Compounds that inhibit or degrade Bcl6 and their pharmaceutical applications

Abstract

The present invention relates to a compound of general formula (I) or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, an intermediate thereof, and a pharmaceutical composition, and uses thereof in Bcl6-related diseases such as cancer. B-L-K (I)

Description

Technical Field

[0001] The present invention relates to a compound represented by the general formula (I) or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and an intermediate and pharmaceutical composition thereof, and uses in Bcl6-related diseases such as cancer.

Background Art

[0002] Bcl6 is a transcriptional repressor that can regulate the development and function of germinal center B cells. High expression of Bcl6 protein due to various influencing factors such as exon mutations, regulatory pathway mutations, somatic Bcl6 translocations and promoter mutations can promote the generation of B cell lymphoma by rapidly proliferating germinal center B cells. At the same time, Bcl6 can have an inhibitory effect on genes related to cell cycle checkpoints and differentiation and DNA damage response, and preclinical studies suggest that deletion of Bcl6 in lymphoma cells causes tumor progression to stagnate. Therefore, Bcl6 is a potentially suitable target for treating various lymphomas.

[0003] PROTAC (proteolysis targeting chimera) molecules are a type of bifunctional compound that can simultaneously bind to a target protein and an E3 ubiquitin ligase. Such compounds are recognized by the cell's proteasome, cause degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, it becomes possible to apply PROTAC technology to the treatment of various diseases, and in recent years, this technology has been widely noticed at the same time.

[0004] Therefore, for the treatment of tumor diseases related to Bcl6, it is necessary to develop new PROTAC pharmaceuticals targeting Bcl6 protein and E3 ubiquitin ligase.

Summary of the Invention

Problems to be Solved by the Invention

[0005] The object of the present invention is to provide a compound with a novel structure, excellent drug efficacy, high bioavailability, greater safety, and the ability to inhibit and degrade Bcl6 for treating Bcl6-related diseases such as cancer.

Means for Solving the Problems

[0006] The present invention provides a compound or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (I), B-L-K (I), In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (II),

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chemical formula

[0007] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

[0008]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Chemical formula

Chemical formula

[0009]

Table 3-1

Table 3-2

Table 3-3

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0010] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0011]

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

[0012] As a first embodiment of the present invention, it is a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, L is selected from a bond or -C 1-50 -hydrocarbon group-, and in the hydrocarbon group, 1 to 20 methylene units are optionally replaced by -Ak- or -Cy-, Each -Ak- is independently -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q-NR L -、 -(C≡C) q -、 -CH=CH-、 -Si(R L ) 2 -、 -Si(OH)(R L )-、 -Si(OH) 2 -、 -P(=O)(OR L )-、 -P(=O)(R L )-、 -S-、 -S(=O)-、 -S(=O) 2 - or selected from the bonds, wherein the -CH 2 - is optionally substituted with one or two substituents selected from halogen, OH, CN, NH 2 , C 1-6 alkyl group, C 1-6 alkoxy group, C substituted with halogen 1-6 alkyl group, C substituted with hydroxy group 1-6 alkyl group, C substituted with cyano group 1-6 alkyl group, and q is independently selected from 0, 1, 2, 3, 4, 5 or 6, R L is independently selected from H, C 1-6 alkyl group, 3- to 7-membered heterocyclic group, 3- to 7-membered cycloalkyl group, phenyl group or 5- to 6-membered heteroaryl group, wherein the heterocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, each -Cy- is independently selected from a bond, a 4- to 8-membered heteromonocyclic ring, a 4- to 10-membered hetero-condensed ring, a 5- to 12-membered heterospiro ring, a 7- to 10-membered heterobridged ring, C 3-7 monocycloalkyl group, C 4-10 condensed cycloalkyl group, C 5-12 spirocycloalkyl group, C 7-10 bridged cycloalkyl group, 5- to 10-membered heteroaryl group or 6- to 10-membered aryl group, wherein the aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, hetero-condensed ring, heterospiro ring or heterobridged ring is optionally substituted with halogen, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl group, C substituted with halogen 1-4 alkyl group, C substituted with hydroxy group1-4 substituted with 1 to 2 substituents selected from an alkyl group or a C 1-4 alkoxy group, and the heteroaryl group, heteromonocyclic ring, hetero-condensed ring, heterospiro ring or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, optionally, it is substituted with 1 or 2 =O, B is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0013] As a second embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, L is -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5--Ak1 - Ak2 - Ak3 - Ak4 - Cy1 - Cy2 - Cy3 - Cy4 - Ak5 -, -Ak1 - Cy1 - Ak2 - Ak3 - Ak4 - Ak5 - Cy2 - Cy3 - Cy4 -, -Ak1 - Cy1 - Cy2 - Ak2 - Ak3 - Ak4 - Ak5 - Cy3 - Cy4 -, -Ak1 - Cy1 - Cy2 - Cy3 - Ak2 - Ak3 - Ak4 - Ak5 - Cy4 -, -Ak1 - Ak2 - Cy1 - Ak3 - Ak4 - Ak5 - Cy2 - Cy3 - Cy4 -, -Ak1 - Ak2 - Cy1 - Cy2 - Ak3 - Ak4 - Ak5 - Cy3 - Cy4 -, -Ak1 - Ak2 - Cy1 - Cy2 - Cy3 - Ak3 - Ak4 - Ak5 - Cy4 -, -Ak1 - Ak2 - Ak3 - Cy1 - Ak4 - Ak5 - Cy2 - Cy3 - Cy4 -, -Ak1 - Ak2 - Ak3 - Cy1 - Cy2 - Ak4 - Ak5 - Cy3 - Cy4 -, -Ak1 - Ak2 - Ak3 - Cy1 - Cy2 - Cy3 - Ak4 - Ak5 - Cy4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Cy1 - Ak5 - Cy2 - Cy3 - Cy4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Cy1 - Cy2 - Ak5 - Cy3 - Cy4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Cy1 - Cy2 - Cy3 - Ak5 - Cy4 -, -Ak1 -, -Ak1 - Ak2 -, -Ak1 - Ak2 - Ak3 -, -Ak1 - Ak2 - Ak3 - Ak4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 - Ak7 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 - Ak7 - Ak8 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 - Ak7 - Ak8 - Ak9, selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently, -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NRL C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or selected from a bond, wherein said -CH 2 - is optionally substituted with one or two substituents selected from halogen, OH, CN, NH 2 , C 1-4 alkyl group, C 1-4 alkoxy group, C alkyl group substituted with halogen, C 1-4 alkyl group substituted with a hydroxy group, C 1-4 alkyl group substituted with a cyano group, C 1-4 alkyl group, and Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond, a 4- to 7-membered heteromonocyclic ring, a 4- to 10-membered heterocyclic condensed ring, a 5- to 12-membered heterocyclic spiro ring, a 7- to 10-membered heterocyclic bridged ring, a C 3-7 monocycloalkyl group, a C 4-10 condensed cycloalkyl group, a C 5-12 membered spirocycloalkyl group, a C 7-10 membered bridged cycloalkyl group, a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl group, wherein said aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, heterocyclic condensed ring, heterocyclic spiro ring or heterocyclic bridged ring is optionally substituted with one or two substituents selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 alkyl group, C alkyl group substituted with halogen, C 1-4 alkyl group substituted with a hydroxy group, C 1-4 alkyl group or C 1-4 alkoxy group, and said heteroaryl group, heteromonocyclic ring, heterocyclic condensed ring, heterocyclic spiro ring or heterocyclic bridged ring contains 1 to 4 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, it is optionally substituted with one or two =O, q is each independently selected from 0, 1, 2, 3 or 4, R Lis independently selected from H or C 1-6 and is selected from an alkyl group, and other definitions are the same as those in the first embodiment of the present invention.

[0014] As a third embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, and the -CH 2 - is optionally substituted with one or two substituents selected from F, Cl, Br, I, OH, CN, NH 2 , CF 3 , a hydroxymethyl group, a C 1-4 alkyl group, and a C 1-4 alkoxy group, R L is independently selected from H or a C 1-4 alkyl group, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently a bond, a 4- to 7-membered nitrogen-containing monocyclic ring, a 4- to 10-membered nitrogen-containing condensed ring, a 5- to 12-membered nitrogen-containing spiro ring, a 7- to 10-membered nitrogen-containing bridged ring, C 3-7Monocyclic alkyl group, C 4-10 Fused cycloalkyl group, C 5-12 Spirocycloalkyl group, C 7-10 Selected from a bridged cycloalkyl group, a 5- to 10-membered heteroaryl group, or a 6- to 10-membered aryl group, wherein the heteromonocyclic ring, hetero-fused ring, hetero-bridged ring, hetero-spiro ring, cycloalkyl group, aryl group, or heteroaryl group is optionally substituted with one or two substituents selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , =O, C 1-4 Alkyl group, C substituted with halogen 1-4 Alkyl group, C substituted with a hydroxy group 1-4 Alkyl group or C 1-4 Substituted with one or two substituents selected from an alkoxy group, the heteromonocyclic ring, hetero-fused ring, hetero-bridged ring, hetero-spiro ring, or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally substituted with one or two =O, R Y Is selected from H, a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cyclopropyl group, and the methyl group, ethyl group, propyl group, isopropyl group, and cyclopropyl group are optionally substituted with halogen, OH, a cyano group, NH 2 , C 1-4 Alkyl group, C substituted with halogen 1-4 Alkyl group, C substituted with a hydroxy group 1-4 Alkyl group, C substituted with a cyano group 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-6 Substituted with 1 to 3 substituents selected from a carbocyclic ring or a 3- to 6-membered heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N, R 1 Is selected from H, OH, NR 1a R 1b Selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, and a methoxy group, and the methyl group, ethyl group, propyl group, isopropyl group, and methoxy group are optionally substituted with halogen, OH, a cyano group, NH 2 , C 1-4 Alkyl group, C substituted with halogen1-4 C substituted with an alkyl group and a hydroxy group 1-4 C substituted with an alkyl group and a cyano group 1-4 C substituted with an alkyl group 1-4 substituted with 1 to 3 substituents selected from an alkoxy group, R 1a , R 1b are each independently H, OH, NH 2 , a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, a propargyl group, a propynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, propargyl group, propynyl group are optionally halogen, OH, cyano group, NH 2 , C 1-4 C substituted with an alkyl group and a halogen 1-4 C substituted with an alkyl group and a hydroxy group 1-4 C substituted with an alkyl group and a cyano group 1-4 C substituted with an alkyl group 1-4 an alkoxy group, C 2-4 substituted with 1 to 3 substituents selected from an alkynyl group, R 3a or R 4 are each independently H, OH, NH 2 , a methyl group, an ethyl group, a propyl group, a propargyl group, a propynyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and the methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, propargyl group, propynyl group are optionally halogen, OH, cyano group, NH 2 , C 1-4 C substituted with an alkyl group and a halogen 1-4 C substituted with an alkyl group and a hydroxy group 1-4 C substituted with an alkyl group and a cyano group 1-4 C substituted with an alkyl group 1-4 an alkoxy group, C 2-4 an alkynyl group, C 3-6A cycloalkyloxy group, C 3-6 substituted with 1 to 3 substituents selected from a carbocyclic ring or a 3- to 6-membered heterocyclic ring, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N, R 3b or R 5 is, independently of each other, H, F, Cl, Br, I, a cyano group, NH 2 , OH, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an ethynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, ethynyl group are optionally substituted with a halogen, OH, a cyano group, NH 2 , C 1-4 alkyl group, C 1-4 alkyl group substituted with a halogen, C 1-4 alkyl group substituted with a hydroxy group, C 1-4 alkyl group substituted with a cyano group, C 1-4 alkoxy group, C 3-6 substituted with 1 to 3 substituents selected from a carbocyclic ring or a 3- to 6-membered heterocyclic ring, wherein the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N, F1 is, independently of each other, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a piperidinyl group, a piperazinyl group, a phenyl group, a naphthyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, a pyridazinone group, a pyrimidinyl group, phthalazin-1(2H)-one, benzod[d][1,2,3]triazin-4(3H)-one, a thienyl group, a benzothienyl group, a triazole group,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0015] As a fourth embodiment of the present invention, there is provided a compound represented by the above-mentioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharma- ceutically acceptable salt or cocrystal thereof, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 each independently represent -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, 2 - is optionally F, Cl, Br, I, OH, CN, NH 2 , C.F. 3 , substituted with 1 to 2 substituents selected from a hydroxymethyl group, a methyl group, an ethyl group, a methoxy group, or an ethoxy group; R L is selected from H, a methyl group or an ethyl group, Each q is independently selected from 0, 1, 2, or 3; Cy1, Cy2, Cy3, Cy4 or Cy5 is each independently a cycloalkyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, pyrrolidinyl group, azacyclohexenyl group, piperidinyl group, morpholinyl group, piperazinyl group, 1,4-diazepanyl group, phenyl group, pyridyl group, cyclopropyl-fused cyclopropyl group, cyclopropyl-fused cyclobutyl group, cyclopropyl-fused cyclopentyl group, cyclopropyl-fused cyclohexyl group, cyclobutyl-fused cyclobutyl group, cyclobutyl-fused cyclopentyl group, cyclobutyl-fused cyclohexyl group, cyclopentyl-fused cyclopentyl group, cyclopentyl-fused cyclohexyl group, cyclohexyl-fused cyclohexyl group, cyclopropyl-spiro-cyclopropyl group, cyclopropyl-spiro-cyclobutyl group, cyclopropyl-spiro-cyclopentyl group, cyclopropyl-spiro-cyclohexyl group, cyclobutyl-spiro-cyclobutyl group, cyclobutyl-spiro-cyclopentyl group, cyclobutyl-spiro-cyclohexyl group, cyclopentyl-spiro-cyclopentyl group, cyclopentyl-spiro-cyclohexyl group, cyclohexyl-spiro-cyclohexyl group, cyclopropyl-fused azetidinyl group, cyclopropyl-fused pyrrolidinyl group, cyclopropyl-fused piperidinyl group, cyclobutyl-fused azetidinyl group, cyclobutyl-fused pyrrolidinyl group, cyclobutyl-fused piperidinyl group, cyclopentyl-fused azetidinyl group, cyclopentyl-fused pyrrolidinyl group, cyclopentyl-fused piperidinyl group, cyclohexyl-fused azetidinyl group, cyclohexyl-fused pyrrolidinyl group, cyclohexyl-fused piperidinyl group, azetidinyl-fused azetidinyl group, azetidinyl-fused pyrrolidinyl group, azetidinyl-fused piperidinyl group, pyrrolidinyl-fused azetidinyl group, pyrrolidinyl-fused pyrrolidinyl group, pyrrolidinyl-fused piperidinyl group, piperidinyl-fused azetidinyl group, piperidinyl-fused pyrrolidinyl group, piperidinyl-fused piperidinyl group, cyclopropyl-spiro-azetidinyl group, cyclopropyl-spiro-pyrrolidinyl group, cyclopropyl-spiro-piperidinyl group, cyclopropyl-spiro-piperazinyl group, cyclobutyl-spiro-azetidinyl group, cyclobutyl-spiro-pyrrolidinyl group, which is bonded or substituted or unsubstituted.Cyclobutyl-spiro-piperidinyl group, cyclopentyl-spiro-azetidinyl group, cyclopentyl-spiro-pyrrolidinyl group, cyclopentyl-spiro-piperidinyl group, cyclohexyl-spiro-azetidinyl group, cyclohexyl-spiro-pyrrolidinyl group, cyclohexyl-spiro-piperidinyl group, azetidinyl-spiro-azetidinyl group, azetidinyl-spiro-pyrrolidinyl group, azetidinyl-spiro-piperidinyl group, pyrrolidinyl-spiro-azetidinyl group, pyrrolidinyl-spiro-pyrrolidinyl group, pyrrolidinyl-spiro-piperidinyl group, piperidinyl-spiro-azetidinyl group, piperidinyl-spiro-pyrrolidinyl group, piperidinyl-spiro-piperidinyl group, cyclopropyl-spiro-piperazinyl group, [Chemical formula] selected from one of the following groups, and when substituted, optionally with F, Cl, Br, I, OH, NH 2 , COOH, CN, =O, C 1-4 alkyl group, C substituted with halogen 1-4 alkyl group, C substituted with hydroxy group 1-4 alkyl group or C 1-4 substituted with 1 to 4 substituents selected from alkoxy groups, X is selected from O or S, Y is selected from NH or O, R 1 is H, OH, NR 1a R 1b selected from methyl group, ethyl group, propyl group, isopropyl group, methoxy group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano group, NH 2 , methyl group, ethyl group, CF 3 ; R 1a , R 1b are each independently H, OH, NH 2, selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, a propargyl group, a propynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, propargyl group, propynyl group are optionally F, Cl, Br, I, OH, cyano group, NH 2 , a methyl group, an ethyl group, a methoxy group, an ethynyl group, CF 3 substituted with 1 to 3 substituents selected from R 3a is H, OH, NH 2 , selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a propargyl group, a propynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, propargyl group, propynyl group are optionally F, Cl, Br, I, OH, cyano group, NH 2 , substituted with 1 to 3 substituents selected from a methyl group, an ethyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an ethynyl group, a cyclopropyloxy group, a methoxy group R 4 is each independently selected from H, a methyl group, an ethyl group, a cyclopropyl group R 3b is each independently selected from H, F, Cl, Br, I, OH, CN, a methoxy group, a methyl group, an ethyl group, a cyclopropyl group R 5 is each independently selected from H, F, Cl, Br, I, cyano group, NH 2 , OH, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a cyclopropyl group, an ethynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, ethynyl group are optionally F, Cl, Br, I, OH, cyano group, NH2 substituted with 1 to 3 substituents selected from a methyl group, an ethyl group, and a cyclopropyl group, F1 is each independently a cyclohexane group, a piperidinyl group, a piperazinyl group, a phenyl group, a naphthyl group, a pyrimidinyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl group, a pyridazinone group, phthalazin-1(2H)-one, benzo[d][1,2,3]triazin-4(3H)-one, a thienyl group, a triazole group,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0016] As a fifth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently a bond, -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -C≡C-, -C(CH 3 ) 2 -, -CF 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 ), -NH-, -CH 2 N(CH 3 ), -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 ), -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH-, or -NHC(=O)-, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently a bonded or substituted or unsubstituted [Chemical formula] selected from one of the groups of, and when substituted, are substituted with 1 to 4 substituents selected from F, CF 3 , OH, methyl group, =O, hydroxymethyl group, COOH, CN or NH 2 2 ; B is selected from one of the structural fragments shown in Table B-1; K is selected from one of the structural fragments shown in Table K-1 or K-2; Other definitions are the same as those in the first, second, third or fourth embodiment of the present invention.

[0017] In a sixth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, L is a combination, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5--Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-, selected from Other definitions are the same as those in the first, second, third, fourth, or fifth embodiment of the present invention.

[0018] As a seventh embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, L is selected from a bond or one of the structural fragments shown in Table L-1, where the left side of the group is linked to B, Other definitions are the same as those in the first, second, third, fourth, fifth, or sixth embodiment of the present invention.

[0019] As an eighth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, L is selected from a bond or one of the structural fragments shown in Table L-2, where the left side of the group is linked to B, K is selected from one of the structural fragments shown in Table K-2, Other definitions are the same as those in the first, second, third, fourth, fifth, sixth, or seventh embodiment of the present invention.

[0020] As a ninth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and the compound of general formula (I) is selected from the compounds of general formula (II),

Chemical formula

[0021] In a tenth embodiment of the present invention, a compound represented by the aforementioned general formula (II) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein L1 is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-; Cy1, Cy2, or Cy3 is each independently a bond or a substituted or unsubstituted [Chemical formula] selected from one of the following groups, and when substituted, is substituted with 1 to 4 substituents selected from F, CF 3 , OH, methyl group, =O, hydroxymethyl group, COOH, CN, or NH 2 2 Ak1 is selected from -CH 2 -, -O-, -CH 2 -CH 2 -; B is selected from one of the structural fragments shown in Table B-1; F1 is selected from a phenyl group, a pyrrolyl group, a pyrazolyl group, a triazole group, a pyridyl group, a pyridazinyl group, a pyrazinyl group, a thienyl group, a thiazolyl group, a triazinyl group, [Chemical formula] ; R k1 are each independently H, D, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2, selected from a methyl group, an ethyl group, a methoxy group, and an ethoxy group, p1 is selected from 0, 1, or 2.

[0022] As an eleventh embodiment of the present invention, a compound represented by the aforementioned general formula (II) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein L1 is

Chemical formula

[0023] As a twelfth embodiment of the present invention, a compound represented by the aforementioned general formula (I) or general formula (II) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the compound represented by general formula (I) or general formula (II) is selected from the compounds represented by general formula (III),

Chemical formula

Chemical formula

[0024] The definition of B is the same as that in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment of the present invention.

[0025] As a thirteenth embodiment of the present invention, a compound represented by the aforementioned general formula (III) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, B is

Chemical formula

Chemical formula

[0026] The present invention relates to the following compound or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the compound is selected from one of the structures in Table S-1 below.

[0027]

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 6-5

Table 6-6

Table 6-7

Table 6-8

Table 6-9

Table 6-10

Table 6-11

Table 6-12

Table 6-13

Table 6-14

Table 6-15

Table 6-16

Table 6-17

Table 6-18

Table 6-19

Table 6-20

Table 6-21

Table 6-22

Table 6-23

Table 6-24

Table 6-25

Table 6-26

Table 6-27

Table 6-28

Table 6-29

Table 6-30

Table 6-31

Table 6-32

Table 6-33

Table 6-34

Table 6-35

Table 6-36

Table 6-37

Table 6-38

Table 6-39

Table 6-40

Table 6-41

Table 6-42

Table 6-43

Table 6-44

Table 6-45

Table 6-46

Table 6-47

Table 6-48

Table 6-49

Table 6-50

Table 6-51

Table 6-52

Table 6-53

Table 6-54

Table 6-55

Table 6-56

Table 6-57

Table 6-58

Table 6-59

[0028] The present invention relates to a pharmaceutical composition, which comprises the above compound of the present invention or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0029] The present invention relates to the application of the above compound of the present invention or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the manufacture of a medicament for treating a disease related to Bcl6 activity or expression level.

[0030] The present invention relates to the application of the above compound of the present invention or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the manufacture of a medicament for treating a disease related to the inhibition or degradation of Bcl6.

[0031] The present invention relates to the application of the above compound of the present invention or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and the disease is selected from cancer.

[0032] The present invention relates to a pharmaceutical composition or a pharmaceutical preparation, and the pharmaceutical composition or the pharmaceutical preparation contains a therapeutically effective amount of the compound described in the present invention or its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and an excipient for pharmaceuticals. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "formulation specification").

[0033] The present invention further provides a method for treating a mammalian disease, which comprises administering to the mammal a therapeutically effective amount of the compound described in the present invention or its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or a pharmaceutical composition. In some embodiments, the mammals described in the present invention include humans.

[0034] The "effective amount" or "therapeutically effective amount" recited in this application includes administering a sufficient amount of the compounds disclosed in this application, which alleviates to some extent one or more symptoms of the disease or condition being treated (e.g., cancer). In some embodiments, the result is a decrease and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed in this application that is required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1 to 1500 mg, 1 to 600 mg, 2 to 600 mg, 3 to 600 mg, 4 to 600 mg, 5 to 600 mg, 6 to 600 mg, 10 to 600 mg, 20 to 600 mg, 25 to 600 mg, 30 to 600 mg, 40 to 600 mg, 50 to 600 mg, 60 to 600 mg, 70 to 600 mg, 75 to 600 mg, 80 to 600 mg, 90 to 600 mg, 100 to 600 mg, 200 to 600 mg, 1 to 500 mg, 2 to 500 mg, 3 to 500 mg, 4 to 500 mg, 5 to 500 mg, 6 to 500 mg, 10 to 500 mg, 20 to 500 mg, 25 to 500 mg, 30 to 500 mg, 40 to 500 mg, 50 to 500 mg, 60 to 500 mg, 70 to 500 mg, 75 to 500 mg, 80 to 500 mg, 90 to 500 mg, 100 to 500 mg, 125 to 500 mg, 150 to 500 mg, 200 to 500 mg, 250 to 500 mg, 300 to 500 mg, 400 to 500 mg, 5 to 400 mg, 10 to 400 mg, 20 to 400 mg, 25 to 400 mg, 30 to 400 mg, 40 to 400 mg, 50 to 400 mg, 60 to 400 mg, 70 to 400 mg, 75 to 400 mg, 80 to 400 mg, 90 to 400 mg, 100 to 400 mg, 125 to 400 mg, 150 to 400 mg, 200 to 400 mg, 250 to 400 mg, 300 to 400 mg, 1 to 300 mg, 2 to 300 mg, 5 to 300 mg, 10 to 300 mg, 20 to 300 mg, 25 to 300 mg, 30 to 300 mg, 40 to 300 mg, 50 to 300 mg, 60 to 300 mg, 70 to 300 mg, 75 to 300 mg, 80 to 300 mg, 90 to 300 mg, 100 to 300 mg, 125 to 300 mg, 150 to 300 mg, 200 to 300 mg, 250 to 300 mg, 1 to 200 mg, 2 to 200 mg, 5 to 200 mg, 10 to 200 mg, 20 to 200 mg, 25 to 200 mg, 30 to 200 mg, 40 to 200 mg, 50 to 200 mg, 60 to 200 mg, 70 to 200 mg, 75 to 200 mg, 80 to 200 mg, 90 to 200 mg, 100 to 200 mg, 125 to 200 mg, 150 to 200 mg. In some embodiments, the pharmaceutical composition comprises, but is not limited to, 1 to 1500 mg, 1 to 600 mg, 20 to 400 mg, 25 to 200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of the compound of the present invention or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals.

[0035] A method for treating a mammalian disease, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, the therapeutically effective amount being preferably 1 to 1500 mg, and the disease being preferably cancer.

[0036] A method for treating a mammalian disease, the method comprising administering to a subject the compound of the present invention or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, which is a pharmaceutical, in a daily dose of 1 to 1500 mg / day, the daily dose may be a single dose or a divided dose, and in some embodiments, the daily dose includes, but is not limited to, 10 to 1500 mg / day, 10 to 800 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 200 to 800 mg / day, 25 to 400 mg / day, 50 to 400 mg / day, 100 to 400 mg / day, 200 to 400 mg / day, and in some embodiments, the daily dose includes, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1500 mg / day, 2000 mg / day.

[0037] The present invention relates to a kit, which may contain a composition in the form of a single dose or multiple doses, and the kit contains a compound of the present invention or its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and the amount of the compound of the present invention or its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is the same as its amount in the above pharmaceutical composition.

[0038] In the present invention, the amount of the compound of the present invention or its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is, in each case, converted in the form of the free base.

[0039] Unless otherwise specified, the terms used in the specification and claims of this application have the following meanings.

[0040] "Formulation specification" refers to the weight of the active ingredient contained in one unit formulation, one tablet unit formulation, or each other unit formulation.

[0041] Carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I related to the groups and compounds described in the present invention all include their isotopic situations, and carbon, hydrogen, oxygen, sulfur or nitrogen related to the groups and compounds described in the present invention are optionally further substituted by one or more isotopes corresponding thereto, where the isotopes of carbon are 12 C and 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called triple hydrogen), and the isotopes of oxygen are 16 O and 17 O and 18 O, and the isotopes of sulfur are 32 S and 33 S and 34 S and 36 S, and the isotopes of nitrogen are 14 N and 15 N, and the isotopes of fluorine are17 F and 19 including F, the isotopes of chlorine are 35 Cl and 37 Cl, and the isotopes of bromine are 79 Br and 81 Br.

[0042] "Halogen" refers to F, Cl, Br or I.

[0043] "Halogen substitution" refers to F, Cl, Br or I substitution, including substitution by 1 to 10 substituents selected from F, Cl, Br or I, substitution by 1 to 6 substituents selected from F, Cl, Br or I, but not limited thereto, and preferably substitution by 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substitution" is abbreviated as "halogenation".

[0044] "Alkyl group" refers to a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including an alkyl group having 1 to 20 carbon atoms, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms, but not limited thereto. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and various branched-chain isomers thereof, and the definition of the alkyl group described herein is consistent with this definition. The alkyl group may be monovalent, divalent, trivalent or tetravalent.

[0045] "Alkylene group" is a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, -(CH 2 ) v -(v is an integer from 1 to 10), and examples of the alkylene group include, but are not limited to, methylene group, ethylene group, propylene group and butylene group.

[0046] "Cycloalkyl group" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group, etc. The definition of the cycloalkyl group described in this specification is as described above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0047] "Heterocycloalkyl group" refers to a substituted or unsubstituted saturated heteroatom-containing carbocyclic hydrocarbon group, containing 3 to 10 atoms, including but not limited to 3 to 8 atoms, and containing 1 to 3 heteroatoms selected from N, O or S. Optionally substituted N and S in the ring of the heterocycloalkyl group can be oxidized to various oxidation states. The heterocycloalkyl group may be linked on a heteroatom or a carbon atom, and the heterocycloalkyl group may be linked on an aromatic ring or a non-aromatic ring. A bridged ring or a spiro ring may be linked to the heterocycloalkyl group. Non-limiting examples include an oxiranyl group, an aziridinyl group, an oxetanyl group, an azetidinyl group, a tetrahydrofuranyl group, a tetrahydro-2H-pyranyl group, a dioxolanyl group, a dioxanyl group, a pyrrolidinyl group, a piperidinyl group, an imidazolidinyl group, an oxazolidinyl group, an oxazinanyl group, a morpholinyl group, a hexahydropyrimidinyl group, a piperazinyl group. The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0048] "Alkenyl group" refers to a substituted or unsubstituted linear and branched unsaturated hydrocarbon group, which has at least one, generally 1, 2 or 3 carbon-carbon double bonds, and the main chain contains 2 to 10, 2 to 6 or 2 to 4 carbon atoms, but is not limited thereto. Examples of alkenyl groups include, but are not limited to, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group, 2-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-methyl-1-pentenyl group, 2-methyl-1-pentenyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 1-octenyl group, 3-octenyl group, 1-nonenyl group, 3-nonenyl group, 1-decenyl group, 4-decenyl group, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc. The definition of the alkenyl group described in this specification is consistent with this definition. The alkenyl group may be monovalent, divalent, trivalent or tetravalent.

[0049] "Alkynyl group" refers to a substituted or unsubstituted linear and branched unsaturated hydrocarbon group, which has at least one, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain contains 2 to 10 carbon atoms, there are 2 to 6 carbon atoms in the main chain, and there are 2 to 4 carbon atoms in the main chain, including but not limited to, examples of alkynyl groups are ethynyl group, propargyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-1-butynyl group, 2-methyl-1-butynyl group, 2-methyl-3-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 1-methyl-1-pentynyl group, 2-methyl-1-pentynyl group, 1-heptynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 1-octynyl group, 3-octynyl group, 1-nonynyl group, 3-nonynyl group, 1-decynyl group, 4-decynyl group, etc., including but not limited to, the alkynyl group may be monovalent, divalent, trivalent or tetravalent.

[0050] "Alkoxy group" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, cyclopropoxy group and cyclobutoxy group.

[0051] "Carbon ring group" or "carbon ring" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring or a 10- to 15-membered tricyclic ring system. The carbon ring group may be linked to the aromatic or non-aromatic ring, and the aromatic or non-aromatic ring is optionally a monocyclic ring, a bridged ring or a spiro ring. Non-limiting examples include a cyclopropane group, a cyclobutane group, a cyclopentane group, a cyclohexane group, a cycloheptane group, a 1-cyclopentyl-1-alkenyl group, a 1-cyclopentyl-2-alkenyl group, a 1-cyclopentyl-3-alkenyl group, a cyclohexyl group, a 1-cyclohexyl-2-alkenyl group, a 1-cyclohexyl-3-alkenyl group, a cyclohexenyl group, a benzene ring, a naphthalene ring,

Chemical formula

[0052] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, where the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic or 10- to 15-membered tricyclic system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. Optionally substituted C, N, S in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group may be linked to a heteroatom or a carbon atom, the heterocyclic group may be linked to an aromatic or non-aromatic ring, and a bridged ring or a spiro ring may be linked to the heterocyclic group. Non-limiting examples include oxiranyl group, aziridinyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, azepanyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, imidazolyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, 1,3-dithianyl group, dihydrofuryl group, dihydropyranyl group, dithiolanyl group, tetrahydrofuryl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, pyrrolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, pyrazinyl group, indazolyl group, benzothienyl group, benzofuryl group, benzopyrrolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzopyridyl group, benzopyrimidinyl group, benzopyrazinyl group, piperazinyl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azadamantyl group, oxaspiro[3.3]heptyl group,

Chemical Structure

[0053] "Spiro ring" or "spiro ring group" refers to a polycyclic group that shares one atom (called a spiro atom) between substituted or unsubstituted monocyclic rings. The number of ring atoms in the spiro ring system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10. Here, one or more rings may contain zero or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally, 0 to 5 heteroatoms selected from N, O, or S(=O) n may be included. Non-limiting examples are

Chemical formula

[0054] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent atom pair with another ring in the system. Here, one or more rings may contain zero or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted. Each ring in the fused ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including those selected from N, S(=O) n or O, but not limited to those, where n is 0, 1, or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples are

Chemical formula

[0055] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing two non-directly connected atoms, which may contain zero or more double bonds. Any ring in the bridged ring system may be selected from heteroatoms or contain 0 to 5 groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include

Chemical formula

[0056] "Carbon spiro ring", "spiro ring carbon group", "spiro carbon group" or "carbon spiro ring group" refers to a "spiro ring" whose ring system consists of only carbon atoms. The definitions of "carbon spiro ring", "spiro ring carbon group", "spiro carbon group" or "carbon spiro ring group" described in this specification are consistent with the spiro ring.

[0057] "Carbon fused ring", "fused ring carbon group", "fused carbon group" or "carbon fused ring group" refers to a "fused ring" whose ring system consists of only carbon atoms. The definitions of "carbon fused ring", "fused ring carbon group", "fused carbon group" or "carbon fused ring group" described in this specification are consistent with the fused ring.

[0058] "Carbon bridged ring", "bridged ring carbon group", "bridged carbon group" or "carbon bridged ring group" refers to a "bridged ring" whose ring system consists of only carbon atoms. The definitions of "carbon bridged ring", "bridged ring carbon group", "bridged carbon group" or "carbon bridged ring group" described in this specification are consistent with the bridged ring.

[0059] "Heteromonocyclic ring", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocyclic ring" of a monocyclic system. The definitions of the heterocyclic group, "monocyclic heterocyclic group" or "heteromonocyclic group" described in this specification are consistent with the heterocyclic ring.

[0060] "Condensed heterocyclic ring", "condensed heterocyclic ring group", "condensed ring heterocyclic group" or "hetero-condensed ring group" refers to a "condensed ring" containing a heteroatom. The definitions of the condensed heterocyclic ring, "condensed heterocyclic ring group", "condensed ring heterocyclic group" or "hetero-condensed ring group" described in this specification are consistent with the condensed ring.

[0061] "Hetero-spiro ring", "hetero-spiro ring group", "spiro ring heterocyclic group" or "hetero-spiro ring group" refers to a "spiro ring" containing a heteroatom. The definitions of the hetero-spiro ring, "hetero-spiro ring group", "spiro ring heterocyclic group" or "hetero-spiro ring group" described in this specification are consistent with the spiro ring.

[0062] "Hetero-bridged ring", "hetero-bridged ring group", "bridged ring heterocyclic group" or "hetero-bridged ring group" refers to a "bridged ring" containing a heteroatom. The definitions of the hetero-bridged ring, "hetero-bridged ring group", "bridged ring heterocyclic group" or "hetero-bridged ring group" described in this specification are consistent with the bridged ring.

[0063] "Aryl group" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or condensed ring, and the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring can be condensed with a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring connected to the basic skeleton is an aryl ring. Non-limiting examples include benzene ring, naphthalene ring,

Chemical formula

[0064] "Heteroaryl group" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, which is selected from or contains 1 to 5 groups (including but not limited to N, O or S(=O)n, where n is 0, 1, 2) selected from heteroatoms, and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl group, furyl group, thienyl group, pyridyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, imidazolyl group, benzopyrazolyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, etc. The heteroaryl ring can be condensed with a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring linked to the basic skeleton is a heteroaryl ring, and non-limiting examples include [Chemical formula] including. The definition of the heteroaryl group described in this specification is consistent with this definition. The heteroaryl group may be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the linking site is on the heteroaryl ring.

[0065] "5-membered ring-fused 5-membered heteroaromatic ring" refers to a 5-fused 5-membered fused heteroaromatic ring. In the two fused rings, at least one ring contains one or more heteroatoms (including but not limited to O, S or N), and the whole group has aromaticity. Non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, pyrazolothiophene ring.

[0066] "5-fused 6-membered heteroaromatic ring" refers to a 5-fused 6-membered fused heteroaromatic ring. In the two fused rings, at least one ring contains one or more heteroatoms (including but not limited to O, S or N), and the whole group has aromaticity. Non-limiting examples include benzo 5-membered heteroaryl group, 6-membered heteroaromatic ring-fused 5-membered heteroaromatic ring.

[0067] "Substituted" or "unsubstituted" means substituted with one or more (including, but not limited to, 2, 3, 4, or 5) substituents, and the substituents are H, F, Cl, Br, I, alkyl group, cycloalkyl group, alkoxy group, halogenated alkyl group, thiol group, hydroxy group, nitro group, mercapto group, amino group, cyano group, isocyano group, aryl group, heteroaryl group, heterocyclic group, bridged ring group, spiro ring group, fused ring group, hydroxyalkyl group, =O, carbonyl group, aldehyde, carboxylic acid, formate ester, -(CH 2 ) m -C(=O)-R a 、-O-(CH 2 ) m -C(=O)-R a 、-(CH 2 ) m -C(=O)-NR b R c 、-(CH 2 ) m S(=O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d or -(CH 2 ) m -alkynyl-R a (where m and n are 0, 1, or 2), arylthio group, thiocarbonyl group, silyl group or -NR b R c and the like, including but not limited to, where R b and R c are independently selected from H, hydroxy group, amino group, carbonyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, sulfonyl group, trifluoromethanesulfonyl group, and as one option, R b and R c can form a five- or six-membered cycloalkyl group or heterocyclic group. R a and R dEach is independently selected from an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro ring group or a fused ring group.

[0068] "Containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.

[0069] "Substituted with 1 to X substituents" means substituted with 1, 2, 3... X substituents, where X is selected from any integer from 2 to 10. For example, "substituted with 1 to 4 substituents" means substituted with 1, 2, 3 or 4 substituents. For example, "substituted with 1 to 5 substituents" means substituted with 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally substituted with 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted with 1, 2, 3 or 4 substituents selected from H or F.

[0070] A ring of X to Y members (where X is selected from integers smaller than Y and greater than 3, and Y is selected from any integer from 4 to 12) includes rings of X, X + 1, X + 2, X + 3, X + 4... Y members. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterofused ring, a heterospiro ring or a heterobridged ring. For example, "4 to 7-membered heteromonocyclic ring" means a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5 to 10-membered heterofused ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterofused ring.

[0071] "Optional" or "optionally" means that the event or circumstance described thereafter may occur, but does not necessarily occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "an alkyl group optionally substituted by F" means that the alkyl group may be substituted by F, but does not necessarily have to be substituted by F, indicating that it includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

[0072] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" refers to a salt obtained by the reaction of the compound of the present invention with a non-toxic inorganic base or organic base of the free acid or free base while maintaining the biological effectiveness and properties of the free acid, or the reaction of the free base with a non-toxic inorganic acid or organic acid.

[0073] "Pharmaceutical composition" refers to a mixture composed of one or more compounds described in the present invention, or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and other chemical components, where "other chemical components" refer to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0074] "Carrier" refers to a material that does not cause a significant stimulatory effect on organisms and does not eliminate the biological activity and properties of the administered compound.

[0075] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives and disintegrants.

[0076] "Prodrug" refers to a compound that can be converted in vivo through metabolism into a compound having biological activity of the present invention. The prodrugs of the present invention are produced by modifying the amino group or carboxyl group in the compound of the present invention, and when the modification is by conventional operations or removed in vivo, the parent compound can be obtained. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free amino group or carboxyl group.

[0077] "Co-crystal" refers to a crystal formed by the binding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where the pure states of the API and CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the components. Co-crystals are multi-component crystals, including not only binary co-crystals formed between two neutral solids, but also multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0078] "Animal" includes mammals such as humans, companion animals, zoo animals, and livestock, and preferably refers to humans, horses, or dogs.

[0079] "Stereoisomer" refers to an isomer resulting from different three-dimensional arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0080] "Tautomer" refers to a functional group isomer produced by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol isomers and amide-imido alcohol isomers.

[0081] "IC 50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a certain component in the process, such as an enzyme, receptor, cell, etc.) by half.

Brief Description of the Drawings

[0082]

Figure 1

Embodiments for Carrying Out the Invention

[0083] Hereinafter, the technical solutions of the present invention will be described in detail together with examples. The protection scope of the present invention includes but is not limited to them.

[0084] The structure of the compound was determined by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS). The NMR shift (δ) was given in units of 10 -6 (ppm). The NMR measurement was carried out using a nuclear magnetic meter (Bruker Avance III 400 and Bruker Avance 300), and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). The internal standard was tetramethylsilane (TMS). The MS measurement was carried out using (Agilent 6120B (ESI) and Agilent 6120B (APCI)). The HPLC measurement was carried out using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5 μM). The MicroED measurement was carried out using a Thermo Fisher Thermo Scientific Glacios 200kv cryo transmission electron microscope. The thin-layer chromatography silica gel plate was Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate. The silica gel plate used for thin-layer chromatography (TLC) adopted a specification of 0.15 mm to 0.20 mm, and the separation and purification of products by thin-layer chromatography adopted a specification of 0.4 mm to 0.5 mm. Column chromatography generally used 200-300 mesh silica gel of Yantai Huanghai silica gel as the carrier. Boc: tert-butoxycarbonyl group, Ts: p-toluenesulfonyl group, Cbz: benzyloxycarbonyl group, TMS: trimethylsilyl group, DMF: N,N-dimethylcarboxamide, DIPEA: N,N-diisopropylethylamine.

[0085] Preparation of Intermediate A-5:

Chemical formula

[0086] Step 1: Preparation of A-2 tert-Butyl piperazine-1-carboxylate (82 g, 0.44 mol) was dissolved in 500 mL of DMF, cesium carbonate (215 g, 0.66 mol) was added, and the mixture was stirred at room temperature for 20 min. Then, Compound A-1 (70 g, 0.44 mol) was added, and the reaction was carried out at 50 °C for 16 h under nitrogen gas protection. The reaction solution was cooled to room temperature, quenched by adding 1.5 L of ice water, a large amount of yellow solid was precipitated, filtered, the filter cake was washed twice with 500 mL of water, and dried to obtain Compound A-2 (135 g, yield: 95%).

[0087] LCMS m / z = 326.1 [M+1] + 。

[0088] Step 2: Preparation of A-3 Under nitrogen gas protection, Compound A-2 (83.0 g, 0.255 mol) was dissolved in 400 mL of acetonitrile, placed in an ice bath and stirred for 20 min, 200 mL of 1,4-dioxane hydrochloric acid solution was added, and then the temperature was naturally raised to room temperature and reacted for 1 h. The reaction system was concentrated under reduced pressure to obtain the hydrochloride of crude product A-3 (72 g).

[0089] LCMS m / z = 226.1 [M+1] + 。

[0090] Step 3: Preparation of A-4 The hydrochloride salt (72 g) of the above crude product A-3 was dissolved in 800 mL of toluene. Under the protection of nitrogen gas, sodium acetate (52 g, 0.64 mol) and 60 mL of acetic acid were added in sequence. After stirring at room temperature for 20 min, tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (66 g, 0.28 mol) was added, and a water separation reaction was carried out at 100 °C for 6 h. The reaction system was cooled to room temperature, diatomaceous earth was spread and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Under the protection of nitrogen gas, the above crude product was dissolved in a mixed solvent of 200 mL of ultra-dehydrated methanol and 200 mL of ultra-dehydrated 1,2-dichloroethane, sodium cyanoborohydride (41.4 g, 1.275 mol) was added, and the reaction was carried out at room temperature for 16 h. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain compound A-4 (65 g, two-step yield: 57%).

[0091] LCMS m / z=445.2[M+1] + 。

[0092] Step 4: Preparation of A-5 A-4 (55 g, 0.124 mol) was dissolved in 1000 mL of ethyl acetate, 5.5 g of 10% palladium carbon was added, the system was replaced with hydrogen gas three times, and the reaction was carried out at room temperature for 16 h in a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain A-5 (50.5 g, yield: 98%).

[0093] LCMS m / z=415.2[M+1] + 。

[0094] After separating and purifying compound A-5 by SFC preparative separation, chiral isomer A-5-P1 (23.15 g, the retention time of SFC preparative separation is 0.946 min, the retention time of chiral HPLC is 20.460 min, [α] 20 D =+31.1 o ) and isomer A-5-P2 (19.94 g, the retention time of SFC preparative separation is 1.883 min, the retention time of chiral HPLC is 17.221 min, [α]20 D =-27.1 o )(A-5-P1 and A-5-P2 are one of the structures of compound A-5-a and A-5-b, and A-5-P1 and A-5-P2 are enantiomers of each other) was obtained.

Chemical formula

[0095] SFC chiral separation method: Instrument: Waters 150 SFC, preparative column model number: Chiralpak IC-3 Column (250×30mm, I.D 50mm, 10um particle size), mobile phase: A is CO 2 and B is a solution of isopropyl alcohol and acetonitrile containing 0.1% aqueous ammonia.

[0096] Elution conditions: 35%B isocratic elution, flow rate: 200 mL / min, column pressure: 100 bar, column temperature: 25 °C, detection wavelength: 220 nm, post-treatment: After separation by preparative separation, components with the same retention time were combined and concentrated under reduced pressure to obtain A-5-P1 and A-5-P2 respectively.

[0097] Chiral HPLC analysis conditions: Instrument: Shimadzu LC-20A, chiral column: CHIRALCEL OD-H, 4.6×250mm, 5μm, mobile phase: n-hexane (containing 0.1% diethylamine)-isopropyl alcohol (v / v)=70:30, flow rate: 1 mL / min, column temperature: 35 °C, detection wavelength: 210 nm, Sample injection volume: 10 μL, running time: 30 min.

[0098] Optical rotation measurement method: Instrument model number: Anton Paar MCP 4100, length of measurement tube: 1 dm, detection solvent: methanol,

[0099] Sample amount: A-5-P1: 100.66 mg, A-5-P2: 104.50 mg,

[0100] Sample concentration: A-5-P1: 3.8024 mg / mL, A-5-P2: 3.8024 mg / mL.

[0101] Production of intermediate A-6-P1:

Chem.

[0102] LCMS m / z = 526.7 [M+1] + 。

[0103] Production of intermediate A-6-P2:

Chem.

[0104] LCMS m / z = 526.2 [M+1] + 。

[0105] Example 1: Preparation of Compound 1

Chemical Structure

[0106] Step 1: Preparation of 1b Under a nitrogen gas atmosphere, 1a (0.50 g, 1.48 mmol) (for the synthesis method, refer to WO2019060742), tert-butyl 4-(methyl(piperidin-4-yl)amino)piperidine-1-carboxylate (0.66 g, 2.22 mmol) (for the synthesis method, refer to WO2021058017), RuPhos Pd G3 (CAS: 1445085-77-7) (0.25 g, 0.30 mmol), and RuPhos (CAS: 787618-22-8) (0.14 g, 0.30 mmol) were respectively added to a reaction flask. Then, 5 mL of toluene and a THF solution of 1 mol / L LiHMDS (8.8 mL, 8.8 mmol) were added, and the mixture was reacted at 80 °C for 1.5 h. The reaction solution was cooled to 0 °C in an ice bath, 10 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction system, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1 to 1:2) to obtain 1b (0.19 g, yield: 23%).

[0107] LCMS m / z = 555.4[M+1] + 。

[0108] Step 2: Preparation of the trifluoroacetate salt of 1c 1b (0.13 g, 0.23 mmol), 0.5 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 1c (0.15 g).

[0109] LCMS m / z = 455.3[M+1] + 。

[0110] Step 3: Preparation of Compound 1 To the reaction flask were added the trifluoroacetate of the above crude product 1c (0.15 g), sodium bicarbonate (0.097 g, 1.15 mmol), and 5 mL of DMSO, respectively. After stirring at room temperature for 0.5 h, 1D (0.090 g, 0.23 mmol) (for the synthesis method, refer to WO2021077010) and 0.19 mL of DIPEA were added, and the mixture was stirred at 100 °C for 7 h. The reaction system was cooled to room temperature, poured into 50 mL of water, filtered, and the filter cake was collected. The filter cake was dissolved in a 50 mL dichloromethane / methanol mixed solvent (v / v) = 2:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was passed through Pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative liquid was used, and the model number of the preparative column is Phenomenex C18). Preparative method: The crude product was dissolved in acetonitrile and water, filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: Aqueous solution containing 10 mmol / L ammonium bicarbonate / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 27% to 57% (elution time 10 min), and freeze-dried to obtain Compound 1 (25 mg, yield: 13%).

[0111] 1 H NMR (400MHz,DMSO-d 6 ) δ 11.03 (s,1H),8.81 (s,1H),8.03 (s,1H),7.91 (d,1H),7.71 (dd,1H),7.46 (d,1H),7.04 (s,1H),6.92 (d,1H),6.81 (d,1H),6.62 (dd,1H),5.34 - 5.22 (m,1H),4.90 (s,2H),4.59 - 4.45 (m,2H),3.67 (s,3H),3.65 - 3.54 (m,2H),3.40 - 3.20 (m,3H),2.97 - 2.75 (m,4H),2.75 - 2.55 (m,5H),2.23 - 2.14 (m,6H),2.05 - 1.92 (m,1H),1.85 - 1.55 (m,6H),1.50 - 1.32 (m,2H).

[0112] LCMS m / z=811.3[M+1] + 。

[0113] Example 2: Preparation of Compound 2

Chem.

[0114] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 8.82 (s, 1H), 8.03 (s, 1H), 7.94 - 7.88 (m, 1H), 7.71 (dd, 1H), 7.52 - 7.41 (m, 1H), 7.04 (s, 1H), 7.01 - 6.82 (m, 3H), 5.34 (dd, 1H), 4.91 (s, 2H), 4.62 - 4.42 (m, 2H), 3.67 (s, 3H), 3.63 (s, 3H), 3.19 - 3.05 (m, 2H), 2.96 - 2.56 (m, 9H), 2.26 - 2.15 (m, 6H), 2.08 - 1.92 (m, 1H), 1.90 - 1.58 (m, 6H), 1.52 - 1.31 (m, 2H).

[0115] LCMS m / z = 811.9 [M + 1] + .

[0116] Example 3: Preparation of Compound 3

Chem.

[0117] 1 H NMR (400 MHz, DMSO-d 6) δ 10.74 (s,1H), 8.80 (s,1H), 8.03 (s,1H), 7.94 - 7.87 (m,1H), 7.71 (dd,1H), 7.50 - 7.41 (m,1H), 7.08 - 6.97 (m,3H), 6.94 - 6.82 (m,2H), 4.90 (s,2H), 4.59 - 4.44 (m,2H), 3.77 - 3.60 (m,6H), 2.92 - 2.74 (m,3H), 2.72 - 2.56 (m,4H), 2.49 - 2.37 (m,1H), 2.24 - 1.94 (m,8H), 1.84 - 1.30 (m,8H).

[0118] LCMS m / z = 741.3 [M+1] + .

[0119] Example 4: Preparation of Compound 4

Chemical Structure

[0120] Step 1: Preparation of the trifluoroacetate of 4a To the reaction flask, A-6-P2 (100 mg, 0.19 mmol), 1 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of crude product 4a (100 mg).

[0121] Step 2: Preparation of Compound 4 To the reaction flask were added the trifluoroacetate of the above crude product 4a (100 mg), solid sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO, and after reacting at room temperature for 0.5 h, 4B (78 mg, 0.19 mmol) (for the synthesis method, refer to WO2021077010) and 0.16 mL of DIPEA were added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 18 min), and freeze-dried to obtain compound 4 (24 mg, yield: 16%).

[0122] LCMS m / z=797.2[M+1] + 。

[0123] Example 5: Preparation of the trifluoroacetate of compound 5

Chemical Structure

[0124] LCMS m / z=782.2[M+1] + 。

[0125] Example 6: Preparation of Compound 6

Chemical Structure

[0126] Step 1: Preparation of the trifluoroacetate of 6a Add A-6-P1 (100 mg, 0.19 mmol), 1 mL of trifluoroacetic acid, and 2 mL of dichloromethane to the reaction flask, and react at room temperature for 2 h. Concentrate the reaction solution under reduced pressure to obtain the trifluoroacetate of crude product 6a (100 mg).

[0127] Step 2: Preparation of Compound 6 To the reaction flask, add the trifluoroacetate salt of the above crude product 6a (100 mg), sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO respectively. After reacting at room temperature for 0.5 h, add 1D (75 mg, 0.19 mmol) and 0.16 mL of DIPEA, and react at 100 °C for 7 h. Cool to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: ammonium acetate aqueous solution (5 mmol / L) / acetonitrile. Gradient elution method: Elute 70% of acetonitrile with a gradient of 10% (elution time 15 min), and lyophilize to obtain compound 6 (15.0 mg, yield: 10%).

[0128] LCMS m / z=782.2[M+1] + 。

[0129] Example 7: Preparation of the trifluoroacetate salt of compound 7

Chemical formula

[0130] LCMS m / z=797.2[M+1] + 。

[0131] Example 8: Preparation of Compound 8

Chemical formula

[0132] Step 1: Preparation of 8b Under a nitrogen gas atmosphere, 8a (0.2 g, 0.75 mmol) (for the synthesis method, refer to WO2017197046), tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (0.32 g, 1.13 mmol) (for the synthesis method, refer to WO2020201080), RuPhos Pd G3 (0.13 g, 0.16 mmol), and RuPhos (0.07 g, 0.15 mmol) were respectively added to a reaction flask. 5 mL of toluene and a THF solution of LiHMDS (4.5 mL, 1 mol / L) were added, and the reaction was carried out at 80 °C for 1.5 h. The reaction solution was cooled to 0 °C, saturated aqueous ammonium chloride solution (10 mL) was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1) to obtain 8b (0.09 g, yield: 25%).

[0133] LCMS m / z=471.6[M+1] + 。

[0134] Step 2: Preparation of the trifluoroacetate salt of 8c 8b (0.09 g, 0.19 mmol), 1.0 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to a reaction flask, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of the crude product 8c (0.09 g).

[0135] Step 3: Preparation of compound 8 To a reaction flask, the trifluoroacetate salt of crude product 8c (90 mg), sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO were added respectively. After stirring at room temperature for 0.5 h, 4B (78 mg, 0.19 mmol) (for the synthesis method, refer to WO2021077010) and 0.16 mL of DIPEA were added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature and passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: ammonium acetate aqueous solution (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 15 min), and freeze-dried to obtain compound 8 (20 mg, yield: 14%).

[0136] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.80 (s,1H),9.09 (s,1H),8.16 (s,1H),8.01 - 7.93 (m,1H),7.91 (d,1H),7.72 (dd,1H),7.52 - 7.46 (m,1H),7.17 (s,1H),7.14 - 7.06 (m,2H),7.06 - 6.94 (m,2H),4.60 (s,2H),4.56 - 4.42 (m,2H),3.80 - 3.65 (m,6H),3.64 - 3.52 (m,2H),3.40 - 3.23 (m,2H),3.15 - 2.97 (m,4H),2.89 - 2.71 (m,2H),2.71 - 2.57 (m,4H),2.50 - 2.42 (m,1H),2.24 - 1.94 (m,3H),1.92 - 1.79 (m,2H),1.46 - 1.28 (m,2H).

[0137] LCMS m / z=742.3[M+1] + 。

[0138] Example 9: Preparation of Compound 9 [Chemistry]

[0139] Step 1: Preparation of 9b Under a nitrogen gas atmosphere, 9a (0.60 g, 1.78 mmol) (for the synthesis method, refer to WO2021158634), tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (0.75 g, 2.65 mmol), RuPhos Pd G3 (0.30 g, 0.36 mmol), and RuPhos (0.17 g, 0.36 mmol) were respectively added to a reaction flask. Then, 10 mL of toluene and a THF solution of 1 mol / L LiHMDS (10.6 mL, 10.6 mmol) were added, and the mixture was reacted at 80 °C for 1.5 h. The reaction solution was cooled to 0 °C in an ice bath, 10 mL of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction system, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1 to 10:1) to obtain 9b (0.14 g, yield: 15%).

[0140] Step 2: Preparation of the trifluoroacetate salt of 9c 9b (0.07 g, 0.13 mmol), 1.0 mL of trifluoroacetic acid, and 2 mL of dichloromethane were added to a reaction flask, and the mixture was reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 9c (0.07 g).

[0141] Step 3: Preparation of Compound 9 To the reaction flask, add the trifluoroacetate of crude product 9c (70 mg), sodium hydrogen carbonate (55 mg, 0.65 mmol), and 5 mL of DMSO respectively. After stirring at room temperature for 0.5 h, add 4B (53 mg, 0.13 mmol) (for the synthesis method, refer to WO2021077010) and 0.11 mL of DIPEA, and react at 100 °C for 7 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Elute 70% of acetonitrile with a gradient of 10% (elution time 14 min), and lyophilize to obtain compound 9 (22 mg, yield: 21%).

[0142] 1 H NMR (400MHz,DMSO-d 6 ) δ 11.06 (s,1H),8.80 (s,1H),8.04 (s,1H),7.99 - 7.89 (m,2H),7.82 - 7.71 (m,1H),7.54 - 7.44 (m,1H),7.12 (s,1H),7.03 - 6.84 (m,3H),5.41 - 5.29 (m,1H),4.58 (s,2H),4.54 - 4.41 (m,2H),3.68 (s,3H),3.62 (s,3H),3.10 - 2.55 (m,14H),2.40 - 1.68 (m,8H),1.14 - 0.96 (m,2H).

[0143] LCMS m / z=812.3[M+1] + .

[0144] Example 10: Preparation of Compound 10

Chemical formula

[0145] 1 H NMR (400MHz,DMSO-d 6 ) δ 11.06 (br.s,1H),8.80 (s,1H),8.03 (s,1H),7.94 - 7.85 (m,1H),7.78 - 7.67 (m,1H),7.52 - 7.42 (m,1H),7.06 - 6.82 (m,4H),5.40 - 5.29 (m,1H),4.91 (s,2H),4.56 - 4.42 (m,2H),3.67 (s,3H),3.62 (s,3H),3.11 - 2.55 (m,11H),2.35 - 2.10 (m,7H),2.06 - 1.93 (m,1H),1.88 - 1.70 (m,3H),1.15 - 0.97 (m,2H).

[0146] LCMS m / z=797.3[M+1] + .

[0147] Example 11: Preparation of trifluoroacetate of compound 11

Chemical formula

[0148] 1 H NMR (400MHz,DMSO-d 6 ) δ 11.08 (s,1H),8.97 (s,1H),8.10 (s,1H),8.02 - 7.90 (m,2H),7.78 - 7.70 (m,1H),7.53 - 7.44 (m,1H),7.13 (s,1H),7.04 - 6.86 (m,3H),5.41 - 5.31 (m,1H),4.70 - 4.56 (m,4H),3.86 - 3.48 (m,8H),3.28 - 3.15 (m,2H),3.04 - 2.56 (m,13H),2.25 - 1.47 (m,9H).

[0149] LCMS m / z=827.0[M+1] + .

[0150] Example 12: Preparation of Compound 12

Chemical formula

[0151] Step 1: Preparation of 12b To the reaction flask, add tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (0.18 g, 0.64 mmol) (for the synthesis method, refer to WO2020201080), 12a (0.12 g, 0.41 mmol) (for the synthesis method, refer to WO2020113233), 0.1 mL of glacial acetic acid, 3 mL of 1,2-dichloroethane, and 1 mL of DMSO respectively. After stirring at room temperature for 0.5 h, add sodium triacetoxyborohydride (0.18 g, 0.85 mmol), and react at room temperature for 16 h. Add 10 mL of saturated aqueous sodium bicarbonate solution to the reaction system, extract with ethyl acetate (20 mL × 3), combine the organic phases, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product by column chromatography on silica gel (dichloromethane / methanol (v / v) = 10:1) to obtain 12b (95 mg, yield: 42%).

[0152] LCMS m / z = 555.8[M+1] + 。

[0153] Step 2: Preparation of the trifluoroacetate of 12c Add 12b (95 mg, 0.17 mmol), 0.5 mL of trifluoroacetic acid, and 2 mL of dichloromethane to the reaction flask, and react at room temperature for 2 h. Concentrate the reaction solution under reduced pressure to obtain the trifluoroacetate of crude product 12c (90 mg).

[0154] Step 3: Preparation of Compound 12 To the reaction flask, add the trifluoroacetate salt (90 mg) of the above crude product 12c, sodium bicarbonate (71 mg, 0.85 mmol), and 5 mL of DMSO respectively. After stirring at room temperature for 0.5 h, add 4B (69 mg, 0.17 mmol) and 0.14 mL of DIPEA, and react at 100 °C for 7 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Manufacturing method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Elute 70% of acetonitrile with a gradient of 10% (elution time 12 min), and lyophilize to obtain compound 12 (20 mg, yield: 14%).

[0155] 1 H NMR (400MHz,DMSO-d 6 ) δ 8.83 (s,1H),8.04 (s,1H),7.99 - 7.89 (m,2H),7.77 - 7.70 (m,1H),7.50 - 7.42 (m,1H),7.12 (s,1H),7.09 - 7.02 (m,1H),6.99 - 6.91 (m,1H),6.90 - 6.83 (m,1H),5.44 - 5.30 (m,1H),4.58 (s,2H),3.72 - 3.54 (m,12H),2.96 - 2.56 (m,8H),2.41 - 2.28 (m,4H),2.18 - 1.90 (m,5H),1.74 - 1.46 (m,3H),1.14 - 0.98 (m,2H).

[0156] LCMS m / z=826.3[M+1] + .

[0157] Example 13: Preparation of trifluoroacetate salt of compound 13

Chemical formula

[0158] Step 1: Preparation of trifluoroacetate of 13b Into a 50 mL reaction flask, 13a (0.10 g, 0.21 mmol) (for the synthesis method, refer to WO2022133285), dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) were added in sequence, and the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of crude 13b (0.10 g).

[0159] Step 2: Preparation of trifluoroacetate of compound 13 Into a 25 mL reaction flask, the above trifluoroacetate of crude 13b (0.10 g), 1D (0.075 g, 0.19 mmol) (for the synthesis method, refer to WO2021077010), DIPEA (0.31 mL), and DMSO (5 mL) were added in sequence, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 12 min), and then freeze-dried to obtain the trifluoroacetate of compound 13 (15 mg).

[0160] 1 H NMR (400MHz,DMSO-d 6) δ 10.77 (s,1H),8.99 (s,1H),8.08 (s,1H),7.84 (d,1H),7.72 (dd,1H),7.45 (d,1H),7.15 - 7.06 (m,3H),7.01 - 6.94 (m,2H),4.93 - 4.87 (m,2H),4.53 - 4.39 (m,2H),4.00 - 3.50 (m,8H),3.25 - 2.83 (m,8H),2.73 - 2.57 (m,1H),2.50 - 2.42 (m,1H),2.24 - 1.94 (m,6H),1.84 - 1.69 (m,2H),1.27 - 1.07 (m,2H).

[0161] LCMS m / z=727.3[M+1] + .

[0162] Example 14: Preparation of trifluoroacetate of Compound 14 [Chemical formula] To a 25 mL reaction flask, trifluoroacetate of the above crude product 13b (0.10 g), 4B (0.078 g, 0.19 mmol), DIPEA (0.31 mL) and DMSO (5 mL) were added in sequence, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 13 min), and freeze-dried to obtain trifluoroacetate of Compound 14 (20 mg).

[0163] 1 H NMR (400MHz,DMSO-d 6) δ 10.78 (s,1H),9.00 - 8.91 (m,1H),8.08 (s,1H),8.01 - 7.88 (m,2H),7.74 (dd,1H),7.47 (d,1H),7.16 - 7.06 (m,3H),7.02 - 6.93 (m,2H),4.59 (s,2H),4.55 - 4.40 (m,2H),3.87 - 3.72 (m,3H),3.68 (s,3H),3.65 - 3.54 (m,2H),3.26 - 2.84 (m,8H),2.71 - 2.58 (m,4H),2.49 - 2.41 (m,1H),2.23 - 2.08 (m,2H),2.07 - 1.95 (m,1H),1.85 - 1.71 (m,2H),1.27 - 1.11 (m,2H).

[0164] LCMS m / z=742.3[M+1] + .

[0165] Example 15: Preparation of Compound 15

Chemical Structure

[0166] Step 1: Preparation of 15b 15A (synthesis method refers to WO2017197046) (0.30 g, 1.12 mmol), 15a (synthesis method refers to WO2022019597) (0.30 g, 1.11 mmol) and 10 mL of toluene were added to a reaction flask respectively. Under the protection of nitrogen gas, RuPhos (0.10 g, 0.21 mmol), RuPhos Pd G3 (0.19 g, 0.227 mmol), and a THF solution of 1 mol / L LiHMDS (6.72 mL, 6.72 mmol) were added in sequence, and the reaction was carried out at 80 °C for 1.5 h. The reaction solution was cooled to room temperature, 15 mL of saturated ammonium chloride aqueous solution was added, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (dichloromethane / methanol (v / v) = 10:1) to obtain 15b (0.23 g, yield: 45%).

[0167] LCMS m / z = 457.6 [M+1] + 。

[0168] Step 2: Preparation of trifluoroacetate of 15c 15b (0.28 g, 0.61 mmol), 1.5 mL of trifluoroacetic acid and 5 mL of dichloromethane were added to the reaction flask, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain crude trifluoroacetate of 15c (0.30 g).

[0169] Step 3: Preparation of Compound 15 The crude trifluoroacetate of 15c (0.15 g), DIPEA (0.54 g, 4.2 mmol) and 5 mL of DMSO were respectively added to the reaction flask. After stirring at room temperature for 0.5 h, 1D (0.15 g, 0.38 mmol) (for the synthesis method, refer to WO2021077010) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and then freeze-dried to obtain Compound 15 (10 mg, yield: 4%).

[0170] 1 H NMR (400 MHz, DMSO-d 6) δ 10.74 (s,1H),8.82 (s,1H),8.04 (s,1H),7.94 - 7.86 (m,1H),7.70 (dd,1H),7.46 (d,1H),7.08 - 6.99 (m,3H),6.93 - 6.82 (m,2H),4.90 (s,2H),4.60 - 4.40 (m,2H),3.76 - 3.64 (m,4H),3.14 - 3.04 (m,4H),2.92 - 2.77 (m,2H),2.71 - 2.56 (m,5H),2.49 - 2.39 (m,2H),2.24 - 1.94 (m,5H),1.89 - 1.75 (m,2H),1.52 - 1.20 (m,2H).

[0171] LCMS m / z=713.8[M+1] + .

[0172] Example 16: Preparation of Compound 16 [Chemical Structure] To the reaction flask were added the trifluoroacetate of the above crude product 15c (0.15 g), DIPEA (0.54 g, 4.2 mmol), and 5 mL of DMSO, respectively. After stirring at room temperature for 0.5 h, 4B (0.15 g, 0.37 mmol) (for the synthesis method, refer to WO2021077010) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparative method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and freeze-dried to obtain Compound 16 (15 mg, yield: 6%).

[0173] 1 H NMR (400MHz,DMSO-d 6) δ 10.75 (s,1H),8.83 (s,1H),8.07 - 7.89 (m,3H),7.80 - 7.72 (m,1H),7.52 - 7.45 (m,1H),7.18 - 6.98 (m,3H),6.94 - 6.82 (m,2H),4.63 - 4.42 (m,4H),3.77 - 3.61 (m,4H),3.15 - 3.03 (m,4H),2.94 - 2.80 (m,2H),2.73 - 2.56 (m,8H),2.55 - 2.38 (m,2H),2.20 - 1.92 (m,2H),1.90 - 1.80 (m,2H),1.54 - 1.18 (m,2H).

[0174] LCMS m / z=728.3[M+1] + 。

[0175] Example 17: Preparation of the trifluoroacetate salt of Compound 17

Chemical Structure

[0176] Step 1: Preparation of the trifluoroacetate salt of 17b To a 50 mL reaction flask, 17a (0.22 g, 0.59 mmol) (for the synthesis method, refer to WO2022133285), dichloromethane (2 mL) and trifluoroacetic acid (1.0 mL) were added in sequence, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 17b (0.22 g).

[0177] Step 2: Preparation of the trifluoroacetate salt of Compound 17 To a 25 mL reaction flask, trifluoroacetate of the above crude product 17b (0.11 g), 1D (0.11 g, 0.28 mmol) (for the synthesis method, refer to WO2021077010), DIPEA (0.46 mL) and DMSO (5 mL) were added in sequence, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparative method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 11 min), and freeze-dried to obtain trifluoroacetate of compound 17 (10 mg).

[0178] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.75 (s,1H),9.00 (s,1H),8.11 (s,1H),7.90 (d,1H),7.71 (dd,1H),7.48 (d,1H),7.13 - 7.03 (m,3H),7.00 - 6.92 (m,2H),4.91 (s,2H),3.84 - 3.70 (m,5H),3.68 (s,3H),3.24 - 3.13 (m,4H),2.71 - 2.56 (m,1H),2.50 - 2.41 (m,1H),2.24 - 1.95 (m,5H).

[0179] LCMS m / z=630.2[M+1] + 。

[0180] Example 18: Preparation of Compound 18

Chemical formula

[0181] 11H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 7.94 - 7.88 (m, 1H), 7.71 (dd, 1H), 7.45 (d, 1H), 7.07 - 6.97 (m, 3H), 6.93 - 6.83 (m, 2H), 4.90 (s, 2H), 4.60 - 4.45 (m, 2H), 3.78 - 3.61 (m, 6H), 2.84 - 2.51 (m, 5H), 2.49 - 2.40 (m, 1H), 2.25 - 1.92 (m, 5H), 1.85 - 1.65 (m, 4H), 1.46 - 1.02 (m, 6H).

[0182] LCMS m / z = 356.7 [M / 2 + 1] + .

[0183] Example 19: Preparation of Compound 19 [Chemical Structure] To a reaction flask were added the trifluoroacetate of the above crude product 18c (0.15 g), DIPEA (0.39 g, 3.02 mmol), and 5 mL of DMSO, respectively. After stirring at room temperature for 0.5 h, 4B (0.11 g, 0.27 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and freeze-dried to obtain Compound 19 (15 mg, yield: 8%).

[0184] 1 1H NMR (400 MHz, DMSO-d 6) δ 10.83 (s,1H),9.16 (s,1H),8.10 (s,1H),8.02 - 7.88 (m,2H),7.74 (dd,1H),7.54 - 7.46 (m,1H),7.34 - 6.95 (m,5H),4.58 (s,2H),4.55 - 4.42 (m,2H),3.90 - 3.77 (m,1H),3.73 - 3.57 (m,5H),3.25 - 2.95 (m,2H),2.94 - 2.76 (m,2H),2.74 - 2.57 (m,4H),2.50 - 2.42 (m,1H),2.27 - 2.10 (m,1H),2.07 - 1.95 (m,1H),1.95 - 1.82 (m,2H),1.82 - 1.70 (m,2H),1.60 - 1.27 (m,4H),1.25 - 1.05 (m,2H).

[0185] Example 20: Preparation of trifluoroacetate of Compound 20 [Chemical formula] To a 25 mL reaction flask, trifluoroacetate of crude product 17b (0.11 g), 4B (0.11 g, 0.27 mmol), DIPEA (0.46 mL) and DMSO (5 mL) were added in sequence, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 13 min), and freeze-dried to obtain trifluoroacetate of Compound 20 (18 mg).

[0186] 1 H NMR (400MHz,DMSO-d 6) δ 10.76 (s,1H),9.21 - 9.07 (m,1H),8.17 - 8.10 (m,1H),8.03 - 7.92 (m,2H),7.75 (dd,1H),7.51 (d,1H),7.18 (s,1H),7.13 - 7.04 (m,2H),7.03 - 6.94 (m,2H),4.60 (s,2H),4.00 - 3.68 (m,8H),3.28 - 3.15 (m,4H),2.72 - 2.57 (m,4H),2.50 - 2.39 (m,1H),2.22 - 1.94 (m,2H).

[0187] LCMS m / z=645.2[M+1] + .

[0188] Example 21: Preparation of trifluoroacetate of Compound 21 [Chemical formula]

[0189] Step 1: Preparation of 21b 21a (2.93 g, 10.34 mmol), potassium carbonate (6.49 g, 46.96 mmol), 21A (3.0 g, 9.41 mmol), L-proline (0.43 g, 3.73 mmol) and CuI (0.36 g, 1.89 mmol) were added to a reaction flask, DMSO (80 mL) was added, replaced three times with nitrogen gas, and reacted at 90 °C for 12 h. The reaction solution was cooled to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, the aqueous phase was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 100:1 to 1:1) to obtain 21b (2.0 g, yield: 45%).

[0190] LCMS m / z=474.6[M+1] + .

[0191] Step 2: Preparation of 21c 21b (1.50 g, 3.16 mmol), 21B (for the synthesis method, refer to WO2021262812) (1.45 g, 3.47 mmol), Pd(dppf)Cl 2 ·DCM (CAS: 95464 - 05 - 4) (0.26 g, 0.32 mmol) and cesium carbonate (2.06 g, 6.32 mmol) were added to the reaction flask, 1,4 - dioxane (10 mL) and water (2 mL) were added, the mixture was purged with nitrogen gas three times, and reacted at 100 °C for 20 h. The reaction solution was cooled to room temperature, 100 mL of water and 100 mL of ethyl acetate were added, separated, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, the combined organic phase was washed with 20 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=1:0~20:1) to obtain 21c (0.85 g, yield: 39%).

[0192] LCMS m / z = 685.4[M + 1] + 。

[0193] Step 3: Preparation of 21d 21c (450 mg, 0.66 mmol), 10% palladium on carbon (330 mg) and methanol (15 mL) were sequentially added to the reaction flask, purged with hydrogen gas three times, and reacted at 45 °C for 20 h under a hydrogen gas balloon atmosphere. The reaction system was cooled to room temperature, suction filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 21d (0.30 g).

[0194] LCMS m / z = 507.3[M + 1] + 。

[0195] Step 4: Preparation of the trifluoroacetate salt of 21e The above - mentioned crude product 21d (150 mg) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate salt of the crude product 21e (160 mg).

[0196] LCMS m / z = 407.5[M + 1]+ .

[0197] Step 5: Preparation of Trifluoroacetate Salt of Compound 21 To the reaction flask, add the trifluoroacetate salt (78 mg) of the above crude product 21e, DIPEA (200 mg, 1.55 mmol), and 15 mL of DMSO respectively, add 4B (61 mg, 0.15 mmol), and react at 100 °C for 7 h. Cool the reaction system to room temperature, and pass the crude product through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Elute 50% of acetonitrile with a gradient of 10% (elution time 15 min), and lyophilize to obtain the trifluoroacetate salt (15 mg) of Compound 21.

[0198] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.86 (s,1H),9.07 (s,1H),8.15 (s,1H),8.01 - 7.87 (m,2H),7.72 (dd,1H),7.48 (d,1H),7.17 (s,1H),6.71 - 6.59 (m,2H),4.59 (s,2H),4.55 - 4.40 (m,2H),4.10 - 4.00 (m,1H),3.87 - 3.75 (m,2H),3.68 (s,3H),3.63 - 3.51 (m,2H),3.41 - 3.23 (m,2H),3.14 - 2.97 (m,4H),2.86 - 2.71 (m,3H),2.66 (d,3H),2.56 - 2.51 (m,1H),2.20 - 1.70 (m,5H),1.37 - 1.15 (m,2H).

[0199] LCMS m / z=778.8[M+1] + .

[0200] Example 22: Preparation of Compound 22

Chem.

[0201] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.85 (s, 1H), 8.85 (s, 1H), 8.04 (s, 1H), 7.93 - 7.86 (m, 1H), 7.70 (dd, 1H), 7.50 - 7.42 (m, 1H), 7.05 (s, 1H), 6.70 - 6.53 (m, 2H), 4.91 (s, 2H), 4.09 - 3.98 (m, 1H), 3.81 - 3.70 (m, 2H), 3.66 (s, 3H), 3.65 - 3.58 (m, 4H), 2.85 - 2.64 (m, 4H), 2.44 - 2.30 (m, 4H), 2.24 - 1.90 (m, 7H), 1.85 - 1.67 (m, 3H), 1.20 - 1.05 (m, 2H).

[0202] LCMS m / z = 763.9 [M + 1] + .

[0203] Example 23: Preparation of Compound 23

Chem.

[0204] Step 1: Preparation of 23b To the reaction flask, add 23A (1.5 g, 13.02 mmol), potassium carbonate (3.6 g, 26.05 mmol), 23a (3.92 g, 13.03 mmol), L-proline (0.6 g, 5.21 mmol) and CuI (0.5 g, 2.63 mmol), add DMSO (30 mL), replace with nitrogen gas three times, and react at 50 °C for 16 h. Cool the reaction solution to room temperature, add 50 mL of water, extract with ethyl acetate (30 mL × 3), dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product by a column for silica gel chromatography (petroleum ether:ethyl acetate (v / v) = 3:2) to obtain 23b (2.5 g, yield: 67%).

[0205] LCMS m / z = 288.3 [M+1] + .

[0206] Step 2: Preparation of 23c Under the protection of nitrogen gas, add 23b (2.5 g, 8.70 mmol), 23B (for the synthesis method, refer to WO2021262812) (12.68 g, 30.34 mmol), Pd(dppf)Cl 2 ·DCM (CAS: 95464-05-4) (0.71 g, 0.87 mmol) and cesium carbonate (11.31 g, 34.71 mmol) to the reaction flask, add 40 mL of 1,4-dioxane and 8 mL of water, replace with nitrogen gas three times, and react at 100 °C for 6 h. Cool the reaction solution to room temperature, add 30 mL of water, extract with ethyl acetate (50 mL × 3), dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product by a column for silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain 23c (3.2 g, yield: 74%).

[0207] LCMS m / z = 499.3 [M+1] + .

[0208] Step 3: Preparation of 23d 23c (3.2 g, 6.42 mmol) and 10% palladium on carbon (3 g) were added to 100 mL of THF, and the mixture was purged with hydrogen gas three times. The reaction was carried out at room temperature for 16 h under a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography on silica gel (dichloromethane / methanol (v / v) = 20:1) to obtain 23d (0.91 g, yield: 44%).

[0209] LCMS m / z = 321.4 [M+1] + 。

[0210] Step 4: Preparation of 23e 23d (0.30 g, 0.94 mmol) was dissolved in DMSO (3 mL), 2-iodobenzoyl benzoic acid (0.42 g, 1.50 mmol) was added, and the reaction was carried out at 50 °C for 2 h. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 23e (0.28 g).

[0211] LCMS m / z = 319.3 [M+1] + 。

[0212] Step 5: Preparation of 23f The above crude product 23e (0.28 g) was dissolved in 1,2-dichloroethane (30 ml), tert-butyl piperazine-1-carboxylate (0.25 g, 1.34 mmol) was added, 0.33 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.56 g, 2.64 mmol) was added, and the reaction was carried out at room temperature for 16 h. 50 mL of saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution, and the mixture was extracted with 30 mL of dichloromethane. The organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1) to obtain 23f (0.33 g, yield: 50%).

[0213] LCMS m / z = 489.3 [M+1] + 。

[0214] Step 6: Preparation of 23g trifluoroacetate 23f (330 mg, 0.676 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain crude 23g trifluoroacetate (340 mg).

[0215] LCMS m / z = 389.3 [M+1] + 。

[0216] Step 7: Preparation of Compound 23 To the reaction flask were added the above-mentioned crude 23g trifluoroacetate (150 mg), DIPEA (301 mg, 2.33 mmol), and 10 mL of DMSO, respectively, and 1D (100 mg, 0.25 mmol) (for the synthesis method, refer to WO2021077010) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and freeze-dried to obtain Compound 23 (24 mg, yield: 13%).

[0217] 1 H NMR (400 MHz, DMSO-d 6) δ 10.78 (s,1H),8.85 (s,1H),8.05 (s,1H),7.89 (d,1H),7.70 (dd,1H),7.45 (d,1H),7.12 - 7.00 (m,2H),6.77 - 6.63 (m,2H),4.91 (s,2H),3.93 - 3.82 (m,1H),3.77 - 3.55 (m,9H),2.78 - 2.60 (m,3H),2.58 - 2.45 (m,1H),2.44 - 2.30 (m,4H),2.25 - 2.06 (m,6H),2.03 - 1.90 (m,1H),1.85 - 1.63 (m,3H),1.28 - 1.08 (m,2H).

[0218] LCMS m / z=745.3[M+1] + .

[0219] Example 24: Preparation of trifluoroacetate of Compound 24 [Chemical formula] To the reaction flask were added 23 g of the above crude trifluoroacetate (140 mg), DIPEA (301 mg, 2.33 mmol) and 10 mL of DMSO respectively, 4B (100 mg, 0.24 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and freeze-dried to obtain 50 mg of trifluoroacetate of Compound 24.

[0220] 1 H NMR (400MHz,DMSO-d 6) δ 10.80 (s, 1H), 9.07 (s, 1H), 8.15 (s, 1H), 8.00 - 7.86 (m, 2H), 7.72 (dd, 1H), 7.48 (d, 1H), 7.17 (s, 1H), 7.13 - 7.03 (m, 1H), 6.82 - 6.68 (m, 2H), 4.62 - 4.38 (m, 4H), 3.94 - 3.83 (m, 1H), 3.83 - 3.70 (m, 2H), 3.68 (s, 3H), 3.64 - 3.50 (m, 2H), 3.40 - 3.22 (m, 2H), 3.15 - 2.95 (m, 4H), 2.80 - 2.60 (m, 6H), 2.57 - 2.47 (m, 1H), 2.25 - 1.89 (m, 3H), 1.88 - 1.73 (m, 2H), 1.43 - 1.20 (m, 2H).

[0221] LCMS m / z = 760.8 [M + 1] + .

[0222] The trifluoroacetate salt of Compound 24 was subjected to chiral resolution to obtain Chiral Isomer 1 and Chiral Isomer 2, respectively. The resolution conditions are as follows.

[0223] 1. Instrument: Waters 150 Prep - SFC E, Chromatography column: Chiralcel AD column.

[0224] 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution.

[0225] 3. Preparative chromatography conditions: a. The mobile phase consists of System A and System B: Mobile phase A: CO 2 , Mobile phase B: A mixed solvent of methanol / acetonitrile containing 0.1% aqueous ammonia; b. Isocratic elution was performed, and the content of Mobile phase B was 65%; c. The flow rate was 100 mL / min.

[0226] Chiral analysis method: 1. Instrument: SHIMAZU LC-30AD, Chromatography column: Chiral AD column.

[0227] 2. Analytical chromatography conditions: a. The mobile phase is composed of System A and System B: Mobile phase A: CO 2 , Mobile phase B: Isopropyl alcohol and acetonitrile solution of 0.05% diethylamine, b. Isocratic elution, the content of mobile phase B is 60%, c. The flow rate is 3 mL / min.

[0228] Peak time: Chiral isomer 1: 1.028 min, Chiral isomer 2: 1.431 min.

[0229] Nuclear magnetic characterization of chiral isomer 1: 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.77 (s, 1H), 8.84 (s, 1H), 8.20 - 8.00 (m, 1H), 7.98 - 7.87 (m, 2H), 7.74 (dd, 1H), 7.47 (d, 1H), 7.17 - 7.00 (m, 2H), 6.75 - 6.62 (m, 2H), 4.58 (s, 2H), 3.94 - 3.82 (m, 1H), 3.76 - 3.58 (m, 9H), 2.80 - 2.59 (m, 6H), 2.56 - 2.45 (m, 1H), 2.44 - 2.32 (m, 4H), 2.25 - 2.05 (m, 3H), 2.03 - 1.88 (m, 1H), 1.86 - 1.64 (m, 3H), 1.30 - 1.10 (m, 2H). Nuclear magnetic characterization of chiral isomer 2: 1 H NMR (400 MHz, DMSO-d 6) δ 10.77 (s,1H),8.84 (s,1H),8.20 - 8.00 (m,1H),7.98 - 7.87 (m,2H),7.74 (dd,1H),7.47 (d,1H),7.17 - 7.00 (m,2H),6.75 - 6.62 (m,2H),4.58 (s,2H),3.94 - 3.82 (m,1H),3.76 - 3.58 (m,9H),2.80 - 2.59 (m,6H),2.56 - 2.45 (m,1H),2.44 - 2.32 (m,4H),2.25 - 2.05 (m,3H),2.03 - 1.88 (m,1H),1.86 - 1.64 (m,3H),1.30 - 1.10 (m,2H).

[0230] Example 25: Preparation of trifluoroacetate of compound 25

Chemical formula

[0231] Step 1: Preparation of 25b To a 50 mL reaction flask, 25a (0.3 g, 1.15 mmol) (for the synthesis method, refer to WO2019119138), 2,4-dichloropyrimidine (0.21 g, 1.41 mmol), DIPEA (0.45 g, 3.48 mmol) and DMF (5 mL) were added respectively. The reaction system was purged with nitrogen gas three times and reacted at 80 °C for 2 h. The reaction system was cooled to room temperature, and a solid was precipitated. The solid was filtered, and the filter cake was washed with 6 mL of a mixed solvent of dichloromethane / methanol (v / v) = 2:1. The filter cake was dried under reduced pressure to obtain 25b (0.23 g, yield: 54%).

[0232] LCMS m / z = 374.1 [M+1] + .

[0233] Step 2: Preparation of trifluoroacetate of compound 25 To the reaction flask, add the trifluoroacetate salt of the above crude product 8c (70 mg), 25b (71 mg, 0.19 mmol), DIPEA (0.12 g, 0.93 mmol), and DMSO (5 mL) respectively. Replace the gas three times with nitrogen gas and react at 100 °C for 16 h. Cool the reaction system to room temperature and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparative method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Elute 50% of acetonitrile with a gradient of 10% (elution time 20 min), and lyophilize to obtain the trifluoroacetate salt (10.0 mg) of compound 25.

[0234] 1 H NMR (400MHz,DMSO-d 6 ) δ 9.36 (s,1H),8.01 - 7.88 (m,3H),7.67 (dd,1H),7.46 (d,1H),7.12 (s,1H),7.07 - 6.99 (m,2H),6.93 - 6.84 (m,2H),6.05 (d,1H),4.58 (s,2H),3.76 - 3.62 (m,10H),2.71 - 2.57 (m,6H),2.49 - 2.38 (m,5H),2.26 - 1.94 (m,4H),1.90 - 1.60 (m,3H),1.33 - 1.12 (m,2H).

[0235] LCMS m / z=355.0[M / 2+1] + .

[0236] Example 26: Preparation of Compound 26

Chemical formula

[0237] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 9.32 (s, 1H), 7.93 (d, 1H), 7.87 (d, 1H), 7.66 (dd, 1H), 7.44 (d, 1H), 7.08 - 6.98 (m, 3H), 6.93 - 6.84 (m, 2H), 6.04 (d, 1H), 4.91 (s, 2H), 3.80 - 3.58 (m, 10H), 2.72 - 2.57 (m, 3H), 2.50 - 2.35 (m, 5H), 2.26 - 1.94 (m, 7H), 1.90 - 1.61 (m, 3H), 1.33 - 1.14 (m, 2H).

[0238] LCMS m / z = 693.4 [M + 1] + .

[0239] Example 27: Preparation of the trifluoroacetate salt of compound 27 [Chemical formula]

[0240] Step 1: Preparation of 27b To the reaction flask were added 27a (5.00 g, 21.71 mmol), 4-bromo-1-fluoro-2-nitrobenzene (7.16 g, 32.55 mmol), cesium carbonate (21.22 g, 65.13 mmol) and 30 mL of DMSO, and the mixture was reacted at 110 °C for 2 h. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate and 50 mL of water were added, the pH was adjusted to 5 with 3 mol / L hydrochloric acid, the layers were separated, the aqueous phase was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to obtain 27b (7.6 g, yield: 81%).

[0241] Step 2: Preparation of 27c To the reaction flask were added 27b (6.60 g, 15.34 mmol), zinc powder (5.02 g, 77.234 mmol), ammonium chloride (8.21 g, 153.48 mmol) and 80 mL of ethanol, and the mixture was refluxed for 4 h. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. 50 mL of ethyl acetate and 50 mL of water were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography on silica gel (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain 27c (2.30 g, yield: 39%).

[0242] Step 3: Preparation of 27d To the reaction flask were added 27c (1.40 g, 3.66 mmol), 20 mL of 1,4-dioxane and 5 mL of water respectively. Under nitrogen gas protection, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.58 g, 10.98 mmol) (for the synthesis method, refer to WO2021262812), cesium carbonate (3.58 g, 10.99 mmol) and Pd(dppf)Cl 2 (0.27 g, 0.37 mmol) were added. The reaction system was purged with nitrogen gas three times and reacted at 100 °C for 16 h. The reaction system was cooled to room temperature, filtered through diatomaceous earth, 50 mL of ethyl acetate and 50 mL of water were added to the filtrate. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography on silica gel (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain 27d (2.0 g, yield: 92%).

[0243] Step 4: Preparation of 27e To the reaction flask were added 27d (2.0 g, 3.37 mmol), 40 mL of THF and 10% Pd / C (1.00 g) respectively, and the mixture was replaced with hydrogen gas three times. Then, the reaction was carried out at room temperature for 16 h under a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 27e (0.85 g, yield: 61%).

[0244] Step 5: Preparation of 27f To the reaction flask were added 27e (0.30 g, 0.72 mmol), 1.5 mL of trifluoroacetic acid and 5 mL of dichloromethane, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, and then it was concentrated under reduced pressure. 6 mL of THF was added to the residue, and tert-butyl 4-formylpiperidine-1-carboxylate (0.20 g, 0.94 mmol), 0.5 mL of acetic acid and sodium triacetoxyborohydride (0.31 g, 1.46 mmol) were added in sequence, and the reaction was carried out at room temperature for 16 h. 10 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate solution were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (5 mL×3), the organic phases were combined, the organic phase was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 27f (0.31 g, yield: 84%).

[0245] LCMS m / z = 512.3 [M+1] + 。

[0246] Step 6: Preparation of trifluoroacetate of 27g To the reaction flask were added 27f (0.31 g, 0.61 mmol), 1.5 mL of trifluoroacetic acid and 5 mL of dichloromethane, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of crude product 27g (0.38 g).

[0247] Step 7: Preparation of trifluoroacetate of compound 27 To the reaction flask, 27 g of the above crude product as trifluoroacetate (0.19 g), DIPEA (0.47 g, 3.64 mmol), and 5 mL of DMSO were added respectively. After stirring at room temperature for 0.5 h, 4B (0.12 g, 0.29 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and then freeze-dried to obtain 66 mg of the trifluoroacetate of compound 27.

[0248] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.81 (s,2H),8.99 (s,1H),8.09 (s,1H),8.02 - 7.89 (m,2H),7.75 (dd,1H),7.47 (d,1H),7.12 (s,1H),6.93 - 6.82 (m,2H),6.76 - 6.69 (m,1H),4.59 (s,2H),4.54 - 4.40 (m,2H),4.00 - 3.62 (m,8H),3.35 - 2.86 (m,7H),2.74 - 2.58 (m,4H),2.54 - 2.42 (m,1H),2.35 - 1.92 (m,3H),1.89 - 1.71 (m,2H),1.30 - 1.10 (m,2H).

[0249] LCMS m / z=392.2[M / 2+1] + .

[0250] Example 28: Preparation of Compound 28

Chemical formula

[0251] Step 1: Preparation of 28a 27c (1.3 g, 3.40 mmol), iodomethane (1.45 g, 10.22 mmol), cesium carbonate (3.32 g, 10.19 mmol) and 30 mL of DMF were added to a reaction flask and reacted at room temperature for 16 h. The reaction solution was cooled to room temperature, 20 mL of ethyl acetate and 20 mL of water were added, and liquid separation was performed. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain 28a (1.25 g, yield: 93%).

[0252] Step 2: Preparation of 28b 28a (1.30 g, 3.28 mmol), 20 mL of 1,4-dioxane and 5 mL of water were respectively added to a reaction flask. Under the protection of nitrogen gas, 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.11 g, 9.85 mmol) (for the synthesis method, refer to WO2021262812), cesium carbonate (3.21 g, 9.85 mmol) and Pd(dppf)Cl 2 (0.24 g, 0.33 mmol) were added, replaced three times with nitrogen gas, and reacted at 100 °C for 16 h. The reaction system was cooled to room temperature, diatomaceous earth was laid and filtered. 50 mL of ethyl acetate and 50 mL of water were added to the filtrate. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain 28b (1.80 g, yield: 90%).

[0253] Step 3: Preparation of 28c To the reaction flask, 28b (1.8 g, 2.97 mmol), 40 mL of THF and 10% Pd / C (0.9 g) were added respectively, and the system was purged with hydrogen gas three times. The reaction was carried out at room temperature for 16 h under a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 28c (0.90 g, yield: 71%).

[0254] Step 4: Preparation of 28d To the reaction flask, 28c (0.30 g, 0.70 mmol), 1.5 mL of trifluoroacetic acid and 5 mL of dichloromethane were added, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, and then concentrated under reduced pressure. 6 mL of THF was added, and tert-butyl 4-formylpiperidine-1-carboxylate (0.19 g, 0.891 mmol), 0.5 mL of acetic acid and sodium triacetoxyborohydride (0.30 g, 1.42 mmol) were added in sequence. The reaction was carried out at room temperature for 16 h. 10 mL of ethyl acetate and 10 mL of saturated aqueous sodium bicarbonate solution were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 28d (0.30 g, yield: 82%).

[0255] LCMS m / z = 526.3 [M+1] + 。

[0256] Step 5: Preparation of the trifluoroacetate salt of 28e To the reaction flask, 28d (0.30 g, 0.57 mmol), 1.5 mL of trifluoroacetic acid and 5 mL of dichloromethane were added, and the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 28e (0.36 g).

[0257] Step 6: Preparation of compound 28 To the reaction flask were added trifluoroacetate (0.18 g) of the above crude product 28e, DIPEA (0.43 g, 3.30 mmol), and 5 mL of DMSO, respectively. After stirring at room temperature for 0.5 h, 4B (0.11 g, 0.27 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and freeze-dried to obtain compound 28 (70 mg, yield: 33%).

[0258] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.78 (s,1H),8.79 (s,1H),8.03 (s,1H),7.98 - 7.88 (m,2H),7.77 (dd,1H),7.47 (d,1H),7.10 (s,1H),6.98 - 6.92 (m,1H),6.91 - 6.77 (m,2H),4.63 - 4.41 (m,4H),3.85 - 3.74 (m,1H),3.73 - 3.63 (m,3H),3.58 - 3.47 (m,1H),3.47 - 3.37 (m,1H),3.25 (s,3H),3.00 - 2.78 (m,3H),2.76 - 2.58 (m,5H),2.56 - 2.43 (m,2H),2.34 - 2.16 (m,3H),2.14 - 1.95 (m,3H),1.90 - 1.70 (m,3H),1.15 - 0.97 (m,2H).

[0259] LCMS m / z=399.5[M / 2+1] + .

[0260] Example 29: Preparation of Compound 29

Chemical formula

[0261] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.78 (s,1H),10.46 (s,1H),8.79 (s,1H),8.03 (s,1H),7.90 (d,1H),7.72 (dd,1H),7.45 (d,1H),7.02 (s,1H),6.83 - 6.73 (m,2H),6.66 (s,1H),4.89 (s,2H),4.55 - 4.40 (m,2H),3.77 - 3.68 (m,1H),3.66 (s,3H),3.63 - 3.51 (m,1H),3.47 - 3.37 (m,1H),3.30 - 3.22 (m,1H),2.99 - 2.77 (m,3H),2.75 - 2.57 (m,2H),2.50 - 2.41 (m,1H),2.30 - 2.21 (m,2H),2.18 (s,3H),2.14 - 1.92 (m,4H),1.90 - 1.65 (m,3H),1.14 - 0.96 (m,2H).

[0262] LCMS m / z=384.6[M / 2+1] + 。

[0263] Example 30: Preparation of Compound 30 [Chemical formula] To the reaction flask, add the trifluoroacetate of the above crude product 28e (0.18 g), DIPEA (0.43 g, 3.30 mmol), and 5 mL of DMSO respectively. After stirring at room temperature for 0.5 h, add 30A (0.10 g, 0.26 mmol) (for the synthesis method, refer to WO2021077010), and react at 100 °C for 7 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Elute 70% of acetonitrile with a gradient of 10% (elution time 12 min), and lyophilize to obtain Compound 30 (20 mg, yield: 10%).

[0264] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 8.79 (s, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 7.72 (dd, 1H), 7.45 (d, 1H), 7.02 (s, 1H), 6.98 - 6.92 (m, 1H), 6.91 - 6.78 (m, 2H), 4.89 (s, 2H), 4.56 - 4.40 (m, 2H), 3.85 - 3.75 (m, 1H), 3.66 (s, 3H), 3.58 - 3.48 (m, 1H), 3.42 (dd, 1H), 3.37 - 3.28 (m, 1H), 3.25 (s, 3H), 3.02 - 2.77 (m, 3H), 2.77 - 2.57 (m, 2H), 2.55 - 2.42 (m, 1H), 2.35 - 2.14 (m, 6H), 2.14 - 1.95 (m, 3H), 1.92 - 1.65 (m, 3H), 1.14 - 0.95 (m, 2H).

[0265] LCMS m / z = 391.7 [M / 2 + 1] + 。

[0266] Example 31: Preparation of Trifluoroacetate Salt of Compound 31

Chem.

[0267] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 2H), 8.94 (s, 1H), 8.08 (s, 1H), 8.02 - 7.90 (m, 2H), 7.75 (dd, 1H), 7.47 (d, 1H), 7.12 (s, 1H), 6.93 - 6.81 (m, 2H), 6.73 (s, 1H), 4.59 (s, 2H), 4.54 - 4.40 (m, 2H), 4.05 - 3.45 (m, 8H), 3.34 - 2.85 (m, 7H), 2.74 - 2.57 (m, 4H), 2.55 - 2.40 (m, 1H), 2.37 - 1.93 (m, 3H), 1.88 - 1.70 (m, 2H), 1.30 - 1.10 (m, 2H).

[0268] LCMS m / z = 392.4 [M / 2 + 1] + 。

[0269] Example 32: Preparation of Trifluoroacetate Salt of Compound 32

Chem.

[0270] 1 H NMR (400 MHz, DMSO-d 6) δ 10.81 (s,1H),9.07 (s,1H),8.11 (s,1H),8.04 - 7.86 (m,2H),7.79 - 7.69 (m,1H),7.47 (d,1H),7.12 (s,1H),7.05 (s,1H),6.99 - 6.90 (m,2H),4.59 (s,2H),4.52 - 4.39 (m,2H),4.03 - 3.71 (m,5H),3.68 (s,3H),3.37 - 2.88 (m,10H),2.74 - 2.61 (m,4H),2.58 - 2.47 (m,1H),2.37 - 2.13 (m,2H),2.08 - 1.93 (m,1H),1.90 - 1.72 (m,2H),1.30 - 1.10 (m,2H).

[0271] LCMS m / z=399.4[M / 2+1] + .

[0272] Example 33: Preparation of the trifluoroacetate salt of compound 33 [Chemical formula]

[0273] Step 1: Preparation of 33b 33a (9.90 g, 51.53 mmol), bromomethylcyclopropane (10.43 g, 77.26 mmol), potassium carbonate (17.80 g, 128.8 mmol) and 100 mL of DMF were added to a reaction flask and reacted at room temperature for 16 h. 100 mL of ethyl acetate and 100 mL of saturated aqueous sodium chloride solution were added to the reaction solution, the pH was adjusted to 6 with 1 mol / L hydrochloric acid solution, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, the organic phase was washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (12 g). The above crude product (12 g), DIPEA (11.74 g, 90.83 mmol), HATU (18.99 g, 49.94 mmol) and 200 mL of dichloromethane were added to a reaction flask respectively and reacted at room temperature for 2 h. 100 mL of water was added to the reaction solution, liquid separation was carried out, the aqueous phase was extracted with dichloromethane (50 mL × 2), the organic phases were combined, the organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain 33b (5.2 g, two-step yield: 41%).

[0274] LCMS m / z = 247.0 [M+1] + 。

[0275] Step 2: Preparation of 33c 33b (5.2 g, 21.14 mmol), triethylamine (4.45 g, 43.98 mmol) and 100 mL of ethanol were added to a reaction flask. Under nitrogen gas protection, a solution of 2 mol / L trimethylsilyldiazomethane in n - hexane (22.00 mL, 44 mmol) was added dropwise, and the mixture was reacted at room temperature for 3 h. 300 mL of ethyl acetate and 300 mL of saturated aqueous sodium chloride solution were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (petroleum ether:ethyl acetate (v / v)=1:1) to obtain 33c (3.1 g, yield: 53%).

[0276] LCMS m / z = 275.1[M + 1] + 。

[0277] Step 3: Preparation of 33d 33c (3.1 g, 11.30 mmol) and 50 mL of dichloromethane were added to a reaction flask. Under nitrogen gas protection, the temperature was lowered to 0 °C, and a solution of 1 mol / L boron tribromide in dichloromethane (33.90 mL, 33.90 mmol) was added dropwise, and the mixture was reacted at room temperature for 2 h. 30 mL of dichloromethane was added to the reaction solution, and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a silica gel chromatography column (petroleum ether:ethyl acetate (v / v)=1:1) to obtain 33d (2.3 g, yield: 78%).

[0278] LCMS m / z = 261.2[M + 1] + 。

[0279] Step 4: Preparation of 33e 33d (2.1 g, 8.07 mmol), cesium carbonate (5.26 g, 16.14 mmol), 2-bromo-N-methylacetamide (1.47 g, 9.67 mmol) and 40 mL of DMF were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was poured into 200 mL of ice water, filtered, and the filter cake was washed with 10 mL of water to obtain crude product 33e (9.0 g).

[0280] Step 5: Preparation of 33f The above crude product 33e (9.0 g), 70 mL of dichloromethane, 70 mL of methanol and 10% Pd / C (1.6 g) were added to a reaction flask, replaced with hydrogen gas three times, and reacted at room temperature for 16 h under a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain crude product 33f (2.1 g).

[0281] LCMS m / z = 302.3 [M+1] + 。

[0282] Step 6: Preparation of 33g The above crude product 33f (2.1 g), 2,4,5-trichloropyrimidine (1.53 g, 8.34 mmol) and 30 mL of DMF were added to a reaction flask and reacted at 70 °C for 2 h. The reaction solution was cooled to room temperature, poured into 150 mL of ice water, filtered, and the filter cake was washed with 20 mL of water. The filter cake was dried by blowing air at 50 °C to obtain crude product 33g (2.9 g).

[0283] Step 7: Preparation of the trifluoroacetate salt of compound 33 To the reaction flask were added trifluoroacetate (0.25 g) of the above crude product 8c, DIPEA (0.67 g, 5.18 mmol), and 5 mL of DMSO respectively. After stirring at room temperature for 0.5 h, the above crude product 33 g (0.19 g) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and then freeze-dried to obtain trifluoroacetate (200 mg) of compound 33.

[0284] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.83 - 10.77 (m,1H),9.16 - 9.06 (m,1H),8.19 - 8.14 (m,1H),8.05 - 7.91 (m,2H),7.77 - 7.69 (m,1H),7.65 - 7.58 (m,1H),7.27 - 7.09 (m,5H),4.65 - 4.40 (m,4H),4.30 - 4.18 (m,2H),3.88 - 3.50 (m,5H),3.45 - 3.22 (m,2H),3.20 - 2.88 (m,6H),2.74 - 2.57 (m,4H),2.55 - 2.43 (m,1H),2.28 - 1.80 (m,5H),1.60 - 1.18 (m,3H),0.54 - 0.40 (m,4H).

[0285] LCMS m / z=391.7[M / 2+1] + .

[0286] Example 34: Preparation of trifluoroacetate of compound 34

Chemical formula

[0287] Step 1: Preparation of 34b To a reaction flask were added 34a (1.50 g, 7.81 mmol), 12 mL of acetone and 6 mL of water. Under the protection of nitrogen gas, sodium azide (2.55 g, 39.2 mmol) was added, and the reaction was carried out at room temperature for 16 h. The reaction solution was cooled to room temperature, 30 mL of ethyl acetate and 50 mL of saturated aqueous sodium chloride solution were added, and liquid separation was performed. The aqueous phase was extracted with ethyl acetate (15 mL×2). The organic phases were combined, the organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and crude product 34b (0.92 g) was obtained.

[0288] Step 2: Preparation of 34c To a reaction flask were respectively added the above crude product 34b (0.20 g), 1-Boc-4-ethynylpiperidine (0.33 g, 1.58 mmol), anhydrous copper sulfate (0.02 g, 0.125 mmol), sodium ascorbate (0.10 g, 0.505 mmol), 3 mL of THF and 1 mL of water, and the reaction was carried out at room temperature for 3 h. The reaction system was filtered, 10 mL of ethyl acetate and 10 mL of water were added to the filtrate, the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, the organic phase was washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (dichloromethane:methanol (v / v)=10:1) to obtain 34c (0.45 g, yield: 78%).

[0289] Step 3: Preparation of 34d 34c (0.45 g, 1.24 mmol), 2 mL of trifluoroacetic acid and 5 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 7 with triethylamine, concentrated under reduced pressure, 10 mL of THF was added, tert-butyl 4-formylpiperidine-1-carboxylate (0.29 g, 1.36 mmol), 0.5 mL of acetic acid and sodium triacetoxyborohydride (0.53 g, 2.50 mmol) were added in sequence, and reacted at room temperature for 16 h. 20 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate solution were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phase was washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (dichloromethane:methanol (v / v)=5:1) to obtain 34d (0.38 g, yield: 67%).

[0290] Step 4: Preparation of trifluoroacetate of 34e 34d (0.19 g, 0.41 mmol), 1 mL of trifluoroacetic acid and 3 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of crude product 34e (0.23 g).

[0291] Step 5: Preparation of trifluoroacetate of compound 34 To the reaction flask, add the trifluoroacetate of the above crude product 34e (0.38 g), DIPEA (0.62 g, 4.8 mmol), and 5 mL of DMSO respectively. After stirring at room temperature for 0.5 h, add 4B (0.16 g, 0.39 mmol), and react at 100 °C for 7 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Elute 50% of acetonitrile with a gradient of 10% (elution time 15 min), and lyophilize to obtain the trifluoroacetate of compound 34 (60 mg).

[0292] 1 H NMR (400MHz,DMSO-d 6 ) δ 11.23 (s,1H),9.09 - 8.97 (m,1H),8.17 - 7.89 (m,4H),7.88 - 7.68 (m,1H),7.47 (d,1H),7.12 (s,1H),5.84 - 5.72 (m,1H),4.60 (s,2H),4.53 - 4.40 (m,2H),3.74 - 3.55 (m,5H),3.26 - 2.77 (m,8H),2.75 - 2.55 (m,5H),2.37 - 1.69 (m,8H),1.30 - 1.05 (m,2H).

[0293] LCMS m / z=732.9[M+1] + 。

[0294] Example 35: Preparation of Compound 35

Chemical formula

[0295] Step 1: Preparation of 35b 35a (see the synthesis method in Bioorg. Med. Chem., 2016, 26, 5877) (1.50 g, 4.08 mmol), 35A (see the synthesis method in WO2022171123) (3.41 g, 8.16 mmol), Pd(dppf)Cl 2 ·DCM (0.33 g, 0.41 mmol) and cesium carbonate (2.66 g, 8.16 mmol) were sequentially added to the reaction flask, 1,4-dioxane (30 mL) and water (3 mL) were added, replaced with nitrogen gas three times, and reacted at 100 °C for 20 h. The reaction system was cooled to room temperature, 200 mL of water and 200 mL of ethyl acetate were added, separated, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phases were combined, the combined organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 9:1) to obtain 35b (2.36 g, yield: >99%).

[0296] Step 2: Preparation of 35c 35b (0.95 g, 1.64 mmol) was dissolved in THF (30 mL), 10% palladium on carbon (0.87 g) was added, replaced with hydrogen gas three times, and reacted at 45 °C for 20 h in a hydrogen gas balloon atmosphere. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (methanol:dichloromethane (v / v) = 0:1 to 5:95) to obtain 35c (0.60 g, yield: 92%).

[0297] LCMS m / z = 400.4 [M+1] + 。

[0298] Step 3: Preparation of 35d 35c (600 mg, 1.50 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and concentrated under reduced pressure to obtain the crude product 35d (450 mg).

[0299] LCMS m / z = 300.4 [M+1] + 。

[0300] Step 4: Preparation of 35e The above crude product 35d (0.45 g) was dissolved in dichloroethane (30 mL), tert-butyl 4-formylpiperidine-1-carboxylate (0.48 g, 2.25 mmol) was added, 3 mL of acetic acid was added, and after stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.64 g, 3.0 mmol) was added and reacted at room temperature for 16 h. 50 mL of saturated aqueous sodium hydrogen carbonate solution was slowly added to the reaction solution, and the mixture was extracted twice with 50 mL of dichloromethane. The organic phase was washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 35e (0.33 g, yield: 30%).

[0301] LCMS m / z = 497.3 [M+1] + 。

[0302] Step 5: Preparation of the trifluoroacetate salt of 35f 35e (100 mg, 6.65 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude product 35f (100 mg).

[0303] LCMS m / z = 397.3 [M+1] + 。

[0304] Step 6: Preparation of Compound 35 To the reaction flask, add the trifluoroacetate of the above crude product 35f (100 mg), DIPEA (200 mg, 1.55 mmol), and 15 mL of DMSO, respectively. Add 4B (80 mg, 0.20 mmol), and react at 100 °C for 7 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: aqueous ammonium acetate solution (5 mmol / L) / acetonitrile. Gradient elution method: Elute 70% of acetonitrile with a gradient of 10% (elution time 12 min), and lyophilize to obtain compound 35 (10 mg, yield: 7%).

[0305] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.72 (s, 1H), 8.80 (s, 1H), 8.08 - 7.86 (m, 3H), 7.77 (dd, 1H), 7.47 (d, 1H), 7.12 (s, 1H), 6.90 - 6.70 (m, 3H), 4.64 - 4.38 (m, 4H), 3.78 - 3.60 (m, 6H), 2.97 - 2.55 (m, 12H), 2.50 - 2.37 (m, 1H), 2.22 - 1.92 (m, 5H), 1.90 - 1.50 (m, 5H), 1.14 - 0.94 (m, 2H).

[0306] LCMS m / z = 768.3[M+1] + .

[0307] Example 36: Preparation of trifluoroacetate of compound 36

Chemical formula

[0308] Step 1: Preparation of 36a and 36b To the reaction flask, 33a (10 g, 52.05 mmol), cyclopropylboronic acid (8.94 g, 104.07 mmol), sodium carbonate (11.03 g, 104.07 mmol), 2,2'-bipyridine (8.13 g, 52.06 mmol), copper(II) acetate anhydrous (9.45 g, 52.03 mmol) and 1,2-dichloroethane (200 mL) were added, and the reaction was carried out at 70 °C for 16 h under an air atmosphere. The reaction solution was cooled to room temperature, 200 mL of aqueous ammonium chloride solution was added, the pH was adjusted to 6 with 1 mol / L hydrochloric acid, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, the combined organic phase was washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (first eluted with petroleum ether:ethyl acetate (v / v) = 2:1, and then eluted with dichloromethane:methanol (v / v) = 5:1) to obtain 36b (0.79 g, yield: 7%) and crude 36a (3.5 g), respectively.

[0309] Step 2: Preparation of 36b from 36a To the reaction flask, the above crude 36a (3.5 g), DIPEA (5.42 g, 41.93 mmol), HATU (7.98 g, 20.99 mmol) and 100 mL of dichloromethane were added respectively, and the reaction was carried out at room temperature for 2 h. 100 mL of water was added to the reaction solution, liquid separation was performed, the aqueous phase was extracted with dichloromethane (50 mL × 2), the organic phases were combined, the combined organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain 36b (1.2 g, two-step yield from compound 33a: 10%).

[0310] The trifluoroacetate salt of compound 36 was obtained by freeze-drying by acid fractionation (water (containing 0.1% TFA) / acetonitrile) with compound 36b as the raw material with reference to the synthesis method of Example 33.

[0311] 1 H NMR (400MHz,DMSO-d6 ) δ 10.78 (s, 1H), 9.06 (s, 1H), 8.15 (s, 1H), 8.04 - 7.93 (m, 1H), 7.93 - 7.84 (m, 1H), 7.83 - 7.73 (m, 1H), 7.72 - 7.63 (m, 1H), 7.23 - 7.04 (m, 5H), 4.64 - 4.40 (m, 4H), 3.86 - 3.50 (m, 5H), 3.45 - 3.21 (m, 2H), 3.17 - 2.82 (m, 7H), 2.75 - 2.57 (m, 4H), 2.55 - 2.40 (m, 1H), 2.24 - 1.82 (m, 5H), 1.55 - 1.20 (m, 4H), 0.87 - 0.73 (m, 2H).

[0312] LCMS m / z = 385.0 [M / 2 + 1] + .

[0313] Example 37: Preparation of trifluoroacetate of compound 37 [Chemical formula]

[0314] Step 1: Preparation of 37b To the reaction flask were added 37a (10.0 g, 52.05 mmol) and 100 mL of DMF respectively, cooled to 0 °C, sodium hydride (60%, 3.12 g) was added little by little, after reacting at room temperature for 30 min, 1-bromo-2-butyne (10.38 g, 78.05 mmol) was added dropwise, and the reaction was carried out at room temperature for 16 h. The reaction solution was poured into 300 mL of ice water, filtered, the filter cake was washed with 100 mL of water, the filter cake was collected, and the filter cake was dried under reduced pressure to obtain crude 37b (8.20 g).

[0315] Step 2: Preparation of 37c To a reaction flask were added 37b (8.20 g, 33.58 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.02 g, 6.70 mmol), ethyl diazoacetate (4.84 g, 42.42 mmol) and 150 mL of ethanol respectively, and the mixture was reacted at room temperature for 3 h. Then, rhodium(II) diacetate (74 mg, 0.167 mmol) was added and the reaction was continued at room temperature for 16 h. The reaction system was filtered, the filter cake was collected, washed with 50 mL of ethanol, collected again, and dried under reduced pressure to obtain crude product 37c (4.92 g).

[0316] Step 3: Preparation of 37d To a reaction flask were added the above crude product 37c (4.00 g), sodium hydroxide (1.94 g, 48.5 mmol) and 100 mL of water respectively, and the mixture was refluxed for 16 h. The reaction system was cooled to room temperature, the pH was adjusted to 1 with 1 mol / L hydrochloric acid, filtered, the filter cake was collected, washed with 50 mL of water, collected again, and dried under reduced pressure to obtain crude product 37d (4.03 g).

[0317] LCMS m / z = 303.2 [M+1] + 。

[0318] Step 4: Preparation of 37e To a reaction flask were added the above crude product 37d (4.03 g), lithium chloride (1.70 g, 40.1 mmol), 7 mL of water and 70 mL of DMSO respectively, and the mixture was reacted at 130 °C for 3 h. The reaction system was cooled to room temperature, poured into 300 mL of water, filtered, the filter cake was collected, washed with 100 mL of water, collected again, and dried under reduced pressure to obtain crude product 37e (3.50 g).

[0319] The trifluoroacetate salt of compound 37 was obtained by using compound 37e as a raw material, referring to the synthesis method of Example 33, and performing freeze-drying by acidic fractionation (water (containing 0.1% TFA) / acetonitrile).

[0320] 11H NMR (400 MHz, DMSO-d 6 ) δ 10.76 (s, 1H), 9.06 (s, 1H), 8.16 (s, 1H), 7.99 - 7.91 (m, 2H), 7.73 (dd, 1H), 7.51 (d, 1H), 7.17 (s, 1H), 7.12 - 7.04 (m, 2H), 7.01 - 6.90 (m, 2H), 5.13 - 5.02 (m, 2H), 4.60 (s, 2H), 4.57 - 4.42 (m, 2H), 3.78 - 3.65 (m, 3H), 3.63 - 3.51 (m, 2H), 3.40 - 3.25 (m, 2H), 3.17 - 2.98 (m, 4H), 2.82 - 2.56 (m, 6H), 2.50 - 2.40 (m, 1H), 2.20 - 1.95 (m, 3H), 1.90 - 1.78 (m, 2H), 1.78 - 1.73 (m, 3H), 1.45 - 1.27 (m, 2H). LCMS m / z = 780.3 [M+1] + .

[0321] Example 38: Preparation of Trifluoroacetate Salt of Compound 38

Chem.

[0322] Step 1: Preparation of 38b To the reaction flask were added 38a (10.0 g, 52.05 mmol) and 100 mL of DMF respectively, cooled to 0 °C, and 60% sodium hydride (3.12 g) was added portionwise. After reacting at room temperature for 30 min, 3-bromo-1-trimethylsilyl-1-propyne (14.92 g, 78.06 mmol) was added dropwise, and the reaction was carried out at room temperature for 16 h. The reaction solution was poured into 300 mL of ice water, filtered, the filter cake was washed with 100 mL of water, the filter cake was collected, and the filter cake was dried under reduced pressure to obtain crude 38b (8.40 g).

[0323] Step 2: Preparation of 38c To the reaction flask, the above crude product 38b (0.50 g) and 7 mL of ethanol were added respectively. While stirring, triethylamine (0.37 g, 3.66 mmol) and an n - hexane solution of 2 mol / L trimethylsilyldiazomethane (1.81 mL, 3.62 mmol) were added, and the reaction was carried out at room temperature for 3 h. 30 mL of water was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, the organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether:ethyl acetate (v / v)=4:1) to obtain 38c (0.25 g, two - step yield from compound 38a: 24%).

[0324] LCMS m / z = 331.1[M + 1] + 。

[0325] Step 3: Preparation of 38d To the reaction flask, 38c (0.25 g, 0.76 mmol) and 2 mL of dichloromethane were added respectively, cooled to 0 °C, and a dichloromethane solution of 1 mol / L boron tribromide (2.28 mL) was added dropwise, and the reaction was carried out at room temperature for 2 h. 10 mL of saturated aqueous sodium hydrogen carbonate solution was added to the reaction system, the aqueous phase was extracted with ethyl acetate (30 mL×2), the organic phases were combined, the organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 38d (0.05 g).

[0326] The trifluoroacetate of compound 38 was obtained by using compound 38d as the raw material, referring to the synthesis method of Example 33, and performing freeze - drying by acidic fractionation (water (containing 0.1% TFA) / acetonitrile).

[0327] 1 H NMR (400MHz,DMSO - d 6) δ 10.76 (s,1H), 9.07 (s,1H), 8.16 (s,1H), 8.02 - 7.90 (m,2H), 7.73 (dd,1H), 7.52 (d,1H), 7.19 (s,1H), 7.13 - 7.04 (m,2H), 7.02 - 6.90 (m,2H), 5.18 - 5.10 (m,2H), 4.64 - 4.57 (m,2H), 4.56 - 4.40 (m,2H), 3.80 - 3.65 (m,3H), 3.65 - 3.50 (m,2H), 3.40 - 3.25 (m,3H), 3.17 - 2.97 (m,4H), 2.84 - 2.57 (m,6H), 2.50 - 2.41 (m,1H), 2.20 - 1.93 (m,3H), 1.90 - 1.77 (m,2H), 1.44 - 1.27 (m,2H).

[0328] LCMS m / z = 383.8 [M / 2 + 1] + .

[0329] Example 39: Preparation of Compound 39

Chemical Structure

[0330] Step 1: Preparation of 39b Dissolve 39a (0.25 g, 0.82 mmol) (for the synthesis method, refer to WO2021113557) in DMSO (3 mL), add 2-iodobenzoylbenzoic acid (0.37 g, 1.32 mmol), and react at 55 °C for 2 h. Cool the reaction system to room temperature, add water (100 mL), extract with 100 mL of ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 39b (0.24 g).

[0331] LCMS m / z = 302.3 [M + 1] + .

[0332] Step 2: Preparation of 39c The crude product 39b (0.24 g) was dissolved in 1,2-dichloroethane (30 mL), tert-butyl piperazine-1-carboxylate (0.22 g, 1.18 mmol) was added, 0.3 mL of acetic acid was added, and the reaction was carried out at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.56 g, 2.64 mmol) was added, and the reaction was carried out at room temperature for 16 h. 50 mL of saturated aqueous sodium hydrogen carbonate solution was slowly added to the reaction solution, and the mixture was extracted with 30 mL of dichloromethane. The organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v:v) = 10:1) to obtain 39c (0.20 g, yield: 36%).

[0333] LCMS m / z=472.6[M+1] + 。

[0334] Step 3: Preparation of trifluoroacetate of 39d 39c (200 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate of crude product 39d (200 mg).

[0335] LCMS m / z =372.3[M+1] + 。

[0336] Step 4: Preparation of compound 39 To the reaction flask, add the trifluoroacetate (200 mg) of the above crude product 39d, DIPEA (140 mg, 1.08 mmol), and 10 mL of DMSO respectively. Add 4B (150 mg, 0.375 mmol) (for the synthesis method, refer to WO2021077010), and react at 100 °C for 7 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparative method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Elute 70% of acetonitrile with a gradient of 10% (elution time 12 min), and lyophilize to obtain compound 39 (30 mg, yield: 11%).

[0337] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.77 (s,1H),8.84 (s,1H),8.05 (s,1H),7.98 - 7.86 (m,3H),7.74 (dd,1H),7.47 (d,1H),7.35 (dd,1H),7.12 (s,1H),6.77 (d,1H),4.58 (s,2H),4.34 - 4.17 (m,2H),3.79 - 3.55 (m,8H),2.85 - 2.60 (m,6H),2.57 - 2.45 (m,1H),2.45 - 2.30 (m,4H),2.25 - 2.10 (m,3H),2.04 - 1.92 (m,1H),1.88 - 1.70 (m,3H),1.17 - 0.98 (m,2H).

[0338] LCMS m / z=743.3[M+1] + .

[0339] Example 40: Preparation of trifluoroacetate of compound 40

Chemical formula

[0340] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.77 (s,1H),9.05 (s,1H),8.15 (s,1H),8.00 - 7.91 (m,1H),7.91 - 7.84 (m,1H),7.73 (dd,1H),7.48 (d,1H),7.19 (s,1H),7.02 - 6.84 (m,2H),6.51 (t,1H),4.63 - 4.42 (m,4H),4.15 - 4.02 (m,2H),3.84 - 3.60 (m,6H),3.55 - 3.42 (m,4H),3.33 - 2.95 (m,5H),2.72 - 2.56 (m,4H),2.53 - 2.42 (m,1H),2.24 - 2.06 (m,1H),2.04 - 1.89 (m,1H).

[0341] LCMS m / z=732.8[M+1] + .

[0342] Example 41: Preparation of the trifluoroacetate salt of Compound 41

Chemical Structure

[0343] 1 H NMR (400MHz,DMSO-d 6) δ 10.79 (s,1H),9.06 (s,1H),8.15 (s,1H),8.03 - 7.85 (m,2H),7.72 (dd,1H),7.48 (d,1H),7.18 (s,1H),7.07 - 6.92 (m,3H),4.59 (s,2H),4.56 - 4.40 (m,2H),3.85 - 3.76 (m,1H),3.69 (s,3H),3.65 - 3.52 (m,2H),3.45 - 3.25 (m,4H),3.20 - 2.95 (m,4H),2.77 - 2.60 (m,6H),2.55 - 2.44 (m,1H),2.27 - 2.10 (m,1H),2.10 - 1.94 (m,2H),1.94 - 1.80 (m,2H),1.51 - 1.33 (m,2H).

[0344] LCMS m / z=760.3[M+1] + .

[0345] Example 42: Preparation of the trifluoroacetate salt of Compound 42 [Chemical formula] To a reaction flask were added the trifluoroacetate salt (0.17 g) of the above crude product 8c, DIPEA (0.30 g, 2.32 mmol), and 5 mL of DMSO, respectively. Then, 42A (0.20 g, 0.46 mmol) (for the synthesis method, refer to WO2022221673) was added, and the mixture was reacted at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and then lyophilized to obtain the trifluoroacetate salt (150 mg) of Compound 42.

[0346] 11H NMR (400 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 9.05 (s, 1H), 8.15 (s, 1H), 8.00 - 7.86 (m, 2H), 7.75 - 7.60 (m, 2H), 7.20 - 6.93 (m, 5H), 5.60 - 5.00 (m, 1H), 4.68 - 4.38 (m, 4H), 3.82 - 3.51 (m, 5H), 3.43 - 3.25 (m, 2H), 3.20 - 2.97 (m, 4H), 2.93 - 2.73 (m, 2H), 2.72 - 2.58 (m, 4H), 2.51 - 2.42 (m, 1H), 2.24 - 1.95 (m, 3H), 1.94 - 1.80 (m, 2H), 1.58 (d, 6H), 1.48 - 1.31 (m, 2H).

[0347] LCMS m / z = 385.8 [M / 2 + 1] + .

[0348] Example 43: Preparation of trifluoroacetate of compound 43 [Chemical formula]

[0349] Step 1: Preparation of chiral isomers 1 and 2 of 43a 43a (for the synthesis method, refer to WO2022007866) was chirally resolved. The chiral resolution method is as follows.

[0350] 1. Instrument: SFC Prep 150 AP, chromatography column: Daicel AD-H (19 mm × 250 mm).

[0351] 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution.

[0352] 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: Mobile phase A: CO 2, Mobile Phase B: Methanol, b. Isocratic elution, the content of Mobile Phase B is 25%, c. The flow rate is 40 mL / min.

[0353] Peak time: Chiral isomer 1: 4.65 min, Chiral isomer 2: 5.85 min.

[0354] Chiral isomer 1 and chiral isomer 2 of compound 43a are each one of the isomers of structure 43a-1 or 43a-2.

[0355] Step 2: Preparation of 43b Chiral isomer 2 of 43a (0.55 g, 2.92 mmol) was dissolved in dichloromethane (30 mL), Boc 2 O (1.27 g, 5.82 mmol) was added, DMAP (0.71 g, 5.81 mmol) was added, and the reaction was carried out at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 to 1:9) to obtain 43b (0.78 g, yield: 93%).

[0356] LCMS m / z = 289.3 [M+1] + 。

[0357] Compound 43b is one of the isomers of structure 43b-1 or 43b-2.

[0358] Step 3: Preparation of 43c 43b (0.78 g, 2.71 mmol) was dissolved in acetonitrile (20 mL), NBS (0.53 g, 2.98 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 to 1:9) to obtain 43c (0.85 g, yield: 86%).

[0359] LCMS m / z = 367.3 [M+1] + 。

[0360] Compound 43c is one of the isomers of structure 43c-1 or 43c-2.

[0361] Step 4: Preparation of 43d 43c (1.50 g, 4.10 mmol), 43A (2.89 g, 6.93 mmol) (for the synthesis method, refer to WO2022235945), Pd(dppf)Cl 2 ·DCM (0.19 g, 0.23 mmol) and cesium carbonate (1.51 g, 4.63 mmol) were added to the reaction flask, 1,4-dioxane (30 mL) and water (3 mL) were added, and the reaction was carried out at 100 °C for 20 h under a nitrogen gas atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 9:1) to obtain 43d (0.55 g, yield: 23%).

[0362] Compound 43d is one of the isomers of structure 43d-1 or 43d-2.

[0363] Step 5: Preparation of 43e 43d (0.55 g, 0.95 mmol) was dissolved in THF (20 mL), 10% palladium on carbon (0.51 g) was added, and the reaction was carried out at 45 °C for 20 h under a hydrogen gas balloon atmosphere. The reaction system was cooled to room temperature, suction filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (MeOH / DCM (v / v) = 0:1 to 5:95) to obtain 43e (0.22 g, yield: 58%).

[0364] LCMS m / z = 400.2 [M+1] + 。

[0365] Compound 43e is one of the isomers of structure 43e-1 or 43e-2.

[0366] Step 6: Preparation of 43f 43e (110 mg, 0.276 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and then concentrated under reduced pressure to obtain crude 43f (84 mg).

[0367] LCMS m / z = 300.3 [M+1] + 。

[0368] Compound 43f is one of the isomers of structure 43f-1 or 43f-2.

[0369] Step 7: Preparation of 43g The above crude 43f (0.084 g) was dissolved in 1,2-dichloroethane (30 mL), tert-butyl 4-formylpiperidine-1-carboxylate (0.090 g, 0.42 mmol) was added, 3 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.12 g, 0.57 mmol) was added, and the mixture was reacted at room temperature for 16 h. 50 mL of saturated aqueous sodium hydrogen carbonate solution was slowly added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10:1) to obtain 43g (0.13 g, yield: 62%).

[0370] LCMS m / z = 497.3 [M+1] + 。

[0371] Compound 43g is one of the isomers of structure 43g-1 or 43g-2.

[0372] Step 8: Preparation of trifluoroacetate of 43h 43g (130 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate salt (130 mg) of crude product 43h.

[0373] LCMS m / z = 397.3 [M+1] + 。

[0374] Compound 43h is one of the isomers of structure 43h-1 or 43h-2.

[0375] Step 9: Preparation of the trifluoroacetate salt of compound 43 To the reaction flask were added the trifluoroacetate salt (120 mg) of the above crude product 43h, DIPEA (300 mg, 2.32 mmol), and 10 mL of DMSO, respectively. 4B (100 mg, 0.25 mmol) was added, and the mixture was reacted at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and then freeze-dried to obtain the trifluoroacetate salt (20 mg) of compound 43.

[0376] 1 H NMR (400 MHz, DMSO-d 6) δ 10.76 (s,1H),8.95 (s,1H),8.08 (s,1H),8.03 - 7.89 (m,2H),7.80 - 7.70 (m,1H),7.50 - 7.42 (m,1H),7.14 - 7.07 (m,1H),6.95 - 6.80 (m,3H),4.63 - 4.55 (m,2H),4.55 - 4.42 (m,2H),4.13 - 4.02 (m,1H),3.74 - 3.54 (m,6H),3.35 - 3.20 (m,1H),3.17 - 2.73 (m,8H),2.72 - 2.57 (m,5H),2.49 - 2.40 (m,1H),2.25 - 2.05 (m,2H),2.05 - 1.91 (m,2H),1.87 - 1.70 (m,2H),1.70 - 1.54 (m,1H),1.30 - 1.07 (m,2H).

[0377] Compound 43 is one of the isomers of compound 43-1 or 43-2.

[0378] Example 44: Preparation of trifluoroacetate of compound 44 [Chemical formula]

[0379] Step 1: Preparation of 44b Dissolve 44a (2.8 g, 13.58 mmol) (for the synthesis method, refer to Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877 - 5882) in dichloromethane (50 mL), add Boc 2 O (5.93 g, 27.17 mmol), add DMAP (3.32 g, 27.18 mmol), and react at room temperature for 16 h. Wash the reaction system with 0.5 mol / L hydrochloric acid (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 - 1:9) to obtain the racemate of 44b (3.4 g, yield: 82%).

[0380] The racemate of 44b was subjected to chiral resolution, and the chiral resolution method is as follows.

[0381] 1. Instrument: SFC Prep 150 AP, Chromatography column: Daicel IC-H (19 mm × 250 mm).

[0382] 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution.

[0383] 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: Mobile phase A: CO 2 , Mobile phase B: methanol / isopropyl alcohol (v / v) = 1:1, b. Isocratic elution was performed, and the content of mobile phase B was 20%, c. The flow rate was 40 mL / min.

[0384] Peak time: Chiral isomer 1 (Compound 44b): 5.7 min, Chiral isomer 2 (Compound 46a): 6.47 min.

[0385] Based on the measurement of the MicroED structure of Compound 46b, Compound 44b has an R configuration, and Compound 46a has an S configuration.

[0386] LCMS m / z = 307.3 [M+1] + .

[0387] Step 2: Preparation of 44c 44b (1.8 g, 5.88 mmol) was dissolved in acetonitrile (50 mL), NBS (1.05 g, 5.90 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 to 1:9) to obtain 44c (1.6 g, yield: 71%).

[0388] LCMS m / z = 385.3 [M+1] + .

[0389] Step 3: Preparation of 44d 44c (0.77 g, 2.0 mmol), 44A (1.67 g, 4.0 mmol) (for the synthesis method, refer to WO2022235945), Pd(dppf)Cl 2 ·DCM (0.16 g, 0.20 mmol) and cesium carbonate (1.30 g, 4.0 mmol) were added to a reaction flask, 1,4-dioxane (30 mL) and water (3 mL) were added, and the reaction was carried out at 100 °C for 20 h under a nitrogen gas atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 9:1) to obtain 44d (0.70 g, yield: 59%).

[0390] Step 4: Preparation of 44e 44d (0.70 g, 1.18 mmol) was dissolved in THF (20 mL), 10% palladium on carbon (0.63 g) was added, and the reaction was carried out at 45 °C for 20 h under a hydrogen gas balloon atmosphere. The reaction system was cooled to room temperature, filtered by suction, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (MeOH:DCM (v / v) = 0:1 to 5:95) to obtain 44e (0.25 g, yield: 51%).

[0391] LCMS m / z = 418.1 [M+1] + 。

[0392] Step 5: Preparation of 44f 44e (250 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and concentrated under reduced pressure to obtain the crude product 44f (190 mg).

[0393] LCMS m / z = 318.3 [M+1] + 。

[0394] Step 6: Preparation of 44g The above crude product 44f (0.19 g) was dissolved in 1,4-dichloroethane (30 mL), tert-butyl 4-formylpiperidine-1-carboxylate (0.20 g, 0.93 mmol) was added, 3 mL of acetic acid was added, and after stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.40 g, 1.89 mmol) was added and reacted at room temperature for 16 h. 10 mL of saturated aqueous sodium hydrogen carbonate solution was slowly added to the reaction system, extracted with 50 mL of dichloromethane, the organic phase was washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 44g (0.30 g, yield: 63%).

[0395] LCMS m / z = 515.3 [M+1] + 。

[0396] Step 7: Preparation of 44h 44g (300 mg, 0.58 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure, the pH was adjusted to 9 with saturated aqueous sodium hydrogen carbonate solution, extracted with dichloromethane (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude product 44h (180 mg).

[0397] LCMS m / z = 415.3 [M+1] + 。

[0398] Step 8: Preparation of trifluoroacetate of Compound 44 To the reaction flask, 44h (91 mg) of the above crude product, DIPEA (85 mg, 0.66 mmol), and 10 mL of DMSO were added respectively. Then 4B (90 mg, 0.23 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and then freeze-dried to obtain the trifluoroacetate salt (80 mg) of compound 44.

[0399] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 8.98 (s, 1H), 8.09 (s, 1H), 8.02 - 7.89 (m, 2H), 7.74 (dd, 1H), 7.50 - 7.43 (m, 1H), 7.12 (s, 1H), 6.87 (d, 1H), 6.79 (d, 1H), 4.59 (s, 2H), 4.54 - 4.40 (m, 2H), 4.14 - 4.00 (m, 1H), 3.93 - 3.80 (m, 1H), 3.73 - 3.55 (m, 5H), 3.40 - 3.27 (m, 1H), 3.20 - 2.80 (m, 7H), 2.80 - 2.58 (m, 6H), 2.58 - 2.50 (m, 1H), 2.27 - 2.05 (m, 2H), 2.05 - 1.87 (m, 2H), 1.87 - 1.70 (m, 2H), 1.70 - 1.53 (m, 1H), 1.28 - 1.06 (m, 2H).

[0400] LCMS m / z = 786.3 [M + 1] + .

[0401] Example 45: Preparation of the trifluoroacetate salt of compound 45

Chemical formula

[0402] Step 1: Preparation of 45a The chiral isomer 1 of 43a (0.6 g, 3.19 mmol) was dissolved in dichloromethane (30 mL), Boc 2 O (1.39 g, 6.4 mmol) was added, DMAP (0.39 g, 3.2 mmol) was added, and the reaction was carried out at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 - 1:9) to obtain 45a (0.8 g, yield: 87%).

[0403] Compound 45a is one of the isomers of structure 43b-1 or 43b-2.

[0404] Step 2: Preparation of 45b 45a (0.78 g, 2.70 mmol) was dissolved in acetonitrile (20 mL), NBS (0.53 g, 2.98 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 - 1:9) to obtain 45b (0.86 g, yield: 87%).

[0405] LCMS m / z = 367.5[M+1] + 。

[0406] Compound 45b is one of the isomers of structure 43c-1 or 43c-2.

[0407] Step 3: Preparation of 45c 45b (0.85 g, 2.32 mmol), 45A (2.89 g, 6.93 mmol), Pd(dppf)Cl 2· DCM (0.19 g, 0.23 mmol) and cesium carbonate (1.51 g, 4.63 mmol) were added to a reaction flask, 1,4-dioxane (30 mL) and water (3 mL) were added, and the reaction was carried out at 100 °C for 20 h under a nitrogen gas atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 9:1) to obtain 45c (0.9 g, yield: 67%).

[0408] Compound 45c is one of the isomers of structure 43d-1 or 43d-2.

[0409] Step 4: Preparation of 45d 45c (0.7 g, 1.21 mmol) was dissolved in THF (20 mL), 10% palladium on carbon (0.51 g) was added, and the reaction was carried out at 45 °C for 20 h under a hydrogen gas balloon atmosphere. The reaction system was cooled to room temperature, filtered by suction, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (MeOH:DCM (v / v) = 0:1 to 5:95) to obtain 45d (0.4 g, yield: 83%).

[0410] Compound 45d is one of the isomers of structure 43e-1 or 43e-2.

[0411] Step 5: Preparation of 45e 45d (120 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and concentrated under reduced pressure to obtain crude product 45e (90 mg).

[0412] LCMS m / z = 300.3 [M+1] + 。

[0413] Compound 45e is one of the isomers of structure 43f-1 or 43f-2.

[0414] Step 6: Preparation of 45f The above crude product 45e (0.09 g) was dissolved in 1,2-dichloroethane (20 mL), tert-butyl 4-formylpiperidine-1-carboxylate (0.090 g, 0.42 mmol) was added, 1.5 mL of acetic acid was added, and after stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.12 g, 0.57 mmol) was added and reacted at room temperature for 16 h. 50 mL of saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution, extracted with 50 mL of dichloromethane, the organic phase was washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v:v) = 10:1) to obtain 45f (0.13 g, yield: 62%).

[0415] LCMS m / z = 497.3 [M+1] + 。

[0416] Compound 45f is one of the isomers of structure 43g-1 or 43g-2.

[0417] Step 7: Preparation of trifluoroacetate of 45g 45f (130 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetate of crude product 45g (100 mg).

[0418] LCMS m / z = 397.3 [M+1] + 。

[0419] Compound 45g is one of the isomers of structure 43h-1 or 43h-2.

[0420] Step 8: Preparation of trifluoroacetate of compound 45 45 g of the crude product trifluoroacetate (100 mg), DIPEA (78 mg, 0.60 mmol), and 10 mL of DMSO were added to the reaction flask, respectively. Then 4B (80 mg, 0.20 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and then freeze-dried to obtain 20 mg of the trifluoroacetate of compound 45.

[0421] 1 H NMR (400MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 9.01 (s, 1H), 8.09 (s, 1H), 8.03 - 7.89 (m, 2H), 7.80 - 7.70 (m, 1H), 7.50 - 7.42 (m, 1H), 7.14 - 7.07 (m, 1H), 6.95 - 6.80 (m, 3H), 4.63 - 4.55 (m, 2H), 4.55 - 4.42 (m, 2H), 4.13 - 4.02 (m, 1H), 3.74 - 3.54 (m, 6H), 3.35 - 3.20 (m, 1H), 3.17 - 2.73 (m, 8H), 2.72 - 2.57 (m, 5H), 2.49 - 2.40 (m, 1H), 2.25 - 2.05 (m, 2H), 2.05 - 1.91 (m, 2H), 1.87 - 1.70 (m, 2H), 1.70 - 1.54 (m, 1H), 1.30 - 1.07 (m, 2H).

[0422] Compound 45 is one of the isomers of compound 43-1 or 43-2.

[0423] Example 46: Preparation of the trifluoroacetate of compound 46

Chemical formula

[0424] Step 1: Preparation of 46b 46a (1.4 g, 4.57 mmol) was dissolved in acetonitrile (50 mL), NBS (0.81 g, 4.55 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 to 1:9) to obtain 46b (1.6 g, yield: 92%).

[0425] LCMS m / z = 385.3 [M+1] + .

[0426] According to the MicroED structure measurement, compound 46b has an S configuration.

[0427] Step 2: Preparation of 46c 46b (1.6 g, 4.16 mmol), 46A (3.46 g, 8.29 mmol), Pd(dppf)Cl 2 ·DCM (0.34 g, 0.42 mmol) and cesium carbonate (2.70 g, 8.3 mmol) were added to the reaction flask, 1,4-dioxane (50 mL) and water (5 mL) were added, and the reaction was carried out at 100 °C for 20 h under a nitrogen gas atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 9:1) to obtain 46c (1.4 g, yield: 56%).

[0428] Step 3: Preparation of 46d 46c (1.4 g, 2.35 mmol) was dissolved in THF (50 mL), 10% palladium on carbon (1.25 g) was added, and the reaction was carried out at 45 °C for 20 h under a hydrogen gas balloon atmosphere. The reaction system was cooled to room temperature, suction filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (MeOH:DCM (v / v) = 0:1~5:95) to obtain 46d (0.85 g, yield: 87%).

[0429] LCMS m / z = 418.1 [M+1] + 。

[0430] Step 4: Preparation of 46e 46d (620 mg, 1.49 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain the crude product 46e (460 mg).

[0431] LCMS m / z = 318.3 [M+1] + 。

[0432] Step 5: Preparation of 46f The above crude product 46e (0.46 g) was dissolved in 1,2-dichloroethane (30 mL), tert-butyl 4-formylpiperidine-1-carboxylate (0.46 g, 2.14 mmol) was added, 3 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.92 g, 4.34 mmol) was added, and the reaction was carried out at room temperature for 16 h. 20 mL of saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to obtain 46f (0.70 g, yield: 64%).

[0433] LCMS m / z = 515.3 [M+1] + 。

[0434] Step 6: Preparation of 46g 46f (700 mg, 1.36 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 46g (520 mg).

[0435] LCMS m / z = 415.3 [M+1] + 。

[0436] Step 7: Preparation of trifluoroacetate salt of compound 46 To the reaction flask were added the above crude product 46g (90 mg), DIPEA (85 mg, 0.66 mmol) and 10 mL of DMSO respectively, 4B (90 mg, 0.23 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and freeze-dried to obtain the trifluoroacetate salt of compound 46 (70 mg).

[0437] 1 H NMR (400MHz, DMSO-d 6) δ 10.79 (s,1H),8.98 (s,1H),8.09 (s,1H),8.02 - 7.90 (m,2H),7.74 (dd,1H),7.51 - 7.43 (m,1H),7.12 (s,1H),6.87 (d,1H),6.79 (d,1H),4.59 (s,2H),4.54 - 4.41 (m,2H),4.13 - 4.00 (m,1H),3.92 - 3.80 (m,1H),3.73 - 3.54 (m,5H),3.40 - 3.27 (m,1H),3.20 - 2.80 (m,7H),2.80 - 2.58 (m,6H),2.58 - 2.50 (m,1H),2.27 - 2.05 (m,2H),2.05 - 1.87 (m,2H),1.87 - 1.70 (m,2H),1.70 - 1.53 (m,1H),1.30 - 1.06 (m,2H).

[0438] LCMS m / z=786.3[M+1] + .

[0439] Example 47: Preparation of Compound 47 [Chemical Structure Diagram]

[0440] Step 1: Preparation of 47b To the reaction flask were added 47a (2.00 g, 7.19 mmol) (for the synthesis method, refer to CN112538083), HATU (4.10 g, 10.78 mmol) and 30 mL of DMF respectively. After stirring at room temperature for 2 min, deuterated methylamine hydrochloride (1.52 g, 21.55 mmol) and DIPEA (2.79 g, 21.59 mmol) were added, and the reaction was carried out at room temperature for 16 h. The reaction system was poured into 200 mL of water, filtered, and the filter cake was dried under reduced pressure to obtain crude 47b (1.03 g).

[0441] Step 2: Preparation of 47c To the reaction flask were added the above crude product 47b (1.03 g), 10% palladium carbon (0.6 g), 30 mL of dichloromethane and 30 mL of methanol, and the mixture was reacted at room temperature for 16 h under a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain crude product 47c (0.62 g).

[0442] LCMS m / z = 265.2[M + 1] + 。

[0443] Step 3: Preparation of 47d To the reaction flask were added the above crude product 47c (0.62 g), 2,4,5-trichloropyrimidine (0.47 g, 2.56 mmol), triethylamine (0.48 g, 4.74 mmol) and 5 mL of DMF, and the mixture was reacted at 70 °C for 2 h. The reaction system was cooled to room temperature, added to 50 mL of water, filtered, the filter cake was washed with 20 mL of water, and the filter cake was dried under reduced pressure to obtain crude product 47d (0.70 g).

[0444] Step 4: Preparation of Compound 47 To the reaction flask were added the trifluoroacetate of crude product 8c (90 mg), sodium bicarbonate (80 mg, 0.95 mmol) and 5 mL of DMSO, and after stirring at room temperature for 0.5 h, the above crude product 47d (78 mg) and DIPEA (0.12 g, 0.93 mmol) were added, and the mixture was reacted at 100 °C for 7 h. The reaction system was cooled to room temperature and passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: ammonium acetate aqueous solution (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 15 min), and freeze-dried to obtain Compound 47 (20 mg, 4-step yield from Compound 47a: 3%).

[0445] 11H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.97 - 7.87 (m, 2H), 7.74 (dd, 1H), 7.47 (d, 1H), 7.12 (s, 1H), 7.06 - 6.99 (m, 2H), 6.92 - 6.84 (m, 2H), 4.58 (s, 2H), 3.76 - 3.57 (m, 10H), 2.70 - 2.56 (m, 3H), 2.49 - 2.29 (m, 5H), 2.23 - 1.97 (m, 4H), 1.85 - 1.63 (m, 3H), 1.29 - 1.11 (m, 2H).

[0446] LCMS m / z = 745.3 [M+1] + .

[0447] Example 48: Preparation of Compound 48 [Chemical formula]

[0448] Step 1: Preparation of 48b Add 48a (20.0 g, 104.10 mmol) and 200 mL of DMF to the reaction flask, add 60% sodium hydride (4.16 g) little by little at 0 °C, react at room temperature for 30 min, then dropwise add iodomethane-d (15.09 g, 104.10 mmol), and react at room temperature for 16 h. Pour the reaction solution into 1.0 L of ice water, filter, wash the filter cake with 300 mL of water, and dry the filter cake under reduced pressure to obtain crude 48b (10.2 g).

[0449] Step 2: Preparation of 48c To the reaction flask, add the above crude product 48b (12.5 g), DBU (1.82 g, 11.95 mmol), ethyl diazoacetate (8.61 g, 75.46 mmol), and 200 mL of ethanol respectively, react at room temperature for 3 h, add rhodium diacetate (0.13 g, 0.29 mmol), and react at room temperature for 16 h. Filter the reaction system, wash the filter cake with 50 mL of ethanol, and dry the filter cake under reduced pressure to obtain crude product 48c (14.5 g).

[0450] Step 3: Preparation of 48d To the reaction flask, add the above crude product 48c (14.5 g), sodium hydroxide (9.82 g, 245.5 mmol), and 200 mL of water respectively, and reflux for 16 h. Cool the reaction system to room temperature, adjust the pH to 1 with 1 mol / L hydrochloric acid, filter, wash the filter cake with 50 mL of water, and dry the filter cake under reduced pressure to obtain crude product 48d (11.5 g).

[0451] LCMS m / z = 266.2 [M - 1] - 。

[0452] Step 4: Preparation of 48e To the reaction flask, add the above crude product 48d (11.5 g), LiCl (5.47 g, 129.04 mmol), 10 mL of water, and 200 mL of DMSO respectively, and react at 130 °C for 3 h. Cool the reaction system to room temperature, pour it into 500 mL of water, filter, wash the filter cake with 100 mL of water, and dry the filter cake under reduced pressure to obtain crude product 48e (7.4 g).

[0453] Step 5: Preparation of 48f To the reaction flask, add the above crude product 48e (1.0 g), 2 - bromo - N - methylacetamide (0.82 g, 5.40 mmol), and cesium carbonate (2.92 g, 8.96 mmol) respectively, add 15 mL of DMF, and react at room temperature for 2 h. Pour the reaction solution into 100 mL of water, filter, wash the filter cake successively with 50 mL of water and 5 mL of ethanol, and dry the filter cake under reduced pressure to obtain crude product 48f (1.20 g).

[0454] Step 6: Preparation of 48g To the reaction flask were added crude product 48f (1.20 g), 10% palladium carbon (0.6 g), 30 mL of dichloromethane and 30 mL of methanol respectively, and the mixture was reacted at room temperature for 16 h under a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain crude product 48g (0.56 g).

[0455] LCMS m / z = 265.2 [M+1] + 。

[0456] Step 7: Preparation of 48h To the reaction flask were added the above crude product 48g (0.56 g), 2,4,5-trichloropyrimidine (0.43 g, 2.34 mmol), triethylamine (0.43 g, 4.25 mmol) and 5 mL of DMF respectively, and the mixture was reacted at 70 °C for 2 h. The reaction solution was cooled to room temperature, poured into 50 mL of water, filtered, the filter cake was washed with 20 mL of water, and the filter cake was dried under reduced pressure to obtain crude product 48h (0.71 g).

[0457] LCMS m / z = 411.1 [M+1] + 。

[0458] Step 8: Preparation of Compound 48 To the reaction flask, add the trifluoroacetate salt (90 mg) of the above crude product 8c, sodium bicarbonate (80 mg, 0.95 mmol), and 5 mL of DMSO respectively. After stirring at room temperature for 0.5 h, add the above crude product 48h (78 mg) and DIPEA (0.12 g, 0.93 mmol), and react at 100 °C for 7 h. Cool the reaction system to room temperature and pass it through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: ammonium acetate aqueous solution (5 mmol / L) / acetonitrile. Gradient elution method: Elute 70% of acetonitrile with a gradient of 10% (elution time 15 min), and lyophilize to obtain compound 48 (8 mg, 8-step yield from compound 48a: 0.6%).

[0459] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.75 (s,1H),8.84 (s,1H),8.05 (s,1H),7.97 - 7.87 (m,2H),7.74 (dd,1H),7.47 (d,1H),7.12 (s,1H),7.06 - 6.99 (m,2H),6.92 - 6.84 (m,2H),4.58 (s,2H),3.76 - 3.57 (m,7H),2.70 - 2.56 (m,6H),2.49 - 2.29 (m,5H),2.23 - 1.96 (m,4H),1.85 - 1.63 (m,3H),1.29 - 1.11 (m,2H).

[0460] LCMS m / z=373.2[M / 2+1] + .

[0461] Example 49: Preparation of Compound 49

Chemical formula

[0462] Step 1: Preparation of 49a To the reaction flask were added 48e (3.0 g) of the above crude product, ethyl bromoacetate (2.69 g, 16.11 mmol), cesium carbonate (8.76 g, 26.89 mmol), and 50 mL of DMF, respectively, and the mixture was reacted at room temperature for 3 h. The reaction system was poured into 200 mL of water, filtered, and the filter cake was dried under reduced pressure to obtain 49a (4.00 g) of the crude product.

[0463] Step 2: Preparation of 49b To the reaction flask were added 49a (4.00 g) of the above crude product, lithium hydroxide (1.56 g, 65.14 mmol), 72 mL of methanol, and 18 mL of water, respectively, and the mixture was reacted at room temperature for 2 h. The reaction solution was poured into 200 mL of water, adjusted to pH 1 with 1 mol / L hydrochloric acid, filtered, and the filter cake was dried under reduced pressure to obtain 49b (2.35 g) of the crude product.

[0464] Step 3: Preparation of 49c To the reaction flask were added 49b (1.50 g) of the above crude product, HATU (3.04 g, 8.00 mmol), and 30 mL of DMF, respectively. After stirring at room temperature for 2 min, methylamine hydrochloride-d2 (1.13 g, 16.02 mmol) and DIPEA (2.07 g, 16.02 mmol) were added, and the mixture was reacted at room temperature for 16 h. The reaction system was poured into 200 mL of water, filtered, and the filter cake was dried under reduced pressure to obtain 49c (1.06 g) of the crude product.

[0465] Step 4: Preparation of 49d To the reaction flask were added 49c (1.20 g) of the above crude product, 10% palladium on carbon (0.5 g), 30 mL of dichloromethane, and 30 mL of methanol, respectively, and the mixture was reacted at room temperature for 16 h under a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 49d (0.60 g) of the crude product.

[0466] LCMS m / z = 268.2 [M+1] + 。

[0467] Step 5: Preparation of 49e To the reaction flask, the above crude product 49d (0.60 g), 2,4,5-trichloropyrimidine (0.45 g, 2.45 mmol), triethylamine (0.45 g, 4.45 mmol) and 5 mL of DMF were added respectively, and the reaction was carried out at 70 °C for 2 h. The reaction solution was cooled to room temperature, poured into 50 mL of water, filtered, the filter cake was washed with 20 mL of water, and the filter cake was dried under reduced pressure to obtain crude product 49e (0.70 g).

[0468] Step 6: Preparation of Compound 49 To the reaction flask, the trifluoroacetate of the above crude product 8c (90 mg), sodium bicarbonate (80 mg, 0.95 mmol) and 5 mL of DMSO were added respectively. After stirring at room temperature for 0.5 h, the above crude product 49e (79 mg) and DIPEA (0.12 g, 0.93 mmol) were added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature and passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: ammonium acetate aqueous solution (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 15 min), and freeze-dried to obtain Compound 49 (100 mg, 2-step yield from Compound 8b was 70%).

[0469] 1 H NMR (400MHz,DMSO-d 6) δ 10.75 (s,1H),8.84 (s,1H),8.05 (s,1H),7.97 - 7.87 (m,2H),7.74 (dd,1H),7.47 (d,1H),7.12 (s,1H),7.06 - 6.99 (m,2H),6.92 - 6.84 (m,2H),4.58 (s,2H),3.76 - 3.57 (m,7H),2.70 - 2.56 (m,3H),2.49 - 2.29 (m,5H),2.23 - 1.96 (m,4H),1.85 - 1.63 (m,3H),1.29 - 1.11 (m,2H).

[0470] LCMS m / z=748.6[M+1] + .

[0471] Example 50: Preparation of Compound 50 [Chemical Structure] To the reaction flask were added the trifluoroacetate of the above crude product 35f (57 mg), DIPEA (47 mg, 0.36 mmol), and 5 mL of DMSO, respectively. Then the above crude product 38g (52 mg) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and then freeze-dried to obtain Compound 50 (35 mg, two-step yield from Compound 38f: 35%).

[0472] 1 H NMR (400MHz,DMSO-d 6) δ 10.72 (s,1H),8.82 (s,1H),8.04 (s,1H),8.00 - 7.90 (m,2H),7.78 (dd,1H),7.51 (d,1H),7.12 (s,1H),6.87 - 6.80 (m,1H),6.80 - 6.72 (m,2H),5.20 - 5.05 (m,2H),4.65 - 4.40 (m,4H),3.78 - 3.58 (m,2H),3.29 - 3.23 (m,1H),2.97 - 2.71 (m,6H),2.71 - 2.53 (m,6H),2.48 - 2.38 (m,1H),2.24 - 2.13 (m,2H),2.13 - 1.93 (m,3H),1.90 - 1.69 (m,5H),1.67 - 1.52 (m,1H),1.11 - 0.95 (m,2H).

[0473] LCMS m / z=792.3[M+1] + .

[0474] Example 51: Preparation of Compound 51 [Chemical formula] To the reaction flask were added the trifluoroacetate (57 mg) of the above crude product 35f, DIPEA (47 mg, 0.36 mmol), and 5 mL of DMSO, respectively. Then the above crude product 36g (50 mg) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: Aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and freeze-dried to obtain Compound 51 (25 mg, 4-step yield from 36d: 17%).

[0475] 1 H NMR (400MHz,DMSO-d6 ) δ 10.72 (s,1H),8.77 (s,1H),8.03 (s,1H),7.97 - 7.87 (m,2H),7.78 - 7.67 (m,2H),7.03 (s,1H),6.87 - 6.80 (m,1H),6.80 - 6.72 (m,2H),4.57 - 4.40 (m,4H),3.79 - 3.60 (m,2H),3.05 - 2.96 (m,1H),2.96 - 2.71 (m,6H),2.71 - 2.53 (m,6H),2.48 - 2.39 (m,1H),2.20 - 1.92 (m,5H),1.91 - 1.68 (m,5H),1.67 - 1.51 (m,1H),1.35 - 1.27 (m,2H),1.12 - 0.95 (m,2H),0.83 - 0.73 (m,2H).

[0476] LCMS m / z = 794.3 [M + 1] + .

[0477] Example 52: Preparation of trifluoroacetate of Compound 52 [Chemical formula] To the reaction flask were added 23 g of the above crude trifluoroacetate (47 mg), DIPEA (160 mg, 1.24 mmol) and 5 mL of DMSO respectively, then 38 g (50 mg) of the above crude product was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and then freeze-dried to obtain 40 mg of trifluoroacetate of Compound 52.

[0478] 1 H NMR (400 MHz, DMSO-d6 ) δ 10.79 (s, 1H), 9.08 (s, 1H), 8.16 (s, 1H), 8.00 - 7.92 (m, 2H), 7.74 (dd, 1H), 7.52 (d, 1H), 7.19 (s, 1H), 7.12 - 7.04 (m, 1H), 6.80 - 6.69 (m, 2H), 5.18 - 5.09 (m, 2H), 4.60 (s, 2H), 4.56 - 4.43 (m, 2H), 3.93 - 3.84 (m, 1H), 3.83 - 3.69 (m, 2H), 3.64 - 3.50 (m, 2H), 3.41 - 3.24 (m, 3H), 3.15 - 2.96 (m, 4H), 2.82 - 2.60 (m, 6H), 2.56 - 2.50 (m, 1H), 2.23 - 1.89 (m, 3H), 1.88 - 1.73 (m, 2H), 1.38 - 1.20 (m, 2H).

[0479] LCMS m / z = 784.3 [M + 1] + .

[0480] Example 53: Preparation of Trifluoroacetate Salt of Compound 53 [Chemical formula] To the reaction flask were added 23 g of the above crude trifluoroacetate salt (47 mg), DIPEA (47 mg, 0.36 mmol), and 5 mL of DMSO, respectively. Then 36 g (50 mg) of the above crude product was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and then freeze-dried to obtain 50 mg of the trifluoroacetate salt of Compound 53.

[0481] 11H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 9.04 (s, 1H), 8.15 (s, 1H), 7.98 - 7.91 (m, 1H), 7.90 - 7.84 (m, 1H), 7.82 - 7.74 (m, 1H), 7.68 (dd, 1H), 7.14 - 7.03 (m, 2H), 6.80 - 6.70 (m, 2H), 4.60 - 4.40 (m, 4H), 3.94 - 3.83 (m, 1H), 3.82 - 3.70 (m, 2H), 3.65 - 3.50 (m, 2H), 3.41 - 3.23 (m, 2H), 3.15 - 2.95 (m, 5H), 2.81 - 2.62 (m, 6H), 2.56 - 2.49 (m, 1H), 2.22 - 1.88 (m, 3H), 1.88 - 1.74 (m, 2H), 1.40 - 1.20 (m, 4H), 0.85 - 0.73 (m, 2H).

[0482] LCMS m / z = 786.3 [M+1] + .

[0483] Example 54: Preparation of the trifluoroacetate salt of compound 54 [Chemical formula] To the reaction flask were added the trifluoroacetate salt (61 mg) of the above crude product 35f, DIPEA (54 mg, 0.42 mmol), and 5 mL of DMSO, respectively. Then 42A (61 mg, 0.14 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and then freeze-dried to obtain the trifluoroacetate salt (25 mg) of compound 54.

[0484] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 8.95 (s, 1H), 8.08 (s, 1H), 8.03 - 7.90 (m, 2H), 7.76 - 7.63 (m, 2H), 7.03 (s, 1H), 6.96 - 6.78 (m, 3H), 5.55 - 5.15 (m, 1H), 4.60 - 4.42 (m, 4H), 4.15 - 4.00 (m, 1H), 3.75 - 3.54 (m, 3H), 3.35 - 3.21 (m, 1H), 3.18 - 2.74 (m, 8H), 2.74 - 2.57 (m, 5H), 2.50 - 2.41 (m, 1H), 2.27 - 2.05 (m, 2H), 2.05 - 1.92 (m, 2H), 1.89 - 1.70 (m, 2H), 1.70 - 1.50 (m, 7H), 1.28 - 1.10 (m, 2H).

[0485] LCMS m / z = 796.3 [M+1] + .

[0486] Example 55: Preparation of the trifluoroacetate salt of Compound 55 [Chemical formula] The trifluoroacetate salt of Compound 55 was obtained by using Compound 55a as a raw material, referring to the synthesis method of Example 8, and performing lyophilization by acidic fractionation (aqueous trifluoroacetic acid solution (0.1% TFA) / acetonitrile).

[0487] 1 1H NMR (400 MHz, DMSO-d 6) δ 10.80 (s,1H),9.07 (s,1H),8.15 (s,1H),7.99 - 7.88 (m,2H),7.71 (dd,1H),7.48 (d,1H),7.24 - 7.13 (m,2H),6.94 - 6.80 (m,2H),6.70 - 6.60 (m,1H),4.59 (s,2H),4.56 - 4.42 (m,2H),3.83 - 3.65 (m,6H),3.64 - 3.51 (m,2H),3.39 - 3.25 (m,2H),3.15 - 2.97 (m,4H),2.82 - 2.57 (m,6H),2.55 - 2.42 (m,1H),2.28 - 2.13 (m,1H),2.13 - 1.95 (m,2H),1.93 - 1.75 (m,2H),1.45 - 1.25 (m,2H).

[0488] LCMS m / z=742.2[M+1] + .

[0489] Example 56: Preparation of the trifluoroacetate salt of Compound 56 [Chemical formula] To the reaction flask were added 44h (91 mg) of the above crude product, DIPEA (280 mg, 2.17 mmol), and 10 mL of DMSO, respectively. Then 42A (96 mg, 0.22 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the reaction solution was passed through a Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and then freeze-dried to obtain the trifluoroacetate salt (60 mg) of Compound 56.

[0490] 1 H NMR (400MHz,DMSO-d6 ) δ 10.80 (s, 1H), 9.00 (s, 1H), 8.09 (s, 1H), 8.04 - 7.90 (m, 2H), 7.75 - 7.64 (m, 2H), 7.03 (s, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 5.70 - 4.90 (m, 1H), 4.56 (s, 2H), 4.54 - 4.42 (m, 2H), 4.15 - 4.00 (m, 1H), 3.92 - 3.80 (m, 1H), 3.70 - 3.53 (m, 2H), 3.42 - 3.25 (m, 1H), 3.18 - 3.00 (m, 4H), 3.00 - 2.80 (m, 3H), 2.80 - 2.57 (m, 6H), 2.57 - 2.50 (m, 1H), 2.28 - 2.05 (m, 2H), 2.05 - 1.87 (m, 2H), 1.87 - 1.70 (m, 2H), 1.70 - 1.50 (m, 7H), 1.29 - 1.10 (m, 2H).

[0491] LCMS m / z = 814.2 [M + 1] + .

[0492] Example 57: Preparation of Trifluoroacetate of Compound 57 [Chemical formula] To the reaction flask, 46 g (91 mg) of the above crude product, DIPEA (280 mg, 2.17 mmol), and 10 mL of DMSO were added respectively, 42A (96 mg, 0.22 mmol) was added, and the reaction was carried out at 100 °C for 7 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 70% (elution time 12 min), and freeze-dried to obtain trifluoroacetate of compound 57 (50 mg).

[0493] 1 H NMR (400 MHz, CD 3 OD) δ 8.06 (s, 1H), 8.04 - 7.99 (m, 1H), 7.84 - 7.75 (m, 1H), 7.72 - 7.64 (m, 1H), 7.22 (s, 1H), 6.98 - 6.88 (m, 1H), 6.73 (d, 1H), 5.75 - 5.05 (m, 1H), 4.62 (s, 2H), 4.56 - 4.44 (m, 2H), 4.18 - 4.04 (m, 1H), 3.95 - 3.85 (m, 1H), 3.81 - 3.62 (m, 2H), 3.44 - 3.34 (m, 1H), 3.30 - 3.05 (m, 6H), 3.05 - 2.92 (m, 1H), 2.92 - 2.80 (m, 4H), 2.80 - 2.62 (m, 3H), 2.40 - 2.17 (m, 2H), 2.17 - 2.02 (m, 2H), 2.01 - 1.88 (m, 2H), 1.86 - 1.75 (m, 1H), 1.75 - 1.67 (m, 6H), 1.48 - 1.32 (m, 2H).

[0494] LCMS m / z = 814.2 [M + 1] + .

[0495] The trifluoroacetate of compound 57 was chiral resolved to obtain the trifluoroacetate of chiral isomer 1 and chiral isomer 2, respectively. The resolution conditions are as follows.

[0496] 1. Instrument: Waters 150 Prep-SFC A, chromatography column: Chiralcel OJ column.

[0497] 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter to prepare a sample solution.

[0498] 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: Mobile phase A: CO 2, Mobile phase B: A mixed solvent of methanol / acetonitrile, b. Isocratic elution, the content of mobile phase B is 40%, c. The flow rate is 100 mL / min.

[0499] Chiral analysis method: 1. Instrument: SHIMAZU LC-20AD, Chromatography column: Whelk column.

[0500] 2. Analytical chromatography conditions: a. The mobile phase is composed of systems A and B: Mobile phase A: n-hexane, Mobile phase B: An isopropyl alcohol and acetonitrile solution containing 0.1% isopropylamine, b. Isocratic elution, the content of mobile phase B is 80%, c. The flow rate is 1 mL / min.

[0501] Peak time: Chiral isomer 1: 1.963 min, Chiral isomer 2: 3.594 min.

[0502] Nuclear magnetic characterization of the trifluoroacetate of chiral isomer 1: 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.77 (s, 1H), 8.85 (s, 1H), 8.06 (s, 1H), 8.02 - 7.88 (m, 2H), 7.76 - 7.60 (m, 2H), 7.03 (s, 1H), 6.94 - 6.70 (m, 2H), 5.55 - 4.95 (m, 1H), 4.63 - 4.37 (m, 4H), 4.18 - 3.97 (m, 1H), 3.92 - 3.77 (m, 1H), 3.70 - 3.52 (m, 2H), 3.45 - 3.22 (m, 1H), 3.17 - 2.98 (m, 4H), 2.98 - 2.80 (m, 3H), 2.80 - 2.59 (m, 6H), 2.57 - 2.50 (m, 1H), 2.25 - 2.05 (m, 2H), 2.05 - 1.87 (m, 2H), 1.87 - 1.70 (m, 2H), 1.68 - 1.50 (m, 7H), 1.30 - 1.10 (m, 2H).

[0503] Nuclear magnetic characterization of chiral isomer 2: 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 8.77 (s, 1H), 8.03 (s, 1H), 7.98 - 7.85 (m, 2H), 7.78 - 7.62 (m, 2H), 7.02 (s, 1H), 6.78 (d, 1H), 6.61 (d, 1H), 5.55 - 5.05 (m, 1H), 4.58 - 4.42 (m, 4H), 3.86 - 3.76 (m, 1H), 3.75 - 3.64 (m, 1H), 3.02 - 2.79 (m, 5H), 2.79 - 2.52 (m, 7H), 2.50 - 2.42 (m, 1H), 2.25 - 1.68 (m, 10H), 1.66 - 1.49 (m, 7H), 1.13 - 0.95 (m, 2H).

[0504] Example 58: Preparation of trifluoroacetate of compound 58

Chemical formula

[0505] Step 1: Preparation of 58b The above crude product 46e (0.24 g) and 58a (0.46 g, 1.14 mmol) (for the synthesis method, refer to WO2022221673) were dissolved in acetonitrile (10 mL), triethylamine (0.38 g, 3.76 mmol) was added, and the mixture was stirred at 25 °C for 20 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1 to 1:9) to obtain 58b (0.30 g, yield: 46%).

[0506] LCMS m / z = 571.2 [M + 1] + .

[0507] Step 2: Preparation of 58c 58b (300 mg, 0.53 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 58c (150 mg).

[0508] LCMS m / z = 471.3 [M+1] + 。

[0509] Step 3: Preparation of trifluoroacetate salt of compound 58 The above crude product 58c (61 mg), DIPEA (170 mg, 1.32 mmol), and 10 mL of DMSO were added to the reaction flask respectively, 42A (55 mg, 0.13 mmol) was added, and the reaction was carried out at 100 °C for 20 h. The reaction system was cooled to room temperature, and the crude product was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, the model number of the preparative column was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted at a gradient of 10% to 50% (elution time 15 min), and freeze-dried to obtain the trifluoroacetate salt of compound 58 (40 mg).

[0510] 1 H NMR (400 MHz, DMSO-d 6) δ 10.78 (s,1H),8.96 (s,1H),8.07 (s,1H),8.00 - 7.90 (m,2H),7.73 - 7.62 (m,2H),7.03 (s,1H),6.87 (d,1H),6.80 (d,1H),5.52 - 5.15 (m,1H),4.54 (s,2H),4.38 - 4.25 (m,1H),4.18 - 4.03 (m,3H),3.97 - 3.80 (m,2H),3.65 - 3.43 (m,3H),3.34 - 3.18 (m,3H),3.05 - 2.85 (m,2H),2.82 - 2.50 (m,10H),2.36 - 1.77 (m,7H),1.71 - 1.50 (m,7H),1.49 - 1.33 (m,2H).

[0511] LCMS m / z=870.3[M+1] + .

[0512] Example 59: Preparation of trifluoroacetate of compound 59 [Chemical formula]

[0513] Step 1: Preparation of 59b 59a (1.28 g, 3.48 mmol) (for the synthesis method, refer to Bioorg. Med. Chem. Lett. 2016, 26, 5877 - 5882), cesium carbonate (2.27 g, 6.97 mmol), palladium acetate (0.16 g, 0.71 mmol), XantPhos (0.20 g, 0.35 mmol) and 59A (0.89 g, 4.91 mmol) were added to a 1,4 - dioxane solution (40 mL). Under a nitrogen gas atmosphere, the reaction was carried out at 105 °C for 3 h. The reaction system was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phase was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=1:0 - 7:3) to obtain 59b (1.30 g, yield: 80%).

[0514] LCMS m / z = 468.4 [M+1] + 。

[0515] Step 2: Production of 59c 59b (1.30 g, 2.78 mmol) was added to methanol (10 mL), 10% palladium carbon (1.33 g) and ammonium acetate (1.32 g, 17.13 mmol) were added, and the reaction was carried out at room temperature for 12 h under a hydrogen gas balloon atmosphere. The reaction system was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 1:1) to obtain 59c (0.76 g, yield: 90%).

[0516] LCMS m / z = 304.4 [M+1] + 。

[0517] Step 3: Production of 59d 59c (0.76 g, 2.55 mmol), 59B (0.75 g, 7.49 mmol) and DIPEA (0.97 g, 7.50 mmol) were sequentially added to ethanol (50 mL), and the reaction was carried out at 100 °C for 48 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (methanol / dichloromethane (v / v) = 0:1 to 6:94) to obtain 59d (0.70 g, yield: 68%).

[0518] LCMS m / z = 404.2 [M+1] + 。

[0519] Step 4: Production of 59e 59d (700 mg, 1.74 mmol) and DIPEA (671 mg, 5.19 mmol) were added to THF (20 mL), triphosgene (565 mg, 1.90 mmol) was slowly added, and the reaction was carried out at room temperature for 1 h. Ammonia water (5 mL) was added to the reaction system, and the reaction was carried out at 50 °C for 2 h. The reaction system was cooled to room temperature, water (50 mL) was added, and extraction was performed with ethyl acetate (50 mL × 2). The organic phase was concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (methanol / dichloromethane (v / v) = 0:1 to 1:9) to obtain 59e (700 mg, yield: 90%).

[0520] Step 5: Preparation of 59f 59f (0.70 g, 1.57 mmol) was added to acetonitrile (30 mL), a methanol solution (2 mL) of 40% benzyltrimethylammonium hydroxide was added, and the reaction was carried out at 60 °C for 2 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (methanol / dichloromethane (v / v) = 0:1 to 8:92) to obtain 59f (530 mg, yield: 84%).

[0521] LCMS m / z = 401.4 [M+1] + 。

[0522] Step 6: Preparation of 59g 59f (0.18 g, 0.45 mmol), 1 mL of trifluoroacetic acid and 3 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, concentrated under reduced pressure, the residue was dissolved in 10 mL of THF, tert-butyl 4-formylpiperidine-1-carboxylate (0.12 g, 0.56 mmol), 0.3 mL of acetic acid and sodium triacetoxyborohydride (0.19 g, 0.90 mmol) were added in sequence, and reacted at room temperature for 16 h. 12 mL of ethyl acetate and 12 mL of saturated aqueous sodium bicarbonate solution were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (5 mL × 3), the organic phase was washed with 5 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 59g (0.20 g, yield: 89%).

[0523] LCMS m / z=498.2[M+1] + 。

[0524] Step 7: Preparation of trifluoroacetate of 59h 59g (0.20 g, 0.40 mmol), 1 mL of trifluoroacetic acid and 3 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain crude 59h trifluoroacetate (0.20 g).

[0525] Step 8: Preparation of trifluoroacetate of compound 59 To the reaction flask, add 0.20 g of the trifluoroacetate of the above crude product 59h, 0.25 g (1.93 mmol) of DIPEA, and 5 mL of DMSO respectively. After stirring at room temperature for 0.5 h, add 4B (0.13 g, 0.33 mmol), and react at 100 °C for 7 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid was used, and the model number of the preparative column is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Fractionation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Elute 50% of acetonitrile with a gradient of 10% (elution time 15 min), and lyophilize to obtain 130 mg of the trifluoroacetate of compound 59.

[0526] 1 H NMR (400MHz,DMSO-d 6 ) δ 10.24 (s,1H),9.08 (s,1H),8.11 (s,1H),8.03 - 7.87 (m,2H),7.78 - 7.69 (m,1H),7.53 - 7.42 (m,1H),7.12 (s,1H),7.06 - 6.88 (m,3H),4.65 - 4.55 (m,2H),4.54 - 4.35 (m,2H),4.17 - 4.02 (m,1H),3.75 - 3.55 (m,7H),3.40 - 3.23 (m,1H),3.23 - 2.75 (m,8H),2.75 - 2.60 (m,6H),2.28 - 2.10 (m,1H),2.08 - 1.93 (m,1H),1.90 - 1.72 (m,2H),1.72 - 1.56 (m,1H),1.31 - 1.11 (m,2H).

[0527] LCMS m / z=385.3[M / 2+1] + .

[0528] Example 60: Preparation of the trifluoroacetate of compound 60

Chemical formula

[0529] Step 1: Production of 60b To the reaction flask, 60a (10 g, 49.26 mmol), 1-tert-butoxycarbonylpiperazine (9.18 g, 49.29 mmol), potassium carbonate (8.17 g, 59.18 mmol) and 100 mL of DMSO were added. Under the protection of nitrogen gas, the reaction was carried out at 95 °C for 12 h. The reaction solution was cooled to room temperature, 200 mL of ethyl acetate and 200 mL of water were added. The organic phase was washed with saturated sodium chloride aqueous solution (50 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by a column for silica gel chromatography (petroleum ether:ethyl acetate (v / v)=10:1) to obtain 60b (6.0 g, yield: 33%).

[0530] LCMS m / z = 369.1 [M+1] + 。

[0531] Step 2: Production of 60c To the reaction flask, 60b (6.0 g, 16.3 mmol), p-toluenesulfonylhydrazide (3.03 g, 16.27 mmol) and 60 mL of ethanol were added. Under the protection of nitrogen gas, the reaction was carried out at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude product 60c (5.0 g).

[0532] LCMS m / z = 537.1 [M+1] + 。

[0533] Step 3: Production of 60d Add the above crude product 60c (4.0 g) and 20 mL of toluene to the reaction flask. Under the protection of nitrogen gas, add 60% sodium hydride (0.36 g) little by little. After reacting at room temperature for 20 min under a nitrogen gas atmosphere, react at 135 °C for 2 h. Cool the reaction solution to room temperature, add 100 mL of ethyl acetate and 100 mL of water, wash the organic phase with a saturated aqueous sodium chloride solution (50 mL), concentrate under reduced pressure, and separate and purify the crude product by a column for silica gel chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain 60d (1.6 g, two-step yield from 60b: 35%).

[0534] LCMS m / z=353.3[M+1] + 。

[0535] Step 4: Preparation of 60e Add 60d (1.6 g, 4.54 mmol), 20 mL of 1,4-dioxane and 5 mL of water to the reaction flask respectively. Under the protection of nitrogen gas, add 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.78 g, 9.06 mmol) (for the synthesis method, refer to WO2021262812), cesium carbonate (4.43 g, 13.60 mmol) and Pd(dppf)Cl 2 (0.33 g, 0.45 mmol), and react at 100 °C for 16 h under a nitrogen gas atmosphere. Cool the reaction system to room temperature, filter after laying diatomaceous earth, add 50 mL of ethyl acetate and 50 mL of water to the filtrat...

Claims

1. A compound or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the compounds represented by the general formula (I), B-L-K (I), L is selected from a bond or a -C １－５０ hydrocarbon group-, and in the hydrocarbon group, 1 to 20 methylene units are optionally replaced by -Ak- or -Cy- Each -Ak- is independently selected from -(CH ２ ) ｑ -, -(CH ２ ) ｑ -O-, -O-(CH ２ ) ｑ -, -(CH ２ ) ｑ -NR Ｌ -, -NR Ｌ -(CH ２ ) ｑ -, -(CH ２ ) ｑ -NR Ｌ C(=O)-, -NR Ｌ (CH ２ ) ｑ C(=O)-, -(CH ２ ) ｑ -C(=O)NR Ｌ -, -C(=O)-, -C(=O)-(CH ２ ) ｑ -NR Ｌ -, -(C≡C) ｑ -, -CH=CH-, -Si(R Ｌ ) ２ -, -Si(OH)(R Ｌ ), -Si(OH) ２ -, -P(=O)(OR Ｌ ), -P(=O)(R Ｌ ), -S-, -S(=O)-, -S(=O) ２ - or a bond, and said -CH ２ - is optionally substituted with 1 to 2 substituents selected from halogen, OH, CN, NH ２ , C １－６ alkyl group, C １－６ alkoxy group, C １－６ alkyl group substituted with halogen, C １－６ alkyl group substituted with hydroxy group, C １－６ alkyl group substituted with cyano group q is independently selected from 0, 1, 2, 3, 4, 5 or 6 respectively, R Ｌ is, independently of each other, H, C １－６ selected from an alkyl group, a 3- to 7-membered heterocyclic group, a 3- to 7-membered cycloalkyl group, a phenyl group or a 5- to 6-membered heteroaryl group, and the heterocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N Each -Cy- is independently selected from a bond, a 4- to 8-membered heteromonocyclic ring, a 4- to 10-membered heterocondensed ring, a 5- to 12-membered heterospiro ring, a 7- to 10-membered heterobridged ring, C ３－７ monocycloalkyl group, C ４－１０ condensed cycloalkyl group, C ５－１２ spirocycloalkyl group, C ７－１０ bridged cycloalkyl group, a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, heterocondensed ring, heterospiro ring or heterobridged ring is optionally substituted with one or two substituents selected from halogen, OH, COOH, CN, NH ２ , =O, C １－４ alkyl group, C alkyl group substituted with halogen １－４ alkyl group substituted with a hydroxy group, C １－４ alkyl group or C １－４ alkoxy group, and the heteroaryl group, heteromonocyclic ring, heterocondensed ring, heterospiro ring or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, it is optionally substituted with one or two =O, B is 【Chemical 1】 selected from X is O, S or CH ２ is selected from Y is NR Ｙ or selected from O, R Ｙ is selected from H, C １－６ alkyl group, C ３－１０ a carbocyclic ring or a 3- to 10-membered heterocyclic ring, and the alkyl group, carbocyclic ring or heterocyclic ring is optionally substituted with halogen, OH, a cyano group, NH ２ , C １－６ alkyl group, C １－６ alkyl group substituted with a halogen, C １－６ alkyl group substituted with a hydroxy group, C １－６ alkyl group substituted with a cyano group, C １－６ alkoxy group, C ３－６ substituted with 1 to 3 substituents selected from a carbocyclic ring or a 3- to 8-membered heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N R １ is selected from H, OH, -(CH ２ ) ｔ２ NR １ａ R １ｂ , C １－６ alkyl group, C １－６ alkoxy group, and the alkyl group and alkoxy group are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano group, NH ２ , C １－６ alkyl group, C １－６ alkyl group substituted with halogen, C １－６ alkyl group substituted with hydroxy group, C １－６ alkyl group substituted with cyano group, C １－６ alkoxy group R １ａ 、 R １ｂ are each independently H, OH, NH ２ , C １－４ alkyl group, C ２－６ alkynyl group, C １－４ alkoxy group, and the alkyl group, alkynyl group, and alkoxy group are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano group, NH ２ , C １－６ alkyl group, C １－６ alkyl group substituted with halogen, C １－６ alkyl group substituted with hydroxy group, C １－６ alkyl group substituted with cyano group, C １－６ alkoxy group, C ２－６ alkynyl group or R １ａ , R １ｂ forms a 3- to 10-membered ring together with the atoms linked thereto, R ３ａ or R ４ is, independently of each other, H, OH, NH ２ , C １－６ alkyl group, C ２－６ alkynyl group, C １－６ alkoxy group, C ３－１０ a carbocyclic ring or a 3- to 10-membered heterocyclic ring, and the alkyl group, alkoxy group, alkynyl group, carbocyclic ring or heterocyclic ring is optionally substituted with halogen, OH, cyano group, NH(CH ３ ), N(CH ３ ) ２ , NH(CH ２ CH ３ ), N(CH ２ CH ３ ) ２ , NH ２ , C １－６ alkyl group, C １－６ alkyl group substituted with halogen, C １－６ alkyl group substituted with hydroxy group, C １－６ alkyl group substituted with cyano group, C １－６ alkoxy group, C ２－６ alkynyl group, C ３－６ cycloalkyloxy group, C ３－６ a carbocyclic ring or a 3- to 8-membered heterocyclic ring, and is substituted with 1 to 4 substituents selected therefrom, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N R ３ｂ or R ５ is, independently of one another, H, halogen, cyano group, NH ２ , NO ２ , OH, C １－６ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－６ alkoxy group, C ３－１０ selected from a carbocyclic ring or a 3- to 10-membered heterocyclic ring, and the alkyl group, alkoxy group, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano group, NH ２ , C １－６ alkyl group, C １－６ alkyl group substituted with halogen, C １－６ alkyl group substituted with a hydroxy group, C １－６ alkyl group substituted with a cyano group, C １－６ alkoxy group, C ３－６ substituted with 1 to 4 substituents selected from a carbocyclic ring or a 3- to 8-membered heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N, t1 is selected from 1, 2, 3, 4 or 5, t2 is selected from 0, 1, 2, 3, 4 or 5, m is selected from 0, 1, 2, 3 or 4, n is selected from 0, 1 or 2, K is [[Chemical 2]] selected from F1 is each independently C ３－７ monocyclic carbocyclic ring, C ４－１４ fused carbocyclic ring, C ５－１２ spiro carbocyclic ring, C ５－１０ bridged carbocyclic ring, C ６－１４ aryl group, 6- to 7-membered non-aromatic heteromonocycle, 5- to 14-membered heterobridged ring, 5- to 6-membered heteroaryl group, 11- to 20-membered heterofused ring, phthalazin-1(2H)-one, benzo[d][1,2,3]triazin-4(3H)-one, benzothienyl group, 【Chemical Formula 3】 selected from, the heteromonocyclic, hetero-condensed ring, heterospiro ring, hetero-bridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, provided that when F1 is selected from 6-membered heteroaryl groups, the right-hand linking site on the ring is a carbon atom, E is, independently of each other, C ５－１２ selected from a carbocyclic ring, a 5- to 12-membered heterocyclic ring, and a 5- to 12-membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, or N, F2 is each independently C ３－７ monocyclic non-aromatic carbocyclic ring, C ４－１０ fused-ring non-aromatic carbocyclic ring, C ５－１２ spiro-ring carbocyclic ring, C ５－１０ bridged-ring carbocyclic ring, C １２－１４ aryl group, 4- to 7-membered non-aromatic heteromonocyclic ring, 5- to 14-membered heterospiro ring, 5- to 14-membered heterobridged ring, 11- to 20-membered hetero-fused ring, [Chemical Formula 4] selected from, the heteromonocyclic, hetero-condensed ring, heterospiro ring, hetero-bridged ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, N, 【Chemical Formula 5】 represents that the ring is selected from an aromatic ring or a non-aromatic ring, F is, independently of each other, C ３－７ a monocyclic carbon ring, C ４－２０ a fused-ring carbon ring, C ５－２０ a spiro-ring carbon ring, C ５－２０ a bridged-ring carbon ring, a 4- to 7-membered hetero-monocyclic ring, a 4- to 20-membered hetero-fused ring, a 5- to 20-membered hetero-spiro ring, or a 5- to 20-membered hetero-bridged ring, wherein the hetero-monocyclic ring, hetero-fused ring, hetero-spiro ring, hetero-bridged ring, or hetero-aromatic ring contains 1 to 4 heteroatoms selected from O, S, and N A is C ３－８ selected from a carbocyclic ring, a benzene ring, a 4- to 7-membered heterocyclic ring, or a 5- to 6-membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, or N, Q1 is each independently selected from -O-, -S-, -CH ２ -, -NR ｑ -, or -CO-, Q is, independently of each other, a bond, -O-, -S-, -CH ２ -, -NR ｑ -, -CO-, -NR ｑ CO-, -CONR ｑ - or selected from 4- to 7-membered heterocycles, said heterocycles being optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH ２ , CN, COOH, CONH ２ , C １－４ alkyl group or C １－４ alkoxy group, and said heterocycles contain 1 to 4 heteroatoms selected from O, S or N R ｑ is selected from H or C １－４ alkyl groups, R ｋ１ is, independently of one another, H, D, F, Cl, Br, I, OH, =O, NH ２ , CN, COOH, CONH ２ , C １－６ alkyl group, C １－６ alkoxy group, C ３－６ cycloalkyl group, R ｋ７ａ is selected from, and the alkyl group, alkoxy group, and cycloalkyl group are optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, =O, NH ２ , CN, COOH, CONH ２ , C １－４ alkyl group, C １－４ alkoxy group, C ３－６ cycloalkyl group, R ｋ３ is, independently of each other, H, D, F, Cl, Br, I, OH, =O, NH ２ , CN, COOH, CONH ２ , C １－６ alkyl group, C １－６ alkoxy group, C ３－８ cycloalkyl group or 3- to 8-membered heterocyclic group, and the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, =O, NH ２ , CN, COOH, CONH ２ , C １－４ alkyl group or C １－４ alkoxy group, and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N or two Rs ｋ３ and the carbon atom or ring skeleton directly linked to both is C ３－８ jointly form a carbocyclic ring or a 3- to 8-membered heterocyclic ring, or two Rs ｋ１ and the carbon atom or ring skeleton directly linked to both is C ３－８ jointly form a carbocyclic ring or a 3- to 8-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH ２ , CN, COOH, CONH ２ , C １－４ alkyl group or C １－４ alkoxy group, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N R ｋ４ is each independently selected from H or C １－４ alkyl groups, R ｋ５ are each independently 【Chemical Formula 6】 C(CH ３ ) ２ 、CO、CH ２ 、SO ２ 、 【Chemical Formula 7】 selected from R ｋ６ is, independently of each other, CO, CH, SO, SO ２ , CH ２ , N or NR ｋ７ａ selected from, R ｋ７ are each independently 【Chemical Formula 8】 C(CH ３ ) ２ , CO, CH, N, CH ２ , O, S, NR ｋ７ａ is selected from R ｋ７ａ is selected from H, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－６ cycloalkyl group, 3- to 6-membered heterocycloalkyl group, and the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH ２ , CN, CF ３ , C １－４ alkyl group, C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－６ cycloalkyl group, and is substituted with 1 to 4 substituents selected therefrom. R ｋ８ each independently selected from C, N or CH, R ｋ９ each independently represents a bond, 【Chemical Formula 9】 C(CH ３ ) ２ , CO, CH ２ , CH ２ CH ２ or SO ２ selected from, R ｋａ is selected from O, S or NH, R ｋ１０ is selected from CH ２ or CO, and p1 or p2 is independently selected from 0, 1, 2, 3, 4 or 5 respectively, The compound is optionally a compound or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof substituted with 1 to 30 Ds.

2. L is -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-,-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9 are selected from, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently, -(CH ２ ), ｑ -(CH ２ ), ｑ -O-, -O-(CH ２ ), ｑ -(CH ２ ), ｑ -NR Ｌ -, -NR Ｌ -(CH ２ ), ｑ -(CH ２ ), ｑ -NR Ｌ C(=O)-, -(CH ２ ), ｑ -C(=O)NR Ｌ -, -C(=O)-, -C(=O)-(CH ２ ), ｑ -NR Ｌ -, -(C≡C) ｑ - or a bond, and said -CH ２ - is optionally substituted with 1 to 2 substituents selected from halogen, OH, CN, NH ２ , C １－４ alkyl group, C １－４ alkoxy group, C １－４ alkyl group substituted with halogen, C １－４ alkyl group substituted with hydroxy group, C １－４ alkyl group substituted with cyano group, Cy1, Cy2, Cy3, Cy4 or Cy5 is each independently a bond, a 4- to 7-membered heteromonocyclic ring, a 4- to 10-membered hetero-condensed ring, a 5- to 12-membered heterospiro ring, a 7- to 10-membered heterobridged ring, C ３－７ monocycloalkyl group, C ４－１０ condensed cycloalkyl group, C ５－１２ member spirocycloalkyl group, C ７－１０ member bridged cycloalkyl group, a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl group, and the aryl group, heteroaryl group, cycloalkyl group, heteromonocyclic ring, hetero-condensed ring, heterospiro ring or heterobridged ring is optionally substituted with one or two substituents selected from F, Cl, Br, I, OH, COOH, CN, NH ２ , =O, C １－４ alkyl group, C substituted with halogen １－４ alkyl group, C substituted with a hydroxy group １－４ alkyl group or C １－４ alkoxy group, and the heteroaryl group, heteromonocyclic ring, hetero-condensed ring, heterospiro ring or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, it is optionally substituted with one or two =O q is independently selected from 0, 1, 2, 3 or 4 respectively, R Ｌ is, independently of one another, H or C １－６ The compound according to claim 1 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, which is selected from an alkyl group

3. Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 each independently represent -(CH ２ ) ｑ -, -(CH ２ ) ｑ -O-, -O-(CH ２ ) ｑ -, -(CH ２ ) ｑ -NR Ｌ --, --NR Ｌ - (CH ２ ) ｑ -, -(CH ２ ) ｑ -NR Ｌ C(=O)-,-(CH ２ ) ｑ -C(=O)NR Ｌ -, -C(=O)-, -C(=O)-(CH ２ ) ｑ -NR Ｌ -, -(C≡C) ｑ - or a bond, ２ - is optionally F, Cl, Br, I, OH, CN, NH ２ , C.F. ３ , hydroxymethyl group, C １－４ Alkyl group, C １－４ substituted with 1 to 2 substituents selected from alkoxy groups; R Ｌ is each independently selected from H or C １－４ alkyl groups, Cy1, Cy2, Cy3, Cy4 or Cy5 is each independently a bond, a 4- to 7-membered nitrogen-containing monocyclic ring, a 4- to 10-membered nitrogen-containing condensed ring, a 5- to 12-membered nitrogen-containing spiro ring, a 7- to 10-membered nitrogen-containing bridged ring, C ３－７ monocycloalkyl group, C ４－１０ condensed cycloalkyl group, C ５－１２ spirocycloalkyl group, C ７－１０ bridged cycloalkyl group, a 5- to 10-membered heteroaryl group or a 6- to 10-membered aryl group, and the monocyclic ring, condensed ring, bridged ring, spiro ring, cycloalkyl group, aryl group or heteroaryl group is optionally substituted with 1 to 2 substituents selected from F, Cl, Br, I, OH, COOH, CN, NH ２ , =O, C １－４ alkyl group, C substituted with halogen １－４ alkyl group, C substituted with a hydroxy group １－４ alkyl group or C １－４ alkoxy group, and the monocyclic ring, condensed ring, bridged ring, spiro ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, it is optionally substituted with 1 or 2 =O R Ｙ is selected from H, a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cyclopropyl group, and the methyl group, ethyl group, propyl group, isopropyl group, and cyclopropyl group are optionally halogen, OH, a cyano group, NH ２ , C １－４ alkyl group, C １－４ alkyl group substituted with a halogen, C １－４ alkyl group substituted with a hydroxy group, C １－４ alkyl group substituted with a cyano group, C １－４ alkoxy group, C ３－６ substituted with 1 to 3 substituents selected from a carbocyclic ring or a 3- to 6-membered heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N, R １ is selected from H, OH, NR １ａ R １ｂ , a methyl group, an ethyl group, a propyl group, an isopropyl group, and a methoxy group, and the methyl group, ethyl group, propyl group, isopropyl group, or methoxy group is optionally substituted with one to three substituents selected from halogen, OH, a cyano group, NH ２ , C １－４ alkyl group, C substituted with halogen １－４ alkyl group, C substituted with a hydroxy group １－４ alkyl group, C substituted with a cyano group １－４ alkyl group, C １－４ alkoxy group, R １ａ and R １ｂ are each independently selected from H, OH, NH ２ , a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, a propargyl group, a propynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, propargyl group, propynyl group are optionally substituted with a halogen, OH, a cyano group, NH ２ , C １－４ alkyl group, C １－４ alkyl group substituted with a halogen, C １－４ alkyl group substituted with a hydroxy group, C １－４ alkyl group substituted with a cyano group, C １－４ alkoxy group, C ２－４ alkynyl group, and are substituted with 1 to 3 substituents selected therefrom R ３ａ or R ４ is, independently of each other, H, OH, NH ２ , methyl group, ethyl group, propyl group, propargyl group, propynyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, and is selected from the group consisting of, the methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, propargyl group, propynyl group is optionally, halogen, OH, cyano group, NH ２ , C １－４ alkyl group, C substituted with halogen １－４ alkyl group, C substituted with a hydroxy group １－４ alkyl group, C substituted with a cyano group １－４ alkyl group, C １－４ alkoxy group, C ３－６ cycloalkyloxy group, C ２－４ alkynyl group, C ３－６ substituted with 1 to 3 substituents selected from a carbocyclic ring or a 3- to 6-membered heterocyclic ring, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N R ３ｂ or R ５ is, independently of one another, H, F, Cl, Br, I, a cyano group, NH ２ , OH, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an ethynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, ethynyl group are optionally substituted with a halogen, OH, a cyano group, NH ２ , C １－４ alkyl group, a C １－４ alkyl group substituted with a halogen, a C １－４ alkyl group substituted with a hydroxy group, a C １－４ alkyl group substituted with a cyano group, C １－４ alkoxy group, C ３－６ is substituted with 1 to 3 substituents selected from a carbocyclic ring or a 3- to 6-membered heterocyclic ring, and the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N F1 is independently a cyclobutyl group, cyclopentyl group, cyclohexyl group, piperidinyl group, piperazinyl group, phenyl group, naphthyl group, pyridyl group, pyrazinyl group, pyridazinyl group, pyridazinone group, pyrimidinyl group, phthalazin-1(2H)-one, benzo[d][1,2,3]triazin-4(3H)-one, thienyl group, benzothienyl group, triazole group, 【Chemical Formula 10】 selected from 【Chemical 11】 is selected from a single bond or a double bond, F2 is independently 【Chemical Formula 12】 selected from F is independently selected from a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, a furyl group, a thienyl group, a thiazolyl group, a 2-pyridonyl group, a pyrazolyl group, a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a benzothiazolyl group, an indolyl group, 【Chemical 13】 selected from, E or A is independently selected from a benzene ring, a naphthalene ring or a pyridine ring, E1 is independently, 【Chemical 14】 selected from, E2 is independently selected from a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, a thiophene ring, a furan ring, R ｑ is selected from H, a methyl group, and an ethyl group, R ｋ１ 、R ｋ３ is each independently H, D, F, Cl, Br, I, OH, =O, NH ２ , CF ３ , CN, COOH, CONH ２ , C １－４ alkyl group or C １－４ alkoxy group, R ｋ７ａ is selected from, and the alkyl group or alkoxy group is optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH or NH ２ and is substituted with or two Rs ｋ３ and the carbon atom or ring skeleton directly linked to both is C ３－７ together form a carbocyclic ring or a 3- to 7-membered heterocyclic ring, or two Rs ｋ１ and the carbon atom or ring skeleton directly linked to both is C ３－７ together form a carbocyclic ring or a 3- to 7-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, =O, NH ２ , CN, COOH, CONH ２ , C １－４ alkyl group or C １－４ alkoxy group, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, N R ｋ４ is independently selected from H, a methyl group, an ethyl group or a propyl group, R ｋ５ each independently represents CO, CH ２ , SO ２ or 【Chemical Formula 15】 selected from, R ｋ７ａ is selected from H, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－６ cycloalkyl group, 3- to 6-membered heterocyclic group, and the alkyl group, alkenyl group, alkynyl group, heterocyclic group or cycloalkyl group is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CF ３ , C １－４ alkyl group, C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, C ３－６ cycloalkyl group, R ｋ９ is, independently of one another, CO, SO ２ or CH ２ selected from, R ｋｂ is selected from a bond or CO, R ｋ１０ is selected from CH ２ or CO, and R ｋ１１ is NH, O or CH ２ The compound according to claim 2, or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, selected from

4. Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 each independently represent -(CH ２ ) ｑ -, -(CH ２ ) ｑ -O-, -O-(CH ２ ) ｑ -, -(CH ２ ) ｑ -NR Ｌ --, --NR Ｌ - (CH ２ ) ｑ -, -(CH ２ ) ｑ -NR Ｌ C(=O)-,-(CH ２ ) ｑ -C(=O)NR Ｌ -, -C(=O)-, -C(=O)-(CH ２ ) ｑ -NR Ｌ -, -(C≡C) ｑ - or a bond, ２ - is optionally F, Cl, Br, I, OH, CN, NH ２ , C.F. ３ , substituted with 1 to 2 substituents selected from a hydroxymethyl group, a methyl group, an ethyl group, a methoxy group, or an ethoxy group; R Ｌ is selected from H, a methyl group or an ethyl group, q is independently selected from 0, 1, 2 or 3, Cy1, Cy2, Cy3, Cy4 or Cy5 is each independently a cycloalkyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, pyrrolidinyl group, azacyclohexenyl group, piperidinyl group, morpholinyl group, piperazinyl group, 1,4-diazepanyl group, phenyl group, pyridyl group, cyclopropyl-fused cyclopropyl group, cyclopropyl-fused cyclobutyl group, cyclopropyl-fused cyclopentyl group, cyclopropyl-fused cyclohexyl group, cyclobutyl-fused cyclobutyl group, cyclobutyl-fused cyclopentyl group, cyclobutyl-fused cyclohexyl group, cyclopentyl-fused cyclopentyl group, cyclopentyl-fused cyclohexyl group, cyclohexyl-fused cyclohexyl group, cyclopropyl-spiro-cyclopropyl group, cyclopropyl-spiro-cyclobutyl group, cyclopropyl-spiro-cyclopentyl group, cyclopropyl-spiro-cyclohexyl group, cyclobutyl-spiro-cyclobutyl group, cyclobutyl-spiro-cyclopentyl group, cyclobutyl-spiro-cyclohexyl group, cyclopentyl-spiro-cyclopentyl group, cyclopentyl-spiro-cyclohexyl group, cyclohexyl-spiro-cyclohexyl group, cyclopropyl-fused azetidinyl group, cyclopropyl-fused pyrrolidinyl group, cyclopropyl-fused piperidinyl group, cyclobutyl-fused azetidinyl group, cyclobutyl-fused pyrrolidinyl group, cyclobutyl-fused piperidinyl group, cyclopentyl-fused azetidinyl group, cyclopentyl-fused pyrrolidinyl group, cyclopentyl-fused piperidinyl group, cyclohexyl-fused azetidinyl group, cyclohexyl-fused pyrrolidinyl group, cyclohexyl-fused piperidinyl group, azetidinyl-fused azetidinyl group, azetidinyl-fused pyrrolidinyl group, azetidinyl-fused piperidinyl group, pyrrolidinyl-fused azetidinyl group, pyrrolidinyl-fused pyrrolidinyl group, pyrrolidinyl-fused piperidinyl group, piperidinyl-fused azetidinyl group, piperidinyl-fused pyrrolidinyl group, piperidinyl-fused piperidinyl group, cyclopropyl-spiro-azetidinyl group, cyclopropyl-spiro-pyrrolidinyl group, cyclopropyl-spiro-piperidinyl group, cyclopropyl-spiro-piperazinyl group, cyclobutyl-spiro-azetidinyl group, cyclobutyl-spiro-pyrrolidinyl group, which is bonded or substituted or unsubstituted,Cyclobutyl-spiro-piperidinyl group, cyclopentyl-spiro-azetidinyl group, cyclopentyl-spiro-pyrrolidinyl group, cyclopentyl-spiro-piperidinyl group, cyclohexyl-spiro-azetidinyl group, cyclohexyl-spiro-pyrrolidinyl group, cyclohexyl-spiro-piperidinyl group, azetidinyl-spiro-azetidinyl group, azetidinyl-spiro-pyrrolidinyl group, azetidinyl-spiro-piperidinyl group, pyrrolidinyl-spiro-azetidinyl group, pyrrolidinyl-spiro-pyrrolidinyl group, pyrrolidinyl-spiro-piperidinyl group, piperidinyl-spiro-azetidinyl group, piperidinyl-spiro-pyrrolidinyl group, piperidinyl-spiro-piperidinyl group, cyclopropyl-spiro-piperazinyl group, 【Chemical Formula 16】 selected from one of the groups, and when substituted, optionally, F, Cl, Br, I, OH, NH ２ , COOH, CN, =O, C １－４ alkyl group, C substituted with halogen １－４ alkyl group, C substituted with hydroxy group １－４ alkyl group or C １－４ substituted with 1 to 4 substituents selected from alkoxy groups X is selected from O or S, Y is selected from NH or O, R １ is selected from H, OH, NR １ａ R １ｂ , a methyl group, an ethyl group, a propyl group, an isopropyl group, and a methoxy group, and the methyl group, ethyl group, propyl group, isopropyl group or methoxy group is optionally F, Cl, Br, I, OH, a cyano group, NH ２ , a methyl group, an ethyl group, CF ３ and is substituted with 1 to 3 substituents selected from R １ａ and R １ｂ are each independently selected from H, OH, NH ２ , a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, a propargyl group, a propynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, propargyl group, propynyl group are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, a cyano group, NH ２ , a methyl group, an ethyl group, a methoxy group, an ethynyl group, CF ３ and are substituted with 1 to 3 substituents selected therefrom, R ３ａ is selected from H, OH, NH ２ , methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, propargyl group, propynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, propargyl group, propynyl group are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, cyano group, NH ２ , methyl group, ethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, ethynyl group, methoxy group, cyclopropyloxy group R ４ each independently selected from H, a methyl group, an ethyl group, and a cyclopropyl group R ３ｂ is independently selected from H, F, Cl, Br, I, OH, CN, a methoxy group, a methyl group, an ethyl group, and a cyclopropyl group, R ５ is each independently selected from H, F, Cl, Br, I, a cyano group, NH ２ , OH, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a cyclopropyl group, an ethynyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropyl group, ethynyl group are optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, OH, a cyano group, NH ２ , a methyl group, an ethyl group, a cyclopropyl group, F1 is independently selected from a cyclohexane group, a piperidinyl group, a piperazinyl group, a phenyl group, a naphthyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a pyridazinone group, phthalazin-1(2H)-one, benzo[d][1,2,3]triazin-4(3H)-one, a thienyl group, a triazolyl group, 【Chemical 17】 selected from, F2 is independently, 【Chemical 18】 selected from, F is independently selected from a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, a furyl group, a thienyl group, a thiazolyl group, a 2-pyridonyl group, a pyrazolyl group, a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a benzothiazolyl group, an indolyl group, 【Chemical 19】 selected from, Q1 is selected from -O-, -S-, -CH ２ -, NH, N(CH ３ ) or -CO-, Q is a bond, C(=O), CH ２ , NH, N(CH ３ ), O, S, NH C(=O), C(=O)NH, N(CH ３ ), C(=O), N(CH ３ ), 【Chemical 20】 selected from, R ｋ７ａ is selected from H, a methyl group, an ethyl group, a propyl group, an isopropyl group, a vinyl group, a propenyl group, an allyl group, an ethynyl group, a propynyl group, a propargyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, and the methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group are optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CF ３ , C １－４ alkyl group, C １－４ alkoxy group, vinyl group, propenyl group, allyl group, ethynyl group, propynyl group, propargyl group, C ３－６ cycloalkyl group, and is substituted with R ｋ１ and R ｋ３ are each independently selected from H, D, F, Cl, Br, I, OH, =O, NH ２ , CF ３ , CN, COOH, CONH ２ , a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, an isopropoxy group, an ethynyl group, a cyclopropyl group, an azetidinyl group, and the methyl group, ethyl group, isopropyl group, methoxy group, ethoxy group, isopropoxy group, ethynyl group, cyclopropyl group, azetidinyl group are optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, NH ２ , CN, a cyclopropyl group, and a methoxy group, or two Rs ｋ３ and the carbon atom or ring skeleton directly linked to both is C ３－６ together form a carbocyclic ring or a 3- to 7-membered heterocyclic ring, or two Rs ｋ１ and the carbon atom or ring skeleton directly linked to both is C ３－６ together form a carbocyclic ring or a 3- to 7-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from D, F, Cl, Br, I, OH, =O, NH ２ , CN, COOH, CONH ２ , C １－４ alkyl group or C １－４ alkoxy group, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N p1 or p2 is independently selected from 0, 1, 2 or 3, the compound according to claim 3 or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.

5. Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently a bond, -O-, -OCH ２ -, -CH ２ O-, -OCH ２ CH ２ -, -CH ２ CH ２ O-, -C≡C-, -C(CH ３ ) ２ -, -CF ２ -, -CH ２ -, -CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -N(CH ３ )-, -NH-, -CH ２ N(CH ３ )-, -CH ２ NH-, -NHCH ２ -, -CH ２ CH ２ N(CH ３ )-, -CH ２ CH ２ NH-, -NHCH ２ CH ２ -, -C(=O)-, -C(=O)CH ２ NH-, -CH ２ C(=O)NH-, -C(=O)NH- or -NHC(=O)-, and is selected from Cy1, Cy2, Cy3, Cy4 or Cy5 is independently a bond or a substituted or unsubstituted, 【Chemical 21】 selected from one of the groups, and when substituted, F, CF ３ , OH, methyl group, =O, hydroxymethyl group, COOH, CN or NH ２ substituted with 1 to 4 substituents selected from B is selected from one of the structural fragments shown in Table B-1, K is selected from one of the structural fragments shown in Table K-1 or K-2, the compound according to claim 4 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

6. L is a combination, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5--Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3- selected from, the compound according to claim 5 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

7. L is selected from a bond or one of the structural fragments shown in Table L-1, wherein the left side of the group is linked to B, the compound according to claim 6 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

8. L is selected from a bond or one of the structural fragments shown in Table L-2, wherein the left side of the group is linked to B, K is selected from one of the structural fragments shown in Table K-2, the compound according to claim 6 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. The compound of general formula (I) is selected from the compounds of general formula (II), 【Chemical 22】 L1 is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, Ak1 is -CH ２ -, -O-, -CH ２ -CH ２ - selected from, The definitions of Cy1, Cy2, and Cy3 are the same as those in claim 5, F1 is selected from a phenyl group, a 5- to 6-membered heteroaryl group or a 13- to 14-membered hetero tricyclic condensed ring, The definition of B is the same as that in claim 1, R ｋ１ 、 wherein the definition of p1 is the same as that in claim 4, the compound according to claim 1 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

10. The compound of general formula (I) is selected from the compounds of general formula (III), 【Chemical 23】 The definition of B is the same as that in claim 1, L2 is selected from -Cy1-, -Cy1-Ak1- or -Cy1-Ak1-Cy2-, Cy1 or Cy2 is each independently substituted or unsubstituted, 【Chemical 24】 selected from among one of the groups, and when substituted, F, CF ３ , OH, a methyl group, =O, a hydroxymethyl group, COOH, CN or NH ２ substituted with 1 to 4 substituents selected from Ak1 is -CH ２ -, -O-, -CH ２ -CH ２ - and is selected from R ｋ１ is, independently of each other, H, D, F, Cl, Br, I, OH, =O, NH ２ , CF ３ , CN, COOH, CONH ２ , and is selected from a methyl group, an ethyl group, a methoxy group, and an ethoxy group, p1 is selected from 0, 1 or 2, the compound according to claim 1 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

11. The compound is selected from one of the structures of Table S-1, the compound according to claim 1 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises 1 to 1500 mg of the compound according to any one of Claims 1 to 11 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutical excipient, a pharmaceutical composition or pharmaceutical preparation.

14. Use in the manufacture of a medicament for treating a disease related to Bcl6 activity or expression level of the compound according to any one of Claims 1 to 11 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or the pharmaceutical composition according to Claim 12 or 13.

15. Use in the manufacture of a medicament for treating a disease related to the inhibition or degradation of Bcl6 of the compound according to any one of Claims 1 to 11 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or the pharmaceutical composition according to Claim 12 or 13.

16. The application according to Claim 14 or 15, wherein the disease is selected from cancer.

17. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound according to any one of Claims 1 to 11 or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or the pharmaceutical composition according to Claim 12 or 13, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably cancer.

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