Cyclin-dependent kinase inhibitor and medical use thereof

Abstract

The present invention relates to a cyclin-dependent kinase inhibitor and the medical use thereof. Specifically, the present invention relates to a compound as shown in general formula (I), a pharmaceutical composition containing the compound, a preparation method therefor, and the use thereof as a cyclin-dependent kinase inhibitor in the treatment of diseases related to cyclin-dependent kinase activity.

Description

Cyclin-dependent kinase inhibitors and their medical uses Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a new class of cyclin-dependent kinase inhibitors, a pharmaceutical composition containing the same, a preparation method thereof, and use of the same as a cyclin-dependent kinase inhibitor for treating diseases associated with cyclin-dependent kinase activity. Background Art

[0002] CDK (Cyclin-dependent Kinase), short for "cyclin-dependent kinase," is a key factor in regulating cell growth and division. CDKs are a family of serine / threonine protein kinases that form heterodimers with their respective regulatory cyclin subunits. There are 13 CDK members, divided into three groups based on their function: mitosis-related CDKs (CDK1, CDK2, CDK4, and CDK6), which directly promote cell cycle progression; transcription-related CDKs (CDK7, CDK8, and CDK9); and atypical CDKs (CDK5, CDK14, CDK15, CDK16, CDK17, and CDK18). CDK4 and CDK6 (CDK4 / 6) play a key role in the G1 / S transition. During cell proliferation, a complex formed by cyclin D and CDK4 / 6 phosphorylates the retinoblastoma protein (Rb), releasing the transcription factor E2F. E2F activation drives cell cycle progression from G1 to S phase, entering the cell proliferation cycle. CDK4 / 6 inhibitors can inhibit the formation of the cyclin D-CK4 / 6 complex, blocking the cell cycle from G1 to S phase, thereby inhibiting tumor proliferation (Biomedicines 2022, 10, 685).

[0003] CDK4 / 6 inhibitors combined with endocrine therapy are currently the standard treatment for patients with HR-positive, HER2-negative breast cancer. However, approximately 20% of patients treated with CDK4 / 6 inhibitors experience initial ineffectiveness of treatment, known as primary resistance, and most patients face the problem of developing acquired resistance and disease progression (Precision Oncology (2022) 6:68). Studies have found that inhibiting CDK4 / 6 activity leads to Cyclin E amplification and MYC activation. After MYC upregulates and activates CDK2, CDK2-Cyclin E can act as a compensatory pathway to phosphorylate Rb, release E2F, and promote tumor cell proliferation. This is the main mechanism of acquired resistance to CDK4 / 6 inhibitors (Cancer Cell 39, 1404–1421). Simultaneously inhibiting CDK2 / 4 / 6 will be a new therapeutic approach to inhibit cancer cells, potentially reducing the occurrence of CDK4 / 6 inhibitor resistance.

[0004] At present, new CDK2 / 4 / 6 inhibitors still need to be developed to overcome defects such as drug resistance and meet clinical needs. Summary of the Invention

[0005] After intensive research, the present inventors designed and synthesized a series of pyrimidine cyanothiazole compounds, which exhibited CDK2 / 4 / 6 inhibitory activity and could be developed as drugs for preventing or treating diseases associated with CDK2 / 4 / 6 activity.

[0006] Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0007] in:

[0008] X 1 Selected from-NR 3a -、-O-、-S-、-S(O) p -, -CO-, and -CR 1a R 1b -;

[0009] X 2 Selected from-NR 3b -、-O-、-S-、-S(O) p -、-CO-、-O-(CH2) v -CO- and CR 2a R 2b ;

[0010] A 1 is selected from -CH- or -N-;

[0011] A 2 is selected from -CH2-, -NH-, -O- or -S-;

[0012] R is selected from heterocyclic, heteroaryl, aryl, cycloalkyl, wherein the heterocyclic, heteroaryl, aryl, cycloalkyl is optionally selected from deuterium atoms, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0013] R 1a and R 1bEach is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0014] R 2a and R 2b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0015] R 3a is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0016] R 3b is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0017] Each R 8 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0018] Ra and R b are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, -(CH2) q -NR d R e 、-(CH2) q -OR c 、-(CH2) q -R c 、-(CH2) q -S(O) p R c 、-(CH2) q -C(O)R c 、-(CH2) q -C(O)NR d R e , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently further selected from deuterium atoms, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, -S(O) p R d 、-S(O) p NR d R e 、-C(O)R d 、-C(O)NR d R e 、-NR d C(O)R e 、-COOR d 、-NR d R e 、-SR d 、-OR d 、-(CH2) t -R d 、-(CH2) t -NR d R e 、-(CH2) t -SR d 、-(CH2) t -OR d 、-(CH2) t -S(O) p R d 、-(CH2) t -S(O) p NR d R e 、-(CH2) t -C(O)R d 、-(CH2)t -C(O)NR d R e 、-(CH2) t -NR d C(O)R e 、-(CH2) t -COOR d , alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] Or, R a and R b Together with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0020] R c Selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, -(CH2) q -NR d R e , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0021] R d and R e each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0022] Or, R d and R eTogether with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0023] p is 1 or 2;

[0024] q is an integer from 1 to 4;

[0025] v is an integer from 1 to 4;

[0026] t is an integer from 0 to 4;

[0027] n is an integer from 1 to 4;

[0028] s1 and s2 are each independently 0, 1 or 2.

[0029] In a preferred embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0030] in,

[0031] R 8a and R 8b each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0032] R 8c selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0033] R, X 1 、X 2 、A 1 、A 2 , s1, s2 are as defined in the general formula (I).

[0034] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R is selected from 4 to 10 membered heterocyclic group, 5 to 10 membered heteroaryl, C 6-10 Aryl, C 3-8 Cycloalkyl, the 4 to 10 membered heterocyclic group, the 5 to 10 membered heteroaryl, C 6-10 Aryl, C 3-8 Cycloalkyl is optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0035] R a 、R b 、R c , p are as defined in the general formula (I).

[0036] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R is selected from 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 5-membered heteroaryl, 6-membered heteroaryl, phenyl, C 3-6 Cycloalkyl, the 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group, 7-membered heterocyclic group, 5-membered heteroaryl, 6-membered heteroaryl, phenyl, C 3-6 Cycloalkyl is optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -S(O) p R a 、-S(O) p NR a R b 、-C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0037] R a 、R b 、R c , p are as defined in the general formula (I).

[0038] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R is selected from 6-10 membered bridged heterocyclic group, 6-10 membered spiro heterocyclic group, 6-10 membered fused heterocyclic group, and the 6-10 membered bridged heterocyclic group, 6-10 membered spiro heterocyclic group, 6-10 membered fused heterocyclic group is optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, -S(O) p R a 、-S(O)p NR a R b 、-C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups.

[0039] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R is selected from which are optionally further selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl radical substitution;

[0040] R y Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)Ra 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ;

[0041] R a 、R b 、R c , p, and t are as defined in the general formula (I).

[0042] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (III) or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0043] in:

[0044] Y1, Y2, Y3, and Y4 are each independently selected from CR 5 or N;

[0045] R 4 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 4 Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; More preferably selected from -S(O) p R a 、-S(O) p NR a R b 、-(CH2) t -NR a R b ;

[0046] R 5are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0047] X 1 、X 2 、A 1 、A 2 ,s1,s2,R a 、R b 、R c , p, t are as defined in general formula (I);

[0048] R 8a 、R 8b 、R 8c As defined in general formula (II).

[0049] In another preferred embodiment, the compound represented by the general formula (III) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein one or two of Y1, Y2, Y3, and Y4 are N, and the rest are CR 5 ; or Y1, Y2, Y3, and Y4 are all CR 5 ; R 5 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、-C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0050] R a 、R b 、R c , p are as defined in the general formula (I).

[0051] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from -S(O) p R a 、-S(O) p NR a R b ;

[0052] R a and R b are each independently selected from hydrogen, -(CH2) q -NR d R e 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group are optionally selected from halogen, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0053] Or, R a and R b Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0054] R d and R e are each independently selected from hydrogen, C 1-6 alkyl;

[0055] Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0056] p is 1 or 2;

[0057] q is an integer from 1 to 4.

[0058] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4 Selected from -S(O) p R a 、-S(O) p NR a R b 、-(CH2) t -NR a R b ;

[0059] R a and R b are each independently selected from hydrogen, -(CH2) q -NR d Re 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group are optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0060] Or, R a and R b Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0061] R d and R e are each independently selected from hydrogen, C 1-6 alkyl;

[0062] Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0063] p is 1 or 2;

[0064] q is an integer from 1 to 4;

[0065] t is an integer from 1 to 4.

[0066] In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IV) or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0067] in:

[0068] Z is selected from -N- or -CH-;

[0069] R 6 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 6 Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-ORc 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; More preferably selected from -S(O) p R a 、-S(O) p NR a R b 、

[0070] R 7 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NRa R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0071] Or two adjacent R 7 Together with the atoms to which it is attached, it forms a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0072] m is an integer from 0 to 4;

[0073] n1 and n2 are each independently an integer from 0 to 2;

[0074] X 1 、X 2 、A 1 、A 2 ,s1,s2,R a 、R b 、R c , p is as defined in general formula (I);

[0075] R 8a 、R 8b 、R 8c As defined in general formula (II).

[0076] In another preferred embodiment, the compound represented by general formula (IV) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Z is selected from -N-.

[0077] In another preferred embodiment, the compound represented by general formula (III) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 6 Selected from -S(O) p Ra 、-S(O) p NR a R b 、

[0078] R a and R b are each independently selected from hydrogen, -(CH2) q -NR d R e 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group are optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0079] Or, R a and R b Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0080] R c Selected from C 1-6 alkyl;

[0081] R d and R e are each independently selected from hydrogen, C 1-6 alkyl;

[0082] Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0083] p is 1 or 2;

[0084] q is an integer from 1 to 4.

[0085] In another preferred embodiment, the compound represented by general formula (IV) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 7 Each independently selected from hydrogen, halogen, amino, cyano, hydroxyl, mercapto, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkoxy;

[0086] m is an integer of 0 to 4; preferably an integer of 0 to 2.

[0087] In another preferred embodiment, the compound represented by general formula (IV) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0088] In another preferred embodiment, the compound represented by general formula (IV) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: n1 and n2 are each independently an integer from 0 to 1; preferably 1.

[0089] In another preferred embodiment, the compound represented by general formula (IV) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: s1 is 1 or 2; s2 is 0, 1 or 2.

[0090] In another preferred embodiment, the compound represented by general formula (I), (II), (III) or (IV) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X 1 -NR 3a -, R 3 Selected from hydrogen and C 1-6 alkyl.

[0091] In another preferred embodiment, the compound represented by general formula (I), (II), (III) or (IV) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X 1 It is -O-.

[0092] In another preferred embodiment, the compound represented by general formula (I), (II), (III) or (IV) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X 1 -CR 1a R 1b -, R 1a and R 1b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0093] In another preferred embodiment, the compound represented by general formula (I), (II), (III) or (IV) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X 2 -NR 3b -, R 3b Selected from hydrogen and C 1-6 alkyl.

[0094] In another preferred embodiment, the compound represented by general formula (I), (II), (III) or (IV) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X 2 It is -O-.

[0095] In another preferred embodiment, the compound represented by general formula (I), (II), (III) or (IV) according to the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X 2 -O-(CH2) v -CO-, wherein v is an integer from 1 to 4, preferably 1 or 2.

[0096] In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (V) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0097] in:

[0098] Y is -CH- or -N-;

[0099] R 4a Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 4a Selected from -S(O) p R a 、-S(O)p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; More preferably selected from -S(O) p R a 、-S(O) p NR a R b 、-(CH2) t -NR a R b ;

[0100] R 5a are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0101] s is an integer from 1 to 4;

[0102] X 1 、X 2 、A 1 、A 2 ,s1,s2,R a 、R b 、R c , p is as defined in general formula (I);

[0103] R 8a 、R 8b 、R 8c As defined in general formula (II).

[0104] In another preferred embodiment, the compound represented by general formula (V) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 4a Selected from -S(O) p R a 、-S(O) p NR a R b 、-(CH2) t -NR a R b ;

[0105] R a and R b are each independently selected from hydrogen, -(CH2) q -NR d R e 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group are optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0106] Or, R a and R b Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0107] R d and R e are each independently selected from hydrogen, C 1-6 alkyl;

[0108] Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0109] p is 1 or 2;

[0110] q is an integer from 1 to 4;

[0111] t is an integer from 1 to 4.

[0112] In another preferred embodiment, the compound represented by general formula (V) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0113] R 5a each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0114] s is 1 or 2.

[0115] In another preferred embodiment, the compound represented by general formula (V) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 5a Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0116] In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (VI) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0117] in:

[0118] R 6a Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O)p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 6a Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; More preferably selected from -S(O) p R a 、-S(O) p NR a R b ;

[0119] R 7aare each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0120] m is an integer from 0 to 4;

[0121] n1 and n2 are each independently an integer from 0 to 2;

[0122] X 1 、X 2 、A 1 、A 2 ,s1,s2,R a 、R b 、R c , p is as defined in general formula (I);

[0123] R 8a 、R8b 、R 8c As defined in general formula (II).

[0124] In another preferred embodiment, the compound represented by general formula (VI) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0125] R 6a Selected from -S(O) p R a 、-S(O) p NR a R b ;

[0126] R a and R b are each independently selected from hydrogen, -(CH2) q -NR d R e 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group are optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0127] Or, R a and R b Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0128] R d and R e are each independently selected from hydrogen, C 1-6 alkyl;

[0129] Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0130] p is 1 or 2;

[0131] q is an integer from 1 to 4.

[0132] In another preferred embodiment, the compound represented by general formula (VI) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

[0133] R 7a each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0134] m is an integer of 0 to 2, preferably 0 or 1.

[0135] In another preferred embodiment, the compound represented by the general formula (VI) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R 7a Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0136] In another preferred embodiment, the compound represented by the general formula (VI) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: n1 and n2 are each independently an integer from 0 to 1; preferably 1.

[0137] In another preferred embodiment, the compound represented by general formula (VI) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: s1 is 1 or 2; s2 is 0, 1 or 2.

[0138] In another preferred embodiment, the compound represented by the general formula (I), (II), (III), (IV), (V), (VI) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein: X 1 Selected from -NH- or -O-, preferably -NH-; X 2 Selected from -NH-, -O-(CH2) v-CO- or -O-, preferably -NH-;

[0139] v is an integer of 1 to 4, preferably, v is 1 or 2.

[0140] In another preferred embodiment, the compound represented by the general formula (II), (III), (IV), (V), (VI) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein:

[0141] R 8a Selected from hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, preferably hydrogen or C 1- 6-alkyl;

[0142] R 8b Selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, preferably hydrogen or hydroxy;

[0143] R 8c Selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl; preferably hydrogen or C 1-6 alkyl.

[0144] In another preferred embodiment, the compound represented by the general formula (I), (II), (III), (IV), (V), (VI) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein:

[0145] R a and R b are each independently selected from hydrogen, -(CH2) q -NR d R e 、-(CH2) q -R c 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group are optionally selected from deuterium atoms, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 substituted by one or more haloalkoxy groups or 4-6 membered heterocyclic groups;

[0146] Or, R a and R b Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0147] R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 4-6 membered heterocyclic group are each independently optionally selected from C 1-6 One or more groups are substituted on the alkyl group;

[0148] R d and R e are each independently selected from hydrogen, C 1-6 alkyl;

[0149] Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted;

[0150] p is 1 or 2;

[0151] q is an integer from 1 to 4.

[0152] In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (VIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0153] in,

[0154] Z is -N- or -CH-, preferably -N-;

[0155] A 2 is -O- or -CH2-, preferably -CH2-;

[0156] X 1 is -NH- or -O-, preferably -NH-;

[0157] X 2 is -NH- or -O-, preferably -NH-;

[0158] R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0159] Or two adjacent R 7 Together with the atoms to which it is attached, it forms a phenyl group or a 5-6 membered heteroaryl group, wherein the phenyl group or the 5-6 membered heteroaryl group is optionally substituted with one or more groups selected from halogen;

[0160] R 8a Selected from hydrogen or C 1-6 alkyl;

[0161] R x Selected from-NR a R b 、-(CH2) q -NR d R e 、-(CH2) q -OR c 、-(CH2) q -R c 、-(CH2) q -C(O)R c 、-(CH2) q -C(O)NR d Re 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally selected from deuterium atoms, halogen, cyano, oxo, -NR d C(O)R e 、-COOR d 、-(CH2) t -OR d 、-(CH2) t -S(O) p R d 、-NR d R e 、-(CH2) t -R d 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy or C 3-6 One or more groups in the cycloalkyl group are substituted;

[0162] R a Selected from hydrogen, -(CH2) q -NR d R e 、-(CH2) q -R c 、C 1-6 Alkyl, 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, 4-6 membered heterocyclic group are each independently selected from deuterium atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 substituted by one or more haloalkoxy groups or 4-6 membered heterocyclic groups;

[0163] R b selected from hydrogen;

[0164] or R a and R b Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally further selected from C 1-6 Alkyl, C 1-6One or more haloalkyl groups are substituted;

[0165] R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 4-6 membered heterocyclic group are each independently optionally selected from C 1-6 One or more groups are substituted on the alkyl group;

[0166] R d Selected from hydrogen, C 1-6 Alkyl, cyano;

[0167] R e Selected from hydrogen, C 1-6 alkyl;

[0168] Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more groups in the haloalkoxy group are substituted;

[0169] p is 1 or 2;

[0170] t is an integer from 0 to 4; preferably an integer from 1 to 4;

[0171] q is an integer from 1 to 4;

[0172] n1 is 0, 1, or 2;

[0173] n2 is 0 or 1;

[0174] m is 1 or 2;

[0175] s1 is 1 or 2.

[0176] In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (VA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0177] in:

[0178] Y is -CH- or -N-;

[0179] A 2 is -O- or -CH2-, preferably -CH2-;

[0180] X 1 is -NH- or -O-, preferably -NH-;

[0181] X 2 is -NH- or -O-, preferably -NH-;

[0182] R 5a are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0183] R 8a Selected from hydrogen or C 1-6 alkyl;

[0184] R z Selected from-NR a R b , 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally selected from C 1-6 One or more alkyl or oxo groups are substituted;

[0185] R a Selected from hydrogen, -(CH2) q -NR d R e , 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally selected from C 1-6 substituted with an alkyl group;

[0186] R b selected from hydrogen;

[0187] R d Selected from hydrogen, C 1-6 alkyl;

[0188] R e Selected from hydrogen, C 1-6 alkyl;

[0189] Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0190] q is an integer from 1 to 4;

[0191] s is 1 or 2;

[0192] s1 is 1 or 2.

[0193] Typical compounds of the present invention include, but are not limited to:

[0194] or its meso-, racemic-, enantiomer-, diastereomer-, or mixture thereof, or its pharmaceutically acceptable salt.

[0195] The present invention further provides a method for preparing the compound represented by general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0196] The compound represented by formula (IA) and compound RX 1 H undergoes a substitution reaction or a coupling reaction to obtain a compound represented by the general formula (I) or its meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof;

[0197] Among them, R, R 8 、X 1 、X 2 、A 1 、A 2 , s1, s2, and n are as defined in the general formula (I).

[0198] The present invention further provides a pharmaceutical composition comprising the compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0199] The present invention further relates to the use of the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK2 / 4 / 6 inhibitor.

[0200] The present invention further relates to the use of the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the preparation of a medicament for preventing and / or treating diseases associated with CDK, preferably CDK2 / 4 / 6 activity, preferably cancer and tumor-related diseases.

[0201] The present invention further relates to a compound according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a CDK, preferably CDK2 / 4 / 6 inhibitor.

[0202] The present invention further relates to a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for preventing and / or treating diseases associated with CDK, preferably CDK2 / 4 / 6 activity, preferably cancer and tumor-related diseases.

[0203] The present invention further relates to a method for inhibiting CDK, preferably CDK2 / 4 / 6, comprising administering to a patient in need thereof an effective amount of a compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0204] The present invention further relates to a method for preventing and / or treating diseases associated with CDK, preferably CDK2 / 4 / 6 activity, comprising administering to a patient in need thereof a preventive or therapeutically effective amount of a compound according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the disease is preferably cancer and tumor-related diseases.

[0205] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions and may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time. For example, water-soluble taste masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate may be used.

[0206] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0207] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersing agents or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol alcohols, such as polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose, saccharin, or aspartame.

[0208] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oil suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0209] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavorings, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain demulcents, preservatives, colorants, and antioxidants.

[0210] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.

[0211] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a nontoxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixed oils may conveniently be used as solvents or suspending media. For this purpose, any blended fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids, such as oleic acid, may also be used to prepare injectable formulations.

[0212] The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thereby dissolves and releases the drug in the rectum. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0213] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc. In addition, the optimal treatment method, such as the mode of treatment, the daily dosage of the general formula compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment protocols.

[0214] The present invention may contain a compound and a pharmaceutically acceptable salt, hydrate, or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to form a composition, and then prepared into a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compounds of the present invention may be used as the sole active ingredient or in combination with other anticancer agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately, or sequentially.

[0215] Terminology

[0216] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0217] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0218] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0219] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0220] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 8 or 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0221] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0222] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 6 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0223] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 6-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0224] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0225] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 4 to 8 ring atoms or 4 to 6 ring atoms or 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0226] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 6 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0227] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 8 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0228] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 8 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0229] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0230] wait.

[0231] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0232] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, i.e., a fused ring aryl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0233] Non-limiting examples of base rings include:

[0234] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0235] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, i.e., a fused ring heteroaryl, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0236] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0237] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl and cycloalkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0238] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0239] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0240] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0241] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium groups, wherein alkyl is as defined above.

[0242] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, wherein alkoxy is as defined above.

[0243] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0244] The term "hydroxy" refers to an -OH group.

[0245] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0246] The term "amino" refers to -NH2.

[0247] The term "cyano" refers to -CN.

[0248] The term "nitro" refers to -NO2.

[0249] The term "oxo" refers to =0.

[0250] The term "thio" refers to =S.

[0251] The term "carboxy" refers to -C(O)OH.

[0252] The term "mercapto" refers to -SH.

[0253] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0254] The compounds of the present invention may be in deuterated form. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. Those skilled in the art are able to synthesize deuterated compounds with reference to the relevant literature. Commercially available deuterated starting materials may be used to prepare deuterated compounds, or they may be synthesized using conventional techniques employing deuterated reagents.

[0255] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0256] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0257] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0258] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0259] The compounds of the present invention and their preparation will be further understood by way of the examples, which illustrate some methods of preparing or using the compounds. However, it will be appreciated that these examples do not limit the scope of the present invention. Variations of the present invention as now known or further developed are considered to fall within the scope of the invention as described herein and as claimed.

[0260] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0261] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts' "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0262] The separation and purification of compounds and intermediates can be performed using appropriate methods and steps depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize the compounds and intermediates.

[0263] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using an Oxford WNMR-I-400 MHz NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0264] MS was determined using a 1260 Infinity II 6125B single quadrupole liquid chromatography-mass spectrometer (manufacturer: Agilent), a Kinetex XB-C18 100A 1.7 μm (30*3 mm) column (manufacturer: Fenome), and an acetonitrile / water (0.1% FA) mobile phase.

[0265] The preparative liquid chromatography method used a 1260 Infinity II preparative liquid phase (manufacturer: Agilent), a chromatographic column was an Xtimate C18 5 μm (21.2*250 mm) (manufacturer: Yuexu Technology), and the mobile phase was acetonitrile / water.

[0266] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring were of a size of 0.20 mm to 0.25 mm, and the silica gel plates used for separation and purification were of a size of 0.5 mm.

[0267] Silica gel column chromatography method uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0268] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, exploration platforms, Booker Mall, Lanbo.com, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinoke, Anaiji Chemical, Shanghai Bid, Shanghai Leyan, Nanjing Yaoshi and other companies.

[0269] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0270] Argon atmosphere, nitrogen atmosphere or hydrogen atmosphere means that the reaction bottle is connected to an argon, nitrogen or hydrogen balloon with a volume of about 1 L.

[0271] The reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane (DCM), diethyl ether, methanol (MeOH), ethanol (EtOH), dimethyl sulfoxide (DMSO), 1,4-dioxane, nitrogen-methylpyrrolidone (NMP), pyridine, water, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0272] The chemical reactions described herein are generally carried out under normal pressure. Reaction times and conditions are, for example, between -78°C and 200°C at atmospheric pressure, and are complete within approximately 1 to 24 hours. If the reaction is allowed to proceed overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0273] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and C: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0274] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

[0275] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0276] Example

[0277] Example 1: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (1)

[0278] Step 1: Preparation of 2-(2,4-dimethoxypyrimidin-5-yl)thiazole-4-carboxamide (1-3)

[0279] (2,4-Dimethoxypyrimidin-5-yl)boronic acid (Compound 1-1, 10 g, 54.3 mmol) and 2-bromo-thiazole-4-carboxamide (Compound 1-2, 11.3 g, 54.5 mmol) were dissolved in isopropanol (200 mL) and water (67 mL). Potassium carbonate (14.6 g, 106 mmol) and BrettPhos-Pd-G3 (4.3 g, 4.75 mmol) were added in sequence. The resulting mixture was heated to 85 ° C and stirred for 2 hours. The isopropanol was removed from the reaction solution under reduced pressure, and water (200 mL) and ethyl acetate (200 mL) were added to the reaction solution and stirred for 30 minutes. The insoluble matter was filtered and dried to obtain Compound 1-3 (7.8 g, yield 61%, yellow solid).

[0280] LC-MS (ESI + ): 267.1m / z[M+H] + .

[0281] Step 2: Preparation of 2-(2,4-dihydroxypyrimidin-5-yl)thiazole-4-carboxamide (1-4)

[0282] Compound 1-3 (7.8 g, 32.9 mmol) was dissolved in 4M hydrochloric acid / dioxane (70 mL), heated to 90°C and stirred for 2 hours, and concentrated under reduced pressure to obtain compound 1-4 (8.0 g, yield 100%, white solid).

[0283] LC-MS (ESI + ): 238.1m / z[M+H] + .

[0284] Step 3: Preparation of 2-(2,4-dichloropyrimidin-5-yl)thiazole-4-carbonitrile (1-5)

[0285] Compound 1-4 (8.0 g, 32.9 mmol) was dissolved in acetonitrile (80 mL), and DIEA (21.8 g, 169 mmol) and phosphorus oxychloride (51.8 g, 338 mmol) were added. The resulting mixture was heated to 100°C and stirred for 2 hours. The reaction solution was poured into ice water (150 mL) and extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 1-5 (2.5 g, yield 29%, yellow solid).

[0286] LC-MS (ESI + ): 257.1m / z[M+H] + .

[0287] Step 4: Preparation of 2-(2-chloro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (1-7)

[0288] Compound 1-5 (2.5 g, 9.72 mmol) was dissolved in acetonitrile (20 mL), and (1R,2R)-2-amino-1-methylcyclopentan-1-ol (compound 1-6, 1.12 g, 9.72 mmol) and DIEA (3.68 g, 29.2 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 1-7 (1.94 g, 59.5% yield, as a yellow solid).

[0289] LC-MS (ESI - ): 336.1m / z[MH] - .

[0290] Step 5: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (1)

[0291] Compound 1-7 (1.94 g, 5.79 mmol) was dissolved in DMSO (10 mL), and DIEA (2.25 g, 17.4 mmol) and 1-methanesulfonyl-4-aminopiperidine (compound 1-8, 1.03 g, 5.79 mmol) were added. The resulting mixture was heated to 100°C and stirred for 2 hours. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance preparative liquid chromatography (water / acetonitrile = 95% / 5%-10% / 90%) to obtain compound 1 (2 g, 72% yield, as a white solid).

[0292] LC-MS (ESI + ): 478.1m / z[M+H] + .

[0293] 1 H NMR (400MHz, CD3OD) δ8.42(s,1H),8.31(s,1H),4.51–4.47(m,1H),4.06–4.00(m,1H),3.75(d,J=12.2Hz,2H),2.99(t,J =11.1Hz,2H),2.90(s,3H),2.43–2.36(m,1H),2.15(d,J=9.9Hz,2H),1.98–1.80(m,4H),1.73–1.60(m,3H),1.35(s,3H).

[0294] Example 2: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (2)

[0295] Step 1: Preparation of tert-butyl (1-((trifluoromethyl)sulfonyl)piperidin-4-yl)carbamate (2-3)

[0296] To a solution of trifluoromethylsulfonyl chloride (compound 2-2, 200 mg, 1.19 mmol) and DIPEA (0.62 mL, 3.56 mmol) in DCM (3.0 mL) was added tert-butyl piperidin-4-ylcarbamate (2-1, 238 mg, 1.19 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. Water (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude off-white solid compound 2-3 (400 mg, 100% yield), which was used directly in the next reaction.

[0297] LC-MS (ESI + ): 277.2m / z[M+H-56] + .

[0298] Step 2: Preparation of 1-(trifluoromethyl)sulfonyl)piperidin-4-amine (2-4)

[0299] Compound 2-3 (400 mg, 1.20 mmol) was dissolved in dioxane hydrochloride (2.0 mL, 4 mol / L) and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and NH3MeOH (1.5 mL, 7 mol / L) was added to the residue at 0°C. The mixture was concentrated under reduced pressure to afford the crude product, compound 2-4 (300 mg, 100% yield), as an off-white solid, which was used directly in the next reaction.

[0300] LC-MS (ESI + ): 233.2m / z[M+H] + .

[0301] The remaining steps were the same as in Example 1, except that 1-(trifluoromethyl)sulfonyl)piperidin-4-amine (2-4) was used instead of 1-methylsulfonyl-4-aminopiperidine (1-8) in step 5 to prepare compound 2.

[0302] LC-MS (ESI + ): 532.1m / z[M+H] + .

[0303] 1H NMR (400MHz, DMSO-d6) δ8.87–8.77(m,1H),8.68(s,1H),8.52–8.47(m,1H),7.66–7.48(m,1H),4.88–4.61(m,1H),4.40–4.20(m,1H ),4.19–3.96(m,1H),3.91–3.74(m,2H),2.43–2.18(m,2H),2.14–1.89(m,2H),1.84–1.54(m,7H),1.50–1.35(m,1H),1.25(s,3H).

[0304] The following compounds were obtained by the synthesis method of Example 2 using the corresponding raw materials:

[0305] Example 17: Preparation of 4-((5-(4-cyanothiazol-2-yl)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-2-yl)amino)-N-(((S)-tetrahydrofuran-2-yl)methyl)piperidine-1-sulfonamide (17)

[0306] Step 1: Preparation of tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate (17-1)

[0307] Compound 2-1 (1 g, 5 mmol) and triethylamine (1.2 mL, 10 mmol) were dissolved in dichloromethane, cooled to -20°C, and sulfonyl chloride (0.8 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, water (20 mL) was added to quench the reaction mixture, followed by extraction with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. This afforded compound 17-1 (1.3 g, 87% yield).

[0308] LC-MS (ESI + ):299.0m / z[M+H] + .

[0309] Step 2: Preparation of tert-butyl (S)-(1-(N-((tetrahydrofuran-2-yl)methyl)aminosulfonyl)piperidin-4-yl)carbamate (17-2)

[0310] Compound 17-1 (200 mg, 1.33 mmol) and (S)-(+)-tetrahydrofurfurylamine (135 mg, 1.33 mmol) were dissolved in dichloromethane (5 mL) at room temperature, followed by the addition of N,N-diisopropylethylamine (0.25 mL). The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to afford compound 17-2 (200 mg, 46% yield).

[0311] The remaining steps were the same as in Example 2, except that (S)-(1-(N-((tetrahydrofuran-2-yl)methyl)aminosulfonyl)piperidin-4-yl)carbamic acid tert-butyl ester (17-2) was used instead of (1-((trifluoromethyl)sulfonyl)piperidin-4-yl)carbamic acid tert-butyl ester (2-3) to prepare compound 17.

[0312] LC-MS (ESI + ): 364.0m / z[M+H] + .

[0313] 1 H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.82–8.77(m,1H),8.63–8.49(m,1H),8.26–8.18(m,1H),7.37–7.32(m,1H),4.32–4.26(m,1H),4.00–3 .85(m,2H),3.78–3.73(m,1H),3.65–3.60(m,1H),3.51-3.48(m,2H),2 .99–2.76(m,5H),2.33–2.21(m,1H),2.03–1.37(m,13H),1.27(s,3H).

[0314] The following compounds were obtained by the synthesis method of Example 17 using the corresponding raw materials:

[0315] Examples 22 and 23: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(((3RS,4SR)3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (22, high polarity) and 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(((3RS,4SR)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (23, low polarity)

[0316] Step 1: Preparation of 1-benzyl-3-methylpiperidin-4-amine (22-2)

[0317] To a solution of ammonium acetate (1.90 g, 24.6 mmol) in 5 mL of methanol was added 1-benzyl-3-methyl-4-piperidone (22-1, 500 mg, 2.46 mmol). The mixture was stirred at room temperature for 3 hours, and then sodium cyanoborohydride (102 mg, 1.62 mmol) was added portionwise and stirred for 1 hour. The solvent was removed under reduced pressure, and 5 mL of water was added to the residue, which was then extracted with dichloromethane (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove dichloromethane, yielding compound 22-2 (500 mg, 99% yield). The crude product was used directly for further reaction.

[0318] LC-MS (ESI + ): 205.2m / z[M+H] + .

[0319] Step 2: Preparation of tert-butyl (1-benzyl-3-methylpiperidin-4-yl)carbamate (22-3)

[0320] Di-tert-butyloxy dicarbonate (534 mg, 2.45 mmol) was added portionwise to a solution of compound 22-2 (500 mg, 2.45 mmol) in dichloromethane (4.0 mL), followed by the addition of 0.1 mL of triethylamine. After 90 minutes, 3 mL of water was added, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain compound 22-3 (600 mg, 80% yield).

[0321] LC-MS (ESI + ): 305.2m / z[M+H] + .

[0322] Step 3: Preparation of tert-butyl (3-methylpiperidin-4-yl)carbamate (22-4)

[0323] Compound 22-3 (90 mg, 0.296 mmol) and ammonium formate (130 mg, 2.07 mmol) were dissolved in anhydrous methanol (12 mL) at room temperature. 10% palladium hydroxide (40 mg) was added, and the reaction mixture was stirred at 85°C under a hydrogen atmosphere for 36 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 22-4 (300 mg, 95% yield).

[0324] LC-MS (ESI + ): 215.2m / z[M+H] + .

[0325] The remaining steps were the same as in Example 2, except that tert-butyl (3-methylpiperidin-4-yl)carbamate (22-4) was used instead of tert-butyl piperidin-4-ylcarbamate (2-1), to prepare Compound 22 (high polarity) and Compound 23 (low polarity). Compound 22:

[0326] LC-MS (ESI + ): 492.2m / z[M+H] + .

[0327] 1 H NMR(400MHz,DMSO-d6)δ8.89–8.74(m,1H),8.66–8.64(m,1H),8.47–8.43(m,1H) ,7.52–7.33(m,1H),4.72(s,1H),4.38–4.15(m,1H),3.81–3.47(m,3H),2.90–2.8 7(m,3H),2.85–2.75(m,1H),2.60–2.52(m,1H),2.37–2.21(m,1H),2.08–1.87(m, 1H),1.86–1.56(m,5H),1.57–1.36(m,2H),1.26–1.23(m,3H),0.93–0.87(m,3H).

[0328] Compound 23:

[0329] LC-MS (ESI + ): 492.2m / z[M+H] + .

[0330] 1H NMR (400MHz, DMSO-d6) δ8.91–8.71(m,1H),8.65(s,1H),8.52–8.38(m,1H),7.70–7.42(m,1H),4.72–4.70(m,1H),4.37–4.19(m,3H),3.6 7–3.46(m,1H),3.19–3.06(m,2H),2.86(s,3H),2.37–2.10(m,3H),1.81–1.57(m,5H),1.48–1.32(m,1H),1.24(s,3H),0.93–0.80(m,3H).

[0331] Example 24: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-((1-methylazetidin-3-yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (24)

[0332] Step 1: Preparation of tert-butyl 4-(5-(4-cyanothiazol-2-yl)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-2-yl)aminopiperidine-1-carboxylate (24-1)

[0333] Compound 1-7 (100 mg, 0.29 mmol) was dissolved in DMSO (5 mL), and tert-butyl 4-aminopiperidine-1-carboxylate (60 mg, 0.30 mmol) and DIEA (77 mg, 0.6 mmol) were added. The mixture was heated to 100°C and stirred for 16 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 10) to obtain compound 24-1 (88 mg, yield 59%, yellow solid).

[0334] LC-MS (ESI + ): 500.2m / z[M+H] + .

[0335] Step 2: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(piperidin-4-ylamino)pyrimidin-5-yl)thiazole-4-carbonitrile (24-2)

[0336] Compound 24-1 (88 mg, 0.17 mmol) was dissolved in 1,4-dioxane hydrochloric acid solution (3 mL, 4N), and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 24-2 (46 mg, 65% yield, white solid). The crude product was used directly in the next step without purification.

[0337] LC-MS (ESI + ): 400.2m / z[M+H] + .

[0338] Step 3: Preparation of tert-butyl 3-((4-(5-(4-cyanothiazol-2-yl)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)azetidine-1-carboxylate (24-3)

[0339] Compound 24-2 (46 mg, 0.11 mmol) was dissolved in DCM (5 mL), and N-BOC-azetidine-3-sulfonyl chloride (30 mg, 0.11 mmol) and triethylamine (23 mg, 0.22 mmol) were added. The mixed solution was stirred at room temperature for 16 hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 10) to give compound 24-3 (57 mg, yield 80%, white solid).

[0340] LC-MS (ESI + ): 619.2m / z[M+H] + .

[0341] Step 4: Preparation of 2-(2-((1-(azetidin-3-ylsulfonyl)piperidin-4-yl)amino)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (24-4)

[0342] Compound 24-3 (57 mg, 0.09 mmol) was dissolved in 1,4-dioxane hydrochloric acid solution (3 mL, 4N) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 24-4 (23 mg, 48% yield, white solid). The crude product was used directly in the next step without purification.

[0343] LC-MS (ESI + ): 519.2m / z[M+H] + .

[0344] Step 5: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-((1-methylazetidin-3-yl)sulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (24)

[0345] Compound 24-4 (27 mg, 0.05 mmol) was dissolved in MeOH (2 mL), and aqueous formaldehyde solution (3 mL) and 2-methylpyridine borane (11 mg, 0.1 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to give compound 24 (2.7 mg, 9.8% yield, as a white solid).

[0346] LC-MS (ESI + ): 533.2m / z[M+H] + .

[0347] 1 H NMR(400MHz,DMSO-d6)δ8.88–8.77(m,1H),8.69–8.67(m,1H),8.50–8.46(m ,1H),7.60–7.38(m,1H),4.76(s,1H),4.31–4.23(m,2H),4.02–3.87(m,3H) ,3.71–3.57(m,4H),3.30(s,3H),3.01–2.90(m,2H),2.34–2.22(m,1H),2.0 1–1.89(m,2H),1.79–1.65(m,4H),1.56–1.40(m,3H),1.26(d,J=6.9Hz,3H).

[0348] Example 25: Preparation of 2-(2-((1-((1,1-dioxidotetrahydrothiophen-3-yl)sulfonyl)piperidin-4-yl)amino)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (25)

[0349] Compound 25 was prepared by the same synthesis method as Example 24, except that tetrahydrothiophene-3-sulfonyl chloride 1,1-dioxide was used instead of N-BOC-azetidine-3-sulfonyl chloride.

[0350] LC-MS (ESI + ): 582.2m / z[M+H] + .

[0351] 1H NMR(400MHz,DMSO-d6)δ8.86–8.75(m,1H),8.65(s,1H),8.50–8.44(m,1H),7.5 7–7.36(m,1H),4.72(s,1H),4.36–4.15(m,2H),4.11–3.85(m,1H),3.78–3.57(m ,2H),3.42–3.34(m,2H),3.24–3.04(m,4H),2.61–2.52(m,1H),2.35–2.18(m,2 H),2.06–1.85(m,2H),1.81–1.61(m,4H),1.60–1.37(m,3H),1.25–1.23(m,3H).

[0352] Example 26: Preparation of 2-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (26)

[0353] Compound 26 was prepared by the same synthesis method as in Example 24, except that (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester was used instead of 4-aminopiperidine-1-carboxylic acid tert-butyl ester in step 1, and methanesulfonic anhydride was used instead of N-BOC-azetidine-3-sulfonyl chloride in step 3.

[0354] LC-MS (ESI + ): 496.2m / z[M+H] + .

[0355] 1 H NMR (400MHz, DMSO-d6) δ8.95–8.75(m,1H),8.68(s,1H),8.51–8.48(m,1H),7.79–7.51(m,1H),4.72–4.65(m,2H),4.31–4.24(m,2H),3.7 8–3.65(m,1H),3.49–3.46(m,1H),3.22–3.02(m,2H),2.96(s,3H),2.33–2.02(m,2H),1.76–1.65(m,5H),1.46–1.39(m,1H),1.25(s,3H).

[0356] The following compounds were obtained by the synthesis method of Example 26 using the corresponding raw materials:

[0357] Example 29: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)pyrimidin-5-yl)thiazole-4-carbonitrile (29)

[0358] Step 1: Preparation of 2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)pyrimidin-5-yl)thiazole-4-carbonitrile (29)

[0359] Compound 1-7 (50 mg, 0.15 mmol) was dissolved in THF (7 mL), and 1-(methylsulfonyl)piperidin-4-ol (26 mg, 0.15 mmol) and potassium tert-butoxide (33 mg, 0.3 mmol) were added sequentially. The resulting mixture was stirred at 70°C for 16 hours. The mixture was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) and freeze-dried to obtain compound 29 (13.1 mg, 18% yield, as a white solid).

[0360] LC-MS (ESI + ): 479.2m / z[M+H] + .

[0361] Example 30: Preparation of 4-((5-(4-cyanothiazol-2-yl)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-2-yl)amino)cubane-1-sulfonamide (30)

[0362] Step 1: Preparation of methyl 4-(tert-butylcarbonylamino)cubanecarboxylate (30-2)

[0363] To a solution of 4-(methoxycarbonyl)cubane-1-carboxylic acid (30-1, 4.62 g, 22.4 mmol) in tBuOH (90 mL) at room temperature were added TEA (9.07 g, 90 mmol) and DPPA (9.25 g, 33.6 mmol). The reaction mixture was stirred at room temperature for 2.0 hours. The reaction mixture became a pale yellow viscous substance and was heated and stirred at 85°C for 15 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (EtOAc / PE = 1% to 30%) to obtain compound 30-2 (2.86 g, 46% yield, as a pale yellow solid).

[0364] 1H NMR (400MHz, CDCl3) δ5.26–4.80(m,1H),4.19–3.95(m,6H),3.70(s,3H),1.45(s,9H).

[0365] Step 2: Preparation of 4-((tert-Butyloxycarbonyl)amino)cubane-1-carboxylic acid (30-3)

[0366] To a solution of compound 30-2 (2.86 g, 10.3 mmol) in THF / water (30 mL / 15 mL) was added lithium hydroxide monohydrate (649 mg, 15.5 mmol) at room temperature and stirred at room temperature for 6 hours. The reaction mixture was concentrated, diluted with water, extracted with EtOAc, and the organic phase discarded. The aqueous phase was acidified to pH 4 with 1 M HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 30-3 (2.38 g, 88% yield, as a white solid).

[0367] 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),7.80–7.39(m,1H),3.93(s,6H),1.38(s,9H).

[0368] Step 3: Preparation of 2-thiopyridin-1(2H)-yl 4-((tert-butoxycarbonyl)amino)cubane-1-carboxylate (30-4)

[0369] Isobutyl chloroformate (436 mg, 3.2 mmol) was added dropwise to a solution of compound 30-3 (840 mg, 3.2 mmol) and NMM (323 mg, 3.2 mmol) in DCM (16 mL) at -30°C. After the addition was complete, the EtOAc / dry ice bath was removed and replaced with an ice / ethanol bath. The reaction was stirred at -15°C for 20 minutes. The flask was wrapped in aluminum foil to protect from light. 2-Mercaptopyridine-1-oxide sodium salt (523 mg, 3.5 mmol) was added all at once to the reaction mixture and stirred at -5°C to 0°C for 2.5 hours. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrates were combined and concentrated under reduced pressure (water bath <40°C) to afford compound 30-4 (1.19 g, 100%, yellow-green solid). The crude product was used directly in the next reaction without purification.

[0370] Step 4: Preparation of tert-butyl (4-(pyridin-2-ylthio)cuban-1-yl)carbamate (30-5)

[0371] 2,2'-Disulfide dipyridine (2.11 g, 9.6 mmol) was added to a solution of crude product 30-4 (1.19 g, 3.19 mmol) in anhydrous benzene (32 mL). The atmosphere was replaced with argon three times, and the mixture was irradiated with a 150W halogen lamp for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc / PE = 1% to 20%) to obtain compound 30-5 (528 mg, 50% yield, as a white solid).

[0372] LC-MS (ESI + ): 329.0m / z[M+H] + .

[0373] Step 5: Preparation of tert-butyl (4-(pyridin-2-ylsulfonyl)cuban-1-yl)carbamate (30-6)

[0374] m-CPBA (979 mg, 4.8 mmol, 85% purity) was added to a solution of compound 30-5 (528 g, 1.6 mmol) in DCM (11 mL) and stirred at 30°C for 18 hours. The reaction mixture was quenched with saturated aqueous Na2SO3 (40 mL), diluted with DCM (20 mL), and the layers separated. The organic phase was washed with 1M aqueous NaOH (40 mL) and saturated brine (40 mL). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc / PE = 10% to 80%) to obtain compound 30-6 (490 mg, 85% yield, as a white solid).

[0375] LC-MS (ESI + ): 361.1m / z[M+H] + .

[0376] Step 6: Preparation of sodium 4-((tert-butyloxycarbonyl)amino)cubane-1-sulfinate (30-7)

[0377] EtSNa (343 mg, 4.1 mmol) was added to a solution of compound 30-6 (490 mg, 1.4 mmol) in THF (5.4 mL). The resulting red solution was heated to 60°C and stirred for 20 hours. LC-MS showed that 21% of the starting material was not converted. Additional EtSNa (172 mg, 2.0 mmol) and THF (2 mL) were added, and stirring was continued at 60°C for 18 hours. The reaction solution was quenched with methanol and concentrated under reduced pressure. The residue was triturated in a mixed solvent of MTBE / EtOAc to obtain compound 30-7 (829 mg, yield >100%, yellow solid, 50% purity). The crude product was used directly in the next reaction without purification.

[0378] LC-MS (ESI - ): 281.8m / z[M-Na]- .

[0379] Step 7: Preparation of tert-butyl (4-aminosulfonylcuban-1-yl)carbamate (30-8)

[0380] HOSA (192 mg, 1.7 mmol) and KOAc (166 mg, 1.7 mmol) were added sequentially to a solution of compound 30-7 (829 mg, 1.94 mmol) in water (14 mL). The mixture was stirred at room temperature for 3 hours. Additional HOSA (192 mg, 1.7 mmol) and KOAc (166 mg, 1.7 mmol) were added, and the mixture was stirred at 40°C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 30-8 (364 mg, 90% yield, as a yellow solid).

[0381] LC-MS (ESI - ): 296.8m / z[MH] - .

[0382] The remaining steps were the same as in Example 2, except that tert-butyl (4-aminosulfonylcuban-1-yl)carbamate (30-8) was used instead of tert-butyl (1-((trifluoromethyl)sulfonyl)piperidin-4-yl)carbamate (2-3) to prepare compound 30.

[0383] LC-MS (ESI + ): 498.0m / z[M+H] + .

[0384] 1 H NMR(400MHz,DMSO-d6)δ8.91(d,J=7.9Hz,1H),8.68(s,1H),8.48(s,1H),8.42(s,1H),6.91(s,2H),4 .75(s,1H),4.30–4.02(m,7H),2.29–2.17(m,1H),1.82–1.60(m,4H),1.47–1.36(m,1H),1.28(s,3H).

[0385] Example 31: Preparation of trans-2-(4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((4-((R)-S-methylsulfonylimino)cyclohexyl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (31)

[0386] Step 1: Preparation of cis-4-((tert-Butyloxycarbonyl)amino)cyclohexyl methanesulfonate (31-2)

[0387] To a solution of cis-4-(Boc-amino)cyclohexanol (31-1, 5.00 g, 23.2 mmol) in DCM (46 mL) at 0°C was added TEA (11.75 g, 34.8 mmol) and MsCl (3.99 g, 34.8 mmol). The reaction mixture was stirred at 0°C for 0.5 h, then diluted with water and extracted with DCM. The organic phases were combined and washed with saturated brine. The mixture was concentrated under reduced pressure to afford compound 31-2 (6.68 g, 98% yield, light yellow solid). The crude product was used directly in the next step without purification.

[0388] LC-MS (ESI + ): 315.8m / z[M+Na] + .

[0389] Step 2: Preparation of trans-4-((tert-Butyloxycarbonyl)amino)cyclohexyl)thioacetate (31-3)

[0390] A solution of compound 31-2 (3000 mg, 10.2 mmol) and potassium thioacetate (3504 mg, 30.7 mmol) in DMF (29 mL) was heated to 80°C and stirred for 18 hours. A large amount of white solid was formed. The reaction solution was diluted with water and extracted with EtOAc. The organic phases were combined and washed sequentially with saturated aqueous NH4Cl solution, saturated aqueous NaHCO3 solution, water, and saturated brine. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / PE = 0% to 18%) to obtain compound 31-3 (630 mg, 22% yield, as a brown solid).

[0391] LC-MS (ESI + ): 295.9m / z[M+Na] + .

[0392] Step 3: Preparation of tert-butyl trans-(4-(methylthio)cyclohexyl)carbamate (31-4)

[0393] To a solution of compound 31-3 (200 mg, 0.7 mmol) in MeOH (1.8 mL) at room temperature were added MeONa (158 mg, 2.9 mmol) and MeI (156 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 3.0 hours, then diluted with water and extracted with EtOAc. The organic phases were combined and washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and saturated brine. The mixture was concentrated under reduced pressure to afford compound 31-4 (180 mg, 100% yield, amber solid). The crude product was used directly in the next step without purification.

[0394] 1H NMR(400MHz,DMSO-d6)δ6.71(d,J=8.0Hz,1H),3.22–3.16(m,1H),2.47–2.35(m,1H) ,2.02(s,3H),1.98–1.87(m,2H),1.85–1.74(m,2H),1.37(s,9H),1.29–1.13(m,3H).

[0395] Step 4: Preparation of trans-tert-butyl 4-(S-methylsulfonylimino)cyclohexyl)carbamate (31-5)

[0396] To a solution of compound 31-4 (100 mg, 0.4 mmol) in MeOH (2.7 mL) at room temperature were added PhI(OAc)2 (394 mg, 1.2 mmol) and NH4OAc (126 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 4.0 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0% to 8%) to obtain compound 31-5 (103 mg, 92% yield, yellow solid, 61% content). The crude product was used directly in the next step without purification.

[0397] LC-MS (ESI + ): 277.0m / z[M+H] + .

[0398] Compound 31 was prepared in the same manner as in Example 2, except that compound 31-5 was used instead of tert-butyl (1-((trifluoromethyl)sulfonyl)piperidin-4-yl)carbamate (2-3).

[0399] LC-MS (ESI+): 476.0 m / z [M+H] + .

[0400] 1 H NMR (400MHz, DMSO-d6) δ8.90–8.70(m,1H),8.69–8.57(m,1H),8.56–8.36(m,1H),7.55–7.19(m,1H),4.85–4.68(m,1H),4.36–4.12(m,1H),3.8 4–3.49(m,2H),2.96–2.78(m,4H),2.34–2.22(m,1H),2.21–2.06(m,3H) ,2.01(s,1H),1.81–1.60(m,4H),1.57–1.31(m,5H),1.28–1.19(m,3H).

[0401] The following compounds were obtained by the synthesis method of Example 31 using the corresponding starting materials:

[0402] Example 33: Preparation of 2-(2-((1-((3-(dimethylamino)propyl)sulfonyl)piperidin-4-yl)amino)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (33)

[0403] Step 1: Preparation of tert-butyl (1-((3-chloropropyl)sulfonyl)piperidin-4-yl)carbamate (33-1)

[0404] Compound 2-1 (500 mg, 2.49 mmol) and 3-chloropropanesulfonyl chloride (530 mg, 2.99 mmol) were dissolved in DCM at room temperature, followed by the addition of N,N-diisopropylethylamine (1.2 mL). The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to afford compound 33-1 (700 mg, 82% yield).

[0405] LC-MS (ESI + ): 284.8m / z[M+H-56] + .

[0406] Step 2: Preparation of tert-butyl ((1-((3-(dimethylamino)propyl)sulfonyl)piperidin-4-yl)carbamate (33-2)

[0407] Compound 33-1 (300 mg, 0.88 mmol) and a methanolic solution of dimethylamine (1 mL) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and potassium carbonate (183 mg, 1.3 mmol) was added. The reaction mixture was stirred at 80°C for 3 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain compound 33-2 (300 mg, 97% yield).

[0408] LC-MS (ESI + ): 350.0m / z[M+H] + .

[0409] Step 3: Preparation of 1-((3-(dimethylamino)propyl)sulfonyl)piperidin-4-amine (33-3)

[0410] Compound 33-2 (100 mg, 0.28 mmol) was dissolved in dry dichloromethane (2 mL) at room temperature, and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 1 hour until the starting material disappeared. The reaction mixture was concentrated under reduced pressure to give compound 33-3 (trifluoroacetate salt, 70 mg, 98% yield).

[0411] LC-MS (ESI + ): 250.0m / z[M+H] + .

[0412] The remaining steps were the same as in Example 1, except that compound 33-3 was used instead of compound 1-8 in step 5 to obtain compound 33.

[0413] LC-MS (ESI + ): 549.2m / z[M+H] + .

[0414] Example 34: Synthesis of 4-((5-(4-cyanothiazol-2-yl)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-2-yl)amino)-N-(2-(diisopropylamino)ethyl)benzenesulfonamide (34)

[0415] Step 1: Preparation of tert-butyl (2-(diisopropylamino)ethyl)carbamate (34-2)

[0416] At room temperature, N-tert-butoxycarbonyl-2-aminoacetaldehyde (472 mg, 2.96 mmol) and diisopropylamine (300 mg, 2.96 mmol) were dissolved in a mixture of methanol (5 mL) and acetic acid (0.5 mL). Lutidine borane (634 mg, 5.92 mmol) was then added. The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to afford compound 34-2 (300 mg, 41% yield).

[0417] LC-MS (ESI + ): 245.0m / z[M+H] + .

[0418] Step 2: N 1 ,N 1 - Preparation of diisopropylethane-1,2-diamine trifluoroacetate (34-3)

[0419] Compound 34-2 (300 mg, 1.22 mmol) was dissolved in dry dichloromethane (2 mL) at room temperature, and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 1 hour until the starting material disappeared. The reaction mixture was concentrated under reduced pressure to obtain compound 34-3 (170 mg, 96% yield).

[0420] LC-MS (ESI + ): 145.0m / z[M+H] + .

[0421] Step 3: Preparation of N-(2-(diisopropylamino)ethyl)-4-nitrobenzenesulfonamide (34-4)

[0422] At room temperature, compound 34-3 (170 mg, 1.17 mmol) and p-nitrobenzenesulfonyl chloride (261 mg, 1.17 mmol) were dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (0.7 mL). The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to afford compound 34-4 (300 mg, 77% yield).

[0423] LC-MS (ESI + ): 389.0m / z[M+H] + .

[0424] Step 4: Preparation of 4-amino-N-(2-(diisopropylamino)ethyl)benzenesulfonamide (34-5)

[0425] Compound 34-4 (300 mg, 0.91 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, followed by the addition of 10% palladium on carbon (30 mg). The reaction mixture was purged with hydrogen three times and stirred at 25°C for 12 hours. After completion of the reaction, the palladium on carbon was removed by filtration through celite, and the organic phase was concentrated under reduced pressure to afford crude compound 34-5 (200 mg, 73% yield).

[0426] LC-MS (ESI + ): 300.0m / z[M+H] + .

[0427] Step 5: Preparation of 4-((5-(4-cyanothiazol-2-yl)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-2-yl)amino)-N-(2-(diisopropylamino)ethyl)benzenesulfonamide (34)

[0428] Compound 34-5 (30 mg, 0.1 mmol) and compound 1-7 (33 mg, 0.1 mmol) were dissolved in isopropanol (2 mL) at room temperature, and dextrorotatory camphorsulfonic acid (CSA, 46 mg, 0.2 mmol) was added. The reaction mixture was stirred at 90°C for 12 hours. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (water / acetonitrile = 95% / 5%-10% / 90%) to give compound 34 (22.8 mg, 38% yield).

[0429] LC-MS (ESI + ): 599.3m / z[M+H] + .

[0430] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.07(d,J=8.0Hz,1H),8.81(s,1H),8.71(s,1H),8.09(d,J=8.8Hz,2H),7.75(d,J=8.8Hz,2H),4.84 (s,1H),4.40(q,J=7.6Hz,1H),2.89–2.71(m,4H),2.35(d,J=6.8Hz,2H),1.92–1.69(m,5H),1.57–1.42(m,1H),1.32(s,3H),1.07(s,12H).

[0431] The following compounds were obtained by using the corresponding starting materials according to the synthesis method of Example 34:

[0432] Example 36: Preparation of 4-((5-(4-cyanothiazol-2-yl)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)aminoamino)pyrimidin-2-yl)amino))-N-((S)-1-methylpyrrolidin-3-yl)benzenesulfonamide (36)

[0433] According to the synthesis method of Example 34, compound 36 was prepared by substituting (S)-1-methylpyrrolidin-3-amine for compound 34-3.

[0434] LC-MS (ESI + ): 555.2m / z[M+H] + .

[0435] 1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.07(d,J=8.0Hz,1H),8.81(s,1H),8.72(s,1H) ,8.12–8.06(m,2H),7.85(d,J=6.4Hz,1H),7.78–7.73(m,2H),4.85(s,1H),4.39(q,J= 7.2Hz,1H),3.74–3.71(m,1H),3.05–2.81(m,2H),2.74–2.66(m,1H),2.53(s,3H),2.2 8–2.23(m,1H),2.05-1.99(m,1H),1.89–1.67(m,6H),1.50–1.48(m,1H),1.32(s,3H).

[0436] The following compounds were obtained by the synthesis method of Example 36 using the corresponding raw materials:

[0437] Example 39: Preparation of 4-((5-(4-cyanothiazol-2-yl)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide (39)

[0438] According to the synthesis method of Example 34, compound 39 was prepared by substituting 4-aminobenzenesulfonamide for compound 34-5.

[0439] LC-MS (ESI + ): 472.1m / z[M+H] + .

[0440] Example 40: Preparation of 2-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (40)

[0441] Step 1: Preparation of 2-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)pyrimidin-5-yl)thiazole-4-carbonitrile (40)

[0442] A solution of compound 1-7 (50 mg, 0.15 mmol), 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (39 mg, 0.18 mmol, prepared according to WO2015 / 130540), Pd2(dba)3 (14 mg, 0.015 mmol), XantPhos (17 mg, 0.03 mmol), and Cs2CO3 (145 mg, 0.45 mmol) in 1,4-dioxane was degassed and replaced with nitrogen, then heated to 100°C and stirred for 5 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (MeOH / DCM = 1% to 30%), followed by preparative HPLC chromatography (water / acetonitrile = 95% / 5% to 10% / 90%), and lyophilized to give compound 40 (9.0 mg, 12% yield, as a yellow solid).

[0443] LC-MS (ESI + ): 260.6m / z[M / 2+H] + .

[0444] 1 H NMR (400MHz, DMSO-d6) δ9.84 (s, 1H), 8.98 (d, J = 7.7Hz, 1H), 8.77 (s, 1H), 8.6 7(s,1H),8.32(d,J=8.6Hz,1H),8.17(d,J=2.3Hz,1H),7.69(dd,J=8.6,2.3H z,1H),4.82(br.s,1H),4.35(q,J=7.3Hz,1H),3.43(s,2H),2.47–2.19(m,11 H), 1.84–1.62 (m, 4H), 1.53–1.41 (m, 1H), 1.27 (s, 3H), 0.97 (t, J = 7.1Hz, 3H).

[0445] Biological tests

[0446] Test Example 1: In vitro enzymatic test

[0447] Test Example 1: CDK2 / CyclinE1 Enzymatic Activity of the Compounds of the Invention

[0448] 1) Experimental reagents and consumables

[0449] 2) Experimental methods

[0450] 2.1. Preparation of assay buffer and compounds

[0451] 1× Kinase Buffer: 50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween-20, 2 mM DTT.

[0452] Compound preparation: The compounds of the present invention were prepared in DMSO to 10 mM as test stock solutions.

[0453] 2.2. Prepare the following reagents using 1× kinase buffer

[0454] 2×CDK2 / CyclinE1

[0455] 4×ATP / ULight-4E-BP1(Thr37 / 46) peptide mixture

[0456] 2.3. Prepare the following reagents using PPI-Europium assay buffer

[0457] 4×EDTA

[0458] 4×Eu-anti-P-4E-BP1 (Thr37 / 46) antibody

[0459] 3) Experimental steps

[0460] 3.1. Use an electronic pipette to dilute the compound with 1× kinase buffer and transfer 2.5 μL of the 4× compound dilution to an assay plate (6057480, PerkinElmer). Seal the assay plate and centrifuge it at 300 g for 1 minute.

[0461] 3.2. Add 5 μL of 2×CDK2 / CyclinE1 to the assay plate, seal the plate, and centrifuge the plate at 300 g for 1 minute.

[0462] 3.3. Add 2.5 μL of 4×ATP / ULight-4E-BP1 (Thr37 / 46) peptide mixture to the assay plate, seal the assay plate, centrifuge the assay plate at 300 g for 1 minute, and react in a 23°C incubator for 1 hour.

[0463] 3.4. Add 5 μL 4×EDTA and 5 μL 4×Eu-anti-P-4E-BP1 (Thr37 / 46) antibody, seal the assay plate, centrifuge the assay plate at 300 g for 1 minute, incubate at 23°C for 1 hour, and read the plate using a multifunctional microplate reader.

[0464] 4) Data Analysis

[0465] The data were fitted in Excel using formula (1) to obtain inhibition values.

[0466] Formula (1): Percent inhibition rate = (maximum value - signal value) / (maximum value - minimum value) × 100

[0467] The data were fitted in XL-Fit using equation (2) to obtain IC 50 value.

[0468] Formula (2): 50% inhibitory concentration = minimum concentration + (maximum concentration - minimum concentration) / (1 + (50% inhibitory concentration / compound concentration) 斜率

[0469] Test Example 2: CDK1 / CyclinA2 Enzyme Activity of the Compounds of the Invention

[0470] 1) Experimental reagents and consumables

[0471] 2) Experimental methods

[0472] 2.1. Preparation of assay buffer and compounds

[0473] 1× Kinase Buffer: Dilute 5× Reaction Buffer A with ddH2O to 1× Reaction Buffer A and add DTT (final concentration 50 μM).

[0474] Compound preparation: The compounds of the present invention were prepared in DMSO to 10 mM as test stock solutions.

[0475] 2.2. Prepare the following reagents using 1× kinase buffer

[0476] 2.5×CDK1 / CyclinA2

[0477] 2.5×ATP / histone H1 protein mixture

[0478] 3) Experimental steps

[0479] 3.1. Use an electronic pipette to dilute the compound with 1× kinase buffer and transfer 1 μL of 2.5× compound dilution to an assay plate (6008280, PerkinElmer). Seal the assay plate and centrifuge it at 300 g for 1 minute.

[0480] 3.2. Add 2 μl of 2.5×CDK1 / CyclinA2 to the assay plate, seal the plate, and centrifuge the plate at 300 g for 1 minute.

[0481] 3.3. Add 2 μl of 2.5× ATP / histone H1 protein mixture to the assay plate, seal the assay plate, centrifuge the assay plate at 300 g for 1 minute, and incubate at 23°C for 1 hour.

[0482] 3.4. Add 5 μL of ADP-Glo, seal the assay plate, centrifuge the assay plate at 300 g for 1 minute, and incubate at 23°C for 40 minutes.

[0483] 3.5. Add 5 μL of detection buffer, seal the assay plate, centrifuge the assay plate at 300 g for 1 minute, incubate at 23°C for 60 minutes, and read the plate with a multifunctional microplate reader.

[0484] 4) Data Analysis

[0485] The data were fitted in Excel using formula (1) to obtain inhibition values.

[0486] Formula (1): Percent inhibition rate = (maximum value - signal value) / (maximum value - minimum value) × 100

[0487] The data were fitted in XL-Fit using equation (2) to obtain IC 50 value.

[0488] Formula (2): 50% inhibitory concentration = minimum concentration + (maximum concentration - minimum concentration) / (1 + (50% inhibitory concentration / compound concentration) 斜率

[0489] Test Example 3: CDK4 / CyclinE1 Enzymatic Activity of the Compounds of the Invention

[0490] 1) Experimental reagents and consumables

[0491] 2) Experimental methods

[0492] 2.1. Preparation of assay buffer and compounds

[0493] 1× Kinase Buffer: 50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween-20, 2 mM DTT.

[0494] Compound preparation: The compounds of the present invention were prepared in DMSO to 10 mM as test stock solutions.

[0495] 2.2. Prepare the following reagents using 1× kinase buffer

[0496] 2x CDK4 / Cyclin D1 / ULight-4E-BP1 (Thr37 / 46) peptide cocktail

[0497] 4×ATP

[0498] 2.3. Prepare the following reagents using PPI-Europium assay buffer

[0499] 4×EDTA

[0500] 4×Eu-anti-P-4E-BP1 (Thr37 / 46) antibody

[0501] 3) Experimental steps

[0502] 3.1. Use an electronic pipette to dilute the compound with 1× kinase buffer and transfer 2.5 μL of the 4× compound dilution to an assay plate (6057480, PerkinElmer). Seal the assay plate and centrifuge it at 300 g for 1 minute.

[0503] 3.2. Add 5 μL of 2×CDK4 / Cyclin D1 / ULight-4E-BP1 (Thr37 / 46) peptide mixture to the assay plate, seal the assay plate, and centrifuge the assay plate at 300 g for 1 minute.

[0504] 3.3. Add 2.5 μL of 4×ATP to the assay plate, seal the plate, centrifuge the plate at 300 g for 1 minute, and incubate at 23°C for 1 hour.

[0505] 3.4. Add 5 μL 4×EDTA and 5 μL 4×Eu-anti-P-4E-BP1 (Thr37 / 46) antibody, seal the assay plate, centrifuge the assay plate at 300 g for 1 minute, react in a constant temperature box at 23°C for 1 hour, and read the plate using a multifunctional microplate reader.

[0506] 4) Data Analysis

[0507] The data were fitted in Excel using formula (1) to obtain inhibition values.

[0508] Formula (1): Percent inhibition rate = (maximum value - signal value) / (maximum value - minimum value) × 100

[0509] The data were fitted in XL-Fit using equation (2) to obtain IC 50 value.

[0510] Formula (2): 50% inhibitory concentration = minimum concentration + (maximum concentration - minimum concentration) / (1 + (50% inhibitory concentration / compound concentration) 斜率

[0511] Test Example 4: CDK6 / CycD1 Enzymatic Activity of the Compounds of the Invention

[0512] 1) Experimental reagents and consumables

[0513] 2) Experimental methods

[0514] 2.1. Preparation of assay buffer and compounds

[0515] 1× Kinase Buffer: 50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween-20, 0.01% BSA, 2 mM DTT.

[0516] Compound preparation: The compounds of the present invention were prepared in DMSO to 10 mM as test stock solutions.

[0517] 2.2. Prepare the following reagents using 1× kinase buffer

[0518] 2×CDK6 / CycD1 / ULight-4E-BP1(Thr37 / 46) peptide mixture

[0519] 4×ATP

[0520] 2.3. Prepare the following reagents using PPI-Europium assay buffer

[0521] 4x EDTA

[0522] 4x Eu-anti-P-4E-BP1 (Thr37 / 46) antibody

[0523] 3) Experimental steps

[0524] 3.1. Use an electronic pipette to dilute the compound with 1× kinase buffer and transfer 2.5 μL of the 4× compound dilution to an assay plate (6057480, PerkinElmer). Seal the assay plate and centrifuge it at 300 g for 1 minute.

[0525] 3.2. Add 5 μL of 2×CDK6 / CycD1 / ULight-4E-BP1 (Thr37 / 46) peptide mixture to the assay plate, seal the assay plate, and centrifuge the assay plate at 300 g for 1 minute.

[0526] 3.3. Add 2.5 μL of 4×ATP to the assay plate, seal the plate, centrifuge the plate at 300 g for 1 minute, and incubate at 23°C for 1 hour.

[0527] 3.4. Add 5 μL 4×EDTA and 5 μL 4×Eu-anti-P-4E-BP1 (Thr37 / 46) antibody, seal the assay plate, centrifuge the assay plate at 300 g for 1 minute, react in a constant temperature box at 23°C for 1 hour, and read the plate using a multifunctional microplate reader.

[0528] 4) Data Analysis

[0529] The data were fitted in Excel using formula (1) to obtain inhibition values.

[0530] Formula (1): Percent inhibition rate = (maximum value - signal value) / (maximum value - minimum value) × 100

[0531] The data were fitted in XL-Fit using equation (2) to obtain IC 50 value.

[0532] Formula (2): 50% inhibitory concentration = minimum concentration + (maximum concentration - minimum concentration) / (1 + (50% inhibitory concentration / compound concentration) 斜率

[0533] Experimental results:

[0534] Through the above test methods, the enzymatic inhibitory activities of the compounds of the present invention on CDK2, CDK4, CDK6 and CDK1 were obtained, and the results are shown in Table 1.

[0535] Table 1. IC values ​​of the compounds of the present invention for inhibition of CDK2, CDK4, CDK6 and CDK1 activities 50 value

[0536] Experimental conclusion:

[0537] As shown in the table above, the compounds of the present invention exhibit different CDK2, CDK4, and CDK6 inhibitory activities. The enzyme inhibition IC values ​​of most compounds are 50 The measured value is less than 10nM, and it has good selectivity for CDK1.

[0538] Test Example 2: In vitro cytological test

[0539] Test Example 5: Inhibitory activity of the compounds of the present invention on MCF7 cell proliferation

[0540] The cell lines used in the following experiments are as follows: MCF7 (human breast cancer cells), purchased from Nanjing Kebai Biotechnology Co., Ltd., catalog number: CBP60380.

[0541] Experimental methods: Luminescent Cell Viability Assay)

[0542] 1) Prepare cells

[0543] 1.1 Cell Culture

[0544] All cells were adherent cells. The complete culture medium consisted of MEM+10% FBS+1% non-essential amino acids+1 mM sodium pyruvate. The cells were tested in the logarithmic growth phase.

[0545] 1.2. Preparation of cell suspension

[0546] Harvest cells in the logarithmic growth phase and count them using a Thermo Countess II counter. Ensure cell viability is above 90%. Adjust the concentration to the appropriate level and seed 1000 cells into a 96-well plate, with 180 μL of cell suspension per well.

[0547] 2) Preparation of test compounds

[0548] 2.1. Prepare DMSO stock solutions of test compounds. The concentration of each test compound stock solution is 5 mM.

[0549] 2.2. Preparation of intermediate concentration stock solutions of test compounds: 4 μL of 5 mM compound stock solution was added to 196 μL of complete medium without DMSO, and then diluted 4-fold to 8 concentrations using complete medium containing 2% DMSO.

[0550] 2.3 Compound treatment

[0551] 20 μL of the intermediate concentration stock solution of the compound (DMSO, final concentration 0.2%) was added to each well of a 96-well plate seeded with cells.

[0552] The final concentrations of the test compounds were: 10000.00 nM, 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, 0.61 nM.

[0553] 2.4. Control well setting

[0554] Solvent control: 0.2% DMSO. Blank control: Read the 96-well plate at 0 h after drug addition.

[0555] 2.5. Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 7 days.

[0556] 3) Thaw CTG reagent (G7573, Promega) and equilibrate a 96-well plate to room temperature for 30 minutes. Remove the drug-containing culture medium from the plate and dilute the CTG reagent with PBS. Add 150 μL of the diluted CTG reagent to each well, shake on a shaker for 10 minutes to mix (protect from light), and equilibrate at room temperature for 5 minutes. Read the light signal using a multi-function microplate reader.

[0557] 4) Data processing

[0558] 1) Inhibition rate (%) = (DMSO solvent control well reading - test substance well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0559] 2) Fit the curve and calculate IC50 .

[0560] Test Example 6: Inhibitory activity of the compounds of the present invention on NIH: OVCAR-3 cell proliferation

[0561] The cell lines used in the following experiments are as follows: NIH: OVCAR-3 (human ovarian cancer cells), purchased from ATCC, catalog number: HTB-161.

[0562] Experimental methods: Luminescent Cell Viability Assay)

[0563] 1) Prepare cells

[0564] 1.1 Cell Culture

[0565] All cells were adherent cells, the complete culture medium was RPMI-1640 (30-2001, ATCC) + 20% FBS, and the cells were tested in the logarithmic growth phase.

[0566] 1.2. Preparation of cell suspension

[0567] Harvest cells in the logarithmic growth phase and count them using a Thermo Countess II counter. Ensure cell viability is above 90%. Adjust the concentration to the appropriate level and seed 1000 cells into a 96-well plate, with 180 μL of cell suspension per well.

[0568] 2) Preparation of test compounds

[0569] 2.1. Prepare DMSO stock solutions of test compounds. The concentration of each test compound stock solution is 5 mM.

[0570] 2.2. Preparation of intermediate concentration stock solutions of test compounds: 4 μL of 5 mM compound stock solution was added to 196 μL of complete medium without DMSO, and the solution was serially diluted 4-fold to 8 concentrations using complete medium containing 2% DMSO.

[0571] 2.3 Compound treatment

[0572] 20 μL of the intermediate concentration stock solution of the compound (DMSO, final concentration 0.2%) was added to each well of a 96-well plate seeded with cells.

[0573] The final concentrations of the test compounds were: 10000.00 nM, 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, 0.61 nM.

[0574] 2.4. Control well setting

[0575] Solvent control: 0.2% DMSO. Blank control: Read the 96-well plate at 0 h after drug addition.

[0576] 2.5. Place the 96-well plate in a 37°C, 5% CO2 cell culture incubator and culture for 7 days.

[0577] 3) Thaw CTG reagent (G7573, Promega) and equilibrate a 96-well plate to room temperature for 30 minutes. Remove the drug-containing culture medium from the plate and dilute the CTG reagent with PBS. Add 150 μL of the diluted CTG reagent to each well, shake on a shaker for 10 minutes to mix (protect from light), and equilibrate at room temperature for 5 minutes. Read the light signal using a multi-function microplate reader.

[0578] 4) Data processing

[0579] 4.1 Inhibition rate (%) = (DMSO solvent control well reading - test substance well reading) / (DMSO solvent control well reading - blank control well reading) × 100%;

[0580] 4.2 Fitting the curve and calculating IC 50 .

[0581] Experimental results:

[0582] The above test methods were used to determine the inhibitory activity of the compounds of the present invention on the proliferation of OVCAR-3 and MCF-7 cells. The results are shown in Table 2.

[0583] Table 2. IC values ​​of compounds for inhibition of proliferation of OVCAR3 and MCF-7 cells 50 (nM)

[0584] Experimental conclusion:

[0585] As shown in the table above, the compounds of the present invention exhibit different OVCAR-3 and MCF-7 cell growth inhibitory activities. The cell growth inhibition IC values ​​of some compounds are 50 The measured value was less than 100 nM.

Claims

1. A compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: X 1 Selected from-NR 3a -、-O-、-S-、-S(O) p -, -CO-, and -CR 1a R 1b -; X 2 Selected from-NR 3b -、-O-、-S-、-S(O) p -、-CO-、-O-(CH2) v -CO- and CR 2a R 2b ; A 1 is selected from -CH- or -N-; A 2 is selected from -CH2-, -NH-, -O- or -S-; R is selected from heterocyclic, heteroaryl, aryl, cycloalkyl, wherein the heterocyclic, heteroaryl, aryl, cycloalkyl is optionally selected from deuterium atoms, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 1a and R 1b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 2a and R 2b Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 3a is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 3b is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 8 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R a and R b are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, -(CH2) q -NR d R e 、-(CH2) q -OR c 、-(CH2) q -R c 、-(CH2) q -S(O) p R c 、-(CH2) q -C(O)R c 、-(CH2) q -C(O)NR d R e , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently further selected from deuterium atoms, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, -S(O) p R d 、-S(O) p NR d R e 、-C(O)R d 、-C(O)NR d R e 、-NR d C(O)R e 、-COOR d 、-NR d R e 、-SR d 、-OR d 、-(CH2) t -R d 、-(CH2) t -NR d R e 、-(CH2) t -SR d 、-(CH2) t -OR d 、-(CH2) t -S(O) p R d 、-(CH2) t -S(O) p NR d R e 、-(CH2) t -C(O)R d 、-(CH2) t -C(O)NR d R e 、-(CH2) t -NR d C(O)R e 、-(CH2) t -COOR d , alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Or, R a and R b Together with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R c Selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, -(CH2) q -NR d R e , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R d and R e each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Or, R d and R e Together with the nitrogen atom to which they are attached, they form a heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; p is 1 or 2; q is an integer from 1 to 4; v is an integer from 1 to 4; t is an integer from 0 to 4; n is an integer from 1 to 4; s1 and s2 are each independently 0, 1 or 2.

2. The compound of general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in, R 8a and R 8b each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 8c selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from deuterium atom, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R, X 1 、X 2 、A 1 、A 2 , s1, s2 as defined in claim 1.

3. The compound represented by the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R is selected from 4 to 10 membered heterocyclyl, 5 to 10 membered heteroaryl, C 6-10 Aryl, C 3-8 Cycloalkyl, the 4 to 10 membered heterocyclic group, the 5 to 10 membered heteroaryl, C 6-10 Aryl, C 3-8 Cycloalkyl is optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R a 、R b 、R c , p, t as defined in claim 1.

4. The compound represented by the general formula (I) according to any one of claims 1 to 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R is selected from which are optionally further selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl radical substitution; R y Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; R a 、R b 、R c , p, t as defined in claim 1.

5. The compound represented by the general formula (I) according to any one of claims 1 to 4, or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (III) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: Y1, Y2, Y3, and Y4 are each independently selected from -CR 5 -or-N-; R 4 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 4 Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; More preferably selected from -S(O) p R a 、-S(O) p NR a R b 、-(CH2) t -NR a R b ; R 5 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide; X 1 、X 2 、A 1 、A 2 ,s1,s2,R a 、R b 、R c , p, t as defined in claim 1; R 8a 、R 8b 、R 8c As defined in claim 2.

6. A compound represented by the general formula (I) according to any one of claims 1 to 4, or a tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV) or a tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in: Z is selected from -N- or -CH-; R 6 Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 6 Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; More preferably selected from -S(O) p R a 、-S(O) p NR a R b 、 R 7 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide; Or two adjacent R 7 Together with the atoms to which it is attached, it forms a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; m is an integer from 0 to 4; n1 and n2 are each independently an integer from 0 to 2; X 1 、X 2 、A 1 、A 2 ,s1,s2,R a 、R b 、R c , p, t as defined in claim 1; R 8a 、R 8b 、R 8c As defined in claim 2.

7. A compound of formula (I) according to any one of claims 1 to 4, or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (V) or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: Y is -CH- or -N-; R 4a Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 4a Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; More preferably selected from -S(O) p R a 、-S(O) p NR a R b 、-(CH2) t -NR a R b ; R 5a are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide; s is an integer from 1 to 4; X 1 、X 2 、A 1 、A 2 ,s1,s2,R a 、R b 、R c , p, t as defined in claim 1; R 8a 、R 8b 、R 8c As defined in claim 2.

8. A compound of formula (I) according to any one of claims 1 to 4, or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (VI) or a tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in: R 6a Selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably, R 6a Selected from -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c ; More preferably selected from -S(O) p R a 、-S(O) p NR a R b ; R 7a are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, -S(O) p R a 、-S(O) p NR a R b 、 -C(O)R a 、-C(O)NR a R b 、-COOR c 、-NR a R b 、-SR c 、-OR c 、-(CH2) t -NR a R b 、-(CH2) t -SR c 、-(CH2) t -OR c 、-(CH2) t -S(O) p R a 、-(CH2) t -S(O) p NR a R b 、-(CH2) t -C(O)R a 、-(CH2) t -C(O)NR a R b 、-(CH2) t -COOR c , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; preferably selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide; m is an integer from 0 to 4; n1 and n2 are each independently an integer from 0 to 2; X 1 、X 2 、A 1 、A 2 ,s1,s2,R a 、R b 、R c , p, t as defined in claim 1; R 8a 、R 8b 、R 8c As defined in claim 2.

9. The compound of any one of the general formula (I) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X 1 Selected from -NH- or -O-, preferably -NH-; X 2 Selected from -NH-, -O-(CH2) v -CO- or -O-, preferably -NH-; v is an integer of 1 to 4, preferably, v is 1 or 2.

10. The compound of general formula (I) according to any one of claims 2 to 9, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 8a Selected from hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, preferably hydrogen or C 1- 6-alkyl; R 8b Selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, preferably hydrogen or hydroxy; R 8c Selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl; preferably hydrogen or C 1-6 alkyl.

11. The compound of general formula (I) according to any one of claims 1 to 10, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R a and R b are each independently selected from hydrogen, -(CH2) q -NR d R e 、-(CH2) q -R c 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocyclic group are optionally selected from deuterium atoms, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 substituted by one or more haloalkoxy groups or 4-6 membered heterocyclic groups; Or, R a and R b Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted; R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 4-6 membered heterocyclic group are each independently optionally selected from C 1-6 One or more groups are substituted on the alkyl group; R d and R e are each independently selected from hydrogen, C 1-6 alkyl; Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4- to 8-membered heterocyclic group, which is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more haloalkoxy groups are substituted; p is 1 or 2; q is an integer from 1 to 4.

12. The compound of general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of general formula (VIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in, Z is -N- or -CH-, preferably -N-; A 2 is -O- or -CH2-, preferably -CH2-; X 1 is -NH- or -O-, preferably -NH-; X 2 is -NH- or -O-, preferably -NH-; R 7 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide; Or two adjacent R 7 Together with the atoms to which it is attached, it forms a phenyl group or a 5-6 membered heteroaryl group, wherein the phenyl group or the 5-6 membered heteroaryl group is optionally substituted with one or more groups selected from halogen; R 8a Selected from hydrogen or C 1-6 alkyl; R x Selected from-NR a R b 、-(CH2) q -NR d R e 、-(CH2) q -OR c 、-(CH2) q -R c 、-(CH2) q -C(O)R c 、-(CH2) q -C(O)NR d R e 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently optionally selected from deuterium atoms, halogen, cyano, oxo, -NR d C(O)R e 、-COOR d 、-(CH2) t -OR d 、-(CH2) t -S(O) p R d 、-NR d R e 、-(CH2) t -R d 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy or C 3-6 One or more groups in the cycloalkyl group are substituted; R a Selected from hydrogen, -(CH2) q -NR d R e 、-(CH2) q -R c 、C 1-6 Alkyl, 4-6 membered heterocyclic group, wherein the C 1-6 Alkyl, 4-6 membered heterocyclic group are each independently selected from deuterium atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 substituted by one or more haloalkoxy groups or 4-6 membered heterocyclic groups; R b selected from hydrogen; or R a and R b Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally further selected from C 1-6 Alkyl, C 1-6 One or more haloalkyl groups are substituted; R c Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 4-6 membered heterocyclic group are each independently optionally selected from C 1-6 One or more groups are substituted on the alkyl group; R d Selected from hydrogen, C 1-6 Alkyl, cyano; R e Selected from hydrogen, C 1-6 alkyl; Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally further selected from halogen, amino, cyano, oxo, hydroxy, thiol, carboxyl, ester, C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 One or more groups in the haloalkoxy group are substituted; p is 1 or 2; t is an integer from 0 to 4; preferably an integer from 1 to 4; q is an integer from 1 to 4; n1 is 0, 1, or 2; n2 is 0 or 1; m is 1 or 2; s1 is 1 or 2.

13. The compound of general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound of general formula (VA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, in: Y is -CH- or -N-; A 2 is -O- or -CH2-, preferably -CH2-; X 1 is -NH- or -O-, preferably -NH-; X 2 is -NH- or -O-, preferably -NH-; R 5a are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 alkyl halide; R 8a Selected from hydrogen or C 1-6 alkyl; R z Selected from-NR a R b , 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally selected from C 1-6 One or more alkyl and oxo groups are substituted; R a Selected from hydrogen, -(CH2) q -NR d R e , 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally selected from C 1-6 substituted with an alkyl group; R b selected from hydrogen; R d Selected from hydrogen, C 1-6 alkyl; R e Selected from hydrogen, C 1-6 alkyl; Or, R d and R e Together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic group, which is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, thiol, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; q is an integer from 1 to 4; s is 1 or 2; s1 is 1 or 2.

14. A compound of formula (I) according to any one of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

15. A method for preparing a compound represented by general formula (I) according to any one of claims 1 to 14, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by formula (IA) and compound RX 1 H undergoes a substitution reaction or a coupling reaction to obtain a compound represented by the general formula (I) or its meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof; Among them, R, R 8 、X 1 、X 2 、A 1 、A 2 , s1, s2, n as defined in claim 1.

16. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 14, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

17. Use of the compound represented by general formula (I) according to any one of claims 1 to 14 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 in the preparation of a cyclin-dependent kinase (CDK) inhibitor, preferably a CDK2 / 4 / 6 inhibitor.

18. Use of the compound of general formula (I) according to any one of claims 1 to 14 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing and / or treating diseases associated with CDK, preferably CDK2 / 4 / 6 activity, preferably cancer and tumor-related diseases, preferably breast cancer and ovarian cancer.

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