Tricyclic heterocyclic derivatives, their compositions and applications

Abstract

This invention relates to a tricyclic heterocyclic derivative of formulas (IA) and (IB) and compositions thereof, a method for its preparation, and its use as a therapeutic agent.

Description

Technical Field

[0001] This invention relates to tricyclic heterocyclic derivatives as PKMYT1 inhibitors. The invention also relates to methods for preparing tricyclic heterocyclic derivatives and pharmaceutical compositions thereof, and their use in treating diseases associated with PKMYT1 activity, including, for example, cancer and other diseases. Background Technology

[0002] Cell cycle regulation plays a crucial role in the division and growth of both normal and tumor cells. Generally, the cell cycle can be divided into four phases: pre-DNA synthesis (G1 phase), DNA synthesis (S phase), post-DNA synthesis (G2 phase), and mitosis (M phase). The transition from G1 to S phase and from G2 to M phase (mitosis) is a critical stage for DNA damage repair and the complex and active changes in various intracellular substances. Cells establish a series of cell cycle checkpoints throughout these four phases to ensure the integrity of DNA replication and the completion of damage repair (Kevin J. Barnum, 2014). In some cases, if cells enter mitosis with damaged genomic material, cell cycle disturbances, apoptosis, cancer, and other malignant outcomes may occur. Furthermore, since cancer cells also utilize the cell cycle for tumor cell proliferation, the long-term accumulation of unrepaired DNA damage during the G1-S and G2-M phases will lead to mitotic catastrophe and tumor cell death.

[0003] Protein kinase-membrane-bound tyrosine / threonine 1 (PKMYT1) is a cell cycle regulatory protein belonging to the WEE kinase family. PKMYT1 blocks the transition of cells from G2 phase to M phase by negatively regulating the CDK1-Cyclin B complex. During DNA damage repair, PKMYT1 phosphorylates amino acid sites Tyr15 and Thr14 of the CDK1 protein, keeping the CDK1-Cyclin B complex inactive in G2 phase and ultimately preventing cells from entering mitosis (Dongjun Jeong, 2018), providing sufficient time for DNA damage repair. Simultaneously, WEE1 also participates in the phosphorylation of the Tyr15 amino acid site of CDK1. PKMYT1 knockout or inhibition can cause cells to prematurely enter mitosis without completing DNA damage repair, leading to cell death.

[0004] On the other hand, CCNE1 amplification can disrupt the regulation of cell entry into S phase, triggering DNA replication stress and leading to genomic instability. CCNE1 amplification is prevalent in various tumor types, particularly in high-grade serous ovarian cancer, uterine tumors, and gastroesophageal cancer, with an incidence ranging from 5% to 40%. Cyclin E1, encoded by the CCNE1 gene, promotes the transition of the cell cycle from G1 to S phase by binding to and activating cyclin-dependent kinase 2 (CDK2). A CRISPR-based genome screening study found that high expression / amplification of CCNE1 and inhibition of PKMYT1 have a high synthetic lethal effect (David Gallo, 2022). Excessively accelerated cell cycle progression deprives cells of sufficient opportunity to repair DNA damage, leading to cell death. In a normal cell cycle, cyclin E1 levels are tightly regulated, accumulating in G1 / S phase and completely degraded at the end of S phase. Cyclin E1 degradation can be mediated by FBXW7, an E3 ubiquitin ligase (Chien-Hung Yeh, 2018). Loss-of-function mutations in FBXW7 will result in the loss of its ubiquitination function for Cyclin E, preventing Cyclin E from being degraded and thus leading to overexpression.

[0005] Therefore, PKMYT1 inhibitors can be used as a synthetic lethal therapeutic strategy to treat tumors with certain gene mutations. This invention provides compounds, pharmaceutical compositions containing the compounds, methods for preparing the compounds, and methods of using them. The compounds of this invention can be used to inhibit PKMYT1 in cells with CCNE1 amplification, FBXW7 loss-of-function mutations, or other gene alterations that induce DNA replication stress and genomic instability during G1 to S phase progression. The compounds of this invention can be used in subjects who may require treatment for a disease or condition, such as a disease or condition with symptoms of excessive cell proliferation, such as cancer. The PKMYT1 inhibitory activity of the compounds disclosed in this invention can be used to treat subjects requiring cancer treatment. Summary of the Invention

[0006] This invention relates to a compound represented by formulas (IA) and (IB).

[0007]

[0008] Or pharmaceutically acceptable salts, stereoisomers, transisomers, solvates, N-oxides, isotope variants or prodrugs thereof; wherein the variables are as defined in this invention.

[0009] On the other hand, the present invention provides a pharmaceutical composition comprising: a compound of formula (IA) and (IB), or a pharmaceutically acceptable salt thereof, a stereoisomer, a transisomer thereof, a solvate thereof, an N-oxide thereof, an isotope variant thereof, or a prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0010] On the other hand, the present invention provides a method for suppressing PKMYT1, comprising:

[0011] Contact PKMYT1 with compounds of formulas (IA) and (IB), or pharmaceutically acceptable salts, stereoisomers, transisomers, solvates, N-oxides, isotopic variants, or prodrugs thereof.

[0012] On the other hand, the present invention provides a method for treating cancer and other diseases, comprising: administering to a patient a therapeutically effective amount of a compound represented by formula (IA) and (IB), or a pharmaceutically acceptable salt, stereoisomer, transisomer, solvate, N-oxide, isotope variant, or prodrug thereof.

[0013] Details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will become apparent from the specification and claims. Invention Details

[0015] The invention can be more fully understood by referring to the following description, including the definitions and embodiments. Certain features of the compositions and methods of the invention described in different contexts may also be provided in combination in a single aspect. Alternatively, for the sake of brevity, various features of the compositions and methods of the invention described in the context of a single aspect may also be provided individually or in any sub-combination.

[0016] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein, and it should also be understood that the terminology used in the present invention is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention.

[0017] This invention provides a compound represented by formulas (IA) and (IB):

[0018]

[0019] Or a pharmaceutically acceptable salt, stereoisomer, transisomer, solvate, N-oxide, isotopic variant, or prodrug thereof, wherein:

[0020] Ring A is selected from:

[0021]

[0022] X is N or CR3 ;

[0023] Y is N or CR 9 ;

[0024] L is (CR) 10 R 11 ) n NR 12 (CH2CH2) m , or O(CH2CH2) m ;

[0025] n is 1, 2, or 3; m is 0 or 1;

[0026] R is selected from H, D or C1-C6 alkyl and optionally substituted with substituents selected from F, OH or CN;

[0027] R 1 R 2 and R 3 Selected independently from H, D, halogen, CN, SF5, NR C R D OR A C(O)R B C(O)NR C R D C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)ORa OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b ;

[0028] or R 1 and R 2 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl group or a 4-7 membered heterocyclic group, wherein the C3-C7 cycloalkyl group or the 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 independent substituents selected from the following: D, halogen, CN, NO2, oxo, OR a NHOR a C(O)R b C(O)NR c R dC(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b ;

[0029] or R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl group or a 4-7 membered heterocyclic group, wherein the C3-C7 cycloalkyl group or the 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 independent substituents selected from the following: D, halogen, CN, NO2, oxo, OR a NHOR a C(O)R b C(O)NR c Rd C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b ;

[0030] Each R 4 Independently selected from H, D, NH2, CN, C1-C3 alkyl groups optionally substituted with D, halogen or CN;

[0031] Each R 5 Independently selected from H, D, halogen, CN, C1-C6 alkyl group optionally substituted with D, halogen or CN;

[0032] Each R 6 Independently selected from H, D, halogen, CN, ORB SF5, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic group; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic group is optionally substituted by substituents selected from the following: D, halogen, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl;

[0033] Each R 7 Independently selected from H, D, halogens, Me, CF3, OH, OMe, OCF3;

[0034] Each R 8 The alkyl group is independently selected from H, D, CN, SF5, and C1-C6, and is optionally substituted with D, halogen, or CN;

[0035] R 9 Selected from H, D, CN, halogens, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C3-C5 cycloalkyl;

[0036] R 10 and R 11 The groups are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 ynyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 ynyl groups are optionally substituted by 1, 2, or 3 substituents independently selected from: D, CN, halogen, OR. a OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a NR c S(O)2R b , or NR c S(O)2NR c R d ;

[0037] or R 10 and R 11 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl group or a 4-7 membered heterocyclic group, wherein the C3-C7 cycloalkyl group or the 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 independent substituents selected from the following: D, halogen, CN, NO2, oxo, OR a C(O)R b C(O)NRc R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d , or NR c S(O)2NR c R d ;

[0038] R 12 H, D, C1-C3 alkyl groups are optionally replaced by D, OH, halogen, or CN;

[0039] Each R A Independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR aC(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b ;

[0040] Each R B Independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d );

[0041] R C and R D Each of the following groups is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 heterocyclic, phenyl, 5-6 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC(O)NR c R d NR c R d NR c C(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d );

[0042] or R C and R D Together with the N atom attached thereto, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;

[0043] Each R a Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C3-C7 cycloalkyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclic, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3-C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group may optionally be substituted by 1, 2, or 3 substituents independently selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;

[0044] Each R b Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic;

[0045] R c and R d Each of the following groups is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 6- C 10 Aryl, 5-10 heteroaryl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C10 aryl-4-10 heterocyclic group, C6-C 10 aryl-5-10 heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 Aryl, or 5-10 heteroaryl-5-10 heteroaryl; wherein, the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 6- C 10 Aryl, 5-10 heteroaryl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-5-10 heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 The aryl group, or 5-10 heteroaryl group, is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 heteroaryl, C(O)OR a1 C(O)R b1 S(O)2R b1 C1-C4 alkyl-O-C1-C4 alkyl, and C1-C4 alkyl-O-C1-C4 alkyl-O-;

[0046] or R c and R dTogether with the N atom attached thereto, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 heteroaryl, C(O)OR a1 C(O)R b1 S(O)2R b1 C1-C4 alkoxy-C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkoxy;

[0047] Each R e Independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10-membered heteroaryl-C1-C4 alkyl, or 4-10-membered heterocyclic-C1-C4 alkyl;

[0048] Each R f Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl groups, or 4-10 membered heterocyclic groups;

[0049] Each R a1 Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C3-C7 cycloalkyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclic, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3- C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group may optionally be substituted by 1, 2, or 3 substituents independently selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;

[0050] Each R b1Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic.

[0051] In some embodiments, R is selected from H, D, or a C1-C6 alkyl group, optionally substituted with F, OH, or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is a C1-C6 alkyl group, optionally substituted with F, OH, or CN. In some embodiments, R is Me.

[0052] In some implementations, X is N.

[0053] In some implementations, X is CR 3 .

[0054] In some implementation schemes, R 3 Independently selected from H, D, halogens, CN, SF5, NR C R D OR A C(O)R B C(O)NR C R D C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NRc S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0055] In some implementation schemes, R 3 Independently selected from H, D, halogens, CN, SF5, NR C R D OR A C(O)R B C(O)NR C R D C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group; wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R fP(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0056] In some implementations, for example, including but not limited to, R 3 Independently selected from H, D, halogens, CN, SF5, NH2, OH, OCH3, OCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, CH3, CH2CH3, CF3, CH2CF3, C(O)R B , or C(O)NR C R D .

[0057] In some implementations, Y is N.

[0058] In some implementations, Y is CR 9 R 9 Selected from H, D, CN, halogens, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, and C3-C5 cycloalkyl.

[0059] In some implementation schemes, R 9 For H. In some implementations, R 9 For D. In some implementations, R 9 For CN. In some implementations, R 9 It is a halogen (e.g., F, Cl, Br, I). In some embodiments, R 9 It is a C1-C4 alkyl group. In some embodiments, R 9 It is a C1-C4 haloalkyl group. In some embodiments, R 9 It is an OC1-C4 alkyl group. In some embodiments, R 9 It is an OC1-C4 haloalkyl group. In some embodiments, R 9 It is a C3-C5 cycloalkyl group.

[0060] In some implementation schemes, R 1 Independently selected from H, D, halogens, CN, SF5, NR C R D OR A C(O)R B C(O)NR C R D C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NRc )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0061] In some implementations, L is (CR 10 R 11 ) n NR 12 (CH2CH2) m , or O(CH2CH2) m .

[0062] In some implementations, L is (CR 10 R 11 ) n In some implementations, L is CR 10 R 11 In some implementations, L is (CR 10 R 11 2. In some implementations, L is (CR) 10 R 11 3.

[0063] In some implementations, L is NR 12 (CH2CH2) m In some implementations, L is NR. 12 In some implementations, L is NR. 12 CH2CH2.

[0064] In some implementations, L is O(CH2CH2). mIn some implementations, L is O. In some implementations, L is OCH2CH2.

[0065] In some implementation schemes, R 1 Independently selected from H, D, halogens, CN, SF5, NR C R D OR A C(O)R B C(O)NR C R D C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group; wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2Rb NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0066] In some implementation schemes, R 1 Independently selected from H, D, halogens, CN, SF5, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, CH3, CH2CH3, CF3, CH2CF3, C(O)R B C(O)NR C R D In some implementations, R 2 Independently selected from H, D, halogens, CN, SF5, NR C R D OR A C(O)R B C(O)NR C R D C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic groups; wherein, the C1-C6 alkyl group, C3-C6 alkyl group, and C3-C6 alkyl group are used. 10 The cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR)d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0067] In some implementation schemes, R 2 Independently selected from H, D, halogens, CN, SF5, NR C R D OR A C(O)R B C(O)NR C R D C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group; wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally substituted by 1, 2, or 3 substituents independently selected from: D, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R dNR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0068] In some implementations, for example, including but not limited to, R 2 Independently selected from H, D, halogens, CN, SF5, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, CH3, CH2CH3, CF3, CH2CF3, C(O)R B C(O)NR C R D .

[0069] In some implementation schemes, R 1 and R 2 Together with the carbon atom to which it is attached, a C3-C7 cycloalkyl group is formed, optionally substituted by 1, 2, 3, or 4 independent substituents selected from the following: D, halogen, CN, NO2, oxo, OR. aNHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0070] In some implementation schemes, R 1 and R 2 Together with the carbon atom it is attached to, a 4-7 membered heterocyclic group is formed, which may optionally be substituted by 1, 2, 3, or 4 independent substituents selected from the following: D, halogen, CN, NO2, oxo, OR. a NHOR aC(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0071] In some implementation schemes, R 2 and R 3 Together with the carbon atom to which it is attached, a C3-C7 cycloalkyl group is formed, optionally substituted by 1, 2, 3, or 4 independent substituents selected from the following: D, halogen, CN, NO2, oxo, OR. a NHOR a C(O)R bC(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0072] In some implementation schemes, R 2 and R 3 Together with the carbon atom it is attached to, a 4-7 membered heterocyclic group is formed, which may optionally be substituted by 1, 2, 3, or 4 independent substituents selected from the following: D, halogen, CN, NO2, oxo, OR. a NHOR a C(O)R b C(O)NR cR d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0073] In some implementation schemes, each R 4 It is independently selected from H, D, NH2, or CN. In some embodiments, R 4 For H. In some implementations, R 4 For D. In some implementations, R 4 For NH2. In some implementations, R 4 For CN.

[0074] In some implementation schemes, R4 The C1-C3 alkyl group is optionally substituted with D, halogen, or CN. In some embodiments, R 4 For Me. In some implementations, R 4 For CD3. In some implementations, R 4 It is CF3.

[0075] In some implementation schemes, each R 5 The alkyl group is independently selected from H, D, halogen, CN, or C1-C6 alkyl, which may optionally be substituted with D, halogen, or CN.

[0076] In some implementation schemes, R 5 For H. In some implementations, R 5 For D. In some implementations, R 5 It is a halogen (e.g., F, Cl, Br, I). In some embodiments, R 5 For CN. In some implementations, R 5 The C1-C6 alkyl group is optionally substituted with D, halogen, or CN.

[0077] In some implementations, for example, including but not limited to, each R 5 Independently selected from H, D, halogen, CN, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH.

[0078] In some implementation schemes, each R 6 Independently selected from H, D, halogen, CN, SF5, OR B C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic group; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 heterocyclic group is optionally substituted by a substituent selected from the following: D, halogen, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

[0079] In some implementations, for example, including but not limited to, R 6 It can be H, D, halogen, CN, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH or cyclopropyl.

[0080] In some implementation schemes, each R 7 Independently selected from H, D, halogen, Me, CF3, OH, OMe, OCF3.

[0081] In some implementation schemes, R 7 For H. In some implementations, R 7 For D. In some implementations, R 7 It is a halogen (e.g., F, Cl, Br, or I). In some embodiments, R 7 For OH. In some implementations, R 7 For OMe.

[0082] In some implementation schemes, each R 8 The alkyl group is independently selected from H, D, CN, SF5, and C1-C6, and is optionally substituted with D, halogen, or CN.

[0083] In some implementation schemes, R 8 For H. In some implementations, R 8 For D. In some implementations, R 8 For CN. In some implementations, R 8 It is SF5.

[0084] In some implementation schemes, R 8 The C1-C6 alkyl group is optionally substituted with D, halogen, or CN. In some embodiments, for example, including but not limited to, R 8 For CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3.

[0085] In some embodiments, the compounds represented by formulas (IA) and (IB) are as shown in formulas (IAa), (IAb), (IAc), (IAd), (IAe), (IBa), (IBb), (IBc), (IBd), or (IBe):

[0086]

[0087] Or a pharmaceutically acceptable salt, stereoisomer, transisomer, solvate, N-oxide, isotopic variant, or prodrug thereof; wherein X, Y, L, R, R 1 R 2 R 4 R 5 R 6 R 7 R 8 The definitions are the same as those for (IA) and (IB).

[0088] In some implementations, L is (CR 10 R 11 ) n NR12 (CH2CH2) m , or O(CH2CH2) m .

[0089] In some implementations, L is (CR 10 R 11 ) n In some implementations, L is CR 10 R 11 In some implementations, L is (CR 10 R 11 2. In some implementations, L is (CR) 10 R 11 3.

[0090] In some implementations, L is NR 12 (CH2CH2) m In some implementations, L is NR. 12 In some implementations, L is NR. 12 CH2CH2.

[0091] In some implementations, L is O(CH2CH2). m In some implementations, L is O. In some implementations, L is OCH2CH2.

[0092] In some embodiments, R is selected from H, D, or a C1-C6 alkyl group, optionally substituted with F, OH, or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is Me.

[0093] In some implementation schemes, R 4 Selected from H, D, NH2, or CN. In some embodiments, R 4 For H. In some implementations, R 4 For D. In some implementations, R 4 For NH2. In some implementations, R 4 For CN.

[0094] In some implementation schemes, R 4 The C1-C3 alkyl group is optionally substituted with D, halogen, or CN. In some embodiments, R 4 For Me. In some implementations, R 4 For CD3. In some implementations, R 4 It is CF3.

[0095] In some implementation schemes, R 5 Selected from H, D, halogen, or CN. In some embodiments, R5 For H. In some implementations, R 5 For D. In some implementations, R 5 For CN. In some implementations, R 5 For F. In some implementations, R 5 It is Cl.

[0096] In some implementation schemes, R 5 The C1-C6 alkyl group is optionally substituted with D, halogen, or CN. In some embodiments, R 5 For Me. In some implementations, R 5 For CD3. In some implementations, R 5 It is CF3.

[0097] In some implementation schemes, R 6 Selected from H, D, halogen, CN, SF5, OR B In some implementations, R 6 For H. In some implementations, R 6 For D. In some implementations, R 6 For CN. In some implementations, R 6 For F. In some implementations, R 6 For Cl. In some implementations, R 6 For Br. In some implementations, R 6 It is SF5.

[0098] In some implementation schemes, R 6 The C1-C6 alkyl group is optionally substituted with a substituent selected from the following: D, halogen, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, selectively substituted C3-C7 cycloalkyl, and selectively substituted 4-7 membered heterocyclic groups. In some embodiments, R 6 For Me. In some implementations, R 6 For CD3. In some implementations, R 6 For CF3. In some implementations, R 6 It is cyclopropyl.

[0099] In some implementation schemes, R 7 For H. In some implementations, R 7 The answer is D.

[0100] In some implementation schemes, R 7 It is a halogen. In some implementations, R 7 For F. In some implementations, R 7 It is Cl.

[0101] In some implementation schemes, R 7 For OH. In some implementations, R 7 For OMe.

[0102] In some implementation schemes, R 8 Selected from H, D, CN, SF5. In some implementations, R 8 For H. In some implementations, R 8 For D. In some implementations, R 8 For CN. In some implementations, R 8 It is SF5.

[0103] In some implementation schemes, R 8 The C1-C6 alkyl group is optionally substituted with D, halogen, or CN. In some embodiments, R 8 For Me. In some implementations, R 8 For CD3. In some implementations, R 8 It is CF3.

[0104] In some embodiments, the compounds represented by formulas (IA) and (IB) are as shown in formulas (IIAa), (IIAb), (IIAc), (IIAd), (IIAe), (IIBa), (IIBb), (IIBc), (IIBd), or (IIBe):

[0105]

[0106]

[0107] Or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, isotopic variant, or prodrug thereof; wherein X, Y, L, R, R 1 R 2 R 4 R 5 R 6 R 7 R 8 The definitions are the same as those for (IA) and (IB).

[0108] In some embodiments, the compounds represented by formulas (IA) and (IB) are as shown in formulas (IIIAa), (IIIAb), (IIIAc), (IIIAd), (IIIAe), (IIIBa), (IIIBb), (IIIBc), (IIIBd), or (IIIBe):

[0109]

[0110] Or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, isotopic variant, or prodrug thereof; wherein X, Y, L, R, R 1 R 2 R 4 R 5 R 6 R 7 R 8 The definitions are the same as those for (IA) and (IB).

[0111] In some embodiments, the compounds represented by formulas (IA) and (IB) are as shown in formulas (IIAa), (IIBa), (IIIAa), and (IIIBa):

[0112]

[0113] Or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, isotopic variant, or prodrug thereof; wherein X, Y, L, R, R 1 R 2 R 4 R 5 R 6 R 7 The definitions are the same as those for (IA) and (IB).

[0114] In some implementations, L is (CR 10 R 11 ) n NR 12 (CH2CH2) m , or O(CH2CH2) m .

[0115] In some implementations, L is (CR 10 R 11 ) n In some implementations, L is CR 10 R 11 In some implementations, L is (CR 10 R 11 2. In some implementations, L is (CR) 10 R 11 3.

[0116] In some implementations, L is NR 12 (CH2CH2) m In some implementations, L is NR. 12 In some implementations, L is NR. 12 CH2CH2.

[0117] In some implementations, L is O(CH2CH2). m In some implementations, L is O. In some implementations, L is OCH2CH2.

[0118] In some embodiments, R is selected from H, D, or a C1-C6 alkyl group, optionally substituted with F, OH, or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is Me.

[0119] In some implementation schemes, R 4 Selected from H, D, NH2, or CN. In some embodiments, R 4 For H. In some implementations, R 4 For D. In some implementations, R 4 For NH2. In some implementations, R 4 For CN.

[0120] In some implementation schemes, R 4 The C1-C3 alkyl group is optionally substituted with D, halogen, or CN. In some embodiments, R 4 For Me. In some implementations, R 4 For CD3. In some implementations, R 4 It is CF3.

[0121] In some implementation schemes, R 5 Selected from H, D, halogen, or CN. In some embodiments, R 5 For H. In some implementations, R 5 For D. In some implementations, R 5 For CN. In some implementations, R 5 For F. In some implementations, R 5 It is Cl.

[0122] In some implementation schemes, R 5 The C1-C6 alkyl group is optionally substituted with D, halogen, or CN. In some embodiments, R 5 For Me. In some implementations, R 5 For CD3. In some implementations, R 5 It is CF3.

[0123] In some implementation schemes, R 6 Selected from H, D, halogen, CN, SF5, OR B In some implementations, R 6 For H. In some implementations, R 6 For D. In some implementations, R 6For CN. In some implementations, R 6 For F. In some implementations, R 6 For Cl. In some implementations, R 6 For Br. In some implementations, R 6 It is SF5.

[0124] In some implementation schemes, R 6 The C1-C6 alkyl group is optionally substituted with at least one substituent selected from the following: D, halogen, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, selectively substituted C3-C7 cycloalkyl, selectively substituted 4-7 membered heterocyclic groups. In some embodiments, R 6 For Me. In some implementations, R 6 For CD3. In some implementations, R 6 For CF3. In some implementations, R 6 It is cyclopropyl.

[0125] In some implementation schemes, R 7 For H. In some implementations, R 7 The answer is D.

[0126] In some implementation schemes, R 7 It is a halogen. In some embodiments, F. In some embodiments, Cl.

[0127] In some implementation schemes, R 7 For OH. In some implementations, R 7 For OMe.

[0128] In some implementation schemes, R 8 Selected from H, D, CN, SF5. In some implementations, R 8 For H. In some implementations, R 8 For D. In some implementations, R 8 For CN. In some implementations, R 8 It is SF5.

[0129] In some implementation schemes, R 8 The C1-C6 alkyl group is optionally substituted with D, halogen, or CN. In some embodiments, R 8 For Me. In some implementations, R 8 For CD3. In some implementations, R 8 It is CF3.

[0130] In some embodiments, the compound represented by formula (IB) is as shown in formula (IVBa), (IVBb), or (IVBc):

[0131]

[0132] Or a pharmaceutically acceptable salt, stereoisomer, transisomer, solvate, N-oxide, isotopic variant, or prodrug thereof; wherein Y, R 1 R 2 R 5 R 6 R 7 R 10 R 11 The definition is the same as that of formula (IB).

[0133] In the compounds represented by formulas (IA) and (IB), each R A Independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NRc C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or NR c S(O)(=NR b )R b .

[0134] In some implementation schemes, R A Independently selected from H. In some implementations, R A The answer is D.

[0135] In some implementation schemes, R A The group is independently selected from C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, wherein the C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl is optionally substituted by 1, 2, or 3 substituents independently selected from: D, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NRc R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d NR c S(O)(=NR b )R b .

[0136] In other implementations, R A Independently selected from C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl or 4-10 membered heterocyclic-C1-C6 alkyl may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, CN, halogen, C1-C4 alkyl, NO2, oxo, OR a SR a SF5, NHOR a C(O)R b C(O)NR c R d C(O)OR a OC(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a B(OR) c (OR) d ), C(=NR c )NR c R d NR d C(=NR c )NR c R d NR d C(=NR c )R b P(O)R e R f P(O)OR e OR f OP(O)OR e OR f S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d NR c S(O)(=NR b )R b .

[0137] In the compounds represented by formulas (IA) and (IB), each R B Independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0138] In some implementation schemes, R B Independently selected from H. In some implementations, R B The answer is D.

[0139] In some implementation schemes, R B The C1-C6 alkyl group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d In some implementations, R B It is a C1-C6 alkyl group.

[0140] In some implementation schemes, R B It is isopropyl, isobutyl, or tert-butyl; each substituent is optionally substituted by 1, 2, or 3 independently selected from the following substituents: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl. In some embodiments, R B It is isopropyl. In some embodiments, R B It is isobutyl. In some implementations, R B It is tert-butyl.

[0141] In some implementation schemes, R B The C2-C6 alkynyl group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0142] In some implementation schemes, R B The C2-C6 alkenyl group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR aS(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0143] In some implementation schemes, R B For C3-C 10 The cycloalkyl group is optionally substituted by 1, 2, or 3 substituents independently selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0144] In some implementation schemes, R BThe substituents are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each substituent is optionally substituted by 1, 2, or 3 independently selected from the following substituents: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl.

[0145] In other implementations, R B The 4-10 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0146] In some implementation schemes, R B The azahexacyclobutyl, pyrrolidinyl, piperidinyl, or azahexacycloheptyl group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, C(O)R b OC(O)NR c Rd NR c R d NR c C(O)R b NR c C(O)NR c R d NR c C(O)OR a S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0147] In other implementations, R B For C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C6-C 10 Aryl, 5-10 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C(O)R b OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)NR c R d NR cC(O)OR a S(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0148] In some implementation schemes, each R C Independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC(O)NR c R d NR c R d NR c C(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d, or B(OR) c (OR) d ).

[0149] In some implementation schemes, each R C Independently selected from H. In some implementations, each R C The answer is D.

[0150] In some implementation schemes, each R C Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; each substituent is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC(O)NR c R d NR c R d NR c C(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0151] In some implementation schemes, each R C Independently selected from C3-C7 cycloalkyl, 4-7 heterocyclic, phenyl, 5-6 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; each substituent is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC(O)NR c R d NRc R d NR c C(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0152] In some implementation schemes, each R D Independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC(O)NR c R d NR c R d NR c C(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NRc R d , or B(OR) c (OR) d ).

[0153] In some implementation schemes, each R D Independently selected from H. In some implementations, each R D The answer is D.

[0154] In some implementation schemes, each R D Independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; each substituent is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC(O)NR c R d NR c R d NR c C(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0155] In some implementation schemes, each R D Independently selected from C3-C7 cycloalkyl, 4-7 heterocyclic, phenyl, 5-6 heteroaryl, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; each substituent is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC(O)NRc R d NR c R d NR c C(O)R b S(O)NR c R d S(O)2R b NR c S(O)2R b S(O)2NR c R d NR c S(O)2NR c R d , or B(OR) c (OR) d ).

[0156] In other implementations, R C and R D Together with the N atom attached thereto, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.

[0157] In some implementation schemes, each R a Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C3-C7 cycloalkyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclic; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3- The C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy.

[0158] In some implementation schemes, each R b Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic.

[0159] In some implementation schemes, R c and R d Each of the following groups is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 6- C 10 Aryl, 5-10 heteroaryl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-5-10 heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 Aryl, or 5-10 heteroaryl-5-10 heteroaryl; wherein, the C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 6- C 10 Aryl, 5-10 heteroaryl, C 3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 cycloalkyl, C6-C 10 aryl-4-10 heterocyclic group, C6-C 10 aryl-5-10 heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 heteroaryl-C3-C 10 Cycloalkyl, 5-10-membered heteroaryl-4-10-membered heterocyclic, 5-10-membered heteroaryl-C6-C 10 The aryl group, or 5-10 heteroaryl group, is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 heteroaryl, C(O)OR a1 C(O)R b1 S(O)2R b1 , C1-C4 alkyl-O-C1-C4 alkyl, and C1-C4 alkyl-O-C1-C4 alkyl-O-.

[0160] In some implementation schemes, R c and R d Together with the N atom attached thereto, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C 10 Aryl, 5-10 heteroaryl, C(O)OR a1 C(O)R b1 S(O)2R b1 , C1-C4 alkoxy-C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkoxy.

[0161] In some implementation schemes, each R eIndependently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10 heteroaryl-C1-C4 alkyl, or 4-10 heterocyclic-C1-C4 alkyl.

[0162] In some implementation schemes, each R f Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group.

[0163] In some implementation schemes, each R a1 Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C3-C7 cycloalkyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclic, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3- The C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy.

[0164] In some implementation schemes, each R b1 Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, C6-C 10 aryl-C1-C6 alkyl, 5-10 heteroaryl-C1-C6 alkyl, C3-C 10The cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclic-C1-C6 alkyl, is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic.

[0165] In some embodiments, the compounds represented by formulas (IA) and (IB) are pharmaceutically acceptable salts. In some embodiments, the compounds represented by formulas (IA) and (IB) are stereoisomers. In some embodiments, the compounds represented by formulas (IA) and (IB) are solvates. In some embodiments, the compounds represented by formulas (IA) and (IB) are N-oxides of the compounds represented by formulas (IA) and (IB).

[0166] The present invention also considers, describes, and covers stereoisomers, pharmaceutically acceptable salts, and solvates of the compounds shown in formulas (IA) and (IB). The present invention also describes uses of the compounds shown in formulas (IA) and (IB) and pharmaceutical compositions thereof.

[0167] In some embodiments, the compounds shown in formulas (IA) and (IB) are:

[0168]

[0169] Or a pharmaceutically acceptable salt, stereoisomer, transisomer, solvate, N-oxide, isotope variant or prodrug thereof.

[0170] In some embodiments, the compounds shown in formulas (IA) and (IB) are:

[0171]

[0172] Or a pharmaceutically acceptable salt, stereoisomer, transisomer, solvate, N-oxide, isotope variant or prodrug thereof.

[0173] It is obvious that the compounds represented by formulas (IA) and (IB) of this invention, including all subgenera described herein, may have multiple stereocenters. Therefore, the compounds represented by formulas (IA) and (IB) of this invention (subgenera described herein) exist in multiple stereoisomers (enantiomers and diastereomers). This invention contemplates and covers any stereoisomer of the compounds represented by formulas (IA) and (IB) (subgenera described herein), as well as mixtures of said stereoisomers.

[0174] Pharmaceutically acceptable salts and solvates of the compounds represented by formulas (IA) and (IB) (subgenus described in this invention) are also included within the scope of this invention.

[0175] Isotopic variants of the compounds represented by formulas (IA) and (IB) (subgenus described in this invention) are also included within the scope of this invention.

[0176] The present invention further provides the use of the compounds described herein, or pharmaceutically acceptable salts thereof, in any of the methods described herein. The present invention further provides the use of the compounds of the present invention, or pharmaceutically acceptable salts thereof, in the preparation of a therapeutic medicament, said medicament being used in any of the methods described herein.

[0177] The present invention further provides a pharmaceutical composition comprising: the compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0178] The present invention provides a method for inhibiting PKMYT1 in cells expressing PKMYT1, comprising: contacting the cells with the compound of the present invention.

[0179] In some embodiments, the cells are associated with CCNE1 amplification, FBXW7 loss-of-function mutations, or other PKMYT1-dependent genetic alterations. In some embodiments, the cells are subject cells.

[0180] The present invention provides a method for treating cancer, comprising: administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present invention.

[0181] In some embodiments, the subject has a disease or condition characterized by excessive cell proliferation that requires treatment. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is cancer with CCNE1 amplification, FBXW7 loss-of-function mutation, or other PKMYT1-dependent gene alterations.

[0182] The routes of administration of the compounds in this invention include, but are not limited to, oral, injection, topical, and inhalation.

[0183] definition

[0184] Unless otherwise stated, the following terms have the meanings described below. Other terms are defined elsewhere throughout this specification.

[0185] Unless the context clearly indicates otherwise, the singular forms "a," "an," and "the" as used herein include the plural objects referred to. It should also be noted that claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a prior basis for the use of such exclusive terms, such as "unique," "only," etc., in connection with references to claim elements or the use of the word "negative" limitation.

[0186] In various places within this specification, variables defining divalent linking groups are described. Specifically, each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes -NR(CR'R")- and -(CR'R")NR-, with each form intended to be disclosed separately. When a structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition of that variable lists "alkyl" or "aryl," then it should be understood that "alkyl" or "aryl" respectively represents the linked alkylene or aryl group.

[0187] The term "substituted" means that one atom or group of atoms replaces hydrogen as a "substituent" attached to another group. The term "substitution," unless otherwise specified, refers to any number of substitutions, such as mono-, di-, tri-, tetra-, or penta-substitution, if such substitution is permitted. Substituents are chosen independently, and substitution can occur at any chemically possible position. It should be understood that substitution at a particular atom is limited by valence. The term "optionally substituted" means either unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms.

[0188] The term "Cn-Cm" represents a range including the endpoints, where n and m are integers representing the number of carbon atoms. For example, the term "C1-C6 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. "C0 alkyl" refers to a covalent bond.

[0189] The compounds of the present invention are stable. As used herein, "stable" means that the compound is sufficiently stable during the separation of the compound from the reaction mixture to obtain a useful purity, and preferably means that the compound can be formulated into an effective therapeutic agent.

[0190] It should also be understood that, for clarity, certain features of the invention described in the context of individual embodiments may also be provided in combination with individual embodiments. Conversely, for the sake of brevity, various features of the invention described in the context of individual embodiments may also be provided individually or in any suitable sub-combination.

[0191] As used in this invention, unless otherwise stated, the term "alkyl," as part of a substituent or other substituent, refers to a straight-chain or branched saturated hydrocarbon group. An alkyl group may contain about 1 to about 20, about 2 to about 20, about 1 to about 10, about 1 to about 8, about 1 to about 6, about 1 to about 4, or about 1 to about 3 carbon atoms. Similarly, in C1-C8 alkyl groups, C... 1-8 This refers to a group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, and t-butyl), pentyl (e.g., n-pentyl, isopentyl, and neopentyl), etc.

[0192] As used in this invention, unless otherwise stated, the term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Exemplary alkenyl groups include, but are not limited to, vinyl, propenyl, etc.

[0193] As used in this invention, unless otherwise stated, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, etc.

[0194] As used in this invention, unless otherwise stated, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents. Exemplary haloalkyl groups include, but are not limited to, CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, etc.

[0195] As used herein, unless otherwise stated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings). In some embodiments, the aryl group has about 6 to about 20 carbon atoms. In some embodiments, the aryl group has about 6 to about 14 carbon atoms. In some embodiments, the aryl group has about 6 to about 10 carbon atoms. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthryl, indene, indenyl, etc.

[0196] As used herein, unless otherwise stated, the term "cycloalkyl" refers to an unsubstituted or substituted non-aromatic carbon ring, including cycloalkyl, cycloalkenyl, and cycloynyl groups. Cycloalkyl groups can comprise monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., bridged bicyclic alkyl groups). In some embodiments, the cycloalkyl group has about 3 to about 20 carbon atoms, about 3 to about 14 carbon atoms, about 3 to about 10 carbon atoms, or about 3 to 7 carbon atoms. The cycloalkyl group may also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. The cycloalkyl group may optionally be oxidized or thiolated (e.g., -C(O)- or -C(S)-). The definition of cycloalkyl also includes rings formed by the fusion of a cycloalkyl group with one or more aromatic rings (e.g., having a shared bond with the cycloalkyl group), such as benzo[a] derivatives of pentane, benzo[a] derivatives of pentene, benzo[a] derivatives of hexane, etc. It can be linked to the aromatic or non-aromatic ring of a cycloalkyl group having one or more aromatic rings. One or more cyclic carbon atoms of the cycloalkyl group can be oxidized, for example, by having oxo or thio substituents. In some embodiments, the cycloalkyl group is a C3-C7 monocyclic cycloalkyl group. In some embodiments, the cycloalkyl group is a C3-C7 monocyclic cycloalkyl group. 4- C 10 Spirocyclic or bridged cycloalkyl groups. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinel, norcarelyl, cubic, adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, and spiro[3.3]heptyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl group is a cyclic, non-aromatic hydrocarbon group having 3 to 12 carbon atoms (“C”). 3- C 12 Preferably, it has 3 to 6 carbon atoms (“C”). 3- Exemplary cycloalkyl groups include, for example, cyclopropyl (C6”). 3； 3-yuan), cyclobutyl (C 4； 4-Cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4), 2-methylcyclopentyl (C4), adamantyl (C5) 10 )wait.

[0197] When the term "spirocycloalkyl" is used alone or as part of a substituent, it refers to a non-aromatic cycloalkyl group containing two cycloalkyl groups, wherein, typically, the two cycloalkyl groups share a single carbon atom.

[0198] As used in this invention, unless otherwise stated, "heteroaryl" refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member, such as boron, sulfur, oxygen, or nitrogen. Heteroaryl includes monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Any N atom of a heteroaryl can be oxidized to form an N-oxide. Exemplary heteroaryl includes, but is not limited to, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thiopheneyl, imidazolyl, thiazolyl, indolyl, pyrroleyl, oxazolyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothiopheneyl, purine, carbazoleyl, benzimidazolyl, indololinyl, etc. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and further, in some embodiments, has from 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group comprises 3 to about 14, 3 to about 7, or 5 to 6 cyclic atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

[0199] As used in this invention, unless otherwise stated, "heterocyclic group" refers to an unsubstituted or substituted monocyclic (saturated or partially unsaturated ring) or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more cyclic carbon atoms of the heterocyclic group may be replaced by heteroatoms selected from N, O, S, and B; the cyclic carbon atoms and heteroatoms of the heterocyclic group may optionally be oxidized or thiolated (e.g., C(O), S(O), C(S), or S(O)2, etc.). Heterocyclic groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocyclic groups include monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocyclic groups. Heterocyclic groups also include spirocyclic and bridged rings (e.g., 5-10 membered bridged bicyclic groups, where one or more of the cyclic carbon atoms are replaced by heteroatoms independently selected from N, O, S, and B). The heterocyclic groups can be linked by cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic group comprises 0 to 3 double bonds. In some embodiments, the heterocyclic group comprises 0 to 2 double bonds.

[0200] The heterocyclic group further includes a group having one or more aromatic rings fused to (i.e., having a bond shared with the heterocyclic group) the non-aromatic heterocycle, such as piperidine, morpholine, benzo[a] or thieno[b] derivatives of aziridine-heptane, etc. The heterocyclic group containing the fused aromatic ring can be linked by any cyclic atoms, including the cyclic atoms of the fused aromatic ring. In some embodiments, the heterocyclic group contains 3 to 10 cyclic atoms, 4 to 10 cyclic atoms, 3 to 7 cyclic atoms, or 5 to 6 cyclic atoms. In some embodiments, the heterocyclic group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some embodiments, the heterocyclic group is a monocyclic 4-6 membered heterocyclic group having 1 or 2 heteroatoms independently selected from N, O, S, and B, while having one or more oxygenated ring atoms.

[0201] Exemplary heterocyclic groups, including but not limited to, pyrrolidine-2-one, 1,3-isooxazolidine-2-one, pyranyl, tetrahydropyranyl, oxacyclobutyl, aziridine, morpholine, thiomorpholinyl, piperazine, tetrahydrofuranyl, tetrahydrothiophene, piperidinyl, pyrrolylalkyl, isoxazolylalkyl, isothiazolylalkyl, pyrazolylalkyl, oxazolylalkyl, thiazolylalkyl, imidazolylalkyl, aziridineheptylalkyl, benzozapentenyl, 1, 2,3,4-Tetrahydroisoquinolinyl, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.l]hexyl, azabicyclo[2.2.l]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.l]heptyl, diazabicyclo[3.1.l]heptyl, azabicyclo[3.2.l]octyl, diazabicyclo[3.2.1]octyl alkyl, oxabicyclo[2.2.2]octyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, azaadamantyl, diazaadamantyl, oxaadamantyl, azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, oxa-azaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, oxa-azaspiro[3.4]octyl, Oxa-azaspiro[3.5]nonyl, azaspiro[2.5]octyl, diazaspiro[2.5]octyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, oxa-azaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, diazaspiro[4.4]nonyl, oxa-diazaspiro[4.4]nonyl, octahydropyrrolo[3,4-c]pyrryl, etc.

[0202] In some embodiments, a heterocyclic group refers to any 3- to 10-membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from O, N, and S. The heterocyclic group can be linked by any heteroatom or carbon atom, as long as a stable structure can be generated. Exemplary heterocyclic groups include, but are not limited to, azirrocycloheptanyl, azirrocyclopropyl, azirrocyclobutyl, pyrroliyl, dioxocyclopentyl, imidazoalkyl, pyrazolyl, piperazinyl, piperidinyl, dioxohexacycloyl, morpholinyl, dithiaalkyl, thiomorpholinyl, oxazacycloheptanyl, ethylene oxide, oxazacyclobutyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, etc.

[0203] In some embodiments, the term "spirocyclic heterocyclic group" is used alone or as part of a substituent to refer to a non-aromatic ring comprising two rings, at least one of which is selected from heterocyclic groups, the two rings sharing a single carbon atom.

[0204] As used in this invention, unless otherwise stated, "arylcycloalkyl" refers to a cycloalkyl group substituted with an aryl group.

[0205] As used in this invention, unless otherwise stated, "aryl heterocyclic group" refers to a heterocyclic group substituted with an aryl group.

[0206] As used in this invention, unless otherwise stated, "aryl heteroaryl" refers to a heteroaryl group substituted with an aryl group.

[0207] As used in this invention, unless otherwise stated, "bisaryl" refers to an aryl group that has been substituted with an aryl group.

[0208] As used in this invention, unless otherwise stated, "heteroarylcycloalkyl" refers to a cycloalkyl group substituted with a heteroaryl group.

[0209] As used in this invention, unless otherwise stated, "heteroaryl heterocyclic group" refers to a heterocyclic group substituted with a heteroaryl group.

[0210] As used in this invention, unless otherwise stated, "heteroarylaryl" refers to an aryl group substituted with a heteroaryl group.

[0211] As used in this invention, unless otherwise stated, "diheteroaryl" refers to a heteroaryl group that has been substituted with a heteroaryl group.

[0212] As used in this invention, "halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0213] As used in this invention, unless otherwise stated, "alkoxy" refers to –O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, etc.

[0214] As used in this invention, unless otherwise stated, "hydroxyalkyl" refers to an alkyl group substituted with OH.

[0215] As used in this invention, unless otherwise stated, "cyanoalkyl" refers to an alkyl group substituted with CN.

[0216] As used in this invention, unless otherwise stated, "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0217] As used in this invention, unless otherwise stated, "alkoxyalkoxy" refers to an alkoxy group substituted with an alkoxy group.

[0218] As used in this invention, unless otherwise stated, "haloalkoxy" refers to –O-(haloalkyl).

[0219] As used in this invention, unless otherwise stated, "arylalkyl" refers to an alkyl group substituted with an aryl group, and "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group. An exemplary arylalkyl group is benzyl.

[0220] As used in this invention, unless otherwise stated, "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, and "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group.

[0221] As used in this invention, unless otherwise stated, "oxo" refers to an oxygen substituent (i.e., =O) linked by a double bond.

[0222] As used in this invention, unless otherwise stated, the term "optionally substituted" means either unsubstituted or substituted.

[0223] As used in this invention, unless otherwise stated, the term "substituted" means that one or more hydrogen atoms in a group are each replaced independently by a substituent selected from the same or different substituents. Exemplary substituents include, but are not limited to, D, halogen, oxo, C1-C. -6 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, C1-C6 alkyl-NR c1 R d1 ,-(CH2CH2O) o C1-C6 alkyl groups, where o is 1-10; C 2-6 alkenyl-NR c1 R d1 C 2-6 alkynyl-NR c1 R d1 OC 2-6 Alkyl-NR c1 R d1 CN, NO2, N3, ORa1 SR a1 C(O)R b1 C(O)NR c1 R d1 -CH2C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 -NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)NR c1 R d1 NR c1 C(O)OR a1 C(=NR) g1 )NR c1 R d1 NR c1 C(=NR g1 )NR c1 R d1 , P(R f1 )2, P(OR e1 )2, P(O)R e1 R f1 P(O)OR e1 OR f1 S(O)R b1 -SO(=NR) b1 );S(O)NR c1 R d1 S(O)2R b1 NR c1 S(O)2R b1 S(O)2NR c1 R d1 aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with a substituent selected from the following: D, halogen, oxo, C1-C -6 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, C1-C6 alkyl-NR c1 R d1 C 2-6 alkenyl-NR c1 R d1 C 2-6 alkynyl-NR c1 R d1 OC2-6 Alkyl-NR c1 R d1 CN, NO2, N3, OR a1 SR a1 C(O)R b1 C(O)NR c1 R d1 -CH2C(O)NR c1 R d1 C(O)OR a1 OC(O)R b1 OC(O)NR c1 R d1 -NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)NR c1 R d1 NR c1 C(O)OR a1 C(=NR) g1 )NR c1 R d1 NR c1 C(=NR g1 )NR c1 R d1 , P(R f1 )2, P(OR e1 )2, P(O)R e1 R f1 P(O)OR e1 OR f1 S(O)R b1 S(O)NR c1 R d1 S(O)2R b1 NR c1 S(O)2R b1 S(O)2NR c1 R d1 ;

[0224] Among them, R a1 Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C3-C7 cycloalkyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclic, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3-C7 cycloalkyl, 5-6 heteroaryl, or 4-7 heterocyclic group may optionally be substituted by 1, 2, or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;

[0225] R b1 Independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclic, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl; wherein, the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, phenyl, C 3- C7 cycloalkyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclic, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclic alkyl optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C 6- C 10 Aryl, C 3- C 10 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic;

[0226] R c1 and R d1 Each of the following groups is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclic alkyl; wherein, the C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 ynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclic alkyl optionally substituted by 1, 2 or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or C1-C4 haloalkoxy;

[0227] R c1 and R d1Together with the N atom attached thereto, a 4-7 membered heterocyclic group is optionally substituted by 1, 2, or 3 independent substituents selected from: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C 1-4 Halogenated alkoxy groups;

[0228] Each R e1 Independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy)-C1-C4 alkyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl-C1-C4 alkyl, C3-C 10 Cycloalkyl-C1-C4 alkyl, 5-10-membered heteroaryl-C1-C4 alkyl, or 4-10-membered heterocyclic-C1-C4 alkyl;

[0229] R f1 Independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic groups;

[0230] R g1 Independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclic alkyl; wherein, the C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 ynyl, C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl, 4-10-membered heterocyclic, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclic alkyl may optionally be substituted by 1, 2 or 3 independent substituents selected from the following: D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or C1-C4 haloalkoxy.

[0231] The compounds described in this invention may be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of this invention. Compounds containing asymmetrically substituted carbon atoms may be optically active or racemic. Methods for preparing the optically active form from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometrical isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described in this invention, and all stable isomers are also within the scope of this invention. Cis and trans geometrical isomers of the compounds described in this invention are also within the scope of this invention and can be isolated as mixtures of isomers or as isolated isomeric forms.

[0232] The compounds of this invention also include tautomers. Tautomers arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomers include proton transfer tautomers having the same chemical formula and total charge. Exemplary proton transfer tautomers include keto-enol tautomers, amide-imino tautomers, lactam-lactide tautomers, amide-imino tautomers, and enamine-imino tautomers, in which protons in the cyclic structure can interleave at two or more positions in the heterocyclic system, for example, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole; the tautomers can be balanced or spatially fixed by suitable substitution to form a single form.

[0233] In some cases, the compounds described in this invention may exist in the form of rotational isomers. The description of the compounds of this invention is intended to cover any single rotational isomer, and any mixture of rotational isomers in any proportion, and does not represent any particular rotational isomer. The description of a particular rotational isomer means that the described rotational isomer substantially free of other rotational isomers.

[0234] This invention further includes isotopic labels of the compounds or intermediates described herein. "Isotope" refers to atoms having the same number of atoms but different molecular weights. For example, isotopes of hydrogen include protium and deuterium.

[0235] In some embodiments, the compounds or salts thereof described in this invention are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it was formed or detected. Partial isolation may include, for example, compositions rich in the compounds of this invention. Substantialtive isolation may include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds of this invention or salts thereof. Methods for separating the compounds and their salts are conventional in the art.

[0236] This invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compounds described herein, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Exemplary pharmaceutically acceptable salts include, but are not limited to, mineral acid or organic acid salts of basic residues such as amines; basic salts or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts of this invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods. Typically, the salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0237] The term "pharmaceutically acceptable" is used in this invention to refer to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0238] "Pharmaceutical-acceptable excipients" refer to substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as inert substances, and that are added to or otherwise used as a medium, carrier, or diluent to facilitate the administration of a pharmaceutical agent. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0239] "Solvate" refers to a compound represented by formulas (IA) and (IB) that has one or more solvent molecules.

[0240] "Subject" includes human beings. The terms "human being," "patient," and "subject" are used interchangeably in this invention.

[0241] In one implementation, “treating” any disease or disorder means improving the disease or disorder (i.e., preventing or reducing the development of at least one clinical symptom of the disease or its clinical symptoms). In another implementation, “treating” means improving at least one bodily parameter that the subject may not be able to discern. In yet another implementation, “treating” means modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of bodily parameters), or both. In yet another implementation, “treating” means delaying the onset of the disease or disorder.

[0242] The terms “compounds of the present invention” and equivalent expressions are intended to cover the compounds represented by formulas (IA) and (IB) of the present invention, as well as their respective subgenuses, and, where the context permits, the expression includes stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of the compounds represented by formulas (IA) and (IB), as well as pharmaceutically acceptable salts.

[0243] As used herein, the term "isotope variant" refers to a compound that contains an isotopic proportion greater than the natural abundance at one or more atoms constituting the compound. For example, an "isotope variant" of a compound may be radiolabeled, i.e., containing one or more radioactive isotopes, or may be made of non-radioactive isotopes such as, for example, deuterium. 2 H or D), carbon-13 (H or D), carbon-13 13 C), Nitrogen-15 ( 15 N), etc. It should be understood that in compounds that have undergone such isotopic substitution, if present, the following atoms can be changed such that, for example, any hydrogen atom can be... 2 H / D, any carbon can be 13 C, or any nitrogen, can be 15 N, and the presence and location of such atoms can be determined within the capabilities of those skilled in the art.

[0244] It should also be understood that compounds having the same molecular formula but different atomic bonding properties or sequences or spatial arrangements are called "isomers". Isomers with different spatial arrangements of atoms are called "stereoisomers", such as diastereomers, enantiomers, and rotational isomers. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as separate (R)- or (S)-stereoisomers at each asymmetric center or as mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include all its racemic or other stereoisomers and mixtures thereof. When a structure contains one chiral center but does not show the specific stereochemistry of that center, the structure comprises two enantiomers, individually or as a mixture of enantiomers. When a structure contains more than one chiral center but does not show the specific stereochemistry of that center, the structure comprises all enantiomers and diastereomers, individually or as a mixture thereof. Methods for testing stereochemistry and separating stereoisomers are well known in the art.

[0245] Pharmaceutical Composition

[0246] The present invention also provides pharmaceutical compositions comprising: compounds of formulas (IA) and (IB), or pharmaceutically acceptable salts, stereoisomers, transisomers, solvates, N-oxides, isotope variants or prodrugs thereof, and pharmaceutically acceptable carriers.

[0247] The pharmaceutical composition may be in a form suitable for oral administration (e.g., tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), may be for injection (e.g., aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar drug carriers), may be for topical use (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), may be for inhalation (e.g., fine powders or liquid aerosols), may be for inhalation (e.g., fine powders), or may be for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0248] The composition can be obtained using conventional pharmaceutical excipients well known in the art through routine procedures. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0249] The compounds shown in formulas (IA) and (IB) or their pharmaceutical salts, in medically effective amounts, can effectively treat or prevent the proliferative diseases mentioned herein, slow their progression, and / or alleviate symptoms associated with the diseases.

[0250] The amount of active ingredient required to produce a single dosage form in combination with one or more excipients varies depending on the individual being treated and the specific route of administration. For example, formulations for oral administration to humans typically contain, for example, 0.1 mg to 1000 mg of a compound of formula (IA) and (IB) or a pharmaceutical salt thereof, and a suitable and appropriate amount of excipients, the amount of which may vary from about 5% to about 98% of the total weight of the composition.

[0251] The dosage of compounds of formulas (IA) and (IB) used for therapeutic or preventative purposes varies, according to well-known medical principles, based on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0252] The following describes non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0253] Administration method

[0254] The compounds represented by formulas (IA) and (IB), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient method of administration, whether systemic / peripheral or local (i.e., at the site of desired action).

[0255] Methods of administration include, but are not limited to: oral (e.g., by ingestion); sublingual; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, for example, by aerosols, for example, by mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrathoracic; and by implantation into a reservoir or pouch, for example, subcutaneous or intramuscular.

[0256] How to use

[0257] The method typically involves administering a therapeutically effective amount of the compound of the invention to a subject. The therapeutically effective amount of the combination of target compounds may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the nature of the disease, such as the subject's weight and age, the severity of the disease, the route of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells, such as reduced proliferation or downregulation of target proteins. The specific dose will vary depending on the specific compound selected, the administration regimen followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.

[0258] As used herein, the term "IC" 50 "IC" refers to the half-maximal inhibitory concentration (IC50) of an inhibitor in inhibiting a biological activity or biochemical function. This quantitative measure indicates how much of a specific inhibitor is required to inhibit half of a given biological process (or its components, i.e., enzymes, cells, cell receptors, or microorganisms). In other words, it is the half-maximal (50%) inhibitory concentration (IC50) of a substance (or IC50). 50 ).

[0259] In some embodiments, the test method (PKMYT1 enzyme activity assay) uses an IC50 with a value approximately or less than a predetermined value in in vitro assays. 50 A PKMYT1 inhibitor with a specific value. In some embodiments, the PKMYT1 inhibitor has the following IC50 value for PKMYT1 inhibition. 50Values: Approximately 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less Smaller, 180nM or smaller, 190nM or smaller, 200nM or smaller, 225nM or smaller, 250nM or smaller, 275nM or smaller, 300nM or smaller, 325nM or smaller, 350nM or smaller, 375nM or smaller, 400nM or smaller, 425nM or smaller, 450nM or smaller, 475nM or smaller, 500nM or smaller, 550nM or smaller, 600nM or smaller 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μM or less, 2 μ M or smaller, 5 μM or smaller, 10 μM or smaller, 15 μM or smaller, 20 μM or smaller, 25 μM or smaller, 30 μM or smaller, 40 μM or smaller, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or smaller (or numbers within the range defined by any two of the above numbers and containing any two of the above numbers).

[0260] PKMYT1 is a synthetic lethal target for malignant tumors with specific genetic alterations, such as CCNE1 amplification or FBXW7 loss-of-function mutations, which may present with symptoms of excessive cell proliferation. The investigated methods are useful for treating malignant tumors with CCNE1 amplification, FBXW7 loss-of-function mutations, or other PKMYT1-dependent genetic alterations.

[0261] Non-limiting examples of this disease condition include, but are not limited to, breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, Paget's disease of the breast, hereditary breast-ovarian cancer syndrome, medullary breast cancer, mucinous breast cancer, inflammatory breast cancer, ovarian cancer, ovarian epithelial carcinoma, ovarian germ cell tumors, low-grade malignant potential ovarian tumors, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, prostate cancer, prostate acinar adenocarcinoma, prostate ductal adenocarcinoma, prostate sarcoma, small cell prostate cancer, squamous cell prostate cancer, pancreatic cancer, exocrine pancreatic cancer, neuroendocrine pancreatic cancer, uterine cancer, uterine sarcoma, uterine corpus sarcoma, cervical cancer, cervical squamous cell carcinoma, and cervical adenocarcinoma. Cervical adenosquamous carcinoma, small cell cervical carcinoma, cervical mucinous neoplasm, clear cell cervical carcinoma, cervical lymphoma, cervical sarcoma, endometrial cancer, endometrial carcinoma, endometrioid tumor, lung cancer, non-small cell lung cancer, small cell lung cancer, brain cancer stem cell glioma, brain cancer, cerebellar astrocytoma, brain astrocytoma, head and neck cancer, glioblastoma multiforme, glioma, gliomatosis, ganglioglioma, ganglioneuroma, paraganglioma, primitive neuroectodermal tumor, supratentorial primitive neuroectodermal tumor, visual pathway glioma, schwannoma, neuroblastoma, neurofibroma, neuroma, sensory neuroblastoma, extrahepatic bile duct carcinoma, Bellini duct carcinoma, bile duct carcinoma, acute Eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aggressive NK-cell leukemia, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, chronic neutrophilic leukemia, erythroleukemia, hairy cell leukemia, leukemia, lymphoid leukemia, lymphoma, macroglobulinemia, mast cell leukemia, monocytic leukemia, granulocytic leukemia, T-cell acute lymphoblastic leukemia T-cell large granular lymphoblastic leukemia, T-cell leukemia, T-cell prolymphocytic leukemia, AIDS-associated lymphoma, angioimmunoblastic T-cell lymphoma, B-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, MALT lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma, precursor T-cell lymphoma, primary central nervous system lymphoma, primary exudative lymphoma, small cell lymphoma, T-cell lymphoma, terminal lymphoma.

[0262] The term "CCNE1 amplification" refers to an increase in the CCNE1 gene, resulting in increased expression of cyclin E in diseased cells, such as the expression of cyclin E protein in cancer cells relative to control cells (e.g., non-pathological cells of the same type). The expression level of cyclin E relative to control cells can be at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold, at least 20-fold, or at least 50-fold. Exemplary cancers with CCNE1 amplification include, but are not limited to, uterine carcinosarcoma, ovarian epithelial tumors, endometrial cancer, esophageal and gastric cancer, sarcoma, bladder cancer, adrenocortical carcinoma, non-small cell lung cancer, pancreatic cancer, pleural mesothelioma, breast cancer, head and neck cancer, mature B-cell tumors, cervical cancer, ovarian cancer, hepatobiliary cancer, glioblastoma, colorectal cancer, melanoma, pheochromocytoma, glioma, prostate cancer, uterine cancer, sarcoma, gastric cancer, lung cancer, esophageal cancer, endometrial cancer, osteosarcoma, leukemia, lymphoma, and biliary tract cancer.

[0263] Exemplary FBXW7 loss-of-function mutation cancers include, but are not limited to, uterine cancer, endometrial cancer, colorectal cancer, cervical cancer, esophageal and gastric cancer, bladder cancer, head and neck cancer, melanoma, non-small cell lung cancer, pancreatic cancer, sarcoma, breast cancer, gastric cancer, ovarian epithelial tumors, glioma, hepatobiliary cancer, ocular melanoma, glioblastoma, thyroid cancer, clear cell renal cell carcinoma, non-clear cell renal cell carcinoma, ovarian cancer, lung cancer, and esophageal cancer.

[0264] In some implementations, the method is used to treat or prevent lymphoma, soft tissue tumors, rhabdomyosarcoma, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblastic carcinoma, central nervous system cancer, urinary tract cancer, upper respiratory and digestive system cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer (data from large-scale screening of cancer cell lines indicate that some of the cell lines for the above cancers depend on PKMYT1 for proliferation, see https: / / depmap.org / portal / ).

[0265] In other embodiments, the method is used to treat diseases selected from: breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

[0266] In other embodiments, the method is used to treat cancers that respond poorly to chemotherapy or are resistant to chemotherapy, such as epithelial ovarian cancer.

[0267] In other embodiments, the method is used to treat cancers with P53 or ATM mutations, such as head and neck cancer, non-small cell lung cancer, ovarian epithelial tumors, esophageal and gastric cancer, pancreatic cancer, colorectal cancer, bladder cancer, glioma, sarcoma, endometrial cancer, breast cancer, hepatobiliary cancer, glioblastoma, adrenocortical carcinoma, melanoma, pleural mesothelioma, prostate cancer, bile duct cancer, mature B-cell tumors, cervical cancer, leukemia, non-clear cell renal cell carcinoma, thymic epithelial tumors, clear cell renal cell carcinoma, seminoma, pheochromocytoma, thyroid cancer, and non-seminomatous germ cell tumors.

[0268] In other embodiments, the method is used to treat leukemias such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative neoplasm, chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or squamous cell carcinoma.

[0269] The compounds of the present invention, and pharmaceutical compositions comprising them, may be administered alone or in combination with medical therapies to treat any of the said diseases. Medical therapies include, for example, surgery and radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, whole-body radioisotopes).

[0270] In other methods, the compounds and pharmaceutical compositions thereof described in this invention may be administered alone or in combination with one or more other agents to treat any of the said diseases.

[0271] In other methods, the compounds and pharmaceutical compositions thereof described in this invention may be administered in combination with agonists of nuclear receptor drugs.

[0272] In other methods, the compounds and pharmaceutical compositions thereof described in this invention may be administered in combination with antagonists of nuclear receptor drugs.

[0273] Combination therapy

[0274] The compounds of this invention can be used as a single agent or in combination with other treatments. Such treatments may include one or more of the following cancer therapies: for example, surgery, chemotherapy, radiation therapy, targeted therapy (e.g., growth factor inhibitors, kinase inhibitors, cyclin-dependent kinase inhibitors, etc.), other DDR modulators (e.g., PARP inhibitors, DNA-PK inhibitors, ATM inhibitors, ATR inhibitors, CHK1 inhibitors, LIG4 inhibitors, HIF-1 inhibitors, HDAC inhibitors, RAD51 inhibitors, WRN inhibitors, PRMT5 inhibitors, MAT2A inhibitors, PolQ inhibitors, etc.), immunotherapy, gene and cell therapy.

[0275] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with medical therapies such as surgery, radiation therapy, or chemotherapy. Exemplary radiation therapies include gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotopes. Exemplary suitable chemotherapeutic agents include one or more of the following classes of antitumor agents: other antiproliferative / antitumor drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolate agents, such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as bleomycin, doxorubicin, doxorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin, and scintillans); antimitotic agents (e.g., vinblastine alkaloids such as vincristine, vinblastine, vindesin, and vinorelbine, and antitumor drugs such as paclitaxel and doxorubicin and polo-like kinase inhibitors); topoisomerase inhibitors ( Examples include podophyllotoxins such as etoposide and teniposide, acridine, topotecan, and camptothecin; cell growth inhibitors such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifen, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilumet, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors such as finasteride; anti-invasive agents such as c-Src kinase family inhibitors (AZD0530, dasatinib, and bosutinib), and metalloproteinase family inhibitors (e.g., marimasitol, a family of urokinase plasminogen activator receptor function or heparinase antibodies).

[0276] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with targeted therapies, including growth factor function inhibitors (e.g., anti-erbB2 antibody trastuzumab, anti-EGFR antibody panitumumab, anti-erbB antibody cetuximab, and any growth factor or growth factor antibody disclosed by Stem et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, ppl1-29); such inhibitors also include tyrosine kinase inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, and CI). 1033), ERB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin-derived growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib; serine / threonine kinase inhibitors (e.g., Ras / Raf inhibitors sorafenib, telbifabib, and lonafabib); cell proliferation inhibitors via MEK and / or AKT kinases; c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Flt3 kinase inhibitors, CSF-1R kinase inhibitors; aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, and AX39459); anti-angiogenic agents, such as anti-angiogenic agents that inhibit the action of vascular endothelial growth factor (e.g., anti-vascular endothelial growth factor antibody bevacizumab, e.g., VEGF receptor tyrosine kinase inhibitors). Examples include vandetanib, vataranib, sunitinib, axitinib, pazopanib, and AZD2171; compounds disclosed in international patent applications WO97 / 22596, WO97 / 30035, WO97 / 32856, and WO98 / 13354; and compounds acting through other mechanisms (e.g., linolamine, integrin avβ3 inhibitors, and angiostatin); vascular damaging agents, such as cobustatin A4 and those disclosed in international patent applications WO99 / 02166, WO98 / 22596, WO97 / 30035, WO97 / 32856, and WO98 / 13354. Compounds disclosed in WO0 / 40529, WO00 / 41669, WO01 / 92224, WO02 / 04434 and WO02 / 08213; endothelin receptor antagonists, such as zippertentan or atrasentan; PARP inhibitors such as olaparib, rucaparib, niraparib, tapolazoparib, veriparib, and pamiparib; PARP1 selective inhibitors such as AZD9547, AZD5305, AG-14361 and NMS-P118;Other DNA damage repair modulators include DNA-PK inhibitors (e.g., LY294002, NU7026, NU7441, IC86621, IC87102, IC87361, OK-1035, SU11752, vanillin, NK314, IC486241, BVAN08, M3814, AZD7648, VX-984, doxycycline), ATM inhibitors (e.g., caffeine, wortmannin, CP-466722, KU-55933, KU-60019, and KU-559403), and ATR inhibitors (e.g., schisandrin). B, NU6027, NVP-BEZ235, VE-821, VE-822, AZ20, Elimusertib, RP-3500, and AZD6738), CHK1 inhibitors (e.g., LY2606368, PF-00477736, SRA737, SCH900776, MK8776, CCT244747, and AZD6738), DNA LIG4 inhibitors (e.g., SCR7), HIF-1 inhibitors (e.g., LW6 and PX-478), HDAC inhibitors (e.g., short-chain fatty acids, benzamides, isohydroxamic acid, and cyclic tetrapeptides, succinyl aniline isohydroxamic acid (SAHA), trogostatin A), RAD51 inhibitors (e.g., CYT-0851, SCR-6992, SAT-93 / 101, CAM833, JKYN-1 (IBR120-series, B02-iso)), WRN inhibitors ( For example, NCGC00029283), antisense therapy, such as therapies acting on the above targets, such as ISIS2503, an anti-ras antisense; gene therapy methods, including methods such as replacing abnormal genes, such as abnormal p53, CCNE1 amplification or FBXW7 loss-of-function mutations; GDEPT (gene-guided enzyme prodrug therapy) methods, such as methods using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and methods to increase patient tolerance to chemotherapy or radiotherapy, such as multidrug-resistant gene therapy;And immunotherapy methods, including, for example, in vitro and in vivo methods to increase the immunogenicity of the patient's tumor cells, such as transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor; methods to reduce T cell dysfunction; methods using transfected immune cells such as dendritic cells transfected with cytokines; methods using tumor cell lines transfected with cytokines; methods using anti-idiotype antibodies; methods using immune checkpoint inhibitors, such as CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGF, CD73, CD39, A2AR, A2BR, IDO1, TD02, Arginase, B7-H3, B7-H4; and methods using the above-mentioned immune checkpoint receptor and ligand inhibitors, such as ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, and durvalumab.

[0277] synthesis

[0278] The compounds described in this invention, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, such as those described below.

[0279] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent is one that does not substantially react with the starting material (reactant), the intermediate, or the product at the temperature at which the reaction is carried out; for example, the temperature range can be from the freezing temperature of the solvent to its boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Based on the specific reaction steps described above, those skilled in the art can select a solvent suitable for a particular reaction step.

[0280] The preparation of the compounds of the present invention may involve the above-described protection and deprotection of various chemical groups. The need for the above-described protection and deprotection, and the selection of suitable protecting groups, can be readily determined by those skilled in the art. Disclosed chemical protecting groups include, for example, Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Petrussion et al., "Protecting Groups in Carbohydrate Chemistry," J Chem. Educ, 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed. (Wiley, 2006).

[0281] The reaction can be monitored using any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible light), or mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin-layer chromatography.

[0282] As used in this invention, “ambient temperature,” “room temperature,” and “rt” generally refer to temperature in the art, such as reaction temperature, which refers to the temperature of the space where the reaction is performed, for example, about 20°C to about 30°C.

[0283] The compounds of the present invention can be prepared according to various preparation routes known in the literature. The following methods provide general guidance related to the preparation of the compounds described in the present invention. Those skilled in the art will understand that the preparation methods in the following methods can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Exemplary synthetic methods for preparing the compounds of the present invention are as follows.

[0284] The following examples are provided to illustrate some of the concepts described herein. While these examples are intended to provide embodiments, they should not be construed as limiting the more general embodiments described herein.

[0285] Synthesis scheme

[0286] A series of tricyclic derivatives represented by formula (IA) can be prepared according to the method described in Scheme 1. 2-Amino derivative 1-1 can be converted into 2-hydroxy derivative 1-2, which reacts with a halogenating agent such as SOCl2, POCl3, or POBr3 in or outside DMF (wherein W... 1 The reaction is carried out under the catalysis of Cl or Br, or with TfCl or MsCl (where W 1 In the presence of a base, such as Hunig's base, OTf or OMs can be further converted into the corresponding derivatives 1-3, wherein W 1 The compounds are halogens (e.g., Cl or Br) or pseudohalogens (e.g., OTf or OMs). Compounds 1-3 react with aromatic amines 1-4 under Buchwald coupling conditions (e.g., in the presence of a palladium catalyst such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3, or XantPhos Pd G3 and a base such as t-BuOK, t-BuONa, Cs2CO3, or K2CO3) to give aromatic amine derivatives 1-5. Amine derivatives 1-5 react with malononitriles under palladium catalytic conditions (e.g., in the presence of a palladium catalyst such as Pd(PPh3)2Cl2 or Pd(OAc)2 / PPh3 and a base such as t-BuOK or t-BuONa) to give aminopyrroles 1-6. Hydrolysis of the nitro groups 1-6 under acidic or alkaline conditions yields pyrrole-amide derivatives 1-7, which, in the presence of a trialkyl orthoformate ester 1-8 (where R is methyl or ethyl), can be further converted to indole-pyrimidinones 1-9 by reaction with an acid such as p-TsOH or HCl. Indole-pyrimidinones 1-9 then react with halogenating agents such as SOCl2, POCl3, or POBr3 in DMF (where W... 2 Catalyzed by Cl or Br, or with TfCl or MsCl (where W 2 (OTf or OMs) react in the presence of a base, such as Hunig's base, to convert to intermediates 1-10, wherein W 2 The intermediates are halogens (e.g., Cl, or Br) or pseudohalogens (e.g., OTf or OMs). Intermediates 1-10 react with ammonia or amine derivatives to give the tricyclic derivatives shown in the target formula (IA).

[0287] Option 1

[0288]

[0289] A series of intermediates of formulas 2-4 for preparing tricyclic derivatives of formula (IA) can be prepared according to the method described in scheme 2. Compound 2-1 (W 1 and W2 Malononitrile (e.g., halogens, such as Cl or Br) reacts with malononitrile under palladium catalysis (e.g., in the presence of palladium catalysts such as Pd(PPh3)2Cl2 or Pd(OAc)2 / PPh3, and bases such as t-BuOK or t-BuONa) to give malononitrile derivative 2-2. Malononitrile derivative 2-2 is then coupled with aromatic amine 2-3 under Buchwald coupling conditions (e.g., in the presence of palladium catalysts such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3, or XantPhos Pd G3, and bases such as t-BuOK, t-BuONa, Cs2CO3, or K2CO3) to give aminopyrrole derivative 2-4.

[0290] Option 2

[0291]

[0292] A series of intermediates of formulas 3-6 for the preparation of tricyclic derivatives of formula (IA) can be prepared according to the method described in scheme 3. Aromatic amine 3-1 is reacted with alkyl 2-cyanoacetate 3-2 (wherein R is Me or Et) in palladium-catalyzed conditions (e.g., in the presence of a palladium catalyst such as Pd(PPh3)2Cl2 or Pd(OAc)2 / PPh3, and a base such as t-BuOK or t-BuONa) to give aminopyrrole ester 3-3. The aminopyrrole ester 3-3 is then reacted with cyano derivative 2-4 in the presence of an acid, such as dry HCl, TsOH, or H2SO4, or with ethyl alkyl-carbonimide ester 3-5 to give tricyclic derivative 3-6.

[0293] Option 3

[0294]

[0295] A series of intermediates of formula 4-3 for preparing the tricyclic derivatives shown in formula (IA) can be prepared according to the method described in scheme 4. Compound 4-1 is coupled with borate ester 4-2 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride and a base, such as K3PO4), to give intermediate 4-3.

[0296] Option 4

[0297]

[0298] A series of tricyclic derivatives shown in formulas 5-8 can be prepared according to the method described in scheme 5. Compound 5-1, wherein W 2Halogens (e.g., Cl, Br, or I) and W 1 For halogens (e.g., Br, or Cl), the reaction is carried out first with malononitrile according to the method in Scheme 2, followed by Buchwald's amination with aromatic amine 5-3, or first with aromatic amine 5-3, followed by reaction with malononitrile under palladium catalysis according to the method in Scheme 1 (e.g., in the presence of a palladium catalyst such as Pd(PPh3)2Cl2 or Pd(OAc)2 / PPh3, and a base such as t-BuOK or t-BuONa) to convert compound 1-3 to aminopyrrole 1-6, which can be further converted to aminopyrrole derivative 5-4. Aminopyrrole derivative 5-4, with a suitable reagent, such as N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), or N-iodosuccinimide (NIS), yields compound 5-5, wherein W 3 For halogens (e.g., Cl, Br, or I), in the presence of metal-catalyzed coupling, such as standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) chloride and a base such as K3PO4), or standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) chloride), or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylpalladium)palladium(0)), a suitable R can be produced. 1 Group insertion yields compounds 5-6. Following the method in Scheme 1 for converting compounds 1-6 to formulas (IA) and (IB), compounds 5-6 can be further converted into tricyclic derivatives as shown in target formula 5-8.

[0299] Option 5

[0300]

[0301] Furthermore, a series of tricyclic derivatives of formulas 6-10 can be prepared according to the method described in Scheme 6. Pyrazine-2(1H)-one 6-1 undergoes an O-alkylation reaction with benzyl bromide or benzyl chloride in the presence of a base such as NaH or K2CO3 to yield pyrazine 6-2, which is then hydrolyzed successively with aromatic amine 6-3 and malononitrile according to the method for converting compound 1-3 to 1-7 in Scheme 1, to further convert to aminopyrrolamide 6-6. Hydrogenation of compound 6-6 in the presence of a palladium catalyst such as Pd / C or Pd(OH)2 / C yields the corresponding compound 6-7. The hydroxyl group of compound 6-7 reacts with a trifluorinating agent such as PhNTf2 or Tf2O in the presence of a base such as Et3N or Hunig's base to convert to the corresponding trifluoromethanesulfonate derivative 6-8. Trifluoromethanesulfonate derivative 6-8 can be further converted to the target compound 6-9, which can be further converted to tricyclic derivative 6-10 according to the method described in Scheme 1.

[0302] Option 6

[0303]

[0304] Furthermore, a series of tricyclic derivatives shown in Formulas 7-8 can be prepared according to the method described in Scheme 7. Compounds 7-3 are halogenated with N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), or N-iodosuccinimide (NIS), and R is inserted via metal-catalytic coupling, such as under Suzuki, Negishi, or Stille conditions, according to the method described in Scheme 5. 1 Group. Compound 7-3 can be converted into the target tricyclic derivative 7-8 according to the method described in Scheme 6.

[0305] Option 7

[0306]

[0307] A series of tricyclic derivatives of formulas 8-10 can be prepared according to the method described in Scheme 8. 2-Aminobromine derivative 8-1 (n is 0, 1, or 2) reacts with NaNO2 in the presence of an acid such as HCl or HBr, and then reacts with a halogenating agent such as CuCl, CuBr, or CuI to further convert to the corresponding derivative 8-2, wherein W is a halogen (e.g., Cl, Br, or I). Compound 8-2 is coupled with a suitable aromatic amine 8-3 under Buchwald coupling conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3, or XantPhos Pd G3, and a base, such as t-BuOK, t-BuONa, Cs2CO3, or K2CO3) to give aromatic amine derivative 8-4. The carboxylic acid ester group of said 8-4 can be reduced to the corresponding alcohol 8-5 with a reducing agent such as LiBH4 or NaBH4. The 3-Br of aromatic amine 8-5 is coupled with malononitrile under copper-catalyzed coupling conditions (e.g., CuI in a diamine-base ligand, such as N). 1 N 2 -Dimethylethane-1,2-diamine, N 1 N 2 Aminopyrrole 8-6 can be obtained by reacting -dimethylcyclohexane-1,2-diamine or cyclohexane-1,2-diamine, or under palladium catalysis (e.g., in the presence of a palladium catalyst such as Pd(PPh3)2Cl2 or Pd(OAc)2 / PPh3, and a base such as t-BuOK or t-BuONa). The nitrile of 8-6 is hydrolyzed under acidic or basic conditions to give pyrrole-amide derivative 8-7, which can be further converted to compound 8-8 by reacting with DPPA (diphenyl phosphate) and DBU, or by azide via a Mitsunobo reaction, or by reacting with sodium azide and DEAD or DIAD. The azide group of compound 8-8, reacted with triphenylphosphine or hydrogenated in the presence of a palladium catalyst such as Pd / C, gives the corresponding amine 8-9. The formation of an intramolecular amide yields the target tricyclic derivative shown in formula 8-10.

[0308] Option 8

[0309]

[0310] Furthermore, a series of tricyclic lactam derivatives of formulas 9-10 can be prepared according to the method described in Scheme 9. 3-Bromopyridin-2-amine 9-1 undergoes a condensation reaction with pyruvate in the presence of a palladium catalyst, such as bis(tri-tert-butylphosphine)palladium(0), and a base, such as potassium phosphate, to yield azaindole acid 9-2. Azaindole acid 9-2 reacts with diazomethane (wherein R is Me), or first with oxaloyl chloride and then with an alcohol ROH, to convert to the corresponding azaindole ester 9-3 (wherein R is Me or Et). Azaindole ester 9-3 can be prepared into azaindole derivative 9-4 in various ways: 1) reacting 9-3 with POCl3 in the presence of a catalytic amount of DMF, followed by reaction with an oxidizing agent, such as Ag₂O; 2) reacting 9-3 with anhydrous trifluoroacetic acid, followed by reaction with NaOH; 3) reacting 9-3 with 2,2,2-trichloroacetyl chloride, followed by reaction with NaOH. Indole derivative 9-4 reacts with protected amines such as p-methoxybenzylamine PMB-NH2 in the presence of amide coupling agents such as BOP, ByBOP, HATU, or HBTU, and bases such as Et3N or Hunig's base, to further convert to aza-indole lactam 9-5. Indole lactam 9-5 is coupled with aromatic iodine or aromatic bromine 9-6 under Buchwald coupling conditions (e.g., in the presence of palladium catalysts such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3, or XantPhos Pd G3 and bases such as t-BuOK, t-BuONa, Cs2CO3, or K2CO3) to give aza-indole derivative 9-7, which, along with the product of aza-indole acid 9-8 and DPPA (diphenyl azidophosphate), can be further converted to amino-aza-indole derivative 9-9 via Curtius rearrangement. The protecting group PMB of 9-9 is removed, and hydrogenation is carried out in the presence of a palladium catalyst such as Pd / C or Pd(OH)2 / C, or the reaction is carried out under acidic conditions such as TFA, to give the final tricyclic lactam derivative 9-10.

[0311] Option 9

[0312]

[0313] A series of intermediates of formula 10-6 for preparing tricyclic derivatives of formula (IB) can be prepared according to the method described in scheme 10. The 3-bromine of the aromatic amine 10-1 is substituted with an alkyl 2-cyanoacetate 10-2 (R = Me or Et) under palladium catalysis (e.g., in the presence of a palladium catalyst such as Pd(PPh3)2Cl2 or Pd(OAc)2 / PPh3, and a base such as t-BuOK or t-BuONa) to give aminopyrrole 10-3. The tricyclic derivative 10-6 can be prepared by reacting aminopyrrole 10-3 with a cyano derivative 10-4 in the presence of an acid such as dry HCl, TsOH, or H2SO4, or with an ethylalkyl-carbodiimide 10-5.

[0314] Option 10

[0315]

[0316] A series of intermediates of formula 11-3 for the preparation of tricyclic derivatives of formula (IB) can be prepared according to the method described in scheme 11. Compound 4-1 is coupled with borate ester 11-2 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride and a base such as K3PO4) to give intermediate 11-3.

[0317] Option 11

[0318]

[0319] A series of tricyclic derivatives of formula 12-8 can be prepared according to the method described in scheme 12. Compound 12-1, wherein W 2 Halogens (e.g., Cl, Br, or I) and W 1 For halogens (e.g., Br, or Cl), following the method described in Scheme 9, the compound is first reacted with malononitrile, then subjected to Buchwald's amination with aromatic amine 12-3, or, following the method for converting compound 8-3 to aminopyrrole 8-6 in Scheme 8, first subjected to Buchwald's amination with aromatic amine 12-3, then reacted with malononitrile under palladium catalytic conditions (e.g., in the presence of palladium catalysts such as Pd(PPh3)2Cl2 or Pd(OAc)2 / PPh3, and a base such as t-BuOK or t-BuONa), to further convert to aminopyrrole derivative 12-4. Aminopyrrole derivative 12-4, halogenated with suitable practical substances such as N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), or N-iodosuccinimide (NIS), yields compound 12-5, wherein W 3For halogens (e.g., Cl, Br, or I), R can be converted to halogens in the presence of metal-mediated coupling reactions. 1 Substituting a halogen group for a halogen, for example, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) chloride and a base such as K3PO4), or standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(O) or [1,1′-bis(diphenylphosphine)-ferrocene]palladium(II) chloride), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O),) yields compound 12-6. Compound 12-6 can be further converted into the tricyclic derivatives shown in formula 12-8 by the method of converting compound 8-6 to formulas (IA) and (IB) in scheme 8.

[0320] Option 12

[0321] Example

[0322] Example 1: 3-(4-amino-6-morpholino-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

[0323]

[0324] Step 1: 1-Bromo-2,4-dimethyl-3-nitrobenzene

[0325]

[0326] A solution of Br2 (22.2 g, 139 mmol) in CHCl3 (100 mL) was added to a suspension of 1,3-dimethyl-2-nitrobenzene (20.0 g, 132 mmol) and Fe (2.96 g, 52.9 mmol) in 200 mL CHCl3. The reaction mixture was stirred at 15 °C for 12 h, and then diluted with water (500 mL). The mixture was extracted with DCM (2 x 250 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude target compound (26.0 g) as a light brown solid, which could be used directly in the next step without purification. 1 H NMR: (400MHz, CDCl3) δ7.55 (d, J=8.4, 1H), 7.01 (d, J=8.4, 1H), 2.35 (s, 3H), 2.26 (s, 3H).

[0327] Step 2: 2,4-Dimethyl-3-nitrophenol

[0328]

[0329] A mixture of 1-bromo-2,4-dimethyl-3-nitrobenzene (20.0 g, 86.9 mmol), KOH (14.6 g, 261 mmol), 2'-di-tert-butylphosphine-2,4,6-triisopropylbiphenyl (7.38 g, 17.4 mmol), and bis(benzylacetone)palladium (7.96 g, 8.69 mmol) in dioxane (200 mL) and H₂O (200 mL) was degassed and purged with N₂, purged three times, and stirred at 90 °C for 12 h under N₂ atmosphere. After cooling to rt, the reaction mixture was diluted with water (600 mL), adjusted to pH ~3 with 1 M HCl aq., and extracted with EtOAc (250 mL). The organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column and eluted with EtOAc / PE (2-20%) to give the target compound (10.0 g, crude product) as a light brown solid. 1 H NMR: (400MHz, CDCl3) δ6.95 (d, J=8.4, 1H), 6.78 (d, J=8.4, 1H), 2.22 (s, 3H), 2.17 (s, 3H).

[0330] Step 3: 1-Methoxy-2,4-dimethyl-3-nitrobenzene

[0331]

[0332] To a solution of 2,4-dimethyl-3-nitrophenol (12.0 g, 71.8 mmol) in acetone (84.0 mL), cesium carbonate (46.8 g, 144 mmol) and CH3I (15.3 g, 108 mmol) were added. The reaction mixture was stirred at 15 °C for 12 h. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (2-20%), to give the crude target compound (10 g) as a pale yellow solid.

[0333] Step 4: 3-Methoxy-2,6-Dimethylaniline

[0334]

[0335] Fe (21.6 g, 386 mmol) and NH4Cl (20.7 g, 386 mmol) were added to a solution of 1-methoxy-2,4-dimethyl-3-nitrobenzene (7 g, 38.6 mmol) in EtOH (35.0 mL) and H2O (35.0 mL). The reaction mixture was stirred at 80 °C for 2 h. The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (2-20%), to give the target compound (5.00 g) as a pale yellow oil. 1 H NMR: (400MHz, CDCl3) δ6.90 (d, J=12, 1H), 6.32 (d, J=8.0, 1H), 3.80 (s, 3H), 3.62 (brs, 2H), 2.15 (s, 3H), 2.09 (s, 3H).

[0336] Step 5: 5-Bromo-6-chloropyrazine-2-ol

[0337]

[0338] At 0 °C, NaNO2 (7.28 g, 106 mmol) was carefully added in portions to a concentrated H2SO4 (98%, 140 mL) solution of 5-bromo-6-chloropyrazin-2-amine (20.0 g, 96.0 mmol). The reaction mixture was stirred at 0 °C for 1 h, and then poured into ice water. The solid was collected by filtration and dried under vacuum to give the target compound (20.0 g) as a light brown solid, which could be used directly in the next step without further purification.

[0339] Step 6: 5-(benzyloxy)-2-bromo-3-chloropyrazine

[0340]

[0341] To a solution of 5-bromo-6-chloropyrazin-2-ol (8.00 g, 38.2 mmol) in toluene (140 mL), (bromomethyl)benzene (7.19 g, 42.0 mmol) and Ag₂CO₃ (21.1 g, 76.4 mmol) were added. The reaction mixture was stirred at 15 °C for 3 h. The solid was removed by filtration, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (10–50%), to give the target compound (6.90 g, 60.3% yield) as a brown solid. ¹H NMR: (400 MHz, CDCl₃) δ 7.99 (s, 1H), 7.39–7.47 (m, 5H), 5.38 (s, 2H).

[0342] Step 7: 5-(benzyloxy)-3-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyrazine-2-amine

[0343]

[0344] At rest, potassium tert-butoxide (1.59 g, 14.2 mmol), 3-methoxy-2,6-dimethylaniline (1.61 g, 10.6 mmol), bis(benzylacetone)palladium (487 mg, 0.53 mmol), and Xantphos (616 mg, 1.06 mmol) were added to a toluene (15.0 mL) solution of 5-(benzyloxy)-2-bromo-3-chloropyrazine (3.19 g, 10.6 mmol), bis(benzylacetone)palladium (487 mg, 0.53 mmol), and Xantphos (616 mg, 1.06 mmol) to the reaction mixture. The reaction mixture was degassed and purged with nitrogen three times, and stirred at 80 °C for 1 h. The reaction mixture was cooled to rest, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by rapid chromatography on a silica gel column using EtOAc / PE (0.25–2%) to give the target compound (2.40 g, 60.9% yield) as a pale yellow oil. 1 H NMR: (400MHz, CDCl3) δ7.75 (s, 1H), 7.27-7.65 (m, 5H), 7.08 (d, J=8.4, 1H), 6.77 (d, J=8.4, 1H), 6.06 (s, 1H), 5.30 (s, 2H), 3.84 (s, 3H), 2.15 (s, 3H), 2.09 (s, 3H).

[0345] Step 8: 6-Amino-2-(benzyloxy)-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazine-7-nitrile

[0346]

[0347] Sodium hydride (632 mg, 15.8 mmol) was added to a solution of malononitrile (1.04 g, 15.8 mmol) in dimethyl ether (73.0 mL) under reflux. The reaction mixture was stirred under reflux for 30 mins, and then a solution of 5-(benzyloxy)-3-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyrazine-2-amine (1.46 g, 3.95 mmol) in 1,2-dimethoxyethane (7.30 mL) and tetra(triphenylphosphine)palladium (2.28 g, 1.97 mmol) was added under reflux. The reaction mixture was degassed and purged with nitrogen three times, and stirred at 80–85 °C for 2 h. After cooling, the mixture was quenched with H₂O (100 mL) at 0 °C and extracted with DCM (2 x 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluted with MeOH / DCM (1-50%), to give the target compound (1.90 g, 78.7% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δ7.65 (s, 1H), 7.23-7.53 (m, 6H), 6.97 (d, J=8.4, 1H), 5.49 (s, 2H), 4.85 (s, 2H), 3.87 (s, 3H), 1.93 (s, 3H), 1.86 (s, 3H).

[0348] Step 9: 6-Amino-2-hydroxy-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

[0349]

[0350] A concentrated H₂SO₄ solution (98%, 10 mL) of 6-amino-2-(benzyloxy)-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-onitrile (1.90 g, 4.76 mmol) was stirred at 15 °C for 2 h. The reaction mixture was then added to ice (~50 g) below 10 °C. The pH of the mixture was adjusted to ~8 with NH₃·H₂O (25-30%, ~40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the target compound (1.30 g) as a brown oil, which could be used directly in the next step without purification. 1¹H NMR: (400MHz, CDCl₃) δ 7.52 (s, ¹H), 7.21 (d, J = 8.4, ¹H), 6.95 (d, J = 8.4, ¹H), 6.05 (brs, 2H), 3.87 (s, 3H), 1.95 (s, 3H), 1.88 (s, 3H). LCMS calculated C 16 H 18 N5O3[M+H] + m / z = 328.1; Measured value: 327.9. Step 10: 6-amino-7-formyl-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yltrifluoromethanesulfonate

[0351]

[0352] At rt, cesium carbonate (2.85 g, 8.74 mmol) was added to a DMF (6.00 mL) solution of 6-amino-2-hydroxy-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-carboxamide (1.30 g, 3.97 mmol), followed by N-phenyl-bis(trifluoromethanesulfonylimide) (1.56 g, 4.37 mmol) at 0–5 °C. The reaction mixture was stirred at 0–5 °C for 0.5 h, quenched with water (20.0 mL), and extracted with EtOAc (2 x 5 mL). The combined organic phases were washed with saturated brine (5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluted with EtOAc / PE (10-50%), to give the target compound (0.64 g, 35.1% yield) as a light brown oil. 1 HNMR: (400MHz, CDCl3) δ7.70 (s, 1H), 7.16 (s, 1H), 6.92 (d, J = 8.4, 1H), 3.81 (s, 3H), 1.86 (s, 3H), 1.79 (s, 3H).

[0353] Step 11: 6-Amino-5-(3-methoxy-2,6-dimethylphenyl)-2-morpholine-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

[0354]

[0355] Morpholine (3.0 g, 34.4 mmol) was added to a DMSO (2.0 mL) solution of 6-amino-7-formyl-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yltrifluoromethanesulfonate (0.64 g, 1.39 mmol). The reaction mixture was stirred at 135 °C for 2 h. The reaction mixture was cooled to rt, quenched with water (6.00 mL), and extracted with EtOAc (2 x 5 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (10-50%), to give the target compound (0.34 g, 0.86 mmol) as a light brown foam. 1 HNMR: (400MHz, CDCl3) δ7.70 (brs, 1H), 7.44 (s, 1H), 7.21 (d, J=8.4, 1H), 6.95 (d, J=8.4, 1H), 6.02(brs, 2H), 3.89-3.92(m, 4H), 3.87(s, 3H), 3.48-3.50(m, 4H), 1.95(s, 3H), 1.88(s, 3H).

[0356] Step 12: 9-(3-methoxy-2,6-dimethylphenyl)-6-morpholine-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-ol

[0357]

[0358] A mixture of 6-amino-5-(3-methoxy-2,6-dimethylphenyl)-2-morpholine-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.2 g, 0.5 mmol) and trimethyl orthoformate (4 mL) was added to TsOH·H₂O (9.60 mg, 0.05 mmol). The reaction mixture was stirred at 40 °C for 1 h. The filtrate was concentrated under reduced pressure to give crude target compound (0.2 g), a brown oil, which could be used directly in the next step without purification. LCMS calculated value C 21 H 23 N6O3[M+H] + m / z = 407.2; measured value: 407.1.

[0359] Step 13: 4-(4-chloro-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-6-yl)morpholine

[0360]

[0361] A mixture of 9-(3-methoxy-2,6-dimethylphenyl)-6-morpholine-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-ol (0.20 g, 0.49 mmol) and POCl3 (7.55 g, 49.2 mmol) was stirred at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water (1 mL), adjusted to pH ~8 with saturated NaHCO3 (1 mL), and extracted with EtOAc (2 x 2 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude target compound (0.2 g), a light brown oil, which could be used directly in the next step without purification. LCMS calculated value C 21 H 22 ClN6O2[M+H] + m / z = 425.1; Measured value: 425.0.

[0362] Step 14: 9-(3-methoxy-2,6-dimethylphenyl)-6-morpholine-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0363]

[0364] In a sealed tube, NH3 / MeOH (6M, 20.0 mL) was added to a MeOH solution of 0.2 g (0.47 mmol) of 4-(4-chloro-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-6-yl)morpholine (1.0 mL). The reaction mixture was stirred overnight at 80 °C, and the filtrate was concentrated under reduced pressure to give crude target compound (0.2 g), a light brown oil, which could be used directly in the next step without purification. 1 ¹H NMR: (400MHz, MeOD) δ 8.25 (s, 1H), 7.99 (s, 1H), 7.23 (d, J = 8.4, 1H), 7.08 (d, J = 8.4, 1H), 3.87–3.90 (m, 7H), 3.64–3.66 (m, 4H), 1.80–1.81 (m, 2H), 1.72–1.73 (m, 2H). LCMS calculated Cp 21 H 24 N7O2[M+H] + m / z = 406.2; measured value: 406.3.

[0365] Step 15: 3-(4-amino-6-morpholino-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

[0366] A mixture of 9-(3-methoxy-2,6-dimethylphenyl)-6-morpholine-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (0.2 g, 0.49 mmol) in HBr (40%) (4.47 g, 22.1 mmol, 3 mL) was stirred at 80 °C for 1 h. The reaction mixture was decanted into ice water at 0 °C, and the pH was adjusted to 7–8 with NH3·H2O (25–30%). Extraction was performed with EtOAc (3 x 5 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC on a C18 column, eluting with MeCN / water (30–60% containing 1% NH4HCO3) to give the target compound (0.048 g, 24.5% yield) as a pale yellow solid. 1 ¹H NMR: (400MHz, MeOD) δ 8.25 (s, 1H), 7.99 (s, 1H), 7.08 (d, J = 8.4, 1H), 6.91 (d, J = 8.4, 1H), 3.87–3.90 (m, 4H), 3.64–3.66 (m, 4H), 1.78 (s, 3H), 1.72 (s, 3H). LCMS calculated C0 20 H 22 N7O2[M+H] + m / z = 392.2; measured value: 392.1.

[0367] The compound is a mixture of (3Ra)-(4-amino-6-morpholine-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol and its enantiomer (3Sa)-(4-amino-6-morpholine-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol.

[0368] Example 2: 3-(4-amino-6-methyl-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

[0369]

[0370] Step 1: 6-Amino-5-(3-methoxy-2,6-dimethylphenyl)-2-methyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

[0371]

[0372] A mixture of 6-amino-7-formyl-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yltrifluoromethanesulfonate (1.00 g, 2.18 mmol, Example 1, Step 10), 2,4,6-trimethyl-1,3,5,2,4,6-cycloboroxane (601 mg, 2.39 mmol, 0.67 mL, 50% purity), tetra(triphenylphosphine)palladium (252 mg, 0.22 mmol), and potassium carbonate (902 mg, 6.53 mmol) in dioxane (10.0 mL) was degassed and purged with N2, purged three times, and stirred for 2 h at 140 °C under N2 atmosphere. The mixture was cooled to 15 °C, diluted with H2O (50 mL), and extracted with EtOAc (3 x 25 mL). The combined organic phases were washed with saturated brine (50 mL), dried over Na₂SO₄, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (10-50%) to give the target compound (0.40 g, 56.5% yield) as a light brown foam. LCMS calculated C 17 H 20 N5O2[M+H] + m / z = 326.2; Measured value: 325.9

[0373] Step 2: 3-(4-amino-6-methyl-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

[0374]

[0375] The compound was prepared in a manner similar to steps 12-15 of Example 1, in which 6-amino-5-(3-methoxy-2,6-dimethylphenyl)-2-methyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide was used as the starting material. 1 ¹H NMR: (400MHz, MeOD) δ 8.34 (s, 1H), 8.25 (s, 1H), 7.05 (d, J = 8.4, 1H), 6.92 (d, J = 8.4, 1H), 2.67 (s, 3H), 1.68 (s, 3H), 1.58 (s, 3H). LCMS calculated C 17 H 17 N6O[M+H] + m / z = 321.1; Measured value: 321.1.

[0376] The compound is a mixture of (3Ra)-(4-amino-6-methyl-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol and its enantiomer (3Sa)-(4-amino-6-methyl-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol.

[0377] Example 3: 3-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

[0378]

[0379] Step 1: 3-Bromo-5,6-dimethylpyridin-2-ol

[0380]

[0381] The compound was prepared in a manner similar to step 5 of Example 1, except that 3-bromo-5,6-dimethylpyridine-2-amine was used instead of 5-bromo-6-chloropyrazine-2-amine. 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 11.96 (brs, ¹H), 7.73 (s, ¹H), 2.11 (s, ³H), 1.96 (s, ³H). LCMS calculated value: C₇H₉BrNO[M+H] + m / z = 201.9; measured value: 201.8.

[0382] Step 2: 2,3-Dibromo-5,6-dimethylpyridine

[0383]

[0384] Under a nitrogen atmosphere, a solution of POBr3 (26.2 g, 91.3 mmol, 9.28 mL) in xylene (30.0 mL) was added dropwise to a solution of 3-bromo-5,6-dimethylpyridin-2-ol (12.3 g, 60.9 mmol) in DMF (37.0 mL) and toluene (62.0 mL). The reaction mixture was stirred at 90 °C for 12 h. After cooling to rt, the mixture was slowly poured into water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed successively with NaOH aq. (0.5 N, 30 mL) and water (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (5-20%), to give the target compound (12.0 g, 74.4% yield) as a white solid. 1¹H NMR: (400 MHz, CDCl₃) δ 7.62 (s, 1H), 2.45 (s, 3H), 2.24 (s, 3H). LCMS calculated value: C₇H₈Br₂N[M+H] + m / z = 263.8; Measured value: 263.8.

[0385] Step 3: 3-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridine-2-amine

[0386]

[0387] The compound was prepared in a manner similar to step 7 of Example 1, except that 5-(benzyloxy)-2-bromo-3-chloropyrazine was replaced with 2,3-dibromo-5,6-dimethylpyridine and potassium tert-butoxide was replaced with cesium carbonate. 1 ¹H NMR: (400 MHz, CDCl₃) δ 7.44 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.20 (s, 1H), 3.85 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H). LCMS calculated C 16 H 20 BrN2O[M+H] + m / z = 335.1; Measured value: 335.0.

[0388] Step 4: 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-nitrile

[0389]

[0390] Under a nitrogen atmosphere, sodium tert-butoxide (2.87 g, 29.8 mmol) was added to a solution of malononitrile (1.97 g, 29.8 mmol) in 1,2-dimethoxyethane (35.0 mL). The mixture was stirred at 15 °C for 30 min, and then 3-bromo-N-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (5.00 g, 14.9 mmol) and 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (1.22 g, 1.49 mmol) were added. The reaction mixture was degassed and purged with nitrogen three times, and stirred at 85 °C under a nitrogen atmosphere for 12 h. After cooling to rt, the mixture was diluted with water (40.0 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (10-50%) to give the target compound (4.30 g, 90.0% yield) as a light brown solid. 1 ¹H NMR: (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.50 (brs, 1H), 3.88 (s, 3H), 2.38 (s, 3H), 2.33 (s, 3H), 1.92 (s, 3H), 1.85 (s, 3H). LCMS calculated C 19 H 21 N4O[M+H] + m / z = 321.2; measured value: 321.0.

[0391] Step 5: 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-nitrile

[0392]

[0393] At 0 °C, BBr3 (6.26 g, 25.0 mmol, 2.41 mL) was added dropwise to a DCM solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-onitrile (4.00 g, 12.5 mmol) in 40.0 mL. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (100 mL) at 0 °C and extracted with 2-methyltetrahydrofuran (2 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude target compound (2.00 g) as a pale yellow solid, which could be used directly in the next step without purification.1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 9.50 (s, 1H), 7.37 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 6.4 Hz, 1H), 6.72 (s, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H). LCMS calculated C 18 H 19 N4O[M+H] + m / z = 307.1; Measured value: 307.1.

[0394] Step 6: 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0395]

[0396] The compound was prepared using a method similar to step 9 of Example 1. 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 9.47 (s, 1H), 7.82 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.71 (s, 2H), 6.63 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.73 (s, 3H), 1.65 (s, 3H). LCMS calculated C 18 H 21 N4O2[M+H] + m / z = 325.2; Measured value: 325.2.

[0397] Step 7: 9-(3-hydroxy-2,6-dimethylphenyl)-6,7-dimethyl-3,9-dihydro-4H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-one

[0398]

[0399] The compound was prepared using a method similar to step 12 of Example 1. 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 12.48 (s, 1H), 9.49 (s, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H), 1.67 (s, 3H), 1.57 (s, 3H). LCMS calculated C 19H 19 N4O2[M+H] + m / z = 335.1; Measured value: 335.1.

[0400] Step 8: 3-(4-chloro-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

[0401]

[0402] The compound was prepared in a manner similar to step 13 of Example 1. 1 ¹H NMR: (400MHz, MeOD) δ 8.69 (s, 1H), 8.54 (s, 1H), 7.11 (d, J = 8.4Hz, 1H), 6.95 (d, J = 8.0Hz, 1H), 2.59 (s, 3H), 2.53 (s, 3H), 1.74 (s, 3H), 1.68 (s, 3H). LCMS calculated C0 19 H 18 ClN4O[M+H] + m / z = 353.1; measured value: 353.2.

[0403] Step 9: 3-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

[0404] The compound was prepared in a manner similar to step 14 of Example 1. 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 9.52 (brs, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 8.17 (brs, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H), 2.41 (s, 3H), 1.66 (s, 3H), 1.56 (s, 3H). LCMS calculated C 19 H 20 N5O[M+H] + m / z = 334.2; measured value: 334.1.

[0405] The compound is a mixture of (3Ra)-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol and its enantiomer (3Sa)-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol.

[0406] Example 4: (3Ra)-3-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol and

[0407] Example 5: (3Sa)-3-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-dimethylphenol

[0408]

[0409] Example 3 (204 mg) was separated by Chiral-HPLC to obtain P1 (earlier elution product, 49.8 mg, HPLC retention time in chiral mode = 2.478 min) and P2 (later elution product, 62.9 mg, HPLC retention time in chiral mode = 2.783 min). Chiral HPLC separation conditions: Instrument: Waters-SFC80; Column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); Mobile phase A: supercritical CO2, Mobile phase B: MeOH (0.1% IPAM), Gradient: B% = 33% isocratic elution; Flow rate: 60 g / min; Sample preparation: methanol; Injection volume: 2.0 mL; Detection wavelength: 220 nm; Column temperature: 40 °C; Back pressure: 100 bar. The separated products were determined by chiral HPLC. Chiral HPLC conditions: Column: Chiralcel OJ-3, 150×4.6mm ID, 3μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% IPAm); Flow rate: 2.5ml / min, Run time: 5min; Detection wavelength: 220nm.

[0410] P1 is Example 4. 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 9.39 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.34 (s, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H). LCMS calculated C 19 H 20 N5O[M+H] + m / z = 334.2; measured value: 334.1.

[0411] P2 is Example 5. 1¹H NMR: (400 MHz, DMSO-d⁶) δ 9.42 (s, 1H), 8.59 (s, 1H), 8.19 (s, 1H), 7.34 (s, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H). LCMS calculated C 19 H 20 N5O[M+H] + m / z = 334.2; measured value: 334.1.

[0412] Example 6: 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthidium-3(1H)-one

[0413]

[0414] Step 1: Methyl 2-amino-5-methylpyridine-4-carboxylate

[0415]

[0416] To a solution of methyl 2-amino-5-bromopyridin-4-carboxylate (10.0 g, 43.2 mmol) in 1,4-dioxane (100 mL), trimethyl-1,3,5,2,4,6-cycloboroxane (27.1 g, 216 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (3.17 g, 4.32 mmol), and potassium carbonate (17.9 g, 129 mmol) were added. The reaction mixture was degassed and purged with nitrogen three times, and stirred at 100 °C for 5 h. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (0-40%), to give the target compound (7.00 g, 97% yield) as a yellow solid. LCMS calculated C8H 11 N₂O₂[M+H] + m / z = 167.1; Measured value: 167.1.

[0417] Step 2: Methyl 2-amino-3-bromo-5-methylpyridine-4-carboxylate

[0418]

[0419] To a solution of methyl 2-amino-5-methylpyridine-4-carboxylate (7.00 g, 42.1 mmol) in acetonitrile (50 mL), N-bromosuccinimide (7.50 g, 42.1 mmol) was added. The reaction mixture was stirred overnight at rt and concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (0–50%), to give the target compound (8.20 g, 79% yield) as a white solid. LCMS calculated C8H 10 BrN2O2[M+H] + m / z = 245.0; Measured value: 245.0.

[0420] Step 3: Methyl 2,3-dibromo-5-methylpyridine-4-carboxylate

[0421]

[0422] At -10 °C, a solution of NaNO2 (0.56 g, 8.16 mmol) in H2O (2 mL) was added dropwise to a mixture of methyl 2-amino-3-bromo-5-methylpyridine-4-carboxylate (2.00 g, 8.16 mmol) and HBr (10 mL, 40% aq.). The reaction mixture was stirred at -10 °C for 30 mins, then CuBr (1.40 g, 9.75 mmol) was added, and the mixture was stirred at -5 °C for another 2 h. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with saturated brine (3 x 10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (0-30%), to give the target compound (800 mg, 31% yield) as a pale yellow solid. LCMS calculated value: C8H8Br2NO2[M+H] + m / z = 307.9; Measured value: 307.9.

[0423] Step 4: 1-Bromo-2,4-dimethyl-3-nitrobenzene

[0424]

[0425] A solution of Br2 (22.2 g, 139 mmol) in CHCl3 (100 mL) was added to a suspension of 1,3-dimethyl-2-nitrobenzene (20.0 g, 132 mmol) and Fe (2.96 g, 52.9 mmol) in 200 mL CHCl3. The reaction mixture was stirred at 15 °C for 12 h and then diluted with water (500 mL). The mixture was extracted with DCM (2 x 250 mL). The combined organic phases were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude target compound (26.0 g) as a light brown solid, which could be used directly in the next step without purification. 1 H NMR: (400MHz, CDCl3) δ7.55 (d, J=8.4, 1H), 7.01 (d, J=8.4, 1H), 2.35 (s, 3H), 2.26 (s, 3H).

[0426] Step 5: 2,4-Dimethyl-3-nitrophenol

[0427]

[0428] A mixture of 1-bromo-2,4-dimethyl-3-nitrobenzene (20.0 g, 86.9 mmol), KOH (14.6 g, 261 mmol), 2'-di-tert-butylphosphine-2,4,6-triisopropylbiphenyl (7.38 g, 17.4 mmol), and bis(benzylacetone)palladium (7.96 g, 8.69 mmol) in dioxane (200 mL) and H₂O (200 mL) was degassed and purged with nitrogen, replacing N₂ three times. The mixture was stirred for 12 h at 90 °C under an N₂ atmosphere. After cooling to rt, the reaction mixture was diluted with water (600 mL), adjusted to pH ~3 with 1 M HCl aq., and extracted with EtOAc (250 mL). The organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column and eluted with EtOAc / PE (2-20%) to give the target compound (10.0 g, crude product) as a light brown solid. 1 HNMR: (400MHz, CDCl3) δ6.95 (d, J=8.4, 1H), 6.78 (d, J=8.4, 1H), 2.22 (s, 3H), 2.17 (s, 3H).

[0429] Step 6: 1-Methoxy-2,4-dimethyl-3-nitrobenzene

[0430]

[0431] To a solution of 2,4-dimethyl-3-nitrophenol (12.0 g, 71.8 mmol) in acetone (84.0 mL), cesium carbonate (46.8 g, 144 mmol) and CH3I (15.3 g, 108 mmol) were added. The reaction mixture was stirred at 15 °C for 12 h. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (2-20%), to give the crude target compound (10 g) as a pale yellow solid.

[0432] Step 7: 3-Methoxy-2,6-Dimethylaniline

[0433]

[0434] Fe (21.6 g, 386 mmol) and NH4Cl (20.7 g, 386 mmol) were added to a solution of 1-methoxy-2,4-dimethyl-3-nitrobenzene (7 g, 38.6 mmol) in EtOH (35.0 mL) and H2O (35.0 mL). The reaction mixture was stirred at 80 °C for 2 h. The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (2-20%), to give the target compound (5.00 g) as a pale yellow oil. 1 H NMR: (400MHz, CDCl3) δ6.90 (d, J=12, 1H), 6.32 (d, J=8.0, 1H), 3.80 (s, 3H), 3.62 (brs, 2H), 2.15 (s, 3H), 2.09 (s, 3H).

[0435] Step 8: Methyl 3-bromo-2-[(3-methoxy-2,6-dimethylphenyl)amino]-5-methylpyridine-4-carboxylate

[0436]

[0437] A mixture of methyl 2,3-dibromo-5-methylpyridin-4-carboxylate (100 mg, 0.324 mmol), 3-methoxy-2,6-dimethylaniline (58.7 mg, 0.389 mmol), bis(dibenzylacetone)palladium (29.6 mg, 0.032 mmol), XantPhos (37.4 mg, 0.065 mmol), and potassium tert-butoxide (108 mg, 0.972 mmol) in toluene (5 mL) was degassed and purged with nitrogen three times, and stirred overnight at 80 °C under nitrogen atmosphere. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (0-50%), to give the target compound (45.0 mg, 36% yield) as a yellow solid. LCMS calculated C 17 H 20 BrN2O3[M+H] + m / z = 379.1; Measured value: 379.1.

[0438] Step 9: {3-bromo-2-[(3-methoxy-2,6-dimethylphenyl)amino]-5-methylpyridin-4-yl}methanol

[0439]

[0440] At 0 °C, a solution of methyl 3-bromo-2-[(3-methoxy-2,6-dimethylphenyl)amino]-5-methylpyridine-4-carboxylate (1.15 g, 3.03 g) in tetrahydrofuran (25 mL) was added dropwise to a solution of lithium borohydride in tetrahydrofuran (2 M, 7.6 mL, 15.2 mmol). The reaction mixture was stirred overnight at 60 °C and quenched with water (150 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with saturated brine (2 x 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EtOAc / PE (0-50%), to give the target compound (640 mg, 60% yield) as an off-white solid. LCMS calculated value C 16 H 20 BrN2O2[M+H+2] + m / z = 353.1; Measured value: 353.0. Step 10: 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-nitrile

[0441]

[0442] {3-bromo-2-[(3-methoxy-2,6-dimethylphenyl)amino]-5-methylpyridin-4-yl}methanol (540 mg, 1.54 mmol), malononitrile (203 mg, 3.07 mmol), N 1 N 2 A mixture of DMSO (5 mL) containing dimethylethyl-1,2-diamine (54.2 mg, 0.615 mmol), CuI (58.6 mg, 0.307 mmol), and potassium carbonate (637 mg, 4.61 mmol) was degassed and purged with nitrogen three times. The reaction mixture was reacted in a microwave oven at 130 °C for 1 h, followed by quenching with water (80 mL). The mixture was extracted with EtOAc (3 x 120 mL). The combined organic phases were washed with saturated brine (2 x 40 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc / PE, 1:1) to give the target compound (198 mg, 38% yield) as a yellow solid. LCMS calculated C 19 H 21 N4O2[M+H] + m / z = 337.2; Measured value: 337.1. Step 11: Methyl 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid ester

[0443]

[0444] A mixture of 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-onitrile (198 mg, 0.589 mmol) and HCl (g) in MeOH (4 M, 5 mL) was stirred at 60 °C for 8 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-TLC (EtOAc / PE, 1:1) to give the target compound (121 mg, 56% yield) as a yellow solid. LCMS calculated C 20 H 24 N3O4[M+H] + m / z = 370.2 Measured value: 370.1.

[0445] Step 12: Methyl 2-amino-4-(azidomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylate

[0446]

[0447] A mixture of methyl 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylate (121 mg, 0.328 mmol), diphenyl azide phosphate (450 mg, 1.64 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (249 mg, 1.64 mmol) in tetrahydrofuran (10 mL) was stirred at 60 °C for 6 h and then quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic phases were washed with saturated brine (2 x 30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc / PE, 1 / 1) to give the target compound (77 mg, 60% yield) as a yellow solid. LCMS calculated value C 20 H 23 N6O3[M+H] + m / z = 395.2; Measured value: 395.2.

[0448] Step 13: Methyl 2-amino-4-(aminomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylate

[0449]

[0450] A mixture of methyl 2-amino-4-(azidomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylate (77.0 mg, 0.195 mmol) and triphenylphosphine (102 mg, 0.39 mmol) in water (2 mL) and tetrahydrofuran (10 mL) was stirred overnight under rt and nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 80 mL). The combined organic phases were washed with saturated brine (2 x 30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH / DCM, 1 / 10) to give the target compound (56 mg, 78% yield) as an off-white solid. LCMS calculated C 20 H 25 N4O3[M+H] + m / z = 369.2; measured value: 369.1.

[0451] Step 14: 3-amino-2-(3-methoxy-2,6-dimethylphenyl)-9-methyl-2,6,11-triazine tricyclo[6.3.1.0^{4,12}]dodecanoa-1(11),3,8(12),9-tetraen-5-one

[0452]

[0453] A mixture of methyl 2-amino-4-(aminomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylate (56 mg, 0.152 mmol) and potassium carbonate (63.02 mg, 0.456 mmol) in methanol (4 mL) was stirred overnight at 80 °C and then quenched with water (50 mL). The mixture was extracted with EtOAc (3 x 80 mL). The combined organic phases were washed with saturated brine (2 x 30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc / PE, 1 / 9) to give the target compound (46 mg, 90% yield) as a yellow solid. LCMS calculated C 19 H 21 N4O2[M+H] + m / z = 337.2; measured value: 337.1.

[0454] Step 15: 3-Amino-2-(3-hydroxy-2,6-dimethylphenyl)-9-methyl-2,6,11-triazatricyclo[6.3.1.0^{4,12}]dodec-1(11),3,8(12),9-tetraen-5-one

[0455] A solution of 3-amino-2-(3-methoxy-2,6-dimethylphenyl)-9-methyl-2,6,11-triazatricyclo[6.3.1.0^{4,12}]dodec-1(11),3,8(12),9-tetraen-5-one (50.0 mg, 0.149 mmol) in dichloromethane (3 mL) was added dropwise to a solution of BBr3 (0.447 mL, 1 M DCM solution, 0.447 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at rt for 1 h, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of water and methanol (H2O / MeOH = 1:5, 5 ml), stirred at rt for 1 h, and then directly purified by Prep-HPLC. The product was eluted with MeCN / H2O (20% to 50% containing 0.1% FA) to give the target product (16.8 mg, 35% yield) as an off-white solid. 1¹H NMR (400MHz, DMSO-d⁶) δ 9.49 (s, 1H), 7.55 (s, 1H), 7.04 (d, J = 8.3Hz, 1H), 6.90 (d, J = 8.3Hz, 1H), 6.79 (s, 1H), 5.99 (s, 2H), 4.75 (s, 2H), 2.13 (s, 3H), 1.78 (s, 3H), 1.69 (s, 3H). LCMS calculated C 18 H 19 N4O2[M+H] + m / z = 323.2; measured value: 323.1.

[0456] The target compound in Example 1, step 15, is a mixture of 2-amino-(1Ra)-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthidine-3(1H)-one and its enantiomer 2-amino-(1Sa)-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthidine-3(1H)-one.

[0457] Example 7: 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-6,7-dimethyl-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthidium-3(1H)-one

[0458]

[0459] Step 1: 2-((diphenylmethylene)amino)-6-methylisonicotinic acid methyl ester

[0460]

[0461] A mixture of methyl 2-bromo-6-methylisonicotinic acid (83 g, 361 mmol), benzophenone imine (71.9 g, 399 mmol), Cs₂CO₃ (353 g, 108 mmol), and dioxane (581 mL) of Xantphos (20.9 g, 36.1 mmol) was degassed and purged with N₂, purged three times, and then Pd₂(dba)₃ (16.5 g, 18.0 mmol) was added to the previous mixture. The mixture was degassed and purged with N₂, purged three times, and then stirred overnight at 80 °C under an N₂ atmosphere. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with ethyl acetate / petroleum ether (0.5–3.3%), to give the target compound (160 g, 44.7% yield) as a pale yellow oil. 1¹H NMR: (400 MHz, CDCl₃) δ 7.73–7.74 (m, 2H), 7.62–7.64 (m, 3H), 7.42–7.43 (m, 4H), 7.11–7.19 (m, 2H), 6.82 (s, 1H), 3.77 (s, 3H), 2.42 (s, 3H). LCMS calculated C 21 H 19 N₂O₂[M+H] + m / z = 331.1; measured value: 331.2.

[0462] Step 2: Methyl 2-amino-6-methylisonicotinic acid

[0463]

[0464] To a THF (50 mL) solution of methyl 2-((diphenylmethylene)amino)-6-methylisonicotinic acid (51.6 g, 156 mmol), HCl (6 M, 104 mL) was added. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H₂O (200 mL), the pH was adjusted to 8–9 with NH₃·H₂O (30 mL), and extracted with EA (150 mL x 3). The combined organic phases were washed with saturated brine (150 mL x 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was slurried with MTBE (180 mL) at 20 °C for 2 h to obtain the target compound (60 g, 77.0% yield) as a pale yellow solid. 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 6.76 (s, 2H), 6.20 (s, 2H), 3.82 (s, 3H), 2.28 (s, 3H). LCMS calculated C₈H₅. 11 N₂O₂[M+H] + m / z = 167.1; measured value: 167.2.

[0465] Step 3: Methyl 6-amino-3-bromo-2-methylisonicotinic acid

[0466]

[0467] NBS (19.6 g, 110 mmol) was added to a solution of methyl 2-amino-6-methylisonicotinic acid (18.3 g, 110 mmol) in ACN (112 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was diluted with H₂O (200 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was slurried with MTBE (150 mL) at 20 °C for 1 h to give the target compound (49 g, 60.5% yield) as a yellow solid. 1 ¹H NMR: (400 MHz, CDCl₃) δ 6.53 (s, 1H), 4.58 (s, 2H), 3.93 (s, 3H), 2.55 (s, 3H). LCMS calculated C₈H₂. 10 BrN2O2[M+H] + m / z = 244.9; Measured value: 244.9.

[0468] Step 4: Methyl 6-amino-2,3-dimethylisonicotinic acid

[0469]

[0470] A mixture of methyl 6-amino-3-bromo-2-methylisonicotinic acid (11 g, 44.9 mmol), methylboronic acid (8.06 g, 135 mmol), and dioxane (77 mL) of K₂CO₃ (24.8 g, 180 mmol) was degassed and purged with N₂, and the mixture was purged three times. Pd(dppf)Cl₂ (3.28 g, 4.49 mmol) was added to the mixture, and the mixture was degassed and purged with N₂, and the mixture was purged three times. The mixture was then stirred overnight at 80 °C under an N₂ atmosphere. The reaction mixture was diluted with H₂O (200 mL) and extracted with EA (150 mL x 4). The combined organic phases were washed with saturated brine (500 mL x 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was pulped with MTBE:EA (15 / 1, 84 mL) at 20 °C for 1 h, filtered, and the filter cake was pulped with ACN (40 mL) at 20 °C for 1 h to obtain the target compound (28 g, 86.5% yield) as a yellow solid. 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 6.51 (s, 1H), 5.85 (s, 2H), 3.80 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H). LCMS calculated C₁₆H₁₆. 13 N₂O₂[M+H] + m / z = 181.1; measured value: 180.9.

[0471] Step 5: Methyl 2-amino-3-bromo-5,6-dimethylisonicotinic acid

[0472]

[0473] The compound was prepared in a manner similar to step 2 of Example 6, but with methyl 6-amino-2,3-dimethylisonicotinic acid ester instead of methyl 2-amino-5-methylpyridine-4-carboxylate ester to obtain the target product, which was a yellow solid. 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 6.13 (s, 1H), 3.87 (s, 3H), 2.24 (s, 3H), 1.98 (s, 3H). LCMS calculated C₁₈H₁₈. 12 BrN2O2[M+H] + m / z = 259.0; measured value: 258.9.

[0474] Step 6: Methyl 2,3-dibromo-5,6-dimethylisonicotinic acid

[0475]

[0476] To a solution of methyl 2-amino-3-bromo-5,6-dimethylisonicotinic acid (9.5 g, 36.7 mmol) in dibromomethane (67 mL), benzyltriethylammonium bromide (44.9 g, 165 mmol) and tert-butyl nitrite (37.8 g, 367 mmol) were added. The mixture was stirred at 20 °C for 3 h, diluted with H₂O (80 mL), and extracted with DCM (150 mL x 3). The combined organic phases were washed with saturated brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EA / PE (0.5–35%), to give the target compound (16 g, 67.5% yield) as a colorless oil. 1 H NMR: (400MHz, DMSO-d6) δ 3.98 (s, 3H), 2.44 (s, 3H), 2.19 (s, 3H). LCMS calculated C9H 10 Br2NO2[M+H] + m / z = 323.9; Measured value: 323.9.

[0477] Step 7: methyl 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,6-dimethylisonicotinic acid

[0478]

[0479] A mixture of methyl 2,3-dibromo-5,6-dimethylisonicotinic acid (5.0 g, 15.5 mmol), 3-methoxy-2,6-dimethylaniline (2.34 g, 15.5 mmol), Cs₂CO₃ (12.6 g, 38.7 mmol), Xantphos (896 mg, 1.55 mmol), and Pd₂(dba)₃ (709 mg, 0.774 mmol) in DME (35 mL) was degassed and purged with N₂ three times. The mixture was then stirred overnight at 80 °C under N₂ atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EA / PA (0.5–35%), to give the target compound (8.0 g, 65.7% yield) as a dark brown solid. LCMS calculated value C 18 H 22 BrN2O3[M+H] + m / z = 393.1; Measured value: 393.1.

[0480] Step 8: (3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,6-dimethylpyridin-4-yl)methanol

[0481]

[0482] To a DCM solution (21 mL) of methyl 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,6-dimethylisonicotinic acid (3 g, 7.63 mmol), DIBAL-H (1 M, 21 mL) was added. The mixture was stirred at -70 °C for 2 h, then quenched with H₂O (200 mL) at 0 °C under a N₂ atmosphere, and extracted with DCM (150 mL x 3). The combined organic phases were washed with saturated brine (80 mL x 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluting with EA / PE (0-5%), to give the target compound (3.0 g, 53.8% yield) as a yellow oil. 1 ¹H NMR: (400MHz, CDCl₃) δ 7.05 (d, J = 8.4Hz, 1H), 6.73 (d, J = 8.0Hz, 1H), 6.36 (s, 1H), 4.85 (d, J = 6.4Hz, 2H), 3.85 (s, 3H), 2.27 (s, 3H). 2.25 (s, 3H), 2.16 (s, 3H), 2.09 (s, 3H). LCMS calculated C 17 H 22 BrN2O2[M+H] + m / z = 365.1; Measured value: 365.1.

[0483] Step 9: 2-Amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-nitrile

[0484]

[0485] The compound was prepared in a manner similar to step 10 of Example 6, using (3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,6-dimethylpyridin-4-yl)methanol and malononitrile to obtain the target product, which was a yellow solid. 1 ¹H NMR: (400MHz, CDCl₃) δ 7.12 (d, J = 8.8Hz, 1H), 6.87 (d, J = 8.4Hz, 1H), 5.06 (s, 2H), 4.47 (s, 3H), 3.81 (s, 3H), 2.32 (d, J = 14Hz, 6H), 1.84 (s, 3H), 1.77 (s, 3H). LCMS calculated C 20 H 23 N4O2[M+H] + m / z = 351.2; Measured value: 351.2.

[0486] Step 10: Methyl 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

[0487]

[0488] This compound was prepared in a manner similar to step 11 of Example 6, using 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-nitrile as a starting material to obtain the target product, which was a yellow solid. LCMS calculated value C 21 H 26 N3O4[M+H] + m / z = 384.2; Measured value: 384.2.

[0489] Step 11: Methyl 2-amino-4-(azidomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

[0490]

[0491] The compound was prepared in a manner similar to step 12 of Example 6, using methyl 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate and DPPA as raw materials to obtain the target product, which is a yellow solid. 1 ¹H NMR: (400MHz, DMSO-d⁶) δ 7.25 (d, J = 8.4Hz, 1H), 7.09 (d, J = 8.4Hz, 1H), 6.78 (s, 2H), 5.05–5.14 (m, 2H), 3.83 (d, J = 14.8Hz, 6H), 2.29 (s, 3H), 2.25 (s, 3H), 1.77 (s, 3H), 1.69 (s, 3H). LCMS calculated C 21 H 25 N6O3[M+H] + m / z = 409.2; Measured value: 409.2.

[0492] Step 12: Methyl 2-amino-4-(aminomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

[0493]

[0494] The compound was prepared in a manner similar to step 13 of Example 6, using methyl 2-amino-4-(azidomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate and PPh3 as raw materials to obtain the target product, which was a white solid. 1 ¹H NMR: (400MHz, DMSO-d⁶) δ 7.28 (d, J = 8.0Hz, 1H), 7.08 (d, J = 8.4Hz, 1H), 6.68 (s, 2H), 4.20 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.27 (d, J = 4.0Hz, 6H), 1.78 (s, 3H), 1.68 (s, 3H). LCMS calculated C 21 H 27 N4O3[M+H] + m / z = 383.2; Measured value: 383.2.

[0495] Step 13: 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-6,7-dimethyl-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthidium-3(1H)-one

[0496]

[0497] The compound was prepared in a manner similar to step 14 of Example 6, using methyl 2-amino-4-(aminomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate to obtain the target product, which was a white solid. 1 ¹H NMR: (400MHz, DMSO-d⁶) δ 7.23 (d, J = 8.4Hz, 1H), 7.07 (d, J = 8.4Hz, 1H), 6.76 (s, 1H), 5.84 (s, 2H), 4.75 (s, 2H), 3.85 (s, 3H), 2.28 (s, 3H), 2.06 (s, 3H), 1.84 (s, 3H), 1.73 (s, 3H). LCMS calculated C 20 H 23 N4O2[M+H] + m / z = 351.2; measured value: 351.1.

[0498] Step 14: 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-6,7-dimethyl-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthidium-3(1H)-one

[0499] The compound was prepared in a manner similar to step 15 of Example 6, using 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-6,7-dimethyl-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthidium-3(1H)-one to give the target product as a white solid. 1 ¹H NMR: (400MHz, DMSO-d⁶) δ 9.47 (s, 1H), 7.04 (d, J = 8.4Hz, 1H), 6.90 (d, J = 8.0Hz, 1H), 6.75 (s, 1H), 5.78 (s, 2H), 4.75 (s, 2H), 2.29 (s, 3H), 2.06 (s, 3H), 1.79 (s, 3H), 1.69 (s, 3H). LCMS calculated C 19 H 21 N4O2[M+H] + m / z = 337.2; measured value: 337.1.

[0500] Example 8: 6,7-Dimethyl-9-(6-methylquinolin-5-yl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0501]

[0502] Step 1: N-(3-bromo-5,6-dimethylpyridin-2-yl)-6-methylquinoline-5-amine

[0503]

[0504] A mixture of 2,3-dibromo-5,6-dimethylpyridine (10.0 g, 37.7 mmol, Example 3, step 2), 6-methylquinoline-5-amine (5.97 g, 37.7 mmol), Xantphos (2.18 g, 3.77 mmol), Cs₂CO₃ (30.7 g, 94.4 mmol), and Pd₂(dba)₃ (1.73 g, 1.89 mmol) in DME (60 mL) was degassed and purged with N₂, purged three times, and then stirred overnight at 80 °C under N₂ atmosphere. The reaction mixture was cooled to rt, diluted with water (250 mL), and extracted with EA (50 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography on a silica gel column, eluted with EA / PE (0–5%), to give the target compound (7.50 g, 58.1% yield) as a yellow solid. 1 HNMR: (400MHz, MeOD) δ 8.75 (dd, J = 4.4, 1.6Hz, 1H), 8.33 (dd, J = 8.4, 0.4Hz, 1H), 7.91 (d, J = 8.8Hz, 1H), 7.72 (d, J = 8.8Hz, 1H), 7.61 (s, 1H), 7.45 (dd, J = 8.4, 4.4Hz, 1H), 2.37 (s, 3H), 2.13 (s, 3H), 2.01 (d, J = 3.2Hz, 3H). LCMS calculated C 17 H 17 BrN3[M+H] + m / z = 342.1; Measured value: 342.1.

[0505] Step 2: 2-Amino-5,6-dimethyl-1-(6-methylquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-nitrile

[0506]

[0507] Under a nitrogen atmosphere, t-BuONa (4.2 g, 43.8 mmol) was added to a DME (45 mL) solution of malononitrile (2.89 g, 43.8 mmol), and the mixture was stirred at 25 °C for 0.5 h. Then, N-(3-bromo-5,6-dimethylpyridin-2-yl)-6-methylquinoline-5-amine (7.5 g, 21.9 mmol) was added at 25 °C, followed by Pd(dppf)Cl2.CH2Cl2 (1.79 g, 2.19 mmol). The resulting mixture was stirred overnight at 85 °C under a nitrogen atmosphere. The reaction mixture was quenched dropwise with water (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was slurried with DCM (22 mL). Filter the solution, collect the solid to obtain the target compound (3.5 g, 50% yield), as a yellow solid. LCMS calculated C0 20 H 18 N5[M+H] + m / z = 328.2; Measured value: 328.2.

[0508] Step 3: 2-Amino-5,6-dimethyl-1-(6-methylquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0509]

[0510] The compound was prepared in a manner similar to step 9 of Example 1, using 2-amino-5,6-dimethyl-1-(6-methylquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-nitrile as a starting material to obtain the target product, which was a yellow solid. 1 ¹H NMR: (400MHz, DMSO-d⁶) δ 8.90 (d, J = 2.8Hz, 1H), 8.16 (d, J = 8.8Hz, 1H), 7.87–7.92 (m, 2H), 7.46 (dd, J = 8.4, 4.0Hz, 1H), 7.36–7.38 (m, 1H), 6.90 (s, 2H), 6.74 (s, 2H), 2.27 (s, 3H), 2.14 (d, J = 4.0Hz, 6H). LCMS calculated C 20 H 20 N5O[M+H] + m / z = 346.2; Measured value: 346.2.

[0511] Step 4: 6,7-Dimethyl-9-(6-methylquinolin-5-yl)-3,9-dihydro-4H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-one

[0512]

[0513] The compound was prepared in a manner similar to step 12 of Example 1, using 2-amino-5,6-dimethyl-1-(6-methylquinoline-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide and trimethoxymethane as raw materials to obtain the target product, which is a yellow solid. 1 ¹H NMR: (400MHz, DMSO-d⁶) δ 12.6 (br s, 1H), 8.90 (t, J = 4.0Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 8.8Hz, 1H), 8.06 (s, 1H), 7.90 (d, J = 8.8Hz, 1H), 7.35–7.40 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.05 (s, 3H). LCMS calculated C 21 H 18 N5O[M+H] + m / z = 356.1; measured value: 356.2.

[0514] Step 5: 6,7-Dimethyl-9-(6-methylquinolin-5-yl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0515] The compound was prepared in a manner similar to steps 13-14 of Example 1. In step 13, 6,7-dimethyl-9-(6-methylquinolin-5-yl)-3,9-dihydro-4H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-one was used as a starting material to obtain the target product, which was a white solid. 1 ¹H NMR: (400MHz, CDCl₃) δ 9.19 (d, J = 4.0Hz, 1H), 8.63 (d, J = 8.8Hz, 1H), 8.30–8.31 (m, 2H), 8.05 (d, J = 8.8Hz, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.60–7.63 (m, 1H), 2.53 (s, 3H), 2.49 (s, 3H), 2.22 (s, 3H). LCMS calculated C 21 H 19 N6[M+H] + m / z = 355.2; measured value: 355.1.

[0516] Example 9: 5-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-4,6-dichlorobenzene-1,3-diphenol

[0517]

[0518] Step 1: 3-Bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridine-2-amine

[0519]

[0520] This compound was prepared using a method similar to step 1 of Example 8, using 2,3-dibromo-5,6-dimethylpyridine (step 2 of Example 3) and 2,6-difluoro-3,5-dimethoxyaniline as starting materials to obtain the target product, which was a white solid. LCMS calculated value C0 15 H 16 BrCl2N2O2[M+H]: m / z=407.2; measured value: 407.2.

[0521] Step 2: 2-Amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-nitrile

[0522]

[0523] This compound was prepared using a method similar to step 2 of Example 8, with malononitrile and 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridine-2-amine as starting materials to obtain the target product, which was a brown solid. LCMS calculated value C 18 H 17 Cl2N4O2[M+H] + m / z = 391.1; Measured value: 391.1.

[0524] Step 3: 2-Amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0525]

[0526] This compound was prepared using a method similar to step 9 of Example 1, using 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-nitrile as a starting material to obtain the target product. LCMS calculated value C 18 H 19 Cl2N4O3[M+H] + m / z = 409.2; Measured value: 409.2.

[0527] Step 4: 9-(2,6-dichloro-3,5-dimethoxyphenyl)-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0528]

[0529] This compound was prepared in a manner similar to steps 12-14 of Example 1, in which step 12, 2-amino-1-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide and trimethoxymethane were used to obtain the target product. LCMS calculated value C 19 H 18 Cl2N5O2[M+H] + m / z = 418.1; Measured value: 418.1.

[0530] Step 5: 5-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-4,6-dichlorobenzene-1,3-diol

[0531]

[0532] At 0 °C, BBr3 (0.06 g, 0.24 mmol) was added dropwise to a DCM (5 mL) solution of 9-(2,6-dichloro-3,5-dimethoxyphenyl)-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.12 mmol). The mixture was stirred at rt for 1 h, quenched with H2O (10 mL), and extracted with 2-MeTHF (10 mL x 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC and eluted with MeCN / water (10-95% containing 0.1% NH4HCO3) to give the target product (2.7 mg, yield: 5.8%). 1 H NMR (400 MHz), δ 10.60 (s, 2H), 8.57 (s, 1H), 8.20 (s, 1H), 7.38 (s, 2H), 6.92 (s, 1H), 2.43 (s, 3H), 2.38 (s, 3H). LCMS calculated C 17 H 14 Cl2N5O2[M+H] + m / z = 390.2; Measured value: 390.2.

[0533] Example 10: 5-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-4,6-difluorophenyl-1,3-diol and

[0534] Example 11: 3-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-difluoro-5-methoxyphenol

[0535]

[0536] Step 1: 3-Bromo-N-(2,6-difluoro-3,5-dimethoxyphenyl)-5,6-dimethylpyridine-2-amine

[0537]

[0538] This compound was prepared using a method similar to step 1 of Example 8, using 2,3-dibromo-5,6-dimethylpyridine (step 2 of Example 3) and 2,6-difluoro-3,5-dimethoxyaniline as starting materials to obtain the target product, which was a white solid. LCMS calculated value C0 15 H 16 BrF2N2O2[M+H]: m / z=373.2; measured value: 373.2.

[0539] Step 2: 2-Amino-1-(2,6-difluoro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-nitrile

[0540]

[0541] This compound was prepared using a method similar to step 2 of Example 8, using 3-bromo-N-(2,6-difluoro-3,5-dimethoxyphenyl)-5,6-dimethylpyridine-2-amine as a starting material to obtain the target product, which was a brown solid. The calculated LCMS value was C0. 18 H 17 F2N4O2[M+H] + m / z = 359.2; Measured value: 359.2.

[0542] Step 3: 2-Amino-1-(2,6-difluoro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0543]

[0544] This compound was prepared using a method similar to step 9 of Example 1, using 2-amino-1-(2,6-difluoro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-nitrile as a starting material to obtain the target product. LCMS calculated value C 18 H 19 F2N4O3[M+H] + m / z = 377.2; Measured value: 377.2.

[0545] Step 4: 9-(2,6-difluoro-3,5-dimethoxyphenyl)-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine

[0546]

[0547] This compound was prepared in a manner similar to steps 12-14 of Example 1. In step 12, 2-amino-1-(2,6-difluoro-3,5-dimethoxyphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide and trimethoxymethane were used as starting materials to obtain the target product. LCMS calculated value C 19 H 17 F2N4O3[M+H] + m / z = 387.2; Measured value: 387.2.

[0548] Step 5: 5-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-4,6-difluorobenzene-1,3-diol (Example 10) and 3-(4-amino-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)-2,4-difluoro-5-methoxyphenol (Example 11)

[0549] At 0 °C, BBr3 (0.115 g, 0.46 mmol) was added dropwise to a DCM (10 mL) solution of 9-(2,6-difluoro-3,5-dimethoxyphenyl)-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidine-4-amine (90 mg, 0.23 mmol). The mixture was stirred at rt for 1 h. The reaction mixture was quenched with H2O (10 mL) and extracted with 2-MeTHF (10 mL x 3). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by Prep-HPLC and eluted with MeCN / water (10-95% containing 0.1% NH4HCO3) to give two products: P1 (earlier elution fraction: 5.46 mg, yield: 6.5%) and P2 (later elution fraction: 3.35 mg, yield: 3.8%). P1 is from Example 10. 1 ¹H NMR (400 MHz, DMSO) δ 9.87 (s, 2H), 8.60 (s, 1H), 8.24 (s, 1H), 7.44 (s, 2H), 6.80 (t, J = 8.6 Hz, 1H), 2.46 (s, 3H), 2.39 (s, 3H). LCMS calculated C 17 H 14 F2N5O2[M+H] + m / z = 358.0; Measured value: 358.0. P2 is Example 11. 1 ¹H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 7.45 (s, 2H), 6.97 (t, J = 8.3 Hz, 1H), 3.87 (s, 3H), 2.45 (s, 3H), 2.39 (s, 3H). LCMS calculated C 18 H 16 F2N5O2[M+H] + m / z = 372.0; Measured value: 372.0.

[0550] Example A: PKMYT1 enzyme activity test

[0551] The potential inhibitory effect of candidate compounds was evaluated using the PKMYT1 enzyme activity assay. PKMYT1 was purchased from Carna (catalog number 05-176), aliquoted, and stored at -80°C. The ADP-Glo ​​kit (from Promega) was used to assess the inhibitory effect. TMThe enzyme activity assay kit, #V9102, 10,000 assays, was used to detect the amount of ADP produced from ATP hydrolysis in the PKMYT1 catalytic reaction. Compounds dissolved in DMSO (Sigma, D8418) were added to 384-well plates (Greiner, 784075) using a pipette (Labcyte, Echo 665). Each compound was repeated once, with a 3-fold serial dilution for a total of 10 wells. The assay was performed in a 1× buffer system containing 1× kinase buffer and 50 μM DTT. 2.5 μl of 2× PKMYT1 enzyme mixture was added to the plate. After centrifugation at 1000g for 30 seconds, the plate was sealed and incubated at room temperature for 10 minutes. Then, 2.5 μl of 2× substrate mixture [inactive CDK1 (SignalChem, C22-14G-20) and ATP (Promega, V910B)] was added to initiate the reaction. The final concentration of PKMYT1 enzyme was 2.5 ng / μL; the final concentration of ATP was 200 μM; and the final concentration of inactive CDK1 was 0.01 μg / μL. After incubating the experimental plate at room temperature for 2 hours, 4 μL of ADP-Glo ​​reagent was added, followed by brief centrifugation and sealing. The plate was then incubated at room temperature in the dark for 40 minutes. Subsequently, 8 μL of enzyme detection reagent was added, followed by brief centrifugation again, sealing, and incubation at room temperature in the dark for 40 minutes. Finally, the results were read using a multi-mode microplate reader (Perkin Elmer, Envision 2104) in chemiluminescence mode. The average chemiluminescence signal of the positive control wells (containing 1% DMSO) was set as the positive control (HC); the average chemiluminescence signal of the negative control wells (containing 10000 nM PD0166285) was set as the negative control (LC).

[0552] Inhibition rate % = 100 - 100 * (signal) 化合物 -Signal 阴性对照 ) / (Signal 阳性对照 -Signal 阴性对照 ).

[0553] IC 50 The values ​​were calculated by fitting the Hill Slope to a standard 4-parameter model using GraphPad Prism software. 50 The values ​​are shown in Table 1. +++<=0.1μM, 0.1μM<++<=1μM, +>1μM.

[0554] Example B: Cell viability test

[0555] Cell viability studies were performed in the HCC1569 cell line. Cells were cultured in RPMI 1640 medium (Hyclone, SH3080901B) containing 10% fetal bovine serum (FBS, AusGeneX, FBS500-S) and 1% penicillin-streptomycin (Gibco, 15140122). Cells were seeded at a density of 1500 cells / well in 96-well cell culture plates (PerkinElmer, 6005680). The compound dissolved in DMSO was partitioned in duplicate using a multichannel pipette, and serially diluted 3-fold to nine concentrations, with two replicates per concentration. The final concentration of DMSO in all wells was 0.2%. Cells were incubated at 37°C and 5% CO2 for 7 days. Cell viability was determined using Cell Titer-Glo reagent (Promega, catalog number: G7573) according to the manufacturer's instructions. Fluorescence signals were detected using a multi-functional microplate reader (Perkin Elmer, Envision 2105 or BMG, ClarioStar Plus). The average value of wells containing 0.2% DMSO and cells in each plate was used as the positive control (High Control, HC); the average value of wells containing only culture medium in each plate was used as the negative control (Low Control, LC).

[0556] Inhibition rate = 100 - 100 * (signal) 化合物 -Signal 阴性对照 ) / (Signal 阳性对照 -Signal 阴性对照 ).

[0557] IC 50 The values ​​were calculated by fitting the Hill Slope to a standard 4-parameter model using GraphPad Prism software. 50 The values ​​are shown in Table 1.

[0558] +++<=5μM, 5μM<++<=50μM, +>50μM, ND: not detected.

[0559] Table 1

[0560]

[0561] Although the invention has been fully described by way of examples, it is worth noting that various changes and modifications will be apparent to those skilled in the art. These changes and modifications should be included within the scope of the appended claims.

Claims

1. A compound of formula (IA) and (IB) or a pharmaceutically acceptable salt, atropisomer thereof, characterized in that : Ring A is selected from: X is N or CR 3 ; Y is N; L is (CR 10 R 11 ) n , NR 12 (CH2CH2) m ; n is 1; m is 0 or 1; R is selected from H, D or C1-C6 alkyl optionally substituted with a substituent selected from F, OH or CN; R 1 selected from H or methyl; R 2 selected from methyl or morpholinyl; R 3 selected from H; Each R 4 The alkyl group, independently selected from H, D, NH2, CN, C1-C3, is optionally substituted by a substituent selected from D, halogen, or CN. Each R 5 Independently selected from H, D, halogens, and methyl groups; Each R 6 Independently selected from H, D, halogens, and methyl groups; Each R 7 Independently selected from H, D, OH, OMe, and OCF3; Each R 8 Independently selected from H or D; R 10 and R 11 are each independently selected from H; R 12 is H, D, C1-C3 alkyl optionally substituted with a substituent selected from D, OH, halogen, CN.

2. The compound or pharmaceutically acceptable salt, atropisomer thereof of claim 1, wherein, X is N.

3. The compound or pharmaceutically acceptable salt, atropisomer thereof of claim 1, wherein X is CR 3 R 3 is selected from H.

4. The compound of claim 1, or a atropisomer thereof, wherein R 4 selected from H, D, NH2, CN, Me, CD3, or CF3.

5. The compound of claim 1, or a pharmaceutically acceptable salt, atropisomer thereof, wherein Ring A is 6. The compound of claim 1, or a pharmaceutically acceptable salt, atropisomer thereof, wherein Compounds of formula (IA) and (IB) are as shown in formula (IAa), (IAe), (IBa), or (IBe): wherein the definitions of X, Y, L, R, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined in formula (IA) and (IB).

7. The compound or pharmaceutically acceptable salt, atropisomer thereof of claim 6, wherein, Compounds of formula (IA) and (IB) are as shown in formula (IAa), (IBa): wherein the definitions of X, Y, L, R, R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are as in formula (IA) and (IB).

8. The compound of claim 1, or a pharmaceutically acceptable salt, atropisomer thereof, wherein, Compounds of formula (IA) and (IB) are as shown in formula (IIAa), (IIAe), (IIBa), or (IIBe): wherein X, Y, L, R, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined in formula (IA) and (IB).

9. The compound of claim 1, or a pharmaceutically acceptable salt, atropisomer thereof, wherein, Compounds of formula (IA) and (IB) are as shown in formula (IIIAa), (IIIAe), (IIIBa), or (IIIBe): wherein the definitions of X, Y, L, R, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined for formula (IA) and (IB).

10. The compound of claim 1, or a pharmaceutically acceptable salt, atropisomer thereof, wherein, Compounds of formula (IA) and (IB) are as shown in formula (IIAa), (IIBa), (IIIAa), (IIIBa):

11. The compound of claim 1, or a pharmaceutically acceptable salt, atropisomer thereof, wherein Compounds of formula (IB) are as shown in formula (IVBa), (IVBb), or (IVBc): wherein Y, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 are as defined in formula (IB).

12. The compound of claim 1, or a pharmaceutically acceptable salt, atropisomer thereof, wherein, Compounds of formula (IA) and (IB) are:

13. The compound or pharmaceutically acceptable salt, atropisomer thereof of claim 12, wherein The compound is:

14. A pharmaceutical composition comprising: The compound or pharmaceutically acceptable salt, atropisomer, and pharmaceutically acceptable carrier of claim 1.

15. Use of a compound of claim 1, or a pharmaceutically acceptable salt, atropisomer, or a pharmaceutical composition of claim 14, in the manufacture of a medicament for treating a disease or disorder that is a symptom of cellular hyperproliferation; the disease or disorder is cancer; the cancer is a cancer that has CCNE1 amplification, FBXW7 loss-of-function mutation, or other PKMYT1 -dependent genetic alteration.

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