Nitrogen-containing heterocyclic compound, and preparation method therefor and pharmaceutical use thereof

Abstract

The present invention relates to a nitrogen-containing heterocyclic compound, and a preparation method therefor and a pharmaceutical use thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a PKMYT1 inhibitor. The compound and the pharmaceutical composition containing the compound can be used for treating and / or preventing diseases related to PKMYT1 activity, for example, cancer. The definitions of the groups in the general formula (I) are the same as those in the description.

Description

Nitrogen-containing heterocyclic compounds, preparation methods and medical uses thereof Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to nitrogen-containing heterocyclic compounds, their preparation methods and pharmaceutical compositions containing them, as well as their use as PKMYT1 inhibitors in the treatment and / or prevention of diseases related to PKMYT1 activity. Background Art

[0002] CCNE1 encodes cyclin E1 (CyclinE1), which forms a complex with cyclin-dependent kinase 2 (CDK2) to drive cells from G1 into S phase. In cancer, CCNE1 gene amplification and / or dysregulated CyclinE1 expression often occur in the early stages of tumor development, forcing cancer cells to prematurely enter S phase. Excessive replication, a lack of origins, and an insufficient nucleotide pool lead to replication fork stalling, generating replication stress and DNA damage. When p53 is inactivated, cells enter mitosis with damaged DNA, leading to genomic instability. Cells have evolved a complex array of mechanisms to cope with DNA damage, collectively known as the DNA damage response (DDR). Cell cycle checkpoint activation is a crucial component of the DDR, regulating specific DNA repair mechanisms at each phase of the cell cycle, including the G1, S, G2, and mitotic checkpoints.

[0003] CCNE1 amplification is prevalent in multiple tumor types, including high-grade serous ovarian, uterine, and gastroesophageal cancers. In ovarian cancer, CCNE1 amplification is detected in approximately 20% of tumors, is often mutually exclusive with homologous recombination deficiency, and is enriched in tumors that relapse after platinum treatment. Targeting CDK2, a partner protein of Cyclin E1, can effectively inhibit the proliferation of CCNE1-amplified tumor cells. Although selective CDK2 inhibitors have entered the clinical stage, due to the structural similarities between CDKs, no inhibitors with precise selectivity have yet reached the market. As an alternative approach, identifying potential synthetic lethal targets for Cyclin E1 may provide much-needed new treatment options for CCNE1-amplified tumors. Recent studies have shown that PKMYT1 (membrane-associated tyrosine / threonine protein kinase 1) has been identified as a synthetic lethal target for CCNE1 amplification and is also an attractive target for treating some types of DDR cancers.

[0004] PKMYT1, also known as Myt1, is an evolutionarily conserved protein kinase. Its primary function is to inhibit CDK1 (cdc2) activity by phosphorylating CDK1 at Thr14 and Tyr15, thereby regulating the G2-M cell cycle and allowing cells to enter mitosis. PKMYT1 belongs to the WEE kinase family and is structurally similar to WEE, but it has been less studied. WEE1 is located in the nucleus and regulates the activity of CDK1 and CDK2 by phosphorylating Tyr15 residues on them. It participates in regulating the progression of the S, G2 / M, and M phase cell cycle checkpoints. PKMYT1, on the other hand, is primarily located in the cytoplasm, localized between the inner membrane of the Golgi apparatus and the endoplasmic reticulum. It is a membrane-associated inhibitory kinase that selectively regulates CDK1 phosphorylation and acts only at the G2 / M checkpoint. Compared to WEE1, PKMYT1 exhibits more restricted substrate specificity, as it phosphorylates only CDK1 and not the CDK2 complex. Targeting PKMYT1 has great clinical application prospects. Currently, only one selective inhibitor, RP-6306, has entered the clinical stage. Summary of the Invention

[0005] The present invention designed and synthesized a series of heterocyclic compounds and screened them for PKMYT1 activity. The research results showed that the compounds are potent PKMYT1 inhibitors with selective inhibitory effects on cells with CCNE1 gene amplification. The compounds and pharmaceutical compositions containing the compounds can be used to treat and / or prevent diseases related to PKMYT1 activity, such as cancers carrying CCNE1 gene amplification.

[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 its deuterated substance, solvate, or pharmaceutically acceptable salt,

[0007] in:

[0008] is a single bond or a double bond;

[0009] X and Y are each independently selected from N, O, S, C, NR 7 , CR 7 or CR 7a R 7b ;

[0010] R 1 Selected from hydrogen, halogen or -NR 8a R 8b ;

[0011] R 2 、R3 、R 4 and R 5 are each independently selected from hydrogen, halogen, amino, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9a R 9b 、-SR 9 、-OR 9 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0012] R 6 Selected from hydrogen, halogen, amino, nitro, hydroxy, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally selected from deuterated, halogen, amino, NR 9a R 9b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0013] R 7a 、R 7b and R 7 Each independently selected from hydrogen, halogen, amino, NR 9a R 9b , nitro, hydroxy, mercapto, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -COOR 9 、-C(O)R 10 、-S(O) p R 10、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; or, R 7a With R 7b Together with the carbon atom to which it is attached, it forms an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, the heteroaryl group is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0014] R 8a and R 8b Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl being optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; or, R 8a With R 8bTogether with the nitrogen atom to which it is attached, it forms a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl;

[0015] R 9a 、R 9b and R 9 Each is independently selected from hydrogen, 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, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R 9a With R 9b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl;

[0016] R 10 Selected from hydrogen, halogen, amino, nitro, hydroxy, sulfhydryl, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0017] p is 1 or 2.

[0018] Another aspect of the present invention provides a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated form, solvate, or pharmaceutically acceptable salt.

[0019] in:

[0020] is a double bond;

[0021] X and Y are each independently selected from N or CR 7 ;

[0022] R 1 Selected from hydrogen, halogen or -NR 8a R 8b ;

[0023] R 2 、R 3 、R 4 and R 5 are each independently selected from hydrogen, halogen, amino, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 9a R 9b 、-SR 9 、-OR 9 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0024] R 6 Selected from halogen, amino, nitro, hydroxy, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally selected from deuterated, halogen, -NR 9a R 9b , nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0025] R 7 Selected from hydrogen, halogen, amino, -NR 9a R 9b , nitro, hydroxy, mercapto, cyano, oxo, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -COOR9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0026] R 8a and R 8b Each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl being optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or one or more groups; or, R 8a With R 8b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl;

[0027] R 9a 、R 9b and R 9Each is independently selected from hydrogen, 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, hydroxyl, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R 9a With R 9b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl;

[0028] R 10 Selected from hydrogen, halogen, amino, nitro, hydroxy, sulfhydryl, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, sulfhydryl, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0029] p is 1 or 2.

[0030] In some embodiments, the compound of the general formula (I) of the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt is a compound of the general formula (A) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt,

[0031] Wherein, X and Y are each independently selected from N or CR 7 ;

[0032] R 1 ~R 7 As defined in general formula (I).

[0033] In a specific embodiment, the compound represented by general formula (I) of the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt is a compound represented by general formula (IA) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0034] in, X, Y, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (I).

[0035] In a specific embodiment, the compound represented by general formula (I) of the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt, is a compound represented by general formula (IB) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0036] Among them, X, Y, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (I).

[0037] In another specific embodiment, the compound of the general formula (I) of the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt is a compound of the general formula (II) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0038] in, X, Y, R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (I).

[0039] In another specific embodiment, the compound of the general formula (I) of the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt is a compound of the general formula (IIB) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0040] Among them, X, Y, R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (I).

[0041] In another specific embodiment, the compound of the general formula (I) of the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt is a compound of the general formula (IIA) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0042] in, X, Y, R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (I).

[0043] In another specific embodiment, the compound of the general formula (I) of the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt is a compound of the general formula (IIC) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0044] Among them, X, Y, R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (I).

[0045] In another specific embodiment, the compound of the general formula (I) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt, is a compound of the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0046] in:

[0047] X 1 and Y 1 Each independently selected from N or CR 7 ;

[0048] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 As defined in general formula (I).

[0049] In another specific embodiment, the compound of the general formula (I) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt, is a compound of the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0050] in:

[0051] X 1 and Y 1 Each independently selected from N or CR 7 ;

[0052] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 As defined in general formula (I).

[0053] In a preferred embodiment, the compound represented by the general formula (III) or (IIIA) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, wherein X 1 and Y 1 Selected from CR 7 ; or X1 CR 7 And Y 1 N; or X 1 N and Y 1 CR 7 ; R 7 As defined in general formula (I).

[0054] In another preferred embodiment, the compound represented by the general formula (III) or (IIIA) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, wherein each R 7 are independently selected from hydrogen, halogen, amino, hydroxy, mercapto, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NR 9a R 9b , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b , 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 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 substituted by one or more groups of aryl or 5-10 membered heteroaryl;

[0055] R 9 、R 9a 、R 9b 、R 10, p are as defined in the general formula (I).

[0056] In another preferred embodiment, the compound represented by the general formula (III) or (IIIA) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, wherein each R 7 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -NR 9a R 9b , the C 1-6 The alkyl group is optionally substituted with one or more groups selected from halogen;

[0057] R 9a and R 9b are each independently selected from hydrogen and C 1-6 Alkyl; or R 9a With R 9b Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0058] In another preferred embodiment, the compound represented by the general formula (III) or (IIIA) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, wherein R 7 Selected from hydrogen, halogen, -NR 9a R 9b , oxo, C 1-6 Alkyl, C 1-6 alkyl halide;

[0059] R 9a and R 9b are each independently selected from hydrogen and C 1-6 alkyl;

[0060] or R 9a and R 9b Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0061] In another preferred embodiment, the compound represented by the general formula (III) or (IIIA) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, wherein R 7 Selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution.

[0062] In another preferred embodiment, the compound represented by the general formula (III) or (IIIA) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, wherein R 7 Selected from hydrogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution.

[0063] In another specific embodiment, the compound of the general formula (I) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt, is a compound of the general formula (IVA), general formula (IVB) or general formula (IVC) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0064] in,

[0065] R 7a and R 7b are each independently selected from hydrogen, halogen, -NR 9a R 9b , hydroxyl, thiol, cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution;

[0066] R 9a and R 9b are each independently selected from hydrogen and C 1-6 alkyl;

[0067] or R 9a and R 9b Together with the nitrogen atom to which it is attached, it forms a 5-7 membered heterocyclic group;

[0068] R 2 、R 3 、R 4 、R 5 、R 6 As defined in general formula (I).

[0069] In another specific embodiment, the compound of the general formula (I) of the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt, is a compound of the general formula (IVA-1), general formula (IVB-1) or general formula (IVC-1) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt:

[0070] in,

[0071] R 7a and R 7b are each independently selected from hydrogen, halogen, -NR 9a R 9b , cyano, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution;

[0072] R 9a and R 9b are each independently selected from hydrogen and C 1-6 alkyl;

[0073] or R 9a and R 9b Together with the nitrogen atom to which it is attached, it forms a 5-7 membered heterocyclic group;

[0074] R 2 、R 3 、R 4 、R 5 、R 6 As defined in general formula (I).

[0075] In another preferred embodiment, the compound represented by the general formula (I), (A), (IA), (IB), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt thereof, wherein R 6 Selected from halogen, amino, nitro, hydroxy, mercapto, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 ; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are optionally selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, 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 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 substituted by one or more groups of aryl, 5-10 heteroaryl;

[0076] R 9 、R 9a 、R 9b 、R 10 , p are as defined in the general formula (I).

[0077] In another preferred embodiment, the compound represented by the general formula (I), (A), (IA), (IB), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt thereof, wherein R 6 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, C3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl are optionally selected from deuterated, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, 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 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 The compound is substituted by one or more groups of aryl, 5-10 heteroaryl groups.

[0078] In another preferred embodiment, the compound represented by the general formula (I), (A), (IA), (IB), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt thereof, wherein R 6 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl; the C 1-6 Alkyl is optionally selected from deuterated, halogen, amino, -NR 9a R 9b , substituted by one or more groups of cyano;

[0079] R 9a and R 9b are each independently selected from hydrogen and C 1-6 alkyl.

[0080] In another preferred embodiment, the compound represented by the general formula (I), (A), (IA), (IB), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt thereof, wherein R 6 Selected from C 1-6 Alkyl or C 1-6 Deuterated alkyl, the C 1-6 The alkyl group is optionally replaced by -NR 9a R 9b Replacement, R9a and R 9b are each independently selected from hydrogen and C 1-6 alkyl.

[0081] In another preferred embodiment, the compound represented by the general formula (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, wherein R 7a and R 7b Each independently selected from hydrogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution.

[0082] In another preferred embodiment, the compound represented by general formula (IVA) or (IVA-1) of the present invention, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, wherein:

[0083] R 7a selected from hydrogen;

[0084] R 7b Selected from hydrogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution.

[0085] In another preferred embodiment, the compound represented by the general formula (I), (A), (IA), (IB), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) of the present invention, or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt, wherein R 2 and R 3 Each independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NR9a R 9b 、-SR 9 、-OR 9 ; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, 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 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 substituted by one or more groups of aryl or 5-10 membered heteroaryl;

[0086] R 9 、R 9a 、R 9b 、R 10 , p is as defined in general formula (I);

[0087] Preferably, R 2 and R 3 Each independently selected from C 1-6 alkyl.

[0088] In another preferred embodiment, the compound of the present invention represented by general formula (I), (A), (IA), (IB), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt, wherein: R 4 and R 5 Each independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -NR 9a R 9b 、-SR 9 、-OR9 ; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, 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 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 substituted by one or more groups of aryl or 5-10 membered heteroaryl;

[0089] R 9 、R 9a 、R 9b 、R 10 , p is as defined in general formula (I);

[0090] Preferably, R 4 and R 5 are each independently selected from hydrogen.

[0091] In another preferred embodiment, the compound of the present invention represented by general formula (I), (A), (IA), (IB), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt, wherein: R 2 、R 3 、R 4 and R 5 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl; the C 1-6 The alkyl group is optionally substituted with halogen.

[0092] In another preferred embodiment, the compound of the present invention represented by general formula (I), (A), (IA), (IB), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IVA), (IVB), (IVC), (IVA-1), (IVB-1), (IVC-1) or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt, wherein: R 2 、R 3 、R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0093] In another preferred embodiment, the compound represented by general formula (IVA) or (IVA-1) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt,

[0094] in,

[0095] R 2 Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0096] R 3 Selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0097] R 4 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl;

[0098] R 5 Selected from hydrogen, halogen, C 1-6 alkyl;

[0099] R 6 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl; the C 1-6 Alkyl is optionally selected from halogen, -NR 10a R 10b or cyano substituted;

[0100] R 7a Selected from hydrogen and C 1-6 alkyl;

[0101] R 7b Selected from halogen, -NR9a R 9b , cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution;

[0102] R 9a and R 9b Each independently selected from C 1-6 alkyl;

[0103] or R 9a and R 9b Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group;

[0104] R 10a and R 10b Each independently selected from C 1-6 alkyl.

[0105] In another preferred embodiment, the compound represented by general formula (IVB) or (IVB-1) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt thereof,

[0106] in,

[0107] R 2 Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl, preferably C 1-6 alkyl;

[0108] R 3 Selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; preferably C 1-6 alkyl;

[0109] R 4 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, preferably hydrogen;

[0110] R 5 Selected from hydrogen, halogen, C 1-6 Alkyl, preferably hydrogen;

[0111] R 6 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl; the C 1-6 Alkyl is optionally selected from halogen, -NR 10a R10b or cyano substituted, preferably C 1-6 alkyl;

[0112] R 7b Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0113] R 10a and R 10b Each independently selected from C 1-6 alkyl.

[0114] In another preferred embodiment, the compound represented by general formula (IVC) or (IVC-1) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt,

[0115] in,

[0116] R 2 Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl, preferably C 1-6 alkyl;

[0117] R 3 Selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; preferably C 1-6 alkyl;

[0118] R 4 Selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, preferably hydrogen;

[0119] R 5 Selected from hydrogen, halogen, C 1-6 Alkyl, preferably hydrogen;

[0120] R 6 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl; the C 1-6 Alkyl is optionally selected from halogen, -NR 10a R 10b or cyano substituted, preferably C 1-6 alkyl;

[0121] R 7a is selected from hydrogen and halogen;

[0122] R 10a and R 10b Each independently selected from C 1-6 alkyl.

[0123] In another preferred embodiment, the compound represented by general formula (IVA) or (IVA-1) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt,

[0124] in,

[0125] R 2 Selected from halogen, C 1-6 alkyl;

[0126] R 3 Selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0127] R 4 is selected from hydrogen and halogen;

[0128] R 5 is selected from hydrogen and halogen;

[0129] R 6 Selected from C 1-6 alkyl;

[0130] R 7a Selected from hydrogen and C 1-6 Alkyl, preferably hydrogen;

[0131] R 7b Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution.

[0132] In another preferred embodiment, the compound represented by general formula (IVA) or (IVA-1) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt,

[0133] in,

[0134] R 2 Selected from halogen, C 1-6 alkyl;

[0135] R 3 Selected from halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0136] R 4 is selected from hydrogen and halogen;

[0137] R5 is selected from hydrogen and halogen;

[0138] R 6 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, the C 1-6 The alkyl group is optionally replaced by -NR 9a R 9b Replacement, R 9a and R 9b are each independently selected from hydrogen and C 1-6 alkyl;

[0139] R 7a selected from hydrogen;

[0140] R 7b Selected from hydrogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally substituted by C 1-6 Alkyl substitution.

[0141] Typical compounds of the present invention include, but are not limited to:

[0142] Its tautomers, meso racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or its deuterated substance, or pharmaceutically acceptable salt.

[0143] Another aspect of the present invention provides a method for preparing the compound represented by general formula (II) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0144] The compound represented by the general formula D-1 or a salt thereof is reacted in a solvent, optionally in the presence of a catalyst, to obtain the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a deuterated product thereof, or a pharmaceutically acceptable salt thereof;

[0145] in, X, Y, R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (II).

[0146] Another aspect of the present invention provides a method for preparing the compound represented by general formula (III) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt thereof, comprising the following steps:

[0147] The compound represented by the general formula IIId or a salt thereof is reacted in a solvent, optionally in the presence of a catalyst, to obtain the compound represented by the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof;

[0148] Among them, X, Y, R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (III).

[0149] Another aspect of the present invention provides a pharmaceutical composition comprising the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0150] The present invention further provides use of the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a PKMYT1 inhibitor.

[0151] The present invention further provides the use of the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated form, or pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and / or treating diseases associated with PKMYT1 activity.

[0152] The present invention further provides the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated form, or pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for use as a medicament.

[0153] The present invention further provides the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for use as a PKMYT1 inhibitor.

[0154] The present invention further provides the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated substance, or pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for use in preventing and / or treating diseases related to PKMYT1 activity.

[0155] The present invention further provides a method for inhibiting PKMYT1 activity, comprising administering to a subject in need thereof an effective amount of a compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated substance thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0156] The present invention further provides a method for preventing and / or treating diseases associated with PKMYT1 activity, comprising administering to a subject in need thereof a preventively or therapeutically effective amount of a compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated form thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0157] In a preferred embodiment of the present invention, the disease associated with PKMYT1 activity according to the present invention may be a solid tumor, such as ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, colorectal cancer, esophageal cancer, liver cancer, lung cancer or thyroid cancer.

[0158] The compounds of the present invention can form pharmaceutically acceptable acid addition salts with acids according to conventional methods in the field of the present invention. The acids include inorganic acids and organic acids, with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like being particularly preferred.

[0159] The compounds of the present invention can form pharmaceutically acceptable basic addition salts with bases according to conventional methods in the field of the present invention. The bases include inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide, and the like.

[0160] 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.

[0161] 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.

[0162] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants 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 heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethylene oxide sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0163] 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.

[0164] Dispersible powders and granules suitable for preparing aqueous suspensions can be provided with the active ingredient and a dispersant or wetting agent, a suspending agent, or one or more preservatives for mixing by the addition of water. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavorings, and coloring agents may also be added. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] The present invention may contain a compound represented by general formula (I), 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 drugs for treating diseases related to PKMYT1 activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately, or sequentially.

[0171] Definition of terms

[0172] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0173] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0174] 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, an alkyl group containing 1 to 4 carbon atoms or an alkyl group containing 1 to 3 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. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment and may be 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.

[0175] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12alkylene), more preferably an alkylene containing 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), further preferably an alkylene containing 1 to 4 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (—CH—), 1,1-ethylene (—CH(CH)—), 1,2-ethylene (—CHCH)—, 1,1-propylene (—CH(CHCH)—), 1,2-propylene (—CHCH(CH)—), 1,3-propylene (—CHCHCHCH—), and 1,4-butylene (—CHCHCHCHCH—). Alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0176] 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, preferably an alkenyl group containing 2 to 4 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be 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.

[0177] 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, preferably an alkynyl group containing 2 to 4 carbon atoms or preferably an alkynyl group containing 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents may be 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.

[0178] 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, more preferably 3 to 6 carbon atoms or 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, difluoro, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0179] 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 7 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:

[0180] 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 7 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:

[0181] 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 7-10 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:

[0182] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, tetrahydrobenzofuranyl, tetrahydrobenzoxazolyl, tetrahydrobenzisoxazolyl, cyclopentathienyl, tetrahydrobenzothiazolyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be 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.

[0183] 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 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 4 to 7 ring atoms, of which 1 to 3 are heteroatoms, or it contains 4 to 6 ring atoms, of which 1 to 2 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.

[0184] 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 7 to 12 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral 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 single spiral heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0185] 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 7 to 12 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:

[0186] 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 7 to 12 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:

[0187] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl ring.

[0188] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be 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.

[0189] 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. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0190] The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be 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.

[0191] 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, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0192] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be 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.

[0193] The term "heteroalkyl" refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from O, N, Si and S, wherein alkyl is as defined above, and wherein N and S may be optionally oxidized and N may be optionally quaternized.

[0194] The term "alkoxy" refers to -O-(alkyl), wherein the definition of alkyl 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, substituents can be one or more following groups 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.

[0195] The term "cycloalkoxy" refers to an -O-(cycloalkyl) group, wherein cycloalkyl is as defined above.

[0196] The term "heterocycloalkoxy" refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.

[0197] The term "cycloalkylthio" refers to -S-(cycloalkyl) where cycloalkyl is as defined above.

[0198] The term "heterocycloalkylthio" refers to an -S-(heterocyclyl) group wherein heterocyclyl is as defined above.

[0199] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0200] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0201] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0202] The term "hydroxy" refers to an -OH group.

[0203] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0204] The term "amino" refers to -NH2.

[0205] The term "cyano" refers to -CN.

[0206] The term "nitro" refers to -NO2.

[0207] The term "oxo" refers to =0.

[0208] The term "carboxy" refers to -C(O)OH.

[0209] The term "mercapto" refers to -SH.

[0210] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0211] The term "acyl" refers to a compound containing a -C(O)R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0212] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O.18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., in some embodiments, deuterium.

[0213] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0214] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D," are understood to have an abundance of deuterium at that position that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0215] "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.

[0216] "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.

[0217] 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.

[0218] "Pharmaceutically acceptable salts" or "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.

[0219] "Carrier" refers to a vehicle or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0220] Synthesis method of the compound of the present invention

[0221] The compound represented by the general formula (II) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated form, or pharmaceutically acceptable salt can be prepared using the following technical scheme:

[0222] The compound represented by the general formula A-1 or its salt and the compound represented by the general formula A-2 undergo a substitution reaction in an organic solvent under alkaline conditions, optionally in the presence of a catalyst, to obtain the compound represented by the general formula B-1 or its pharmaceutically acceptable salt;

[0223] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably 1,4-dioxane and toluene; the base includes organic bases and inorganic bases, preferably potassium carbonate and cesium carbonate; the catalyst is a combination of a palladium catalyst and a ligand, and the palladium catalyst includes tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, [1,1' -bis(diphenylphosphino)ferrocene] palladium dichloride, palladium acetate, etc., preferably tris(dibenzylideneacetone)dipalladium, ligands include 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine, isopropylbiphenyl 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, etc., preferably 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.

[0224] The compound represented by the general formula B-1 or a salt thereof reacts with malononitrile in an organic solvent under alkaline conditions, optionally in the presence of a catalyst, to obtain the compound represented by the general formula C-1 or a pharmaceutically acceptable salt thereof;

[0225] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably 1,4-dioxane and toluene; the base includes organic bases and inorganic bases, preferably potassium tert-butoxide and sodium hydride; the catalyst is a palladium catalyst and a copper catalyst, the palladium catalyst includes tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, palladium acetate, etc., the copper catalyst includes cuprous iodide, copper sulfate, etc., preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.

[0226] The compound represented by the general formula C-1 or a salt thereof undergoes a hydrolysis reaction in a solvent to obtain a compound represented by the general formula D-1 or a pharmaceutically acceptable salt thereof;

[0227] The solvent is a physical mixture of one or more solvents, including organic solvents and inorganic solvents. Organic solvents include methanol, ethanol, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc. Inorganic solvents include water, concentrated sulfuric acid, etc., preferably concentrated sulfuric acid.

[0228] The compound represented by the general formula D-1 or a salt thereof is reacted in a solvent, optionally in the presence of a catalyst, to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

[0229] The solvent is a physical mixture of one or more solvents, including organic solvents and inorganic solvents. The organic solvents include methanol, ethanol, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., and the inorganic solvents include water, etc., preferably dichloromethane; the catalyst includes hydrogen bromide, boron tribromide, etc., preferably boron tribromide.

[0230] in, X, Y, R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (II).

[0231] The compound represented by the general formula (III) of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its deuterated form, or pharmaceutically acceptable salt can be prepared using the following technical scheme:

[0232] The compound represented by the general formula IIIa or its salt undergoes a substitution reaction with the compound represented by the general formula A-2 in an organic solvent under alkaline conditions, optionally in the presence of a catalyst, to obtain the compound represented by the general formula IIIb or its pharmaceutically acceptable salt;

[0233] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably 1,4-dioxane and toluene; the base includes organic bases and inorganic bases, preferably potassium carbonate and cesium carbonate; the catalyst is a combination of a palladium catalyst and a ligand, and the palladium catalyst includes tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, [1,1' -bis(diphenylphosphino)ferrocene] palladium dichloride, palladium acetate, etc., preferably tris(dibenzylideneacetone)dipalladium, ligands include 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine, isopropylbiphenyl 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, etc., preferably 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.

[0234] The compound represented by the general formula IIIb or a salt thereof reacts with malononitrile in an organic solvent under alkaline conditions, optionally in the presence of a catalyst, to obtain the compound represented by the general formula IIIc or a pharmaceutically acceptable salt thereof;

[0235] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably 1,4-dioxane and toluene; the base includes organic bases and inorganic bases, preferably potassium tert-butoxide and sodium hydride; the catalyst is a palladium catalyst and a copper catalyst, the palladium catalyst includes tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, palladium acetate, etc., the copper catalyst includes cuprous iodide, copper sulfate, etc., preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.

[0236] The compound represented by the general formula IIIc or a salt thereof undergoes a hydrolysis reaction in a solvent to obtain a compound represented by the general formula IIId or a pharmaceutically acceptable salt thereof;

[0237] The solvent is a physical mixture of one or more solvents, including organic solvents and inorganic solvents. Organic solvents include methanol, ethanol, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc. Inorganic solvents include water, concentrated sulfuric acid, etc., preferably concentrated sulfuric acid.

[0238] The compound represented by the general formula IIId or its salt reacts in a solvent, optionally in the presence of a catalyst, to obtain the compound represented by the general formula (III) or its pharmaceutically acceptable salt;

[0239] The solvent is a physical mixture of one or more solvents, including organic solvents and inorganic solvents. The organic solvents include methanol, ethanol, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., and the inorganic solvents include water, etc., preferably dichloromethane; the catalyst includes hydrogen bromide, boron tribromide, etc., preferably boron tribromide.

[0240] Among them, X, Y, R 2 、R 3 、R 4 、R 5 and R 6 As defined in general formula (III). BRIEF DESCRIPTION OF THE DRAWINGS

[0241] FIG1 is a graph showing the tumor growth inhibition of OVCAR3-CDX model mice by the compounds of the present invention.

[0242] FIG2 is a curve diagram showing the weight change of OVCAR3-CDX model mice in which the compounds of the present invention inhibit tumor growth. DETAILED DESCRIPTION

[0243] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0244] 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 a Bruker dps300 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0245] LC-MS measurements were performed using an 1100 Series LC / MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).

[0246] GC-MS was performed using a GCMS-QP2010 SE.

[0247] Preparative liquid chromatography was performed using an LC3000 high performance liquid chromatograph and an LC6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng). The chromatographic column was a Daisogel C18 10 μm 60A (20 mm × 250 mm).

[0248] High performance liquid chromatography (HPLC) was performed using a Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18 250×4.6 mm 5 μm column) and a Shimadzu LC-2010AHT high pressure liquid chromatograph (Phenomenex C18 250×4.6 mm 5 μm column).

[0249] The thin layer chromatography silica gel plate used was Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

[0250] Column chromatography generally uses Qingdao marine silica gel 100-200 mesh and 200-300 mesh silica gel as the carrier.

[0251] 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, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Yinuokai, Nanjing Yaoshi, Anaiji Chemical and other companies.

[0252] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0253] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0254] The microwave reaction was carried out using a CEM-Scover SP microwave reactor.

[0255] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0256] Unless otherwise specified in the examples, the reaction temperature is room temperature, particularly 20°C to 30°C.

[0257] 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: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0258] 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, ethyl acetate and dichloromethane system, C: 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 acetic acid can also be added for adjustment.

[0259] 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 present invention.

[0260] Example

[0261] Example 1: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (1)

[0262] Step 1: Preparation of 1-methyl-3-nitro-6-(trifluoromethyl)pyridin-2(1H)-one (1a)

[0263] Dissolve 3-nitro-6-(trifluoromethyl)pyridin-2(1H)-one (3.00 g, 14.4 mmol) in N,N-dimethylformamide (30 mL). Add sodium hydride (0.86 g, 21.6 mmol) portionwise at 0°C and continue stirring for 30 minutes. Slowly add iodomethane (2.45 g, 17.3 mmol) dropwise and stir at room temperature overnight. Dilute with water (100 mL) and extract with ethyl acetate (50 mL x 3). The organic phase is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 15%-25%) to obtain 1.74 g of the title compound as a yellow solid in a yield of 54.4%.

[0264] LC-MS: m / z = 223 [M+H] + .

[0265] Step 2: Preparation of 3-amino-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (1b)

[0266] Dissolve 1-methyl-3-nitro-6-(trifluoromethyl)pyridin-2(1H)-one (1.74 g, 7.84 mmol) in 95% ethanol (30 mL). Add reduced iron powder (2.19 g, 39.2 mmol) and ammonium chloride (2.70 g, 50 mmol). Stir at 90°C for 2 hours. Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 35%-55%) to obtain 1.28 g of the title compound as a yellow solid in a yield of 84.8%.

[0267] LC-MS: m / z=193[M+H] + .

[0268] Step 3: Preparation of 3-amino-4-bromo-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (1c)

[0269] Dissolve 3-amino-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (1.28 g, 6.67 mmol) in acetonitrile (20 mL) and slowly add bromosuccinimide (1.31 g, 7.34 mmol). Stir at room temperature overnight. The reaction mixture is concentrated, and the residue is purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 35%-55%) to obtain 1.61 g of the title compound as a yellow solid in an 88.9% yield.

[0270] LC-MS: m / z=271,273[M+H] + .

[0271] Step 4: Preparation of 4-bromo-3-((3-methoxy-2,6-dimethylphenyl)amino)-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (1d)

[0272] 3-Amino-4-bromo-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (1.61 g, 5.94 mmol), 2-iodo-4-methoxy-1,3-dimethylbenzene (1.87 g, 7.13 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (688 mg, 1.19 mmol), tris(dibenzylideneacetone)dipalladium (544 mg, 594 μmol), and cesium carbonate (3.88 g, 11.9 mmol) were dissolved in 1,4-dioxane (30 mL) and reacted at 110°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 15%-25%) to give 130 mg of the title compound as a yellow solid, in a yield of 5.39%.

[0273] LC-MS: m / z: 405,407 [M+H] + .

[0274] Step 5: Preparation of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (1e)

[0275] 4-Bromo-3-((3-methoxy-2,6-dimethylphenyl)amino)-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (130 mg, 0.320 mmol) and malononitrile (25.0 mg, 384 μmol) were dissolved in DMSO (15 mL). Potassium carbonate (132 mg, 0.960 mmol), L-proline (74.0 mg, 640 μmol), and cuprous iodide (67.0 mg, 352 μmol) were added. The mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 35%-55%) to obtain 30.0 mg of the title compound as a yellow solid in a yield of 24.1%.

[0276] LC-MS: m / z: 391 [M+H] + .

[0277] Step 6: Preparation of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (1f)

[0278] 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (30.0 mg, 76.9 μmol) was dissolved in concentrated sulfuric acid (3 mL) and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (30 mL), and the pH was adjusted to 8-9 with aqueous ammonia. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phase was concentrated under reduced pressure to obtain 21.0 mg of the title compound as a yellow solid, in a yield of 66.9%.

[0279] LC-MS: m / z=409[M+H] + .

[0280] Step 7: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (1)

[0281] Dissolve 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (21.0 mg, 51.5 μmol) in dichloromethane (5 mL). Add 1 M boron tribromide in dichloromethane (0.5 mL, 500 μmol) dropwise at -78°C. Stir at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture is concentrated under reduced pressure, and the residue is separated by preparative liquid chromatography (Daisogei 30 mm x 250 mm, C18, 10 μm, 100 Å column, mobile phase: acetonitrile / water, gradient: 30% - 80%) to obtain 15.0 mg of the title compound as a white solid. Yield: 73.9%.

[0282] LC-MS: m / z=395[M+H] + .

[0283] 1 H NMR (400MHz, DMSO-d6) δ9.46 (s, 1H), 7.45 (s, 1H), 7.02 (s, 2H), 6.97 (d, J = 8.4Hz ,1H),6.84(d,J=8.4Hz,1H),6.48(s,2H),3.43(s,3H),1.76(s,3H),1.67(s,3H).

[0284] Example 2: Preparation of S-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide and R-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (1-1 and 1-2)

[0285] Compound 1 was separated by SFC chiral preparative separation under the following conditions: equipment: Waters 150preparative SFC (SFC-26), chiral column: ChiralCel OJ, 250×30 mm ID, 10 μm, temperature: 38°C, mobile phase: supercritical CO2 / EtOH=85 / 15, flow rate: 120 mL / min, back pressure: 100 bar, detection wavelength: 220 nm, cycle time: 4 minutes to obtain two isomers: compound 1-1 (RT=2.774 min) and compound 1-2 (RT=3.090 min).

[0286] Compound 1-1: LC-MS: m / z=395 [M+H] + .

[0287] 1 H NMR (400MHz, DMSO-d6) δ7.45(s,1H),7.02(s,2H),6.97(d,J=8.2Hz,1H),6.84(d,J=8.4Hz,1H),6.48(s,2H),3.43(s,3H),1.76(s,3H),1.67(s,3H).

[0288] Compound 1-2: LC-MS: m / z=395 [M+H] + .

[0289] 1 H NMR (400MHz, DMSO-d6) δ7.45(s,1H),7.02(s,2H),6.97(d,J=8.2Hz,1H),6.84(d,J=8.4Hz,1H),6.48(s,2H),3.43(s,3H),1.76(s,3H),1.67(s,3H).

[0290] Example 3: Preparation of 2-amino-6-ethyl-1-(3-hydroxy-2,6-dimethylphenyl)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (2)

[0291] Step 1: Preparation of 3-iodo-6-(trifluoromethyl)pyridin-2(1H)-one (2a)

[0292] 6-(Trifluoromethyl)pyridin-2(1H)-one (20.0 g, 122.7 mmol) and potassium carbonate (35.2 g, 255 mmol) were dissolved in 100 mL of water at room temperature. Iodine (34.3 g, 134.9 mmol) was added and stirred for 48 hours. LCMS showed the reaction was complete. The product was extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 100:1-2:1) to obtain 7.50 g of the title compound as a yellow solid in a yield of 21.1%.

[0293] LC-MS: m / z: 290.1 ​​[M+H] + .

[0294] Step 2: Preparation of 1-ethyl-3-iodo-6-(trifluoromethyl)pyridin-2(1H)-one (2b)

[0295] 3-Iodo-6-(trifluoromethyl)pyridin-2(1H)-one (6.00 g, 20.7 mmol) was dissolved in N,N-dimethylformamide (60 mL) at room temperature. Sodium hydride (2.48 g, 62.1 mmol) was added and stirred for 30 minutes. Ethyl iodide (3.87 g, 24.8 mmol) was added and the mixture was reacted at room temperature for 16 hours. The mixture was diluted with 300 mL of water and extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 10%-30%) to obtain 6.00 g of the title compound as an oily solid in a yield of 91.2%.

[0296] LC-MS: m / z=318[M+H] + .

[0297] Step 3: Preparation of 1-ethyl-3-((3-methoxy-2,6-dimethylphenyl)amino)-6-(trifluoromethyl)pyridin-2(1H)-one (2c)

[0298] 1-Ethyl-3-iodo-6-(trifluoromethyl)pyridin-2(1H)-one (1.70 g, 5.36 mmol) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, and 3-methoxy-2,6-dimethylaniline (971 mg, 6.34 mmol), cesium carbonate (5.25 g, 16.1 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (312 mg, 0.54 mmol) and tris(dibenzylideneacetone)dipalladium (247 mg, 0.270 mmol) were added. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 20%-40%) to give 1.70 g of the title compound as a yellow solid in a yield of 93.2%.

[0299] LC-MS: m / z=341[M+H] + .

[0300] Step 4: Preparation of 4-bromo-1-ethyl-3-((3-methoxy-2,6-dimethylphenyl)amino)-6-(trifluoromethyl)pyridin-2(1H)-one (2d)

[0301] 1-Ethyl-3-((3-methoxy-2,6-dimethylphenyl)amino)-6-(trifluoromethyl)pyridin-2(1H)-one (1.50 g, 4.41 mmol) was dissolved in N,N-dimethylformamide (30 mL) at room temperature. N-bromosuccinimide (785 mg, 4.41 mmol) was added and stirred for 4 hours. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 15%-25%) to give 1.20 g of the title compound as a yellow solid in a yield of 65.1%.

[0302] LC-MS: m / z=419[M+H] + .

[0303] Step 5: Preparation of 2-amino-6-ethyl-1-(3-methoxy-2,6-dimethylphenyl)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (2e)

[0304] 4-Bromo-1-ethyl-3-((3-methoxy-2,6-dimethylphenyl)amino)-6-(trifluoromethyl)pyridin-2(1H)-one (1.20 g, 2.87 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature. Sodium hydride (343 mg, 8.58 mmol) was added and stirred for 1 hour. [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (262 mg, 0.286 mmol) was added. The atmosphere was replaced with nitrogen three times and stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 15%-25%) to obtain 800 mg of the title compound as a yellow solid in a yield of 69.0%.

[0305] LC-MS: m / z=405[M+H] + .

[0306] Step 6: Preparation of 2-amino-6-ethyl-1-(3-methoxy-2,6-dimethylphenyl)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (2f)

[0307] 2-Amino-6-ethyl-1-(3-methoxy-2,6-dimethylphenyl)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (400 mg, 0.990 mmol) was dissolved in concentrated H₂SO₄ (3 mL) at 0°C and stirred for 2 hours. 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 400 mg of the title compound as a solid.

[0308] LC-MS: m / z=423[M+H] + .

[0309] Step 7: Preparation of 2-amino-6-ethyl-1-(3-hydroxy-2,6-dimethylphenyl)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (2)

[0310] 2-Amino-6-ethyl-1-(3-methoxy-2,6-dimethylphenyl)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (400 mg, 0.948 mmol) was dissolved in dichloromethane (5 mL) at 0°C. Boron tribromide (0.5 mL, 0.500 mmol, 1 M solution in DCM) was added dropwise. The mixture was allowed to warm to room temperature and allowed to react for 2 hours. The mixture was then concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid chromatography (Daisogei 30 mm × 250 mm, C18, 10 μm 100A column, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to afford 47.0 mg of the title compound as a white solid in a yield of 12.1%.

[0311] LC-MS: m / z=409[M+H] + .

[0312] 1 H NMR (400MHz, DMSO-d6) δ7.63(s,1H),7.51(d,J=11.2Hz,2H),7.12(d,J=8.0Hz,1H),6.82 (s, 1H), 6.13 (d, J = 8.0Hz, 1H), 4.47 (q, J = 7.2Hz, 2H), 2.13 (s, 6H), 1.43 (t, J = 7.2Hz, 3H).

[0313] Example 4: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-isopropyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (3)

[0314] Referring to the preparation method of Example 3, the title compound 3 was prepared by replacing iodoethane in step 2 with iodoisopropylane.

[0315] LC-MS: m / z=423[M+H] + .

[0316] 1 H NMR (400MHz, DMSO-d6) δ7.43(s,1H),7.12(dd,J=9.6,8.1Hz,2H),6.88(d,J=8.4Hz,1H),6.09(d,J=7.9Hz,1H ), 5.32 (p, J = 6.2Hz, 1H), 3.79 (s, 3H), 2.04 (s, 3H), 1.95 (s, 3H), 1.40 (d, J = 6.2Hz, 6H), 1.31 (d, J = 6.2Hz, 1H).

[0317] Example 5: Preparation of 2-amino-5-cyclopropyl-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (4)

[0318] Step 1: Preparation of 6-cyclopropyl-1-methylpyridin-2(1H)-one (4a)

[0319] At room temperature, 6-bromo-1-methylpyridin-2(1H)-one (2.01 g, 10.7 mmol), cyclopropylboronic acid (1.84 g, 21.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.780 g, 1.07 mmol), cesium carbonate (10.4 g, 32.1 mmol), dioxane (40 mL), and water (10 mL) were added to a reaction flask. The atmosphere was purged with nitrogen three times and stirred at 90°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1) to obtain 1.20 g of the title compound in a 75.2% yield.

[0320] LC-MS: m / z = 150.1 [M+H] + .

[0321] Step 2: Preparation of 3-bromo-6-cyclopropyl-1-methylpyridin-2(1H)-one (4b)

[0322] 6-Cyclopropyl-1-methylpyridin-2(1H)-one (1.04 g, 6.98 mmol), N-bromosuccinimide (0.740 g, 4.19 mmol), and acetonitrile (20 mL) were added to a reaction flask at room temperature and stirred for 2 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 20:1) to obtain 0.990 g of the title compound in a 62.7% yield.

[0323] LC-MS: m / z=228.1,230.1[M+H] + .

[0324] Step 3: Preparation of 6-cyclopropyl-3-((3-methoxy-2,6-dimethylphenyl)amino)-1-methylpyridin-2(1H)-one (4c)

[0325] At room temperature, 3-bromo-6-cyclopropyl-1-methylpyridin-2(1H)-one (990 mg, 4.36 mmol), 3-methoxy-2,6-dimethylaniline (690 mg, 4.58 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (250 mg, 0.440 mmol), tris(dibenzylideneacetone)dipalladium (200 mg, 0.220 mmol), cesium carbonate (3.55 g, 10.9 mmol) and dioxane (40 mL) were added to a reaction flask, the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1) to obtain 1.14 g of the title compound in a yield of 87.7%.

[0326] LC-MS: m / z = 299.1 [M+H] + .

[0327] Step 4: Preparation of 4-bromo-6-cyclopropyl-3-((3-methoxy-2,6-dimethylphenyl)amino)-1-methylpyridin-2(1H)-one (4d).

[0328] 6-Cyclopropyl-3-((3-methoxy-2,6-dimethylphenyl)amino)-1-methylpyridin-2(1H)-one (630 mg, 2.10 mmol), pyridinium tribromide (1.00 g, 3.16 mmol), and glacial acetic acid (10 mL) were added to a reaction flask at room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 1:1) to obtain 220 mg of the title compound, in a yield of 27.9%.

[0329] LC-MS: m / z=377.0 / 379.0[M+H] + .

[0330] Step 5: Preparation of 2-amino-5-cyclopropyl-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (4e)

[0331] Malononitrile (87.0 mg, 1.32 mmol), NaH (60%, 70.0 mg, 1.76 mmol), and dioxane (10 mL) were added to a reaction flask at room temperature and stirred for 30 minutes. Compound 4d (160 mg, 0.440 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32.0 mg, 0.044 mmol) were then added. The atmosphere was purged with nitrogen three times, and the reaction was continued at 100°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 1:1) to obtain 80.0 mg of the title compound in a 50.3% yield.

[0332] LC-MS: m / z = 363.2 [M+H] + .

[0333] Step 6: Preparation of 2-amino-5-cyclopropyl-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (4)

[0334] 2-Amino-5-cyclopropyl-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (40.0 mg, 0.110 mmol) was dissolved in concentrated sulfuric acid (6 mL) at room temperature and stirred for 4 hours. Saturated aqueous sodium bicarbonate was added to adjust the pH to 7, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (Daisogei 30 mm × 250 mm, C18, 10 μm 100A column, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to obtain 4.80 mg of the title compound as a white solid, in an 11.5% yield.

[0335] LC-MS: m / z = 367.1 [M+H] + .

[0336] 1 H-NMR(400MHz,DMSO-d6)δ7.57(s,2H),7.44(s,1H),6.79(s,2H),5.85(d,J=8.0,1H), 5.55(d,J=4.0,1H),3.70(s,3H),2.11(s,6H),1.24(s,1H),0.87(m,2H),0.60(m,2H).

[0337] Example 6: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (5)

[0338] Referring to the preparation method of Example 5, the cyclopropylboronic acid in step 1 was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole to prepare the title compound 5.

[0339] LC-MS: m / z = 407.18 [M+H] + .

[0340] 1 H-NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.06(s,1H),7.76(s,1H),7.20(s,1H),6.95(d,J=8.0Hz,1H), 6.81(d,J=4.0Hz,1H),6.76(s,2H),6.36(s,2H),3.89(s,3H),3.33(s,3H),1.78(s,3H),1.69(s,3H).

[0341] Example 7: Preparation of 2-amino-5-cyano-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (6)

[0342] Step 1: Preparation of 5-amino-4-bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (6a)

[0343] To a solution of 5-amino-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (498 mg, 2.00 mmol) in dichloromethane (8 mL) was added N-bromosuccinimide (427 mg, 2.40 mmol) at room temperature. The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 35%-85%) to give 617 mg of the title compound as a white solid, yield: 81.0%.

[0344] LC-MS: m / z=228,230[M+H] + .

[0345] Step 2: Preparation of 4-bromo-5-((3-methoxy-2,6-dimethylphenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (6b)

[0346] To a solution of 5-amino-4-bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (617 mg, 2.71 mmol) and (3-methoxy-2,6-dimethylphenyl)boronic acid (974 mg, 5.41 mmol) in dichloromethane (18 mL) at room temperature were added triethylamine (752 μL, 5.41 mmol), 4A molecular sieves (1.80 g), and copper acetate (983 mg, 5.41 mmol). The reaction solution was purged with oxygen three times and stirred at room temperature under an oxygen atmosphere (15 psi) for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 15%-45%) to afford 113 mg of the title compound as a yellow solid in an 11.5% yield.

[0347] LC-MS: m / z=362,364[M+H] + .

[0348] Step 3: Preparation of methyl 2-amino-5-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (6c)

[0349] To a solution of 4-bromo-5-((3-methoxy-2,6-dimethylphenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (100 mg, 276 μmol) and methyl cyanoacetate (55.0 mg, 55.2 μmol) in dimethyl sulfoxide (6 mL) were added potassium carbonate (76.0 mg, 55.2 μmol), L-proline (6.40 mg, 55.2 μmol) and cuprous iodide (5.30 mg, 28.0 μmol) at room temperature. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 90° C. under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 25%-65%) to give 26.0 mg of the title compound as a yellow solid, in a yield of 24.8%.

[0350] LC-MS: m / z=381[M+H] + .

[0351] Step 4: Preparation of 2-amino-5-cyano-1-(3-methoxy-2,6-dimethylphenyl)-N-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (6d)

[0352] To a solution of methyl 2-amino-5-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (15.0 mg, 39.4 μmol) and (4-methoxyphenyl)methanamine (8.10 mg, 59.2 μmol) in 1,4-dioxane (2 mL) was added dropwise trimethylaluminum (99.0 μL, 197 μmol, 2 M solution in hexane) at room temperature. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 90°C under a nitrogen atmosphere for 5 hours. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give 15.0 mg of the title compound as a yellow solid, in a yield of 78.4%.

[0353] LC-MS: m / z=486[M+H] + .

[0354] Step 5: Preparation of 2-amino-5-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (6e)

[0355] To 2-amino-5-cyano-1-(3-methoxy-2,6-dimethylphenyl)-N-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (15.0 mg, 30.9 μmol) was added trifluoroacetic acid (2 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford 21.0 mg of the title compound as a yellow solid (crude product).

[0356] LC-MS: m / z=352[M+H] + .

[0357] Step 6: Preparation of 2-amino-5-cyano-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (6).

[0358] To a solution of 2-amino-5-cyano-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (21.0 mg, 57.5 μmol) in dichloromethane (4 mL) was added dropwise BBr (402 μL, 402 μmol, 1 M solution in DCM) at 0°C. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (column model: Daisogei 30 mm × 250 mm, C18, 10 μm, 100A, mobile phase: acetonitrile / water, gradient: 30%-80%) to give 2.00 mg of the title compound as a white solid, yield: 9.90%.

[0359] LC-MS: m / z = 351.6 [M+H] + .

[0360] 1 H NMR (400MHz, DMSO-d6) δ7.79(s,1H),7.18(s,2H),6.98(s,1H),6.96(s,1H),6.63(s,2H),6.56(s,1H),3.48(s,3H),1.75(s,3H),1.66(s,3H).

[0361] Example 8: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-3-carboxamide (7)

[0362] Step 1: Preparation of 4,5-dibromo-2-methylpyridazin-3(2H)-one (7a)

[0363] 4,5-Dibromopyridazin-3(2H)-one (5.00 g, 19.7 mmol), iodomethane (4.20 g, 29.5 mmol), and potassium carbonate (5.40 g, 39.4 mmol) were added to N,N-dimethylformamide (50 mL) at room temperature and stirred for 16 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (mobile phase EA / PE = 0 / 100 to 40 / 100) to obtain 3.63 g of the product in a yield of 68.2%.

[0364] LC-MS: m / z=269[M+H] + .

[0365] Step 2: Preparation of 5-bromo-4-((3-methoxy-2,6-dimethylphenyl)amino)-2-methylpyridazin-3(2H)-one (7b)

[0366] At room temperature, 4,5-dibromo-2-methylpyridazin-3(2H)-one (3.63 g, 13.5 mmol), 3-methoxy-2,6-dimethylaniline (2.06 g, 13.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.56 g, 2.70 mmol), tris(dibenzylideneacetone)dipalladium (1.24 g, 1.35 mmol) and cesium carbonate (13.2 g, 40.6 mmol) were added to 1,4-dioxane (60 mL). The atmosphere was replaced with nitrogen three times and the mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase EA / PE = 0 / 100-40 / 100) to obtain 3.77 g of the product with a yield of 82.3%.

[0367] LC-MS: m / z=338[M+H] + .

[0368] Step 3: Preparation of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-3-carbonitrile (7c)

[0369] Malononitrile (1.42 g, 21.5 mmol) and potassium tert-butoxide (2.06 g, 21.5 mmol) were added to ethylene glycol dimethyl ether (100 mL) at room temperature and stirred for 1 hour. 5-Bromo-4-((3-methoxy-2,6-dimethylphenyl)amino)-2-methylpyridazin-3(2H)-one (3.62 g, 10.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.785 g, 1.08 mmol) were then added. The atmosphere was replaced with nitrogen three times and stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-40%) to obtain 4.73 g of the product.

[0370] LC-MS: m / z=324[M+H] + .

[0371] Step 4: Preparation of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-3-carboxamide (7d)

[0372] 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-3-carbonitrile (4.73 g, 14.6 mmol) was added to 20 mL of concentrated sulfuric acid at room temperature and stirred for 4 hours. 200 mL of ice water was added, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-40%) to give 2.66 g of the product. The yield for the above two steps was 69.8%.

[0373] LC-MS: m / z=342[M+H] + .

[0374] Step 5: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-3-carboxamide (7)

[0375] 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-3-carboxamide (2.51 g, 7.32 mmol) was dissolved in dichloromethane (20 ml) at 0°C. Boron tribromide (6 ml, 4.04 mmol, 1 M solution in DCM) was added dropwise. The mixture was stirred at room temperature for 2 hours and quenched with methanol. The mixture was concentrated under reduced pressure, and the residue was separated by high pressure preparative liquid chromatography (Daisogei column, 30 mm × 250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to afford 350 mg of the title compound as a yellow solid.

[0376] LC-MS: m / z=328[M+H] + .

[0377] 1 H NMR (400MHz, DMSO-d6) δ10.03–9.91(m,1H),9.74(s,1H),7.41(s,1H),7.12(d,J=8. 3Hz, 1H), 7.04 (s, 1H), 6.96 (d, J = 8.4Hz, 3H), 3.72 (s, 3H), 1.78 (s, 3H), 1.70 (s, 3H).

[0378] Example 9: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (8)

[0379] Referring to the preparation method of Example 8, the title compound 8 was prepared by replacing 4,5-dibromopyridazin-3(2H)-one in step 1 with 3,4-dibromopyridin-2(1H)-one.

[0380] LC-MS: m / z=327[M+H] + .

[0381] 1 H NMR(400MHz,DMSO-d6)δ9.46(s,1H),7.45(s,2H),7.26(d,J=3.6Hz,1H),7.02(d,J=3.6Hz,1H),6 .97(d,J=8.0Hz,1H),6.84(d,J=8.0Hz,1H),6.47(s,2H),3.43(s,3H),1.76(s,3H),1.67(s,3H).

[0382] Example 10: Preparation of 6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (9)

[0383] Step 1: Preparation of 6-chloro-5-iodo-2-methylpyrimidin-4(3H)-one (9a)

[0384] 6-Chloro-2-methylpyrimidin-4(3H)-one (5.00 g, 34.6 mmol) and N-iodosuccinimide (8.56 g, 38.1 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature and stirred at 80°C for 16 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 100:0-20:1) to obtain 9.68 g of the title compound as a yellow solid.

[0385] LC-MS: m / z=271[M+H] + .

[0386] Step 2: Preparation of 6-chloro-5-iodo-2,3-dimethylpyrimidin-4(3H)-one (9b)

[0387] 6-Chloro-5-iodo-2-methylpyrimidin-4(3H)-one (9.68 g, 35.8 mmol), iodomethane (10.2 g, 71.7 mmol), and cesium carbonate (23.4 g, 71.7 mmol) were dissolved in N,N-dimethylformamide (100 mL) at room temperature and stirred for 16 hours. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 100:0-20:1) to obtain 9.00 g of the title compound as a yellow solid. The yield over the two steps was 91.3%.

[0388] LC-MS: m / z = 285 [M+H] + .

[0389] Step 3: Preparation of 6-chloro-5-((3-methoxy-2,6-dimethylphenyl)amino)-2,3-dimethylpyrimidin-4(3H)-one (9c)

[0390] At room temperature, 6-chloro-5-iodo-2,3-dimethylpyrimidin-4(3H)-one (0.500 g, 1.76 mmol), 3-methoxy-2,6-dimethylaniline (0.266 g, 1.76 mmol), tris(dibenzylideneacetone)dipalladium (0.162 g, 0.180 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.204 g, 0.352 mmol) and cesium carbonate (1.15 g, 3.52 mmol) were added to 1,4-dioxane (10 mL). The atmosphere was replaced with nitrogen three times and the mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0-5:1) to obtain 63.0 mg of the title compound as a yellow solid, in a yield of 12.0%.

[0391] LC-MS: m / z=309[M+H] + .

[0392] Step 4: Preparation of 6-amino-5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile (9d)

[0393] Malononitrile (21.6 mg, 0.325 mmol) was dissolved in ethylene glycol dimethyl ether (5 mL) at room temperature, and sodium hydride (60%, 14.3 mg, 0.357 mmol) was added. The mixture was stirred for 1 hour. 6-Chloro-5-((3-methoxy-2,6-dimethylphenyl)amino)-2,3-dimethylpyrimidin-4(3H)-one (50.0 mg, 0.162 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11.8 mg, 0.0162 mmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 100:1-5:2) to obtain 19.2 mg of the title compound as a yellow solid, in a yield of 35.1%.

[0394] LC-MS: m / z=338[M+H] + .

[0395] Step 5: Preparation of 6-amino-5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (9e)

[0396] 6-Amino-5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile (300 mg, 0.89 mmol) was dissolved in 3 mL of concentrated sulfuric acid at room temperature and stirred for 4 hours. 30 mL of ice water was added and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 125 mg of the title compound as a yellow solid in a yield of 39.6%.

[0397] LC-MS: m / z=356[M+H] + .

[0398] Step 6: Preparation of 6-amino-5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (9)

[0399] 6-Amino-5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (125 mg, 0.350 mmol) was dissolved in dichloromethane (10 ml) at 0°C. Boron tribromide (3.51 ml, 3.51 mmol, 1 M solution in DCM) was added dropwise and stirred at room temperature for 2 hours. Methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was separated by high pressure preparative liquid chromatography (column model: Daisogei 30 mm × 250 mm, C18, 10 μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to obtain 28.0 mg of the title compound as a yellow solid.

[0400] LC-MS: m / z=342[M+H] + .

[0401] 1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H),7.61(s,1H),7.09(s,1H),6.97(d,J=8.2Hz,1H),6 .84(d,J=8.2Hz,1H),6.42(s,2H),3.37(s,3H),2.50(s,3H),1.79(s,3H),1.70(s,3H).

[0402] Example 11: Preparation of 2-amino-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (10)

[0403] Referring to the preparation method of Example 1, the title compound 10 was prepared by replacing 2-iodo-4-methoxy-1,3-dimethylbenzene in step 4 with 1-fluoro-3-iodo-5-methoxy-2,4-dimethylbenzene.

[0404] LC-MS: m / z=413[M+H] + .

[0405] 1 H NMR (400MHz, DMSO-d6) δ9.92(s,1H),7.46(s,1H),7.04(s,2H),6.73(d,J=11.1Hz,1H),6.66(s,2H),3.43(s,3H),1.67(d,J=1.7Hz,3H),1.62(s,3H).

[0406] Example 12: Preparation of S-2-amino-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide and R-2-amino-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (10-1 and 10-2)

[0407] Compound 10 was separated by SFC chiral preparative separation under the following conditions: equipment: Waters 150preparative SFC (SFC-26), chiral column: ChiralCel OX, 250×30 mm ID, 10 μm, temperature: 38°C, mobile phase: supercritical CO2 / EtOH=75 / 25, flow rate: 120 mL / min, back pressure: 100 bar, detection wavelength: 220 nm, cycle time: 5 minutes, to obtain two isomers: compound 10-1 (RT=3.881 min) and compound 10-2 (RT=4.268 min).

[0408] Compound 10-1: LC-MS: m / z=413 [M+H] + .

[0409] 1 H NMR (400MHz, DMSO-d6) δ9.92(s,1H),7.46(s,1H),7.04(s,2H),6.73(d,J=11.3Hz,1H),6.66(s,2H),3.43(s,3H),1.67(d,J=1.7Hz,3H),1.62(s,3H).

[0410] Compound 10-2: LC-MS: m / z=413 [M+H] + .

[0411] 1 H NMR (400MHz, DMSO-d6) δ9.92(s,1H),7.46(s,1H),7.04(s,2H),6.73(d,J=11.3Hz,1H),6.66(s,2H),3.43(s,3H),1.67(d,J=1.7Hz,3H),1.62(s,3H).

[0412] Example 13: Preparation of 2-amino-1-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (11)

[0413] Referring to the preparation method of Example 1, the title compound 11 was prepared by replacing 2-iodo-4-methoxy-1,3-dimethylbenzene in step 4 with 1-fluoro-4-iodo-2-methoxy-3,5-dimethylbenzene.

[0414] LC-MS: m / z=413[M+H] + .

[0415] 1 H NMR (400MHz, CHCl3-d) δ9.40 (s, 1H), 7.00 (s, 1H), 6.97 (s, 1H), 6.93 (s, 2H), 5.95 (s, 2H), 3.62 (d, J = 1.3Hz, 3H), 1.94 (s, 3H), 1.91 (s, 3H).

[0416] Example 14: Preparation of 2-amino-1-(4-bromo-3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (12)

[0417] Step 1: Preparation of 4-bromo-3-((4-bromo-3-methoxy-2,6-dimethylphenyl)amino)-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (12a)

[0418] 4-Bromo-3-((3-methoxy-2,6-dimethylphenyl)amino)-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (1d) (7.84 g, 19.4 mmol) was dissolved in acetic acid (100 mL) at room temperature. Pyridine tribromide (6.40 g, 20.0 mmol) was added and stirred for 1 hour. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 100:1-5:1) to obtain 3.20 g of the title compound as a yellow solid in a 34.1% yield.

[0419] LC-MS: m / z=485[M+H] + .

[0420] Step 2: Preparation of 2-amino-1-(4-bromo-3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (12b)

[0421] Malononitrile (0.956 g, 14.4 mmol) and potassium tert-butoxide (1.53 g, 15.9 mmol) were added to ethylene glycol dimethyl ether (50 ml) at room temperature and stirred for 1 hour. 4-Bromo-3-((4-bromo-3-methoxy-2,6-dimethylphenyl)amino)-1-methyl-6-(trifluoromethyl)pyridin-2(1H)-one (3.50 g, 7.20 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (527 mg, 0.720 mmol) were added. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 100:1-5:2) to obtain 2.00 g of the title compound as a yellow solid, in a yield of 59.0%.

[0422] LC-MS: m / z=470[M+H] + .

[0423] Step 3: Preparation of 2-amino-1-(4-bromo-3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (12c)

[0424] 2-Amino-1-(4-bromo-3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonitrile (1.40 g, 3.60 mmol) was dissolved in concentrated sulfuric acid (10 ml) at room temperature and stirred for 4 hours. The mixture was poured into ice water and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.40 g of the title compound as a yellow solid in a yield of 79.1%.

[0425] LC-MS: m / z=488[M+H] + .

[0426] Step 4: Preparation of 2-amino-1-(4-bromo-3-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (12)

[0427] 2-Amino-1-(4-bromo-3-methoxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (1.40 g, 2.90 mmol) was dissolved in dichloromethane (50 mL) at 0°C. Boron tribromide (15 mL, 15.0 mmol, 1 M solution in DCM) was added dropwise and stirred at room temperature for 2 hours. Methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (Daisogei 30 mm × 250 mm, C18, 10 μm 100A column, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to afford 700 mg of the title compound as a white solid in a 51.5% yield.

[0428] LC-MS: m / z=474[M+H] + .

[0429] 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 7.03 (s, 2H), 6.68 (s, 2H), 3.43 (s, 3H), 1.77 (d, J = 4.0Hz, 6H).

[0430] Example 15: Preparation of 2-amino-1-(2-chloro-3-hydroxy-6-methylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (13)

[0431] Referring to the preparation method of Example 1, the title compound 13 was prepared by replacing 2-iodo-4-methoxy-1,3-dimethylbenzene in step 4 with 2-chloro-3-iodo-1-methoxy-4-methylbenzene.

[0432] LC-MS: m / z=415[M+H] + .

[0433] 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),7.44(s,1H),7.13(d,J=8.5Hz,1H),7.07–6.92(m,3H),6.69(s,2H),3.43(s,3H),1.85(s,3H).

[0434] Example 16: Preparation of 2-amino-1-(6-chloro-3-hydroxy-2-methylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (14)

[0435] Referring to the preparation method of Example 1, the title compound 14 was prepared by replacing 2-iodo-4-methoxy-1,3-dimethylbenzene in step 4 with 1-chloro-2-iodo-4-methoxy-3-methylbenzene.

[0436] LC-MS: m / z=415[M+H] + .

[0437] 1 H NMR (400MHz, DMSO-d6) δ9.49 (s, 1H), 7.45 (s, 1H), 7.31 (d, J = 8.4Hz, 1H), 7.02 (s, 2H), 6.77 (d, J = 8.4Hz, 1H), 6.68 (s, 2H), 3.43 (s, 3H), 1.80 (s, 3H).

[0438] Example 17: Preparation of 2-amino-1-(6-cyclopropyl-3-hydroxy-2-methylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (15)

[0439] Referring to the preparation method of Example 1, the title compound 15 was prepared by replacing 2-iodo-4-methoxy-1,3-dimethylbenzene in step 4 with 1-cyclopropyl-2-iodo-4-methoxy-3-methylbenzene.

[0440] LC-MS: m / z=421[M+H] + .

[0441] 1 H NMR (400MHz, DMSO-d6) δ9.45(s,1H),7.45(s,1H),6.99(s,2H),6.85(d,J=8.4Hz,1H),6.76(d ,J=8.4Hz,1H),6.46(s,2H),3.43(s,3H),2.67–2.43(m,1H),1.68(s,3H),0.48–0.41(m,4H).

[0442] Example 18: Preparation of 2-amino-1-(3-chloro-5-hydroxy-2,6-dimethylphenyl)-6-methyl-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (16)

[0443] Referring to the preparation method of Example 1, the title compound 16 was prepared by replacing 2-iodo-4-methoxy-1,3-dimethylbenzene in step 4 with 1-chloro-3-iodo-5-methoxy-2,4-dimethylbenzene.

[0444] LC-MS: m / z=429[M+H] + .

[0445] 1 H NMR (400MHz, DMSO-d6) δ9.91(s,1H),7.47(s,1H),7.14(s,2H),6.74(d,J=8.2Hz,1H),6.62(s,2H),3.43(s,3H),1.68(d,J=1.7Hz,3H),1.62(s,3H).

[0446] Example 19: Preparation of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-(methyl-d3)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (17)

[0447] Referring to the preparation method of Example 1, the title compound 17 was prepared by replacing iodomethane in step 1 with iodomethane-d3.

[0448] LC-MS: m / z=398[M+H] + .

[0449] 1 H NMR (400MHz, DMSO-d6) δ9.40(s,1H),7.44(s,1H),7.01(s,2H),6.97(d,J=8.4Hz,1H),6.84(d,J=8.4Hz,1H),6.47(s,2H),1.76(s,3H),1.67(s,3H).

[0450] Example 20: Preparation of 2-amino-6-(2-(dimethylamino)ethyl)-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (18)

[0451] Referring to the preparation method of Example 1, the title compound 18 was prepared by replacing iodomethane in step 1 with N,N-dimethylaminoethyl bromide hydrobromide, and replacing 2-iodo-4-methoxy-1,3-dimethylbenzene in step 4 with 1-fluoro-3-iodo-5-methoxy-2,4-dimethylbenzene.

[0452] LC-MS: m / z=470.1 [M+H]+.

[0453] 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),7.88(s,1H),7.02(s,2H),6.98(s,2H),6.78(d,J=11.1Hz, 1H), 4.31–4.05 (m, 2H), 2.18 (t, J = 5.4Hz, 2H), 1.96 (s, 6H), 1.67 (d, J = 1.7Hz, 3H), 1.63 (s, 3H).

[0454] Example 21: Preparation of 2-amino-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-6-(2-(methylamino)ethyl)-7-oxo-5-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (19)

[0455] Referring to the preparation method of Example 1, the title compound 19 was prepared by replacing iodomethane in step 1 with tert-butyl (2-chloroethyl)(methyl)carbamate, and replacing 2-iodo-4-methoxy-1,3-dimethylbenzene in step 4 with 1-fluoro-3-iodo-5-methoxy-2,4-dimethylbenzene.

[0456] LC-MS: m / z = 456.1 [M+H] + .

[0457] 1 HNMR(400MHz,DMSO-d6)δ7.90(s,1H),7.03(s,4H),6.82(d,J=11.1Hz,1H),4.12(t,J =5.2Hz,2H),2.42(t,J=5.2Hz,2H),2.13(s,3H),1.68(d,J=1.8Hz,3H),1.64(s,3H).

[0458] Biological tests

[0459] Test Example 1: PKMYT1 Enzyme Experiment

[0460] Experimental materials: Compounds of the present invention, PKMYT1 (Carna, 05-176), ATP (Promega, V9102), DTT (Sigma, 646563), ADP-Glo™ (Promega, V9102), Inactive CDK1 (Signalchem, C22-14G), DTT, HEPES, MgCl2, BRIJ-35, EGTA (Sigma).

[0461] Experimental steps:

[0462] 1.1 Reagent Preparation

[0463] 1× Kinase Reaction Buffer:

[0464] To prepare 1 mL of kinase reaction buffer, dilute the stock solutions of 1M DTT, 1M HEPES, 1M MgCl2, 10% BRIJ-35(%), and 1M EGTA 500X, 20X, 100X, 1000X, and 1000X, respectively, to a final concentration of 2mM DTT, 50mM HEPES, 10mM MgCl2, 0.01% BRIJ-35(%), and 1mM EGTA. Then, add 2uL of DTT, 50uL of HEPES, 10uL of MgCl2, 1uL of BRIJ-35(%), and 1uL of EGTA buffer, respectively. Finally, add 936uL of water and mix thoroughly.

[0465] Preparation of the working solution of the test compound: Add the test compound to DMSO and shake to dissolve it, and prepare a stock solution with a concentration of 10 mM for use.

[0466] 1.2 Experimental Methods

[0467] Prepare the buffer as described above. Using an Echo 655, transfer 50 nL of the prepared test compound working solution to each well of the reaction plate. Seal the plate with a sealing film and centrifuge at 1000 g for 1 minute. Prepare 2× kinase reaction buffer (5 ng / μL) using 1× kinase reaction buffer. Add 2.5 μL of 2× kinase reaction buffer to each well of the reaction plate. Seal the plate with a sealing film and centrifuge at 1000 g for 30 seconds. Incubate at room temperature for 10 minutes. Prepare a 2× kinase substrate mixture of Unactive CDK1 (0.02 ng / μL) and ATP (400 μM) using 1× kinase reaction buffer. Add 2.5 μL of the 2× kinase substrate and ATP mixture to the reaction plate and centrifuge at 1000 g for 30 seconds to initiate the reaction. Seal the plate with a sealing film and allow the kinase reaction to proceed at room temperature for 120 minutes. Add 4 μL of ADP-Glo ​​reagent and incubate at room temperature for 60 minutes. Add 8 μL of kinase detection reagent and incubate at room temperature for 60 minutes. Luminescence signal values ​​were read using Envision (2104) multi-function plate reader.

[0468] 1.3 Data Analysis

[0469] The % inhibition rate is calculated as follows: Inhibition % = 100 - (Signal cmpd - Signal Ave_PC) / (Signal Ave_VC - Signal Ave_PC) × 100

[0470] Signal cmpd: Chemiluminescence value of each concentration of compound

[0471] SignalAve_PC: average value of system chemiluminescence value

[0472] SignalAve_VC: average value of negative control chemiluminescence value

[0473] Computing IC 50 , draw the compound effect dose curve:

[0474] IC was calculated by fitting the percent inhibition values ​​and logarithms of compound concentrations to a nonlinear regression (dose response - variable slope) using Graphpad 6.0. 50 .

[0475] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0476] X: Logarithmic value of inhibitor concentration; Y: Percentage of inhibition rate

[0477] Table 1 provides the in vitro enzymatic activities (IC50 ).

[0478] In Table 1, the PKMYT1 in vitro enzymatic activity values ​​of the compounds are shown as follows: A refers to IC 50 <10nM; B refers to 10nM <IC 50 <100nM; C refers to 100nM <IC 50 <1000nM; D refers to IC 50 >1000nM.

[0479] Table 1. Enzymatic activity of the compounds of the present invention against PKMYT1

[0480] Conclusion: The compounds of the present invention have good inhibitory effects on the enzymatic activity of PKMYT1.

[0481] Experimental Example 2: OVCAR3 cell anti-proliferation experiment

[0482] Experimental materials: compounds of the present invention, RPMI1640 medium (Invitrogen, A10491-01), fetal bovine serum (Gibco, 10099141), human insulin (aladdin, I302196), penicillin / streptomycin antibiotics (Invitrogen, 15140122), CelltiterGlo assay kit (CTG) (Promega, G7573), OVCAR3 cell line (ATCC, HTB-161TM).

[0483] 2.1 Experimental methods

[0484] On day 1, add 45 μL of the cell suspension to each well of a 384-well plate, with 250 viable cells per well. Add 2 μL of the test compound working solution to 198 μL of culture medium for a 100-fold dilution. Then, use a dispenser to serially dilute the compound in culture medium three-fold, using 9+0 concentrations, starting at 100 μM. Add 5 μL of the compound diluted in the middle of the culture medium to 45 μL of cells at the corresponding position in the 384-well plate, setting up duplicate wells. Incubate the cell plates in a 37°C, 5% CO2 incubator for 7 days.

[0485] Then, Promega CellTiter-Glo assay was performed. The cell plate was removed and equilibrated at room temperature for 30 minutes. 20 μL of CTG was added to each well, mixed by vortexing, and incubated at room temperature for 10 minutes. Luminescence was read using a Biotek (Cytation 3) multi-label analyzer.

[0486] 2.2 Data Analysis

[0487] The inhibition rate is calculated as follows: Inhibition % = 100 - (Signal cmpd - Signal Ave_PC) / (Signal Ave_VC - Signal Ave_PC) × 100

[0488] Signal cmpd: Chemiluminescence value of each concentration of compound

[0489] SignalAve_PC: average value of system chemiluminescence value

[0490] SignalAve_VC: average value of negative control chemiluminescence value

[0491] Computing IC 50 , draw the compound effect dose curve:

[0492] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0493] X: logarithmic value of compound concentration; Y: percentage of inhibition rate.

[0494] Table 2 provides the inhibitory activity of the compounds of the present invention on OVCAR3 cell proliferation.

[0495] In Table 2, the inhibitory activity values ​​of the compounds on OVCAR3 cell proliferation are shown as follows: A refers to IC 50 <100nM; B refers to 100nM <IC 50 <1000nM; C refers to 1000nM <IC 50 <10000nM; D refers to IC 50 >10000nM.

[0496] Table 2. Inhibitory activity of the compounds of the present invention on OVCAR3 cell proliferation

[0497] Conclusion: The compounds of the present invention have good anti-proliferative activity against OVCAR3 cells.

[0498] Test Example 3: WEE1 Enzyme Experiment

[0499] Experimental materials: compound of the present invention, WEE1 (BPS, 40412), ATP (Promega, V9103), HEPES (Beyotime, C0217), MgCl2 (Sigma, M1028), MnCl2 (Sigma, M1787), PEG20000 (Sigma, 95172-250G-F), Na3VO4 (NEB, P0758S), DTT (Sigma, 646563), ADP-GloTM (Promega, V9103).

[0500] 3.1. Reagent preparation:

[0501] 1× Kinase Reaction Buffer:

[0502] To prepare 1 mL of kinase reaction buffer, use 1M DTT, 1M HEPES, 1M MgCl2, 1MMnCl2, 1mg / mL PEG20000, and 100mM Na3VO4 stock solutions. Dilute the solutions 833.33X, 14.29X, 333.33X, 333.33X, 20X, and 33333.33X, respectively, to a final concentration of 1.2mM DTT, 70mM HEPES, 3mM MgCl2, 3mM MnCl2, 0.05mg / mL PEG20000, and 0.003mM Na3VO4. Then, add 1.2µl of DTT, 70µl of HEPES, 3µl of MgCl2, 3µl of MnCl2, 50µl of PEG20000, and 0.03µl of Na3VO4 buffer, respectively. Finally, add 869.8µl of water and mix thoroughly.

[0503] 3.2 Experimental methods

[0504] Prepare the buffer using the above method and transfer 150 nL of DMSO-diluted compound solution to each well of the reaction plate using an Echo 655. Seal the reaction plate with a sealing film and centrifuge at 1000 g for 1 minute. Prepare 2× kinase reaction buffer (12 nM) using 1× kinase reaction buffer. Add 7.5 μL of 2× kinase reaction buffer to each well of the reaction plate. Seal the plate with a sealing film and centrifuge at 1000 g for 1 minute. Incubate at room temperature for 15 minutes. Prepare 2× kinase substrate ATP (20 uM) using 1× kinase reaction buffer. Add 7.5 μL of 2× kinase substrate reaction buffer to the reaction plate and centrifuge at 1000 g for 1 minute to initiate the reaction. Seal the plate with a sealing film and incubate the kinase reaction at 30°C for 60 minutes. Add 15 μL of ADP-Glo ​​reagent. Incubate at room temperature for 60 minutes. Add 30 μL of kinase detection reagent and incubate at room temperature for 60 minutes. Read the luminescence signal using an Envision (2104) multi-function plate reader.

[0505] 3.3 Data Analysis

[0506] The % inhibition rate is calculated as follows: Inhibition % = 100 - (Signal cmpd - Signal Ave_PC) / (Signal Ave_VC - Signal Ave_PC) × 100

[0507] Signal cmpd: Chemiluminescence value of each concentration of compound

[0508] SignalAve_PC: average value of system chemiluminescence value

[0509] SignalAve_VC: average value of negative control chemiluminescence value

[0510] Computing IC 50 , draw the compound effect dose curve:

[0511] IC was calculated by fitting the percent inhibition values ​​and logarithms of compound concentrations to a nonlinear regression (dose response - variable slope) using Graphpad 6.0. 50 . Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0512] X: Logarithmic value of inhibitor concentration; Y: Percentage of inhibition rate

[0513] Table 3 provides the in vitro enzymatic activities (IC 50 ).

[0514] In Table 3, the WEE1 in vitro enzymatic activity values ​​of the compounds are: A refers to IC 50 <10nM; B refers to 10nM <IC 50 <100nM; C refers to 100nM <IC 50 <1000nM; D refers to IC 50 >1000nM.

[0515] Table 3 Enzymatic activity of the compounds of the present invention against WEE1

[0516] Conclusion: The compounds of the present invention have weak inhibitory effects on WEE1 kinases of the same family and have good enzyme selectivity.

[0517] Experimental Example 4: HCC1569 cell proliferation inhibition experiment

[0518] Experimental materials: compounds of the present invention, RPMI1640 medium (ATCC, 30-2001), fetal bovine serum (Gibco, 10099141), penicillin / streptomycin antibiotics (Invitrogen, 15140122), Celltiter Glo assay kit (CTG) (Promega, G7572), HCC1569 cell line (Kebai, CBP60372).

[0519] 4.1 Experimental methods

[0520] On day 1, use a Multidrop dispenser to dispense 50 μL of cell suspension into a 384-well plate, with 500 viable cells per well. Add the test compound dissolved in DMSO to the 50 μL cells in the 384-well plate using an ultra-micropipette. Start with a concentration of 10,000 nM and perform a three-fold serial dilution, with 9+0 concentrations, in duplicate. Incubate the cell plates at 37°C in a 5% CO2 incubator for 7 days.

[0521] Then, Promega CellTiter-Glo assay was performed. The cell plate was removed and equilibrated at room temperature for 30 minutes. 20 μL of CTG was added to each well, mixed by vortexing, and incubated at room temperature for 10 minutes. Luminescence was read using a Biotek (Cytation 3) multi-label analyzer.

[0522] 4.2 Data Analysis

[0523] The inhibition rate is calculated as follows: Inhibition % = 100 - (Signal cmpd - Signal Ave_PC) / (Signal Ave_VC - Signal Ave_PC) × 100

[0524] Signal cmpd: Chemiluminescence value of each concentration of compound

[0525] SignalAve_PC: average value of system chemiluminescence value

[0526] SignalAve_VC: average value of negative control chemiluminescence value

[0527] IC was calculated by fitting the percent inhibition values ​​and logarithms of compound concentrations to a nonlinear regression (dose response - variable slope) using Graphpad 6.0. 50 . Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0528] X: logarithmic value of compound concentration; Y: percentage of inhibition rate.

[0529] Table 4 provides the inhibitory activity of the compounds of the present invention on HCC1569 cell proliferation. In Table 4, the inhibitory activity values ​​of the compounds on HCC1569 cell proliferation are: A refers to IC 50 <100nM; B refers to 100nM <IC 50 <1000nM; C refers to 1000nM <IC 50 <10000nM; D refers to IC 50 >10000nM.

[0530] Table 4. Inhibitory activity of the compounds of the present invention on HCC1569 cell proliferation

[0531] Conclusion: The compounds of the present invention have good anti-proliferative activity against HCC1569 cells.

[0532] Test Example 5: Liver microsome metabolic stability experiment

[0533] Experimental Materials:

[0534] 5.1 Experimental methods

[0535] Transfer 25 μL of NADPH (10 mM) or phosphate buffered saline (100 mM, pH 7.4) to the liver microsome incubation system and add 2 μL of the test compound or verapamil at a concentration of 200 μM. For NADPH-supplemented samples, prepare in duplicate; for NADPH-negative samples, prepare in single replicate. At 0, 15, 30, 45, and 60 minutes, a 50 μL sample of the suspension was taken and quenched with 200 μL of acetonitrile containing labetalol at a final concentration of 200 nM. The sample was mixed and centrifuged at 4000 rpm for 30 minutes. 100 μL of the supernatant was added to 100 μL of pure water, vortexed, and centrifuged for 5 minutes before analysis by HPLC-MS / MS to determine the compound content.

[0536] 5.2 Data Analysis

[0537] All data calculations were performed using Microsoft Excel. Peak areas were determined by extracting ion spectra. The in vitro half-life (t 1 / 2 ).

[0538] In vitro half-life (t 1 / 2 ) is calculated by slope: in vitro t 1 / 2 =0.693 / k, where k is the elimination rate constant.

[0539] In vitro clearance Cl int (Unit: μL / min / mg) Calculation: In vitro Cl int =(0.693 / t 1 / 2 )×(incubation volume / protein content).

[0540] The metabolic activity of the compounds of the present invention on liver microsomes was determined by the above experimental method. The data of the metabolic activity of the compounds on liver microsomes in vitro are shown in Table 5.

[0541] Table 5. Liver microsomal metabolic activity of the compounds of the present invention

[0542] Conclusion: The compounds of the present invention exhibit good metabolic stability in mouse, rat and human liver microsomes in vitro.

[0543] Test Example 6: Hepatocyte metabolic stability experiment

[0544] Hepatocytes are stored in liquid nitrogen. Specific information is shown in the table below:

[0545] Reagent Information:

[0546] Preparation of compound working solution: Prepare high concentration stock solution of test substance and reference substance verapamil powder with DMSO, and dilute with DMSO to 100 μM working solution before use. The final concentration of test substance and reference substance verapamil is 1 μM.

[0547] 6.1 Experimental Methods

[0548] Prepare several 96-well sample precipitation plates, designated as TO, T15, T30, T60, T90, TO-MC, T90-MC, and blank matrix. Pre-warm the thawing medium (mixed with 32.695 mL Williams E medium, 13.5 mL Isotonic Percoll, 500 μL GlutaMAX, 750 μL HEPES, 2.5 mL fetal bovine serum, 50 μL human recombinant insulin, and 5 μL 10 mM dexamethasone) and incubation medium (mixed with 49.5 mL Williams E medium and 0.5 mL glutaMAX) in a 37°C water bath. Remove the frozen hepatocytes from the liquid nitrogen tank and immediately immerse them in a 37°C water bath (approximately 90 seconds). Once the frozen portions have thawed and loosened, pour them into centrifuge tubes containing 40 mL of thawing medium. Gently invert the tubes to resuspend the cells in the thawing medium. Centrifuge at 100×g for 5 minutes at room temperature, remove the supernatant, resuspend the hepatocytes with an appropriate volume of incubation medium, and calculate the cell viability by trypan blue staining. 6 For the culture medium control group, 198 μL of incubation medium without hepatocytes was added to the T0-MC and T90-MC incubation plates. All incubation plates were pre-incubated in a 37°C incubator for 10 minutes.

[0549] Add 2 μL of the test article and verapamil working solution, mix thoroughly, and immediately place the plate on a plate shaker in the incubator. Start the timer to initiate the reaction. Prepare two replicates for each compound at each time point. Incubate at 37°C, saturated humidity, and 5% CO2.

[0550] In the test system, the final concentration of the test substance was 1 μM, the final concentration of the control substance was 3 μM, and the final concentration of the hepatocytes was 0.5×10 6The total organic solvent concentration was 0.96%, including 0.1% DMSO. At the end of the incubation period, the plates were removed and 25 μL of the mixture of compound and control compound with cells was added to a sample plate containing 400 μL of acetonitrile stop solution (containing 200 nM labetalol, 100 nM tolbutamide, and 100 nM ketoprofen as internal standards). For the blank sample plate, 25 μL of the incubation medium without hepatocytes was added directly. All sample plates were sealed and shaken on a plate shaker at 600 rpm for 10 minutes, followed by centrifugation at 3220 × g for 20 minutes. The supernatants of the test and control samples were diluted with ultrapure water at a ratio of 1:3. All samples were mixed and analyzed by LC / MS / MS.

[0551] 6.2 Data Analysis

[0552] All data calculations were performed using Microsoft Excel. Peak areas were determined by extracting ion spectra. The in vitro half-life (t 1 / 2 ).

[0553] In vitro half-life (t 1 / 2 ) is calculated by slope: in vitro t 1 / 2 =-(0.693 / k), where k is the slope of the curve.

[0554] In vitro clearance (μL / min / 10 6 cells) were calculated using the following formula: int = kV / NV = incubation volume per well (0.2 mL); N = number of cells per well (0.1 × 10 6 cells);

[0555] k is the slope of the curve.

[0556] The in vitro hepatocyte metabolic properties of the compounds of the present invention were determined by the above experimental method. The results are shown in Table 6.

[0557] Table 6. In vitro hepatocyte metabolic activity data of the compounds of the present invention

[0558] Conclusion: The compound of the present invention has good metabolic stability in hepatocytes.

[0559] Test Example 7: Cytochrome P450 isoenzyme inhibition study

[0560] Experimental Materials:

[0561] Liver microsomes:

[0562] Reagents:

[0563] 7.1 Reagent Preparation

[0564] 7.1.1. Preparation of PBS

[0565] Dissolve 8.71 g of K2HPO4 in 950 mL of water, adjust the pH to 7.4 with HCl, and then make up the volume to 1000 mL with water. Pass through a 0.45 μm filter and store at 4°C for later use.

[0566] 7.1.2. Preparation of internal standard solution

[0567] Terfenadine and tolbutamide were prepared in DMSO to a 1 mg / mL solution, and then diluted in acetonitrile to 5 and 10 ng / mL solutions.

[0568] 7.1.3. Preparation of positive control working solution

[0569] 7.1.4. Preparation of substrate working solution

[0570] 7.1.5 Preparation of Liver Microsome Working Solution

[0571] Preheat liver microsomes in a 37°C water bath.

[0572] 7.1.6. Preparation of NADPH working solution

[0573] NADPH was prepared into a 5 mM solution in PBS.

[0574] 7.1.7. Preparation of compound working solution

[0575] Compounds were prepared as 50 mM stock solutions and subsequently diluted to 2 mM working solutions.

[0576] 7.2 Experimental Methods

[0577] Prepare the reagents using the above method. Add 238.5 μL of liver microsome working solution to a 1.1 mL centrifuge tube, then add 1.5 μL of the test compound or control working solution or DMSO, mix several times with a pipette, and pre-incubate in a 37°C water bath shaker for 5 minutes. After pre-incubation, add 60 μL of NADPH working solution, mix several times with a pipette, and incubate in a 37°C water bath shaker for 10 minutes. After incubation, immediately add 500 μL of internal standard solution to quench and vortex for 1 minute. Centrifuge all samples at 4°C, 4000 rpm, for 15 minutes. Take 300 μL of supernatant for LC-MS / MS analysis.

[0578] 7.3 Data Analysis

[0579] Inhibition percentage (%) and IC50 The CYP inhibitory activity of the compounds of the present invention was determined by the above experimental method. The in vitro CYP inhibitory activity of the compounds is shown in Table 7.

[0580] Table 7. CYP inhibitory activity of the compounds of the present invention

[0581] Conclusion: The compounds of the present invention have no significant inhibitory effect on any subtype of CYP enzymes.

[0582] Test Example 8: Pharmacokinetic Study in Mice

[0583] 7-8 week old male ICR mice were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. and housed in an SPF environment at 20-26°C (with a daily temperature fluctuation of no more than 4°C), 40-70% relative humidity, and 12h / 12h alternating lighting. Animals underwent a 3-5 day acclimatization period. Orally administered animals were fasted overnight one day prior to the experiment. Each test compound was divided into an IV (intravenous administration, n=3) and a PBO (oral gavage, n=3) group. Vehicle: 20% cyclodextrin in normal saline. Mice were dosed iv at 2 mg / kg and po at 10 mg / kg. For the iv group, the solution was prepared by weighing 2 mg of the compound, dissolving it in 150 μL of DMSO, vortexing / sonicating to disperse it, then diluting the volume to 5 mL with 20% cyclodextrin and mixing thoroughly to obtain 5 mL of a working solution at a concentration of 0.4 mg / mL. For the po solution, 3 mg of the compound was dissolved in 90 μL of DMSO, vortexing / sonicating to disperse it, then diluting the volume to 3 mL with 20% cyclodextrin and mixing thoroughly to obtain 3 mL of a working solution at a concentration of 1 mg / mL. Samples were collected at 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours for the oral group and at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours for the intravenous group.

[0584] All samples were centrifuged at 3000 rpm for 10 minutes in a Sorvall ST 8R high-speed low-temperature centrifuge within 60 minutes of blood collection. The upper plasma layer was collected and frozen in a -20°C refrigerator for later use. The compound concentration in the sample was determined using LC-MS / MS analysis. MAS Studio (V1.3.1 stable) software was used to calculate and obtain the plasma concentration-time curve of the compound in mice, as well as the main PK parameter: AUC 0-t 、C max 、T max 、T 1 / 2 and F%,F%=(AUC po ×Dose iv ) / (AUCiv ×Dose po The pharmacokinetic parameters of the compounds of the present invention in mice are shown in Table 8 below.

[0585] Table 8. Pharmacokinetic results in mice

[0586] Conclusion: The compound of the present invention has good pharmacokinetic properties in mice.

[0587] Experimental Example 9: Pharmacodynamics of the compounds of the present invention on the mouse OVCAR3-CDX model

[0588] Female NOG mice aged 5-6 weeks were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. and housed in an SPF environment. After one week of adaptive feeding, they were used to construct a tumor model. Human ovarian cancer cells OVCAR3 were purchased from ATCC and cultured in complete culture medium RPMI-1640 (Gibco, Catalog No. C11875500BT) + 20% FBS (Gibco, Catalog No. 10099141) + 0.01 mg / mL human insulin (Sigma, Catalog No. I9278). After expansion, the cells were collected by centrifugation and a cell suspension was prepared with physiological saline. The suspension was mixed with Matrigel (Corning, Catalog No. 354234) at a ratio of 1:1 and inoculated subcutaneously into the right forelimb of the nude mouse using a pre-cooled syringe. The inoculation volume for each animal was 100 μL, and the cell inoculation amount for each animal was 5×10 6 When the tumor grows to about 150-200 mm 3 Animals were randomly divided into a control group (blank vehicle control group), an oral administration group (compound 5 mg / kg group and compound 15 mg / kg group), a Gem administration group (gemcitabine 20 mg / kg group), and a compound and Gem combination administration group (compound 1-1 15 mg / kg + Gem 20 mg / kg), with 6 animals in each group. Starting from the day of grouping (D1), the oral administration group received the compound twice daily for 3 consecutive weeks; the Gem administration group received intraperitoneal injections of gemcitabine (Gem, purchased from MCE, Cat. No. 262662) once a week for 3 consecutive weeks, with a dosing volume of 10 mL / kg.

[0589] Compound preparation method:

[0590] Control group: Take 0.36 mL of DMSO, dilute to 12 mL with 0.5% methylcellulose, and vortex to mix to prepare the control group solution.

[0591] Oral administration group: 18 mg of the test compound was weighed and fully dissolved in 360 μL DMSO, and the volume was adjusted to 12 mL with 0.5% methylcellulose to prepare a 1.5 mg / mL solution; the compound was prepared twice a week, 12 mL of solution each time, and stored in a refrigerator at 4°C.

[0592] Gem administration group (intraperitoneal injection): 16 mg of Gem compound was weighed and fully dissolved in normal saline, the volume was adjusted to 8 mL, and a 2 mg / mL solution was prepared; the compound was prepared once a week, 8 mL of solution each time, and stored in a 4°C refrigerator.

[0593] During treatment, the patient was weighed 3 times a week and the tumor was measured 2 times. The long diameter L and short diameter W of the tumor were measured with an electronic vernier caliper, and the formula V = L × W was used. 2 / 2, calculate the tumor volume V. Relative tumor proliferation rate T / C% = T RTV / C RTV ×100%(T RTV =RTV of treatment group; C RTV =RTV of the vehicle control group). Tumor growth inhibition (TGI) was calculated according to the formula 1-T / C%, where T is the average tumor volume of the treatment group and C is the average tumor volume of the control group. Relative tumor volume (RTV) was calculated according to RTV=V t / V0 calculation, V t =V0: tumor volume at the end of dosing, V0: tumor volume at the start of the experiment. After dosing, the animals were euthanized. Changes in tumor volume and body weight are shown in Table 9.

[0594] Table 9. Changes in tumor volume and body weight of animals in OVCAR3 model after 21 days of compound treatment

[0595] ( n=6, **P<0.01 vs vehicle)

[0596] Results: The tumor growth curve of the OVCAR3 model after 21 days of treatment with the compound of the present invention is shown in Figure 1, and the changes in animal body weight during the administration period are shown in Figure 2. These results indicate that the compound of the present invention can significantly inhibit the growth of the OVCAR3-induced mouse tumor model and, when used in combination with gemcitabine, exhibits a good synergistic anti-tumor effect.

Claims

1. A compound represented by the general formula (I) or its tautomer, meso form, racemate, enantiomer, diastereomer, or a mixture thereof, or its deuterated form, or a pharmaceutically acceptable salt, Wherein: is a single bond or a double bond; X and Y are each independently selected from N, O, S, C, NR 7 , CR 7 or CR 7a R 7b ; R 1 Selected from hydrogen, halogen or -NR 8a R 8b ; R 2 、R 3 、R 4 and R 5 each independently selected from hydrogen, halogen, amino, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NR 9a R 9b , -SR 9 , -OR 9 ; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R 6 selected from hydrogen, halogen, amino, nitro, hydroxy, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 ; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from deuterium, halogen, amino, NR 9a R 9b 、nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R 7a , R 7b and R 7 are each independently selected from hydrogen, halogen, amino, -NR 9a R 9b , nitro, hydroxyl, mercapto, cyano, oxo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R 7a With R 7b The carbon atom to which it is attached forms an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group is optionally selected from halogen, amino, nitro, cyano, hydroxyl, thiol, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 8a and R 8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -COOR 9 , -C(O)R 10 , -S(O) p R 10 , -C(O)NR 9a R 9b , -S(O) p NR 9a R 9b , oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or, R 8a and R 8b together with the nitrogen atom to which it is attached form a heterocyclic group or heteroaryl, and the heterocyclic group or heteroaryl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R 9a 、R 9b and R 9 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or, R 9a and R 9b together with the nitrogen atom to which it is attached form a heterocyclic group or heteroaryl, and the heterocyclic group or heteroaryl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R 10 selected from hydrogen, halogen, amino, nitro, hydroxy, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; p is 1 or 2.

2. The compound represented by the general formula (I) according to claim 1, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its deuterated compound, or a pharmaceutically acceptable salt, Wherein: is a double bond; X and Y are each independently selected from N or CR 7 ; R 1 Selected from hydrogen, halogen or -NR 8a R 8b ; R 2 、R 3 、R 4 and R 5 each independently selected from hydrogen, halogen, amino, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -NR 9a R 9b , -SR 9 , -OR 9 ; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R 6 is selected from halogen, amino, nitro, hydroxyl, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from deuterated, halogen, -NR 9a R 9b , nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 7 selected from hydrogen, halogen, amino, -NR 9a R 9b , nitro, hydroxy, mercapto, cyano, oxo, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -COOR 9 , -C(O)R 10 , -S(O) p R 10 , -C(O)NR 9a R 9b , -S(O) p NR 9a R 9b , -NR 9a R 9b , -SR 9 , -OR 9 , oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R 8a and R 8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -COOR 9 , -C(O)R 10 , -S(O) p R 10 , -C(O)NR 9a R 9b , -S(O) p NR 9a R 9b , oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; or, R 8a and R 8b together with the nitrogen atom to which it is attached form a heterocyclic group or heteroaryl, and the heterocyclic group or heteroaryl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R 9a , R 9b and R 9 Each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or, R 9a With R 9b Together with the nitrogen atom to which it is attached, it forms a heterocyclic group or a heteroaryl group, wherein the heterocyclic group or the heteroaryl group is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; R 10 selected from hydrogen, halogen, amino, nitro, hydroxy, mercapto, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; p is 1 or 2.

3. The compound of the general formula (I) according to claim 2, or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IA) or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: Among them, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 as defined in claim 2 4. The compound of the general formula (I) as defined in claim 2, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: Among them, X, Y, R 2 , R 3 , R 4 , R 5 and R 6 as defined in claim 2.

5. The compound of the general formula (I) according to claim 2, or its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or its deuterated form, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IIA), or its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or its deuterated form, or a pharmaceutically acceptable salt thereof: Among them, X, Y, R 2 , R 3 , R 4 , R 5 and R 6 as defined in claim 2 6. A compound of the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, which is a compound of the general formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: Wherein: X 1 and Y 1 each independently selected from N or CR 7 ; R 2 、R 3 、R 4 、R 5 、R 6 、R 7 as defined in claim 2.

7. A compound of the general formula (I) as defined in any one of claims 1 to 6, or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 7 is independently selected from hydrogen, halogen, amino, hydroxy, mercapto, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NR 9a R 9b , where the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, -COOR 9 , -C(O)R 10 , -S(O) p R 10 , -C(O)NR 9a R 9b , -S(O) p NR 9a R 9b , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl; R 9 、R 9a 、R 9b 、R 10 、p as defined in claim 2.

8. A compound of the general formula (I) as defined in any one of claims 1 to 6, or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein, R 7 selected from hydrogen, a halogen, -NR 9a R 9b , an oxo group, C 1-6 alkyl, C 1-6 haloalkyl; R 9a and R 9b each independently selected from hydrogen and C 1-6 alkyl; or R 9a and R 9b together with the nitrogen atom connected thereto form a 4- to 6-membered heterocyclic group.

9. A compound of the general formula (I) as defined in any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein, R 7 selected from C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, said 5- to 6-membered heteroaryl optionally substituted with C 1-6 alkyl group.

10. A compound of the general formula (I) according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (IVA), general formula (IVB) or general formula (IVC), or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: Wherein, R 7a and R 7b each independently selected from hydrogen, halogen, -NR 9a R 9b , cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, said 5- to 6-membered heteroaryl being optionally substituted with C 1-6 alkyl; R 9a and R 9b each independently selected from hydrogen and C 1-6 alkyl; or R 9a and R 9b together with the nitrogen atom connected thereto form a 5- to 7-membered heterocyclic group; R 2 、R 3 、R 4 、R 5 、R 6 as defined in claim 2.

11. A compound of formula (I) as defined in any one of claims 1 to 10, or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein: R 6 Selected from halogen, amino, nitro, hydroxy, mercapto, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -COOR 9 、-C(O)R 10 、-S(O) p R 10 、-C(O)NR 9a R 9b 、-S(O) p NR 9a R 9b 、-NR 9a R 9b 、-SR 9 、-OR 9 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl is optionally substituted by one or more groups selected from deuterium, halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl; R 9 、R 9a 、R 9b 、R 10 、p is as defined in claim 2.

12. A compound of the general formula (I) as defined in any one of claims 1 to 11, or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein: R 6 selected from C 1-6 alkyl, C 3-6 cycloalkyl; the C 1-6 alkyl is optionally substituted by one or more groups selected from deuterium, halogen, amino, -NR 9a R 9b , cyano; R 9a and R 9b each independently selected from hydrogen and C 1-6 alkyl; Preferably, R 6 is C 1-6 alkyl or C 1-6 deuterated alkyl, and the C 1-6 alkyl is optionally substituted with -NR 9a R 9b , and R 9a and R 9b are each independently selected from hydrogen or C 1-6 alkyl.

13. The compound represented by the general formula (I) according to any one of claims 10 to 12, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its deuterated compound, or a pharmaceutically acceptable salt, wherein: R 7a and R 7b each independently selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 5- or 6-membered heteroaryl, said 5- or 6-membered heteroaryl optionally substituted with C 1-6 alkyl.

14. A compound of the general formula (I) as defined in any one of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 each independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NR 9a R 9b , -SR 9 , -OR 9 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl; R 9 、R 9a 、R 9b 、R 10 、p as defined in claim 2; Preferably, R 2 and R 3 are each independently selected from C 1-6 alkyl.

15. A compound of the general formula (I) according to any one of claims 1 to 14, or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4 and R 5 each independently selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, -NR 9a R 9b , -SR 9 , -OR 9 ; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester group, oxo group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl; R 9 、R 9a 、R 9b 、R 10 、p as defined in claim 2; Preferably, R 4 and R 5 are each independently selected from hydrogen.

16. A compound of the general formula (I) as claimed in any one of claims 1 to 15, or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl; said C 1-6 The alkyl group is optionally substituted with halogen; preferably, R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl.

17. A compound of the general formula (I) as defined in any one of claims 1 to 16, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

18. A method for preparing a compound of the general formula (II) or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by the general formula D-1 or its salt reacts in a solvent, optionally in the presence of a catalyst, to obtain the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its deuterated compound, or a pharmaceutically acceptable salt; Among them, X, Y, R 2 , R 3 , R 4 , R 5 and R 6 as defined in claim 4 19. A method for preparing a compound of formula (III) or a tautomer, meso form, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a deuterated form thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps: The compound represented by the general formula IIId or its salt reacts in a solvent, optionally in the presence of a catalyst, to obtain the compound represented by the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its deuterated compound, or a pharmaceutically acceptable salt; Among them, X, Y, R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 6.

20. A pharmaceutical composition comprising the compound represented by the general formula (I) according to any one of claims 1 to 17, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its deuterated compound, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

21. Use of the compound represented by the general formula (I) according to any one of claims 1 to 17, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its deuterated compound, or a pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 20, in the preparation of a membrane-associated tyrosine / threonine protein kinase 1 (PKMYT1) inhibitor.

22. Use of the compound represented by the general formula (I) according to any one of claims 1 to 17, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or its deuterated compound, or a pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 20, in the preparation of a drug for preventing and / or treating a disease associated with the activity of membrane-associated tyrosine / threonine protein kinase 1 (PKMYT1), preferably a tumor disease, such as ovarian cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, colorectal cancer, esophageal cancer, liver cancer, lung cancer, or thyroid cancer.

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