WO2020207260A1

WO2020207260A1 - Cdk inhibitor and application thereof

Info

Publication number: WO2020207260A1
Application number: PCT/CN2020/081432
Authority: WO
Inventors: 林星雨; 陆婷婷
Original assignee: 珠海宇繁生物科技有限责任公司
Priority date: 2019-04-08
Filing date: 2020-03-26
Publication date: 2020-10-15
Also published as: CN113661164A

Abstract

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

Description

A CDK kinase inhibitor and its application

Technical field

The invention belongs to the field of medicine, and specifically relates to a cyclin-dependent kinase inhibitor and its application.

Background technique

Cyclin-dependent kinases (CDK) is a Ser/Thr kinase system corresponding to the cell cycle process. Cyclin-dependent protein kinases are a group of serine/threonine protein kinases. CDK drives the cell cycle by chemically acting on serine/threonine proteins. It acts in concert with cyclin and is an important factor in cell cycle regulation. CDK can combine with cyclin to form a heterodimer, where CDK is a catalytic subunit, and cyclin is a regulatory subunit. Different cyclin-CDK complexes can catalyze the phosphorylation of different substrates through CDK activity, and achieve different timing of the cell cycle. Phase advancement and transformation. The activity of CDK depends on the sequential expression of its positive regulatory subunit cyclin and the concentration of its negative regulatory subunit CKI (cyclindependent 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.

There are 8 types of CDK family, including CDK 1-8. Each CDK binds to different types of cyclin to form a complex, which regulates the process of cells transitioning from G1 phase to S phase or G2 phase to M phase and exiting M phase. Various CDKs are activated alternately along the cell cycle phase, phosphorylating the corresponding substrates, so that cell cycle events proceed in an orderly manner.

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 Enter or exit phase M). Various CDKs are activated at specific times in the cell cycle, and through phosphorylation of substrates, drive cells to complete the cell cycle.

Patent document CN200680047113.0 provides a novel imidazo[1,2-a]pyrazine compound as a cyclin-dependent kinase inhibitor, the general formula of the compound is

The compound or pharmaceutical composition can be used to treat, prevent, inhibit or alleviate one or more diseases related to CDKs.

J Clin Oncol, the Journal of Clinical Oncology published in 1998 a CDK inhibitor flavopiridol with the structure

Is a non-selective CDK inhibitor, currently undergoing human clinical trials.

Patent document CN200680025008.7 discloses a new class of compounds with the structure

The pharmaceutical composition containing the compound can be used to treat or prevent diseases or disorders related to abnormal or unregulated kinase activity, especially abnormal activation of CDKs, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR kinase The method of the disease or disorder.

Based on the above background, the present invention provides a novel compound and pharmaceutical composition to treat diseases and disorders related to CDK.

Summary of the invention

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

The purpose of the present invention is achieved through the following technical solutions:

The present invention provides a compound of general formula I:

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

R _{1 is} selected from -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, -N (C _0-10 alkyl) (C _0-10 alkyl) , C _3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -OH, -NO ₂ , carboxy 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 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 ring Alkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl, -S heterocyclic aryl.

R _{2 is} 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) Group), k=0-2, wherein the H on the above group can be substituted by the following groups: halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OH, C _1-10 straight chain /Branched 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 aryl, -O heterocyclic aryl, -S heterocyclic aryl.

When B is N, R ₃ does not exist. When B is C, R _{3 is} 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 linear/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 aryl, -O heterocyclic aryl, -S heterocyclic aryl.

R _{4 is} 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 , -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 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 linear/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 Group, -O heterocyclic aromatic group, -S heterocyclic aromatic group

In the general formula I, the dotted line represents a single bond (ie, R ₆ and R ₇ are connected through the single bond to form a ring with the carbon atom to which they are connected) or absent (ie, R ₆ and R _{7 are} not connected).

R ₅ , R ₆ and R _{7 are} 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, -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 substitution Group, -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 group or -S heterocyclic aromatic group, wherein H on the above groups can 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 aryl, -O heterocyclic aryl, -S heterocyclic aryl, wherein the alkyl part of the group can be optionally 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 , The atoms between R ₇ and R ₆ and R ₇ form a C _3-8 cycloalkyl group or a C _3-8 heterocycloalkyl group containing O, N or S.

The ring Ar is fused with the ring R _g , and the fused bond is any bond on the ring Ar.

The ring Ar is selected from an aromatic five-membered heterocyclic group, an aromatic six-membered heterocyclic group or a phenyl group, and the aromatic five-membered heterocyclic group is selected from: imidazolyl, thiazolyl, oxazolyl, and pyrrolyl , Pyrazolyl, furyl or thienyl, the aromatic six-membered heterocyclic group is selected from: pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally the aromatic five-membered heterocyclic group Group, aromatic six-membered heterocyclic group or phenyl group can be substituted by the following groups: halogen, -CN, -OCF ₃ , C _1-10 linear/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 cycloalkyl, -O heterocycloalkyl , -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic, -O heterocyclic aromatic or -S heterocyclic aromatic.

In an embodiment of the present invention, ring Ar is pyrrolyl, such as

The ring R _{g is} selected from C _3-8 saturated/unsaturated cycloalkyl or C _3-8 saturated/unsaturated heterocycloalkyl containing -O-, -N-, -S-, and optionally the C _{3 -8} saturated/unsaturated cycloalkyl or C _3-8 saturated/unsaturated heterocycloalkyl containing -O-, -N-, -S- can be substituted by the following groups: halogen, -CN, -OCF ₃ , C _1-10 linear/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 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl Or -S heterocyclic aromatic group.

In one embodiment of the invention, the ring R _g is

R _{8 is} selected from O, S or NR ₉ , R _{9 is} 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, -O heterocycloalkyl, -N heterocycloalkyl , -S heterocycloalkyl.

Preferably, the general formula of the compound is as follows:

Preferably, R _{1 is} selected from -H, halogen, -CN, -OC _0-10 alkyl, C _1-10 linear/branched alkyl, more preferably, R _{1 is} selected from H, -CN, -CH _3. -CH ₂ CH ₃ .

Preferably, B is N and R _{3 is} not present.

R ₅ , R ₆ and R _{7 are} independently selected from halogen, -CN, -CF ₃ , -OCF ₃ , -OC _0-10 alkyl, C _1-10 linear/branched 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 aryl, N, O substituted fused ring alkyl, N, O substituted spiro cycloalkyl, N, O substituted bridged cycloalkyl, wherein the H on the above group 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 linear/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 aryl, -O heterocyclic aromatic group, wherein the alkyl part of the group can be optionally substituted by one or more of the following groups: halogen, -CN, -OH, C _1-4 linear/branched alkyl, -N (C _0-10 alkyl) (C _0-10 alkyl), C _3-4 cycloalkyl, carbonyl, or the atoms between R ₆ , R ₇ and R ₆ and R ₇ form a C _3-8 cycloalkane Group or N-containing C _3-8 heterocycloalkyl.

Preferably, R ₄ and R _{5 are} independently selected from -H, halogen, -CN, -CF ₃ , -OC _0-10 alkyl, C _1-10 linear/branched alkyl; more preferably, R ₄ And R _{5 are} independently selected from H, -CN, -CH ₃ , and -CH ₂ CH ₃ .

Preferably, R _{7 is} 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 alkane Group, -N(C _0-10 alkyl)(C _0-10 alkyl), C _3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl; More preferably, R _{7 is} selected from H, -CN, -CH ₃ , and -CH ₂ CH ₃ .

R ₁₄ , R ₁₅ and R _{16 are} 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 heterocycloalkane Group, -S heterocycloalkyl, carboxy and its substituents, -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 _0-10 alkyl)(C _0-10 alkyl), S(O)k(C _0-10 alkyl), k=0-2, wherein the above groups The H above can be substituted by the following groups: halogen, -CN, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , -OH, C _1-10 linear/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 group, -O heterocyclic aromatic group, -S heterocyclic aromatic group.

Preferably, R ₁₄ , R ₁₅ and R _{16 are} independently selected from -H, halogen, -CN, -CF ₃ , -OC _0-10 alkyl, and C _1-10 linear/branched alkyl.

More preferably, R ₁₄ , R ₁₅ and R _{16 are} independently selected from H, -CN, -CH ₃ , and -CH ₂ CH ₃ .

In a preferred embodiment of the present invention, the general formula of the compound is as follows:

Preferably, the ring Ar is selected from imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl or phenyl, optionally the imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl or benzene The H on the group can be substituted by the following groups: halogen, -CN, -OCF ₃ , C _1-10 linear/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 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycle Alkyl group, -N heterocyclic aromatic group, -O heterocyclic aromatic group or -S heterocyclic aromatic group.

Preferably, the ring R _{g is} selected from C _5-7 saturated/unsaturated cycloalkyl or C _5-7 saturated/unsaturated heterocycloalkyl containing -O-, -N-, optionally the C _{5- 7} saturated/unsaturated cycloalkyl or C _5-7 saturated/unsaturated heterocycloalkyl containing -O-, -N- 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 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic, -O heterocyclic aromatic or -S heterocyclic Aromatic base.

R _{8 is} selected from O, ring R _g is C _5-7 saturated/unsaturated cyclic ketone, C _5-7 saturated/unsaturated cyclic lactone, C _5-7 saturated/unsaturated cyclic lactam.

In a preferred embodiment of the present invention, the condensed ring structure formed by ring Ar and ring R _g is as follows:

R ₁₁ , R ₁₂ , R ₁₃ , R ₁₃ 'are 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/branched chain alkyl, -N (C _0-10 alkyl) (C _0-10 alkyl), C _3-10 cycloalkyl, -O heterocycloalkyl,- N heterocycloalkyl, -S heterocycloalkyl.

Preferably, R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₃ ′ are independently selected from -H, halogen, -NO ₂ , -CN, -CF ₃ , C _1-6 linear/branched chain alkyl, -N( C _0-10 alkyl) (C _0-10 alkyl), C _3-7 cycloalkyl.

More preferably, R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₃ ′ are independently selected from -H, halogen, -CN, and -CH ₃ .

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

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

Preferably, A is N and B is N.

R _{2 is} 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 above groups The H on the group can be substituted by the following groups: halogen, -CN, -OH, C _1-10 linear/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.

In a preferred embodiment of the present invention, the R _{2 is} selected from -H or F.

Preferably, R _{6 is} selected from halogen, -OC _0-10 alkyl, C _1-6 linear/branched 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 group, N, O substituted fused ring alkyl, N, O substituted spiro cycloalkyl, N, O substituted bridged cycloalkyl, wherein H on the above groups can 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 linear/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 aryl, -O heterocyclic aryl, wherein the alkyl part of the group can be replaced by one or more of the following groups Optional substitution: -OH, C _1-4 linear/branched chain alkyl, -N (C _0-10 alkyl) (C _0-10 alkyl), C _3-4 cycloalkyl, carbonyl.

Preferably, R _{6 is} selected from

Wherein, X is selected from N or O; Y is selected from C, N, O or S; m is selected from an integer between 0-4, such as 0, 1, 2, 3, 4; p, q, s are selected from 1 An integer between -4, such as 1, 2, 3, 4; R _{17 is} selected from: -OH, halogen, C _1-6 linear/branched chain alkyl, -N (C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-5 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, wherein the alkyl part of the group may be substituted by a carbonyl group .

In a preferred embodiment of the present invention, said R _{6 is} selected from:

R _{10 is} selected from halogen, -CN, -CF ₃ , -OC _0-10 alkyl, C _1-10 linear/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 hetero Cycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic group, wherein 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 linear/branched chain alkane Group, -N (C _0-10 alkyl) (C _0-10 alkyl), -OC _0-10 alkyl, C _3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl , -N heterocyclic aromatic group, -O heterocyclic aromatic group, wherein the alkyl part of the group can be optionally substituted by one or more of the following groups: halogen, -CN, -OH, C _1-4 straight chain /Branched alkyl, -N(C _0-10 alkyl) (C _0-10 alkyl), C _3-4 cycloalkyl, carbonyl.

Preferably, R _{10 is} selected from -OC _0-10 alkyl, C _1-10 linear/branched 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, of which the above The H on the group 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 linear/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 aryl, -O heterocyclic aryl, wherein the group The alkyl part of can be optionally 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.

Preferably, R _{10 is} selected from H, C _1-5 straight chain/branched chain alkyl, hydroxy substituted C _1-5 straight chain/branched chain alkyl,

Wherein, X is selected from N or O; Y is selected from C, N, O or S; m is selected from an integer between 0-4, such as 0, 1, 2, 3, 4; p, q, s are selected from 1 An integer between -4, such as 1, 2, 3, 4; f is selected from an integer between 1-3, such as 1, 2, 3; g is 1 or 2; R _{17 is} 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, -O hetero Cycloalkyl, -N heterocycloalkyl, wherein the alkyl part of the group may be substituted by a carbonyl group.

In a preferred embodiment of the present invention, the R _{10 is} selected from:

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

The present invention provides a pharmaceutical composition comprising a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, and also includes pharmaceutics Acceptable excipients.

Specifically, the auxiliary materials are selected from: carriers, diluents, binders, lubricants, wetting agents and the like.

Preferably, the pharmaceutical composition contains a therapeutically effective amount of a compound of formula I.

In some embodiments, the pharmaceutical composition can be used alone or in combination with other kinds of pharmaceutical preparations.

The other types of pharmaceutical preparations include: DNA mutual interference agents such as cisplatin or doxorubicin, paclitaxel, docetaxel or epsilon, tamoxifen, methotrexate, uracil mustard, nitrogen mustard, iso Cyclophosphamide, melphalan, chlorambucil, piperamide, triptamide, triethylene thiophosphoramide, busulfan, carmustine, lomustine, streptozocin, tar Carpazine, fluorouracil deoxynucleoside, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, racovanin, oxaliplatin, doxorubicin Star, trastuzumab, fulvestrant, exemestane, rituximab.

Preferably, the pharmaceutical composition further includes antioxidants, buffers, bacteriostatic agents, etc., and solutes that make the preparation isotonic with the blood of the subject, as well as aqueous and non-aqueous sterile suspending agents, which may include suspending agents. Agents, solubilizers, thickeners, stabilizers and preservatives.

The pharmaceutical composition is suitable for gastrointestinal administration or parenteral administration, such as administration by intravenous, intramuscular, intradermal and subcutaneous routes.

The pharmaceutical composition can be prepared into the following forms of pharmaceutical preparations: injections, syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, creams, ointments, lotions, gels , Emulsion, etc.

When preparing injections, any commonly used carriers in the art can be used, such as: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol and polyethylene sorbitan fat Acid esters and so on. In addition, common dissolving agents and buffers can also be added.

The present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds in the preparation of inhibiting one or more cyclin-dependent kinases (CDK ) In the application of drugs.

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

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

The disease related to cyclin-dependent kinase (CDK) is a proliferative disease, selected from cancer, autoimmune disease, viral disease, fungal disease, neuropathy, arthritis, inflammation, neuronal disease, hair loss and cardiovascular disease disease.

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, tumors of the central and peripheral nervous system.

The malignant tumor is selected from: 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.

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

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

The tumor of mesenchymal origin is selected from: fibrosarcoma and rhabdomyosarcoma.

The tumors of the central and peripheral nervous system are selected from the group consisting of astrocytoma, fibroblastic neuroma, glioma and schwannoma.

The autoimmune disease is selected from: systemic lupus, lupus erythematosus, autoimmune-regulated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes.

The viral infection is selected from: herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus.

The neuropathy is selected from: Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar decline.

Preferably, the compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds can be used alone or in combination with other types of pharmaceutical preparations and/or treatments. Methods are used in combination.

The other types of pharmaceutical preparations include, but are not limited to: cell growth inhibitors, cytotoxic agents, tubulin interaction agents, hormone agents, antimetabolites, and antitumor agents, and the treatment methods include but are not limited to: hormone therapy , Immunotherapy, radiotherapy; preferably used in combination with hormone therapy and immunotherapy.

The cytotoxic agent is selected from: DNA mutual interference agents such as cisplatin or doxorubicin.

The tubulin interaction agent is selected from the group consisting of paclitaxel, docetaxel or epsilon.

The hormone agent is selected from: tamoxifen.

The antimetabolite is selected from: methotrexate.

The anti-tumor agent is selected from the group consisting of: uracil mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, piperamide, trataamide, triethylene thiophosphoramide, and buxiao An, carmustine, lomustine, streptozocin, dacarbazine, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, ol Saliplatin, racovanin, oxaliplatin, doxorubicin, trastuzumab, fulvestrant, exemestane, rituximab.

The present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds in the prevention and/or treatment of cancer, autoimmune diseases, and viral diseases. , Fungal diseases, neuropathy, arthritis, inflammation, neuronal diseases, hair loss and cardiovascular diseases.

The present invention provides a compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds for the preparation of prevention and/or treatment of cancer, autoimmune diseases, viruses Disease, fungal disease, neuropathy, arthritis, inflammation, neuronal disease, hair loss and cardiovascular disease drug application.

In the present invention, the term C _0-10 alkyl, C ₀ alkyl refers to H, therefore, C _0-10 alkyl includes 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.

The term C _1-10 straight chain/branched chain alkyl in the present invention includes methyl, ethyl, C ₃ straight chain/branched chain alkyl, C ₄ straight chain/branched chain alkyl, C ₅ straight 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 alkyl.

The term C _3-10 branched chain alkyl in the present invention includes isopropyl, isobutyl, tert-butyl and isopentyl.

The term C _3-10 cycloalkyl in the present invention includes C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, C ₈ cycloalkyl Group, C ₉ cycloalkyl, C ₁₀ cycloalkyl.

The term halogen in the present invention includes fluorine, chlorine, bromine and iodine.

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

The term heterocyclic aromatic group in the present invention refers to an aromatic monocyclic or polycyclic ring system containing 5-14 ring atoms, preferably 5-10 ring atoms, wherein one or more ring atoms are not carbon atoms, and It is, for example, a nitrogen, oxygen or sulfur atom. Preferred heterocyclic aromatic groups contain 5-6 ring atoms. Representative heterocyclic aromatic groups include pyrazinyl, furyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyrazolyl , Triazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3-diaza naphthyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl , Indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridyl, imidazo Pyridyl, isoquinolyl, 1,2,4-triazinyl, benzothiazolyl, etc.

detailed description

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present invention, but not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.

Example 1 Preparation of Compound C1

The synthetic route of the compound is as follows:

step 1:

Add 1 (1.0g, 6.03mmol), 2 (2.18g, 6.03mmol), bis(triphenylphosphine) palladium dichloride (212mg, 0.30mmol) and DMF (10mL) in a 50ml single-mouth bottle, nitrogen protection, 120 React for 2 hours at temperature. Add 4N hydrochloric acid at 50°C, stir for 2 hours, add water, extract with ethyl acetate (20mL x 3), wash the organic phase with saturated brine (20mLx2), dry with anhydrous sodium sulfate, spin dry, and pass through column chromatography ( Petroleum ether: ethyl acetate = 5:1) to obtain a brown solid as the target product (800 mg, yield: 76.2%). LC-MS: 175[M+H] ⁺ .

Step 2:

Add 3 (800 mg, 4.60 mmol), acetic acid (5.0 mL) and bromine (0.3 mL, 5.52 mmol) into a 25 mL single-neck round bottom flask, and react at room temperature for 4 hours. After adding water, it was extracted with ethyl acetate (10mL x 3), the organic phase was washed with 10% sodium thiosulfate (10mL x 3), saturated brine (10mL x 3), dried with anhydrous sodium sulfate, spin-dried, and passed through Column chromatography (petroleum ether: ethyl acetate = 5:1) gave a brown solid as the target product (800 mg, yield: 69.0%). LC-MS:253[M+H] ⁺

Step 3:

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 (20mL x 3), wash with saturated brine (20mL x 3), dry with anhydrous sodium sulfate, spin dry, pass through the column (DCM: MeOH = 30:1) to obtain a yellow solid as The target product (500 mg, yield: 59.3%). LC-MS: 267[M+H]+

Step 4:

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

Step 5:

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

Step 6:

Add 10 (300mg, 1.36mmo), 6 (302mg, 1.14mmol), Pd ₂ (dba) ₃ (52mg, 0.06mmol), X-Phos (54mg, 0.01mmol), potassium carbonate (315mg, 2.28mmol) and toluene (4mL), reacted at 100 degrees Celsius for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and a white solid was prepared 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 = 11.0 Hz, 1H), 2.28 (s, 6H), 1.87 (d, J = 11.9 Hz, 2H), 1.54 (tt, J = 11.6, 5.9 Hz, 2H).

Example 2 Preparation of Compound C2

The synthetic route of the compound is as follows:

step 1:

Add 1 (1.0g, 6.03mmol), 2 (2.18g, 6.03mmol), bis(triphenylphosphine) palladium dichloride (212mg, 0.30mmol) and DMF (10mL) in a 50ml single-mouth bottle, nitrogen protection, 120 React for 2 hours at temperature. Add 4N hydrochloric acid at 50°C, stir for 2 hours, add water, extract with ethyl acetate (20mL x 3), wash the organic phase with saturated brine (20mL x 2), dry with anhydrous sodium sulfate, spin dry, and pass through the column After analysis (petroleum ether: ethyl acetate = 5:1), a brown solid was obtained as the target product (800 mg, yield: 76.2%). LC-MS:175[M+H] ⁺

Step 2:

Step 3:

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

Step 4:

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

Step 6:

Step 7:

Add 10 (300mg, 1.36mmo), 11 (319mg, 1.14mmol), Pd ₂ (dba) ₃ (52mg, 0.06 mmol), X-Phos (54mg, 0.01mmol), potassium carbonate (315mg, 2.28mmol) and toluene (4mL), reacted at 100 degrees Celsius for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and a white solid was prepared as the target product (30 mg, yield: 5.7%). LC-MS: 465[M+H]+, ¹ H NMR: ¹ H 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 = 11.0 Hz, 2H), 2.27 (s, 6H), 1.88 (d, J = 11.7 Hz, 2H), 1.54 (dt, J = 19.9, 7.6 Hz, 2H).

Example 3 Preparation of Compound C3

The synthetic route of the compound is as follows:

step 1:

Add 1 (45g, 271.2mmol), 2 (98.21g, 271.2mmol), bis(triphenylphosphine) palladium dichloride (9.58g, 13.56mmol) and DMF (200mL) in a 500ml single-mouth flask, nitrogen protection, 120 React for 2 hours at temperature. Add 4N hydrochloric acid at 50°C, stir for 2 hours, add water, extract with ethyl acetate (600mL x 3), wash the organic phase with saturated brine (300mL x 3), dry with anhydrous sodium sulfate, spin dry, and pass through the column After analysis (petroleum ether: ethyl acetate = 5:1), a brown solid was obtained as the target product (33.1 g, yield: 70.1%). LC-MS:175[M+H] ⁺

Step 2:

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

Step 3:

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) were added to a 500 ml single-necked flask, and reacted at room temperature for 1 hour. Add water to quench, extract with dichloromethane (200mL x 3), wash with saturated brine (200mL x 3), dry with anhydrous sodium sulfate, spin dry, and pass through the column (DCM: MeOH = 30:1) to obtain a yellow solid as The target product (22 g, yield: 69.4%). LC-MS: 267[M+H]+

Step 4:

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

Step 5:

Add 8 (1.55g, 17.83mmol), 9 (3.0g, 14.86mmol), Pd ₂ (dba) ₃ (680mg, 0.74mmol), X-Phos (710mg, 1.49mmol), potassium carbonate ( 4.10g, 29.72mmol) and toluene (30mL), reacted at 100°C for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried and passed through column chromatography (petroleum ether: ethyl acetate=3:1) to obtain a yellow solid as the target product (1.45 g, yield: 46.7%). LC-MS: 210[M+H]+

Step 6:

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

Step 7:

Add 11 (330mg, 1.84mmol), 7 (430mg, 1.54mmol), Pd ₂ (dba) ₃ (70mg, 0.08mmol), X-Phos (72mg, 0.15mmol), potassium carbonate (425mg, 3.08mmol) and toluene (5mL), reacted at 100°C for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and a white solid was prepared 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,1H),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).

Example 4 Preparation of Compound C4

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

Add 10 (740 mg, 2.40 mmol), methanol (7.0 mL) and Pd/C (70 mg) into a 25 mL single-mouth flask, and react at room temperature under a hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (600 mg, yield: 89.9%). LC-MS: 279[M+H] ⁺

Step 7:

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

Step 8:

In a 25mL single-neck flask, add 12 (150mg, 0.29mmol), DCM (2.0mL) and trifluoroacetic acid (0.5mL), react for 2 hours at room temperature, spin dry, and prepare the target product as a white solid (20mg, 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=3.8Hz,1H),3.99(s,3H),3.63(t,J=7.0Hz,2H),3.41(s,5H),3.33(dt,J = 3.3, 1.6 Hz, 3H), 2.99 (t, J = 7.0 Hz, 2H).

Example 5 Preparation of Compound C5

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

Add 10 (410 mg, 1.74 mmol), methanol (4.0 mL) and Pd/C (40 mg) into a 25 mL single-mouth flask, and react at room temperature under a hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (300 mg, yield: 83.6%). LC-MS: 207[M+H] ⁺

Step 7:

Add 11 (150mg, 0.73mmol), 7 (170mg, 0.61mmol), Pd ₂ (dba) ₃ (27mg, 0.03mmol), X-Phos (29mg, 0.06mmol), potassium carbonate (168mg, 1.22mmol) and toluene (3mL), reacted at 100°C for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and a white solid was prepared as the target product (8 mg, yield: 2.9%). LC-MS: 451[M+H]+, ¹ H NMR(400MHz, 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 = 6.7 Hz, 2H), 2.73 (s, 4H), 2.58 (d, J = 7.3 Hz, 2H), 1.19 (t, J=7.2Hz, 3H).

Example 6 Preparation of Compound C6

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

Add 10 (530 mg, 1.65 mmol), methanol (5.0 mL) and Pd/C (50 mg) into a 25 mL single-necked flask, and react at room temperature under a hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (460 mg, yield: 95.4%). LC-MS: 293[M+H] ⁺

Step 7:

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

Step 8:

In a 25mL single-mouth flask, add 12 (58mg, 0.11mmol), DCM (1.0mL) and trifluoroacetic acid (0.2mL), react for 2 hours at room temperature, spin dry, and prepare the target product as a white solid (10mg, Yield: 20.8%). LC-MS: 437[M+H]+, ¹ H 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 = 6.8 Hz, 4H), 3.44 (s, 2H), 3.34 (d, J = 1.6 Hz, 2H), 2.97 (t, J =6.9 Hz, 2H), 2.23 (s, 2H).

Example 7 Preparation of Compound C7

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

Add 10 (430 mg, 1.81 mmol), methanol (4.0 mL) and Pd/C (43 mg) into a 25 mL single-necked flask, and react at room temperature under hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (300 mg, yield: 80.4%). LC-MS: 208[M+H] ⁺

Step 7:

Add 11 (150mg, 0.72mmol), 7 (169mg, 0.60mmol), Pd ₂ (dba) ₃ (27mg, 0.03 mmol), X-Phos (29mg, 0.06mmol), potassium carbonate (166mg, 1.20mmol) and toluene (3mL), reacted at 100°C for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and a white solid was prepared as the target product (30 mg, yield: 11.1%). LC-MS: 452[M+H]+, ¹ H NMR(400MHz, 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 = 10.7 Hz, 2H), 2.97 (t, J = 6.7 Hz, 2H), 2.47 (t, J = 10.9 Hz, 2H), 1.30 (d, J = 6.3 Hz, 6H).

Example 8 Preparation of Compound C8

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

Add 10 (650 mg, 2.60 mmol), methanol (5.0 mL) and Pd/C (65 mg) into a 25 mL single-mouth flask, and react at room temperature under a hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (450 mg, yield: 78.6%). LC-MS: 221[M+H] ⁺

Step 7:

Add 11 (230mg, 1.04mmol), 7 (244mg, 0.87mmol), Pd ₂ (dba) ₃ (40mg, 0.04mmol), BINAP (54mg, 0.09mmol), sodium tert-butoxide (167mg, 1.74mmol) and toluene (3mL), react at 90°C for 4 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and a white solid was prepared 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),7.04(d,J=4.1Hz,1H),3.93( s, 3H), 3.60 (d, J = 4.4 Hz, 4H), 3.45 (dd, J = 6.7, 4.4 Hz, 2H), 3.18–3.04 (m, 4H), 2.91 (t, J = 6.8 Hz, 2H ), 2.05 (d, J=5.0 Hz, 3H).

Example 9 Preparation of Compound C9

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

Add 8 (4.5g, 20.80mmol), 9 (3.5g, 17.33mmol), Pd ₂ (dba) ₃ (793mg, 0.87mmol), X-Phos (826mg, 1.73mmol), potassium carbonate ( 4.78g, 34.66mmol) and toluene (40mL), reacted at 100°C for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried and passed through column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid as the target product (1.6 g, yield: 27.5%). LC-MS: 337[M+H]+

Step 6:

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

Step 7:

Add 11 (440 mg, 1.0 mmol), methanol (4.0 mL) and Pd/C (44 mg) into a 25 mL single-mouth flask, and react at room temperature for 18 hours under a hydrogen atmosphere. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (300 mg, yield: 73.8%). LC-MS: 407[M+H] ⁺

Step 8:

Add 12 (300mg, 0.74mmol), 7 (172mg, 0.62mmol), Pd ₂ (dba) ₃ (27mg, 0.03mmol), X-Phos (29mg, 0.06mmol), potassium carbonate (171mg, 1.24mmol) and toluene (5mL), reacted at 100°C for 18 hours under a nitrogen atmosphere. After suction 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]+

Step 9:

In a 25mL single-neck flask, add 13 (150mg, 0.23mmol), DCM (2.0mL) and trifluoroacetic acid (0.5mL), react for 2 hours at room temperature, spin dry, and prepare the target product as a white solid (30mg, 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=12.2 Hz, 2H).

Example 10 Preparation of Compound C10

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

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

Step 7:

Add 11 (960mg, 6.76mmol), 12 (1.64g, 8.11mmol), potassium carbonate (2.80g, 20.3mmol and DMF (15mL) in a 250ml single-mouth flask, react at 140°C for 2 hours under nitrogen atmosphere. Add water (50mL) ) Was quenched, extracted with ethyl acetate (80mL×3), washed with saturated brine (80mL×2), dried with anhydrous sodium sulfate, spin-dried, and obtained by column chromatography (dichloromethane: methanol = 10:1) The target product is a yellow solid (470mg, yield: 26.3%). LC-MS: 265[M+H]+

Step 8:

Add 13 (470mg, 1.78mmol), triethylamine (539mg, 5.34mmol), DMAP (21.7mg, 0.178mmol) dichloromethane (10mL) and Boc ₂ O (582mg, 2.67mmol) to a 250ml single-mouth bottle at 40 degrees React for 16 hours. It was quenched with water (20mL), extracted with dichloromethane (15mL×3), washed with saturated brine (15mL×2), dried over anhydrous sodium sulfate, spin-dried, and passed through column chromatography (dichloromethane: methanol = 12: 1) The target product is a yellow solid (160 mg, yield: 24.7%). LC-MS: 365[M+H]+

Step 9:

Add 11 (160mg, 0.440mmol), methanol (50mL) and Pd(OH) ₂ /C (40mg) into a 25mL single-mouth flask, and react at room temperature under hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (130 mg, yield: 85.5%). LC-MS: 335[M+H] ⁺

Step 10:

Add 15 (130mg, 0.390mmol), 7 (197mg, 0.702mmol), Pd ₂ (dba) ₃ (17.9mg, 0.0195mmol), BIANP (36.4mg, 0.0585mmol), sodium tert-butoxide ( 112 mg, 1.17 mmol) and toluene (8 mL), reacted at 100°C for 16 hours under a nitrogen atmosphere. After suction 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]+

Step 11:

In a 25mL single-mouth flask, add 16 (79mg, 0.137mmol), DCM (5mL) and trifluoroacetic acid (1mL), react for 3 hours at room temperature, spin dry, and prepare the target product as a yellow solid (12mg, 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 = 4.2 Hz, 1H), 3.93 (d, J = 11.1 Hz, 5H), 3.48 (ddd, J = 16.2, 9.0, 6.8 Hz ,4H),3.09(dd,J=12.8,5.7Hz,3H),3.00–2.77(m,5H),1.99(d,J=13.9Hz,2H),1.83(s,1H),1.40(d, J = 13.4 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H).

Example 11 Preparation of Compound C11

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

Add 10 (1.20g, 4.41mmol), dioxane (10.0mL) and a dioxane solution (15mL, 4M) of hydrochloric acid gas into a 250mL single-mouth flask, and react at room temperature for 16 hours. It was spin-dried to obtain a yellow solid as the target product (1.10 g, crude product). LC-MS: 173[M+H] ⁺

Step 7:

Add 11 (1.10g, 6.40mmol), 12 (1.64g, 8.11mmol), potassium carbonate (2.65g, 19.2mmol and DMF (15mL) in a 250ml single-mouth flask, react at 140°C for 2 hours under a nitrogen atmosphere. Add water ( 50mL), extracted with ethyl acetate (80mL×3), washed with saturated brine (80mL×2), dried over anhydrous sodium sulfate, spin-dried, and passed through column chromatography (dichloromethane: methanol = 15:1) The target product was obtained as a yellow solid (540mg, yield: 27.8%). LC-MS: 295[M+H]+

Step 8:

Add 13 (540mg, 1.84mmol), triethylamine (539mg, 5.34mmol), DMAP (21.7mg, 0.178mmol) dichloromethane (10mL) and Boc ₂ O (582mg, 2.67mmol) to a 250ml single-mouth flask at 40 degrees React for 16 hours. It was quenched with water (20mL), extracted with dichloromethane (15mL×3), washed with saturated brine (15mL×2), dried over anhydrous sodium sulfate, spin-dried, and passed through column chromatography (dichloromethane: methanol = 12: 1) The target product is a yellow solid (110 mg, yield: 15.2%). LC-MS: 395[M+H]+

Step 9:

Add 11 (110 mg, 0.279 mmol), methanol (20 mL) and Pd(OH) ₂ /C (35 mg) into a 25 mL single-mouth flask, and react at room temperature under a hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (100 mg, yield: 98.4%). LC-MS: 365[M+H] ⁺

Step 10:

Add 15 (100mg, 0.275mmol), 7 (550mg, 0.550mmol), Pd ₂ (dba) ₃ (12.6mg, 0.0138mmol), BIANP (25.7mg, 0.0413mmol), sodium tert-butoxide ( 79.2mg, 0.825mmol) and toluene (8mL), reacted at 100°C for 16 hours under a nitrogen atmosphere. After suction 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]+

Step 11:

In a 25mL single-mouth flask, add 16 (45mg, 0.0740mmol), DCM (5mL) and trifluoroacetic acid (1mL), react at room temperature for 3 hours, spin dry, prepare the target product as a yellow solid (8mg, 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, 2.5 Hz, 1H), 7.21 (s, 1H), 6.98 (d, J = 4.0 Hz, 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 = 23.5 Hz, 3H), 1.42-1.29 (m, 2H).

Example 12 Preparation of Compound C12

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

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

Step 7:

Add 12 (670mg, 1.96mmol) to a 250ml single-necked flask, and react with tetrahydrofuran (10mL) concentrated hydrochloric acid (10mL) at room temperature for 16 hours. It was spin-dried, and the target product was obtained as a yellow solid (340 mg, yield: 97.7%) by column chromatography (dichloromethane: methanol=15:1). LC-MS: 178[M+H]+

Step 8:

Add 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 ( 302mg, 3.15mmol) and toluene (10mL), reacted at 100°C for 16 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and the target product was prepared as a yellow solid (35 mg, yield: 7.91%) through a high-pressure liquid phase. 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).

Example 13 Preparation of Compound C13

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

Add 10 (1.00g, 4.46mmol), 11 (0.848g, 4.68mmol), Pd ₂ (dba) ₃ (204mg, 0.223mmol), Xantphos (387mg, 0.669mmol), cesium carbonate (6.95g) into a 250ml single-mouth flask , 11.2mmol) and dioxane (25mL), under a nitrogen atmosphere, microwave reaction at 120 degrees for 2 hours. It was spin-dried, and the target product was obtained as a yellow solid (1.48 mg, yield: 89.8%) by column chromatography (dichloromethane: methanol = 20:1). LC-MS: 370[M+H] ⁺

Step 7:

12 (936mg, 2.54mmol) was added to a 250ml single-necked flask, and tetrahydrofuran (10mL) concentrated hydrochloric acid (10mL) was reacted at room temperature for 16 hours. It was spin-dried, and the target product was obtained as a yellow solid (500 mg, yield: 96.0%) by column chromatography (dichloromethane: methanol = 15:1). LC-MS: 206[M+H]+

Step 8:

Add 13 (205mg, 1.00mmol), 7 (504mg, 1.80mmol), Pd ₂ (dba) ₃ (45.8mg, 0.0500mmol), BIANP (93.5mg, 0.150mmol), sodium tert-butoxide ( 288mg, 3.00mmol) and toluene (10mL), reacted at 100°C for 16 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and the target product was prepared as a yellow solid (39 mg, yield: 6.46%) through a high-pressure liquid phase. 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, 8.7 Hz, 2H), 7.28 (s, 1H), 7.11 (d, J = 4.1 Hz, 1H), 4.71-4.55 (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).

Example 14 Preparation of Compound C14

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

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

Step 7:

Add 10 (410 mg, 1.74 mmol), methanol (10.0 mL) and Pd/C (40 mg) into a 25 mL single-necked flask, and react at room temperature under a hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (300 mg, yield: 83.6%). LC-MS: 207[M+H] ⁺

Step 8:

Add 12 (300mg, 1.46mmol), 8 (771mg, 2.62mmol), Pd ₂ (dba) ₃ (66.9mg, 0.0730mmol), BIANP (136mg, 0.219mmol), sodium tert-butoxide (420mg , 4.38mmol) and toluene (15mL), react at 100°C for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and a white solid was prepared as the target product (30 mg, yield: 4.44%). LC-MS: 565[M+H]+, ¹ H NMR (400MHz, DMSO) δ 10.66 (s, 1H), 9.84 (s, 1H), 8.59 (d, J = 3.6 Hz, 1H), 8.03 ( s, 1H), 7.84 (s, 1H), 7.10 (d, J = 4.2 Hz, 1H), 3.94 (s, 3H), 3.82 (t, J = 18.5 Hz, 2H), 3.62 (d, J = 7.0 Hz, 4H), 3.22 (d, J = 6.8 Hz, 4H), 3.02 (s, 4H), 2.93 (s, 3H), 1.27 (t, J = 7.3 Hz, 3H).

Example 15 Preparation of Compound C15

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

7 (1.10g, 3.93mmol) and dioxane (20mL) were added to a 250ml single-necked flask, DDQ (1.34g, 5.90mmol) was added at room temperature, and reacted at room temperature for 18 hours. Rotate to dryness and pass through column chromatography (dichloromethane: methanol = 10:1) to obtain a yellow solid as the target product (300 mg, yield: 27.5%). LC-MS: 279[M+H]+

Step 6:

Step 7:

Step 8:

Add 12 (87.0mg, 0.422mmol), 8 (117mg, 0.422mmol), Pd ₂ (dba) ₃ (19.3mg, 0.0221mmol), BIANP (39.4mg, 0.0633mmol), sodium tert-butoxide into a 50ml single-mouth bottle (122mg, 1.27mmol) and toluene (8mL), reacted at 100°C for 18 hours under a nitrogen atmosphere. After suction filtration, the filtrate was spin-dried, and a white solid was prepared as the target product (2.52 mg, yield: 2.77%). LC-MS: 449[M+H]+, ¹ H NMR(400MHz, CDCl ₃ )δ8.38(d,J=2.9Hz,1H), 8.17(d,J=8.9 Hz,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).

Example 16 Preparation of Compound C16

The synthetic route of the compound is as follows:

step 1:

Step 2:

Step 3:

Step 4:

Step 5:

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

Step 6:

Add 10 (260mg, 0.98mmol), tetrahydrofuran (3.0mL) and BH ₃ THF (1.0mL, 2.0mmol) in a 25ml single-necked flask, reflux for 12 hours, add methanol to quench, spin dry, and pass through column chromatography (petroleum Ether: ethyl acetate = 8:1) to obtain a yellow solid as the target product (50 mg, yield: 20.4%). LC-MS: 251[M+H]+

Step 7:

Add 11 (50mg, 0.20mmol), methanol (1.0mL) and Pd/C (5mg) into a 25mL single-necked flask, and react at room temperature under a hydrogen atmosphere for 18 hours. After suction filtration, the filtrate was concentrated to obtain a white solid as the target product (40 mg, yield: 90.8%). LC-MS: 221[M+H] ⁺

Step 8:

Add 12 (40mg, 0.18mmol), 7 (42mg, 0.15mmol), Pd ₂ (dba) ₃ (14mg, 0.015mmol), X-Phos (14mg, 0.03mmol), potassium carbonate (41mg, 0.30mmol) and toluene (2mL), reacted at 100°C for 18 hours under a nitrogen atmosphere. After suction 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,1H), 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=7.3 Hz, 3H).

Example 17 CDK4/CycD3 Enzymology Experiment of Compound

Experimental Materials:

CDK4/CycD3 recombinant human protease was purchased from Carna (Cat#04-105), ATP was purchased from Sigma (Cat#A7699-5G), staurosporine was purchased from MedChemExpress (Cat#HY-15141), HTRF

Toolbox For Kinases CDK4 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: #62SDBRDD).

experimental method:

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

data analysis:

Convert the 665/615 signal ratio into a percentage inhibition rate. Inhibition rate %=(max-sample)/(max-min)*100. "min" represents the ratio of signal value of 665/615 of the control well without enzyme, and "max" represents the ratio of signal value of 665/615 of the DMSO control well . The IC50 value of the compound was calculated by XLFit in the excel add-in. Equation: Y=Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope).

result:

According to the above experimental method, the measured IC50 of the compound is shown in the following table:

Table 1 Experimental results

化合物Compound	IC50(nM)IC50(nM)
C1C1	<20nM<20nM
C2C2	<20nM<20nM
C3C3	20nM<IC50<100nM20nM<IC50<100nM
C4C4	<20nM<20nM
C5C5	<20nM<20nM
C6C6	<20nM<20nM
C7C7	20nM<IC50<100nM20nM<IC50<100nM
C8C8	<20nM<20nM
C9C9	<20nM<20nM
C10C10	<20nM<20nM
C11C11	<20nM<20nM
C12C12	<20nM<20nM
C13C13	<20nM<20nM
C14C14	20nM<IC50<100nM20nM<IC50<100nM
C15C15	<20nM<20nM
C16C16	20nM<IC50<100nM20nM<IC50<100nM

Example 18 CDK6/CycD3 Enzymology Experiment of Compound

Experimental Materials:

CDK6/CycD3 recombinant human protease was purchased from Carna (Cat#04-107), ATP was purchased from Sigma (Cat#A7699-5G), staurosporine was purchased from MedChemExpress (Cat#HY-15141), HTRF

Toolbox For Kinases CDK 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).

experimental method:

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

data analysis:

result:

Table 2 Experimental results

化合物Compound	IC50(nM)IC50(nM)
C1C1	<20nM<20nM
C2C2	<20nM<20nM

Example 19 Cell Experiment

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

Table 3 Experimental results

化合物Compound	IC50(nM)IC50(nM)
C1C1	<100nM<100nM
C2C2	100nM<IC50<1,000nM100nM<IC50<1,000nM
C3C3	<100nM<100nM
C4C4	<100nM<100nM
C5C5	<100nM<100nM
C6C6	100nM<IC50<1,000nM100nM<IC50<1,000nM
C7C7	100nM<IC50<1,000nM100nM<IC50<1,000nM
C8C8	100nM<IC50<1,000nM100nM<IC50<1,000nM
C9C9	100nM<IC50<1,000nM100nM<IC50<1,000nM

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand: It is still possible to modify the technical solutions described in the foregoing embodiments, or equivalently replace some or all of the technical features; these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the technical solutions of the embodiments of the present invention range.

Claims

A compound of general formula I, or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof:

Wherein, A is selected from C or N, and B is selected from C or N;

R 1 is selected from -H, halogen, -CN, -OC 0-10 alkyl, C 1-10 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl) , C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -OH, -NO 2 , carboxy 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 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 ring Alkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl, -S heterocyclic aryl;

R 2 is 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) Group), k=0-2, wherein the H on the above group can be substituted by the following groups: halogen, -CN, -OCH 2 F, -OCHF 2 , -OCF 3 , -OH, C 1-10 straight chain /Branched 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 aryl, -O heterocyclic aryl, -S heterocyclic aryl;

When B is N, R 3 does not exist. When B is C, R 3 is 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 linear/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 aryl, -O heterocyclic aryl, -S heterocyclic aryl;

R 4 is 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 , -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 H on the above groups can be replaced by the following groups Substitution: halogen, -CN, -OCH 2 F, -OCHF 2 , -OCF 3 , -OH, C 1-10 linear/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 aryl, -O Heterocyclic aromatic group, -S heterocyclic aromatic group;

R 5 , R 6 and R 7 are 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, -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 substitution Group, -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 group or -S heterocyclic aromatic group, wherein H on the above groups can 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 aryl, -O heterocyclic aryl, -S heterocyclic aryl, wherein the alkyl part of the group can be optionally 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 , The atoms between R 7 and R 6 and R 7 form a C 3-8 cycloalkyl group or a C 3-8 heterocycloalkyl group containing O, N or S;

Ring Ar is fused with ring R g , and the fused bond is any bond on ring Ar;

The ring Ar is selected from an aromatic five-membered heterocyclic group, an aromatic six-membered heterocyclic group or a phenyl group, optionally the aromatic five-membered heterocyclic group, an aromatic six-membered heterocyclic group or a phenyl group The H above can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 linear/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 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl Group, -N heterocyclic aromatic group, -O heterocyclic aromatic group or -S heterocyclic aromatic group;

The ring R g is selected from C 3-8 saturated/unsaturated cycloalkyl or C 3-8 saturated/unsaturated heterocycloalkyl containing -O-, -N-, -S-, and optionally the C 3 -8 saturated/unsaturated cycloalkyl or C 3-8 saturated/unsaturated heterocycloalkyl containing -O-, -N-, -S- can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 linear/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 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl Or -S heterocyclic aromatic group;

R 8 is selected from O, S or NR 9 , R 9 is 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, -O heterocycloalkyl, -N heterocycloalkyl , -S heterocycloalkyl.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein the general formula of the compound is as follows:

Wherein, R 10 is selected from halogen, -CN, -CF 3 , -OC 0-10 alkyl, C 1-10 linear/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 group, wherein H on the above groups can be substituted by the following groups: halogen, -CN, -OH, -CON(C 0-10 alkane Group) (C 0-10 alkyl), -CO (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), C 1-10 linear/branched Alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -OC 0-10 alkyl, C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocyclic Alkyl, -N heterocyclic aryl, -O heterocyclic aryl, wherein the alkyl part of the group can be optionally 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;

R 14 , R 15 and R 16 are 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 heterocycloalkane Group, -S heterocycloalkyl, carboxy and its substituents, -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 0-10 alkyl)(C 0-10 alkyl), S(O)k(C 0-10 alkyl), k=0-2, wherein the above groups The H above can be substituted by the following groups: halogen, -CN, -OCH 2 F, -OCHF 2 , -OCF 3 , -OH, C 1-10 linear/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 group, -O heterocyclic aromatic group, -S heterocyclic aromatic group.
The compound according to claim 2 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein R 1 is selected from -H, halogen, -CN, -OC 0-10 alkyl, C 1-10 straight chain/branched chain alkyl;

R 5 , R 6 and R 7 are independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OC 0-10 alkyl, C 1-10 linear/branched 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 aryl, N, O substituted fused ring alkyl, N, O substituted spiro cycloalkyl, N, O substituted bridged cycloalkyl, wherein the H on the above group 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 linear/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 aryl, -O heterocyclic aromatic group, wherein the alkyl part of the group can be optionally substituted by one or more of the following groups: halogen, -CN, -OH, C 1-4 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-4 cycloalkyl, carbonyl, or the atoms between R 6 , R 7 and R 6 and R 7 form a C 3-8 cycloalkane Group or N-containing C 3-8 heterocycloalkyl;

R 14 , R 15 and R 16 are independently selected from -H, halogen, -CN, -CF 3 , -OC 0-10 alkyl, and C 1-10 linear/branched alkyl.
The compound according to claim 3, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein R 4 and R 5 are independently selected from -H, Halogen, -CN, -CF 3 , -OC 0-10 alkyl, C 1-10 linear/branched chain alkyl;

R 7 is selected from -H, halogen, -CN, -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 F, -OC 0-10 alkyl, C 1-10 linear/branched alkyl,- N(C 0-10 alkyl)(C 0-10 alkyl), C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl.
The compound according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein R 1 is selected from H, -CN, -CH 3 , -CH 2 CH 3 ;

B is N, R 3 does not exist;

R 4 and R 5 are independently selected from H, -CN, -CH 3 , -CH 2 CH 3 ;

R 7 is selected from H, -CN, -CH 3 , -CH 2 CH 3 ;

R 14 , R 15 and R 16 are independently selected from H, -CN, -CH 3 , and -CH 2 CH 3 .
The compound according to claim 5 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein the general formula of the compound is as follows:

Wherein, the ring Ar is selected from imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl or phenyl, optionally the imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl or phenyl The H above can be substituted by the following groups: halogen, -CN, -OCF 3 , C 1-10 linear/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 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl Group, -N heterocyclic aromatic group, -O heterocyclic aromatic group or -S heterocyclic aromatic group;

The ring R g is selected from C 5-7 saturated/unsaturated cycloalkyl or C 5-7 saturated/unsaturated heterocycloalkyl containing -O-, -N-, optionally the C 5-7 saturated/ The H on the unsaturated cycloalkyl group or C 5-7 saturated/unsaturated heterocycloalkyl group containing -O-, -N- 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 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, -S heterocycloalkyl, -N heterocyclic aryl, -O heterocyclic aryl or -S heterocyclic aryl;

Preferably, R 8 is selected from O, and ring R g is C 5-7 saturated/unsaturated cyclic ketone, C 5-7 saturated/unsaturated cyclic lactone, C 5-7 saturated/unsaturated cyclic lactam.
The compound according to claim 6 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein the fused ring structure formed by ring Ar and ring R g is as follows :

Wherein, R 11 , R 12 , R 13 , R 13 ′ are 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; n is an integer between 0-6, such as 0, 1, 2, 3, 4, 5, and 6.
The compound according to claim 7 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein 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, preferably, R 11 , R 12 , R 13 , and R 13 ′ are independently selected from -H, halogen, -CN, and -CH 3 .
The compound according to claim 8 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein the structural formula of the compound is as follows:

Among them, A is N, B is N,

R 2 is 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 above groups The H on the group can be substituted by the following groups: halogen, -CN, -OH, C 1-10 linear/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;

R 6 is selected from halogen, -OC 0-10 alkyl, C 1-6 linear/branched alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), C 3-10 ring Alkyl, -CO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -O heterocycloalkyl, -N heterocycloalkyl, -N hetero Cyclic aromatic group, N, O substituted fused ring alkyl, N, O substituted spiro cycloalkyl, N, O substituted bridged cycloalkyl, wherein the H on the above groups can 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 linear/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 aryl, -O heterocyclic aryl, wherein the alkyl part of the group can be optionally 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;

R 10 is selected from halogen, -CN, -CF 3 , -OC 0-10 alkyl, C 1-10 linear/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 hetero Cycloalkyl, -S heterocycloalkyl, -N heterocyclic aromatic group, wherein 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 linear/branched chain alkane Group, -N (C 0-10 alkyl) (C 0-10 alkyl), -OC 0-10 alkyl, C 3-10 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl , -N heterocyclic aromatic group, -O heterocyclic aromatic group, wherein the alkyl part of the group can be optionally substituted by one or more of the following groups: halogen, -CN, -OH, C 1-4 straight chain /Branched alkyl, -N(C 0-10 alkyl) (C 0-10 alkyl), C 3-4 cycloalkyl, carbonyl.
The compound according to claim 9 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein R 6 is selected from

Wherein, X is selected from N or O;

Y is selected from C, N, O or S;

m is selected from an integer between 0-4, such as 0, 1, 2, 3, 4;

p, q, and s are independently selected from integers between 1-4, such as 1, 2, 3, 4;

R 17 is selected from: -OH, halogen, C 1-6 linear/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -OC 0-10 alkyl, C 3-5 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, wherein the alkyl part of the group may be substituted by a carbonyl group.
The compound according to claim 10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein the R 2 is selected from -H or F;

The R 6 is selected from:

R 10 is selected from -OC 0-10 alkyl, C 1-10 linear/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 above groups are The H of 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 linear/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 aryl, -O heterocyclic aryl, wherein the alkyl group of the group Part can be optionally 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.
The compound according to claim 11 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein R 10 is selected from H, C 1-5 linear /Branched chain alkyl, hydroxy substituted C 1-5 straight chain/branched chain alkyl,

Wherein, X is selected from N or O;

Y is selected from C, N, O or S;

m is selected from an integer between 0-4, such as 0, 1, 2, 3, 4;

p, q, and s are independently selected from integers between 1-4, such as 1, 2, 3, 4;

f is selected from an integer between 1-3, such as 1, 2, 3;

g is 1 or 2;

R 17 is selected from: -OH, halogen, C 1-6 linear/branched chain alkyl, -N (C 0-10 alkyl) (C 0-10 alkyl), -OC 0-10 alkyl, C 3-5 cycloalkyl, -O heterocycloalkyl, -N heterocycloalkyl, wherein the alkyl part of the group may be substituted by a carbonyl group.
The compound according to claim 12 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein the R 10 is selected from: -H,
The compound according to claim 13 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, wherein the structural formula of the compound is as follows:
A pharmaceutical composition comprising the compound of any one of claims 1-14 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, It also includes pharmaceutically acceptable excipients.
A compound according to any one of claims 1-14 and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds are prepared to inhibit one or more cyclins Application in kinase-dependent drugs.
A compound according to any one of claims 1-14 and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds are used in the preparation and treatment of one or more cyclins Application in drugs for kinase-dependent diseases, preferably, the cyclin kinase-dependent diseases are proliferative diseases, selected from cancer, autoimmune diseases, viral diseases, fungal diseases, neuropathy, arthritis, inflammation , Neuron disease, hair loss and cardiovascular disease.
The application according to claim 17, wherein the compound of general formula I and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds are used alone, or in combination with Other types of pharmaceutical preparations and/or treatment methods are used in combination. The other types of pharmaceutical preparations include, but are not limited to: cell growth inhibitors, cytotoxic agents, tubulin interaction agents, hormone agents, antimetabolites, and anti-tumor agents. The treatment methods include, but are not limited to: hormone therapy, immunotherapy, radiotherapy; preferably, hormone therapy and immunotherapy are combined.