A CDK kinase inhibitor and its application

Abstract

The present invention discloses a compound of general formula I, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and a composition containing the compound of general formula I, and use of the compound of general formula I, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof in the preparation of a drug for treating one or more cyclin-dependent kinase-related diseases.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a cyclin-dependent kinase inhibitor and application thereof. Background Art

[0002] Cyclin-dependent kinases (CDKs) are a set of Ser / Thr kinase systems corresponding to the cell cycle process. Cyclin-dependent protein kinases are a group of serine / threonine protein kinases. CDKs drive the cell cycle through chemical effects on serine / threonine proteins and work synergistically with cyclin, an important factor in cell cycle regulation. CDKs can bind to cyclin to form heterodimers, in which CDKs are catalytic subunits and cyclins are regulatory subunits. Different cyclin-CDK complexes, through CDK activity, catalyze the phosphorylation of different substrates, thereby achieving the promotion and transformation of different phases of the cell cycle. The activity of CDK depends on the sequential expression of its positive regulatory subunit cyclin and the concentration of its negative regulatory subunit CKI (cyclin dependent kinase inhibitor, CDK inhibitor). At the same time, the activity of CDK is also regulated by phosphorylation and dephosphorylation, as well as oncogenes and tumor suppressor genes.

[0003] There are 8 types of CDK family, including CDK 1-8. Each CDK binds to different types of cyclins to form a complex, regulating the transition of cells from G1 phase to S phase or G2 phase to M phase and exit from M phase. Various CDKs are activated alternately along the cell cycle phases, phosphorylating corresponding substrates, so that cell cycle events proceed in an orderly manner.

[0004] CDKs have three important functional domains. The first functional domain is the binding site of ATP and the active part of the enzyme; the second functional domain is the binding site of the regulatory subunit (Cyclin); the third functional domain is the binding site of P13suc1 (P13suc1 can inhibit kinase activity and prevent cells from entering or exiting the M phase). Various CDKs are activated at specific times during the cell cycle and drive cells to complete the cell cycle by phosphorylating substrates.

[0005] Patent document CN200680047113.0 provides a novel imidazo[1,2-a]pyrazine compound as a cyclin-dependent kinase inhibitor, the general formula of which is The compound or pharmaceutical composition can be used to treat, prevent, inhibit or alleviate one or more diseases associated with CDKs.

[0006] In 1998, J Clin Oncol published a CDK inhibitor, flavopiridol, with the structure It is a non-selective CDK inhibitor currently undergoing human clinical trials.

[0007] Patent document CN200680025008.7 discloses a new class of compounds having the structure The pharmaceutical composition containing the compound can be used to treat or prevent diseases or disorders associated with abnormal or unregulated kinase activity, especially diseases or disorders associated with abnormal activation of CDKs, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR kinases.

[0008] Based on the above background, the present invention provides a novel compound and a pharmaceutical composition thereof for treating diseases and disorders associated with CDK. Summary of the invention

[0009] One object of the present invention is to provide a compound of general formula I and a preparation method thereof, wherein the compound is a CDK kinase inhibitor; another object of the present invention is to provide a use of the compound.

[0010] The objective of the present invention is achieved through the following technical solutions:

[0011] The present invention provides a compound of general formula I:

[0012]

[0013] Wherein, A is selected from C or N, and B is selected from C or N.

[0014] R 1 Selected from -H, halogen, -CN, -OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -OH, -NO 2 , carboxyl and its substituents, -S(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2(C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 alkyl), S(O)k(C 0-10 alkyl), k = 0-2, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -OCH 2 F, -OCHF 2 、-OCF 3 、-OH、C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, -Sheterocycloalkyl, -Nheteroaromatic, -Oheteroaromatic, -Sheteroaromatic.

[0015] R 2 Selected from -H, halogen, -NO 2 、-CN、C 1-5 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, -OC 0-10 Alkyl, -OH, carboxyl and its substituents, -S(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 alkyl), S(O)k(C 0-10 alkyl), k = 0-2, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -OCH 2 F, -OCHF 2 、-OCF 3 、-OH、C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC0-10 Alkyl, C 3-10 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, -Sheterocycloalkyl, -Nheteroaromatic, -Oheteroaromatic, -Sheteroaromatic.

[0016] When B is N, R 3 does not exist, when B is C, R 3 Selected from -H, halogen, -NO 2 、-CN、C 1-5 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, -OC 0-10 Alkyl, -OH, carboxyl and its substituents, -S(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 alkyl), S(O)k(C 0-10 alkyl), k = 0-2, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -OCH 2 F, -OCHF 2 、-OCF 3 、-OH、C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, -Sheterocycloalkyl, -Nheteroaromatic, -Oheteroaromatic, -Sheteroaromatic.

[0017] R 4 Selected from -H, halogen, -NO 2 、-CN、-CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, -OC0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -OH, -NO 2 , carboxyl and its substituents, -S(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 alkyl), S(O)k(C 0-10 alkyl), k = 0-2, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -OCH 2 F, -OCHF 2 、-OCF 3 、-OH、C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, -Sheterocycloalkyl, -Nheteroaromatic, -Oheteroaromatic, -Sheteroaromatic.

[0018] In Formula I, the dashed line represents a single bond (i.e., R 6 and R 7 connected by the single bond, forming a ring with the carbon atom to which it is attached) or not present (i.e., R 6 and R 7 Not connected).

[0019] R 5 , R 6 and R 7 independently selected from -H, halogen, -NO 2 、-CN、-CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, -OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic, carboxyl and its substituents, -N(O)(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10 Alkyl)(C 0-10 alkyl), S(O)k(C 0-10 alkyl), k=0-2, N, O or S substituted fused cycloalkyl, N, O or S substituted spirocycloalkyl, N, O or S substituted bridged cycloalkyl, -O heterocyclic aromatic or -S heterocyclic aromatic, wherein the H on the above groups may be substituted by the following groups: halogen, -CN, -OCH 2 F, -OCHF 2 、-OCF 3 、-OH、-CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)COO(C 0-10 Alkyl), -OCON(C 0-10 Alkyl)(C 0-10 Alkyl), C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic, -O heterocyclic aromatic, -S heterocyclic aromatic, wherein the alkyl portion of the group may be arbitrarily substituted by one or more of the following groups: halogen, -CN, -OH, C 1-4 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-4 Cycloalkyl, carbonyl, or R 6 , R7 With R 6 and R 7 The atoms between them form C 3-8 Cycloalkyl or C containing O, N or S 3-8 Heterocycloalkyl.

[0020] Ring Ar and Ring R g Fused, the fused bond is any bond on the ring Ar.

[0021] Ring Ar is selected from an aromatic five-membered heterocyclic group, an aromatic six-membered heterocyclic group or a phenyl group, wherein the aromatic five-membered heterocyclic group is selected from: imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, furanyl or thienyl, and the aromatic six-membered heterocyclic group is selected from: pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, and the H on the optional aromatic five-membered heterocyclic group, aromatic six-membered heterocyclic group or phenyl group may be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO 2 、-SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO 2 N(C 0-10 alkyl)CON(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 、-N(C 0-10 alkyl)CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 The cycloalkyl radicals are -0, -0, -1, -2 ...

[0022] In one embodiment of the present invention, ring Ar is pyrrolyl, such as

[0023] Ring R g Selected from C 3-8 Saturated / unsaturated cycloalkyl or C containing -O-, -N-, -S- 3-8 Saturated / unsaturated heterocycloalkyl, optionally C 3-8 Saturated / unsaturated cycloalkyl or C containing -O-, -N-, -S- 3-8The H on the saturated / unsaturated heterocycloalkyl group can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO 2 、-SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO 2 N(C 0-10 alkyl)CON(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 、-N(C 0-10 alkyl)CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 The cycloalkyl radicals are -0, -0, -1, -2 ...

[0024] In one embodiment of the present invention, ring R g for R 8 Selected from O, S or N-R 9 , R 9 Selected from -H, halogen, -CN, -CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, -OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, -Sheterocycloalkyl.

[0025] Preferably, the compound has the following general formula:

[0026]

[0027] Preferably, R 1 Selected from -H, halogen, -CN, -OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, more preferably, R 1 Selected from H, -CN, -CH3 、-CH 2 CH 3 .

[0028] Preferably, B is N, R 3 Does not exist.

[0029] R 5 , R 6 and R 7 Independently selected from halogen, -CN, -CF 3 、-OCF 3 、-OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic, N, O substituted fused cycloalkyl, N, O substituted spirocycloalkyl, N, O substituted bridged cycloalkyl, wherein the H on the above groups may be substituted by the following groups: halogen, -CN, -OH, -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aromatic, -O heterocyclic aromatic, wherein the alkyl portion of the group may be arbitrarily substituted by one or more of the following groups: halogen, -CN, -OH, C 1-4 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-4 Cycloalkyl, carbonyl, or R 6 , R 7 With R 6 and R 7 The atoms between them form C 3-8 Cycloalkyl or N-containing C 3-8 Heterocycloalkyl.

[0030] Preferably, R 4 and R 5 Independently selected from -H, halogen, -CN, -CF3 、-OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl; more preferably, R 4 and R 5 Independently selected from H, -CN, -CH 3 、-CH 2 CH 3 .

[0031] Preferably, R 7 Selected from -H, halogen, -CN, -CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, -OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 More preferably, R 7 Selected from H, -CN, -CH 3 、-CH 2 CH 3 .

[0032] R 14 , R 15 and R 16 independently selected from -H, halogen, -NO 2 、-CN、-CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, -OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, carboxyl and substituents thereof, -CON(C 0-10 Alkyl)(C 0-10 alkyl), -N(O)(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 (C 0-10 Alkyl), -SO 2 N(C 0-10Alkyl)(C 0-10 alkyl), S(O)k(C 0-10 alkyl), k = 0-2, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -OCH 2 F, -OCHF 2 、-OCF 3 、-OH、C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, -Sheterocycloalkyl, -Nheteroaromatic, -Oheteroaromatic, -Sheteroaromatic.

[0033] Preferably, R 14 , R 15 and R 16 Independently selected from -H, halogen, -CN, -CF 3 、-OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl.

[0034] More preferably, R 14 , R 15 and R 16 Independently selected from H, -CN, -CH 3 、-CH 2 CH 3 .

[0035] In a preferred embodiment of the present invention, the compound has the following general formula:

[0036]

[0037] Preferably, the ring Ar is selected from imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl or phenyl, and optionally the H on the imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl or phenyl may be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO 2 、-SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO 2 N(C 0-10 alkyl)CON(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2 、-N(C 0-10 alkyl)CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 The cycloalkyl radicals are -0, -0, -1, -2 ...

[0038] Preferably, ring R g Selected from C 5-7 Saturated / unsaturated cycloalkyl or C containing -O-, -N- 5-7 Saturated / unsaturated heterocycloalkyl, optionally C 5-7 Saturated / unsaturated cycloalkyl or C containing -O-, -N- 5-7 The H on the saturated / unsaturated heterocycloalkyl group can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO 2 、-SO 2 N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO 2 N(C 0-10 alkyl)CON(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)SO 2 、-N(C 0-10 alkyl)CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 The cycloalkyl radicals are -0, -0, -1, -2 ...

[0039] R 8 Selected from O, ring R g C 5-7 Saturated / unsaturated cyclic ketone, C 5-7 Saturated / unsaturated cyclic lactone, C 5-7 Saturated / unsaturated cyclic lactams.

[0040] In a preferred embodiment of the present invention, ring Ar and ring R g The fused ring structure formed is as follows:

[0041]

[0042] R 11 , R 12 , R 13 , R 13 'Independently selected from -H, halogen, -NO 2 、-CN、-CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, -OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, -Sheterocycloalkyl.

[0043] Preferably, R 11 , R 12 , R 13 , R 13 'Independently selected from -H, halogen, -NO 2 、-CN、-CF 3 , C 1-6 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-7 Cycloalkyl.

[0044] More preferably, R 11 , R 12 , R 13 , R 13 'Independently selected from -H, halogen, -CN, -CH 3 .

[0045] n is an integer between 0-6, such as 0, 1, 2, 3, 4, 5 and 6.

[0046] In a preferred embodiment of the present invention, the structural formula of the compound is as follows:

[0047]

[0048]

[0049]

[0050] Preferably, A is N and B is N.

[0051] R 2 Selected from -H, halogen, -CN, C 1-5 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -CF 3 , wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -OH, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, -Sheterocycloalkyl.

[0052] In a preferred embodiment of the present invention, the R 1 Select from -H or F.

[0053] Preferably, R 6 Selected from halogen, -OC 0-10 Alkyl, C 1-6 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aromatic, N, O substituted fused cycloalkyl, N, O substituted spirocycloalkyl, N, O substituted bridged cycloalkyl, wherein the H on the above groups may be substituted by the following groups: -CN, -OH, -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aromatic, -O heterocyclic aromatic, wherein the alkyl portion of the group may be arbitrarily substituted by one or more of the following groups: -OH, C 1-4 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-4 Cycloalkyl, carbonyl.

[0054] Preferably, R6 Selected from

[0055] Wherein, X is selected from N or O; Y is selected from C, N, O or S; m is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4; p, q, s are selected from an integer between 1 and 4, such as 1, 2, 3, 4; R 17 Selected from: -OH, halogen, C 1-6 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-5 Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, wherein the alkyl part of said groups may be substituted by a carbonyl group.

[0056] In a preferred embodiment of the present invention, the R 6 Selected from:

[0057] R 10 Selected from halogen, -CN, -CF 3 、-OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -OH, -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aromatic, -O heterocyclic aromatic, wherein the alkyl portion of the group may be arbitrarily substituted by one or more of the following groups: halogen, -CN, -OH, C 1-4 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10Alkyl), C 3-4 Cycloalkyl, carbonyl.

[0058] Preferably, R 10 Selected from -OC 0-10 Alkyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, wherein the H on the above groups may be substituted by the following groups: halogen, -CN, -OH, -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -N heterocyclic aromatic, -O heterocyclic aromatic, wherein the alkyl portion of the group may be arbitrarily substituted by one or more of the following groups: halogen, -CN, -OH, C 1-4 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), C 3-4 Cycloalkyl, carbonyl.

[0059] Preferably, R 10 Selected from H, C 1-5 Straight chain / branched alkyl, hydroxy substituted C 1-5 Straight chain / branched chain alkyl,

[0060] Wherein, X is selected from N or O; Y is selected from C, N, O or S; m is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4; p, q, s are selected from an integer between 1 and 4, such as 1, 2, 3, 4; f is selected from an integer between 1 and 3, such as 1, 2, 3; g is 1 or 2; R 17 Selected from: -OH, halogen, C 1-6 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-5Cycloalkyl, -Oheterocycloalkyl, -Nheterocycloalkyl, wherein the alkyl part of said groups may be substituted by a carbonyl group.

[0061] In a preferred embodiment of the present invention, the R 10 Selected from: -H,

[0062] In a preferred embodiment of the present invention, the structural formula of the compound is as follows:

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071] The general compounds of the present invention also include pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof.

[0072] The present invention provides a pharmaceutical composition, which comprises a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and also comprises a pharmaceutically acceptable excipient.

[0073] Specifically, the auxiliary materials are selected from: carriers, diluents, adhesives, lubricants, wetting agents and the like.

[0074] Preferably, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I.

[0075] In certain embodiments, the pharmaceutical composition can be used alone or in combination with other types of pharmaceutical preparations.

[0076] The other types of drug preparations include: DNA interfering agents such as cisplatin or doxorubicin, paclitaxel, docetaxel or eplastidone, tamoxifen, methotrexate, uracil nitrogen mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, pipobroman, trothamide, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorouracil deoxynucleoside, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, levofloxacin, oxaliplatin, doxorubicin, trastuzumab, fulvestrant, exemestane, rituximab.

[0077] Preferably, the pharmaceutical composition also includes antioxidants, buffers, antibacterial agents, etc., and solutes that make the preparation isotonic with the subject's blood, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents, solubilizers, thickeners, stabilizers and preservatives, etc.

[0078] The pharmaceutical composition is suitable for enteral or parenteral administration, such as administration via intravenous, intramuscular, intradermal and subcutaneous routes.

[0079] The pharmaceutical composition can be prepared into pharmaceutical preparations in the following forms: injection, syrup, elixir, suspension, powder, granule, tablet, capsule, lozenge, cream, ointment, lotion, gel, emulsion, etc.

[0080] When preparing injections, any commonly used carrier in the art can be used, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, etc. In addition, commonly used solvents and buffers can also be added.

[0081] The present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds for use in preparing drugs for inhibiting one or more cyclin-dependent kinases (CDKs).

[0082] The present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds for use in preparing drugs for treating one or more cyclin-dependent kinase (CDK)-related diseases.

[0083] Preferably, the cyclin-dependent kinase is CDK1-8, and more preferably, the cyclin-dependent kinase is CDK4 or CDK6.

[0084] The disease associated with cyclin dependent kinase (CDK) is a proliferative disease selected from cancer, autoimmune disease, viral disease, fungal disease, neuropathy, arthritis, inflammation, neuronal disease, alopecia and cardiovascular disease.

[0085] The cancer includes but is not limited to malignant tumors, hematopoietic tumors of the lymphatic system, hematopoietic tumors of the bone marrow system, tumors of mesenchymal origin, and tumors of the central and peripheral nervous systems.

[0086] The malignant tumor is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer), head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer.

[0087] The hematopoietic tumor of the lymphatic system is selected from the group consisting of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma.

[0088] The hematopoietic tumor of the myeloid system is selected from the group consisting of acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia.

[0089] The tumor of mesenchymal origin is selected from the group consisting of fibrosarcoma and rhabdomyosarcoma.

[0090] The tumors of the central and peripheral nervous systems are selected from the group consisting of astrocytomas, neurofibromas, gliomas and schwannomas.

[0091] The autoimmune disease is selected from the group consisting of systemic lupus, lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes.

[0092] The viral infection is selected from the group consisting of: herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus.

[0093] The neuropathic condition is selected from the group consisting of Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration.

[0094] Preferably, the compound of formula I and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof can be used alone or in combination with other types of pharmaceutical preparations and / or therapeutic methods.

[0095] The other types of pharmaceutical preparations include, but are not limited to, cell growth inhibitors, cytotoxic agents, microtubule protein interaction agents, hormone agents, anti-metabolites, and anti-tumor agents. The treatment methods include, but are not limited to, hormone therapy, immunotherapy, and radiotherapy; preferably, hormone therapy is used in combination with immunotherapy.

[0096] The cytotoxic agent is selected from: DNA interfering agents such as cisplatin or doxorubicin.

[0097] The microtubule protein interaction agent is selected from: paclitaxel, docetaxel or epsilon.

[0098] The hormonal agent is selected from: tamoxifen.

[0099] The antimetabolite is selected from the group consisting of: methotrexate.

[0100] The anti-tumor agent is selected from: uracil mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, pipobroman, trothamide, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorouracil deoxyribonucleoside, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, levofloxacin, oxaliplatin, doxorubicin, trastuzumab, fulvestrant, exemestane, rituximab.

[0101] The present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds for use in preventing and / or treating cancer, autoimmune diseases, viral diseases, fungal diseases, neuropathy, arthritis, inflammation, neuronal diseases, alopecia and cardiovascular diseases.

[0102] The present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds for use in preparing drugs for preventing and / or treating cancer, autoimmune diseases, viral diseases, fungal diseases, neuropathy, arthritis, inflammation, neuronal diseases, alopecia and cardiovascular diseases.

[0103] The term C in the present invention 0-10 Alkyl, C 0 Alkyl refers to H, so C 0-10 Alkyl groups include H, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, C 7 Alkyl, C 8 Alkyl, C 9 Alkyl, C 10 alkyl.

[0104] The term C in the present invention 1-10 Straight chain / branched alkyl, including methyl, ethyl, C 3 Straight chain / branched chain alkyl, C 4 Straight chain / branched chain alkyl, C 5Straight chain / branched chain alkyl, C 6 Straight chain / branched chain alkyl, C 7 Straight chain / branched chain alkyl, C 8 Straight chain / branched chain alkyl, C 9 Straight chain / branched chain alkyl, C 10 Straight chain / branched chain alkyl.

[0105] The term C in the present invention 3-10 Branched chain alkyl groups include isopropyl, isobutyl, tert-butyl and isopentyl.

[0106] The term C in the present invention 3-10 Cycloalkyl, including C 3 Cycloalkyl, C 4 Cycloalkyl, C 5 Cycloalkyl, C 6 Cycloalkyl, C 7 Cycloalkyl, C 8 Cycloalkyl, C 9 Cycloalkyl, C 10 Cycloalkyl.

[0107] The term halogen described in the present invention includes fluorine, chlorine, bromine and iodine.

[0108] The term heterocycloalkyl as used herein refers to a non-aromatic, saturated monocyclic or polycyclic ring system containing 3 to 10 ring atoms, preferably 5 to 10 ring atoms, wherein one or more of the ring atoms are not carbon atoms but are, for example, nitrogen, oxygen or sulfur atoms. Preferred heterocycloalkyls contain 5 to 6 ring atoms. The prefix aza, oxa or thia before heterocycloalkyl means that there is at least one nitrogen, oxygen or sulfur atom, respectively, as a ring atom.

[0109] The term heterocyclic aromatic group as used herein refers to an aromatic monocyclic or polycyclic ring system containing 5 to 14 ring atoms, preferably 5 to 10 ring atoms, wherein one or more of the ring atoms are not carbon atoms but are, for example, nitrogen, oxygen or sulfur atoms. Preferred heterocyclic aromatic groups contain 5 to 6 ring atoms. Representative heterocyclic aromatic groups include pyrazinyl, furanyl, thienyl, pyridinyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3-diazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolyl, imidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolyl, 1,2,4-triazinyl, benzothiazolyl, and the like. DETAILED DESCRIPTION

[0110] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only some embodiments of the present invention, not all. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0111] Example 1 Preparation of Compound C1

[0112] The synthetic route of the compound is as follows:

[0113]

[0114] Step 1:

[0115]

[0116] In a 50ml single-mouth bottle, 1 (1.0g, 6.03mmol), 2 (2.18g, 6.03mmol), bistriphenylphosphine palladium dichloride (212mg, 0.30mmol) and DMF (10mL) were added. The mixture was protected by nitrogen and reacted at 120 degrees for 2 hours. 4N hydrochloric acid was added at 50 degrees. After stirring for 2 hours, water was added, and ethyl acetate was extracted (20mL x 3). The organic phase was washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, and dried by spin drying. The brown solid was obtained as the target product (800mg, yield: 76.2%) by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] + .

[0117] Step 2:

[0118]

[0119] 3 (800 mg, 4.60 mmol), acetic acid (5.0 mL) and bromine (0.3 mL, 5.52 mmol) were added to a 25 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with 10% sodium thiosulfate (10 mL x 3), saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (800 mg, yield: 69.0%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0120] Step 3:

[0121]

[0122] Add 4 (800 mg, 3.17 mmol), 5 (359 mg, 3.17 mmol), ammonium acetate (489 mg, 6.34 mmol) and ethanol (10 mL) to a 25 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (20 mL x 3), wash with saturated brine (20 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (500 mg, yield: 59.3%). LC-MS: 267 [M+H] +

[0123] Step 4:

[0124]

[0125] In a 50 ml single-necked bottle, 7 (500 mg, 3.90 mmol), 8 (657 mg, 3.25 mmol), Pd 2 (dba) 3 (183 mg, 0.20 mmol), X-Phos (186 mg, 0.39 mmol), potassium carbonate (1.08 g, 7.8 mmol) and toluene (10 mL), react at 100 degrees Celsius for 18 hours under a nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (600 mg, yield: 61.5%). LC-MS: 251 [M+H] +

[0126] Step 5:

[0127]

[0128] Add 9 (210 mg, 0.43 mmol), methanol (4.0 mL) and Pd / C (136 mg, 0.86 mmol) to a 25 mL single-mouth bottle and react at room temperature for 18 hours under a hydrogen atmosphere. Filter and concentrate the filtrate to obtain a white solid as the target product (450 mg, yield: 85.2%). LC-MS: 221 [M+H] +

[0129] Step 6:

[0130]

[0131] In a 50 ml single-mouth bottle, 10 (300 mg, 1.36 mmol), 6 (302 mg, 1.14 mmol), Pd 2 (dba) 3(52 mg, 0.06 mmol), X-Phos (54 mg, 0.01 mmol), potassium carbonate (315 mg, 2.28 mmol) and toluene (4 mL) were reacted at 100 degrees Celsius for 18 hours under a nitrogen atmosphere. After filtration, the filtrate was spin-dried to obtain a white solid as the target product (30 mg, yield: 5.8%). LC-MS: 451 [M+H] +, 1 H NMR: 1 H NMR (400MHz, DMSO) δ8.98 (s, 1H), 8.49 (d, J = 3.3Hz, 1H), 8.27 (s, 1H), 8.08 (d, J = 9.1Hz, 1H ), 8.00 (d, J = 2.8Hz, 1H), 7.43 (dd, J = 9.1, 2.9Hz, 1H), 7.21 (s, 1H), 7.06 (d, J = 3.0Hz, 1H), 3.66 (d, J=12.3Hz, 2H), 3.50-3.34 (m, 2H), 2.91 (t, J=6.8Hz, 2H), 2.65 (t, J=11.2Hz, 2H), 2.36 (t, J=11.0Hz, 1H), 2.28 (s, 6H), 1.87 (d, J=11.9Hz, 2H), 1.54 (tt, J=11.6, 5.9Hz, 2H).

[0132] Example 2 Preparation of Compound C2

[0133] The synthetic route of the compound is as follows:

[0134]

[0135] Step 1:

[0136]

[0137] In a 50ml single-mouth bottle, 1 (1.0g, 6.03mmol), 2 (2.18g, 6.03mmol), bistriphenylphosphine palladium dichloride (212mg, 0.30mmol) and DMF (10mL) were added. The mixture was protected by nitrogen and reacted at 120 degrees for 2 hours. 4N hydrochloric acid was added at 50 degrees. After stirring for 2 hours, water was added and extracted with ethyl acetate (20mL x 3). The organic phase was washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, and dried by spin drying. The brown solid was obtained as the target product (800mg, yield: 76.2%) by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0138] Step 2:

[0139]

[0140] 3 (800 mg, 4.60 mmol), acetic acid (5.0 mL) and bromine (0.3 mL, 5.52 mmol) were added to a 25 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with 10% sodium thiosulfate (10 mL x 3), saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (800 mg, yield: 69.0%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0141] Step 3:

[0142]

[0143] Add 4 (800 mg, 3.17 mmol), 5 (359 mg, 3.17 mmol), ammonium acetate (489 mg, 6.34 mmol) and ethanol (10 mL) to a 25 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (20 mL x 3), wash with saturated brine (20 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (500 mg, yield: 59.3%). LC-MS: 267 [M+H] +

[0144] Step 4:

[0145]

[0146] Add 6 (500 mg, 1.88 mmol) and DMF (3.0 mL) to a 25 ml single-necked flask, add sodium hydride (150 mg, 3.76 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (542 mg, 3.76 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (10 mL x 3), wash with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1: 1) to obtain a yellow solid as the target product (500 mg, yield: 95.0%). LC-MS: 281 [M + H] + Step 5:

[0147]

[0148] In a 50 ml single-necked bottle, 7 (500 mg, 3.90 mmol), 8 (657 mg, 3.25 mmol), Pd 2 (dba) 3(183 mg, 0.20 mmol), X-Phos (186 mg, 0.39 mmol), potassium carbonate (1.08 g, 7.8 mmol) and toluene (10 mL), react at 100 degrees Celsius for 18 hours under a nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (600 mg, yield: 61.5%). LC-MS: 251 [M+H] +

[0149] Step 6:

[0150]

[0151] Add 9 (210 mg, 0.43 mmol), methanol (4.0 mL) and Pd / C (136 mg, 0.86 mmol) to a 25 mL single-mouth bottle and react at room temperature for 18 hours under a hydrogen atmosphere. Filter and concentrate the filtrate to obtain a white solid as the target product (450 mg, yield: 85.2%). LC-MS: 221 [M+H] +

[0152] Step 7:

[0153]

[0154] In a 50 ml single-mouth bottle, 10 (300 mg, 1.36 mmol), 11 (319 mg, 1.14 mmol), Pd 2 (dba) 3 (52 mg, 0.06 mmol), X-Phos (54 mg, 0.01 mmol), potassium carbonate (315 mg, 2.28 mmol) and toluene (4 mL), react at 100 degrees Celsius for 18 hours under a nitrogen atmosphere. After filtration, the filtrate was spin-dried to obtain a white solid as the target product (30 mg, yield: 5.7%). LC-MS: 465 [M+H] +, 1 H NMR: 1H NMR (400MHz, DMSO) δ9.65 (s, 1H), 8.49 (d, J = 3.6Hz, 1H), 8.20 (s, 1H), 8.00 (d, J = 2.9Hz, 1H ), 7.89 (d, J = 9.1Hz, 1H), 7.43 (dd, J = 9.1, 3.0Hz, 1H), 7.21 (s, 1H), 7.04 (d, J = 4.2Hz, 1H), 3.93 (s, 3H), 3.66 (d, J = 12.4Hz, 2H), 3.45 (td, J = 6.8, 2.4Hz, 2H), 2.91 (t, J = 6.8Hz, 2H), 2 .67 (t, J=11.0Hz, 2H), 2.27 (s, 6H), 1.88 (d, J=11.7Hz, 2H), 1.54 (dt, J=19.9, 7.6Hz, 2H).

[0155] Example 3 Preparation of Compound C3

[0156] The synthetic route of the compound is as follows:

[0157]

[0158] Step 1:

[0159]

[0160] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0161] Step 2:

[0162]

[0163] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0164] Step 3:

[0165]

[0166] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0167] Step 4:

[0168]

[0169] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0170] Step 5:

[0171]

[0172] In a 100 ml single-necked bottle, 8 (1.55 g, 17.83 mmol), 9 (3.0 g, 14.86 mmol), Pd2 (dba) 3 (680 mg, 0.74 mmol), X-Phos (710 mg, 1.49 mmol), potassium carbonate (4.10 g, 29.72 mmol) and toluene (30 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (1.45 g, yield: 46.7%). LC-MS: 210 [M+H] +

[0173] Step 6:

[0174]

[0175] 10 (1.45 g, 6.94 mmol), methanol (12.0 mL) and Pd / C (145 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (830 mg, yield: 66.8%). LC-MS: 180 [M+H] +

[0176] Step 7:

[0177]

[0178] In a 50 ml single-necked bottle, 11 (330 mg, 1.84 mmol), 7 (430 mg, 1.54 mmol), Pd 2 (dba) 3 (70 mg, 0.08 mmol), X-Phos (72 mg, 0.15 mmol), potassium carbonate (425 mg, 3.08 mmol) and toluene (5 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried to obtain a white solid as the target product (10 mg, yield: 1.5%). LC-MS: 423.8 [M+H] +, 1 H NMR (400MHz, DMSO) δ9.72 (s, 1H), 8.51 (d, J = 3.6Hz, 1H), 8.01 (d, J = 2.9Hz, 1H), 7.93 (d, J = 9.1Hz, 1H), 7.44 (dd, J = 9.0, 3.0Hz, 1H), 7.23 (s, 1 H), 7.04 (d, J=4.1Hz, 1H), 3.93 (s, 3H), 3.79-3.73 (m, 3H), 3.45 (d, J=2.3Hz, 2H), 3.13-3.07 (m, 3H), 2.91 (s, 2H), 2.68 (s, 1H), 2.34 (s, 1H).

[0179] Example 4 Preparation of Compound C4

[0180] The synthetic route of the compound is as follows:

[0181]

[0182] Step 1:

[0183]

[0184] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0185] Step 2:

[0186]

[0187] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0188] Step 3:

[0189]

[0190] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0191] Step 4:

[0192]

[0193] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0194] Step 5:

[0195]

[0196] In a 100 ml single-necked bottle, 8 (1.1 g, 5.94 mmol), 9 (1.0 g, 4.95 mmol), Pd 2 (dba) 3 (226 mg, 0.25 mmol), X-Phos (236 mg, 0.5 mmol), potassium carbonate (1.37 g, 9.90 mmol) and toluene (10 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (740 mg, yield: 48.5%). LC-MS: 309 [M+H] +

[0197] Step 6:

[0198]

[0199] 10 (740 mg, 2.40 mmol), methanol (7.0 mL) and Pd / C (70 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (600 mg, yield: 89.9%). LC-MS: 279 [M+H] +

[0200] Step 7:

[0201]

[0202] In a 50 ml single-necked bottle, 11 (200 mg, 0.72 mmol), 7 (168 mg, 0.60 mmol), Pd 2 (dba) 3 (27 mg, 0.03 mmol), X-Phos (29 mg, 0.06 mmol), potassium carbonate (166 mg, 1.20 mmol) and toluene (3 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and the target product was obtained by column chromatography (petroleum ether: ethyl acetate = 2: 1) as a yellow solid (150 mg, yield: 47.9%). LC-MS: 523 [M+H] +

[0203] Step 8:

[0204]

[0205] In a 25 mL single-mouth bottle, 12 (150 mg, 0.29 mmol), DCM (2.0 mL) and trifluoroacetic acid (0.5 mL) were added, reacted at room temperature for 2 hours, and then spin-dried to obtain the target product as a white solid (20 mg, yield: 16.3%). LC-MS: 423 [M+H] + , 1 H NMR (400MHz, MeOD) δ8.37 (d, J=3.4Hz, 1H), 8.13-7.95 (m, 2H), 7.55 (dd, J=9.1, 2.8Hz, 1H), 7.31 (d, J=3.8H z, 1H), 3.99 (s, 3H), 3.63 (t, J=7.0Hz, 2H), 3.41 (s, 5H), 3.33 (dt, J=3.3, 1.6Hz, 3H), 2.99 (t, J=7.0Hz, 2H).

[0206] Example 5 Preparation of Compound C5

[0207] The synthetic route of the compound is as follows:

[0208]

[0209] Step 1:

[0210]

[0211] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0212] Step 2:

[0213]

[0214] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0215] Step 3:

[0216]

[0217] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0218] Step 4:

[0219]

[0220] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0221] Step 5:

[0222]

[0223] In a 100 ml single-necked bottle, 8 (678 mg, 5.94 mmol), 9 (1.0 g, 4.95 mmol), Pd 2 (dba) 3 (226 mg, 0.25 mmol), X-Phos (236 mg, 0.5 mmol), potassium carbonate (1.37 g, 9.90 mmol) and toluene (10 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (410 mg, yield: 35.1%). LC-MS: 237 [M+H] +

[0224] Step 6:

[0225]

[0226] 10 (410 mg, 1.74 mmol), methanol (4.0 mL) and Pd / C (40 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (300 mg, yield: 83.6%). LC-MS: 207 [M+H] +

[0227] Step 7:

[0228]

[0229] In a 50 ml single-necked bottle, 11 (150 mg, 0.73 mmol), 7 (170 mg, 0.61 mmol), Pd 2 (dba)3 (27 mg, 0.03 mmol), X-Phos (29 mg, 0.06 mmol), potassium carbonate (168 mg, 1.22 mmol) and toluene (3 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried to obtain a white solid as the target product (8 mg, yield: 2.9%). LC-MS: 451 [M+H] +, 1 H NMR (400 MHz, CDCl 3 )δ8.33 (t, J=8.8Hz, 1H), 8.17 (d, J=9.0Hz, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.46 (d, J=3.7Hz, 1H), 7.38-7.33 (m, 1H), 5.45 (s, 1H), 3.97 (s, 3H), 3.68 (d, J=6.3Hz, 2H), 3.24 (s, 4H), 2.97 (t, J=6.7Hz, 2H), 2.73 (s, 4H), 2.58 (d, J=7.3Hz, 2H), 1.19 (t, J=7.2Hz, 3H).

[0230] Example 6 Preparation of Compound C6

[0231] The synthetic route of the compound is as follows:

[0232]

[0233] Step 1:

[0234]

[0235] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0236] Step 2:

[0237]

[0238] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0239] Step 3:

[0240]

[0241] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0242] Step 4:

[0243]

[0244] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0245] Step 5:

[0246]

[0247] In a 100 ml single-necked bottle, 8 (1.19 g, 5.94 mmol), 9 (1.0 g, 4.95 mmol), Pd 2(dba) 3 (226 mg, 0.25 mmol), X-Phos (236 mg, 0.5 mmol), potassium carbonate (1.37 g, 9.90 mmol) and toluene (10 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (530 mg, yield: 33.2%). LC-MS: 323 [M+H] +

[0248] Step 6:

[0249]

[0250] 10 (530 mg, 1.65 mmol), methanol (5.0 mL) and Pd / C (50 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (460 mg, yield: 95.4%). LC-MS: 293 [M+H] +

[0251] Step 7:

[0252]

[0253] In a 50 ml single-necked bottle, 11 (209 mg, 0.72 mmol), 7 (168 mg, 0.60 mmol), Pd 2 (dba) 3 (27 mg, 0.03 mmol), X-Phos (29 mg, 0.06 mmol), potassium carbonate (166 mg, 1.20 mmol) and toluene (3 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and the target product was obtained by column chromatography (petroleum ether: ethyl acetate = 2: 1) as a yellow solid (58 mg, yield: 18.0%). LC-MS: 537 [M+H] +

[0254] Step 8:

[0255]

[0256] In a 25 mL single-mouth bottle, 12 (58 mg, 0.11 mmol), DCM (1.0 mL) and trifluoroacetic acid (0.2 mL) were added, reacted at room temperature for 2 hours, and then spin-dried to obtain the target product as a white solid (10 mg, yield: 20.8%). LC-MS: 437 [M+H] +, 1H NMR (400MHz, MeOD) δ8.33 (s, 1H), 7.91 (s, 2H), 7.33 (dd, J=39.6, 5.8Hz, 2H), 3.96 (s, 3H), 3.79 (s, 2H), 3.62 (t, J=6.8Hz, 4H), 3.44 (s, 2H), 3.34 (d, J=1.6Hz, 2H), 2.97 (t, J=6.9Hz, 2H), 2.23 (s, 2H).

[0257] Example 7 Preparation of Compound C7

[0258] The synthetic route of the compound is as follows:

[0259]

[0260] Step 1:

[0261]

[0262] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0263] Step 2:

[0264]

[0265] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0266] Step 3:

[0267]

[0268] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0269] Step 4:

[0270]

[0271] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0272] Step 5:

[0273]

[0274] In a 100 ml single-necked bottle, 8 (684 mg, 5.94 mmol), 9 (1.0 g, 4.95 mmol), Pd 2 (dba) 3 (226 mg, 0.25 mmol), X-Phos (236 mg, 0.5 mmol), potassium carbonate (1.37 g, 9.90 mmol) and toluene (10 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (430 mg, yield: 36.6%). LC-MS: 238 [M+H] +

[0275] Step 6:

[0276]

[0277] 10 (430 mg, 1.81 mmol), methanol (4.0 mL) and Pd / C (43 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (300 mg, yield: 80.4%). LC-MS: 208 [M+H] +

[0278] Step 7:

[0279]

[0280] In a 50 ml single-necked bottle, 11 (150 mg, 0.72 mmol), 7 (169 mg, 0.60 mmol), Pd 2 (dba) 3 (27 mg, 0.03 mmol), X-Phos (29 mg, 0.06 mmol), potassium carbonate (166 mg, 1.20 mmol) and toluene (3 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried to obtain a white solid as the target product (30 mg, yield: 11.1%). LC-MS: 452 [M+H] +, 1 H NMR (400 MHz, CDCl 3 )δ8.35-8.25 (m, 2H), 7.88 (s, 1H), 7.49 (d, J=3.7Hz, 1H), 7.41 (d, J=7.0Hz, 1H), 5.44 (s, 1H), 4.01 (s, 3H), 3.91-3.81 (m, 2H ), 3.69 (dd, J=6.7, 4.5Hz, 2H), 3.38 (d, J=10.7Hz, 2H), 2.97 (t, J=6.7Hz, 2H), 2.47 (t, J=10.9Hz, 2H), 1.30 (d, J=6.3Hz, 6H).

[0281] Example 8 Preparation of Compound C8

[0282] The synthetic route of the compound is as follows:

[0283]

[0284] Step 1:

[0285]

[0286] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0287] Step 2:

[0288]

[0289] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0290] Step 3:

[0291]

[0292] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0293] Step 4:

[0294]

[0295] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0296] Step 5:

[0297]

[0298] In a 100 ml single-necked bottle, 8 (2.0 g, 15.61 mmol), 9 (2.63 g, 13.01 mmol), Pd 2 (dba) 3 (595 mg, 0.65 mmol), X-Phos (620 mg, 1.3 mmol), potassium carbonate (3.59 g, 26.02 mmol) and toluene (30 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (650 mg, yield: 20.0%). LC-MS: 251 [M+H] +

[0299] Step 6:

[0300]

[0301] 10 (650 mg, 2.60 mmol), methanol (5.0 mL) and Pd / C (65 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (450 mg, yield: 78.6%). LC-MS: 221 [M+H] +

[0302] Step 7:

[0303]

[0304] In a 25 ml single-necked bottle, 11 (230 mg, 1.04 mmol), 7 (244 mg, 0.87 mmol), Pd 2 (dba) 3(40 mg, 0.04 mmol), BINAP (54 mg, 0.09 mmol), sodium tert-butoxide (167 mg, 1.74 mmol) and toluene (3 mL), react at 90 degrees for 4 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried to obtain a white solid as the target product (30 mg, yield: 7.4%). LC-MS: 465 [M+H] +, 1 H NMR (400MHz, DMSO) δ9.75 (s, 1H), 8.51 (d, J = 3.6Hz, 1H), 8.03 (d, J = 2.8Hz, 1H), 7.94 (d, J = 9.1Hz, 1H), 7.46 (dd, J = 9.1, 3.0Hz, 1H), 7.23 (s, 1H), 7.0 4 (d, J=4.1Hz, 1H), 3.93 (s, 3H), 3.60 (d, J=4.4Hz, 4H), 3.45 (dd, J=6.7, 4. 4Hz, 2H), 3.18-3.04 (m, 4H), 2.91 (t, J=6.8Hz, 2H), 2.05 (d, J=5.0Hz, 3H).

[0305] Example 9 Preparation of Compound C9

[0306] The synthetic route of the compound is as follows:

[0307]

[0308] Step 1:

[0309]

[0310] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0311] Step 2:

[0312]

[0313] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0314] Step 3:

[0315]

[0316] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0317] Step 4:

[0318]

[0319] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0320] Step 5:

[0321]

[0322] In a 100 ml single-necked bottle, 8 (4.5 g, 20.80 mmol), 9 (3.5 g, 17.33 mmol), Pd2 (dba) 3 (793 mg, 0.87 mmol), X-Phos (826 mg, 1.73 mmol), potassium carbonate (4.78 g, 34.66 mmol) and toluene (40 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 1: 1) was used to obtain a yellow solid as the target product (1.6 g, yield: 27.5%). LC-MS: 337 [M+H] +

[0323] Step 6:

[0324]

[0325] In a 25 ml single-mouth bottle, 10 (400 mg, 1.19 mmol), tetrahydrofuran (5.0 mL), di-tert-butyl dicarbonate (467 mg, 2.14 mmol), triethylamine (241 mg, 2.38 mmol) and DMAP (2 mg, 0.01 mmol) were added. After reflux for 24 hours, the mixture was spin-dried and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a yellow solid as the target product (440 mg, yield: 84.8%). LC-MS: 437 [M+H]+

[0326] Step 7:

[0327]

[0328] 11 (440 mg, 1.0 mmol), methanol (4.0 mL) and Pd / C (44 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (300 mg, yield: 73.8%). LC-MS: 407 [M+H] +

[0329] Step 8:

[0330]

[0331] In a 50 ml single-necked bottle, 12 (300 mg, 0.74 mmol), 7 (172 mg, 0.62 mmol), Pd 2 (dba) 3(27 mg, 0.03 mmol), X-Phos (29 mg, 0.06 mmol), potassium carbonate (171 mg, 1.24 mmol) and toluene (5 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and the target product was obtained as a white solid (150 mg, yield: 37.2%) by column chromatography (dichloromethane: methanol = 30: 1). LC-MS: 651 [M+H] +

[0332] Step 9:

[0333]

[0334] In a 25 mL single-mouth bottle, 13 (150 mg, 0.23 mmol), DCM (2.0 mL) and trifluoroacetic acid (0.5 mL) were added, reacted at room temperature for 2 hours, and then spin-dried to obtain the target product as a white solid (30 mg, yield: 29.0%). LC-MS: 451 [M+H] + , 1 H NMR (400MHz, DMSO) δ9.03 (s, 1H), 8.52-8.30 (m, 2H), 8.07 (d, J=2.4Hz, 1H), 7.54 (dd, J=8.8, 2.6Hz, 1H), 7.21 (s, 1H), 6.98 (d, J=4.1Hz, 1H), 6.47 (d, J=8 .9Hz, 2H), 3.79 (s, 3H), 3.47-3.38 (m, 2H), 3.24-3.07 (m, 4H), 2.88 (t, J=6. 8Hz, 2H), 2.76-2.70 (m, 2H), 1.80 (d, J=11.5Hz, 3H), 1.27 (d, J=12.2Hz, 2H).

[0335] Example 10 Preparation of Compound C10

[0336] The synthetic route of the compound is as follows:

[0337]

[0338] Step 1:

[0339]

[0340] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0341] Step 2:

[0342]

[0343] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0344] Step 3:

[0345]

[0346] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0347] Step 4:

[0348]

[0349] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0350] Step 5:

[0351]

[0352] Add 8 (1.30 g, 6.08 mmol), acetic acid (1.09 g, 18.2 mmol), tetraisopropyl titanate (2.07 g, 7.30 mmol), sodium cyanoborohydride (1.15 g, 18.2 mmol), methanol (5 mL) and acetaldehyde (18.2 mL, 18.2 mmol, 1 M methanol solution) to a 100 ml single-mouth bottle and react at room temperature for 3 hours. Add water (100 mL) to quench, extract with dichloromethane (150 mL x 3), wash with saturated brine (150 mL x 2), dry over anhydrous sodium sulfate, spin dry, and pass through a column (dichloromethane: methanol = 15: 1) to obtain a yellow solid as the target product (1.25 g, yield: 85.0%). LC-MS: 243 [M + H] +

[0353] Step 6:

[0354]

[0355] Add 10 (1.25 g, 5.17 mmol), dioxane (10.0 mL) and a solution of hydrochloric acid in dioxane (15 mL, 4 M) into a 250 mL single-mouth bottle and react at room temperature for 16 hours. Spin dry to obtain a yellow solid as the target product (960 mg, crude product). LC-MS: 143 [M+H] +

[0356] Step 7:

[0357]

[0358] 11 (960 mg, 6.76 mmol), 12 (1.64 g, 8.11 mmol), potassium carbonate (2.80 g, 20.3 mmol) and DMF (15 mL) were added to a 250 ml single-mouth bottle and reacted at 140 degrees for 2 hours under a nitrogen atmosphere. Water (50 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (80 mL × 3), washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, and spin-dried. The target product was obtained by column chromatography (dichloromethane: methanol = 10: 1) as a yellow solid (470 mg, yield: 26.3%). LC-MS: 265 [M+H] +

[0359] Step 8:

[0360]

[0361] In a 250 ml single-necked bottle, 13 (470 mg, 1.78 mmol), triethylamine (539 mg, 5.34 mmol), DMAP (21.7 mg, 0.178 mmol), dichloromethane (10 mL) and Boc 2 O (582 mg, 2.67 mmol) was reacted at 40 degrees for 16 hours. Water (20 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (15 mL × 3), washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and spin-dried. The target product was obtained as a yellow solid (160 mg, yield: 24.7%) by column chromatography (dichloromethane: methanol = 12: 1). LC-MS: 365 [M+H] +

[0362] Step 9:

[0363]

[0364] In a 25 mL single-necked bottle, 11 (160 mg, 0.440 mmol), methanol (50 mL) and Pd(OH) were added. 2 / C (40 mg), react at room temperature for 18 hours under hydrogen atmosphere. Filter by suction, and concentrate the filtrate to obtain a white solid as the target product (130 mg, yield: 85.5%). LC-MS: 335 [M+H] +

[0365] Step 10:

[0366]

[0367] In a 50 ml single-necked bottle, 15 (130 mg, 0.390 mmol), 7 (197 mg, 0.702 mmol), Pd 2 (dba) 3(17.9 mg, 0.0195 mmol), BIANP (36.4 mg, 0.0585 mmol), sodium tert-butoxide (112 mg, 1.17 mmol) and toluene (8 mL), react at 100 degrees for 16 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and the target product was obtained as a white solid (79 mg, yield: 35.1%) by column chromatography (dichloromethane: methanol = 13: 1). LC-MS: 579 [M+H] +

[0368] Step 11:

[0369]

[0370] In a 25 mL single-mouth bottle, 16 (79 mg, 0.137 mmol), DCM (5 mL) and trifluoroacetic acid (1 mL) were added, reacted at room temperature for 3 hours, and then dried by rotation to obtain the target product as a yellow solid (12 mg, yield: 18.4%). LC-MS: 479 [M+H] + , 1 H NMR (400MHz, DMSO) δ11.09 (s, 1H), 9.24 (s, 1H), 8.61 (d, J=3.4Hz, 1H), 7.82-7. 50 (m, 3H), 7.31 (s, 1H), 7.15 (d, J = 4.2Hz, 1H), 3.93 (d, J = 11.1Hz, 5H), 3.48 (ddd , J=16.2, 9.0, 6.8Hz, 4H), 3.09 (dd, J=12.8, 5.7Hz, 3H), 3.00-2.77 (m, 5H), 1.9 9 (d, J=13.9Hz, 2H), 1.83 (s, 1H), 1.40 (d, J=13.4Hz, 2H), 1.22 (t, J=7.2Hz, 3H).

[0371] Example 11 Preparation of Compound C11

[0372] The synthetic route of the compound is as follows:

[0373]

[0374] Step 1:

[0375]

[0376] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0377] Step 2:

[0378]

[0379] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0380] Step 3:

[0381]

[0382] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0383] Step 4:

[0384]

[0385] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0386] Step 5:

[0387]

[0388] Add 8 (1.08 g, 5.05 mmol), 9 (1.42 g, 15.1 mmol), acetonitrile (15 mL), potassium carbonate (2.08 g, 15.1 mmol) to a 100 ml single-mouth bottle and react at room temperature for 3 hours. Add water (100 mL) to quench, extract with dichloromethane (150 mL x 3), wash with saturated brine (150 mL x 2), dry over anhydrous sodium sulfate, spin dry, and pass through a column (dichloromethane: methanol = 15: 1) to obtain a yellow solid as the target product (1.20 g, yield: 87.4%). LC-MS: 273 [M+H] +

[0389] Step 6:

[0390]

[0391] In a 250 mL single-mouth bottle, add 10 (1.20 g, 4.41 mmol), dioxane (10.0 mL) and a solution of hydrochloric acid in dioxane (15 mL, 4 M) and react at room temperature for 16 hours. The yellow solid obtained by spin drying is the target product (1.10 g, crude product). LC-MS: 173 [M+H] +

[0392] Step 7:

[0393]

[0394] 11 (1.10 g, 6.40 mmol), 12 (1.64 g, 8.11 mmol), potassium carbonate (2.65 g, 19.2 mmol) and DMF (15 mL) were added to a 250 ml single-mouth bottle and reacted at 140 degrees for 2 hours under a nitrogen atmosphere. Water (50 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (80 mL × 3), washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, and spin-dried. The target product was obtained by column chromatography (dichloromethane: methanol = 15: 1) as a yellow solid (540 mg, yield: 27.8%). LC-MS: 295 [M+H] +

[0395] Step 8:

[0396]

[0397] In a 250 ml single-necked bottle, 13 (540 mg, 1.84 mmol), triethylamine (539 mg, 5.34 mmol), DMAP (21.7 mg, 0.178 mmol), dichloromethane (10 mL) and Boc 2 O (582 mg, 2.67 mmol) was reacted at 40 degrees for 16 hours. Water (20 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (15 mL × 3), washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and spin-dried. The target product was obtained as a yellow solid (110 mg, yield: 15.2%) by column chromatography (dichloromethane: methanol = 12: 1). LC-MS: 395 [M+H] +

[0398] Step 9:

[0399]

[0400] In a 25 mL single-necked bottle, 11 (110 mg, 0.279 mmol), methanol (20 mL) and Pd(OH) were added. 2 / C (35 mg), react at room temperature for 18 hours under hydrogen atmosphere. Filter by suction, and concentrate the filtrate to obtain a white solid as the target product (100 mg, yield: 98.4%). LC-MS: 365 [M+H] +

[0401] Step 10:

[0402]

[0403] In a 50 ml single-necked bottle, 15 (100 mg, 0.275 mmol), 7 (550 mg, 0.550 mmol), Pd 2 (dba) 3(12.6 mg, 0.0138 mmol), BIANP (25.7 mg, 0.0413 mmol), sodium tert-butoxide (79.2 mg, 0.825 mmol) and toluene (8 mL), react at 100 degrees for 16 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and the target product was obtained as a white solid (45 mg, yield: 29.6%) by column chromatography (dichloromethane: methanol = 13: 1). LC-MS: 609 [M+H] +

[0404] Step 11:

[0405]

[0406] In a 25 mL single-mouth bottle, 16 (45 mg, 0.0740 mmol), DCM (5 mL) and trifluoroacetic acid (1 mL) were added, reacted at room temperature for 3 hours, and then spin-dried to obtain the target product as a yellow solid (8 mg, yield: 21.2%). LC-MS: 509 [M+H] + , 1 H NMR (400MHz, DMSO) δ9.03 (s, 1H), 8.38 (d, J = 3.6Hz, 1H), 8.07 (d, J = 2.2Hz, 1H), 7.54 (dd, J=8.9, 2.5Hz, 1H), 7.21 (s, 1H), 6.98 (d, J=4.0Hz, 1H), 6.58-6.33 (m, 2H), 3.79 (s, 3H), 3.56 (t, J=5.3Hz, 3H), 3.45-3.40 (m, 3H), 3.26 (s, 3H), 3.20- 3.10 (m, 4H), 2.88 (t, J=6.6Hz, 4H), 1.75 (t, J=23.5Hz, 3H), 1.42-1.29 (m, 2H).

[0407] Example 12 Preparation of Compound C12

[0408] The synthetic route of the compound is as follows:

[0409]

[0410] Step 1:

[0411]

[0412] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0413] Step 2:

[0414]

[0415] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0416] Step 3:

[0417]

[0418] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0419] Step 4:

[0420]

[0421] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0422] Step 5:

[0423]

[0424] Add 8 (2.25 g, 13.4 mmol), acetic acid (2.01 g, 33.5 mmol), tetraisopropyl titanate (1.92 g, 6.70 mmol), sodium cyanoborohydride (2.53 g, 40.2 mmol), methanol (25 mL) and acetaldehyde (26.8 mL, 26.8 mmol, 1 M methanol solution) to a 250 ml single-mouth bottle and react at room temperature for 3 hours. Add water (200 mL) to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 2), dry over anhydrous sodium sulfate, spin dry, and pass through a column (dichloromethane: methanol = 15: 1) to obtain a yellow solid as the target product (1.90 g, yield: 72.0%). LC-MS: 197 [M+H] +

[0425] Step 6:

[0426]

[0427] In a 250 ml single-necked bottle, 10 (160 mg, 8.16 mmol), 11 (1.77 g, 9.79 mmol), Pd 2 (dba) 3 (747 mg, 0.816 mmol), Xantphos (1.41 mg, 2.45 mmol), cesium carbonate (15.3 g, 24.5 mmol) and dioxane (25 mL), under nitrogen atmosphere, microwave reaction at 120 degrees for 2 hours. Spin dry, column chromatography (dichloromethane: methanol = 18: 1) to obtain the target product as a yellow solid (670 mg, yield: 35.0%). LC-MS: 342 [M+H] +

[0428] Step 7:

[0429]

[0430] In a 250 ml single-mouth bottle, add 12 (670 mg, 1.96 mmol), tetrahydrofuran (10 mL) and concentrated hydrochloric acid (10 mL) and react at room temperature for 16 hours. Spin dry, and obtain the target product as a yellow solid (340 mg, yield: 97.7%) through column chromatography (dichloromethane: methanol = 15: 1). LC-MS: 178 [M+H] +

[0431] Step 8:

[0432]

[0433] In a 50 ml single-necked bottle, 13 (186 mg, 1.05 mmol), 7 (530 mg, 1.89 mmol), Pd 2 (dba) 3 (48.1 mg, 0.0195 mmol), BIANP (98.1 mg, 0.158 mmol), sodium tert-butoxide (302 mg, 3.15 mmol) and toluene (10 mL) were reacted at 100 degrees for 16 hours under a nitrogen atmosphere. After filtration, the filtrate was dried and the target product was prepared by high pressure liquid phase as a yellow solid (35 mg, yield: 7.91%). LC-MS: 422 [M+H] + 1 H NMR (400MHz, DMSO) δ9.88 (s, 1H), 8.53 (d, J = 3.6Hz, 1H), 7.89 (d, J = 8.4Hz, 1H), 7.45 (d, J = 8.5Hz, 1H), 7.24 (s, 1H), 7.06 (d, J = 4.2Hz, 1H), 3.96 (s, 3H), 3.47 (dd, J=17.5, 15.1Hz, 4H), 2.92 (d, J=6.8Hz, 2H), 2.86-2.68 (m, 4H), 2.58-2.52 (m, 2H), 1.11 (t, J=7.1Hz, 3H).

[0434] Example 13 Preparation of Compound C13

[0435] The synthetic route of the compound is as follows:

[0436]

[0437] Step 1:

[0438]

[0439] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0440] Step 2:

[0441]

[0442] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0443] Step 3:

[0444]

[0445] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0446] Step 4:

[0447]

[0448] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0449] Step 5:

[0450]

[0451] Add 8 (1.68 g, 10.0 mmol), DIEA (3.23 g, 25.0 mmol) and tetrahydrofuran (25 mL) into a 250 ml single-mouth bottle, slowly drop propionyl chloride (1.84 g, 20.0 mmol) at 0 degrees Celsius, and react at 0 degrees Celsius for 2 hours. Add water (100 mL) to quench, extract with dichloromethane (100 mL x 3), wash with saturated brine (100 mL x 2), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oily substance as the target product (1.39 g, yield: 62.1%). LC-MS: 225 [M+H] +

[0452] Step 6:

[0453]

[0454] In a 250 ml single-necked bottle, 10 (1.00 g, 4.46 mmol), 11 (0.848 g, 4.68 mmol), Pd 2 (dba) 3 (204 mg, 0.223 mmol), Xantphos (387 mg, 0.669 mmol), cesium carbonate (6.95 g, 11.2 mmol) and dioxane (25 mL), under nitrogen atmosphere, microwave reaction at 120 degrees for 2 hours. Spin dry, column chromatography (dichloromethane: methanol = 20: 1) to obtain the target product as a yellow solid (1.48 mg, yield: 89.8%). LC-MS: 370 [M+H] +

[0455] Step 7:

[0456]

[0457] In a 250 ml single-mouth bottle, add 12 (936 mg, 2.54 mmol), tetrahydrofuran (10 mL) and concentrated hydrochloric acid (10 mL) and react at room temperature for 16 hours. Spin dry, and obtain the target product as a yellow solid (500 mg, yield: 96.0%) by column chromatography (dichloromethane: methanol = 15:1). LC-MS: 206 [M+H] +

[0458] Step 8:

[0459]

[0460] In a 50 ml single-necked bottle, 13 (205 mg, 1.00 mmol), 7 (504 mg, 1.80 mmol), Pd 2 (dba) 3 (45.8 mg, 0.0500 mmol), BIANP (93.5 mg, 0.150 mmol), sodium tert-butoxide (288 mg, 3.00 mmol) and toluene (10 mL) were reacted at 100 degrees for 16 hours under a nitrogen atmosphere. After filtration, the filtrate was spin-dried and the target product was prepared by high pressure liquid phase as a yellow solid (39 mg, yield: 6.46%). LC-MS: 450 [M+H] +] +1 H NMR (400MHz, DMSO) δ10.57 (s, 1H), 8.61 (d, J = 3.3Hz, 1H), 7.80 (ddd, J = 25.7, 17.2, 8.7Hz, 2H), 7.28 (s, 1H), 7.11 (d, J = 4.1Hz, 1H), 4.7 1-4.55 (m, 2H), 4.15-3.90 (m, 3H), 3.88-3.67 (m, 2H), 3.57-3.37 (m, 2H), 3.13-2.82 (m, 4H), 2.48-2.39 (m, 2H), 1.03 (t, J=6.1Hz, 3H).

[0461] Example 14 Preparation of Compound C14

[0462] The synthetic route of the compound is as follows:

[0463]

[0464] Step 1:

[0465]

[0466] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0467] Step 2:

[0468]

[0469] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0470] Step 3:

[0471]

[0472] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0473] Step 4:

[0474]

[0475] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0476] Step 5:

[0477]

[0478] Add 7 (1.10 g, 3.93 mmol) and DMF (20 mL) to a 250 ml single-necked flask, add sodium hydride (236 mg, 5.90 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (838 mg, 5.90 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (dichloromethane: methanol = 12: 1) to obtain a yellow solid as the target product (1.00 g, yield: 86.6%). LC-MS: 295 [M+H] +

[0479] Step 6:

[0480]

[0481] In a 100 ml single-necked bottle, 9 (678 mg, 5.94 mmol), 10 (1.0 g, 4.95 mmol), Pd 2 (dba) 3 (226 mg, 0.25 mmol), X-Phos (236 mg, 0.5 mmol), potassium carbonate (1.37 g, 9.90 mmol) and toluene (10 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (410 mg, yield: 35.1%). LC-MS: 237 [M+H] +

[0482] Step 7:

[0483]

[0484] 10 (410 mg, 1.74 mmol), methanol (10.0 mL) and Pd / C (40 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (300 mg, yield: 83.6%). LC-MS: 207 [M+H] +

[0485] Step 8:

[0486]

[0487] In a 50 ml single-necked bottle, 12 (300 mg, 1.46 mmol), 8 (771 mg, 2.62 mmol), Pd 2 (dba) 3 (66.9 mg, 0.0730 mmol), BIANP (136 mg, 0.219 mmol), sodium tert-butoxide (420 mg, 4.38 mmol) and toluene (15 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried to obtain a white solid as the target product (30 mg, yield: 4.44%). LC-MS: 565 [M+H] +, 1 H NMR (400MHz, DMSO) δ10.66 (s, 1H), 9.84 (s, 1H), 8.59 (d, J = 3.6Hz, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.10 (d, J = 4.2Hz, 1H), 3.94 ( s, 3H), 3.82 (t, J=18.5Hz, 2H), 3.62 (d, J=7.0Hz, 4H), 3.22 (d, J=6.8Hz, 4H), 3.02 (s, 4H), 2.93 (s, 3H), 1.27 (t, J=7.3Hz, 3H).

[0488] Example 15 Preparation of Compound C15

[0489] The synthetic route of the compound is as follows:

[0490]

[0491] Step 1:

[0492]

[0493] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0494] Step 2:

[0495]

[0496] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0497] Step 3:

[0498]

[0499] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0500] Step 4:

[0501]

[0502] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0503] Step 5:

[0504]

[0505] Add 7 (1.10 g, 3.93 mmol) and dioxane (20 mL) to a 250 ml single-necked flask, add DDQ (1.34 g, 5.90 mmol) at room temperature, and react at room temperature for 18 hours. Spin dry, and obtain a yellow solid as the target product (300 mg, yield: 27.5%) by column chromatography (dichloromethane: methanol = 10: 1). LC-MS: 279 [M+H] +

[0506] Step 6:

[0507]

[0508] In a 100 ml single-necked bottle, 9 (678 mg, 5.94 mmol), 10 (1.0 g, 4.95 mmol), Pd 2 (dba) 3 (226 mg, 0.25 mmol), X-Phos (236 mg, 0.5 mmol), potassium carbonate (1.37 g, 9.90 mmol) and toluene (10 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and column chromatography (petroleum ether: ethyl acetate = 3: 1) was used to obtain a yellow solid as the target product (410 mg, yield: 35.1%). LC-MS: 237 [M+H] +

[0509] Step 7:

[0510]

[0511] 10 (410 mg, 1.74 mmol), methanol (10.0 mL) and Pd / C (40 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (300 mg, yield: 83.6%). LC-MS: 207 [M+H] +

[0512] Step 8:

[0513]

[0514] In a 50 ml single-necked bottle, 12 (87.0 mg, 0.422 mmol), 8 (117 mg, 0.422 mmol), Pd 2 (dba) 3 (19.3 mg, 0.0221 mmol), BIANP (39.4 mg, 0.0633 mmol), sodium tert-butoxide (122 mg, 1.27 mmol) and toluene (8 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried to obtain a white solid as the target product (2.52 mg, yield: 2.77%). LC-MS: 449 [M+H] +, 1 H NMR (400 MHz, CDCl 3 )δ8.38 (d, J=2.9Hz, 1H), 8.17 (d, J=8.9Hz, 1H), 7.97 (d, J=2.7Hz, 1H), 7.60 (t, J=6.2Hz, 1H), 7.38 (dd, J=9.1, 2. 8Hz, 1H), 7.17 (d, J=7.3Hz, 1H), 6.54 (d, J=7.3Hz, 1H), 4.07 (s, 3H), 3.29 (s, 2H), 3.04-2.48 (m, 8H), 1.26 (s, 3H).

[0515] Example 16 Preparation of Compound C16

[0516] The synthetic route of the compound is as follows:

[0517]

[0518] Step 1:

[0519]

[0520] In a 500ml single-mouth bottle, add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bistriphenylphosphine palladium dichloride (9.58g, 13.56mmol) and DMF (200mL), under nitrogen protection, react at 120 degrees for 2 hours. Add 4N hydrochloric acid at 50 degrees, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a brown solid as the target product (33.1g, yield: 70.1%) through column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 175 [M+H] +

[0521] Step 2:

[0522]

[0523] 3 (33.1 g, 190.2 mmol), acetic acid (150 mL) and bromine (11.7 mL, 228.2 mmol) were added to a 500 mL single-necked round-bottom flask and reacted at room temperature for 4 h. After adding water, the mixture was extracted with ethyl acetate (200 mL x 3). The organic phase was washed with 10% sodium thiosulfate (200 mL x 3), saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, and spin-dried. The target product (30 g, yield: 62.6%) was obtained as a brown solid by column chromatography (petroleum ether: ethyl acetate = 5:1). LC-MS: 253 [M+H] +

[0524] Step 3:

[0525]

[0526] Add 4 (30 g, 119.1 mmol), 5 (13.46 g, 119.1 mmol), ammonium acetate (18.36 g, 238.2 mmol) and ethanol (150 mL) to a 500 ml single-necked flask and react at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (DCM: MeOH = 30: 1) to obtain a yellow solid as the target product (22 g, yield: 69.4%). LC-MS: 267 [M+H] +

[0527] Step 4:

[0528]

[0529] Add 6 (12.6 g, 47.36 mmol) and DMF (60 mL) to a 250 ml single-necked flask, add sodium hydride (3.79 g, 94.72 mmol) at 0 degrees, stir at room temperature for 30 minutes, add iodomethane (13.64 g, 94.72 mmol), and react at room temperature for 18 hours. Add water to quench, extract with ethyl acetate (200 mL x 3), wash with saturated brine (200 mL x 3), dry over anhydrous sodium sulfate, spin dry, and pass through a column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (5.35 g, yield: 40.3%). LC-MS: 281 [M + H] +

[0530] Step 5:

[0531]

[0532] Add 8 (200 mg, 1.19 mmol), 9 (163 mg, 1.43 mmol), HATU (678 mg, 1.79 mmol), DIEA (307 mg, 2.38 mmol) and dichloromethane (5.0 mL) to a 25 ml single-mouth bottle and react at room temperature for 5 hours. Add water, extract with dichloromethane (10 mL x 3), wash with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, spin dry, and obtain a yellow solid as the target product (260 mg, yield: 82.7%) by column chromatography (petroleum ether: ethyl acetate = 4:1). LC-MS: 265 [M+H] +

[0533] Step 6:

[0534]

[0535] In a 25 ml single-necked bottle, 10 (260 mg, 0.98 mmol), tetrahydrofuran (3.0 mL) and BH 3 ·THF (1.0 mL, 2.0 mmol), after reflux for 12 hours, methanol was added to quench, spin-dried, and column chromatography (petroleum ether: ethyl acetate = 8: 1) was performed to obtain a yellow solid as the target product (50 mg, yield: 20.4%). LC-MS: 251 [M+H]+

[0536] Step 7:

[0537]

[0538] 11 (50 mg, 0.20 mmol), methanol (1.0 mL) and Pd / C (5 mg) were added to a 25 mL single-mouth bottle and reacted at room temperature for 18 hours under a hydrogen atmosphere. The filtrate was filtered and concentrated to obtain a white solid as the target product (40 mg, yield: 90.8%). LC-MS: 221 [M+H]+

[0539] Step 8:

[0540]

[0541] In a 25 ml single-mouth bottle, 12 (40 mg, 0.18 mmol), 7 (42 mg, 0.15 mmol), Pd 2 (dba) 3 (14 mg, 0.015 mmol), X-Phos (14 mg, 0.03 mmol), potassium carbonate (41 mg, 0.30 mmol) and toluene (2 mL), react at 100 degrees for 18 hours under nitrogen atmosphere. After filtration, the filtrate was spin-dried and YF-PRJ8-1024 was obtained as a white solid (6 mg, yield: 8.6%) by thin layer chromatography (dichloromethane: methanol = 30: 1). LC-MS: 465 [M+H] +, 1 H NMR (400MHz, DMSO) δ10.52 (s, 1H), 8.60 (d, J = 3.5Hz, 1H), 8.27 (s, 1H), 8.04 (d, J = 8.6Hz, 1H), 7.84 (d, J = 8.7Hz, 1H), 7.26 (s, 1 H), 7.09 (d, J=4.2Hz, 1H), 4.45 (s, 2H), 3.96 (s, 3H), 3.74 (s, 2H), 3.56-3.33 (m, 4H), 3.26-2.82 (m, 8H), 1.19 (t, J=7.3Hz, 3H).

[0542] CDK4 / CycD3 Enzyme Assay of Compounds in Example 17

[0543] Experimental Materials:

[0544] CDK4 / CycD3 recombinant human protease was purchased from Carna (Cat#04-105), ATP was purchased from Sigma (Cat#A7699-5G), and staurosporine was purchased from MedChemExpress (Cat#HY-15141). Toolbox For KinasesCDK4 kit was purchased from Cisbio (Rbpeptide-biotin: Cat#64CUS000C01B; Anti-pRb(Ser780)EuK: Cat#64CUSKAY; Streptavidin-XL665: Cat#610SAXLB; 5X Enzymatic buffer: Cat#62EZBFDD; Detection buffer: Cat#62SDBRDD).

[0545] Experimental methods:

[0546] The phosphorylation of the retinoblastoma gene product (Rb) can be detected using the HTRF assay kit. The experimental reaction was carried out in a 384-well plate (Greiner, Cat#784075) with a total reaction volume of 20 μL. The reaction system mainly included 1× kinase buffer, 50 mM MgCl 2 , 1mM DTT, 1μM RB protein and 70μM ATP. Compound C1 prepared in Example 1 and Compound C2 prepared in Example 2 were diluted with DMSO to 10 concentration points, and 50nL were transferred to the experimental assay plate. The experimental reaction started after adding 12nM CDK4 / CycD3. After reacting at 25 degrees Celsius for 90 minutes, the detection reagent was added to terminate the reaction (0.167nM Anti-pRb (Ser780) -EuK, 62.5nM Streptavidin-XL665). After standing at room temperature for 60 minutes, the FRET signal was read on a Spark 10M or envision plate reader. (HTRF665 / 615 = signal value at 665nm / signal value at 615nm).

[0547] Data Analysis:

[0548] The 665 / 615 signal ratio was converted to percent inhibition. Inhibition % = (max-sample) / (max-min)*100. "min" represents the ratio of the 665 / 615 signal values ​​of the control wells without enzyme, and "max" represents the ratio of the 665 / 615 signal values ​​of the DMSO control wells. The IC50 value of the compound was calculated using XLFit in the Excel add-in. Equation: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X)^HillSlope).

[0549] result:

[0550] According to the above experimental method, the IC50 of the measured compounds is shown in the following table:

[0551] Table 1 Experimental results

[0552] Compound IC50(nM) C1 <20nM C2 <20nM C3 20nM<IC50<100nM C4 <20nM C5 <20nM C6 <20nM C7 20nM<IC50<100nM C8 <20nM C9 <20nM C10 <20nM C11 <20nM C12 <20nM C13 <20nM C14 20nM<IC50<100nM C15 <20nM C16 20nM<IC50<100nM

[0553] Example 18 CDK6 / CycD3 Enzyme Assay of Compounds

[0554] Experimental Materials:

[0555] CDK6 / CycD3 recombinant human protease was purchased from Carna (Cat#04-107), ATP was purchased from Sigma (Cat#A7699-5G), and staurosporine was purchased from MedChemExpress (Cat#HY-15141). Toolbox For KinasesCDK 4 kit was purchased from Cisbio (Rbpeptide-biotin: Cat#64CUS000C01B; Anti-pRb(Ser780)-EuK: Cat#64CUSKAY; Streptavidin-XL665: Cat#610SAXLB; 5X Enzymatic buffer: Cat#62EZBFDD; Detection buffer: Cat#62SDBRDD).

[0556] Experimental methods:

[0557] The phosphorylation of the retinoblastoma gene product (Rb) can be detected using the HTRF assay kit. The experimental reaction was carried out in a 384-well plate (Greiner, Cat#784075) with a total reaction volume of 20 μL. The reaction system mainly included 1× kinase buffer, 50 mM MgCl 2 , 1mM DTT, 1μM RB protein and 140μM ATP. Compound C1 prepared in Example 1 and Compound C2 prepared in Example 2 were diluted with DMSO to 10 concentration points, and 100nL were transferred to the experimental assay plate. The experimental reaction started after adding 12.5nM CDK6 / CycD3. After reacting at 25 degrees Celsius for 120 minutes, the detection reagent was added to terminate the reaction (0.167nM Anti-pRb(Ser780)-EuK, 62.5nM Streptavidin-XL665). After standing at room temperature for 60 minutes, the FRET signal was read on a Spark 10M or envision plate reader. (HTRF665 / 615=665nm signal value / 615nm signal value).

[0558] Data Analysis:

[0559] The 665 / 615 signal ratio was converted to percent inhibition. Inhibition % = (max-sample) / (max-min)*100. "min" represents the ratio of the 665 / 615 signal values ​​of the control wells without enzyme, and "max" represents the ratio of the 665 / 615 signal values ​​of the DMSO control wells. The IC50 value of the compound was calculated using XLFit in the Excel add-in. Equation: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X)^HillSlope).

[0560] result:

[0561] According to the above experimental method, the IC50 of the measured compounds is shown in the following table:

[0562] Table 2 Experimental results

[0563] Compound IC50(nM) C1 <20nM C2 <20nM

[0564] Example 19 Cell experiment

[0565] Compounds C1 and C2 of different concentrations ranging from 10 mM to 1.52 μM obtained by 3-fold dilution were added to 100 μL / well MDA-MB-453 tumor cell suspension at a ratio of 1:1000 and placed at 37°C, 5% CO 2 Incubate in an incubator for 48 hours. Add 10 μL of CCK-8 solution to each well to avoid bubbles. After incubating at 37°C for 2 hours, measure the absorbance at 450 nm with an ELISA reader. Calculate cell inhibition using 1-[A(drug added)-A(blank)] / [A(no drug added)-A(blank)]×100, and fit the curve to obtain the IC50 of the compound. According to the above experimental method, the IC50 of the measured compound is shown in the following table:

[0566] Table 3 Experimental results

[0567] Compound IC50(nM) C1 <100nM C2 100nM<IC50<1,000nM C3 <100nM C4 <100nM C5 <100nM C6 100nM<IC50<1,000nM C7 100nM<IC50<1,000nM C8 100nM<IC50<1,000nM C9 100nM<IC50<1,000nM

[0568] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structural formula: in, A is N, B is N; R2 is selected from -H, halogen; R 10 Selected from: C 1-10 Straight chain / branched chain alkyl, -CO(C 0-10 alkyl); R 12 , R 13 Independently selected from -H, C 1-10 Straight chain / branched chain alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 12 , R 13 Independently selected from -H, C 1-6 Straight chain / branched chain alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that: R 12 , R 13 Independently selected from -H, -CH3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Said R2 is selected from -H or F; 。 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R 10 Selected from: 。 6. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The structural formula of the compound is as follows: 。 7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable excipient.

8. Use of the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting one or more cyclin-dependent kinases, wherein the cyclin-dependent kinase is CDK4 or CDK6.

9. Use of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating one or more cyclin-dependent kinase-related diseases, wherein the cyclin-dependent kinase-related diseases are selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Burkett's lymphoma, acute myeloid leukemia, myelodysplastic syndrome, rhabdomyosarcoma, astrocytoma and glioma.

10. The use according to claim 9, characterized in that: The compound and its pharmaceutically acceptable salt are used alone or in combination with other types of pharmaceutical preparations and / or treatment methods, wherein the other types of pharmaceutical preparations are selected from: cell growth inhibitors, cytotoxic agents, microtubule protein interaction agents, hormone agents, anti-metabolites, anti-tumor agents, and the treatment methods are selected from: hormone therapy, immunotherapy, and radiotherapy.

11. The use according to claim 10, characterized in that: The treatment method is a combination of hormone therapy and immunotherapy.

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