organic phase was then dried and purified by column chromatography (PE / DCM (v / v) = 10 / 1 to 1 / 1) to yield 137.8 mg of a light yellow oil in a 70.77% yield. MS (ESI, pos. ion) m / z: 263.2 [M+H]+ .

[0690] Step 4: Synthesis of compound 57-4

[0691] 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 h, TLC indicated that the starting material had reacted substantially. The pH was adjusted to 8 with 20% potassium phosphate solution, and DCM (30 mL) was added for extraction. The organic phase was dried and purified by column chromatography using DCM as the eluent to obtain 104 mg of a red oil. The yield was 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).

[0692] Step 5: Synthesis of compound 57-5

[0693] 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 a reaction flask under nitrogen. Compound 57-4 (0.10 g, 0.62 mmol) was dissolved in 1,4-dioxane (5 mL) and added to the reaction flask. The atmosphere was again purged with nitrogen and the temperature was raised to 80°C for reaction. After 1 h, TLC analysis indicated complete reaction. The filtrate was filtered, dried, and purified by column chromatography (DCM / EA (v / v) = 20 / 1 to 5 / 1) to afford 0.16 g of a yellow solid in a 46.70% yield. 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).

[0694] Step 6: Synthesis of compound 57

[0695] 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 h, TLC confirmed complete reaction. The temperature was lowered to 0°C and the pH was adjusted to 8 with pre-cooled 20% potassium phosphate solution. DCM (30 mL) was added and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate and spin-dried. Purification by column chromatography (DCM / MeOH (v / v) = 1 / 0-50 / 1) afforded 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).

[0696] Example 58: Synthesis of Compound 58

[0697] Step 1: Synthesis of compound 58-1

[0698] To a 100 mL reaction flask, 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 and the mixture was heated to 95°C for 8 h. TLC confirmed complete reaction. Water (160 mL) was added and extracted with EA (160 mL x 3). The organic phases were combined, washed with sodium chloride solution (120 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. Purification by column chromatography (PE / EA (v / v) = 3 / 1) afforded 4.56 g of a green solid. Yield: 77.84%. MS (ESI, pos. ion) m / z: 284.0 [M+H] + .

[0699] Step 2: Synthesis of compound 58-2

[0700] Compound 58-1 (0.2 g, 0.70 mmol), triisopropylsilyl acetylene (0.13 g, 0.70 mmol), cuprous iodide (0.0067 g, 0.035 mmol), and bistriphenylphosphine palladium dichloride (0.025 g, 0.035 mmol) were added to a 50 mL two-necked flask under nitrogen. Diisopropylamine (6 mL) was then added, the atmosphere replaced with nitrogen, and the temperature was raised to 100°C for 3.5 h. TLC analysis indicated complete reaction. The reaction mixture was concentrated, dissolved in EA (10 mL), and filtered. The filter cake was rinsed 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 phases were dried over anhydrous sodium sulfate, spin-dried, and eluted with column chromatography (PE / EA (v / v) = 15 / 1 to 5 / 1). The mixture was collected and spin-dried to yield 0.2 g of a brown oil. The yield was 73.68%. MS (ESI, pos.ion) m / z: 386.1 [M+H] + .

[0701] Step 3: Synthesis of compound 58-3

[0702] Raw 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 two-necked flask and purged with nitrogen. 1,4-dioxane (15 mL) was added, and the atmosphere was purged with nitrogen again. The temperature was raised to 80°C and the reaction was allowed to react for 1.5 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 then spin-dried. Purification by column chromatography (DCM / EA (v / v) = 15 / 1 to 3 / 1) afforded 0.41 g, a yield of 75.42%. MS (ESI, pos.ion) m / z: 779.4 [M+H] + .

[0703] Step 5: Synthesis of compound 58-4

[0704] 58-4 (0.4 g, 0.51 mmol) and DMF (6 mL) were added to a 2 mL flask, followed by cesium fluoride (0.15 g, 1.02 mmol) and allowed to react at room temperature for 2 h. TLC confirmed complete reaction. 20 mL of water was added, and the mixture was extracted with EA (25 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and purified by column chromatography (DCM / EA (v / v) = 1 / 0-5 / 1). 0.27 g of a brown oil was obtained, yielding 84.45%. MS (ESI, pos. ion) m / z: 623.2 [M+H] + .

[0705] Step 6: Synthesis of compound 58

[0706] Raw material 58-5 (0.27 g, 0.43 mmol) was added to DCM (10 mL) and stirred until dissolved. Trifluoroacetic acid (3.92 g, 34.4 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 4.5 h. TLC indicated complete reaction. The reaction was stopped, and 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 layers were separated and the organic phase was dried by spin drying. Purification by column chromatography (DCM / MeOH (v / v) = 1 / 0-25 / 1) afforded 0.18 g of a white solid in a yield of 82.61%. 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).

[0707] Example 59: Synthesis of Compound 59

[0708] Step 1: Synthesis of compound 59-1

[0709] 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) were added to a 100 mL two-necked flask, and the atmosphere was replaced with nitrogen. N,N'-dimethylethylenediamine (0.26 g, 2.94 mmol) was dissolved in 1,4-dioxane (11 The mixture was added to a flask and reacted at room temperature. After about 17 hours of reaction, TLC monitoring showed that the raw material was basically reacted. The mixture was filtered and the filter cake was rinsed with 50 mL of dichloromethane. The organic phase was collected and washed once with 20 mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA (v / v=5 / 1) to obtain 0.4 g of a white solid with a yield of 23.93%. MS (ESI, pos. ion) m / z: 284.0 [M+H] + .

[0710] Step 2: Synthesis of compound 59-2

[0711] Compound 59-1 (0.15 g, 0.53 mmol), cuprous iodide (0.02 g, 0.11 mmol), and bistriphenylphosphine palladium dichloride (0.074 g, 0.11 mmol) were added to a 50 mL two-necked flask. The atmosphere was purged with nitrogen. 1-(Trimethylsilyl)propyne (0.071 g, 0.64 mmol), triethylamine (0.27 g, 2.65 mmol), and tetrahydrofuran (5 mL) were then added. Tetrabutylammonium fluoride (0.80 mL, 0.80 mmol) was then added dropwise at room temperature. After approximately 1.5 h of reaction at room temperature, TLC monitoring indicated that the reaction was essentially complete. The reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate (20 mL). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (PE / EA (v / v) = 5 / 1-4 / 1) afforded 0.1 g of a pale yellow solid with a yield of 77.86%. MS (ESI, pos.ion) m / z: 242.3 [M+H] + .

[0712] Step 3: Synthesis of compound 59-3

[0713] To a 50 mL two-necked flask were added 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). The atmosphere was purged with nitrogen, and 1,4-dioxane (5 mL) was added. The reaction was heated to 80°C. After approximately 2 h of reaction, TLC monitoring indicated that the starting materials had essentially reacted. The product was filtered, and the filter cake was rinsed with dichloromethane (20 mL). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. Purification by column chromatography (DCM / EA (v / v) = 1 / 0 to 9 / 1) afforded 160 mg of a yellow solid in a 61.13% yield. 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).

[0714] Step 4: Synthesis of compound 59

[0715] Compound 59-3 (0.21 g, 0.35 mmol) and dichloromethane (11 mL) were added to a 100 mL single-necked flask and stirred at room temperature until dissolved. Trifluoroacetic acid (2.39 g, 21 mmol) was then added dropwise and allowed to react at room temperature. After approximately 2 h of reaction, TLC confirmed complete reaction. The mixture was cooled to 0°C and the pH was adjusted to approximately 8 with aqueous potassium phosphate (20% by mass). The layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / CH3OH (v / v) = 1 / 0 to 50 / 1) to yield 110 mg of a green solid in a 65.26% yield. MS (ESI, pos. ion) m / z: 517.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.43–8.37(m,2H),8.03(d,J=12.7Hz,2H),7.75(dd,J=9.3,2.1Hz, 1H),7.68(dd,J=7.2,1.7Hz,1H),7.20(dd,J=8.1,2.1Hz,1H),6.43(t,J=7.3Hz,1H),6.31 (d,J=5.2Hz,1H),5.49(s,1H),4.62–4.56(m,1H),3.84(dd,J=15.3,7.5Hz,1H),3.40(s, 3H),3.12(d,J=5.2Hz,3H),2.34(dd,J=18.5,8.3Hz,2H),2.14(s,3H),1.78–1.69(m,2H).

[0716] Example 60: Synthesis of Compound 60

[0717] Step 1: Synthesis of compound 60-1

[0718] Compound 59-1 (0.1 g, 0.35 mmol), cuprous iodide (0.003 g, 0.017 mmol), and bistriphenylphosphine palladium dichloride (0.012 g, 0.017 mmol) were added to a 50 mL two-necked flask. The atmosphere was purged with nitrogen. Triethylamine (0.18 g, 1.75 mmol) and tetrahydrofuran (5 mL) were then added to the flask. Triisopropylsilyl acetylene (0.07 g, 0.39 mmol) was then added dropwise at room temperature. After approximately 1.5 h of reaction at room temperature, TLC monitoring indicated that the reaction of the starting materials was essentially complete. The reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate (20 mL). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (PE / EA (v / v=5 / 1) afforded 0.13 g of an orange solid with a yield of 95.79%. MS (ESI, pos.ion) m / z: 386.1 [M+H] + .

[0719] Step 2: Synthesis of compound 60-2

[0720] To a 50 mL two-necked flask were added compound 18-1 (88 mg, 0.2 mmol), BrettPhos-G3-Pd (15 mg, 0.017 mmol), BrettPhos (18 mg, 0.034 mmol), cesium carbonate (110 mg, 0.34 mmol), and compound 60-1 (65 mg, 0.17 mmol). The atmosphere was purged with nitrogen, and 1,4-dioxane (5 mL) was added. The mixture was heated to 80°C for reaction. After approximately 2 h, TLC monitoring indicated that the starting materials had essentially reacted. The mixture was filtered, and the filter cake was rinsed with dichloromethane (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / EA (v / v) = 1 / 0-9 / 1) to afford 60 mg of a yellow solid in a yield of 45.69%. MS (ESI, pos. ion) m / z: 779.4 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.47(s,1H),8.38(dd,J=7.3,1.5Hz,1H),8.16(d,J=8.7Hz,1H),8.00(s,1H),7.80(dd,J=9.3,2.0Hz,1H),7 .75(dd,J=7.2,1.5Hz,1H),7.27(d,J=2.1Hz,1H),7.19(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),6.46(t,J=7.3Hz,1H) ,5.55(s,1H),5.17(s,2H),4.65–4.59(m,1H),3.89–3.85(m,1H),3.81(s,3H),3.41(s,3H),3.09(s,3H),2.34(dd,J =18.5,9.6Hz,1H),2.21–2.14(m,1H),1.77–1.72(m,1H),1.52(d,J=9.4Hz,1H),1.20(s,3H),1.17(d,J=4.3Hz,18H).

[0721] Step 3: Synthesis of compound 60-3

[0722] Compound 60-2 (0.12 g, 0.15 mmol) and dichloromethane (6 mL) were added to a 100 mL single-necked flask and stirred at room temperature until dissolved. Trifluoroacetic acid (1.03 g, 9 mmol) was then added dropwise and allowed to react at room temperature. After approximately 1.5 h of reaction, TLC confirmed complete reaction. The mixture was cooled to 0°C and the pH was adjusted to approximately 8 with aqueous potassium phosphate (20% by mass). The layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM / CH3OH (v / v) = 1 / 0-50 / 1) to yield 110 mg of a green solid in a 65.26% yield. MS (ESI, pos. ion) m / z: 659.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.45–8.38(m,2H),8.07–7.99(m,2H),7.84–7.79(m,1H),7.76–7. 72(m,1H),7.34(s,1H),6.45(t,J=7.2Hz,1H),6.31(d,J=4.9Hz,1H),5.49(s,1H),4.63 –4.57(m,1H),3.85(dd,J=15.4,7.8Hz,1H),3.40(s,3H),3.12(d,J=5.2Hz,3H),2.34(d d,J=18.9,8.6Hz,2H),2.17(d,J=9.2Hz,2H),1.25–1.20(m,3H),1.17(d,J=4.3Hz,18H).

[0723] Step 4: Synthesis of compound 60

[0724] Compound 60-3 (0.065 g, 0.099 mmol) and tetrahydrofuran (4 mL) were added to a 50 mL two-necked flask, cooled to 0°C, and tetrabutylammonium fluoride (0.2 mL, 0.2 mmol) was added dropwise. After approximately 10 minutes of reaction, TLC monitoring indicated that the starting material had reacted completely. The reaction was stopped and quenched with water (5 mL). The mixture was then extracted with dichloromethane (15 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (DCM / CH3OH = 1 / 0 to 50 / 1) afforded 46 mg of a white solid in a 92.79% yield. MS (ESI, pos. ion) m / z: 503.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.46–8.37(m,2H),8.02(d,J=13.5Hz,2H),7.89(dd,J=9.3,2.0Hz,1H ),7.72(dd,J=7.2,1.6Hz,1H),7.32(dd,J=7.8,2.1Hz,1H),6.45(t,J=7.3Hz,1H),6.31(d,J =5.2Hz,1H),5.50(s,1H),4.63–4.56(m,1H),3.84(dd,J=15.2,7.9Hz,1H),3.40(s,3H),3.3 2(s,1H),3.12(d,J=5.2Hz,3H),2.34(dd,J=19.4,9.3Hz,2H),2.17(dd,J=17.9,9.1Hz,2H).

[0725] Example 61: Synthesis of Compound 61

[0726] Step 1: Synthesis of compound 61-1

[0727] To a 50 mL two-necked flask, 4,6-dichloropyrimidine (1.0 g, 6.71 mmol), 3-amino-2-hydroxypyridine (0.74 g, 6.71 mmol), cesium carbonate (4.37 g, 13.42 mmol), and N,N-dimethylacetamide (6 mL) were added. The mixture was reacted at 60°C for 5 h. TLC confirmed the complete reaction of the starting materials. The mixture was diluted with EA (50 mL) and filtered. The filter cake was washed with EA (50 mL). The organic phases were combine...

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, pyridyl, pyrimidinyl or pyrazinyl, wherein the 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 by; 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 by; 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.

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, -OC H2OCH2CH3, -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)(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.

17. The compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 is used for preventing, treating or alleviating TYK2-related diseases.

18. The compound or pharmaceutical composition according to claim 17, 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.

19. A method for preventing, treating or alleviating a TYK2-related disease, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 to a patient.

20. The method according to claim 19, 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.

Images