Tricyclic heterocyclic derivative as well as composition and application thereof

Abstract

The invention relates to tricyclic heterocyclic derivatives as shown in formulae (IA) and (IB), and a composition, a preparation method and application of the tricyclic heterocyclic derivatives as a therapeutic agent. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to tricyclic heterocyclic derivatives as PKMYT1 inhibitors, methods for preparing the tricyclic heterocyclic derivatives and pharmaceutical compositions thereof, and uses thereof in treating diseases associated with PKMYT1 activity, including, for example, cancer and other diseases. Background Art

[0002] Cell cycle regulation plays an important role in the division and growth of normal cells or tumor cells. In general, 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 of cells from G1 phase to S phase and G2 phase to M phase (mitosis phase) is an important phase for DNA damage repair and complex and active changes in various substances in cells. Cells set up a series of cell cycle checkpoints in the 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 the mitosis phase with damaged genomic material, cell cycle disorders, apoptosis, cancer, and other malignant results may occur. In addition, since cancer also uses the cell cycle for tumor cell proliferation, the long-term accumulation of unrepaired DNA damage in the G1 to S phase and the G2 to M phase 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 cells from entering the M phase from the G2 phase by negatively regulating the CDK1-cyclin B (CDK1-Cyclin B) complex. During the DNA damage repair process, PKMYT1 phosphorylates the amino acid sites of Tyr15 and Thr14 of the CDK1 protein, keeping the CDK1-Cyclin B complex inactive in the G2 phase, and ultimately preventing cells from entering mitosis (DongjunJeong, 2018), which provides sufficient time for DNA damage repair. At the same time, Wee1 is also involved in the phosphorylation of the Tyr15 amino acid site of CDK1. PKMYT1 knockout or inhibition can cause cells to enter mitosis prematurely without completing DNA damage repair, leading to cell death.

[0004] On the other hand, CCNE1 amplification can disrupt the regulation of cell entry into the S phase, trigger DNA replication stress, and lead to genomic instability. CCNE1 amplification is prevalent in a variety of tumor types, especially in high-grade serous ovarian cancer, uterine tumors, and gastroesophageal cancer, with an incidence of 5-40%. Cyclin E1, encoded by the CCNE1 gene, promotes the transition of the cell cycle from the G1 phase to the S phase by binding and activating cyclin-dependent protein kinase 2 (CDK2). In a genomic screening study based on CRISPR technology, it was found that high expression / amplification of CCNE1 and inhibition of PKMYT1 had a high degree of synthetic lethality (David Gallo, 2022), and over-accelerated cell cycle progression deprived cells of the opportunity to fully repair DNA damage and led to cell death. In the normal cell cycle, cyclin E1 levels are strictly regulated, accumulated in the G1 / S phase, and completely degraded at the end of the S phase. The degradation of Cyclin E1 can be mediated by FBXW7, an E3 ubiquitin ligase (Chien-Hung Yeh, 2018). Loss-of-function mutations of FBXW7 will lead to the loss of its ubiquitination function on Cyclin E, making Cyclin E unable to be degraded and thus overexpressed.

[0005] Therefore, PKMYT1 inhibitors can be used as synthetic lethal treatment strategies for treating tumors with certain genetic mutations. The present invention provides compounds, pharmaceutical compositions containing compounds, methods for preparing compounds, and methods of use thereof. The compounds of the present invention can be used to inhibit PKMYT1 in cells with CCNE1 amplification, FBXW7 loss-of-function mutations, or other genetic changes that induce DNA replication stress and genomic instability during G1 to S phase progression. The compounds of the present invention can be used for subjects who may need to be treated for a disease or condition, such as a disease or condition with symptoms of cell hyperproliferation, such as cancer. The PKMYT1 inhibitory activity of the compounds disclosed in the present invention can be used to treat subjects in need of cancer treatment. Summary of the invention

[0006] The present invention relates to a compound represented by formula (IA) and (IB),

[0007]

[0008] or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or a prodrug thereof; wherein the variables are respectively as defined in the present invention.

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

[0010] In another aspect, the present invention provides a method for inhibiting PKMYT1, comprising:

[0011] PKMYT1 is contacted with a compound represented by formula (IA) and (IB), or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or prodrug 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, atropisomer, solvate, N-oxide, isotopic variant or a prodrug thereof.

[0013] The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the compositions and methods of the present invention described in different contexts may also be provided in a single aspect in a combined form. Alternatively, for the sake of brevity, various features of the compositions and methods of the present invention described in the context of a single aspect may also be provided individually or in any subcombination.

[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 only for the purpose of describing specific embodiments and is not intended to limit the scope of the present invention.

[0017] The present invention provides a compound represented by formula (IA) and (IB):

[0018]

[0019] or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or a 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 optionally substituted by a substituent selected from the following: F, OH or CN;

[0027] R 1 , R 2 and R 3 Each independently selected 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 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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, the 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OR a , 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 ;

[0029] or R 2 and R 3 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group, or a 4-7 membered heterocyclyl group, wherein the C3-C7 cycloalkyl group, the 4-7 membered heterocyclyl group is optionally substituted by 1, 2, 3 or 4 substituents independently 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] Every R 4 independently selected from H, D, NH2, CN, C1-C3 alkyl optionally substituted by D, halogen or CN;

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

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

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

[0034] Every R 8 Independently selected from H, D, CN, SF5, C1-C6 alkyl optionally substituted by D, halogen or CN;

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

[0036] R 10 and R 11 are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl is optionally substituted by 1, 2, or 3 substituents independently selected from the following: 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, the 4-7 membered heterocyclic group is optionally substituted by 1, 2, 3 or 4 substituents independently 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 is H, D, C1-C3 alkyl optionally substituted by D, OH, halogen, CN;

[0039] Every 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 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 ;

[0040] Every 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 membered heteroaryl, C6-C 10Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 are independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 The 4-7 membered heterocyclyl group, taken together with the nitrogen atom to which it is attached, is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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] Every R a independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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] Every 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 heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 heterocyclyl;

[0045] R c and R d are independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 6- C 10 Aryl, 5-10 membered heteroaryl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclyl-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 Cycloalkyl, C6-C10 Aryl-4-10 membered heterocyclic group, C6-C 10 Aryl-5-10 membered heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 membered heteroaryl-C3-C 10 Cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocyclyl, 5-10 membered heteroaryl-C6-C 10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6- C 10 Aryl, 5-10 membered heteroaryl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclyl-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 Cycloalkyl, C6-C 10 Aryl-4-10 membered heterocyclic group, C6-C 10 Aryl-5-10 membered heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 membered heteroaryl-C3-C 10 Cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocyclyl, 5-10 membered heteroaryl-C6-C 10 The aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 membered 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 dThe heterocyclic group formed by the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 membered 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] Every 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 membered 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 heterocyclyl-C1-C4 alkyl;

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

[0049] Every R a1 independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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] Every 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 heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 heterocyclyl.

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

[0052] In some embodiments, X is N.

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

[0054] In some embodiments, R 3 Independently selected 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 membered heteroaryl, C6-C 10Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, R 3 Independently selected 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, C3-C6 cycloalkyl, 4-6 membered heterocyclyl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently 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 .

[0056] In some embodiments, for example, including but not limited to, R 3 independently selected from H, D, halogen, 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 embodiments, Y is N.

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

[0059] In some embodiments, R 9 is H. In some embodiments, R 9 is D. In some embodiments, R 9 In some embodiments, R 9 is halogen (eg, F, Cl, Br, I). 9 is C1-C4 alkyl. 9 is C1-C4 haloalkyl. 9 is OC1-C4 alkyl. 9 is OC1-C4 haloalkyl. 9 It is a C3-C5 cycloalkyl group.

[0060] In some embodiments, R 1 Independently selected 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 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, L is (CR 10 R 11 ) n , NR 12 (CH2CH2) m , or O(CH2CH2) m .

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

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

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

[0065] In some embodiments, R 1 Independently selected 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, C3-C6 cycloalkyl or 4-6 membered heterocyclyl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently 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)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 embodiments, R 1 independently selected from H, D, halogen, 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 embodiments, R 2 Independently selected 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, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group; wherein the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 )(ORd ), 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 embodiments, R 2 Independently selected 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, C3-C6 cycloalkyl or 4-6 membered heterocyclyl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently 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 , or NR c S(O)(=NR b )R b .

[0068] In some embodiments, for example, including but not limited to, R 2 independently selected from H, D, halogen, 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 embodiments, R 1 and R 2 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a, 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 .

[0070] In some embodiments, R 1 and R 2 The carbon atom to which it is attached forms a 4-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a , 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 .

[0071] In some embodiments, R 2 and R 3 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a , 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 .

[0072] In some embodiments, R 2 and R 3 The carbon atom to which it is attached forms a 4-7 membered heterocyclic group optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of 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 embodiments, each R 4 are independently selected from H, D, NH2, or CN. In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is NH2. In some embodiments, R 4 For CN.

[0074] In some embodiments, R4 is C1-C3 alkyl optionally substituted by D, halogen or CN. 4 In some embodiments, R 4 In some embodiments, R 4 It is CF3.

[0075] In some embodiments, each R 5 Independently selected from H, D, halogen, CN or C1-C6 alkyl optionally substituted with D, halogen or CN.

[0076] In some embodiments, R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 is halogen (eg, F, Cl, Br, I). 5 In some embodiments, R 5 is C1-C6 alkyl optionally substituted by D, halogen or CN.

[0077] In some embodiments, 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 embodiments, each R 6 Independently selected from H, D, halogen, CN, SF5, OR B , C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl; wherein, the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl are optionally substituted by substituents selected from the following: D, halogen, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.

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

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

[0081] In some embodiments, R 7 is H. In some embodiments, R 7 is D. In some embodiments, R 7 is halogen (eg, F, Cl, Br or I). 7 In some embodiments, R 7 It is OMe.

[0082] In some embodiments, each R 8 Independently selected from H, D, CN, SF5, C1-C6 alkyl optionally substituted by D, halogen or CN.

[0083] In some embodiments, R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 In some embodiments, R 8 For SF5.

[0084] In some embodiments, R 8 is C1-C6 alkyl optionally substituted by 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 compound represented by formula (IA) and (IB) is represented by formula (IAa), (IAb), (IAc), (IAd), (IAe), (IBa), (IBb), (IBc), (IBd), or (IBe):

[0086]

[0087] or a pharmaceutically acceptable salt, stereoisomer, atropisomer, 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 same definition as in formula (IA) and (IB).

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

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

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

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

[0092] In some embodiments, R is selected from H, D or C1-C6 alkyl 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 embodiments, R 4 is selected from H, D, NH2, or CN. In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is NH2. In some embodiments, R 4 For CN.

[0094] In some embodiments, R 4 is C1-C3 alkyl optionally substituted by D, halogen or CN. 4 In some embodiments, R 4 In some embodiments, R 4 It is CF3.

[0095] In some embodiments, R 5 is selected from H, D, halogen, or CN. In some embodiments, R5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 In some embodiments, R 5 is F. In some embodiments, R 5 For Cl.

[0096] In some embodiments, R 5 is C1-C6 alkyl optionally substituted by D, halogen or CN. 5 In some embodiments, R 5 In some embodiments, R 5 It is CF3.

[0097] In some embodiments, R 6 Selected from H, D, halogen, CN, SF5, OR B In some embodiments, R 6 is H. In some embodiments, R 6 is D. In some embodiments, R 6 In some embodiments, R 6 is F. In some embodiments, R 6 In some embodiments, R 6 is Br. In some embodiments, R 6 For SF5.

[0098] In some embodiments, R 6 is C1-C6 alkyl optionally substituted by a substituent selected from the group consisting of D, halogen, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 4-7 membered heterocyclyl. 6 In some embodiments, R 6 In some embodiments, R 6 is CF3. In some embodiments, R 6 It is cyclopropyl.

[0099] In some embodiments, R 7 is H. In some embodiments, R 7 is D.

[0100] In some embodiments, R 7 In some embodiments, R 7 is F. In some embodiments, R 7 For Cl.

[0101] In some embodiments, R 7 In some embodiments, R 7 It is OMe.

[0102] In some embodiments, R 8 In some embodiments, R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 In some embodiments, R 8 For SF5.

[0103] In some embodiments, R 8 is C1-C6 alkyl optionally substituted by D, halogen or CN. 8 In some embodiments, R 8 In some embodiments, R 8 It is CF3.

[0104] In some embodiments, the compound represented by formula (IA) and (IB) is represented by formula (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 same definition as in formula (IA) and (IB).

[0108] In some embodiments, the compound represented by formula (IA) and (IB) is represented by formula (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 same definition as in formula (IA) and (IB).

[0111] In some embodiments, the compounds represented by formula (IA) and (IB) are represented by formula (IIAa), (IIBa), (IIIAa), (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 same definition as in formula (IA) and (IB).

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

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

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

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

[0118] In some embodiments, R is selected from H, D or C1-C6 alkyl 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 embodiments, R 4 is selected from H, D, NH2, or CN. In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is NH2. In some embodiments, R 4 For CN.

[0120] In some embodiments, R 4 is C1-C3 alkyl optionally substituted by D, halogen or CN. 4 In some embodiments, R 4 In some embodiments, R 4 It is CF3.

[0121] In some embodiments, R 5 is selected from H, D, halogen, or CN. In some embodiments, R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 In some embodiments, R 5 is F. In some embodiments, R 5 For Cl.

[0122] In some embodiments, R 5 is C1-C6 alkyl optionally substituted by D, halogen or CN. 5 In some embodiments, R 5 In some embodiments, R 5 It is CF3.

[0123] In some embodiments, R 6 Selected from H, D, halogen, CN, SF5, OR B In some embodiments, R 6 is H. In some embodiments, R 6 is D. In some embodiments, R 6In some embodiments, R 6 is F. In some embodiments, R 6 In some embodiments, R 6 is Br. In some embodiments, R 6 For SF5.

[0124] In some embodiments, R 6 is C1-C6 alkyl optionally substituted by at least one substituent selected from the group consisting of D, halogen, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 4-7 membered heterocyclyl. 6 In some embodiments, R 6 In some embodiments, R 6 is CF3. In some embodiments, R 6 It is cyclopropyl.

[0125] In some embodiments, R 7 is H. In some embodiments, R 7 is D.

[0126] In some embodiments, R 7 In some embodiments, F is halogen. In some embodiments, Cl is

[0127] In some embodiments, R 7 In some embodiments, R 7 It is OMe.

[0128] In some embodiments, R 8 In some embodiments, R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 In some embodiments, R 8 For SF5.

[0129] In some embodiments, R 8 is C1-C6 alkyl optionally substituted by D, halogen or CN. 8 In some embodiments, R 8 In some embodiments, R 8 It is CF3.

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

[0131]

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

[0133] In the compounds represented by formula (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 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, R A In some embodiments, R A Independently selected from D.

[0135] In some embodiments, R A 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 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 , 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 embodiments, R A Independently selected from C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 formula (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 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, R B In some embodiments, R B Independently selected from D.

[0139] In some embodiments, R B is C1-C6 alkyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, R B It is a C1-C6 alkyl group.

[0140] In some embodiments, R B is isopropyl, isobutyl, tert-butyl; each substituent 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. In some embodiments, R B In some embodiments, R B In some embodiments, R B It is tert-butyl.

[0141] In some embodiments, R B is C2-C6 alkynyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, R B is C2-C6 alkenyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 ).

[0143] In some embodiments, R B C3-C 10 The cycloalkyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, R Bis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; each substituent 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.

[0145] In other embodiments, R B is a 4-10 membered heterocyclic group optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, R B is azetidinyl, pyrrolidinyl, piperidinyl or azepanyl optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, R B C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, each R C independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, each R C In some embodiments, each R C Independently selected from D.

[0150] In some embodiments, 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 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, 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 embodiments, each R C independently selected from C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; each substituent 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, 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 embodiments, each R D independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, each R D In some embodiments, each R D Independently selected from D.

[0154] In some embodiments, 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 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, 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 embodiments, each R D independently selected from C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; each substituent 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, 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 embodiments, R C and R D The 4-7 membered heterocyclyl formed together with the N atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, each R a independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, 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 heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 heterocyclyl.

[0159] In some embodiments, R c and R d are independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 6- C 10 Aryl, 5-10 membered heteroaryl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 Cycloalkyl, C6-C 10 Aryl-4-10 membered heterocyclic group, C6-C 10 Aryl-5-10 membered heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 membered heteroaryl-C3-C 10 Cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocyclyl, 5-10 membered heteroaryl-C6-C 10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6- C 10 Aryl, 5-10 membered heteroaryl, C 3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 Cycloalkyl, C6-C 10 Aryl-4-10 membered heterocyclic group, C6-C 10 Aryl-5-10 membered heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 membered heteroaryl-C3-C 10 Cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocyclyl, 5-10 membered heteroaryl-C6-C 10 The aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 membered 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 embodiments, R c and R d The heterocyclic group formed by the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 membered 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 embodiments, 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 membered 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 heterocyclyl-C1-C4 alkyl.

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

[0163] In some embodiments, each R a1 independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 embodiments, 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 heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 heterocyclyl.

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

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

[0167] In some embodiments, the compounds represented by formula (IA) and (IB) are:

[0168]

[0169] or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or a prodrug thereof.

[0170] In some embodiments, the compounds represented by formula (IA) and (IB) are:

[0171]

[0172] or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or a prodrug thereof.

[0173] It is apparent that the compounds of formula (IA) and (IB) of the present invention, including all subgenera described herein, may have multiple stereocenters. Therefore, the compounds of formula (IA) and (IB) of the present invention (subgenera described herein) exist in multiple stereoisomers (enantiomers and diastereomers). The present invention contemplates and encompasses any stereoisomer of the compounds of formula (IA) and (IB) (subgenera described herein), as well as mixtures of such stereoisomers.

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

[0175] Isotopic variations of the compounds of formula (IA) and (IB) (subgenera described herein) are also encompassed within the scope of the present invention.

[0176] The present invention further provides the use of the compounds described in the present invention or their pharmaceutically acceptable salts in any of the methods described in the present invention. The present invention further provides the use of the compounds described in the present invention or their pharmaceutically acceptable salts in the preparation of therapeutic drugs, which are used in any of the methods described in the present invention.

[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 a cell expressing PKMYT1, comprising: contacting the cell with a compound of the present invention.

[0179] In some embodiments, the cell is associated with CCNE1 amplification, FBXW7 loss-of-function mutation, or other PKMYT1-dependent genetic alterations. In some embodiments, the cell is a subject cell.

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

[0181] In some embodiments, the subject has and needs treatment for a disease or disorder with symptoms of cellular hyperproliferation. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a cancer with CCNE1 amplification, FBXW7 loss-of-function mutation, or other genetic alterations that are dependent on PKMYT1.

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

[0183] definition

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

[0185] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims may be drafted to exclude any optional elements. Thus, this statement is intended to serve as antecedent basis for use of such exclusive terminology, such as "solely," "only," and the like, in connection with recitation of claim elements or use of a "negative" limitation.

[0186] At various places in this specification, variables defining divalent linking groups are described. Specifically, each linking substituent includes both forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes -NR(CR'R")- and -(CR'R")NR-, and each form is 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 for the variable lists "alkyl" or "aryl", it is understood that "alkyl" or "aryl" means a linked alkylene or arylene group, respectively.

[0187] The term "substituted" means that an atom or group of atoms replaces hydrogen as a "substituent" connected to another group. The term "substituted", unless otherwise specified, refers to any number of substitutions, for example, single-, double-, three-, four- or five-substitutions, if such substitutions are allowed. Substituents are independently selected, and substitutions can occur at any chemically possible position. It should be understood that substitutions at specific atoms are limited by valence. The term "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms.

[0188] The term "Cn-Cm" means a range including the endpoints, wherein n and m are integers representing the number of carbons. 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 to be isolated to a useful degree of purity from a reaction mixture, and preferably the compound can be formulated into an effective therapeutic agent.

[0190] It should also be understood that certain features of the present invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the present invention described in the context of a single embodiment for simplicity may also be provided individually or in any suitable sub-combination.

[0191] As used herein, unless otherwise indicated, the term "alkyl", as a substituent or part of a substituent, refers to a straight or branched saturated hydrocarbon group. The alkyl group may contain from about 1 to about 20, from about 2 to about 20, from about 1 to about 10, from about 1 to about 8, from about 1 to about 6, from about 1 to about 4, or from about 1 to about 3 carbon atoms. Similarly, in the C1-C8 alkyl group, C 1-8 It means that the group has 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched form. 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) and the like.

[0192] As used herein, unless otherwise specified, 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, ethenyl, propenyl, and the like.

[0193] As used herein, unless otherwise specified, 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, and the like.

[0194] As used in the present invention, unless otherwise specified, 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 in the present invention, unless otherwise indicated, the term "aryl" refers to unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbons. In certain embodiments, the aryl has about 6 to about 20 carbon atoms. In certain embodiments, the aryl has about 6 to about 14 carbon atoms. In certain embodiments, the aryl has about 6 to about 10 carbon atoms. Exemplary aryl, includes but is not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl etc.

[0196] As used in the present invention, unless otherwise indicated, the term "cycloalkyl" refers to an unsubstituted or substituted non-aromatic carbocyclic ring, including cycloalkyl, cycloalkenyl, cycloalkynyl. Cycloalkyl can include a monocyclic- or polycyclic (e.g., having 2, 3, or 4 fused rings) ring system, including fused rings, spiro rings, and bridged rings (e.g., bridged bicycloalkyl). In certain embodiments, cycloalkyl 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. Cycloalkyl can also have 0, 1, 2, or 3 double bonds and / or 0, 1, or 2 triple bonds. Cycloalkyl can optionally be oxo or thio (e.g., -C(O)- or -C(S)-). The definition of cycloalkyl also includes a ring formed by cycloalkyl fused with one or more aromatic rings (e.g., having a common bond with cycloalkyl), for example, benzo derivatives of pentane, benzo derivatives of pentene, benzo derivatives of hexane, etc. The cycloalkyl group may be connected to an aromatic ring or a non-aromatic ring of a cycloalkyl group having one or more aromatic rings. One or more ring-forming carbon atoms of the cycloalkyl group may be oxidized, for example, with an oxo or thio substituent. In certain embodiments, the cycloalkyl group is a C3-C7 monocyclic cycloalkyl group. In certain embodiments, the cycloalkyl group is C 4- C 10 Spiro or bridged ring cycloalkyl. Exemplary cycloalkyl, include but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinenyl, norcarbyl, cubic alkyl, 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 certain embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, cycloalkyl is a ring-containing, non-aromatic hydrocarbon group having 3 to 12 carbon atoms ("C 3- C 12 ”), preferably from 3 to 6 carbon atoms (“C 3- C6”). Exemplary cycloalkyl groups include, for example, cyclopropyl (C 3； 3-membered), cyclobutyl (C 4； 4-membered), cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4), 2-methylcyclopentyl (C4), adamantyl (C 10 )wait.

[0197] The term "spirocyclic cycloalkyl" used alone or as part of a substituent group refers to a non-aromatic cycloalkyl group containing two cycloalkyl groups, wherein, typically, the two cycloalkyl groups share one carbon atom.

[0198] As used in the present invention, unless otherwise specified, "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, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolyl, 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 contains 3 to about 14, 3 to about 7, or 5 to 6 ring 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 the present invention, unless otherwise specified, "heterocyclyl" 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 ring-forming carbon atoms of the heterocyclyl may be replaced by a heteroatom selected from N, O, S, and B; the ring-forming carbon atoms and heteroatoms of the heterocyclyl may be optionally replaced by one or more oxo or thio (e.g., C(O), S(O), C(S), or S(O)2, etc.). Heterocyclyl includes monocyclic and polycyclic (e.g., having 2 fused rings) systems. Heterocyclyl includes monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocyclyls. Heterocyclic groups also include spirocyclic and bridged rings (e.g., 5-10 membered bridged biheterocyclic groups, with one or more of the ring-forming carbon atoms being replaced by heteroatoms independently selected from N, O, S, and B). The heterocyclic group can be connected by ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocyclic group contains 0 to 3 double bonds. In some embodiments, the heterocyclic group contains 0 to 2 double bonds.

[0200] The heterocyclic group also includes a group having one or more aromatic rings fused to (i.e., having a common bond with the heterocyclic group) the non-aromatic heterocyclic ring, for example, piperidine, morpholine, benzo or thieno derivatives of azepane, etc. The heterocyclic group containing the fused aromatic ring can be connected by any ring-forming atom, including the ring-forming atom of the fused aromatic ring. In some embodiments, the heterocyclic group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming 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 with 1 or 2 heteroatoms independently selected from N, O, S and B, and has one or more ring atoms substituted with oxygen.

[0201] Exemplary heterocyclyl groups include, but are not limited to, pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyranyl, oxetanyl, azetidinyl, morpholine, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepine, 1,3-oxazolidinyl, 1,3-isoxazolidin-2-one ... 2,3,4-tetrahydroisoquinolyl, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.1]hexyl, azabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, diazabicyclo[3.1.1]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl yl, 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]pyrrolyl and the like.

[0202] In some embodiments, heterocyclyl 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 heterocyclyl can be connected through any heteroatom or carbon atom thereof, as long as a stable structure can be generated. Exemplary heterocyclyls include, but are not limited to, azepanyl, aziridine, azetidinyl, pyrrolidinyl, dioxolane, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, etc.

[0203] In some embodiments, the term "spirocyclic heterocyclyl" used alone or as part of a substituent group refers to a non-aromatic ring comprising two rings, at least one ring selected from heterocyclyl, and the two rings share one carbon atom.

[0204] As used herein, unless otherwise specified, "arylcycloalkyl" refers to a cycloalkyl group substituted with an aryl group.

[0205] As used herein, unless otherwise specified, "arylheterocyclyl" refers to a heterocyclyl group substituted with an aryl group.

[0206] As used herein, unless otherwise specified, "arylheteroaryl" refers to a heteroaryl group substituted with an aryl group.

[0207] As used herein, unless otherwise specified, "biaryl" refers to an aryl group substituted with an aryl group.

[0208] As used herein, unless otherwise specified, "heteroarylcycloalkyl" refers to a cycloalkyl group substituted with a heteroaryl group.

[0209] As used herein, unless otherwise specified, "heteroarylheterocyclyl" refers to a heterocyclyl substituted with a heteroaryl group.

[0210] As used herein, unless otherwise specified, "heteroarylaryl" refers to an aryl group substituted with a heteroaryl group.

[0211] As used herein, unless otherwise specified, "biheteroaryl" refers to a heteroaryl group substituted with a heteroaryl group.

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

[0213] As used herein, unless otherwise specified, "alkoxy" refers to -O-alkyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy, and the like.

[0214] As used herein, unless otherwise specified, "hydroxyalkyl" refers to an alkyl group substituted with OH.

[0215] As used herein, unless otherwise specified, "cyanoalkyl" refers to an alkyl group substituted with CN.

[0216] As used herein, unless otherwise specified, "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group.

[0217] As used herein, unless otherwise specified, "alkoxyalkoxy" refers to an alkoxy group substituted with an alkoxy group.

[0218] As used herein, unless otherwise specified, "haloalkoxy" refers to -O-(haloalkyl).

[0219] As used herein, unless otherwise specified, "arylalkyl" refers to an alkyl group substituted by an aryl group, and "cycloalkylalkyl" refers to an alkyl group substituted by a cycloalkyl group. An exemplary arylalkyl group is benzyl.

[0220] As used herein, unless otherwise specified, "heteroarylalkyl" refers to an alkyl group substituted by a heteroaryl group, and "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group.

[0221] As used herein, unless otherwise indicated, "oxo" refers to an oxygen substituent attached through a double bond (ie, =0).

[0222] As used in the present invention, unless otherwise specified, the term "optionally substituted" means unsubstituted or substituted.

[0223] As used in the present invention, unless otherwise specified, the term "substituted" refers to one or more hydrogen atoms in a group being replaced by a substituent independently selected from the same or different groups. Exemplary substituents include, but are not limited to, D, halogen, oxo, C1-C -6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkyl-NR c1 R d1 , -(CH2CH2O) o C1-C6 alkyl, wherein o is 1-10; C 2-6 Alkenyl-NR c1 R d1 , C 2-6 Alkynyl-NR c1 R d1 , O.C. 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 by a substituent selected from the group consisting of D, halogen, oxo, C1-C -6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 , O.C.2-6 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 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), 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 heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 heterocyclyl;

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

[0227] R c1 and R d1The 4-7 membered heterocyclic group formed together with the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 alkyl. 1-4 Haloalkoxy;

[0228] Every 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 membered 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 heterocyclyl-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 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group;

[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 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclylalkyl; wherein the C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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 the present invention may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of the present invention. Compounds described in the present invention containing asymmetrically substituted carbon atoms may be optically active or racemates. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc., may also be present in the compounds described in the present invention, and all stable isomers are also within the scope of the present invention. The cis and trans geometric isomers of the compounds described in the present invention are also within the scope of the present invention and can be separated into mixtures of isomers or separated isomeric forms.

[0232] The compounds of the present invention also include tautomers. Tautomers are produced by the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomers include proton transfer tautomers, which have the same chemical formula and total charge. Exemplary proton transfer tautomers include keto-enol tautomerism, amide-imidic acid tautomerism, lactam-lactide tautomerism, amide-imidic acid tautomerism and enamine-imine tautomerism, and protons in the ring structure can be interconverted at two or more positions in the heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole; tautomers can be balanced, or they can be fixed in space by suitable substitution to form a form.

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

[0234] The present invention further includes isotope labels of the compounds or intermediates of the present invention. "Isotope" refers to atoms with the same atomic number but different molecular weights. For example, isotopes of hydrogen include protium and deuterium.

[0235] In certain embodiments, compound of the present invention or its salt is substantially separated.With regard to " substantially separated ", it refers to that compound is formed from it or is detected in the environment at least partially or substantially separated.Partial separation may include, for example, a composition rich in the compounds of this invention.Substantially separation may include a composition containing at least about 50 % by weight, at least about 60 % by weight, at least about 70 % by weight, at least about 80 % by weight, at least about 90 % by weight, at least about 95 % by weight, at least about 97 % by weight or at least about 99 % by weight of the compounds of this invention or its salt.The method for separating compounds and their salts is conventional in the art.

[0236] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives 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 acids or organic acid salts of basic residues such as amines; alkali salts or organic salts of acidic residues such as carboxylic acids, etc. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed by non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, the salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., 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 the present invention to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0238] "Pharmaceutically acceptable excipient" refers to a substance, such as an inert substance, that is added to a pharmacological composition or otherwise used as a vehicle, carrier or diluent to facilitate administration of the medicament and is compatible therewith, that is non-toxic, biologically tolerable and otherwise biologically suitable for administration to a subject. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0239] "Solvate" refers to a compound of formula (IA) or (IB) with one or more solvent molecules.

[0240] "Subject" includes humans. The terms "human", "patient" and "subject" are used interchangeably in the present invention.

[0241] In one embodiment, "treating" or "treatment" of any disease or disorder refers to ameliorating the disease or disorder (i.e., preventing or reducing the development of at least one of the disease or its clinical symptoms). In another embodiment, "treating" refers to improving at least one physical parameter that the subject may not be able to discern. In another embodiment, "treating" refers to regulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In another embodiment, "treating" refers to delaying the onset of a disease or disorder.

[0242] "Compounds of the present invention" and equivalent expressions are intended to cover the compounds of formula (IA) and (IB) described in the present invention, and their respective subgenera. Where the context permits, the expression includes stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of the compounds of formula (IA) and (IB) and pharmaceutically acceptable salts.

[0243] As used herein, the term "isotopic variant" refers to a compound that contains an isotopic ratio greater than the natural abundance at one or more of the atoms that make up the compound. For example, an "isotopic variant" of a compound may be radiolabeled, i.e., contain one or more radioactive isotopes, or may be labeled with a non-radioactive isotope such as, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15( 15 It will be appreciated that in compounds subject to such isotopic substitution, if present, the following atoms may vary, such that, for example, any hydrogen may be 2 H / D, any carbon can be 13 C, or any nitrogen can be 15 N, and the presence and position of such atoms can be determined within the capabilities of those skilled in the art.

[0244] It is also understood that compounds having the same molecular formula but differing in the nature or order of bonding of the atoms or the arrangement of the atoms in space are referred to as "isomers". Isomers that differ in the arrangement of atoms in space are referred to as "stereoisomers", such as diastereomers, enantiomers, and rotamers. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)-stereoisomers at each asymmetric center or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures thereof, racemic or otherwise. When there is one chiral center in a structure, but the specific stereochemistry of the center is not shown, the structure includes two enantiomers, either individually or as a mixture of enantiomers. When there is more than one chiral center in a structure, but the specific stereochemistry of the center is not shown, the structure includes all enantiomers and diastereomers, either individually or as a mixture. Methods for testing stereochemistry and separating stereoisomers are well known in the art.

[0245] Pharmaceutical composition

[0246] The present invention also provides a pharmaceutical composition comprising: a compound represented by formula (IA) and (IB), or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or a prodrug thereof, and a pharmaceutically acceptable carrier.

[0247] The pharmaceutical composition can be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), can be used 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 pharmaceutical carriers), can be used topically (e.g., creams, ointments, gels, or aqueous or oily solutions or suspensions), can be used for inhalation (e.g., fine powders or liquid aerosols), can be administered by insufflation (e.g., fine powders), or can be administered parenterally (e.g., sterile aqueous oil solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

[0248] The compositions can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and / or preservatives.

[0249] The therapeutically effective amount of the compound represented by formula (IA) and (IB) or a pharmaceutical salt thereof can effectively treat or prevent the proliferative disorders mentioned herein, slow down their progression and / or alleviate the symptoms associated with the disorders.

[0250] The amount of active ingredient required to be combined with one or more excipients to produce a single dosage form varies depending on the individual being treated and the specific route of administration. For example, a formulation for oral administration to humans typically contains, 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 excipient, the amount of which may vary from about 5 to about 98% by weight of the total composition.

[0251] The dose of the compounds of formula (IA) and (IB) for therapeutic or preventive purposes will vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0252] Described below are non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0253] Dosage

[0254] The compounds represented by formula (IA) and (IB) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising these compounds can be administered to the subject by any convenient administration method, whether systemically / peripherally or locally (i.e., at the desired site of action).

[0255] Methods of administration include, but are not limited to: oral (e.g., by ingestion); buccal; 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 insufflation therapy, e.g., by aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrathoracic; by implantation of a reservoir or depot, e.g., subcutaneous or intramuscular.

[0256] How to use

[0257] The method generally includes administering a therapeutically effective amount of the compound of the present invention to a subject. The therapeutically effective amount of the combination of the target compound can be varied according to the intended application (in vitro or in vivo) or the subject and the disease condition to be treated, for example, the subject's weight and age, the severity of the disease condition, the mode of administration, etc., which can be easily determined by a person of ordinary skill in the art. The term is also applicable to the dosage of inducing a specific response in the target cell, for example, a reduction in the proliferation of the target protein or a reduction in the activity. The specific dosage will vary according to the selected specific compound, the dosage regimen followed, whether it is administered in combination with other compounds, the administration time, the tissue to which it is administered, and the physical delivery system to which it is carried.

[0258] As used herein, the term "IC 50 " refers to the half-maximal inhibitory concentration of an inhibitor in inhibiting a biological activity or biochemical function. This quantitative measure indicates how much of a particular inhibitor is required to inhibit a given biological process (or component of a process, i.e., an enzyme, cell, cell receptor, or microorganism) by half. In other words, it is the half-maximal (50%) inhibitory concentration (IC) of a substance (50% IC or IC 50 ).

[0259] In some embodiments, the test method (PKMYT1 enzyme activity test) uses a sample having an IC value of about or less than a predetermined value in an in vitro assay. 50 In some embodiments, the PKMYT1 inhibitor has an IC value of 50Value: about 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 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less, 550nM or less, 600nM or less , 650nM or less, 700nM or less, 750nM or less, 800nM or less, 850nM or less, 900nM or less, 950nM or less, 1μΜ or less, 1.1μΜ or less, 1.2μΜ or less, 1.3μΜ or less, 1.4μΜ or less, 1.5μΜ or less, 1.6μΜ or less, 1.7μΜ or less, 1.8μΜ or less, 1.9μΜ or less, 2μ In some embodiments, the present invention relates to an aqueous solution of at least 5 μM or less, 5 μM or less, 6 μM or less, 7 μM or less, 8 μM or less, 9 μM or less, 10 μM or less, 15 μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or less (or a number within the range defined by and including any two of the above numbers).

[0260] PKMYT1 is a synthetic lethal target for malignancies with specific genetic alterations, e.g., CCNE1 amplification or FBXW7 loss-of-function mutations, which may present symptoms of cellular hyperproliferation. The subject methods are useful for treating malignancies with CCNE1 amplification, FBXW7 loss-of-function mutations, or other genetic alterations that are dependent on PKMYT1.

[0261] Non-limiting examples of such disease states 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 cancer, ovarian germ cell tumor, ovarian low-grade malignant potential tumor, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor, gastrointestinal stromal tumor, 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, cervical adenocarcinoma , adenosquamous carcinoma of the cervix, small cell cervical cancer, mucinous cervical neoplasm, clear cell cervical cancer, cervical lymphoma, cervical sarcoma, endometrial carcinoma, 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, glioma cerebri, ganglioglioma, ganglioneuroma, paraganglioma, primitive neuroectodermal tumor, supratentorial primitive neuroectodermal tumor, visual pathway glioma, schwannoma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, esthesia neuroblastoma, extrahepatic bile duct carcinoma, Bellini duct carcinoma, cholangiocarcinoma, acute Eosinophilic leukemia, acute lymphocytic leukemia, acute megakaryocyte leukemia, acute monocytic leukemia, acute myeloblastic leukemia, acute myeloid dendritic cell leukemia, acute granulocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aggressive NK-cell leukemia, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloproliferative disease, chronic neutrophilic leukemia, erythroleukemia, hairy cell leukemia, leukemia, lymphoid leukemia, lymphoma, macroglobulinemia, mast cell leukemia, monocytic leukemia, granulocytic leukemia, T-cell acute lymphocytic leukemia, T-cell large granular lymphocytic leukemia, T-cell leukemia, T-cell prolymphocytic leukemia, AIDS-related 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, Hodgkin lymphoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, MALT lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma, precursor T-lymphocytic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, small cell lymphoma, T-cell lymphoma, terminal lymphoma.

[0262] The term "CCNE1 amplification" refers to an increase in the CCNE1 gene, resulting in an increase in the 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-diseased cells of the same type). The expression of cyclin E relative to control cells can be at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 10 times, at least 20 times, at least 50 times. Exemplary CCNE1-amplified cancers include, but are not limited to, uterine carcinosarcoma, ovarian epithelial tumors, endometrial cancer, esophageal 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, renal clear cell carcinoma, renal non-clear cell carcinoma, ovarian cancer, lung cancer, and esophageal cancer.

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

[0265] In other embodiments, the method is used to treat a disease selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

[0266] In other embodiments, the methods are used to treat cancers that are poorly responsive or 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 carcinoma, mature B-cell tumors, cervical cancer, leukemia, renal non-clear cell carcinoma, thymic epithelial tumor, renal clear cell carcinoma, seminoma, pheochromocytoma, thyroid cancer and non-seminomatous germ cell tumors.

[0268] In other embodiments, the method is used to treat a leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, 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 can be administered alone or in combination with medical therapy to treat any of the diseases described. Medical therapy includes, for example, surgery and radiation therapy (e.g., gamma-irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, systemic radioisotopes).

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

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

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

[0273] Combination therapy

[0274] The compounds of the present 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, radiotherapy, targeted therapy (e.g., growth factor inhibitors, kinase inhibitors, cyclin-dependent kinase inhibitors, etc.), other DDR regulators (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 invention can be used in combination with medical therapies such as surgery, radiotherapy or chemotherapy. Exemplary radiotherapy includes gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and systemic radioisotopes. Exemplary suitable chemotherapeutic agents include one or more anti-tumor agents from the following classes: other anti-proliferative / antineoplastic drugs used in medical oncology and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines, such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); anti-tumor antibiotics (e.g., anthracyclines such as bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, actinomycin, and mithramycin); anti-mitotic agents (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine, and anti-tumor drugs such as paclitaxel and taxotere and polo-like kinase inhibitors); topoisomerase inhibitors ( For example, podophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin); cytostatic agents such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazol and exemestane) and 5α-reductase inhibitors such as finasteride; anti-invasive agents such as inhibitors of the c-Src kinase family (AZD0530, dasatinib and bosutinib), and the metalloproteinase family (e.g., marimastat, family of urokinase plasminogen activator receptor function or heparanase 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, Vo1.54, ppl1-29); such inhibitors also include tyrosine kinase inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib and CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib; serine / threonine kinase inhibitors (such as the Ras / Raf inhibitors sorafenib, tipifarnib and lonafarnib), cell proliferation inhibitors through MEK and / or AKT kinases; c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Flt3 kinase inhibitors, CSF-1R kinase inhibitors; Aurora kinase inhibitors (such as 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 (such as the anti-vascular endothelial growth factor antibody bevacizumab, such as VEGF receptor tyrosine kinase inhibitors , such as vandetanib, vatalanib, sunitinib, axitinib, pazopanib and AZD2171, compounds disclosed in international patent applications WO97 / 22596, WO97 / 30035, WO97 / 32856 and WO98 / 13354 and compounds acting by other mechanisms (such as linomide, integrin avβ3 function inhibitors and angiostatin); vascular damaging agents, such as combretastatin A4 and compounds disclosed in international patent applications WO99 / 02166, WO Compounds disclosed in WO00 / 40529, WO00 / 41669, WO01 / 92224, WO02 / 04434 and WO02 / 08213; endothelin receptor antagonists, such as zilpotentan or atrasentan; PARP inhibitors such as olaparib, rucaparib, niraparib, talazoparib, veliparib, and pamiparib; PARP1 selective inhibitors such as AZD9547, AZD5305, AG-14361 and NMS-P118;Other DNA damage repair modulators such as 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), 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, hydroxamic acids, and cyclic tetrapeptides, suberoylanilide hydroxamic acid (SAHA), trichostatin 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, for example, therapy that acts on the above targets, for example, ISIS2503, an anti-ras antisense; gene therapy methods, including, for example, methods of replacing abnormal genes, for example, abnormal p53, CCNE1 amplification or FBXW7 loss-of-function mutations; GDEPT (gene-directed enzyme prodrug therapy) methods, for example, methods using cytosine deaminase, thymidine kinase or bacterial nitroreductase, and methods of increasing a patient's tolerance to chemotherapy or radiation therapy, for example, multidrug resistance gene therapy;and immunotherapy methods, including, for example, in vitro and in vivo methods to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, methods to reduce T cell anergy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines and methods using anti-idiotypic 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; methods using the above immune checkpoint receptor and ligand inhibitors, such as ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, and durvalumab. ;

[0277] synthesis

[0278] The compounds of the present 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 the schemes described below.

[0279] The reaction of preparing the compound of the present invention can be carried out in a suitable solvent, and the solvent can be easily selected by the technician in the field of organic synthesis. Suitable solvent can be substantially unreacted with the starting material (reactant), the intermediate or the product at the temperature of carrying out the reaction, for example, the temperature range can be from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to the above-mentioned specific reaction steps, those skilled in the art can select the solvent suitable for the specific reaction steps.

[0280] The preparation of the compounds of the present invention may involve the above-mentioned protection and deprotection of various chemical groups. The need for the above-mentioned protection and deprotection, as well as the selection of the appropriate protecting group, can be easily determined by those skilled in the art. Disclosed chemical protecting groups are as follows, for example, in 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); Peturssion 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 by 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., UV-Vis), or mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0282] As expressed, the terms "ambient temperature", "room temperature" and "rt" used in the present invention generally refer to temperature in the art, such as reaction temperature, which refers to the temperature of the space during the reaction operation, for example, a temperature of about 20°C to about 30°C.

[0283] The compounds of the present invention can be prepared according to a variety of preparation routes known in the literature. The following schemes provide general guidance related to the preparation of the compounds of the present invention. It should be understood by those skilled in the art that the preparation methods in the following schemes 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 shown in the following schemes.

[0284] The following examples are provided to illustrate some of the above concepts described in this summary. While the examples are considered to provide embodiments, they should not be considered to limit 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. The 2-amino derivative 1-1 can be converted into a 2-hydroxy derivative 1-2, which is reacted with a halogenating agent such as SOCl2, POCl3 or POBr3 in or without DMF (wherein W 1 Cl or Br) catalyzed, or with TfCl or MsCl (where W 1 OTf or OMs) can be further converted into the corresponding derivatives 1-3 in the presence of a base such as Hunig's base, wherein W 1 is halogen (e.g., Cl or Br) or pseudohalogen (e.g., OTf or OMs). Compound 1-3 and aromatic amine 1-4 can be reacted 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 1-5. Amine derivative 1-5 and malononitrile can be reacted under palladium catalysis 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 1-6. The nitro group of 1-6 is hydrolyzed under acidic or alkaline conditions to obtain pyrrole-amide derivative 1-7, which can be further converted into indole-pyrimidone 1-9 by reacting with trialkyl orthoformate 1-8 (where R is methyl or ethyl) in the presence of an acid such as p-TsOH or HCl. Indole-pyrimidone 1-9 is reacted with a halogenating agent such as SOCl2, POCl3 or POBr3 in DMF (where W is methyl or ethyl). 2 Cl or Br) or with TfCl or MsCl (where W 2 (OTf or OMs) in the presence of a base such as Hunig's base, can be converted into intermediate 1-10, wherein W 2 is halogen (eg, Cl or Br) or pseudohalogen (eg, OTf or OMs). The intermediate 1-10 reacts with ammonia or an amine derivative to obtain the target tricyclic derivative represented by formula (IA).

[0287] Solution 1

[0288]

[0289] A series of intermediates of formula 2-4 for preparing the tricyclic derivatives of formula (IA) can be prepared according to the method described in Scheme 2. Compound 2-1 (W 1 and W2 The malononitrile derivative 2-2 can be obtained by reacting the malononitrile derivative 2-2 with the aromatic amine 2-3 under Buchwald coupling conditions (for example, in the presence of a palladium catalyst such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos PdG3 and a base such as t-BuOK, t-BuONa, Cs2CO3, or K2CO3).

[0290] Solution 2

[0291]

[0292] A series of intermediates of formula 3-6 for preparing 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) under palladium catalysis (for example, 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 obtain aminopyrrol ester 3-3. The aminopyrrol ester 3-3 is reacted with cyano derivative 2-4 in the presence of an acid such as dry HCl, TsOH or H2SO4, or with alkyl-carbonyl imide acid ethyl ester 3-5 to obtain tricyclic derivative 3-6.

[0293] Solution 3

[0294]

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

[0296] Solution 4

[0297]

[0298] A series of tricyclic derivatives represented by formula 5-8 can be prepared according to the method described in Scheme 5. Compound 5-1, wherein W 2is a halogen (e.g., Cl, Br, or I) and W 1 W is a halogen (e.g., Br, or Cl), and is first reacted with malononitrile according to the method in Scheme 2, and then subjected to Buchwald's amination with aromatic amine 5-3, or first subjected to Buchwald's amination with aromatic amine 5-3, and then converted into aminopyrrole 1-6 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), and reacted with malononitrile under palladium catalysis conditions, which can be further converted into aminopyrrole derivative 5-4. Aminopyrrole derivative 5-4 can be reacted with a suitable reagent, such as N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) to obtain compound 5-5, wherein W 3 Wherein: wherein the appropriate R is halogen (e.g., Cl, Br, or I), and ... 1 The group is inserted to obtain compound 5-6. According to the method of converting compound 1-6 into formula (IA) and (IB) in Scheme 1, compound 5-6 can be further converted into the target tricyclic derivative represented by formula 5-8.

[0299] Solution 5

[0300]

[0301] In addition, a series of tricyclic derivatives shown in formula 6-10 can be prepared according to the method described in Scheme 6. Pyrazine-2(1H)-one 6-1 is subjected to O-alkylation reaction with benzyl bromide or benzyl chloride in the presence of a base such as NaH or K2CO3 to obtain pyrazine 6-2, which is successively hydrolyzed with aromatic amine 6-3 and malononitrile according to the method for converting compound 1-3 to 1-7 in Scheme 1, and can be further converted into aminopyrrolamide 6-6. Compound 6-6 is hydrogenated in the presence of a palladium catalyst such as Pd / C or Pd(OH)2 / C to obtain the corresponding compound 6-7. The hydroxyl group of compound 6-7 is reacted with a trifluorination agent such as PhNTf2 or Tf2O in the presence of a base such as Et3N or Hunig's base to be converted into the corresponding trifluoromethanesulfonate derivative 6-8. Trifluoromethanesulfonate derivative 6-8 can be further converted into target compound 6-9, and tricyclic derivative 6-10 can be further obtained according to the method described in Scheme 1.

[0302] Solution 6

[0303]

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

[0305] Solution 7

[0306]

[0307] A series of tricyclic derivatives shown in formula 8-10 can be prepared according to the method described in Scheme 8. 2-Aminobromo 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, which can be further converted into 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 obtain an aromatic amine derivative 8-4. The carboxylate group of 8-4 can be reduced to the corresponding alcohol 8-5 using a reducing agent such as LiBH4 or NaBH4. The 3-Br of aromatic amine 8-5 reacts with malononitrile under copper-catalyzed coupling conditions (e.g., CuI in the presence of a diamine-base ligand such as N 1 ,N 2 -Dimethylethane-1,2-diamine, N 1 ,N 2 -dimethylcyclohexane-1,2-diamine or cyclohexane-1,2-diamine) or under palladium catalytic conditions (for example, 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), aminopyrrole 8-6 can be obtained. The nitrile of 8-6 is hydrolyzed under acidic or basic conditions to obtain a pyrrole-amide derivative 8-7, which is further converted into compound 8-8 by reacting with DPPA (diphenyl phosphate) and DBU, or by Mitsunobo reaction with azide or by reaction with sodium azide and DEAD or DIAD. The azide group of compound 8-8 is reacted with triphenylphosphine or hydrogenated in the presence of a palladium catalyst such as Pd / C to obtain the corresponding amine 8-9. The formation of a molecular lactam can obtain the target tricyclic derivative shown in formula 8-10.

[0308] Solution 8

[0309]

[0310] In addition, a series of tricyclic lactam derivatives of formula 9-10 can be prepared according to the method described in Scheme 9. 3-Bromopyridin-2-amine 9-1 is subjected to condensation reaction with pyruvic acid in the presence of a palladium catalyst such as bis(tri-tert-butylphosphine)palladium(0) and a base such as potassium phosphate to obtain azaindole acid 9-2. Azaindole acid 9-2 can be converted into the corresponding azaindole ester 9-3 (wherein R is Me or Et) by reacting with diazomethane (wherein R is Me) or first with oxalyl chloride and then with alcohol ROH. 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 and then with an oxidizing agent such as Ag2O; 2) reacting 9-3 with anhydrous trifluoroacetic acid and then with NaOH; 3) reacting 9-3 with 2,2,2-trichloroacetyl chloride and then with NaOH. Indole derivative 9-4 can be further converted to azaindole lactam 9-5 by reacting with protected amine such as p-methoxybenzylamine PMB-NH2 in the presence of an amide coupling reagent such as BOP, ByBOP, HATU or HBTU, and a base such as Et3N or Hunig's base. Indole lactam 9-5 can be coupled with aromatic iodine or aromatic bromide 9-6 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 aza-indole derivative 9-7, which can be further converted to amino-azaindole derivative 9-9 by Curtius rearrangement with the product of azaindole acid 9-8 and DPPA (diphenylphosphorylazide). The PMB protecting group of 9-9 is removed and hydrogenated in the presence of a palladium catalyst such as Pd / C or Pd(OH)2 / C or reacted under acidic conditions such as TFA to give the final tricyclic lactam derivative 9-10.

[0311] Solution 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-bromo group 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 aminopyrrolyl ester 10-3. The tricyclic derivative 10-6 can be prepared by reacting the aminopyrrolyl ester 10-3 with a cyano derivative 10-4 in the presence of an acid such as dry HCl, TsOH or H2SO4) or an ethylalkyl-carbodiimide 10-5.

[0314] Solution 10

[0315]

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

[0317] Solution 11

[0318]

[0319] A series of tricyclic derivatives represented by formula 12-8 can be prepared according to the method described in Scheme 12. Compound 12-1 wherein W 2 is a halogen (e.g., Cl, Br, or I) and W 1 W is a halogen (e.g., Br, or Cl), and can be further converted to an aminopyrrole derivative 12-4 by first reacting with malononitrile according to the method described in Scheme 9, and then subjecting the compound 8-3 to Buchwald's amination with an aromatic amine 12-3, or by first subjecting the compound 8-3 to Buchwald's amination with an aromatic amine 12-3 and then subjecting the compound to Buchwald's amination 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). The aminopyrrole derivative 12-4 can be halogenated with a suitable amine such as N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) to afford compound 12-5, wherein W 3is a halogen (e.g., Cl, Br, or I), R 1 The halogen is replaced by a group, such as standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 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(diphenylphosphino)-ferrocene]dichloropalladium(II)), or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), to give compound 12-6. Compound 12-6 can be further converted to the tricyclic derivative shown in formula 12-8 according to the method for converting compound 8-6 to formula (IA) and (IB) in Scheme 8.

[0320] Solution 12

[0321] Example

[0322] Example 1: 3-(4-amino-6-morpholine-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] To a suspension of 1,3-dimethyl-2-nitrobenzene (20.0 g, 132 mmol) and Fe (2.96 g, 52.9 mmol) in CHCl3 (200 mL) was added a solution of Br2 (22.2 g, 139 mmol) in CHCl3 (100 mL). 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 was 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-butylphosphino-2,4,6-triisopropylbiphenyl (7.38 g, 17.4 mmol) and bis(dibenzylideneacetone)palladium (7.96 g, 8.69 mmol) in dioxane (200 mL) and H2O (200 mL) was degassed and filled with N2, replaced 3 times, and stirred at 90°C under N2 atmosphere for 12 h. After cooling to rt, the reaction mixture was diluted with water (600 mL), adjusted to pH ~ 3 with 1M 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 flash chromatography on silica gel column eluting with EtOAc / PE (2-20%) to give the title compound (10.0 g, crude) 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) was added cesium carbonate (46.8 g, 144 mmol) and CH3I (15.3 g, 108 mmol). 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 flash chromatography on a silica gel column eluted with EtOAc / PE (2-20%) to give the crude target compound (10 g) as a light yellow solid.

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

[0334]

[0335] 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) were added Fe (21.6 g, 386 mmol) and NH4Cl (20.7 g, 386 mmol). 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 flash chromatography on a silica gel column eluted with EtOAc / PE (2-20%) to give the target compound (5.00 g) as a light 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-chloropyrazin-2-ol

[0337]

[0338] To a solution of 5-bromo-6-chloropyrazin-2-amine (20.0 g, 96.0 mmol) in concentrated H2SO4 (98%, 140 mL) at 0°C, NaNO2 (7.28 g, 106 mmol) was carefully added in portions. 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 title compound (20.0 g) as a light brown solid, which was 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) were added (bromomethyl)benzene (7.19 g, 42.0 mmol) and Ag2CO3 (21.1 g, 76.4 mmol). 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 flash chromatography on a silica gel column eluted 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) δ7.99 (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)pyrazin-2-amine

[0343]

[0344] To a solution of 5-(benzyloxy)-2-bromo-3-chloropyrazine (3.19 g, 10.6 mmol) in toluene (15.0 mL) were added potassium tert-butoxide (1.59 g, 14.2 mmol), 3-methoxy-2,6-dimethylaniline (1.61 g, 10.6 mmol), bis(dibenzylideneacetone)palladium (487 mg, 0.53 mmol) and Xantphos (616 mg, 1.06 mmol) at rt. The reaction mixture was degassed and filled with nitrogen, replaced 3 times, and stirred at 80 °C for 1 h. The reaction mixture was cooled to rt and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on a silica gel column eluting with EtOAc / PE (0.25-2%) to give the title compound (2.40 g, 60.9% yield) as a light 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-carbonitrile

[0346]

[0347] To a solution of malononitrile (1.04 g, 15.8 mmol) in dimethyl ether (73.0 mL) was added sodium hydride (632 mg, 15.8 mmol) at rt. The reaction mixture was stirred at rt for 30 mins, then a solution of 5-(benzyloxy)-3-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyrazin-2-amine (1.46 g, 3.95 mmol) in 1,2-dimethoxyethane (7.30 mL) and tetrakis(triphenylphosphine)palladium (2.28 g, 1.97 mmol) were added at rt. The reaction mixture was degassed and filled with nitrogen, replaced 3 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 flash chromatography on silica gel column eluting with MeOH / DCM (1-50%) to afford the title 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 solution of 6-amino-2-(benzyloxy)-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile (1.90 g, 4.76 mmol) in concentrated H2SO4 (98%, 10 mL) was stirred at 15°C for 2 h, and the reaction mixture was added to ice (~50 g) at below 10°C. The mixture was adjusted to pH ~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 was used directly in the next step without purification. 1H NMR: (400 MHz, 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 value C 16 H 18 N5O3[M+H] + : m / z = 328.1; found: 327.9. Step 10: 6-amino-7-formyl-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl trifluoromethanesulfonate

[0351]

[0352] To a solution of 6-amino-2-hydroxy-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (1.30 g, 3.97 mmol) in DMF (6.00 mL) at rt, cesium carbonate (2.85 g, 8.74 mmol) was added, followed by N-phenyl-bis(trifluoromethanesulfonimide) (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 flash chromatography on a silica gel column eluting with EtOAc / PE (10-50%) to afford the title 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-morpholino-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

[0354]

[0355] To a solution of 6-amino-7-formyl-5-(3-methoxy-2,6-dimethylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl trifluoromethanesulfonate (0.64 g, 1.39 mmol) in DMSO (2.0 mL) was added morpholine (3.0 g, 34.4 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 flash chromatography on a silica gel column eluted with EtOAc / PE (10-50%) to give the title 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-morpholino-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-ol

[0357]

[0358] To 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), TsOH.H2O (9.60 mg, 0.05 mmol) was added. The reaction mixture was stirred at 40°C for 1 h. The filtrate was concentrated under reduced pressure to give the crude target compound (0.2 g) as a brown oil, which was 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-morpholino-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 the crude target compound (0.2 g) as a light brown oil, which was used directly in the next step without purification. LCMS calculated value C 21 H 22 ClN6O2[M+H] + :m / z=425.1; Found: 425.0.

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

[0363]

[0364] To a solution of 4-(4-chloro-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrazino[2',3':4,5]pyrrolo[2,3-d]pyrimidin-6-yl)morpholine (0.2 g, 0.47 mmol) in MeOH (1.0 mL) was added NH3 / MeOH (6 M, 20.0 mL) in a sealed tube. The reaction mixture was stirred at 80°C overnight, and the filtrate was concentrated under reduced pressure to give the crude target compound (0.2 g) as a light brown oil, which was used directly in the next step without purification. 1 H NMR: (400 MHz, 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 value C 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-morpholino-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 poured into ice water at 0°C, pH 7-8 was adjusted with NH3.H2O (25-30%), and extracted 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 title compound (0.048 g, 24.5% yield) as a light yellow solid. 1 H NMR: (400 MHz, 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 value C 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-yl trifluoromethanesulfonate (1.00 g, 2.18 mmol, step 10 of Example 1), 2,4,6-trimethyl-1,3,5,2,4,6-cyclotriboroxane (601 mg, 2.39 mmol, 0.67 mL, 50% purity), tetrakis(triphenylphosphine)palladium (252 mg, 0.22 mmol) and potassium carbonate (902 mg, 6.53 mmol) in dioxane (10.0 mL) was degassed and filled with N2 for 3 times, and stirred at 140° C. under N2 atmosphere for 2 h. After cooling to 15° C., the reaction mixture was 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 flash chromatography on a silica gel column, eluted with EtOAc / PE (10-50%) to give the title compound (0.40 g, 56.5% yield) as a light brown foam. LCMS calculated value C 17 H 20 N5O2[M+H] + :m / z=326.2; Found: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] This compound was prepared in a similar manner to steps 12-15 of Example 1. In step 12, 6-amino-5-(3-methoxy-2,6-dimethylphenyl)-2-methyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide was used as a starting material. 1 H NMR: (400 MHz, 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 value 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] This compound was prepared in a similar manner to that of Step 5 of Example 1, using 3-bromo-5,6-dimethylpyridin-2-amine instead of 5-bromo-6-chloropyrazin-2-amine. 1 H 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] 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) was added dropwise a solution of POBr3 (26.2 g, 91.3 mmol, 9.28 mL) in xylene (30.0 mL) at 90°C under nitrogen atmosphere. 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 with NaOH aq. (0.5 N, 30 mL), water (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (5-20%) to give the title compound (12.0 g, 74.4% yield) as a white solid. 1H 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; Found: 263.8.

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

[0386]

[0387] This compound was prepared in a similar manner to step 7 of Example 1, except that 2,3-dibromo-5,6-dimethylpyridine was used instead of 5-(benzyloxy)-2-bromo-3-chloropyrazine, and cesium carbonate was used instead of potassium tert-butoxide. 1 H 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 value 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-carbonitrile

[0389]

[0390] To a solution of malononitrile (1.97 g, 29.8 mmol) in 1,2-dimethoxyethane (35.0 mL) under N2 atmosphere, sodium tert-butoxide (2.87 g, 29.8 mmol) was added. 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), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1.22 g, 1.49 mmol) were added. The reaction mixture was degassed and filled with nitrogen, replaced 3 times, and stirred at 85 °C under N2 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 flash chromatography on a silica gel column eluting with EtOAc / PE (10-50%) to give the title compound (4.30 g, 90.0% yield) as a light brown solid. 1 H 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 value C 19 H 21 N4O[M+H] + : m / z = 321.2; found value: 321.0.

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

[0392]

[0393] To a solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (4.00 g, 12.5 mmol) in DCM (40.0 mL) was added BBr3 (6.26 g, 25.0 mmol, 2.41 mL) dropwise at 0°C. 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 the crude target compound (2.00 g) as a light yellow solid, which was used directly in the next step without purification.1 H 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 value C 18 H 19 N4O[M+H] + : m / z = 307.1; Found: 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] This compound was prepared in a similar manner to that in Step 9 of Example 1. 1 H 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 value C 18 H 21 N4O2[M+H] + : m / z = 325.2; Found: 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] This compound was prepared in a similar manner to that of Example 1, Step 12. 1 H 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 value C 19H 19 N4O2[M+H] + : m / z = 335.1; found 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] This compound was prepared in a similar manner to that in Step 13 of Example 1. 1 H NMR: (400 MHz, MeOD) δ 8.69 (s, 1H), 8.54 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 2.59 (s, 3H), 2.53 (s, 3H), 1.74 (s, 3H), 1.68 (s, 3H). LCMS calculated value C 19 H 18 ClN4O[M+H] + : m / z = 353.1; found 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] This compound was prepared in a similar manner to that of Example 1, Step 14. 1 H 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 value C 19 H 20 N5O[M+H] + : m / z = 334.2; found 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 (early eluting product, 49.8 mg, HPLC retention time in hand type = 2.478 min) and P2 (latter eluting product, 62.9 mg, HPLC retention time in hand type = 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 hand-type HPLC. Chiral HPLC conditions: column: Chiralcel OJ-3, 150×4.6 mm ID, 3 μm; mobile phase A: CO2, mobile phase B: MeOH (0.1% IPAm); flow rate: 2.5 ml / min, run time: 5 min; detection wavelength: 220 nm.

[0410] P1 is Example 4. 1 H 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 value C 19 H 20 N5O[M+H] + : m / z = 334.2; found value: 334.1.

[0411] P2 is Example 5. 1H 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 value C 19 H 20 N5O[M+H] + : m / z = 334.2; found 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]naphthyridin-3(1H)-one

[0413]

[0414] Step 1: 2-amino-5-methylpyridine-4-carboxylic acid methyl ester

[0415]

[0416] To a solution of methyl 2-amino-5-bromopyridine-4-carboxylate (10.0 g, 43.2 mmol) in 1,4-dioxane (100 mL) was added trimethyl-1,3,5,2,4,6-cyclotriboroxane (27.1 g, 216 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.17 g, 4.32 mmol) and potassium carbonate (17.9 g, 129 mmol). The reaction mixture was degassed and filled with nitrogen, replaced 3 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 flash chromatography on a silica gel column eluted with EtOAc / PE (0-40%) to give the target compound (7.00 g, 97% yield) as a yellow solid. LCMS calculated for C8H 11 N2O2[M+H] + :m / z=167.1; Found: 167.1.

[0417] Step 2: 2-amino-3-bromo-5-methylpyridine-4-carboxylic acid methyl ester

[0418]

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

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

[0421]

[0422] 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.) was added dropwise a solution of NaNO2 (0.56 g, 8.16 mmol) in H2O (2 mL) at -10°C. The reaction mixture was stirred at -10°C for 30 mins, then CuBr (1.40 g, 9.75 mmol) was added and 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 flash chromatography on a silica gel column eluting with EtOAc / PE (0-30%) to give the title compound (800 mg, 31% yield) as a light yellow solid. LCMS calculated for C8H8Br2NO2 [M+H] + : m / z = 307.9; Found: 307.9.

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

[0424]

[0425] To a suspension of 1,3-dimethyl-2-nitrobenzene (20.0 g, 132 mmol) and Fe (2.96 g, 52.9 mmol) in CHCl3 (200 mL) was added a solution of Br2 (22.2 g, 139 mmol) in CHCl3 (100 mL). 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 was 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-butylphosphino-2,4,6-triisopropylbiphenyl (7.38 g, 17.4 mmol) and bis(dibenzylideneacetone)palladium (7.96 g, 8.69 mmol) in dioxane (200 mL) and H2O (200 mL) was degassed and filled with nitrogen, replaced with N2 3 times, and stirred at 90°C under N2 atmosphere for 12 h. After cooling to rt, the reaction mixture was diluted with water (600 mL), adjusted to pH ~ 3 with 1M 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 flash chromatography on silica gel column eluting with EtOAc / PE (2-20%) to give the title compound (10.0 g, crude) 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) was added cesium carbonate (46.8 g, 144 mmol) and CH3I (15.3 g, 108 mmol). 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 flash chromatography on a silica gel column eluted with EtOAc / PE (2-20%) to give the crude target compound (10 g) as a light yellow solid.

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

[0433]

[0434] 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) were added Fe (21.6 g, 386 mmol) and NH4Cl (20.7 g, 386 mmol). 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 flash chromatography on a silica gel column eluted with EtOAc / PE (2-20%) to give the target compound (5.00 g) as a light 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: 3-Bromo-2-[(3-methoxy-2,6-dimethylphenyl)amino]-5-methylpyridine-4-carboxylic acid methyl ester

[0436]

[0437] A mixture of methyl 2,3-dibromo-5-methylpyridine-4-carboxylate (100 mg, 0.324 mmol), 3-methoxy-2,6-dimethylaniline (58.7 mg, 0.389 mmol), bis(dibenzylideneacetone)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 filled with nitrogen, replaced 3 times, and stirred overnight at 80 ° C under nitrogen atmosphere. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc / PE (0-50%) to give the target compound (45.0 mg, 36% yield) as a yellow solid. LCMS calculated value 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] To a solution of 3-bromo-2-[(3-methoxy-2,6-dimethylphenyl)amino]-5-methylpyridine-4-carboxylic acid methyl ester (1.15 g, 3.03) in tetrahydrofuran (25 mL) was added dropwise a solution of lithium borohydride in tetrahydrofuran (2M, 7.6 mL, 15.2 mmol) at 0°C. The reaction mixture was stirred at 60°C overnight 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 flash chromatography on a silica gel column eluted 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; found: 353.0. Step 10: 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carbonitrile

[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 -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) in DMSO (5 mL) were degassed and filled with nitrogen, and replaced 3 times. The reaction mixture was reacted in a microwave oven at 130 ° C for 1 h and then quenched with water (80 mL). The mixture was extracted with EtOAc (3x 120 mL). The combined organic phase was washed with saturated brine (2x 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 value C 19 H 21 N4O2[M+H] + : m / z = 337.2; found: 337.1. Step 11: 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester

[0443]

[0444] A mixture of 2-amino-4-(hydroxymethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carbonitrile (198 mg, 0.589 mmol) and HCl (g) in MeOH (4M, 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 title compound (121 mg, 56% yield) as a yellow solid. LCMS calculated value C 20 H 24 N3O4[M+H] + :m / z=370.2 Measured value: 370.1.

[0445] Step 12: 2-amino-4-(azidomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester

[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), diphenylphosphoryl azide (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 (3x 80 mL). The combined organic phases were washed with saturated brine (2x30 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; Found: 395.2.

[0448] Step 13: 2-amino-4-(aminomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester

[0449]

[0450] A mixture of 2-amino-4-(azidomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (77.0 mg, 0.195 mmol) and triphenylphosphine (102 mg, 0.39 mmol) in water (2 mL) and tetrahydrofuran (10 mL) was stirred overnight at rt under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x80 mL). The combined organic phase was washed with saturated brine (2x 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 value 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-triazinetricyclo[6.3.1.0^{4,12}]dodeca-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 at 80 ° C overnight and then quenched with water (50 mL). The mixture was extracted with EtOAc (3x 80 mL). The combined organic phases were washed with saturated brine (2x 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 value C 19 H 21 N4O2[M+H] + :m / z=337.2; Found: 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}]dodecan-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}]dodeca-1(11),3,8(12),9-tetraene-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 in DCM, 0.447 mmol) in dichloromethane (5 mL) at -78°C. 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) and stirred at rt for 1 h. It was directly purified by Prep-HPLC eluting 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. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 7.55 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 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 value C 18 H 19 N4O2[M+H] + :m / z=323.2; measured value: 323.1.

[0456] The target compound 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]naphthyridine-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]naphthyridine-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]naphthyridin-3(1H)-one

[0458]

[0459] Step 1: 2-((Diphenylmethylenyl)amino)-6-methylisonicotinate

[0460]

[0461] A mixture of 2-bromo-6-methylisonicotinic acid methyl ester (83 g, 361 mmol), benzophenone imine (71.9 g, 399 mmol), Cs2CO3 (353 g, 108 mmol) and Xantphos (20.9 g, 36.1 mmol) in dioxane (581 mL) was degassed and charged with N2 for 3 replacements, and Pd2(dba)3 (16.5 g, 18.0 mmol) was added to the previous mixture. The mixture was degassed and charged with N2 for 3 replacements, and then the mixture was stirred at 80°C under N2 atmosphere overnight. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column, eluted with ethyl acetate / petroleum ether (0.5-3.3%) to give the target compound (160 g, 44.7% yield) as a light yellow oil. 1H 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 value C 21 H 19 N2O2[M+H] + :m / z=331.1; measured value: 331.2.

[0462] Step 2: 2-amino-6-methylisonicotinate

[0463]

[0464] To a solution of methyl 2-((diphenylmethylenyl)amino)-6-methylisonicotinate (51.6 g, 156 mmol) in THF (50 mL) was added HCl (6 M, 104 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (200 mL) and the pH was adjusted to 8-9 with NH3.H2O (30 mL). , 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 a 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 light yellow solid. 1 H NMR: (400 MHz, DMSO-d6) δ 6.76 (s, 2H), 6.20 (s, 2H), 3.82 (s, 3H), 2.28 (s, 3H). LCMS calculated value C8H 11 N2O2[M+H] + :m / z=167.1; measured value: 167.2.

[0465] Step 3: 6-amino-3-bromo-2-methylisonicotinate

[0466]

[0467] To a solution of 2-amino-6-methylisonicotinate (18.3 g, 110 mmol) in ACN (112 mL) was added NBS (19.6 g, 110 mmol). 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 phase was washed with saturated brine (200 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was slurried with MTBE (150 mL) at 20 ° C for 1 h to obtain the target compound (49 g, 60.5% yield) as a yellow solid. 1 H NMR: (400 MHz, CDCl3) δ 6.53 (s, 1H), 4.58 (s, 2H), 3.93 (s, 3H), 2.55 (s, 3H). LCMS calculated value C8H 10 BrN2O2[M+H] + :m / z=244.9; Found: 244.9.

[0468] Step 4: 6-amino-2,3-dimethylisonicotinate

[0469]

[0470] A mixture of 6-amino-3-bromo-2-methylisonicotinate (11 g, 44.9 mmol), methylboronic acid (8.06 g, 135 mmol), and K2CO3 (24.8 g, 180 mmol) in dioxane (77 mL) was degassed and filled with N2 for 3 times. Pd(dppf)Cl2 (3.28 g, 4.49 mmol) was added to the above mixture, degassed and filled with N2 for 3 times. The mixture was then stirred at 80°C under N2 atmosphere overnight. The reaction mixture was diluted with H2O (200 mL) and extracted with EA (150 mL x 4). The combined organic phase was washed with saturated brine (500 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was slurried with MTBE:EA (15 / 1, 84 mL) at 20 °C for 1 h, filtered, and the filter cake was slurried with ACN (40 mL) at 20 °C for 1 h to give the title compound (28 g, 86.5% yield) as a yellow solid. 1 H 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 value C9H 13 N2O2[M+H] + :m / z=181.1; measured value: 180.9.

[0471] Step 5: 2-amino-3-bromo-5,6-dimethylisonicotinate

[0472]

[0473] This compound was prepared in a similar manner to step 2 of Example 6, using 6-amino-2,3-dimethylisonicotinate instead of 2-amino-5-methylpyridine-4-carboxylic acid methyl ester to give the desired product as a yellow solid. 1 H NMR: (400 MHz, DMSO-d6) δ 6.13 (s, 1H), 3.87 (s, 3H), 2.24 (s, 3H), 1.98 (s, 3H). LCMS calculated value C9H 12 BrN2O2[M+H] + :m / z=259.0; Found: 258.9.

[0474] Step 6: 2,3-Dibromo-5,6-dimethylisonicotinate

[0475]

[0476] To a solution of 2-amino-3-bromo-5,6-dimethylisonicotinic acid methyl ester (9.5 g, 36.7 mmol) in dibromomethane (67 mL) were added benzyltriethylammonium bromide (44.9 g, 165 mmol) and tert-butyl nitrite (37.8 g, 367 mmol). 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 flash chromatography on a silica gel column, eluted with EA / PE (0.5-35%) to obtain the target compound (16 g, 67.5% yield) as a colorless oil. 1 H NMR: (400 MHz, DMSO-d6) δ 3.98 (s, 3H), 2.44 (s, 3H), 2.19 (s, 3H). LCMS calculated value C9H 10 Br2NO2[M+H] + :m / z=323.9; Found: 323.9.

[0477] Step 7: 3-Bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,6-dimethylisonicotinate

[0478]

[0479] A mixture of 2,3-dibromo-5,6-dimethylisonicotinic acid methyl ester (5.0 g, 15.5 mmol), 3-methoxy-2,6-dimethyl-aniline (2.34 g, 15.5 mmol,), Cs2CO3 (12.6 g, 38.7 mmol) and Xantphos (896 mg, 1.55 mmol), Pd2(dba)3 (709 mg, 0.774 mmol) in DME (35 mL) was degassed and filled with N2, replaced 3 times, and then the mixture was stirred overnight at 80 ° C under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column, eluted with EA / PA (0.5-35%) to obtain 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; Found: 393.1.

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

[0481]

[0482] To a solution of methyl 3-bromo-2-((3-methoxy-2,6-dimethylphenyl)amino)-5,6-dimethylisonicotinate (3 g, 7.63 mmol) in DCM (21 mL) was added DIBAL-H (1 M, 21 mL). The mixture was stirred at -70 °C for 2 h., then quenched by adding H2O (200 mL) at 0 °C under 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 flash chromatography on a silica gel column eluted with EA / PE (0-5%) to give the title compound (3.0 g, 53.8% yield) as a yellow oil. 1 H NMR: (400 MHz, CDCl3) δ 7.05 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.36 (s, 1H), 4.85 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 2.27 (s, 3H). 2.25 (s, 3H), 2.16 (s, 3H), 2.09 (s, 3H). LCMS calculated value 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-carbonitrile

[0484]

[0485] This compound was prepared in a similar manner 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 give the desired product as a yellow solid. 1 H NMR: (400 MHz, CDCl3) δ 7.12 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.06 (s, 2H), 4.47 (s, 3H), 3.81 (s, 3H), 2.32 (d, J = 14 Hz, 6H), 1.84 (s, 3H), 1.77 (s, 3H). LCMS calculated value C 20 H 23 N4O2[M+H] + :m / z=351.2; measured value: 351.2.

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

[0487]

[0488] This compound was prepared in a similar manner 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-carbonitrile as the starting material to obtain the target product as a yellow solid. LCMS calculated value C 21 H 26 N3O4[M+H] + :m / z=384.2; Found: 384.2.

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

[0490]

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

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

[0493]

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

[0496]

[0497] This compound was prepared in a similar manner to step 14 of Example 6 using 2-amino-4-(aminomethyl)-1-(3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester to give the desired product as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 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 value 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]naphthyridin-3(1H)-one

[0499] This compound was prepared in a similar manner 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]naphthyridine-3(1H)-one to give the desired product as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.0 Hz, 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 value C 19 H 21 N4O2[M+H] + :m / z=337.2; Found: 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-methylquinolin-5-amine

[0503]

[0504] A mixture of 2,3-dibromo-5,6-dimethylpyridine (10.0 g, 37.7 mmol, step 2 of Example 3), 6-methylquinolin-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 filled with N2, replaced 3 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 flash chromatography on a silica gel column eluting with EA / PE (0-5%) to give the title compound (7.50 g, 58.1% yield) as a yellow solid. 1 HNMR: (400 MHz, MeOD) δ 8.75 (dd, J = 4.4, 1.6 Hz, 1H), 8.33 (dd, J = 8.4, 0.4 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.45 (dd, J = 8.4, 4.4 Hz, 1H), 2.37 (s, 3H), 2.13 (s, 3H), 2.01 (d, J = 3.2 Hz, 3H). LCMS calculated value 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-carbonitrile

[0506]

[0507] Under N2 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 and N2 atmosphere. The reaction mixture was quenched dropwise with water (50 mL) and extracted with EA (50 mL x3). The combined organic phase was 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 and collect the solid to give the target compound (3.5 g, 50% yield) as a yellow solid. LCMS calculated value C 20 H 18 N5[M+H] + :m / z=328.2; Found: 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] This compound was prepared in a similar manner to step 9 of Example 1 using 2-amino-5,6-dimethyl-1-(6-methylquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile as a starting material to give the desired product as a yellow solid. 1 H NMR: (400 MHz, DMSO-d6) δ 8.90 (d, J = 2.8 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.87-7.92 (m, 2H), 7.46 (dd, J = 8.4, 4.0 Hz, 1H), 7.36-7.38 (m, 1H), 6.90 (s, 2H), 6.74 (s, 2H), 2.27 (s, 3H), 2.14 (d, J = 4.0 Hz, 6H). LCMS calculated value C 20 H 20 N5O[M+H] + :m / z=346.2; Found: 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] This compound was prepared in a similar manner to step 12 of Example 1 using 2-amino-5,6-dimethyl-1-(6-methylquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide and trimethoxymethane as starting materials to give the desired product as a yellow solid. 1 H NMR: (400 MHz, DMSO-d6) δ 12.6 (br s, 1H), 8.90 (t, J = 4.0 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.06 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.35-7.40 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.05 (s, 3H). LCMS calculated value 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] This compound was prepared in a similar manner to steps 13-14 of Example 1, wherein 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 raw material to obtain the target product as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 9.19 (d, J = 4.0 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.30-8.31 (m, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.60-7.63 (m, 1H), 2.53 (s, 3H), 2.49 (s, 3H), 2.22 (s, 3H). LCMS calculated value 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-dimethylpyridin-2-amine

[0519]

[0520] This compound was prepared in a similar manner 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 raw materials to obtain the target product as a white solid. LCMS calculated value C 15 H 16 BrCl2N2O2[M+H]: m / z=407.2; found: 407.2.

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

[0522]

[0523] This compound was prepared in a similar manner to step 2 of Example 8, using malononitrile and 3-bromo-N-(2,6-dichloro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine as starting materials to obtain the target product as 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 in a similar manner 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-carbonitrile as a raw material to obtain the target product. LCMS calculated value C 18 H 19 Cl2N4O3[M+H] + : m / z = 409.2; Found: 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] The compound was prepared in a similar manner to steps 12-14 of Example 1. In 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; Found: 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] To a 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) in DCM (5 mL) at 0°C, BBr3 (0.06 g, 0.24 mmol) was added dropwise. 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 eluting with MeCN / water (10-95% containing 0.1% NH4HCO3) to give the desired product (2.7 mg, yield: 5.8%). 1 HNMR (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 value C 17 H 14 Cl2N5O2[M+H] + : m / z = 390.2; Found: 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-difluorobenzene-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-dimethylpyridin-2-amine

[0537]

[0538] This compound was prepared in a similar manner 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 raw materials to obtain the target product as a white solid. LCMS calculated value C 15 H 16 BrF2N2O2[M+H]: m / z=373.2; found: 373.2.

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

[0540]

[0541] This compound was prepared in a similar manner to step 2 of Example 8, using 3-bromo-N-(2,6-difluoro-3,5-dimethoxyphenyl)-5,6-dimethylpyridin-2-amine as a starting material to obtain the target product as a brown solid. LCMS calculated value C 18 H 17 F2N4O2[M+H] + : m / z = 359.2; Found: 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 in a similar manner 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-carbonitrile as a raw material to obtain the target product. LCMS calculated value C 18 H 19 F2N4O3[M+H] + : m / z = 377.2; found 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] The compound was prepared in a similar manner 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 raw materials to obtain the target product. LCMS calculated value C 19 H 17 F2N4O3[M+H] + : m / z = 387.2; Found: 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] To a solution of 9-(2,6-difluoro-3,5-dimethoxyphenyl)-6,7-dimethyl-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (90 mg, 0.23 mmol) in DCM (10 mL) at 0°C, BBr3 (0.115 g, 0.46 mmol) was added dropwise. 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 phase was washed with saturated brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and purified by Prep-HPLC using MeCN / water (10-95% containing 0.1% NH4HCO3) as eluent to obtain two products: P1 (early eluting portion: 5.46 mg, yield: 6.5%) and P2 (latter eluting portion: 3.35 mg, yield: 3.8%). P1 is Example 10. 1 H 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 value C 17 H 14 F2N5O2[M+H] + : m / z = 358.0; found: 358.0. P2 is Example 11. 1 H 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 value C 18 H 16 F2N5O2[M+H] + :m / z=372.0; Found: 372.0.

[0550] Example A: PKMYT1 enzyme activity test

[0551] The PKMYT1 enzyme activity test was used to evaluate the potential inhibitory effect of candidate compounds. PKMYT1 was purchased from Carna (Cat. No. 05-176) and stored at -80°C after aliquoting. The ADP-Glo ​​kit (ADP-Glo ​​from Promega) was used to TMEnzyme activity test kit, #V9102, 10 000 assays, ), to detect the amount of ADP generated from ATP hydrolysis in the PKMYT1 catalytic reaction. Compounds dissolved in DMSO (Sigma, D8418) were added to a 384-well assay plate (Greiner, 784075) using a pipetting workstation (Labcyte, Echo 665), with each compound diluted once, 3-fold serial dilution, and a total of 10 dilution points. The assay was performed in a 1× buffer system containing 1× kinase buffer and 50μM DTT. 2.5μl of 2× PKMYT1 enzyme mixture was added to the assay plate. After centrifugation at 1000g for 30 seconds, the assay plate was sealed and incubated at room temperature for 10 minutes, and then 2.5μl 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 the experimental plate was incubated at room temperature for 2 hours, 4 μL of ADP-Glo ​​reagent was added, and then the plate was briefly centrifuged and sealed, and then incubated at room temperature in the dark for 40 minutes. Subsequently, 8 μL of enzyme detection reagent was added, and the plate was briefly centrifuged again, sealed, and incubated at room temperature in the dark for 40 minutes. Finally, the plate was read in chemiluminescence mode on a multifunctional microplate reader (Perkin Elmer, Envision 2104). The average chemiluminescence signal of the positive control well (well containing 1% DMSO) was set as the positive control (HC); the average chemiluminescence signal of the negative control well (well containing 10000nM 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 the standard 4-parameter using GraphPad Prism software. 50 The value data are shown in Table 1. +++<=0.1 μM, 0.1 μM<++<=1 μM, +>1 μM.

[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 into 96-well cell culture plates (PerkinElmer, 6005680) at a density of 1500 cells / well. Compounds dissolved in DMSO were distributed in duplicate using a multichannel pipette and 3-fold gradient dilutions were performed to 9 concentrations, with 2 replicates for each concentration. The final concentration of DMSO in all wells was 0.2%. Cells were incubated in an incubator 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 instructions. The fluorescence signal was detected using a multifunctional microplate reader (Perkin Elmer, Envision 2105 or BMG, ClarioStar Plus). The average value of the wells containing 0.2% DMSO and cells in each plate was used as the positive control (High Control, HC); the average value of the 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 Values ​​were calculated by fitting the Hill Slope to a standard 4-parameter calculation using GraphPad Prism software. 50 The value data are shown in Table 1.

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

[0559] Table 1

[0560]

[0561] Although the present invention has been fully described through embodiments, it is noteworthy that various changes and modifications will be apparent to those skilled in the art, and these changes and modifications should be included within the scope of the appended claims of the present invention.

Claims

1. A compound represented by formula (IA) and (IB), or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or prodrug thereof, characterized in that : Ring A is selected from: X is N or CR 3 ; Y is N or CR 9 ; L is (CR 10 R 11 ) n , NR 12 (CH2CH2) m , or O(CH2CH2) m ; n is 1, 2 or 3; m is 0 or 1; R is selected from H, D or C1-C6 alkyl optionally substituted by a substituent selected from the following: F, OH or CN; R 1 , R 2 and R 3 Each independently selected 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 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 ; or R 1 and R 2 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group, or a 4-7 membered heterocyclyl group, wherein the C3-C7 cycloalkyl group, the 4-7 membered heterocyclyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OR a , 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 ; or R 2 and R 3 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group, or a 4-7 membered heterocyclyl group, wherein the C3-C7 cycloalkyl group, the 4-7 membered heterocyclyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OR a , 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 ; Every R 4 Independently selected from H, D, NH2, CN, C1-C3 alkyl is optionally substituted with a substituent selected from: D, halogen or CN; Every R 5 Independently selected from H, D, halogen, CN, C1-C6 alkyl is optionally substituted with a substituent selected from: D, halogen or CN; Every R 6 Independently selected from H, D, halogen, CN, OR B , SF5, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl; wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl are optionally substituted by substituents independently selected from the following: D, halogen, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl; Every R 7 Independently selected from H, D, halogen, Me, CF3, OH, OMe, OCF3; Every R 8 Independently selected from H, D, CN, SF5, C1-C6 alkyl is optionally substituted by a substituent selected from: D, halogen or CN; Every R 9 Independently selected from H, D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C3-C5 cycloalkyl; R 10 and R 11 are independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl is optionally substituted by 1, 2, or 3 substituents independently selected from the following: 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 ; or R 10 and R 11 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group, or a 4-7 membered heterocyclyl group, wherein the C3-C7 cycloalkyl group, the 4-7 membered heterocyclyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following: D, halogen, CN, NO2, oxo, OR 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 , 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 ; R 12 is H, D, C1-C3 alkyl is optionally substituted by a substituent selected from the group consisting of D, OH, halogen, CN; Every 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 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 , or NR c S(O)(=NR b )R b ; Every 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 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 ); R C and R D are independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 ); or R C and R D The 4-7 membered heterocyclic group formed together with the N atom to which it is attached is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, oxo, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), halogen, or C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl; Every R a independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; Every 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 heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 heterocyclyl; R c and R d are independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C 6- C 10 Aryl, 5-10 membered heteroaryl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 Cycloalkyl, C6-C 10 Aryl-4-10 membered heterocyclic group, C6-C 10 Aryl-5-10 membered heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 membered heteroaryl-C3-C 10 Cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocyclyl, 5-10 membered heteroaryl-C6-C 10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl; wherein the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6- C 10 Aryl, 5-10 membered heteroaryl, C 3- C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, 4-10 membered heterocyclyl-C1-C6 alkyl, C6-C 10 Aryl-C3-C 10 Cycloalkyl, C6-C 10 Aryl-4-10 membered heterocyclic group, C6-C 10 Aryl-5-10 membered heteroaryl, C6-C 10 Aryl-C6-C 10 Aryl, 5-10 membered heteroaryl-C3-C 10 Cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocyclyl, 5-10 membered heteroaryl-C6-C 10 The aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), 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 membered 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-; or R c and R d The heterocyclic group formed by the nitrogen atom to which it is attached is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), 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 membered 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; Every 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 membered 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 heterocyclyl-C1-C4 alkyl; Every R f independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, or 4-10 membered heterocyclic group; Every R a1 independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of D, OH, CN, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy; Every 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 group, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C 3- C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclic group, C6-C 10 Aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C 10 Cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocyclyl-C1-C6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of 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 heterocyclyl.

2. The compound according to claim 1, characterized in that X is N.

3. The compound according to claim 1, characterized in that X is CR 3 .

4. The compound according to claim 3, characterized in that R 3 Independently selected 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, C3-C6 cycloalkyl, 4-6 membered heterocyclyl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently 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 .

5. The compound according to claim 3, characterized in that R 3 independently selected from H, D, halogen, CN, SF5, NH2, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, NH(CH3)2, CH3, CH2CH3, CF3, CH2CF3, C(O)R B , or C(O)NR C R D .

6. The compound according to any one of claims 1 to 5, characterized in that R is selected from H, D or C1-C6 alkyl optionally substituted by a substituent selected from the following: F, OH or CN.

7. The compound according to any one of claims 1 to 6, characterized in that R 1 Independently selected 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, C3-C6 cycloalkyl or 4-6 membered heterocyclyl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently 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 Preferably, R 1 independently selected from H, D, halogen, CN, SF5, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, NH(CH3)2, CH3, CH2CH3, CF3, CH2CF3, C(O)R B , C(O)NR C R D .

8. The compound according to any one of claims 1 to 7, characterized in that R 2 Independently selected 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, C3-C6 cycloalkyl or 4-6 membered heterocyclyl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently 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 Preferably, R 2 independently selected from H, D, halogen, CN, SF5, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, NH(CH3)2, CH3, CH2CH3, CF3, CH2CF3, C(O)R B , C(O)NR C R D .

9. The compound according to any one of claims 1 to 6, characterized in that R 1 and R 2 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a , 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 .

10. The compound according to any one of claims 1 to 6, characterized in that R 1 and R 2 The carbon atom to which it is attached forms a 4-7 membered heterocyclic group which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a , 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 .

11. The compound according to any one of claims 1 to 3, characterized in that R 2 and R 3 The carbon atom to which it is attached forms a C3-C7 cycloalkyl group which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a , 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 .

12. The compound according to any one of claims 1 to 3, characterized in that R 2 and R 3 The carbon atom to which it is attached forms a 4-7 membered heterocyclic group which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of D, halogen, CN, NO2, oxo, OR a , 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 .

13. The compound according to any one of claims 1 to 12, characterized in that R 4 Selected from H, D, NH2, CN, Me, CD3 or CF3.

14. The compound according to any one of claims 1 to 13, characterized in that R 5 Selected from H, D, halogen, CN, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH.

15. The compound according to any one of claims 1 to 15, characterized in that R 6 Selected from H, D, halogen, CN, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH.

16. The compound according to any one of claims 1 to 15, characterized in that R 7 is H, D, F, Cl, Me, CF3, OH, OMe.

17. The compound according to any one of claims 1 to 16, characterized in that R 8 Choose H, D, CN, SF5, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3.

18. The compound according to any one of claims 1 to 17, characterized in that The compounds represented by formula (IA) and (IB) are represented by formula (IAa), (IAb), (IAc), (IAd), (IAe), (IBa), (IBb), (IBc), (IBd), or (IBe): or a pharmaceutically acceptable salt, stereoisomer, atropisomer, 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 same definition as in formula (IA) and (IB).

19. The compound according to claim 18, characterized in that The compounds represented by formula (IA) and (IB) are represented by formula (IAa) and (IBa): or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or prodrug thereof; wherein X, Y, L, R, R 1 , R 2 , R 4 , R 5 , R 6 and R 7 The same definition as in formula (IA) and (IB).

20. The compound according to any one of claims 1 to 19, characterized in that The compounds represented by formula (IA) and (IB) are represented by formula (IIAa), (IIAb), (IIAc), (IIAd), (IIAe), (IIBa), (IIBb), (IIBc), (IIBd), or (IIBe): or a pharmaceutically acceptable salt, stereoisomer, atropisomer, 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 same definition as in formula (IA) and (IB).

21. The compound according to any one of claims 1 to 20, characterized in that The compounds represented by formula (IA) and (IB) are represented by formula (IIIAa), (IIIAb), (IIIAc), (IIIAd), (IIIAe), (IIIBa), (IIIBb), (IIIBc), (IIIBd), or (IIIBe): or a pharmaceutically acceptable salt, stereoisomer, atropisomer, 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 same definition as in formula (IA) and (IB).

22. The compound according to any one of claims 1 to 21, characterized in that The compounds represented by formula (IA) and (IB) are represented by formula (IIAa), (IIBa), (IIIAa), (IIIBa): 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 same definition as in formula (IA) and (IB).

23. The compound according to any one of claims 1 to 22, characterized in that The compound represented by formula (IB) is represented by formula (IVBa), (IVBb), or (IVBc): or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or a prodrug thereof; wherein Y, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 The definition of is the same as that of formula (IB).

24. The compound according to any one of claims 1 to 23, characterized in that The compounds shown in formula (IA) and (IB) are: or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or a prodrug thereof.

25. The compound according to claim 24, characterized in that The compound is: or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or a prodrug thereof.

26. A pharmaceutical composition comprising: A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 25, and a pharmaceutically acceptable carrier.

27. A method for treating cancer, comprising administering to the subject the compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26.

28. The method according to claim 27, characterized in that The subject has a disease or disorder characterized by cellular hyperproliferation and is in need of treatment.

29. The method according to claim 28, characterized in that The disease or condition is cancer.

30. The method according to claim 29, characterized in that The cancer is a cancer with CCNE1 amplification, FBXW7 loss-of-function mutation, or other genetic alterations that are dependent on PKMYT1.

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