Fused ring compound and pharmaceutical composition comprising same and use thereof

Abstract

The present application relates to a fused ring compound and a pharmaceutical composition comprising same and a use thereof. Specifically, provided is a fused ring compound represented by formula (I), which can be used for preparing a drug, in particular for preparing a drug for preventing and / or treating diseases or conditions caused by or associated with dysregulation of lymphocyte development or activity. Groups in formula (I) are as defined in the description.

Description

Fused ring compounds, pharmaceutical compositions thereof and uses thereof

[0001] Cross-reference to related applications

[0002] This application is based on and claims priority to the following CN applications, the contents of all of which are incorporated herein in their entireties:

[0003] (1) Application No. 2024113161344, filing date: September 20, 2024;

[0004] (2) Application No. 2024115670300, filing date: November 05, 2024;

[0005] (3) Application No. 2024116340543, filing date: November 15, 2024;

[0006] (4) Application No. 2024117153883, filing date: November 27, 2024;

[0007] (5) Application No. 2024118809847, filing date: December 19, 2024;

[0008] (6) Application No. 2025100229428, filing date: January 07, 2025;

[0009] (7) Application No. 2025101964360, filing date: February 21, 2025;

[0010] (8) Application No. 2025105281353, filing date: April 25, 2025;

[0011] (9) Application No. 2025110403219, filing date: July 28, 2025;

[0012] (10) Application No. 2025110839177, filing date: August 04, 2025;

[0013] (11) Application No. 202511310241.0, filing date: September 12, 2025. TECHNICAL FIELD

[0014] The present application belongs to the field of medicine, and particularly relates to a fused ring compound, a pharmaceutical composition thereof and uses thereof, which can be used as a VAV1 degrading agent. BACKGROUND

[0015] VAV1 (Vav guanine nucleotide exchange factor 1) is a member of the VAV family, which is a group of signal transduction proteins that act as phosphorylation-dependent GDP / GTP exchange factors (GEFs) and adaptor molecules for Rho subfamily GTPases. In vertebrates, the family consists of three members - VAV1, VAV2 and VAV3. VAV1 is mainly expressed in hematopoietic stem cells, including T cells, B cells, monocytes, natural killer (NK) cells, granulocytes and dendritic cells, while the family members VAV2 and VAV3 are more universally expressed. The VAV protein family is essential for the homeostasis of the central nervous system, cardiovascular system and immune system, and is involved in the occurrence and development of diseases such as autoimmune diseases, transplant rejection and cancer.

[0016] VAV1 has multiple domains, which determine its dual functions as a GEF and a scaffold protein. In the resting state, non-phosphorylated VAV1 exhibits a closed, inactive conformation: the amino-terminal CH-AC domain and the carboxy-terminal SH3 domain are folded towards the middle and bind to the catalytic core (DH-PH-ZF domain), which inhibits GEF activity and linker protein function. When the AC structure of VAV1 is phosphorylated, the inhibitory folding of the protein is released, forming an open, active conformation, and performing GEF function and linker protein function. The main substrate of VAV1 in GEF function is Rac1, which is involved in the regulation of actin dynamics signaling pathway and cytoskeleton remodeling, and realizes the migration, adhesion and immune synapse formation of immune cells. The function of the scaffold protein: interacts with various protein complexes to form a TCR / BCR proximal complex, plays a linker protein function, and regulates T cell receptor and B cell receptor activation signal transduction.

[0017] VAV1 is a key component of the antigen receptor signaling complex and is associated with the T cell receptor (TCR) / CD3 and B cell receptor. In T cells, a 76 kDa leukocyte protein containing Src homology (SH) 2 domains (SLP76) is recruited to the transmembrane adaptor, linker for activation of T cells (LAT), through its SH2 domains, thereby activating the T cell. The LAT / SLP76 complex is a critical scaffold for other proteins in the TCR proximal signaling complex, including VAV1. VAV1 interacts with other proteins through SH2 and proline-rich region / SH3 domains. In B cells, VAV1 interacts with a signaling complex that includes a scaffolding protein homologous to SLP76, SLP65 (also known as B cell linker protein), Bruton's tyrosine kinase (BTK), Grb2, and phospholipase-gamma (PLC gamma) 2. Assembly of these protein complexes activates downstream events, including phosphorylation of PLC gamma 1 / 2; activation of Ca2+, protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK)-mediated signaling pathways; regulation of transcription factors, including nuclear factor of activated T cells (NFAT), nuclear factor kappa B (NF-KB), and activator protein-1 (AP-1). VAV1 does not depend on the "scaffolding" function of guanine nucleotide exchange factors (GEFs) and appears to depend on its participation in these antigen receptor-proximal signaling complexes. The primary function of VAV1 that depends on GEFs is to activate the Rac / Rho family GTPases. Optimal phosphorylation of VAV1 and activation of downstream signaling pathways are critical in T cells and B cells through co-stimulation of CD28 and CD19, respectively. The exact mechanism of VAV1 co-receptor activation remains to be fully determined. Although the exact role of VAV1 in human disease remains to be clinically validated, multiple lines of evidence suggest that VAV1 is associated with autoimmune and chronic inflammatory diseases, supporting its role as a therapeutic target.

[0018] Targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets. This technology can specifically recognize target proteins and directly degrade pathogenic target proteins using the intrinsic protein degradation pathway in cells. Targeted protein degradation (TPD) currently mainly degrades target proteins through ubiquitin proteasome and lysosome, and can be further divided into nearly 10 different technical routes according to the specific action principle, among which the molecular glue and targeted proteolysis chimeric (PROTAC) technology is the fastest growing. Molecular glue is a small molecule that induces proximity, which can accurately control the timing of various biological processes, such as signal transduction, transcription, chromatin regulation, and protein folding, localization and degradation. As a proximity chemical inducer, molecular glue can promote the dimerization or co-localization of two proteins by forming a ternary complex, thereby producing a variety of biological and pharmacological functions. Generally speaking, molecular glue has small molecular weight and its physicochemical properties are easy to optimize. Molecular glue mainly induces or stabilizes the protein interaction between ubiquitin ligase and substrate protein, thereby leading to protein degradation, and can degrade inaccessible target proteins without the need for a binding pocket on the target protein. This mechanism provides a new way for targeting “undruggable” proteins, greatly expanding the scope and application prospects of drug design. VAV1 does not have a clear binding pocket, and there are many challenges in developing small molecule inhibitors. Novartis has studied VAV1 small molecule inhibitors (targeting GEF activity), but only disclosed the structure and in vitro activity information at the 2018 ACS meeting, with no subsequent research progress disclosed. Therefore, ubiquitination degradation of this type of protein through molecular glue is a good research direction. Currently, only Monte Rosa company has developed VAV1 molecular glue MRT-6160, which is in phase 1 clinical trial, and more molecular glue with novel structure is needed to verify the druggability of VAV1 target. SUMMARY

[0019] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0020] wherein:

[0021] Z is CR 4 or N;

[0022] R 1 and R 2 are the same or different, and each is independently selected from H, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl;

[0023] or R 1 and R 2 form a C 3-8cycloalkyl or 3-8 membered heterocyclyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C 1-6 alkyl;

[0024] R 3 selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl and C 3-8 halocycloalkyl;

[0025] R 4 and R 5 are the same or different and each independently selected from the group consisting of H, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0026] R 6 and R 7 are the same or different and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0027] R 8 and R 9 are the same or different and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0028] R10 selected from 11-20 membered heterocyclyl, 11-20 membered heteroaryl, and -K-R 0 , said 11-20 membered heterocyclyl and 11-20 membered heteroaryl being optionally substituted with one or more R 11 ;

[0029] Alternatively, any one of the groups R 10 and R 8 , R 10 and R 9 , together with the phenyl ring to which they are attached, form a fused ring group, said fused ring group being a 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl or 11-20 membered heteroaryl being optionally substituted with one or more R 11 ;

[0030] K is selected from O, S, NH, and N-C 1-6 alkyl;

[0031] R 0 is 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl and 11-20 membered heteroaryl being optionally substituted with one or more R 11 ;

[0032] R 11 are the same or different, and each is independently selected from halogen, deuterium, oxo, thioxo, =NR j , C 1-6 alkyl, -C 1-6 alkylene-5-10 membered heteroaryl, -C 1-6 alkylene-3-8 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, C(O)R a , SF5, S(O) 0-2 R b , NR j R k , C(O)NR j R k , -NR j C(O)R a , C(O)OR g , S(O)(=NR j )R b, S(O)2NR j R k , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy and 3-8 membered heterocyclyloxy, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 1-6 alkylene-5-10 membered heteroaryl and -C 1-6 alkylene-3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy and 3-8 membered heterocyclyloxy are optionally substituted with one or more R v ;

[0033] or two R 11 , together with the atom to which they are attached, form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally substituted with one or more R 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano and amino;

[0034] or two R 11 , together with the atom to which they are attached, form a

[0035] R 20 and R 21 are the same or different and each is independently selected from the group consisting of H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, hydroxyl, cyano and amino;

[0036] R v are the same or different and each is independently selected from the group consisting of halogen, deuterium, C 1-6 alkyl, hydroxyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C(O)R a , S(O) 0-2 R b , NR j R k , C(O)NR j R k , -NR j C(O)R a , C(O)OR g , S(O)(=NR j )R b , S(O)2NR j R k , C 6-10 aryl and 5- to 10-membered heteroaryl;

[0037] R a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl;

[0038] R b is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, NR j R k , C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl

[0039] R j and R k are the same or different and each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl;

[0040] or R j and R ktogether with the nitrogen atom to which it is attached form C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein said C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxyl, and C 1-6 alkyl;

[0041] R g is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl.

[0042] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 11 are the same or different and each is independently selected from halogen, deuterium, oxo, =NR j , C 1-6 alkyl, -C 1-6 alkylene-5-10 membered heteroaryl, -C 1-6 alkylene-3-8 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxyl, cyano, C(O)R a , SF5, S(O) 0-2 R b , NR j R k , C(O)NR j R k , -NR j C(O)R a , C(O)OR g , S(O)(=NR j )R b , S(O)2NR j R k , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy, and 3-8 membered heterocyclyloxy, said C 1-6 alkyl, C 1-6 alkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 1-6 alkylene-5-10 membered heteroaryl, and -C 1-6 alkylene-3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy, and 3-8 membered heterocyclyloxy optionally substituted with one or more R v substituents; R a , R b , R j , R k , R g , and R v are as defined above;

[0043] R 20 and R 21 are selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxyl, cyano, and amino.

[0044] In some embodiments, R j and R k together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, hydroxyl, and C 1-6 alkyl.

[0045] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein R 11 are the same or different and each is independently selected from halogen, deuterium, oxo, C 1-6 alkyl, -C 1-6 alkylene-5-10 membered heteroaryl, -C 1-6 alkylene-3-8 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxyl, cyano, amino, C(O)R a , S(O)0-2 R b , C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 1-6 alkylene-5-10 membered heteroaryl and -C 1-6 alkylene-3-8 membered heterocyclyl is optionally substituted with one or more R v ;

[0046] or two R 11 , together with the atom to which they are attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with one or more R 1-6 selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano and amino;

[0047] R v selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0048] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein R 11 are the same or different and each is independently selected from halo, deuterium, oxo, =NR j , C 1-6 alkyl, -C 1-6 alkylene-5-10 membered heteroaryl, -C 1-6 alkylene-3-8 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6Deuterated alkoxy, hydroxyl, cyano, C(O)R a S(O) 0-2 R b NR j R k C(O)NR j R k C(O)OR g S(O)(=NR) j )R b S(O)2NR j R k C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 1-6 alkylene-5-10 heteroaryl and -C 1-6 Alkyl-3-8-membered heterocyclic groups are optionally surrounded by one or more R groups. v replace;

[0049] Or two Rs 11 Together with the atoms attached to it, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1- One or more substitutions of 6-hydroxyalkyl, hydroxyl, cyano, and amino;

[0050] R g Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups.

[0051] R a R b R g R j R k and R v As defined by compound (I).

[0052] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 11 They may be the same or different, and each is independently selected from halogens, deuterium, oxometalates, and carbon.1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, amino, C(O)R a , S(O) 0-2 R b , C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R a and R b are as defined for the compound of Formula (I).

[0053] In some embodiments, K is O.

[0054] In some embodiments, K is S.

[0055] In some embodiments, K is NH.

[0056] In some embodiments, K is N-C 1-6 alkyl.

[0057] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (I-1) or Formula (I-2):

[0058] wherein R 1 , R 2 , R 3 , Z, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in the application.

[0059] In some embodiments, the compound of Formula (I), Formula (I-1) or Formula (I-2) or pharmaceutically acceptable salt thereof, wherein R 10 is 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl and 11-20 membered heteroaryl being optionally substituted with one or more R 11 ;

[0060] or R 10 and R 8 , R 10and R 9 together with the phenyl ring to which they are attached form a fused ring group, said fused ring group is an 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl or 11-20 membered heteroaryl is optionally substituted with one or more R 11 .

[0061] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 and R 9 together with the phenyl ring to which they are attached form a fused ring group, said fused ring group is an 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl or 11-20 membered heteroaryl is optionally substituted with one or more R 11 ;

[0062] or, R 10 and R 8 together with the phenyl ring to which they are attached form a fused ring group, said fused ring group is an 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl or 11-20 membered heteroaryl is optionally substituted with one or more R 11 ;

[0063] R 11 as defined herein.

[0064] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein said 11-20 membered heterocyclyl is a 11-membered, 12-membered, 13-membered, 14-membered, 15-membered, 16-membered, 17-membered, 18-membered, 19-membered, or 20-membered heterocyclyl; and said 11-20 membered heteroaryl is a 11-membered, 12-membered, 13-membered, 14-membered, 15-membered, 16-membered, 17-membered, 19-membered, or 20-membered heteroaryl.

[0065] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from:

[0066] is a single or double bond;

[0067] X is CR X or CR X R Y ;

[0068] R X and R Y are the same or different, each independently selected from H, halogen, deuterium, C 1-6alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano and amino;

[0069] G1is selected from CR 11a , CR 11a R 11b , N and NR 11c ;

[0070] R 11a and R 11b are the same or different, each independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano and amino;

[0071] or, R 11a and R 11b together with the atoms to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl being optionally substituted with one or more selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano and amino;

[0072] R 11c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl and C 1-6 hydroxyalkyl;

[0073] R N is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl and C 1-6 hydroxyalkyl;

[0074] or, R N and R X , R X and R 11a , R X and R 11c are taken together with the atoms to which they are attached to form a 5-12 membered heterocyclyl or 5-12 membered heteroaryl; said 5-12 membered heterocyclyl and 5-12 membered heteroaryl are optionally substituted with one or more R 11 ;

[0075] L 1 and L 2 are the same or different and each is independently selected from a bond, O, S, NR L , S(O), S(O)2, C(O), S(O)(=NR L ), C(O)NR L , S(O)2NR L , C 1-6 alkylene and C 2-6 alkenylene, one, two, three, four or five CH2in said C 1-6 alkylene and C 2-6 alkenylene is optionally replaced, the same or different, with one or more groups selected from O, S, NR L , S(O), S(O)2, S(O)(=NR L ), C(O)NR L and S(O)2NR L , said C 1-6 alkylene and C 2-6 alkenylene is optionally substituted with one or more R u ;

[0076] R u are the same or different and each is independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0077] or, two R u are taken together with the atoms to which they are attached to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more substituents independently selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino;

[0078] R L selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl and C 3-8 cycloalkyl;

[0079] Ring A is selected from phenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, and 5-10 membered heteroaryl;

[0080] Ring B is selected from 7-12 membered cycloalkyl, 7-12 membered heterocyclyl, and 7-12 membered heteroaryl;

[0081] Ring C is selected from phenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, and 5-10 membered heteroaryl;

[0082] n is 0, 1, 2, 3, or 4;

[0083] R 6 , R 7 , R 8 , R 9 , and R 11 as defined herein. In some embodiments, R 6 , R 7 are each H.

[0084] In some embodiments, R N and R X together with the atom to which they are attached form a 5-12 membered heterocyclyl or 5-12 membered heteroaryl; said 5-12 membered heterocyclyl and 5-12 membered heteroaryl are optionally substituted with one or more R 11 .

[0085] In some embodiments, R X and R 11a together with the atom to which they are attached form a 5-12 membered heterocyclyl or 5-12 membered heteroaryl; said 5-12 membered heterocyclyl and 5-12 membered heteroaryl are optionally substituted with one or more R 11substituted.

[0086] In some embodiments, R X and R 11c together with the atom to which they are attached form a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl; said 5-12 membered heterocyclyl and 5-12 membered heteroaryl are optionally substituted with one or more R 11 .

[0087] In some embodiments, L 1 and L 2 are the same or different and each is independently selected from a bond, O, S, NR L , S(O), S(O)2, S(O)(=NR L ), C(O)NR L , S(O)2NR L , C 1-6 alkylene, and C 2-6 alkenylene, one, two, three, four, or five CH2in said C 1-6 alkylene and C 2-6 alkenylene is optionally replaced, the same or different, with one or more groups selected from O, S, NR L , S(O), S(O)2, S(O)(=NR L ), C(O)NR L , and S(O)2NR L , said C 1-6 alkylene and C 2-6 alkenylene is optionally substituted with one or more R u .

[0088] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is

[0089] ring B, R 6 , R 7 , R 8 , R 9 , R 11 , and n are as defined herein. In some embodiments, R 6 , R 7 are each H.

[0090] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein ring B is a 7-10 membered cycloalkyl or a 7-10 membered heterocyclyl.

[0091] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from:

[0092] G1, X, L 1 , L 2 , ring A, ring C, R 6 , R 7 , R 8 , R 9 , R 11 and n are as defined herein. In some embodiments, R 6 , R 7 each is H.

[0093] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from:

[0094] G1, X, L 1 , L 2 , ring A, R 6 , R 7 , R 8 , R 9 , R 11 and n are as defined herein. In some embodiments, R 6 , R 7 each is H.

[0095] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein L 1 and L 2 are the same or different, each independently selected from a bond, C 1-6 alkylene, C(O), NR L , O, S, O-C 1-6 alkylene, O-C 1-6 alkylene-O, -C 1-3 alkylene-O-C 1-3 alkylene, -C 1-3 alkylene-NR L -C 1-3 alkylene, NR L -C 1-6 alkylene and C(O)-C 1-6 alkylene, said C 1-6alkylene is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, and amino; L selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, and C 1-6 hydroxyalkyl;

[0096] ring A is selected from the group consisting of phenyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl.

[0097] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of

[0098] is a single or double bond;

[0099] W1and W2are the same or different, and each is independently selected from the group consisting of -O-, -NR w1 -, -CR w2 R w3 -, -C(O)-, and -S-;

[0100] W3is selected from the group consisting of -NR w1 -, -CR w2 R w3 -, and -C(O)-;

[0101] R w1 is selected from the group consisting of H, C(O)R a , C 1-6 alkyl, and -C 1-6 alkylene-5-10 membered heteroaryl, -C 1-6 alkylene-3-8 membered heterocyclyl, said C 1-6 alkyl, -C 1-6 alkylene-5-10 membered heteroaryl, and -C 1-6 alkylene-3-8 membered heterocyclyl is optionally substituted with one or more R v ;

[0102] R w2 and R W3 are the same or different, each being independently selected from the group consisting of H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino;

[0103] or R w2 and R W3 together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with one or more of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino;

[0104] or R w2 and R W3 together with the atom to which they are attached form

[0105] R 11a and R 11b together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with one or more of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino;

[0106] R 11x , R 11y , R 11z , R 11u , R 11v and R 11w are the same or different, each being independently selected from the group consisting of H, halo, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, and amino;

[0107] or R 11x and R 11y , R 11u and R 11v , R 11z and R 11w any one of which groups, together with the atom to which it is attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with one or more of halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, and amino;

[0108] or, R 11u and R 11w , together with the atom to which they are attached, form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl is optionally substituted with one or more of halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, and amino;

[0109] or R 11x and R 11y , R 11u and R 11v , R 11z and R 11w any one of which groups, together with the atom to which it is attached, form a

[0110] R 20 and R 21 are the same or different and each is independently selected from the group consisting of H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxyl, cyano, and amino;

[0111] H on N can be replaced by R 11 ;

[0112] R 6 , R 7 , R 8 , R 9 , R 11 , R v , R a and n are as defined herein. In some embodiments, R 6 , R 7 are each H.

[0113] In some embodiments, R 11x and R 11y , together with the atom to which they are attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl being optionally substituted with one or more of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, and amino.

[0114] In some embodiments, R 11u and R 11v , together with the atom to which they are attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl being optionally substituted with one or more of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, and amino.

[0115] In some embodiments, R 11z and R 11w , together with the atom to which they are attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl being optionally substituted with one or more of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, and amino.

[0116] In some embodiments, R11u and R 11w together with the atom to which they are attached form C 5-8 cycloalkyl or 5-8 membered heterocyclyl, said C 5-8 cycloalkyl and 5-8 membered heterocyclyl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, and amino.

[0117] In some embodiments, the compound according to Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein Z is CR 4 ; R 4 is as defined herein. In some embodiments, R 4 is H.

[0118] In some embodiments, the compound according to Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from

[0119] R Y is selected from H, halo, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, hydroxyl, cyano, and amino;

[0120] R N and R X together with the atom to which they are attached form 5-12 membered heterocyclyl or 5-12 membered heteroaryl; said 5-12 membered heterocyclyl and 5-12 membered heteroaryl are optionally substituted with one or more R 11 ;

[0121] G1, R 6 , R 7 , R 8 , R 9 and R 11 are as defined herein. In some embodiments, R 6 , R 7 are each H.

[0122] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein Selected from

[0123] R Y Selected from H, halogens, deuterium, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, hydroxyl, cyano, and amino groups;

[0124] R N and R X Together with the atoms attached thereto, they form a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group; the 5-12 membered heterocyclic group and the 5-12 membered heteroaryl group are optionally bonded by one or more R 11 Replaced;

[0125] G1, R 6 R 7 R 8 R 9 and R 11 As defined in this application. In some implementations, R 6 R 7 Each is represented by H.

[0126] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein Selected from

[0127] R N R X R Y R 11a R 11b R 11c R 6 R 7 and R 8 As defined in this application.

[0128] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R N and R X The ring formed together with the atoms attached to it is selected from H on NH can be replaced by R 11 ; R 11 and n are as defined in the application.

[0129] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from H on NH can be replaced by R 11 ; R 11 and n are as defined in the application.

[0130] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from H on NH can be replaced by R 11 ; R 11 and n are as defined in the application.

[0131] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is

[0132] L 1 and L 2 are the same or different, each being independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, C(O), NR L , O, C(O)NR L , S, S(O), S(O)2, S(O)(=NR L ), S(O)2NR L , a-C 1-3 alkylene-C(O)NR L , a-C(O)NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L C(O)-, a-NR L C(O)-C 1-3 alkylene, a-O-C 1-3 alkylene-, a-C 1-3 alkylene-O-, -O-C 1-3alkylene-O-, -C 1-3 alkylene-O-C 1-3 alkylene, -C 1-3 alkylene-NR L -C 1-3 alkylene, a-NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L -, a-C(O)-C 1-3 alkylene, a-C 1-3 alkylene-C(O), a-C 1-3 alkylene-S(O) 0-2 , a-S(O) 0-2 -C 1-3 alkylene, -C 1-3 alkylene-S(O) 0-2 -C 1-3 alkylene, a-C 1-3 alkylene-S(O)(=NR L ), a-S(O)(=NR L )-C 1-3 alkylene, -C 1-3 alkylene-S(O)(=NR L )-C 1-3 alkylene, -C 1-3 alkylene-C(O)NR L -C 1-3 alkylene, -C 1-3 alkylene-C(O)-C 1-3 alkylene, a-C 1-3 alkylene-S(O)2NR L , a-S(O)2NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L S(O)2, a-NR L S(O)2-C 1-3 alkylene and -C 1-3 alkylene-S(O)2NR L -C 1-3 alkylene, a end attached to the phenyl ring, said C 1-4 alkylene, C 1-3 alkylene and C 2-4 alkylene is optionally substituted with one or more R u ; ring A is selected from phenyl, 5-12 membered heterocyclyl, and 5-10 membered heteroaryl; R 6 , R 7 , R 8 , R 9 , R11 R L R u And n is as defined in this application. In some implementations, R 6 R 7 Each is represented by H.

[0133] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein

[0134] L 1 and L 2 Whether the two are the same or different, they are each independently selected from chemical bonds, C 1-3 Alkylene, C(O), NH, N(CH3), O, aOC 1-3 Alkylene-, aC 1-3 Alkylene-O-, -OC 1-3 Alkylene -O-, -C 1-3 Alkylene-OC 1-3 Alkylene, -C 1-3 Alkylene-NH-C 1-3 Alkylene, -C 1-3 Alkylene-N(CH3)-C 1-3 Alkylene, α-NH-C 1-3 Alkylene, aC 1-3 Alkylene-NH-, aN(CH3)-C 1-3 Alkylene, aC 1-3 Alkylene-N(CH3)-, aC(O)-C 1-3 Alkylene and aC 1-3 alkylene-C(O), with the α-terminus connected to a benzene ring, wherein the C 1-3 Alkylenes are optionally selected from halogens, hydroxyl groups, C... 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 The substance is substituted by one or more substituents selected from hydroxyalkyl, cyano, and amino groups;

[0135] Ring A is selected from phenyl, 5-6 membered heterocyclic groups, and 5-6 membered heteroaryl groups;

[0136] R 6 R 7 R 8 R 9 R 11 And n is as defined in this application. In some implementations, R 6 R 7 Each is represented by H.

[0137] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein L 1 and L 2 are the same or different, each independently selected from a bond, C 1-3 alkylene, C(O), NH, N(CH3), O, a-O-C 1- 3alkylene-, a-C 1-3 alkylene-O-, a-NH-C 1-3 alkylene, a-C 1-3 alkylene-NH-, a-N(CH3)-C 1-3 alkylene, a-C 1-3 alkylene-N(CH3)-, a-C(O)-C 1-3 alkylene, and a-C 1-3 alkylene-C(O), a is attached to the phenyl ring, and said C 1-3 alkylene is optionally substituted with one or more substituents selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, cyano, and amino.

[0138] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyrimidinyl, dihydropyrimidinyl, pyrrolyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, oxazinyl, pyrazolyl, imidazolyl, imidazolidinyl, imidazolidinonyl, oxazolyl, oxazolidinyl, oxazolidinonyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and phenyl.

[0139] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from

[0140] is a single or double bond;

[0141] L 1 and L 2 are the same or different, each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, C(O), NR L , O, C(O)NR L , S, S(O), S(O)2, S(O)(=NR L ), S(O)2NRL , a-C 1-3 alkylene-C(O)NR L , a-C(O)NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L C(O)-, a-NR L C(O)-C 1-3 alkylene, a-O-C 1-3 alkylene-, a-C 1-3 alkylene-O-, -O-C 1-3 alkylene-O-, -C 1-3 alkylene-O-C 1-3 alkylene, -C 1-3 alkylene-NR L -C 1-3 alkylene, a-NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L -, a-C(O)-C 1-3 alkylene, a-C 1-3 alkylene-C(O), a-C 1-3 alkylene-S(O) 0-2 , a-S(O) 0-2 -C 1-3 alkylene, -C 1-3 alkylene-S(O) 0-2 -C 1-3 alkylene, a-C 1-3 alkylene-S(O)(=NR L ), a-S(O)(=NR L )-C 1-3 alkylene, -C 1-3 alkylene-S(O)(=NR L )-C 1-3 alkylene, -C 1-3 alkylene-C(O)NR L -C 1-3 alkylene, -C 1-3 alkylene-C(O)-C 1-3 alkylene, a-C 1-3 alkylene-S(O)2NR L , a-S(O)2NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L S(O)2, a-NR L S(O)2-C 1-3 alkylene and -C1-3 alkylene-S(O)2NR L -C 1-3 alkylene, the C 1-4 alkylene, C 1-3 alkylene and C 2-4 alkenylene is optionally substituted by one or more R u ;

[0142] T 1 is C or N;

[0143] T 3 is selected from the group consisting of absent, C, N, O and S;

[0144] T 2 , T 4 and T 5 are the same or different and each is independently selected from the group consisting of C, CH, N, O and S;

[0145] R 6 , R 7 , R 8 , R 9 , R 11 , R u and n are as defined herein. In some embodiments, R 6 , R 7 each is H.

[0146] In some embodiments, the compound of Formula (I), Formula (I-1) or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of the H on NH can be replaced with R 11 , T 2 , T 3 , T 4 and T 5 are the same or different and each is independently selected from the group consisting of C, N, O and S; L 1 , L 2 , R 6 , R 7 , R 8 , R 9 , R 11 and n are as defined herein. In some embodiments, R 6 , R 7 each is H.

[0147] In some embodiments, the compound of Formula (I), Formula (I-1) or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein L 1 and L2 the same or different, are each independently selected from a bond, C 1-3 alkylene, C(O), NH, N(CH3), O, a-O-C 1- alkylene-, a-C 1-3 alkylene-O-, a-NH-C 1-3 alkylene, a-C 1-3 alkylene-NH-, a-N(CH3)-C 1-3 alkylene, a-C 1-3 alkylene-N(CH3)-, a-C(O)-C 1-3 alkylene and a-C 1-3 alkylene-C(O), a is attached to the phenyl ring, and said C 1-3 alkylene is optionally substituted with one or more substituents selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, cyano, and amino.

[0148] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein L 1 the same or different, are each independently selected from a bond, C 1-3 alkylene, C(O), NH, N(CH3), O, a-O-C 1-3 alkylene-, a-C 1-3 alkylene-O-, -O-C 1-3 alkylene-O-, -C 1-3 alkylene-O-C 1-3 alkylene, -C 1-3 alkylene-NH-C 1-3 alkylene, -C 1-3 alkylene-N(CH3)-C 1-3 alkylene, a-NH-C 1-3 alkylene, a-C 1-3 alkylene-NH-, a-N(CH3)-C 1-3 alkylene, a-C 1-3 alkylene-N(CH3)-, a-C(O)-C 1-3 alkylene and a-C 1-3 alkylene-C(O), a is attached to the phenyl ring, and said C 1-3 alkylene is optionally substituted with one or more substituents selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, cyano, and amino.

[0149] L 2a bond or C 1-3 alkylene.

[0150] In some embodiments of a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein

[0151] L 1 a bond or C 1-3 alkylene;

[0152] L 2 selected from a bond, C 1-3 alkylene, C(O), NH, N(CH3), O, a-O-C 1-3 alkylene-, a-C 1-3 alkylene-O-, -O-C 1-3 alkylene-O-, -C 1-3 alkylene-O-C 1-3 alkylene, -C 1-3 alkylene-NH-C 1-3 alkylene, -C 1-3 alkylene-N(CH3)-C 1-3 alkylene, a-NH-C 1-3 alkylene, a-C 1-3 alkylene-NH-, a-N(CH3)-C 1-3 alkylene, a-C 1-3 alkylene-N(CH3)-, a-C(O)-C 1-3 alkylene and a-C 1-3 alkylene-C(O), attached at the a position to the phenyl ring, said C 1-3 alkylene is optionally substituted with one or more substituents selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, cyano, and amino.

[0153] In some embodiments of a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein selected from

[0154] L 1 selected from a bond, C 1-3 alkylene, C(O), NH, N(CH3), O, a-O-C 1-3 alkylene-, a-C 1-3 alkylene-O-, -O-C 1-3 alkylene-O-, -C 1-3 alkylene-O-C 1-3alkylene, -C 1-3 alkylene-NH-C 1-3 alkylene, -C 1-3 alkylene-N(CH3)-C 1-3 alkylene, a-NH-C 1-3 alkylene, a-C 1-3 alkylene-NH-, a-N(CH3)-C 1-3 alkylene, a-C 1-3 alkylene-N(CH3)-, a-C(O)-C 1-3 alkylene and a-C 1-3 alkylene-C(O), attached at the a terminus to the phenyl ring, said C 1-3 alkylene is optionally substituted with one or more substituents selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, cyano, and amino;

[0155] L 2 is a bond or C 1-3 alkylene;

[0156] T 2 , T 4 , and T 5 are the same or different and each is independently selected from C, N, O, and S;

[0157] R 6 , R 7 , R 8 , R 11 , and n are as defined herein. In some embodiments, R 6 , R 7 each is H.

[0158] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is L 1 , L 2 , R 6 , R 7 , R 8 , and R 11 are as defined herein. In some embodiments, R 6 , R 7 each is H.

[0159] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10is 11-20 membered heterocyclyl or 11-20 membered heteroaryl, wherein the 11-20 membered heterocyclyl and 11-20 membered heteroaryl are optionally substituted with one or more R 11 R 11 as defined in the application.

[0160] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from:

[0161] G2is CR 11d or N;

[0162] G3and G4are the same or different, each independently selected from CR 11e , CR 11e R 11f , N and NR 11g ;

[0163] G7is selected from CR 11e R 11f , NR 11g , O and S;

[0164] R 11d is selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxyl, cyano, and amino;

[0165] R 11e and R 11f are the same or different, each independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, cyano, amino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy, 3-8 membered heterocyclyloxy, SF5, S(O) 0-2 R b , NR j R k , C(O)NR j R k , -NR j C(O)Ra C(O)OR g S(O)(=NR j )R b and S(O)2NR j R k wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy, and 3-8 membered heterocyclyloxy is optionally substituted with one or more selected from the group consisting of halo, oxo, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino;

[0166] Alternatively, R 11e and R 11f , together with the atom to which they are attached, form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl is optionally substituted with one or more selected from the group consisting of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino;

[0167] R 11g is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, and C 1-6 hydroxyalkyl;

[0168] R F is selected from the group consisting of H, halo, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino;

[0169] R D and R E , R D and R F , R D and R 11d , R E and R 11d , together with the atoms to which they are attached, form a 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; said 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl is optionally substituted with one or more R 11 ;

[0170] Ring E is selected from phenyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl;

[0171] G5 is C or N;

[0172] Ring F is selected from phenyl, C 5-8 cycloalkyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl;

[0173] each R 12 is the same or different, each being independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- 6deuteroalkoxy, hydroxyl, cyano, and amino;

[0174] Ring Q is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl;

[0175] each R 13 is the same or different, each being independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- 6deuteroalkoxy, hydroxyl, cyano, and amino;

[0176] or two R 13together with the atom to which it is attached form C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxyl, cyano, and amino;

[0177] when R is in D and R F are taken together to form a ring, R E is absent;

[0178] G6is CR 11h R 11i or NR 11j ;

[0179] R 11h and R 11i are the same or different, each being independently selected from H, halo, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxyl, cyano, and amino;

[0180] R 11j is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, and C 1- 6hydroxyalkyl;

[0181] m is 0, 1, 2, 3, or 4;

[0182] f is 0, 1, 2, 3, or 4;

[0183] q is 0, 1, 2, 3, or 4;

[0184] and R 11 are as defined in the application.

[0185] In some embodiments, R D and RE with the atom to which it is attached, form a 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; said 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl optionally substituted with one or more R 11 substituents.

[0186] In some embodiments, R D and R F with the atom to which it is attached, form a 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; said 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl optionally substituted with one or more R 11 substituents.

[0187] In some embodiments, R D and R 11d with the atom to which it is attached, form a 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; said 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl optionally substituted with one or more R 11 substituents.

[0188] In some embodiments, R E and R 11d with the atom to which it is attached, form a 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; said 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl optionally substituted with one or more R 11 substituents.

[0189] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11e and R 11f are the same or different, each being independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxyl, cyano, and amino;

[0190] Alternatively, R 11e and R 11f , together with the atom to which they are attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 One or more substitutions of hydroxyalkyl, hydroxy, cyano, and amino;

[0191] In some embodiments, the compound represented by formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein ring E is selected from phenyl, 5-6 membered heterocyclic and 5-6 membered heteroaryl;

[0192] Ring F is selected from phenyl, 5-6 membered heterocyclic group and 5-6 membered heteroaryl group;

[0193] Ring Q is selected from 7-10 member monocyclic cycloalkyl, 7-10 member spirocycloalkyl, 7-10 member bridged cycloalkyl, 7-10 member monocyclic heterocyclic, 7-10 member spiroheterocyclic and 7-10 member bridged heterocyclic.

[0194] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from:

[0195] R D and R E R D and R F At least one group of atoms attached thereto forms a 5-12 membered heterocyclic group or a 5-12 membered heteroaryl group; the 5-12 membered heterocyclic group and the 5-12 membered heteroaryl group are optionally surrounded by one or more R 11 Replaced; when R in D and R F When forming a ring, R E It does not exist;

[0196] Ring E is selected from phenyl, 5-6 membered heterocyclic and 5-6 membered heteroaryl;

[0197] G 2 G 3 G 4 R F R 11a R 11b R 11 And m is as defined in this application.

[0198] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein ring E is selected from tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyranyl, dihydropyranyl, pyrrolyl, pyranyl, piperidinyl, piperazinyl, oxazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and phenyl.

[0199] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein R 10 is selected from:

[0200] is a single or double bond;

[0201] G3and G4are the same or different, each independently selected from CR 11e , CR 11e R 11f , N, and NR 11g ;

[0202] V1, V2, V3, and V4are selected from any combination of the following:

[0203] (1) V1is selected from N, O, S, CR 11d , and CR 11e R 11f ; V2is CR E ; V3is NR D ; V4is C or N;

[0204] (2) V1is selected from N, O, S, CR 11d , and CR 11e R 11f ; V2is NR D ; V3is CR E ; V4is C or N;

[0205] (3) V1is CR E ; V2is NR D ; V3is selected from N, O, S, CR 11d , and CR 11e R 11f ; V4is C or N;

[0206] (4) V2is CR E ; V1is NR D ; V3is selected from N, O, S, CR 11d , and CR 11e R 11f ; V4is C or N;

[0207] (5) V1 is CR E ; V2 is selected from N, O, S, CR 11d and CR 11e R 11f ; V3 is NR D ; V4 is C or N;

[0208] (6) V1 is NR D ; V2 is selected from N, O, S, CR 11d and CR 11e R 11f ; V3 is CR E ; V4 is C or N;

[0209] (7) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is CR E ; V3 is CR D ; V4 is C or N;

[0210] (8) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is CR 11 R E ; V3 is CR D ; V4 is C or N;

[0211] (9) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is CR D ; V3 is CR 11 R E ; V4 is C or N;

[0212] (10) V1 is CR E ; V2 is CR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ; V4 is C or N;

[0213] (11) V1 is CR 11 R E ; V2 is CR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ; V4 is C or N;

[0214] (12) V1 is CR D ; V2 is CR 11 RE ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ; V4 is C or N; R D and R E , together with the atom to which they are attached, form a 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; said 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with one or more R 11 , R 11e , R 11f , R 11g , R 11d , R 11 and m are as defined herein.

[0215] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from:

[0216] R D and R E , together with the atom to which they are attached, form a 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; said 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with one or more R 11 , G2, G3, G4, R 11 and are as defined herein.

[0217] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 is -K-R 0 ; K is O; R 0 is selected from 11-, 12-, 13-, 14-, 15-, or 16-membered heterocyclyl and 11-, 12-, 13-, 14-, 15-, or 16-membered heteroaryl.

[0218] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 0 is selected from:

[0219] G2 is CR 11d or N;

[0220] V4 is C or N;

[0221] V1, V2 and V3 are selected from any combination of:

[0222] (1) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is CR E ; V3 is NR D ;

[0223] (2) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is NR D ; V3 is CR E ;

[0224] (3) V1 is CR E ; V2 is NR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ;

[0225] (4) V2 is CR E ; V1 is NR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ;

[0226] (5) V1 is CR E ; V2 is selected from N, O, S, CR 11d and CR 11e R 11f ; V3 is NR D ;

[0227] (6) V1 is NR D ; V2 is selected from N, O, S, CR 11d and CR 11e R 11f ; V3 is CR E ;

[0228] (7) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is CR E ; V3 is CR D ;

[0229] (8) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is CR11 R E ; V3 is CR D ;

[0230] (9) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is CR D ; V3 is CR 11 R E ;

[0231] (10) V1 is CR E ; V2 is CR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ;

[0232] (11) V1 is CR 11 R E ; V2 is CR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ;

[0233] (12) V1 is CR D ; V2 is CR 11 R E ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ;

[0234] R D and R E , together with the atom to which they are attached, form a 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; said 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with one or more R 11 ;

[0235] R 11 , R 11d , R 11e , R 11f as defined in the application.

[0236] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 0 is selected from: R D and R Ewith the atom to which it is attached to form a 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; said 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl optionally substituted with one or more R 11 24substituted; 55

[0237] 56R 11 25and R 11d 26as defined herein. 57

[0238] 58In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R D 27and R E 28with the atom to which it is attached to form a 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; said 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl optionally substituted with one or more R 11 29; R 11 30as defined herein. 59

[0239] 60In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 31is 61 62

[0240] 63R 11e 32and R 11f 33are the same or different and each is independently selected from H, halogen, deuterium, oxo, C 1-3 34alkyl, C 1-3 35haloalkyl, C 1-3 36deuteroalkyl, C 1-3 37hydroxyalkyl, C 1-3 38alkoxy, hydroxyl, cyano, amino, -C 1-3 39alkylene-5-6 membered heteroaryl, C(O)C 1-3 40alkyl, S(O)2C 1-3 41alkyl, NH(C 1-3 42alkyl), N(C 1-3 43alkyl)2, NHC(O)C 1-3 44alkyl, NHC(O)C 3-6 45cycloalkyl, -SC 1-3 46alkyl, SF5, -S(O)C 1-3 47alkyl, -S(O)2C 1-3 48alkyl, S(O)2NH2, S(O)2NH(C 1-3 49alkyl), S(O)2N(C 1-3 50alkyl)2, C(O)NH2, C(O)NH(C 1-3 51alkyl), C(O)N(C 1-3 52alkyl)2, C(O)OC 1-3 alkyl, S(O)(=NH)C 1-3 alkyl, S(O)(=NCH3)C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy and 3-8 membered heterocyclyloxy, wherein said C 1-3 alkyl, C 1-3 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy and 3-8 membered heterocyclyloxy optionally substituted with one or more of halo, oxo, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 one or more of hydroxyalkyl, hydroxy, cyano, and amino;

[0241] or, R 11e and R 11f together with the atom to which they are attached form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl optionally substituted with one or more of halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 one or more of hydroxyalkyl, hydroxy, cyano, and amino;

[0242] G2, R D and R E as defined herein.

[0243] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is G2, R D and R E as defined herein.

[0244] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein is R D and R E as defined herein.

[0245] In some embodiments, a compound of Formula (I), (I-l), or (I-2), or a pharmaceutically acceptable salt thereof, wherein R D and R E together with the atoms to which they are attached form a ring selected from H on the NH can be replaced with R 11 ; R 11 and m are as defined herein.

[0246] In some embodiments, a compound of Formula (I), (I-l), or (I-2), or a pharmaceutically acceptable salt thereof, wherein ring F is selected from tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyranyl, dihydropyranyl, pyrrolyl, pyranyl, piperidinyl, piperazinyl, oxazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and phenyl.

[0247] In some embodiments, a compound of Formula (I), (I-l), or (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from

[0248] each R 12 is the same or different, each being independently selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, hydroxy, cyano, and amino; f is 0, 1, or 2.

[0249] In some embodiments, a compound of Formula (I), (I-l), or (I-2), or a pharmaceutically acceptable salt thereof, wherein is selected from each R 13 is the same or different, each being independently selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6deuteroalkoxy, hydroxyl, cyano, and amino; q is 0, 1, or 2.

[0250] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from:

[0251] Y 1 and Y 2 are the same or different, and each is independently CR 11a or N;

[0252] Y 3 is selected from CR 11a R 11b , NR 11c , O, and S;

[0253] Y 4 is selected from N or CR 11a ;

[0254] p is 0, 1, 2, 3, or 4;

[0255] G 2 , G 3 , G 4 , R 11a , R 11b , R 11c , R 11 , and m are as defined herein.

[0256] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from:

[0257] T is selected from CR 11h R 11i , NR 11j , O, and S;

[0258] R 11h and R 11i are the same or different, each is independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6haloalkyl, C 1-6 deuteroalkyl, C

[0259] R 11j selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl and C 1- 6hydroxyalkyl;

[0260] Y 1 , Y 2 , Y 3 , Y 4 , G6, R 11 , R 11a , R 11b and p are as defined herein.

[0261] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, the 5-12 membered heterocyclyl is selected from 5-8 membered monocyclic heterocyclyl, 6-12 membered fused heterocyclyl, 6-12 membered spiro heterocyclyl, 6-12 membered bridged heterocyclyl;

[0262] 5-12 membered heteroaryl is 5-6 membered monocyclic heteroaryl or 7-12 membered fused heteroaryl;

[0263] the heteroatoms in said heterocyclyl and heteroaryl are selected from N, O or S; the number of said heteroatoms can be 1, 2, 3 or 4.

[0264] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, deuterium and halogen.

[0265] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, deuterium, fluorine, chlorine, bromine, iodine.

[0266] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, deuterium, fluorine.

[0267] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is H or halogen.

[0268] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

[0269] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen.

[0270] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is deuterium or fluorine. In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is deuterium.

[0271] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 1 is fluorine.

[0272] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen.

[0273] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 2 is Cl.

[0274] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , and R 5 are the same or different and each is independently selected from H, halogen, and C 1-6 alkyl.

[0275] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

[0276] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

[0277] In some embodiments, a compound of Formula (I), Formula (I-l), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

[0278] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 , and R 9 are the same or different and each is independently selected from H, halogen, and C 1-6 alkyl.

[0279] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

[0280] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 7 is H.

[0281] In some embodiments, a compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from halogen, deuterium, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, hydroxy, cyano, amino, -C 1-3 alkylene-5-6 membered heteroaryl, C(O)C 1-3 alkyl, S(O)2C 1-3 alkyl, NH(C 1-3 alkyl), N(C 1-3 alkyl)2, NHC(O)C 1-3 alkyl, NHC(O)C 3-6 cycloalkyl, -SC 1-3 alkyl, SF5, -S(O)C 1-3 alkyl, -S(O)2C 1-3 alkyl, S(O)2NH2, S(O)2NH(C 1-3 alkyl), S(O)2N(C 1-3 alkyl)2, C(O)NH2, C(O)NH(C 1-3 alkyl), C(O)N(C 1-3 alkyl)2, C(O)OC 1-3 alkyl, S(O)(=NH)C 1-3 alkyl, S(O)(=NCH3)C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8Cycloalkyloxy and 3-8 membered heterocyclic alkyloxy, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 cycloalkyl, -C 1-3 alkylene-5-6-membered heteroaryl, 3-8-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C 3-8 Cycloalkyloxy and 3-8 membered heterocyclic alkyloxy groups are optionally surrounded by one or more R v replace;

[0282] Or two Rs 11 Together with the atoms attached to it, they form C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, and 5-6 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 3-6-membered heterocyclic, phenyl, and 5-6-membered heteroaryl groups are optionally selected from halogens, hydroxyl groups, oxo groups, and C-terminal groups. 1-6 Alkyl and C 1-6 One or more substitutions in a haloalkyl group; R v As defined in this application.

[0283] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from halogens, deuterium, oxometalates, and carbon. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy, hydroxy, cyano, amino, -C 1-3 alkylene-5-6-membered heteroaryl, C(O)C 1-3 Alkyl, S(O)2C 1-3 Alkyl, NH(C) 1-3 Alkyl), N(C) 1-3 Alkyl)2, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 cycloalkyl, -C 1-3 Alkyl-5-6-membered heteroaryl and 3-8-membered heterocyclic groups are optionally surrounded by one or more R v replace;

[0284] Or two Rs 11 Together with the atoms attached to it, they form C 3-6 cycloalkyl, the C 3-6 Cycloalkyl groups are optionally selected from halogens, hydroxyl groups, oxo groups, and C-type groups. 1-6 Alkyl and C 1-6 One or more substitutions in a haloalkyl group;

[0285] R v selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, C(O)C 1-3 alkyl, S(O)2C 1-3 alkyl, NH(C 1-3 alkyl), N(C 1-3 alkyl)2, S(O)2NH2, S(O)2NH(C 1-3 alkyl), S(O)2N(C 1-3 alkyl)2, C(O)NH2, C(O)NH(C 1-3 alkyl), C(O)N(C 1-3 alkyl)2, C(O)OC 1-3 alkyl, S(O)(=NH)C 1-3 alkyl, S(O)(=NCH3)C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl.

[0286] In some embodiments, the compound of Formula (I), Formula (I-1), or Formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from halogen, deuterium, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-3 alkoxy, hydroxy, cyano, amino, -C 1-3 alkylene-5-6 membered heteroaryl, C(O)C 1-3 alkyl, S(O)2C 1-3 alkyl, NH(C 1-3 alkyl), N(C 1-3 alkyl)2, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-8 cycloalkyl, -C 1-3 alkylene-5-6 membered heteroaryl and 3-8 membered heterocyclyl is optionally substituted with one or more R v ;

[0287] or two R 11 together with the atom to which they are attached form a C 3-6 cycloalkyl, said C 3-6 cycloalkyl is optionally substituted with one or more selected from halogen, hydroxy, oxo, C 1-6 alkyl and C 1-6 haloalkyl;

[0288] R v selected from halogen, C 1-6 alkyl, hydroxyl, cyano, C(O)C 1-3 alkyl, S(O)2C 1-3 alkyl, NH(C 1-3 alkyl), N(C 1-3 alkyl)2, S(O)2NH2, S(O)2NH(C 1-3 alkyl), S(O)2N(C 1-3 alkyl)2, C(O)NH2, C(O)NH(C 1-3 alkyl), C(O)N(C 1-3 alkyl)2, C(O)OC 1-3 alkyl, S(O)(=NH)C 1-3 alkyl, S(O)(=NCH3)C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl.

[0289] In some embodiments, compounds of Formula (I), Formula (I-1), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein R 11 is selected from halogen, deuterium, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-3 alkoxy, hydroxyl, cyano, amino, -C 1-3 alkylene-5-6 membered heteroaryl, C(O)C 1-3 alkyl, C(O)NH(C 1-3 alkyl), C(O)N(C 1-3 alkyl)2, S(O)2C 1-3 alkyl and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and -C 1-3 alkylene-5-6 membered heteroaryl is optionally substituted with one or more R v ;

[0290] or two R 11 , together with the atom to which they are attached, form a C 3-6 cycloalkyl, said C 3-6 cycloalkyl is optionally substituted with one or more selected from halogen, oxo, C 1-6 alkyl and C 1-6 haloalkyl;

[0291] Rv halo or C 1-6 alkyl.

[0292] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein R 11 is selected from halo, deuterium, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-3 alkoxy, hydroxy, cyano, amino, C(O)C 1-3 alkylene-5-6 membered heteroaryl, C(O)C 1-3 alkyl, S(O)2C 1-3 alkyl and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and -C 1-3 alkylene-5-6 membered heteroaryl is optionally substituted with one or more R v ;

[0293] or two R 11 , together with the atom to which they are attached, form a C 3-6 cycloalkyl, said C 3-6 cycloalkyl is optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl and C 1-6 haloalkyl;

[0294] R v is halo or C 1-6 alkyl.

[0295] In some embodiments, compounds of Formula (I), Formula (I-l), or Formula (I-2), or pharmaceutically acceptable salts thereof, wherein R 11 is selected from halo, deuterium, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuteroalkyl, C 1-6 hydroxyalkyl, C 1-3 alkoxy, hydroxy, cyano, amino, C(O)C 1-3 alkyl, S(O)2C 1-3 alkyl and C 3-6 cycloalkyl;

[0296] or two R 11 , together with the atom to which they are attached, form a C 3-6 cycloalkyl, said C 3-6Cycloalkyl groups are optionally selected from halogens, oxo-alkyl groups, and C-alkyl groups. 1-6 Alkyl and C 1-6 One or more substitutions in a haloalkyl group.

[0297] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from H, halogen, deuterium, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy, hydroxy, cyano, amino, C(O)C 1-3 Alkyl, C(O)NH(C) 1-3 Alkyl), C(O)N(C 1-3 Alkyl)2, S(O)2C 1-3 Alkyl and C 3-6 Cycloalkyl.

[0298] In some embodiments, the compound represented by formula (I), formula (I-1), or formula (I-2), or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from H, halogen, deuterium, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy, hydroxy, cyano, amino, C(O)C 1-3 Alkyl, S(O)2C 1-3 Alkyl and C 3-6 Cycloalkyl. In some embodiments, the compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from H, halogens, deuterium, and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0299] Exemplary specific compounds shown in this application include, but are not limited to, the structures in Table A below:

[0300] Table A

[0301] Table B

[0302] In some embodiments, the compounds in Tables A and B of this application include for

[0303] In another aspect, this application provides isotope labels for compounds of formula (I), formula (I-1), or formula (I-2), as shown in Tables A and B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0304] This application also provides a method for preparing a compound of formula (I), comprising the following steps: a coupling reaction of a compound of formula (IA) and a compound of formula (IB) in the presence of a catalyst to obtain a compound of formula (I).

[0305] in:

[0306] Rt For

[0307] X is halogen or OTf; preferably, X is Br or I;

[0308] R 1 , R 2 , R 3 , Z, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in the compound of formula (I).

[0309] The present application also provides a method for preparing a compound of formula (I), comprising the step of coupling a compound of formula (IC) with a compound of formula (ID) in the presence of a catalyst to obtain a compound of formula (I),

[0310] wherein:

[0311] R t is

[0312] X is halogen or OTf; preferably, X is Br or I;

[0313] R 1 , R 2 , R 3 , Z, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in the compound of formula (I).

[0314] In some embodiments, the method for preparing a compound of formula (I), wherein the catalyst is a metal catalyst.

[0315] In some embodiments, the method for preparing a compound of formula (I), wherein the catalyst is a palladium catalyst.

[0316] In some embodiments, the method for preparing a compound of formula (I), wherein the catalyst is selected from the group consisting of 1,1'-bis(diphenylphosphino) ferrocene palladium(II) dichloride (Pd(dppf)Cl2), [1,1'-bis(diphenylphosphino) ferrocene]palladium dichloride dichloromethane complex (Pd(dppf)Cl2-CH2Cl2), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), and tris(dibenzylideneacetone)palladium (Pd2(dba)3), and the like.

[0317] In some embodiments, the method of preparing a compound of formula (I) under basic conditions, the basic reagent providing the basic conditions is selected from K3PO4, KHCO3, NaHCO3, Na2CO3, Ba(OH)2, Cs2CO3, K2CO3, KF, CsF, KCN, NaCN, NaOH, KOH, Et3N, N,N-diisopropylethylamine (DIPEA), triethylenediamine (DABCO), NaOMe, NaOEt, t-BuOK, t-BuONa, NaH and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.

[0318] In another aspect of the present application, there is provided a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0319] In another aspect of the present application, there is provided the use of a compound of formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for degrading VAV1 protein.

[0320] In another aspect of the present application, there is provided the use of a compound of formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for mediating the interaction of VAV1 protein with E3 ligase, thereby increasing the degradation of VAV1 protein; preferably, the compound interacts with E3 ligase prior to the interaction of VAV1 protein with E3 ligase.

[0321] In another aspect of the present application, there is provided the use of a compound of formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for contacting E3 ligase, interacting the contacted E3 ligase with VAV1, thereby degrading VAV1.

[0322] In another aspect of the present application, there is provided the use of a compound of formula (I), formula (I-1) or formula (I-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for preventing and / or treating a disease or disorder caused by or associated with a disorder in the development or activity of lymphocytes.

[0323] In the present application, the lymphocytes can be T cells.

[0324] In the present application, the lymphocytes can be B cells.

[0325] The present application also provides a use of a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease or a cancer.

[0326] The autoimmune disease described in the present application can be selected from multiple sclerosis, rheumatoid arthritis, systemic lupus, thyroiditis, myasthenia gravis, type I diabetes, type II diabetes, vasculitis, pernicious anemia, dry eye, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic dermatitis, rhinitis, conjunctivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0327] The present application also provides a method for degrading VAV1 protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0328] The present application also provides a method for degrading VAV1 protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which mediates the interaction of VAV1 protein with E3 ligase, thereby increasing the degradation of VAV1 protein.

[0329] The present application also provides a method for degrading VAV1 protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which interacts with E3 ligase before the interaction of VAV1 protein with E3 ligase.

[0330] The present application also provides a method of degrading VAV1 protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the compound (i) contacts E3 ligase, and (ii) allows the contacted E3 ligase to interact with VAV1, thereby degrading VAV1 protein.

[0331] The present application also provides a method of preventing and / or treating a disease or disorder caused by or associated with a disorder of lymphocyte development or activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (II), Formula (III) and Formula (IV), or a compound represented by Table A, Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0332] The present application also provides a method of preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease or a cancer, comprising administering to a patient in need thereof a prophylactically and / or therapeutically effective amount of a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0333] The present application also provides a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0334] The present application also provides a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a VAV1 degrader.

[0335] The present application also provides a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating a disease or disorder caused by or associated with a disorder of lymphocyte development or activity.

[0336] The present application also provides a compound represented by Formula (I), Formula (I-1) or Formula (I-2), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease or a cancer.

[0337] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0338] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof.

[0339] In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof.

[0340] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of one or more pharmaceutically acceptable excipients.

[0341] As a medicament, the compounds of the present application can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes depending upon whether local or systemic treatment is desired and upon the area to be treated. They can be administered topically (e.g., transdermal, transcutaneous, ophthalmic, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., through the use of an inhaler or insufflator; intratracheal, intranasal), oral, or parenteral. Parenteral infusions include intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injections or infusion; or intracranial, e.g., intrathecal or intracerebroventricular administration. They can be administered parenterally, such as in a single dose, or can be administered, for example, by a continuous perfusion pump.

[0342] In making the compositions of the present application, the active ingredient is typically mixed with an excipient, which can take a wide variety of forms depending upon the form of composition desired for administration. The compositions can take the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0343] The "excipient" as used herein refers to an ingredient other than the active ingredient, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0344] In another aspect, pharmaceutically acceptable salts of the compounds described herein can be inorganic or organic salts, acid addition salts if the compounds have a basic center, base addition salts if the compounds have an acid center, and internal salts if the compounds contain both an acid center and a basic center (e.g., a carboxylate group and a tertiary nitrogen).

[0345] In another aspect, the compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such isomers, including those that can be produced by resolution of racemic forms. The present application also relates to the use of compounds of any individual isomer, as well as the use of mixtures of two or more isomers. Geometric isomers include cis and trans isomers. Stereoisomers include enantiomers, diastereomers, and racemic mixtures in various proportions. Enantiomeric mixtures include, but are not limited to, racemic mixtures and other mixtures of two or more enantiomers. Diastereomeric mixtures include, but are not limited to, mixtures of two or more diastereomers. Other mixtures include, but are not limited to, scalemic mixtures, and other mixtures of two or more isomers. All such isomers, including those that can be produced by resolution of racemic forms, are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are intended to be within the scope of the present application.

[0346] In the chemical structures of the compounds described herein, a bond indicates unspecified configuration, indicates absolute configuration, i.e., if chiral isomers are present in the chemical structure, a bond may be or both configurations, indicates the presence of an axis chirality.

[0347] a bond indicates unspecified configuration, including either the cis (E) or trans (Z) configuration.

[0348] In addition, the compounds and intermediates of the present application can also exist in different tautomeric forms and all such forms are embraced within the scope of the present application. "Tautomers" refer to different energy structures that can interconvert through a low energy barrier. For example, prototropic tautomers (also known as proton shift tautomers) include interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds of the present application are within the scope of the present application. The naming of a compound in a single form does not exclude any tautomers.

[0349] The present application also includes isotopically-labeled compounds of the present application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H,​3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, and the like. All isotopically-labeled compounds of the application having various isotopes of atoms are within the scope of the application. For example, the compounds of the application can include compounds where one or more hydrogen atoms is replaced by a deuterium or tritium atom, or where one or more carbon atoms is replaced by13C- or14C- atoms, or where one or more nitrogen atoms is replaced by15N- atoms, or where one or more oxygen atoms is replaced by an oxygen isotope, or where one or more sulfur atoms is replaced by a sulfur isotope, or where one or more fluorine atoms is replaced by a fluorine isotope, or where one or more chlorine atoms is replaced by a chlorine isotope, etc. All isotopically-labeled compounds of the application, whether radioactive or not, are included within the scope of the application.

[0350] Unless otherwise indicated, when a position is designated specifically as deuterium (D), the position is understood to have deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). In exemplary compounds, the deuterium can be in an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art are capable of synthesizing compounds in deuterated form by reference to the literature. In preparing compounds in deuterated form, commercially available deuterated starting materials can be used, or they can be synthesized using conventional techniques employing deuterated reagents, including but not limited to deuterated borane, trideuteroborane in tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide, and deuterated methyl iodide, and the like.

[0351] A "therapeutically effective amount" of the present application refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by person of skill in the art, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed to the disease, disorder and / or condition but has not yet experienced or displayed the pathology or symptomatology of the disease; (2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition (i.e., retarding the development of a pathology and / or symptomology) in an individual that is experiencing or displaying the pathology or symptomology of the disease; (3) relieving the disease: for example, relieving a disease, disorder or condition (i.e., reversing a pathology and / or symptomology) in an individual that is experiencing or displaying the pathology or symptomology of the disease. For a pharmaceutical or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the pharmaceutical or agent to provide the desired effect without undue adverse side effects. The exact amount required will vary from subject to subject, depending on the nature of the active agent, the disease or condition, the severity of the disease or condition, the age and general health of the subject, etc. Appropriate effective amounts can be determined by one of ordinary skill in the art using only routine experimentation.

[0352] "Pharmaceutically acceptable" means, in the present application, that the compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0353] "Patient" means, in the present application, any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, most preferably humans. Beneficial effects

[0354] The present application provides a small molecule compound that can be used as a VAV1 degrader, which can be used for effectively treating or preventing autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases or cancers.

[0355] Definitions and explanations of terms

[0356] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0357] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched-chain groups, preferably containing 1 to 20 carbon atoms, more preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and even more preferably 1 to 6 carbon atoms (C1-C6alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, hexyl, 3-methyl-hexyl, and the like. 1-6Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted.

[0358] The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined herein. Preferred are C 1-6 The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined herein. Preferred are C

[0359] The term "alkylene" refers to a saturated divalent hydrocarbyl radical resulting from the removal of two H from a saturated straight chain or branched chain hydrocarbyl group, which can contain 1-20 carbon atoms, preferably comprising 1-12 carbon atoms, more preferably C 1-6 The term "alkylene" refers to a saturated divalent hydrocarbyl radical resulting from the removal of two H from a saturated straight chain or branched chain hydrocarbyl group, which can contain 1-20 carbon atoms, preferably comprising 1-12 carbon atoms, more preferably C

[0360] The term "alkylene" refers to a divalent hydrocarbyl radical resulting from the removal of two H from a straight chain or branched chain hydrocarbyl group comprising one or more double bonds, which can contain 2-20 carbon atoms, preferably comprising 2-12 carbon atoms, more preferably C 2-6 The term "alkylene" refers to a divalent hydrocarbyl radical resulting from the removal of two H from a straight chain or branched chain hydrocarbyl group comprising one or more double bonds, which can contain 2-20 carbon atoms, preferably comprising 2-12 carbon atoms, more preferably C

[0361] The term "alkenyl" is understood to mean preferably a straight chain or branched monovalent hydrocarbon group which contains one or more double bonds and has 2 to 20 carbon atoms, preferably "C 2-10 alkenyl". "C 2-10 The term "alkenyl" is understood to mean preferably a straight chain or branched monovalent hydrocarbon group which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 alkenyl". "C 2-3alkenyl). It is to be understood that in case the alkenyl group comprises more than one double bond, the double bonds can be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl. The alkenyl group can be substituted or unsubstituted.

[0362] The term "alkynyl" is to be understood as meaning a straight-chain or branched one- valent hydrocarbon group which comprises one or more triple bonds and has 2 to 20 carbon atoms, preferably "C 2-10 alkynyl". The term "C 2-10 alkynyl" is to be understood as preferably meaning a straight-chain or branched one- valent hydrocarbon group which comprises one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. "C 2-6 alkynyl"). The term "C 2-3The term "alkynyl" refers to a straight or branched hydrocarbon chain that contains one or more triple bonds. The term "alkynyl" includes, but is not limited to, ethynyl, propynyl, propynyl, butynyl, butynyl, butynyl, pentynyl, pentynyl, pentynyl, pentynyl, hexynyl, hexynyl, hexynyl, hexynyl, hexynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl. The alkynyl group can be substituted or unsubstituted.

[0363] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably containing 3 to 6 carbon atoms, which can optionally be oxidized by an oxo group (=0) that is part of the ring. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0364] The term "spirocycloalkyl" refers to a 5- to 20-membered, polycyclic group in which each single ring shares one carbon atom (termed a spiro atom) in the system, which can contain one or more double bonds. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spirocycloalkyl groups are classified as mono-, bi-, or polyspirocycloalkyl groups, preferably mono- and bi-spirocycloalkyl groups, depending on the number of spiro atoms shared between rings. More preferably, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0365] The term "fused ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, where each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings can contain one or more double bonds. Preferably, 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bi-, tri-, tetra-, or polycyclic fused ring alkyl, preferably bi- or tri-cyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bi-cyclic alkyl. Non-limiting examples of fused ring alkyl include:

[0366] The term "bridged ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, where any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds. Preferably, 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bi-, tri-, tetra-, or polycyclic bridged ring alkyl, preferably bi-, tri-, or tetra-cyclic, more preferably bi- or tri-cyclic. Non-limiting examples of bridged ring alkyl include:

[0367] The cycloalkyl ring includes cycloalkyl (including monocyclic, spirocyclic, fused, and bridged) fused to an aryl ring as described herein, where the ring that is attached to the parent structure can be a cycloalkyl ring or an aryl ring, non-limiting examples include The cycloalkyl can be substituted or unsubstituted.

[0368] ​The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring-like substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), but not ring moieties of -0-0-, -0-S-, or -S-S-, the remainder of which are carbon, which can optionally be oxidized, the ring carbons of which can be considered to be part of the ring. Preferably, there are 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, there are 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, there are 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, there are 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spirocyclic, fused, and bridged heterocyclyl groups.

[0369] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each single ring shares one atom (referred to as a spiro atom) with another ring, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remainder of which are carbon. It can contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bispiroheterocyclyl groups, depending on the number of spiro atoms shared between rings. More preferably, it is a 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, or 5 / 6- membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups include:

[0370] The term "fused heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 20 members, each ring in the system sharing a pair of adjacent atoms with another ring in the system, one or more rings can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, and 6 / 6 bicyclic fused heterocyclyl, according to the number of rings comprising the ring. Non-limiting examples of fused heterocyclyl groups include:

[0371] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 14 members, any two rings sharing two non-adjacent atoms, which can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0372] The heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic, and bridged heterocyclic) as described herein fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure can be a heterocyclyl ring or an aryl, heteroaryl, or cycloalkyl ring, non-limiting examples of which include:

[0373] The heterocyclyl group can be substituted or unsubstituted.

[0374] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares a pair of adjacent carbon atoms) radical with a conjugated pi electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl group can be substituted or unsubstituted.

[0375] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 membered or 6 membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl fused to an aryl ring as described herein, wherein the rings connected together can be a heteroaryl ring or an aryl ring, non-limiting examples of which include:

[0376] and the like. The heteroaryl group can be substituted or unsubstituted.

[0377] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl", and "heteroaryl" and the like in the present application can be substituted or unsubstituted; when substituted, it can be substituted at any available attachment point with one or more, the same or different, substituents independently optionally selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0378] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived from removal of one H from a ring atom of the parent, or removal of two H from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

[0379] The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined herein.

[0380] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0381] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein. The term "C 1-6 The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein. The term "C 1-6 The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein. The term "C

[0382] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein. The term "C 1-6 The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein. The term "C 1-6 The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein. The term "C

[0383] The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined herein. The term "C1-6 "Deuterated alkyl" refers to C 1-6 The alkyl group is substituted with one or more deuterium groups.

[0384] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein the alkoxy group is as defined in this application. The term "C" 1-6 "Deuterated alkoxy" refers to C 1-6 The alkoxy group is substituted with one or more deuterium groups.

[0385] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined in this application. The term "C" 1-6 "Hydroxyalkyl" refers to C 1-6 The alkyl group is replaced by one or more hydroxyl groups.

[0386] The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups, wherein the alkyl group is as defined in this application. The term "C" 1-6 "Cyanoalkyl" refers to C 1-6 The alkyl group is replaced by one or more cyano groups.

[0387] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is as defined in this application. The term "C" 1-6 "Aminoalkyl" refers to C 1-6 The alkyl group is replaced by one or more amino groups.

[0388] The term "halogen" refers to F, Cl, Br, or I.

[0389] The term "hydroxyl group" refers to -OH.

[0390] The term "amino" refers to -NH2.

[0391] The term "cyano" refers to -CN.

[0392] The term "nitro" refers to -NO2.

[0393] The term "oxo" or "oxo" refers to "=O" when it substitutes on C, and "=O" when it substitutes on N.

[0394] The term "carbonyl" refers to C=O.

[0395] The term "carboxyl group" refers to -C(O)OH.

[0396] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined in this application.

[0397] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocycloalkyl optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes instances where the heterocycloalkyl group is substituted with alkyl and instances where the heterocycloalkyl group is not substituted with alkyl.

[0398] "Substituted" means that one or more H's in the given structure are replaced by the named substituent. It is understood that substituents are only at their available sites and that one of skill in the art can, without undue effort, determine (experimentally or theoretically) what is possible or impossible for substitution. Further, when the group is substituted with more than one of the named substituents, the substituents are independent of one another (i.e., the named substituents can be the same or different).

[0399] It should be understood that the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In addition, the term "comprising" is to be construed as developmentally open-ended, i.e., as "including but not limited to," unless otherwise indicated. DETAILED DESCRIPTION

[0400] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustrative and explanatory of the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology implemented based on the above description of the present application is included in the scope of protection intended by the present application.

[0401] Unless otherwise indicated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0402] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shift (δ) is given in units of 10 -6 (ppm). The determination of NMR is made by Bruker ASCEND TM -400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The determination of MS is made by Agilent 6110, Agilent 1100, Agilent 6120, Agilent G6125B liquid chromatograph-mass spectrometer.

[0403] The determination of HPLC uses Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um chromatographic column).

[0404] Chiral HPLC analysis determination using THAR SFC X5.

[0405] Thin layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm, the specification of product used in thin layer chromatography separation and purification is 0.4mm-0.5mm.

[0406] Column chromatography generally uses Qingdao marine silica gel 200-300 mesh silica gel as carrier.

[0407] High performance liquid preparation uses Waters 2767, Waters 2545, and innovative constant LC3000 preparative chromatograph.

[0408] Chiral preparative column chromatography uses Shimadzu LC-20AP, THAR SFC PREP 80.

[0409] CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

[0410] Pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G type hydrogen generator.

[0411] Microwave reaction uses Biotage initiator+ type microwave reactor.

[0412] In the experimental examples, unless otherwise specified, the reaction was carried out under argon atmosphere or nitrogen atmosphere.

[0413] Argon atmosphere or nitrogen atmosphere refers to connecting a about 1 liter volume of argon or nitrogen balloon to the reaction bottle.

[0414] Hydrogen atmosphere refers to connecting a about 1 liter volume of hydrogen balloon to the reaction bottle.

[0415] In the experimental examples, unless otherwise specified, the reaction temperature is room temperature, and the temperature range is 20℃-30℃.

[0416] The skilled person in the art should understand that the chiral compounds which are split can be distinguished by the order of retention time in the chiral chromatographic column, therefore, the chiral compounds which are split according to the order of retention time are distinguished by the number suffixes P1, P2, etc. That is, for example, the suffix P1 corresponds to the chiral compound with a certain chiral structure which is eluted out of the chiral chromatographic column earlier, and the suffix P2 corresponds to the chiral compound with a certain chiral structure which is eluted out of the chiral chromatographic column later. If the absolute configuration of the compound is listed in the structural formula, it does not mean that it directly corresponds to the compound with the number suffix P1, P2, but only indicates the two existing forms of the absolute configuration. The absolute configuration of the compound with the number suffix P1, P2 is subject to the objective corresponding absolute configuration marked by the specific retention time.

[0417] In the following examples, the compound number 91b in the chemical formula is the same structure as 404a; the number 88b is the same structure as 363a; the number 146h is the same structure as 1191a.

[0418] Example 1 (compound 2)

[0419] First step: synthesis of compound 2b

[0420] Compound 2a (5-bromo-2-fluorobenzaldehyde) (1 g, 4.93 mmol) was dissolved in DMF (10 mL), and compound N-methylpiperazine (0.74 g, 7.39 mmol) and anhydrous potassium carbonate (1.02 g, 7.39 mmol) were added in turn, and the reaction mixture was stirred at 100°C for 3 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, quenched with water (15 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-8%) to obtain compound 2b (0.99 g). MS m / z (ESI): 283.0, 285.0 [M+1, M+3] + .

[0421] Second step: synthesis of compound 2c

[0422] Compound 2b (570 mg, 2.01 mmol) was dissolved in anhydrous toluene (6 mL), and then d-camphorsulfonic acid (93 mg, 0.4 mmol), dichlorobis(4-methylisopropylphenyl)ruthenium(II) (123 mg, 0.2 mmol) and 4A molecular sieves (570 mg) were added successively. The reaction mixture was heated to 160 °C under nitrogen protection and stirred for 7 hours. After the reaction was completed, it was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (methanol / methylene chloride = 0-3%) to obtain compound 2c (109 mg). MS m / z (ESI): 265.0, 267.0 [M+1, M+3] +

[0423] Third step: synthesis of compound 2

[0424] Compound 2d (52 mg, 0.15 mmol, synthesis method refer to WO2024151547A1 specification page P184 synthesis of Intermediate A) was dissolved in 1,4-dioxane (4 mL), and then compound 2c (40 mg, 0.15 mmol), potassium phosphate (95.5 mg, 0.45 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11 mg, 0.015 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction liquid was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / methylene chloride = 0-5%) to obtain a crude product (39 mg, crude), which was further purified by high performance liquid preparative chromatography (column: OBD-C18; 19x 250mm, 10μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-30%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm) to obtain compound 2 (1.78 mg). MS m / z (ESI): 408.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.47 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.32 (dd, J = 6.3, 3.1 Hz, 2H), 7.10 (d, J = 8.3 Hz, 1H), 6.22 (s, 1H), 4.34 (dd, J = 12.1, 4.9 Hz, 1H), 4.10 (d, J = 8.0 Hz, 2H), 3.72 (s, 2H), 2.89 (t, J = 4.0 Hz, 2H), 2.83 - 2.75 (m, 1H), 2.56-2.51 (m, 1H), 2.42 (s, 3H), 2.35-2.33 (m, 1H), 2.08-2.05 (m, 1H).

[0425] Example 2 (Compound 30)

[0426] First Step: Synthesis of Compound 30c

[0427] Compound 30a (5-bromoindole) (1 g, 5.1 mmol) was dissolved in N,N- dimethylacetamide (10 mL) and water (0.9 mL), and compound 30b (1,3- dibromopropane) (2.57 g, 12.5 mmol), cesium carbonate (3.32 g, 10.2 mmol) and bis(acetonitrile)dichloropalladium(ll) (130 mg, 0.51 mmol) were added successively. The reaction mixture was heated to 80 °C and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain compound 30c (124 mg). MS m / z (ESI): 236.0 [M+1] +

[0428] Second Step: Synthesis of Compound 30

[0429] Compound 30c (20 mg, 0.085 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 2d (29.72 mg, 0.085 mmol), potassium phosphate (54.13 mg, 0.26 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(ll) (6.22 mg, 0.0085 mmol) were added successively. The reaction mixture was heated to 100 °C and stirred for 16 h under nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 30 (0.54 mg). MS m / z (ESI): 379.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.45-7.29 (m, 5H), 7.05 (dd, J = 8.3, 1.6 Hz, 1H), 6.16 (s, 1H), 4.33 (dd, J = 4.0, 12.0 Hz, 1H), 4.09 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.79-2.70 (m, 1H), 2.65-2.54 (m, 3H), 2.45-2.28 (m, 1H), 2.07-1.99 (m, 1H).

[0430] Example 3 (Compound 84)

[0431] First Step: Synthesis of compound 84b

[0432] Sodium hydroxide (1.35 g, 33.7 mmol) was added to a solution of compound 84a (6-hydroxy-3,4-dihydro-2(lH)-quinolinone) (5.0 g, 30.64 mmol) and benzyl bromide (5.76 g, 33.7 mmol) in ethanol (100 mL) at room temperature. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (30 mL) was added, and a solid was precipitated. The solid was filtered, and the filter cake was dried by an oil pump to give compound 84b (5.35 g). MS m / z (ESI): 254.0 [M+1] + .

[0433] Second Step: Synthesis of compound 84c

[0434] Compound 84b (500 mg, 1.97 mmol) was dissolved in a mixed solution of acetonitrile and triethylamine (6 mL / 2 mL), and phosphorus pentasulfide (525.5 mg, 2.36 mmol) was added. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 10% to 35%) to give compound 84c (360 mg). MS m / z (ESI): 270.0 [M+1] +

[0435] Third Step: Synthesis of compound 84e

[0436] Compound 84c (360 mg, 1.34 mmol) was dissolved in anhydrous ethanol (10 mL) at room temperature, and compound 84d (aminoacetaldehyde dimethyl acetal) (141 mg, 1.34 mmol) and N,N-dimethylethaneamine (519.5 mg, 4.02 mmol) were added sequentially. The reaction mixture was heated to 80 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to give compound 84e (460 mg), which was used directly in the next reaction. MS m / z (ESI): 341.1 [M+1] +

[0437] Fourth Step: Synthesis of compound 84f

[0438] Compound 84e (460 mg, 1.35 mmol) was dissolved in acetic acid (5 mL), and the reaction mixture was heated to 100 °C and stirred for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0% to 5%) to give compound 84f (90 mg). MS m / z (ESI): 277.1 M+1] +

[0439] Fifth Step: Synthesis of compound 84g

[0440] Compound 84f (90 mg, 0.33 mmol) was dissolved in anhydrous ethanol (5 mL), and palladium on carbon (30 mg) was added. The reaction mixture was heated to 60 °C under a hydrogen atmosphere and stirred for 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated to give compound 84g (57 mg). MS m / z (ESI): 187.1 [M+1] +

[0441] Sixth Step: Synthesis of compound 84h

[0442] Triflic anhydride (87.5 mg, 0.31 mmol) was slowly added to a solution of compound 84g (57 mg, 0.31 mmol) and 2,6-lutidine (53.4 mg, 0.37 mmol) in dichloromethane (5 mL) under ice bath. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was quenched with water (5 mL). The product was extracted with dichloromethane (15 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0% to 3%) to give compound 84h (34 mg). MS m / z (ESI): 318.9 [M+1] +

[0443] Seventh Step: Synthesis of compound 84

[0444] Compound 2d (36 mg, 0.10 mmol) was dissolved in 1,4-dioxane (4 mL), and compound 84h (31.8 mg, 0.10 mmol), potassium phosphate (63.7 mg, 0.30 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (7.3 mg, 0.01 mmol) were added sequentially. The reaction mixture was heated to 100 °C and stirred for 16 h under nitrogen. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0% to 3%) to give compound 84 (6.3 mg). MS m / z (ESI): 392.1 [M+1]+ . 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.87(d,J=1.3Hz,1H),7.68(d,J=8.3Hz,1H),7.46–7.31(m,5H),7.01(d,J=1.3Hz,1H), 4.35(dd,J=12.2,5.2Hz,1H),3.09–2.93(m,4H),2.86–2.73(m,1H),2.57-2.56(m,1H),2.38–2.27(m,1H),2.06–1.96(m,1H).

[0445] Example 4 (Compound 146)

[0446] Step 1: Synthesis of compound 146b

[0447] At 0 °C, phosphorus oxychloride (10.4 mL, 113.94 mmol) was dissolved in N,N-dimethylformamide (10 mL), stirred in an ice bath for 10 minutes, stirred at room temperature for 15 minutes, and then cooled to 0 °C. Compound 146a (cyclopentanone) (5.99 g, 71.22 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was quenched with ice water (100 mL), extracted with ethyl acetate (200 mL x 3), the organic phases were combined and dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane = 100%) to give compound 146b (4.6 g). 1 H NMR (400MHz, CDCl3) δ9.93(s,1H),2.78–2.72(m,2H),2.54–2.49(m,2H),1.97–1.90(m,2H).

[0448] Step 2: Synthesis of compound 146d

[0449] Compound 146b (2.6 g, 19.91 mmol), compound 146c (2-piperazinone) (1.99 g, 19.91 mmol), and N-methylmorpholine (6.04 g, 59.73 mmol) were added to N,N-dimethylformamide (50 mL). The reaction mixture was stirred at 115 °C for 16 hours. After the reaction was complete, the reaction solution was added to water (500 mL) and stirred until the solid completely precipitated. The mixture was then filtered, and the filter cake was dried under reduced pressure to obtain compound 146d (2.7 g). MS m / z (ESI): 177.1 [M+1] +

[0450] Step 3: Synthesis of compound 146f

[0451] Compound 146d (1 g, 5.67 mmol) and compound 146e (p-bromoiodobenzene) (2.41 g, 8.501 mmol), cuprous iodide (0.11 g, 0.57 mmol), potassium carbonate (2.35 g, 17.01 mmol) were added into dimethyl sulfoxide (20 mL), the reaction mixture was stirred at 120 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was added into water (200 mL), and after stirring until the solid was completely precipitated, it was filtered, and the filter cake was dried under reduced pressure to obtain compound 146f (440 mg). MS m / z (ESI): 331.0, 332.9 [M+1, M+3] +

[0452] Fourth step: synthesis of compound 146g

[0453] Compound 146f (200 mg, 0.6 mmol) was dissolved in 1,4-dioxane (10 mL), and bis(pinacolato)diboron (304.73 mg, 1.2 mmol), potassium acetate (176.65 mg, 1.8 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (43.90 mg, 0.06 mmol) were added in turn. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 146g (100 mg). MS m / z (ESI): 379.1 [M+1] +

[0454] Fifth step: synthesis of compound 146

[0455] Compound 146g (70 mg, 0.19 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 146h (synthesis method, refer to WO2024151547A1 specification page P184 synthesis of Intermediate AA-1) (57.48 mg, 0.19 mmol), potassium phosphate (120.99 mg, 0.57 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (13.9 mg, 0.019 mmol) were added in turn. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 146 (2.59 mg). MS m / z (ESI): 474.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.48 - 7.33 (m, 7H), 6.54 (s, 1H), 4.36 (dd, J = 12.1, 5.0 Hz, 1H), 4.18 (dd, J = 7.0, 4.0 Hz, 2H), 4.11 (dd, J = 7.5, 4.5 Hz, 2H), 2.85 - 2.75 (m, 1H), 2.74 - 2.68 (m, 2H), 2.57 (t, J = 6.8 Hz, 3H), 2.42 - 2.31 (m, 3H), 2.11 - 2.01 (m, 1H).

[0456] Example 5 (Compound 153)

[0457] First Step: Synthesis of Compound 153c

[0458] Potassium tert-butoxide (460 mg, 4.10 mmol) was dissolved in toluene (10 mL), compound 153a (5-bromoindole-2-carboxylic acid ethyl ester) (1 g, 3.73 mmol) and compound 153b (tert-butyl acrylate) (320 mg 3.73 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was adjusted to pH = 3-4 with 2N HCl. The reaction solution was extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid (10 mL), the reaction solution was heated to 80 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was rotary evaporated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-0 / 1) to give compound 153c (330 mg) MS m / z (ESI): 249.9, 251.9 [M+1, M+3] +

[0459] Second Step: Synthesis of Compound 153

[0460] Compound 153c (40 mg, 0.16 mmol) was dissolved in 1,4-dioxane (2 mL), compound 2d (56 mg, 0.16 mmol), potassium phosphate (102 mg, 0.48 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12 mg, 0.016 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to give compound 153 (4.7 mg). MS m / z (ESI): 393.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.76 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.45 - 7.32 (m, 4H), 7.00 (s, 1H), 4.51 (t, J = 6.1 Hz, 2H), 4.35 (dd, J = 12.1, 5.0 Hz, 1H), 3.23 (t, J = 6.1 Hz, 2H), 2.85 - 2.75 (m, 1H), 2.57 - 2.55 (m, 1H), 2.36 - 2.42 (m, 1H), 2.01 - 2.12 (m, 1H).

[0461] Example 6 (Compound 183)

[0462] First Step: Synthesis of compound 183b

[0463] Compound 146b (synthesis method refer to the first step of synthesis of compound 146 of Example 4 compound 146b) (4.6 g, 35.23 mmol) and compound 183a (ethoxycarbonylmethylidene triphenyl phosphonium) (12.27 g, 35.23 mmol) were added to dichloromethane (50 mL), the reaction mixture was stirred at 40 °C for 16 hours, after the reaction was completed, the reaction liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 183b (4.6 g). MS m / z (ESI): 200.9 [M+1] +

[0464] Second Step: Synthesis of compound 183c

[0465] Compound 183b (3.6 g, 17.94 mmol) and sodium azide (1.75 g, 26.91 mmol) were added to dimethyl sulfoxide (50 mL), the reaction mixture was stirred at 65 °C for 16 hours. After the reaction was completed, the reaction liquid was added to water (200 mL) and stirred until the solid was completely precipitated, then filtered, and the filter cake was dried under reduced pressure to obtain compound 183c (700 mg). MS m / z (ESI): 180.1 [M+1] +

[0466] Third Step: Synthesis of compound 183e

[0467] Compound 183c (900 mg, 5.02 mmol), compound 183d (2-bromo-1,1-dimethoxyethane) (1.27 g, 7.53 mmol) and cesium carbonate (4.91 g, 15.06 mmol) were added into N,N-dimethylformamide (10 mL), the reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction liquid was added into water (200 mL) and diluted, extracted with ethyl acetate (100 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 183e (1.7 g). MS m / z (ESI): 268.1 [M+1] +

[0468] Fourth step: synthesis of compound 183f

[0469] Compound 183e (1.6 g, 5.99 mmol) and lithium hydroxide (1.43 g, 59.90 mmol) were added into water (2 mL) and ethanol (10 mL), the reaction mixture was stirred at 50 °C for 16 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to remove ethanol, the residue was dissolved in water (200 mL), 1 mol / L dilute hydrochloric acid was slowly added to adjust pH < 6, stirred until the solid was completely precipitated, and then filtered, and the filter cake was dried under reduced pressure to give compound 183f (900 mg). MS m / z (ESI): 240.1 [M+1] +

[0470] Fifth step: synthesis of compound 183g

[0471] Compound 183f (300 mg, 1.25 mmol), ammonium chloride (0.33 g, 6.25 mmol), N,N-diisopropylethylamine (0.65 g, 5 mmol) and 2-(7-azobenzenetriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.71 g, 1.88 mmol) were added into N,N-dimethylformamide (10 mL), the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction liquid was added into water (100 mL) and stirred until the solid was completely precipitated, and then filtered, and the filter cake was dried under reduced pressure to give compound 183g (200 mg). MS m / z (ESI): 239.1 [M+1] +

[0472] Sixth step: synthesis of compound 183h

[0473] Compound 183g (0.35 g, 1.47 mmol) was added to glacial acetic acid (5 mL), the reaction mixture was stirred at 110 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), the pH was adjusted to >7 by slowly adding saturated sodium bicarbonate solution, and after stirring until the solid was completely precipitated, it was filtered, and the filter cake was dried under reduced pressure to obtain compound 183h (260 mg). MS m / z (ESI): 175.1 [M+1] +

[0474] Seventh step: synthesis of compound 183i

[0475] Compound 183h (0.23 g, 1.32 mmol) and compound 146e (p-bromoiodobenzene) (0.56 g, 1.98 mmol), cuprous iodide (0.025 g, 0.13 mmol), potassium carbonate (0.55 g, 3.96 mmol) were added to dimethyl sulfoxide (10 mL), and the reaction mixture was stirred at 120 °C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-15%) to obtain compound 183i (160 mg). MS m / z (ESI): 328.9, 330.9 [M+1, M+3] +

[0476] Eighth step: synthesis of compound 183k

[0477] Compound 183i (100 mg, 0.3 mmol) was dissolved in 1,4-dioxane (10 mL), and 183j (bis(pinacolato)diboron) (152.36 mg, 0.6 mmol), potassium acetate (88.33 mg, 0.9 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (21.95 mg, 0.03 mmol) were sequentially added. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-15%) to obtain compound 183k (50 mg). MS m / z (ESI): 377.2 [M+1] +

[0478] Ninth step: synthesis of compound 183

[0479] Compound 183k (40 mg, 0.11 mmol) was dissolved in 1,4-dioxane (10 mL), and compound 146h (33.28 mg, 0.11 mmol), potassium phosphate (70.05 mg, 0.33 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8.05 mg, 0.011 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) and then by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 183 (5.34 mg). MS m / z (ESI): 472.0 [M+1] + . 1 H NMR (400 MHz, CDC13) δ 8.07 (s, 1H), 7.43 (s, 4H), 7.27 (dd, J = 7.2, 5.1 Hz, 2H), 7.15 (dd, J = 6.6, 2.8 Hz, 1H), 6.93 (s, 1H), 6.79 (d, J = 5.9 Hz, 1H), 6.56 (d, J = 5.9 Hz, 1H), 4.27 (dd, J = 10.5, 5.7 Hz, 1H), 2.78 (t, J = 7.1 Hz, 2H), 2.76 - 2.70 (m, 3H), 2.69 - 2.59 (m, 1H), 2.52 - 2.44 (m, 2H), 2.31 - 2.20 (m, 2H).

[0480] Example 7 (Compound 62)

[0481] First Step: Synthesis of compound 62c

[0482] Compound 62a (2,4-dibromoaniline) (2 g, 7.97 mmol) was dissolved in N,N-dimethylformamide (20 mL), and compound 62b (allyltributylstannane) (3.17 g, 9.56 mmol) and dichlorobis(triphenylphosphine)palladium (280 mg, 0.40 mmol) were added successively. The reaction mixture was stirred at 80 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated aqueous potassium fluoride solution (200 mL), stirred at room temperature for 20 min, filtered with celite, and the filtrate was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to give compound 62c (670 mg). MS m / z (ESI): 211.9, 213.9 [M+1, M+3]+

[0483] Step 2: Synthesis of compound 62e

[0484] Compound 62c (450 mg, 2.12 mmol) was dissolved in dichloromethane (10 mL), 62d (bromoacetyl chloride) (385 mg, 1.91 mmol), potassium carbonate (879 mg, 6.36 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (150 mL x 3). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-100%) to give compound 62e (515 mg). MS m / z (ESI): 332.0, 334.0 [M+1, M+3] +

[0485] Step 3: Synthesis of compound 62f

[0486] Compound 62e (415 mg, 1.25 mmol) was dissolved in anhydrous acetonitrile (5 mL), potassium carbonate (518 mg, 3.75 mmol), and palladium acetate (28 mg, 0.13 mmol) were added successively. The reaction mixture was heated to 40°C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0%-3%) to give compound 62f (127 mg). MS m / z (ESI): 251.9, 253.9 [M+1, M+3] +

[0487] Step 4: Synthesis of compound 62g

[0488] Compound 62f (87 mg, 0.35 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and borane-dimethyl sulfide solution (2.8 mL, 2M, 5.25 mmol) was added. The reaction mixture was heated to 60°C under nitrogen protection and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to 0°C in an ice bath, quenched with methanol (2 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0%-3%) to give compound 62g (40 mg). MS m / z (ESI): 237.9, 239.9 [M+1, M+3] +

[0489] Step 5: Synthesis of compound 62

[0490] Compound 62g (40 mg, 0.17 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 2d (59 mg, 0.17 mmol), potassium phosphate (108 mg, 0.51 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12 mg, 0.017 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain compound 62 (6.52 mg). MS m / z (ESI): 381.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.32 (d, J = 4.0 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1H), 4.32 (dd, J = 12.0, 5.2 Hz, 1H), 3.89 (dt, J = 12.8, 6.4 Hz, 1H), 3.20 - 3.10 (m, 2H), 3.00 - 2.90 (m, 1H), 2.84 - 2.73 (m, 1H), 2.55-2.53 (m, 1H), 2.33-2.27 (m, 1H), 2.10 - 2.01 (m, 1H), 1.93 - 1.76 (m, 3H), 1.34 - 1.13 (m, 2H).

[0491] Example 8 (Compound 83)

[0492] First Step: Synthesis of compound 83c

[0493] Compound 83a (2-bromo-3-nitropyridine) (1.1 g, 4.93 mmol) was dissolved in tetrahydrofuran (15 mL), and compound 83b (4-bromophenylboronic acid) (1.63 g, 8.1 mmol), potassium phosphate (2.29 g, 10.8 mmol), and [1,1 / '-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.04 g, 0.5 mmol) were added successively. The reaction mixture was heated to 60 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10%-30%) to obtain compound 83c (1.4 g). MS (ES, m / z): 279.0 [M+1] + .

[0494] Second Step: Synthesis of compound 83d

[0495] Compound 83c (1.4 g, 5.0 mmol) was added to a single-neck flask at room temperature, and the reaction mixture was heated to 150 °C under nitrogen protection for 0.5 h with stirring. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain compound 83d (540 mg). MS (ES, m / z): 247.0 [M+1] + .

[0496] Third Step: Synthesis of compound 83

[0497] Compound 2d (173.16 mg, 0.73 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (10 / 1, 3 mL), and compound 83d (120 mg, 0.48 mmol), potassium phosphate (206.2 mg, 0.97 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19.83 mg, 0.02 mmol) were added in turn. The reaction mixture was heated to 100 °C under nitrogen protection for 16 h with stirring. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain a crude product (150 mg), which was further purified by high performance liquid chromatography (preparative column: Gemini-C18; 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 20-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to obtain compound 83 (34.7 mg). MS m / z (ES): 390.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.96 (s, 1H), 8.70 (d, J = 4.8 Hz, 1H), 8.44-8.32 (m, 2H), 7.80-7.67 (m, 2H), 7.51-7.35 (m, 4H), 4.38 (dd, J = 12.0 Hz, 5.0 Hz, 1H), 2.88-2.75 (m, 1H), 2.70-2.57 (m, 1H), 2.44-2.31 (m, 1H), 2.16-2.04 (m, 1H).

[0498] Example 9 (Compound 88)

[0499] First Step: Synthesis of compound 88b

[0500] Compound 88a (6-bromo-1-tetralone) (1 g, 4.44 mmol) was dissolved in dichloromethane (15 mL), and N-bromosuccinimide (0.87 g, 4.89 mmol) and p-toluenesulfonic acid (38 mg, 0.22 mmol) were added successively. The reaction mixture was heated to 50 °C and stirred for 6 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (15 mL), extracted with dichloromethane (15 mL), and the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-15%) to give compound 88b (1 g). MS m / z (ESI): 303.0 [M+1] + .

[0501] Second step: synthesis of compound 88c

[0502] Compound 88b (500 mg, 1.64 mmol) was dissolved in formic acid (7 mL), and formamide (6 mL) and ammonium formate (7.3 g, 115.87 mmol) were added successively. The reaction mixture was heated to 165 °C in a reaction kettle and stirred for 1 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0%-5%) to give compound 88c (200 mg). MS m / z (ESI): 249.0 [M+1] + .

[0503] Third step: synthesis of compounds 88d and 88e

[0504] Sodium hydride (23.12 mg, 0.96 mmol) was added to a solution of compound 88c (200 mg, 0.8 mmol) in N,N-dimethylformamide (10 mL) under ice bath, and the reaction mixture was stirred for 30 min under ice bath, and then iodomethane (171 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-5%) to give a mixture of compounds 88d and 88e (150 mg). MS m / z (ESI): 263.0 [M+1] + .

[0505] Fourth step: synthesis of compound 88

[0506] A mixture of compounds 88d and 88e (synthesis method refer to the synthesis of compound 88d and 88e in the third step of compound 88 in example 9) (80 mg, 0.3 mmol) was dissolved in 1,4-dioxane (4 mL) and water (0.5 mL), compound 2d (117.24 mg, 0.33 mmol), potassium phosphate (97 mg, 0.46 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain a crude product (50 mg), which was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 20 / 1) to obtain compound 296 (4 mg). MS m / z (ESI): 406.0 [M+1] + . 1 HNMR (400 MHz, CDC13) δ 8.07 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.36 - 7.29 (m, 3H), 7.24 (s, 1H), 7.21 - 7.15 (m, 1H), 4.34 (dd, J = 10.4, 5.6 Hz, 1H), 3.66 (s, 3H), 3.13 (t, J = 8.0 Hz, 2H), 2.87 (t, J = 8.0 Hz, 2H), 2.81 - 2.65 (m, 2H), 2.40 - 2.28 (m, 2H).

[0507] Example 10 (compound 296)

[0508] First step: synthesis of compound 296

[0509] A mixture of compounds 88d and 88e (synthesis method refer to the synthesis of compound 88d and 88e in the third step of compound 88 in example 9) (80 mg, 0.3 mmol) was dissolved in 1,4-dioxane (4 mL) and water (0.5 mL), compound 2d (117.24 mg, 0.33 mmol), potassium phosphate (97 mg, 0.46 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain a crude product (50 mg), which was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 20 / 1) to obtain compound 296 (4 mg). MS m / z (ESI): 406.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.43 - 7.26 (m, 5H), 4.35 (dd, J = 12.1, 5.0 Hz, 1H), 3.94 (s, 3H), 2.97 (t, J = 7.7 Hz, 2H), 2.86 - 2.66 (m, 4H), 2.40 - 2.27 (m, 1H), 2.11 - 2.02 (m, 1H).

[0510] Example 11 (Compound 91)

[0511] First Step: Synthesis of compound 91b

[0512] Compound 91a (6-bromo-3,4-dihydro-lH-2-naphthalenone) (2 g, 8.9 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (15 mL), then p-toluenesulfonic acid (33 mg, 0.178 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound 91b (1.8 g). MS m / z (ESI): 280.0 [M+1] +

[0513] Second Step: Synthesis of compound 91c

[0514] Compound 91b (1.8 g, 6.4 mmol) was dissolved in anhydrous methanol (10 mL), then hydrazine hydrate (0.96 g, 19.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain compound 91c (1.5 g). MS m / z (ESI): 249.1, 251.1 [M+1, M+3] +

[0515] Third Step: Synthesis of compound 91d and compound 91e

[0516] Compound 91c (1.5 g, 6 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydride (60%, 0.48 g, 12 mmol) was added slowly under ice-bath. After the reaction solution was stirred for 15 min, iodomethane (1.7 g, 12 mmol) was added dropwise slowly. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction was quenched by water (30 mL), extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-20%) to give compound 91d (100 mg) and compound 91e (110 mg).

[0517] Fourth Step: Synthesis of compound 91

[0518] Compound 91d (70 mg, 0.266 mmol) was dissolved in 1,4-dioxane / water (10:1, 5.5 mL), compound 2d (63 mg, 0.266 mmol), potassium phosphate (112 mg, 0.532 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19 mg, 0.0266 mmol) were added successively. The reaction mixture was heated to 90 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-9%) to give the crude product (62 mg), which was further purified by high performance liquid preparative chromatography (column: Gemini-C18 150 x 21.2 mm, 5 µm; mobile phase: acetonitrile: water (0.1% formic acid); gradient: 37-63%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to give compound 91 (21.8 mg). MS m / z (ESI): 406.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.77 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34-7.31 (m, 2H), 7.28-7.25 (m, 2H), 7.18 (dd, J = 5.9, 3.4 Hz, 1H), 4.33 (dd, J = 10.6, 5.6 Hz, 1H), 3.86 (s, 3H), 3.08 (t, J = 7.5 Hz, 2H), 2.94-2.87 (m, 2H), 2.80-2.65 (m, 2H), 2.38-2.24 (m, 2H).

[0519] Example 12 (Compound 295)

[0520] First Step: Synthesis of compound 295

[0521] Compound 91e (synthesis method refer to the synthesis of compound 91d and compound 91e in the third step of compound 91 in Example 11) (80 mg, 0.304 mmol) was dissolved in 1,4-dioxane / water (10:1, 5.5 mL), compound 2d (72 mg, 0.304 mmol), potassium phosphate (128 mg, 0.608 mmol and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (22 mg, 0.0304 mmol) were added successively. The reaction mixture was heated to 90 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-9%) to obtain a crude product (50 mg), which was further purified by high performance liquid preparative chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile: water (0.1% formic acid); gradient: 37-63%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to obtain compound 295 (10.7 mg). MS m / z (ESI): 406.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.60 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.31 (s, 2H), 7.26 (s, 2H), 7.19 (d, J = 4.7 Hz, 1H), 4.40 - 4.23 (m, 1H), 3.96 (s, 3H), 3.05 - 3.29 (m, 4H), 2.84 - 2.61 (m, 2H), 2.48 - 2.18 (m, 2H).

[0522] Example 13 (compound 250)

[0523] First step: synthesis of compound 250

[0524] Compound 2d (38 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 250a (9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine) (30 mg, 0.11 mmol), potassium phosphate (70 mg, 0.33 mmol), and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8 mg, 0.11 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 250 (6.97 mg). MS m / z (ESI): 408.0 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.37 - 7.34 (m, 2H), 7.14 (dd, J = 8.4, 2.0 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 4.50-4.46 (m, 4H), 4.35 (dd, J = 12.0, 5.2 Hz, 1H), 2.83 - 2.75 (m, 1H), 2.67 - 2.52 (m, 1H), 2.38 - 2.32 (m, 1H), 2.10 - 2.02 (m, 1H).

[0525] Example 14 (Compound 286)

[0526] First Step: Synthesis of Compound 286

[0527] Compound 286a (8-bromo-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one) (14.57 mg, 0.06 mmol) was dissolved in 1,4-dioxane (1 mL), and compound 2d (30.0 mg, 0.086 mmol), potassium phosphate (54.77 mg, 0.26 mmol), and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12.59 mg, 0.017 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 3 days. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 286 (2.67 mg). MS m / z (ESI): 384.9 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.38 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.35 - 7.32 (m, 1H), 7.16 - 7.14 (m, 1H), 7.02 (s, 1H), 4.35 - 4.33 (m, 3H), 2.84 - 2.75 (m, 1H), 2.56-2.54 (m, 1H), 2.38 - 2.33 (m, 1H), 2.06 - 1.97 (m, 3H).

[0528] Example 15 (Compound 287)

[0529] First Step: Synthesis of compound 287c

[0530] Compound 287b (1,3-propanediol) (1.38 g, 18.2 mmol) was dissolved in N,N- dimethylformamide (10 mL) under ice-bath nitrogen, sodium hydride (131.04 mg, 5.46 mmol) was added, the reaction mixture was stirred under ice-bath for 0.5 hour, then compound 287a (2-fluoro-4-bromonitrobenzene) (1.0 g, 4.55 mmol) was added, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction liquid was poured into saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain compound 287c (884 mg). MS m / z (ESI): 275.9 [M+1] + .

[0531] Second Step: Synthesis of compound 287d

[0532] Compound 287c (660 mg, 2.39 mmol) was dissolved in acetone (7 mL) under ice-bath, Jones reagent (950 mg, 4.78 mmol) was added, the reaction mixture was stirred under ice-bath for 2 hours. After the reaction was completed, the reaction liquid was poured into water (50 mL), extracted with ethyl acetate (30 ml x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-100%) to obtain compound 287d (572 mg). MS m / z (ESI): 311.8 [M+23] + .

[0533] Third Step: Synthesis of compound 287e

[0534] Compound 287d (470 mg, 1.62 mmol) was dissolved in ethanol and saturated aqueous ammonium chloride (6 mL / 1.5 mL) at room temperature, and iron powder (452.39 mg, 8.10 mmol) was added. The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-100%) to obtain compound 287e (440 mg). MS m / z (ESI): 259.9 [M+1] + .

[0535] Fourth step: synthesis of compound 287f

[0536] Compound 287e (20 mg, 0.069 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature, and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (39.35 mg, 0.10 mmol), N,N-diisopropylethylamine (26.75 mg, 0.21 mmol) were added successively. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 ml x 3). The combined organic phase was washed with saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 70-100%) to obtain compound 287f (21 mg). MS m / z (ESI): 241.9 [M+1] + .

[0537] Fifth step: synthesis of compound 287

[0538] Compound 2d (30 mg, 0.086 mmol) was dissolved in 1,4-dioxane (1 mL), and compound 287f (21 mg, 0.065 mmol), potassium phosphate (54.77 mg, 0.26 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12.59 mg, 0.017 mmol) were added successively. The reaction mixture was heated to 90 °C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-5%) to obtain a crude product, which was further purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 10 / 1) to obtain compound 287 (3.43 mg). MS m / z (ESI): 385.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.87 (s, 1H), 7.43 - 7.37 (m, 1H), 7.36 - 7.34 (m, 1H), 7.33 - 7.29 (m, 1H), 7.16 - 7.08 (m, 1H), 7.05 (dd, J = 8.2, 2.0 Hz, 1H), 7.01 (d, J = 1.9 Hz, 1H), 4.42 - 4.36 (m, 2H), 4.33 (dd, J = 12.1, 5.0 Hz, 1H), 2.79 - 2.75 (m, 2H), 2.55 (d, J = 5.9 Hz, 1H), 2.35 - 2.28 (m, 1H), 2.08 - 1.97 (m, 2H).

[0539] Example 16 (Compound 288)

[0540] First Step: Synthesis of Compound 288

[0541] Compound 288a (7-bromo-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one) (16.42 mg, 0.068 mmol) was dissolved in 1,4-dioxane (1 mL), and compound 2d (20.0 mg, 0.057 mmol), potassium phosphate (36.30 mg, 0.17 mmol), and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8.34 mg, 0.011 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 288 (5.23 mg). MS m / z (ESI): 383.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.62 (s, 1H), 7.40 - 7.35 (m, 2H), 7.33 - 7.26 (m, 3H), 7.04 (d, J = 8.0 Hz, 1H), 4.34 (dd, J = 12.0, 4.0 Hz, 1H), 2.83 - 2.72 (m, 3H), 2.56-2.54 (m, 1H), 2.38 - 2.28 (m, 1H), 2.21 - 2.19 (m, 2H), 2.16 - 2.11 (m, 2H), 2.06 - 2.02 (m, 1H).

[0542] Example 17 (Compound 294)

[0543] First Step: Synthesis of Compound 294b

[0544] Phosphorous tribromide (1.75 g, 6.69 mmol) was added to a solution of compound 294a ((1-methyl-1H-pyrazol-3-yl)methanol) (500.0 mg, 4.46 mmol) in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at 25 °C for 16 h. After the reaction was completed, the reaction solution was quenched with water solution (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 5 / 1) to give compound 294b (400.0 mg). MS m / z (ESI): 175.1 [M+1] + .

[0545] Second Step: Synthesis of compound 294c

[0546] Sodium hydride (18.0 mg, 0.75 mmol) was added to a solution of compound 286a (121.0 mg, 0.50 mmol) in tetrahydrofuran (2 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then compound 294b (88.0 mg, 0.50 mmol) was added and the reaction mixture was stirred at 60 °C for 16 h. After the reaction was completed, the reaction solution was quenched with water solution (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 5 / 1) to give compound 294c (60.0 mg). MS m / z (ESI): 335.9 [M+1] + .

[0547] Third Step: Synthesis of compound 294

[0548] Compound 2d (62.9 mg, 0.18 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12.2 mg, 0.015 mmol), potassium phosphate (95.5 mg, 0.45 mmol) were added into a solution of compound 294c (50.0 mg, 0.15 mmol) in dioxane (3 mL) under nitrogen at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 10 / 1) to give compound 294 (12.3 mg). MS m / z (ESI): 479.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.34 (dd, J = 6.8, 2.5 Hz, 1H), 7.20 (dd, J = 8.1, 1.7 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.17 (d, J = 2.2 Hz, 1H), 4.70 (s, 2H), 4.39 - 4.24 (m, 3H), 3.81 (s, 3H), 3.58 (t, J = 4.9 Hz, 2H), 2.88-2.75 (m, 1H), 2.57-2.55 (m, 1H), 2.35-2.30 (m, 1H), 2.07-2.01 (m, 1H).

[0549] Example 18 (Compound 312)

[0550] First Step: Synthesis of compound 312b

[0551] Phosphorus oxychloride (7.5 g, 48.91 mmol) was dissolved in N,N-dimethylformamide (30 mL) under ice-bath, stirred for 15 min under ice-bath, and stirred for 15 min at room temperature. Compound 312a (3.0 g, 30.57 mmol) was added under ice-bath, and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / dichloromethane = 0-2%) to give compound 312b (2.8 g).

[0552] Step 2: Synthesis of compound 312c

[0553] Compound 312b (300 mg, 2.07 mmol) was dissolved in N,N-dimethylformamide (5 mL) at room temperature, compound 146c (210 mg, 2.07 mmol), N-methylmorpholine (630 mg, 6.21 mmol) were added successively, and the reaction mixture was stirred at 115 °C for 1 day. After the reaction was completed, the reaction liquid was poured into water (50 mL) and extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-40%) to obtain compound 312c (175 mg). MS m / z (ESI): 191.1 [M+1] +

[0554] Step 3: Synthesis of compound 312d

[0555] Compound 312c (75 mg, 0.39 mmol) was dissolved in dimethyl sulfoxide (2 mL) under nitrogen at room temperature, compound 146e (170 mg, 0.58 mmol), cuprous iodide (14.86 mg, 0.08 mmol), potassium carbonate (160 mg, 1.17 mmol) were added successively, and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction liquid was poured into water (50 mL) and extracted with ethyl acetate (30 ml x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain compound 312d (100 mg). MS m / z (ESI): 344.9 [M+1] +

[0556] Step 4: Synthesis of compound 312

[0557] Compound 2d (38.85 mg, 0.10 mmol) was dissolved in 1,4-dioxane (1 mL), and compound 312d (30 mg, 0.09 mmol), potassium phosphate (55.40 mg, 0.26 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (12.73 mg, 0.02 mmol) were added successively. The reaction mixture was heated to 90 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0-3%) to obtain compound 312 (1.35 mg). MS m / z (ESI): 487.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.47-7.33 (m, 7H), 6.55 (s, 1H), 4.36 (dd, J = 12.0, 8.0 Hz, 1H), 4.11 (s, 4H), 2.85-2.77 (m, 1H), 2.76-2.72 (m, 2H), 2.57-2.56 (m, 1H), 2.39-2.30 (m, 1H), 2.07-2.04 (m, 2H), 1.79-1.77 (m, 2H), 1.70-1.68 (m, 2H).

[0558] Example 19 (Compound 94)

[0559] First Step: Synthesis of compound 94c

[0560] Sodium hydride (60%, 0.48 g, 11.4 mmol) was added to compound 94a (5-bromo-2,3- dihydroisoindol-l-one) (1.2 g, 5.7 mmol) in N,N-dimethylformamide (15 mL) under ice bath, after stirring for 15 minutes, compound 94b (2-(2-bromoethyl)-l,3-dioxolane) (1.24 g, 6.84 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed, water (30 mL) was added for quenching, and the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-4%) to obtain compound 94c (1.6 g). MS m / z (ESI): 312.0 [M+1] + .

[0561] Second Step: Synthesis of compound 94d

[0562] Compound 94c (1.6 g, 5.1 mmol) was dissolved in tetrahydrofuran (10 mL), then 2N hydrochloric acid solution (10 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction liquid was extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 94d (710 mg). MS m / z (ESI): 268.0 [M+1] + .

[0563] Step 3: Synthesis of compound 94e

[0564] Compound 94d (600 mg, 2.23 mmol) was dissolved in methanol (10 mL), then p-toluenesulfonyl hydrazide (384 mg, 2.23 mmol) was added, and the reaction mixture was stirred at 55°C for 16 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-4%) to obtain compound 94e (620 mg). MS m / z (ESI): 436.0 [M+1] + .

[0565] Step 4: Synthesis of compound 94f

[0566] Compound 94e (580 mg, 1.326 mmol) was dissolved in ethylene glycol dimethyl ether (10 mL), and meso-tetraphenylporphyrin cobalt (44 mg, 0.0663 mmol) and cesium carbonate (648 mg, 1.989 mmol) were sequentially added, and the reaction mixture was stirred at 60°C for 16 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-35%) and thin layer chromatography (ethyl acetate / petroleum ether = 2:1) to obtain compound 94f (60 mg). MS m / z (ESI): 252.0 [M+1] + .

[0567] Step 5: Synthesis of compound 94

[0568] Compound 94f (40 mg, 0.158 mmol) was dissolved in 1,4-dioxane (5 mL) and one drop of water, followed by the addition of compound 2d (55 mg, 0.158 mmol), potassium phosphate (67 mg, 0.317 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11 mg, 0.0158 mmol). The reaction mixture was heated to 80 °C under nitrogen protection for 5 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-5%) to give a crude product (150 mg), which was further purified by high performance liquid chromatography (preparative column: Gemini-C18 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile: water (0.1% formic acid); gradient: 40-60%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to give compound 94 (1 mg). MS m / z (ESI): 395.0 [M+1] + .

[0569] Example 20 (Compound 107)

[0570] First Step: Synthesis of compound 107c

[0571] Compound 107a (4-chloro-3-nitropyridine) (2 g, 12.62 mmol) was dissolved in ethanol (20 mL) at room temperature, followed by the addition of compound 107b (tetrahydropyrrole) (2.69 g, 37.86 mmol), and then the reaction mixture was heated to 70 °C for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to give compound 107c (2.43 g). MS m / z (ESI): 194.1 [M+1] +

[0572] Second Step: Synthesis of compound 107d

[0573] Compound 107c (2.43 g, 12.58 mmol) was dissolved in triethyl phosphite (20 mL) at room temperature, and then the reaction mixture was heated to 110 °C for 12 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-10 / 1) to give compound 107d (213 mg). MS m / z (ESI): 160.2 [M+1] +

[0574] Third Step: Synthesis of compound 107e

[0575] Compound 107d (213 mg, 1.34 mmol) was dissolved in dichloromethane (5 mL) under ice-bath condition, then m-chloroperoxybenzoic acid (462 mg, 2.68 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10 / 1) to obtain compound 107e (160 mg). MS m / z (ESI): 176.1 [M+1] +

[0576] Fourth step: synthesis of compound 107f

[0577] Compound 107e (160 mg, 0.91 mmol) was dissolved in acetic anhydride (2 mL) at room temperature, and the reaction mixture was warmed to 140°C and stirred for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10 / 1) to obtain compound 107f (90 mg). MS m / z (ESI): 176.1 [M+1] +

[0578] Fifth step: synthesis of compound 107g

[0579] Compound 107f (90 mg, 0.51 mmol) was dissolved in dimethyl sulfoxide (2 mL) under nitrogen atmosphere, and compound 146e (144 mg, 0.51 mmol), cuprous iodide (29 mg, 0.15 mmol), and potassium carbonate (211 mg, 1.53 mmol) were added, and the reaction mixture was warmed to 120°C and stirred for 12 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10 / 1) to obtain compound 107g (140 mg). MS m / z (ESI): 330.0 [M+1] +

[0580] Sixth step: synthesis of compound 107

[0581] Compound 107g (70 mg, 0.21 mmol) was dissolved in 1,4-dioxane (4 mL), and compound 2d (73 mg, 0.21 mmol), potassium phosphate (134 mg, 0.63 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (15 mg, 0.021 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 107 (33.58 mg). MS m / z (ESI): 473.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.53 - 7.46 (m, 3H), 7.46 - 7.34 (m, 3H), 6.69 (d, J = 7.2 Hz, 1H), 4.38 (dd, J = 12.2, 4.9 Hz, 1H), 4.11 (t, J = 7.0 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.86 - 2.76 (m, 1H), 2.67-2.61 (m, 2H), 2.59-2.54 (m, 1H), 2.41-2.32 (m, 1H), 2.09-2.05 (m, 1H).

[0582] Example 21 (Compound 192)

[0583] First Step: Synthesis of Compound 192b

[0584] Compound 192a (1,4,5,6-tetrahydro-3-cyclopentenopyrazole carboxylic acid ethyl ester) (1.0 g, 5.55 mmol) was dissolved in a mixed solution of tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL), and sodium hydroxide (1.10 g, 27.50 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to 6 with 1N hydrochloric acid. The filter cake was collected by filtration to obtain compound 192b (0.80 g). MS m / z (ESI): 153.1 [M+1] + .

[0585] Second Step: Synthesis of Compound 192c

[0586] Compound 192b (700 mg, 4.60 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.49 g, 9.20 mmol), N,N-diisopropylethylamine (1.18 g, 9.20 mmol) and 84d (0.48 g, 4.60 mmol) were added successively. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water (100 mL) was added, and the combined organic phase was extracted with ethyl acetate (90 mL x 2), washed with saturated brine (90 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-3%) to obtain compound 192c (0.50 g). MS m / z (ESI): 240.1 [M+1] + .

[0587] Third step: synthesis of compound 192d

[0588] Compound 192c (500 mg, 2.08 mmol) was dissolved in a mixed solution of trifluoroacetic acid (2.5 mL) and dichloromethane (2.5 mL). The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-30%) to obtain compound 192d (300 mg). MS m / z (ESI): 176.1 [M+1] + .

[0589] Fourth step: synthesis of compound 192e

[0590] Compound 192d (300 mg, 1.71 mmol) was dissolved in 1,4-dioxane solution (3 mL), and compound 146e (484 mg, 1.71 mmol), potassium phosphate (727 mg, 3.42 mmol), N,N'-dimethylethylenediamine (30 mg, 0.34 mmol) and cuprous iodide (32 mg, 0.17 mmol) were added successively. The reaction mixture was heated to 100°C and stirred for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-30%) to obtain compound 192e (150 mg). MS m / z (ESI): 330.0 [M+1] + .

[0591] Fifth step: synthesis of compound 192

[0592] Compound 192e (70 mg, 0.21 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (10 / 1, 3 mL), compound 2d (74.1 mg, 0.21 mmol), potassium phosphate (90 mg, 0.42 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (15.5 mg, 0.02 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel preparative plate (ethyl acetate / dichloromethane = 2:1) to obtain compound 192 (7.1 mg). MS m / z (ESI): 473.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.72 (d, J = 6.1 Hz, 1H), 7.57 (s, 4H), 7.46 - 7.36 (m, 3H), 7.07 (d, J = 6.1 Hz, 1H), 4.38 (dd, J = 12.2, 5.0 Hz, 1H), 2.89 - 2.85 (m, 2H), 2.84 - 2.74 (m, 3H), 2.59 - 2.52 (m, 1H), 2.48 - 2.39 (m, 2H), 2.38 - 2.30 (m, 1H), 2.10 - 2.02 (m, 1H).

[0593] Example 22 (Compound 201)

[0594] First Step: Synthesis of compound 201c

[0595] Sodium cyanide (60%, 167.4 mg, 4.19 mmol) was added to N,N- dimethylformamide (3 mL) at 0 °C under nitrogen protection, a solution of compound 201a (2,4,5,6-tetrahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester) (500 mg, 2.79 mmol) in N,N-dimethylformamide (2 mL) was added dropwise, and the reaction was allowed to react at room temperature for 15 minutes. Compound 201b (tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide) (934.3 mg, 4.19 mmol) was added under ice-bath conditions, and the reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain compound 201c (730 mg). MS m / z (ESI): 267.0 [M+1-56] +

[0596] Second step: synthesis of compound 201d

[0597] Compound 201c (100 mg, 0.31 mmol) was dissolved in dichloromethane (1 mL) at room temperature, and trifluoroacetic acid (0.3 mL) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was added to methanol (1 mL). Potassium carbonate (128.5 mg, 0.93 mmol) was added, and the reaction mixture was heated to 60 °C and reacted for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain compound 201d (32 mg). MS m / z (ESI): 177.0 [M+1] +

[0598] Third step: synthesis of compound 201f

[0599] Compound 201d (32 mg, 0.18 mmol) was dissolved in dimethyl sulfoxide (1 mL). Compound 201e (1,4-diiodobenzene) (59 mg, 0.18 mmol), cuprous iodide (7 mg, 0.036 mmol), potassium carbonate (75 mg, 0.54 mmol) were added. The reaction mixture was heated to 120 °C under nitrogen protection for 16 h. After the reaction was completed, ethyl acetate (20 mL) was added for dilution, washed with water (10 mL x 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain compound 201f (37 mg). MS m / z (ESI): 379.0 [M+1] +

[0600] Fourth step: synthesis of compound 201

[0601] Compound 2d (35 mg, 0.10 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 201f (30 mg, 0.10 mmol), potassium phosphate (64 mg, 0.30 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (7 mg, 0.010 mmol) were added in turn. The reaction mixture was heated to 100 °C under nitrogen protection for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 70%-100%) to obtain compound 201 (1.92 mg). MS m / z (ESI): 474.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.47-7.41 (m, 4H), 7.39 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 4.36 (dd, J = 7.2, 12.0 Hz, 1H), 4.25-4.22 (m, 2H), 4.12-4.09 (m, 2H), 2.73-2.67 (m, 2H), 2.59-2.54 (m, 2H), 2.47-2.33 (m, 2H), 2.30-2.28 (m, 2H), 2.12-2.08 (m, 2H).

[0602] Example 23 (compound 202)

[0603] First step: synthesis of compound 202c

[0604] Compound 202a (7-nitroindole) (500 mg, 3.08 mmol) was dissolved in acetonitrile (10 mL) at room temperature, and compound 202b (bromoethyl acetate) (510 mg, 3.08 mmol), potassium carbonate (1.3 g, 9.24 mmol) were added successively. The reaction mixture was stirred at 60 °C for 16 h. After the reaction was completed, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 ml x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to obtain compound 202c (439 mg). MS m / z (ESI): 249.0 [M+1] +

[0605] Second step: synthesis of compound 202d

[0606] Compound 202c (335 mg, 1.35 mmol) was dissolved in a mixed solution of dichloromethane and methanol (3 mL / 1.5 mL) under hydrogen at room temperature, and Pd / C (74.71 mg) was added. The reaction mixture was stirred at room temperature for 2 days. After the reaction was completed, the reaction solution was filtered with diatomite, and the filter cake was rinsed with methanol (10 ml x 3) and dichloromethane (10 ml x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 202d (239 mg). MS m / z (ESI): 173.1 [M+1] +

[0607] Third step: synthesis of compound 202f

[0608] Compound 202d (100 mg, 0.52 mmol) was dissolved in dichloromethane (5 mL) under oxygen at room temperature, and compound 202e (4-iodobenzenboronic acid) (154.65 mg, 0.62 mmol), triethylamine (105.24 mg, 1.04 mmol), pyridine (82.26 mg, 1.04 mmol), copper acetate (141.67 mg, 0.78 mmol) were added successively. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain compound 202f (49 mg). MS m / z (ESI): 374.9 [M+1] +

[0609] Fourth step: synthesis of compound 202

[0610] Compound 2d (29.93 mg, 0.08 mmol) was dissolved in 1,4-dioxane (1 mL), and compound 202f (25 mg, 0.07 mmol), potassium phosphate (42.67 mg, 0.20 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (9.80 mg, 0.01 mmol) were added successively. The reaction mixture was heated to 90 °C under nitrogen protection and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0-1%) to obtain compound 202 (4.79 mg). MS m / z (ESI): 470.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.65-7.63 (m, 2H), 7.51-7.49 (m, 2H), 7.47-7.40 (m, 4H), 7.22 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 6.57 (d, J = 4.0 Hz, 1H), 5.94 (d, J = 8.0 Hz, 1H), 5.33-5.27 (m, 2H), 4.39 (dd, J = 12.0, 8.0 Hz, 1H), 2.83-2.79 (m, 1H), 2.59-2.58 (m, 1H), 2.39-2.33 (m, 1H), 2.13-2.05 (m, 1H).

[0611] Example 24 (Compound 289)

[0612] First Step: Synthesis of compound 289c

[0613] Compound 289a (4-bromo-2-hydroxybenzaldehyde) (2 g, 9.95 mmol) was dissolved in methanol (30 mL) at room temperature, and compound 289b (4-methoxybenzylamine) (1.36 g, 9.95 mmol), acetic acid (59.75 mg, 0.99 mmol), and sodium cyanoborohydride (2.5 g, 39.8 mmol) were added successively. The reaction mixture was stirred at 50 °C for 16 h. After the reaction was completed, ice water (200 mL) was added to quench the reaction, and dichloromethane (200 mL x 3) was used to extract the product. The organic phase was combined and dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-15%) to obtain compound 289c (3.5 g). MS m / z (ESI): 322.0 [M+1] + .

[0614] Step 2: Synthesis of compound 289e

[0615] Compound 289c (2 g, 9.95 mmol) was dissolved in toluene (30 mL) and compound 289d (chloroacetyl chloride) (1.1 g, 9.78 mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution containing compound 289e was obtained without treatment for the next step.

[0616] Step 3: Synthesis of compound 289f

[0617] The reaction solution of compound 289e was added to N,N-dimethylformamide (25 mL) and sodium hydride (1.12 g, 27.93 mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, ice water (200 mL) was added to quench the reaction and extracted with ethyl acetate (200 mL x 3). The organic phase was combined and dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 289f (1.6 g). MS m / z (ESI): 361.9 [M+1] + .

[0618] Step 4: Synthesis of compound 289g

[0619] Compound 289f (200 mg, 0.55 mmol) was added to trifluoroacetic acid (5 mL) and the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was added to dichloromethane (200 mL) and concentrated under reduced pressure and dried to obtain compound 289g (220 mg).

[0620] Step 5: Synthesis of compound 289

[0621] Compound 289g (160 mg, 0.66 mmol) was dissolved in 1,4-dioxane (10 mL) and compound 2d (230.75 mg, 0.66 mmol), potassium phosphate (420.29 mg, 1.89 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (48.29 mg, 0.066 mmol) were sequentially added. The reaction mixture was heated to 90°C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) and the obtained crude product was slurried with dichloromethane to obtain compound 289 (43.7 mg). MS m / z (ESI): 385.1 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.41 (t, J = 4.6 Hz, 1H), 7.46 - 7.25 (m, 4H), 7.15 - 6.91 (m, 2H), 4.63 (s, 2H), 4.44 - 4.26 (m, 3H), 2.85 - 2.74 (m, 1H), 2.56 - 2.54 (m, 1H), 2.37 - 2.29 (m, 1H), 2.06 - 2.03 (m, 1H).

[0622] Example 25 (Compound 303)

[0623] First Step: Synthesis of compound 303c

[0624] Sodium hydride (1.48 g, 36.95 mmol) was added to compound 303b (2-pyrrolidone) (2.52 g, 29.56 mmol) in N,N-dimethylformamide (50 mL) in batches under ice bath, stirred at room temperature for 30 minutes. Then the reaction was cooled to 0 °C, and compound 303a (3-fluoro-2-nitropyridine) (3.5 g, 24.63 mmol) in N,N-dimethylformamide (5 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction was quenched with water (20 mL), extracted with ethyl acetate (40 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%-100%) to give compound 303c (1.4 g). MS m / z (ESI): 208.0 [M+1] + .

[0625] Second Step: Synthesis of compound 303d

[0626] Compound 303c (1.4 g, 6.76 mmol) was dissolved in anhydrous methanol (30 mL), and palladium on carbon (600 mg) was added, and the reaction mixture was stirred at room temperature for 16 hours under hydrogen atmosphere. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated to give compound 303d (1.19 g). MS m / z (ESI): 178.0 [M+1] + .

[0627] Third Step: Synthesis of compound 303e

[0628] Compound 303d (1.19 g, 6.72 mmol) was dissolved in acetic acid (15 mL) at room temperature, and the reaction mixture was heated to 110 °C and stirred for 48 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0% to 10%) to give compound 303e (970 mg). MS m / z (ESI): 160.1 [M+1] + .

[0629] Fourth Step: Synthesis of compound 303f

[0630] M-chloroperbenzoic acid (2.8 g, 12.18 mmol) was added to compound 303e (970 mg, 6.09 mmol) in dichloromethane (20 mL) under ice bath, and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0% to 10%) to give compound 303f (640 mg). MS m / z (ESI): 176.1 [M+1] + .

[0631] Fifth Step: Synthesis of compound 303g

[0632] Compound 303f (640 mg, 3.65 mmol) was dissolved in acetic anhydride (15 mL) at room temperature, and the reaction mixture was heated to 140 °C and stirred for 3 h. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0% to 10%) to give compound 303g (430 mg). MS m / z (ESI): 218.1 [M+1] + .

[0633] Sixth Step: Synthesis of compound 303h

[0634] Compound 303g (430 mg, 1.98 mmol) was dissolved in methanol (15 mL) at room temperature, and potassium carbonate (547.3 mg, 3.96 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0% to 10%) to give compound 303h (243 mg). MS m / z (ESI): 176.1 [M+1] + .

[0635] Seventh Step: Synthesis of compound 303i

[0636] Compound 303h (50 mg, 0.29 mmol) was dissolved in dimethyl sulfoxide (2 mL), compound 146e (98.5 mg, 0.35 mmol), cuprous iodide (16.6 mg, 0.087 mmol) and potassium carbonate (120.2 mg, 0.87 mmol) were added, and the reaction mixture was heated to 120 °C under nitrogen protection for 10 hours. After the reaction was completed, the reaction was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain compound 303i (10 mg). MS m / z (ESI): 330.1, 331.9 [M+1, M+3] + .

[0637] Eighth step: synthesis of compound 303

[0638] Compound 303i (10 mg, 0.03 mmol) was dissolved in 1,4-dioxane (1 mL), compound 2d (13 mg, 0.036 mmol), potassium phosphate (19 mg, 0.09 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (2.2 mg, 0.003 mmol) were added in turn. The reaction mixture was heated to 100 °C under nitrogen protection for 16 hours. After the reaction was completed, the reaction was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%-5%) to obtain a crude product (12 mg). The crude product was further purified by preparative thin layer chromatography (dichloromethane / methanol = 15 / 1) to obtain compound 303 (0.51 mg). MS m / z (ESI): 473.1 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.84 (d, J = 9.4 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.48 - 7.35 (m, 5H), 6.24 (d, J = 9.4 Hz, 1H), 4.39 (dd, J = 11.7, 4.5 Hz, 1H), 4.14 (t, J = 6.9 Hz, 2H), 2.93 - 2.77 (m, 3H), 2.57 - 2.55 (m, 3H), 2.41 - 2.33 (m, 1H), 2.13 - 2.05 (m, 1H).

[0639] Example 26 (compound 406)

[0640] First step: synthesis of compound 406a

[0641] Compound 201a was dissolved in a mixture solution of tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), and sodium hydroxide (557.94 g, 13.94 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to 6 with 1 N hydrochloric acid. The filtrate was collected by filtration to obtain compound 406a (370 mg). MS (ES, m / z): 152.2 [M+1] + .

[0642] Second Step: Synthesis of compound 406b

[0643] Compound 406a (370 mg, 2.44 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.86 g, 4.89 mmol), N,N-diisopropylethylamine (632 mg, 4.89 mmol), and 84d (257 mg, 2.44 mmol) were sequentially added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, water (100 mL) was added, and the combined organic phase was extracted with ethyl acetate (90 mL x 2), washed with saturated brine (90 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-3%) to obtain compound 406b (200 mg). MS (ES, m / z): 239.1 [M+1] + .

[0644] Third Step: Synthesis of compound 406c

[0645] Compound 406b (150 mg, 0.62 mmol) was dissolved in a mixture solution of trifluoroacetic acid (1 mL) and dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-30%) to obtain compound 406c (100 mg). MS (ES, m / z): 175.1 [M+1] + .

[0646] Fourth Step: Synthesis of compound 406d

[0647] Compound 406c (100 mg, 0.57 mmol) was dissolved in 1,4-dioxane solution (2 mL), and compound 146e (162 mg, 0.57 mmol), potassium phosphate (243 mg, 1.14 mmol), N,N'-dimethylethylenediamine (10 mg, 0.11 mmol) and cuprous iodide (10 mg, 0.057 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-30%) to obtain compound 406d (100 mg). MS (ES, m / z): 329.0 [M+1] + .

[0648] Fifth step: synthesis of compound 406

[0649] To a mixture solution of compound 406d (50.0 mg, 0.15 mmol), compound 2d (53.1 mg, 0.15 mmol) and potassium phosphate (64.5 mg, 0.30 mmol) in 1,4-dioxane and water (50 / 1, 2.55 mL) was added 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11.1 mg, 0.02 mmol) at room temperature. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and concentrated under reduced pressure to obtain a crude product (50 mg), which was purified by high performance liquid chromatography (preparative column: Gemini-C18; 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-70%; column temperature: 25 °C; flow rate: 25 mL / min; wavelength: 214 nm / 254 nm) to obtain compound 406 (5.6 mg). MS m / z (ES): 472.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.52 (s, 4H), 7.46 - 7.35 (m, 4H), 7.18 (s, 1H), 6.81 (d, J = 5.8 Hz, 1H), 4.37 (dd, J = 11.9, 4.6 Hz, 1H), 2.87 (d, J = 7.1 Hz, 2H), 2.79 (dd, J = 21.3, 9.0 Hz, 1H), 2.69 (d, J = 7.0 Hz, 2H), 2.57 - 2.53 (m, 1H), 2.40 - 2.30 (m, 3H), 2.07 - 1.98 (m, 1H).

[0650] Example 27 (compound 86)

[0651] First Step: Synthesis of compound 86b

[0652] Compound 86a (7-bromo-2H-l,4-benzoxazin-3(4H)-one) (1.0 g, 4.40 mmol) was dissolved in xylene (10 mL), compound 84d (0.93 g, 8.80 mmol) and titanium tetrachloride (0.33 g, 1.76 mmol) were added successively. The reaction mixture was stirred at 140 °C for 24 h. After the reaction was completed, water (100 mL) was added, and the combined organic phase was extracted with ethyl acetate (90 mL x 2), washed with saturated brine (90 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-50%) to give compound 86b (90 mg). MS m / z (ESI): 251.1 [M+1] + .

[0653] Second Step: Synthesis of compound 86

[0654] Compound 86b (80 mg, 0.31 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (10 / 1, 2 mL), compound 2d (110 mg, 0.31 mmol), potassium phosphate (135 mg, 0.63 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (23 mg, 0.031 mmol) were added successively. The reaction mixture was heated to 100 °C and stirred for 1 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-3%) to give the crude product (50 mg), which was further purified by high performance liquid chromatography (preparative column: Gemini-C18; 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 20-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to give compound 86 (15.0 mg). MS m / z (ESI): 394.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.10 (d, J = 25.5 Hz, 1H), 7.90 - 7.79 (m, 1H), 7.46 - 7.33 (m, 4H), 7.25 - 7.17 (m, 2H), 5.43 (d, J = 15.5 Hz, 2H), 4.35 (dd, J = 12.1, 5.0 Hz, 1H), 2.89 - 2.73 (m, 1H), 2.45 - 2.21 (m, 2H), 2.12 - 1.99 (m, 1H).

[0655] Example 28 (Compound 186)

[0656] First Step: Synthesis of compound 186b

[0657] Sodium hydride (223.68 mg, 9.32 mmol) was slowly added to a solution of compound 186a (4,5,6,7-tetrahydro-lH-indole-2-carboxylic acid ethyl ester) (900 mg, 4.66 mmol) in N,N-dimethylformamide (10 mL) under ice-bath, stirred at room temperature for half an hour, then 183e (1575.27 mg, 9.32 mmol) was added to the reaction solution, the reaction was warmed to 80 °C and stirred for 30 hours. After the reaction was completed, water (2 mL) was added to quench, the reaction solution was rotary evaporated, and then purified directly by reverse column (methanol / water = 0-100%) to give compound 186b (400 mg). MS m / z (ESI): 282.0 [M+1] + .

[0658] Second Step: Synthesis of compound 186c

[0659] Sodium hydroxide (568 mg, 14.2 mmol) in water (2 mL) was added to a solution of compound 186b (400 mg, 1.42 mmol) in methanol (5 mL) at room temperature, and the reaction mixture was stirred at 50 °C for 16 hours. After the reaction was completed, the organic solvent in the reaction solution was rotary evaporated under reduced pressure, then the pH of the reaction solution was adjusted to 7-8 with hydrochloric acid, and a solid was precipitated. After filtration, rotary evaporation was performed to give compound 186c (360 mg). MS m / z (ESI): 254.0 [M+1] + .

[0660] Third Step: Synthesis of compound 186d

[0661] (7-Azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (673.01 mg, 1.77 mmol) was added to a solution of compound 186c (300 mg, 1.18 mmol), ammonium chloride (315.59 mg, 5.90 mmol), N,N-diisopropylethylamine (915.02 mg, 7.08 mmol) in N,N-dimethylformamide (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, rotary evaporated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-70%) to give compound 186d (200 mg). MS m / z (ESI): 253.0 [M+1] + .

[0662] Fourth Step: Synthesis of compound 186e

[0663] Compound 186d (370 mg, 1.47 mmol) was added to acetic acid (20 mL) at room temperature, and the reaction mixture was stirred at 110 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into saturated sodium carbonate solution (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to give compound 186e (330 mg). MS m / z (ESI): 189.1 [M+1] + .

[0664] Fifth Step: Synthesis of compound 186f

[0665] Compound 186e (200 mg, 1.06 mmol) was added to 201e (349.69 mg, 1.06 mmol), cuprous iodide (40.38 mg, 0.21 mmol) and potassium carbonate (439.51 mg, 3.18 mmol) in dimethyl sulfoxide (10 mL) at room temperature, and the reaction mixture was stirred at 120 °C for 1 hour. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), concentrated under reduced pressure, and purified by silica gel column separation (ethyl acetate / petroleum ether = 0-100%) to give compound 186f (100 mg). MS m / z (ESI): 390.9 [M+1] + .

[0666] Sixth Step: Synthesis of compound 186

[0667] Compound 186f (40 mg, 0.10 mmol), compound 2d (34.96 mg, 0.10 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (14.63 mg, 0.020 mmol) were sequentially added to potassium carbonate (41.46 mg, 0.30 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) at room temperature, and the reaction mixture was stirred at 80 °C under nitrogen protection in a sealed tube for 2 hours. After the reaction was completed, the reaction solution was filtered and directly purified by reverse column (methanol / water = 0-100%) to give compound 186 (6 mg). MS m / z (ESI): 486.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.54 (s, 4H), 7.46 - 7.36 (m, 3H), 7.25 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 6.0 Hz, 1H), 6.79 (s, 1H), 4.38 (dd, J = 12.3, 5.0 Hz, 1H), 2.73 (t, J = 6.3 Hz, 2H), 2.62 - 2.57 (m, 2H), 2.41 - 2.32 (m, 2H), 2.11 - 1.96 (m, 2H), 1.88 - 1.83 (m, 2H), 1.78 - 1.72 (m, 2H).

[0668] Example 29 (Compound 206)

[0669] First Step: Synthesis of compound 206b

[0670] To a solution of compound 206a (4-nitroaniline) (1.5 g, 10.86 mmol) in 1,2-dichloroethane (30 mL) was added slowly with triphosgene (1.61 g, 5.43 mmol) under ice-bath. The reaction mixture was heated to 80 °C and stirred for 30 min. After the reaction was completed, the reaction solution was concentrated to remove the solvent to give compound 206b (1.7 g) as a crude product, which was used directly in the next step. MS m / z (ESI): 197.1 [M+32] +

[0671] Second Step: Synthesis of compound 206d

[0672] To a solution of compound 206c (indan-5-carbaldehyde) (4.5 g, 30.78 mmol) in anhydrous methanol (50 mL) was added sodium borohydride (1.75 g, 46.17 mmol) under ice-bath. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated. The residue was added water (40 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 206d (4.5 g) as a crude product, which was used directly in the next step. MS m / z (ESI): 149.0 [M+1] +

[0673] Third Step: Synthesis of compound 206e

[0674] Compound 206d (4.8 g, 32.39 mmol) was dissolved in dichloromethane (50 mL), and carbon tetrabromide (16.11 g, 48.59 mmol) and triphenylphosphine (12.74 g, 48.59 mmol) were added successively under ice-bath. The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% ~ 5%) to obtain compound 206e (6.5 g). MS m / z (ESI): 211.0, 213.0 [M+1, M+3] +

[0675] Fourth step: synthesis of compound 206f

[0676] Tetrabutylammonium fluoride (46.19 mL, 1M in tetrahydrofuran solution) was slowly added to a solution of compound 206e (6.5 g, 30.79 mmol) and trimethylsilyl cyanide (4.58 g, 46.19 mmol) in dichloromethane (100 mL) under ice-bath. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with water (40 mL), extracted with dichloromethane (100 mL x 2), combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% ~ 15%) to obtain compound 206f (2.28 g). MS m / z (ESI): 158.0 [M+1] + .

[0677] Fifth step: synthesis of compound 206g

[0678] Compound 206f (2.0 g, 12.72 mmol) was dissolved in anhydrous methanol (40 mL), and di-tert-butyl dicarbonate (2.78 g, 12.72 mmol) and Raney nickel (2.0 g) were added successively. The reaction mixture was continuously stirred under hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% ~ 15%) to obtain compound 206g (1.63 g). MS m / z (ESI): 262.1 [M+1] + .

[0679] Sixth step: synthesis of compound 206h

[0680] Hydrochloric acid-dioxane (8 mL) was added to compound 206g (1.63 g, 6.24 mmol) in dichloromethane (32 mL) under ice-bath, and the reaction mixture was continuously stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound 206h (1.0 g). MS m / z (ESI): 162.2 [M+1] + .

[0681] Step 7: Synthesis of compound 206i

[0682] Compound 206h (1.0 g, 6.2 mmol) was dissolved in dichloromethane (40 mL), compound 206b (1.53 g, 9.3 mmol) and triethylamine (3.14 g, 31 mmol) were added, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with dichloromethane (25 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 206i (1.8 g). MS m / z (ESI): 326.0 [M+1] + .

[0683] Step 8: Synthesis of compound 206j and compound 206k

[0684] Trifluoromethanesulfonic acid (5.91 g, 39.36 mmol) was added to compound 206i (800 mg, 2.46 mmol) in dichloromethane (20 mL) under ice bath, the reaction mixture was heated to 60 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated, the residue was diluted with water (20 mL), extracted with dichloromethane (40 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0% - 5%) to give a mixture of compound 206j and compound 206k (90 mg) (used for the next step after synthesis in multiple batches according to this synthesis method). MS m / z (ESI): 188.1 [M+1] + .

[0685] Step 9: Synthesis of compound 206l and compound 206m

[0686] The mixture of compound 206j and compound 206k (135 mg, 0.72 mmol) was dissolved in dimethyl sulfoxide (5 mL) at room temperature, compound 146e (305.5 mg, 1.08 mmol), cuprous iodide (41.1 mg, 0.22 mmol) and potassium carbonate (298.5 mg, 2.16 mmol) were added, the reaction mixture was heated to 120 °C under nitrogen protection and stirred for 10 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% ~ 25%) to give compound 206l (135 mg) and compound 206m (10 mg). Compound 206l: MS m / z (ESI): 342.0, 344.0 [M+1, M+3] + . 1H NMR (400 MHz, CDC13) δ 7.98 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.09 (s, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.09 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 7.5 Hz, 4H), 2.18 - 2.03 (m, 2H). Compound 206m: MS m / z (ESI): 342.0, 344.0 [M+1] + .

[0687] Tenth step: synthesis of compound 206

[0688] Compound 2061 (60 mg, 0.18 mmol) was dissolved in 1,4-dioxane (3 mL), and compound 2d (75.52 mg, 0.22 mmol), potassium phosphate (114.6 mg, 0.54 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (13.2 mg, 0.018 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 h. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0% ~ 5%) to obtain a crude product (40 mg), which was further purified by preparative thin layer chromatography (dichloromethane / methanol = 15 / 1) to obtain compound 206 (17.43 mg). MS m / z (ESI): 485.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.81 (s, 1H), 7.52 - 7.45 (m, 1H), 7.43 - 7.34 (m, 3H), 7.23 (s, 1H), 4.37 (dd, J = 12.2, 5.0 Hz, 1H), 3.99 (t, J = 6.4 Hz, 2H), 3.10 (t, J = 6.3 Hz, 2H), 2.91 (dd, J = 13.4, 7.0 Hz, 4H), 2.85 - 2.74 (m, 1H), 2.58 - 2.54 (m, 1H), 2.41 - 2.29 (m, 1H), 2.10 - 1.98 (m, 3H).

[0689] Example 30 (compound 672)

[0690] First step: synthesis of compound 672

[0691] Compound 206m (synthesis method refer to compound 2061 of the ninth step of Reference Example 29 and synthesis of compound 206m) (10 mg, 0.03 mmol) was dissolved in 1,4-dioxane (1 mL), and compound 2d (12.2 mg, 0.035 mmol), potassium phosphate (18.5 mg, 0.09 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (2.1 mg, 0.003 mmol) were added sequentially. The reaction mixture was heated to 100°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0% ~ 5%) to obtain compound 672 (1.03 mg). MS m / z (ESI): 485.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.53 - 7.44 (m, 4H), 7.43 - 7.33 (m, 4H), 7.15 (d, J = 7.6 Hz, 1H), 4.37 (dd, J = 12.2, 4.9 Hz, 1H), 3.97 (t, J = 6.2 Hz, 2H), 3.22 (t, J = 7.5 Hz, 2H), 3.10 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 7.3 Hz, 2H), 2.81 - 2.76 (m, 1H), 2.59 - 2.56 (m, 1H), 2.38 - 2.34 (m, 1H), 2.03 - 1.97 (m, 3H).

[0692] Example 31 (Compound 365)

[0693] First Step: Synthesis of compound 365c

[0694] Compound 88a (150 mg, 0.66 mmol), sodium chloroaurate dihydrate (5.3 mg, 0.013 mmol), 365a (propargylamine) (58.7 mg, 1.06 mmol) were dissolved in ethanol (4 mL). The reaction mixture was stirred in a sealed tube at 130°C for 12 hours. The reaction solution was directly mixed with silica gel and dried in a rotary evaporator, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% ~ 75%) to obtain compound 365b (130 mg). MS (ES, m / z): 260.0 [M+1] + .

[0695] Second Step: Synthesis of compound 365

[0696] Compound 365b (70 mg, 0.26 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (10 / 1, 4.4 mL), compound 2d (94 mg, 0.26 mmol), potassium phosphate (114.2 mg, 0.53 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19.6 mg, 0.02 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 ml), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 2) again, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / ethyl acetate = 1 / 2) to obtain compound 365 (13.4 mg). MS m / z (ES): 403.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.53 (dd, J = 4.7, 1.6 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 7.6, 1.5 Hz, 1H), 7.43 - 7.33 (m, 5H), 7.28 (dd, J = 7.6, 4.8 Hz, 1H), 4.36 (dd, J = 12.1, 5.0 Hz, 1H), 2.97 (s, 4H), 2.85 - 2.73 (m, 1H), 2.59 - 2.54 (m, 1H), 2.38 - 2.30 (m, 1H), 2.11 - 2.02 (m, 1H)

[0697] Example 32 (Compound 366)

[0698] First Step: Synthesis of compound 366b

[0699] Compound 88a (250 mg, 1.11 mmol), p-toluenesulfonic acid monohydrate (211.2 mg, 1.11 mmol), hexamethyldisilazane (896.2 mg, 5.55 mmol) were dissolved in 366a (formamide) (15 g). The reaction mixture was subjected to microwave reaction at 215 °C for 10 min. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (10 ml), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 2) again, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 10%-50%) to obtain compound 366b (130 mg). MS (ES, m / z): 261.0 [M+H] + .

[0700] Step 2: Synthesis of compound 366

[0701] Compound 366b (70 mg, 0.26 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 / 1, 4.4 mL), compound 2d (93.7 mg, 0.26 mmol), potassium phosphate (113.8 mg, 0.53 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19.6 mg, 0.02 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 ml), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / ethyl acetate = 1 / 2) to give compound 366 (16.4 mg). MS m / z (ES): 404.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.11 (s, 1H), 8.71 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.50 - 7.32 (m, 5H), 4.37 (dd, J = 12.2, 5.0 Hz, 1H), 3.07 - 2.92 (m, 4H), 2.88 - 2.74 (m, 1H), 2.60 - 2.53 (m, 1H), 2.36-2.32 (m, 1H), 2.12 - 1.98 (m, 1H).

[0702] Example 33 (compound 404)

[0703] Step 1: Synthesis of compound 404a

[0704] Compound 91a (4.0 g, 17.80 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (21.21 g, 178 mmol), p-toluenesulfonic acid (0.07 g, 0.40 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 404a (4 g), which was used in the next step without further purification. MS (ES, m / z): 280.0 [M+H] + .

[0705] Step 2: Synthesis of compound 404b

[0706] ​​​​​​​​​​Compound 404a (4 g, 14.3 mmol) was dissolved in methanol (40 mL), hydrazine hydrate (1.15 g, 35.7 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with ethyl acetate (90 mL x 2). The combined organic phase was washed with saturated brine (90 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-3%) to give compound 404b (2.5 g). MS (ES, m / z): 249.0 [M+H] + .

[0707] Step 3: Synthesis of compound 404c

[0708] Compound 404b (200 mg, 0.80 mmol) was dissolved in dichloromethane (2.5 mL), di-tert-butyl dicarbonate (210.2 mg, 0.96 mmol), and 4-dimethylaminopyridine (19.62 mg, 0.16 mmol) were added successively. The reaction mixture was stirred at 25 °C for 12 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-3%) to give compound 404c (220 mg). MS (ES, m / z): 293.0 [M+H-56] + .

[0709] Step 4: Synthesis of compound 404d

[0710] Compound 404c (149.8 mg, 0.42 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (10 / 1, 3 mL), compound 2d (150 mg, 0.42 mmol), potassium phosphate (182 mg, 0.85 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (31.4 mg, 0.04 mmol) were added successively. The reaction mixture was heated to 100 °C and stirred for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 404d (40 mg). MS m / z (ES): 436.4 [M+H-56] + .

[0711] Step 5: Synthesis of compound 404

[0712] Compound 404d (30 mg, 0.06 mmol) was dissolved in hydrochloric acid-dioxane (2 mL), the reaction mixture was stirred at 25 °C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 404 (21 mg). MS m / z (ES): 392.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ 10.92 (s, 1H), 8.04 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.41-7.21 (m, 6H), 4.34 (dd, J = 12.2, 5.0 Hz, 1H), 2.98 (t, J = 7.4 Hz, 2H), 2.86-2.75 (m, 3H), 2.56-2.55 (m, 1H), 2.39-2.34 (m, 1H), 2.07-2.03 (m, 1H).

[0713] Example 34 (Compound 329)

[0714] First Step: Synthesis of compound 329b

[0715] Compound 329a (4.5 g, 28.38 mmol) was added to 1,4-dioxane (50 mL), compound 303b (2.9 g, 34.06 mmol), cesium carbonate (27.74 g, 85.14 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.3 g, 5.68 mmol), palladium acetate (637 mg, 2.84 mmol) were added, and the reaction was stirred at 100 °C for 16 h under nitrogen protection. The reaction was monitored by LCMS, and the reaction was completed. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-100%) to obtain compound 329b (3 g). MS m / z (ESI): 208.0 [M+1] + .

[0716] Second Step: Synthesis of compound 329c

[0717] Compound 329b (2.7 g, 13.03 mmol) was dissolved in ethanol (30 mL) and water (3 mL), and iron powder (3.64 g, 65.15 mmol), ammonium chloride (6, 97 g, 130.30 mmol) were added. The reaction was stirred at 80 °C for 3 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0%-100%) to obtain compound 329c (1.5 g). MS m / z (ESI): 178.2 [M+1] + .

[0718] Step 3: Synthesis of compound 329d

[0719] Compound 329c (1.5 g, 8.47 mmol) was dissolved in acetic acid (15 mL). The reaction was stirred at 110 °C for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0%-10%) to give compound 329d (1 g). MS m / z (ESI): 160.2 [M+1] + .

[0720] Step 4: Synthesis of compound 329e

[0721] Compound 329d (1 g, 6.28 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (1.44 g, 6.28 mmol, 75%) was added. The reaction was stirred at 25 °C for 16 h. After the reaction was completed, the reaction solution was diluted with dichloromethane (200 mL), and the organic phase was washed with an aqueous sodium sulfite solution (100 mL x 3, 10%), washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0%-10%) to give compound 329e (0.9 g). MS m / z (ESI): 176.0 [M+1] + .

[0722] Step 5: Synthesis of compound 329f

[0723] Compound 329e (0.9 g, 5,14 mmol) was dissolved in acetic anhydride (10 mL), and the reaction was stirred at 140 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0%-10%) to give compound 329f (0.8 g). MS m / z (ESI): 218.1 [M+1] + .

[0724] Step 6: Synthesis of compound 329g

[0725] Compound 329f (0.8 g, 3.68 mmol) was dissolved in methanol (10 mL), and potassium carbonate (1.02 g, 7.36 mmol) was added. The reaction was stirred at 25 °C for 2 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0%-10%) to give compound 329g (430 mg). MS m / z (ESI): 176.1 [M+1] + .

[0726] Step 7: Synthesis of compound 329h

[0727] Compound 329g (165 mg, 0.94 mmol) was dissolved in dimethyl sulfoxide (3 mL), compound 201e (310 mg, 0.94 mmol), cuprous iodide (35.8 mg, 0.19 mmol), potassium carbonate (390 mg, 2.82 mmol) were added, the reaction was stirred at 120 °C for 16 hours. The reaction was monitored by LCMS. The reaction was filtered, the filtrate was diluted with ethyl acetate (100 mL), the organic phase was washed with water (100 mL), brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%-10%) to give compound 329h (30 mg). MS m / z (ESI): 377.9 [M+1] + .

[0728] Eighth Step: Synthesis of compound 329

[0729] Compound 2d (31 mg, 0.091 mmol) was dissolved in 1,4-dioxane (2 mL), compound 329h (30 mg, 0.091 mmol), potassium phosphate (58 mg, 0.27 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (6.6 mg, 0.0091 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction was cooled to room temperature and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 70-100%) to give compound 329 (5.5 mg). MS m / z (ESI): 473.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.36 (dd, J = 6.4, 3.6 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 4.36 (dd, J = 12.0, 4.8 Hz, 1H), 4.07 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.763-2.59 (m, 1H), 2.57–2.52 (m, 3H), 2.35-2.34 (m, 1H), 2.10-2.03 (m, 1H).

[0730] Example 35 (Compound 345)

[0731] First Step: Synthesis of compound 345b

[0732] Compound 107b (1.08 g, 15.12 mmol) was added to a solution of compound 345a (4-chloro-2-methoxy-5-nitropyridine) (1.90 g, 10.08 mmol) in ethanol (20 mL) at room temperature, and the reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction, the reaction solution was quenched with an aqueous solution (50 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100 / 0 ~ 1 / 1) to give compound 345b (1.70 g). MS m / z (ESI): 224.1 [M+1] + .

[0733] Second Step: Synthesis of compound 345c

[0734] Compound 345b (1.05 g, 4.70 mmol) was added to a solution of triethyl phosphite (10 mL) at room temperature, and the reaction mixture was stirred at 120 °C for 24 h. After completion of the reaction, the reaction solution was quenched with an aqueous solution (20 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 5 / 1) to give compound 345c (200.0 mg). MS m / z (ESI): 190.1 [M+1] + .

[0735] Third Step: Synthesis of compound 345d

[0736] Pyridine hydrochloride (122.4 mg, 1.06 mmol) was added to a solution of compound 345c (100.0 mg, 0.53 mmol) in N,N-dimethylformamide (3 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction solution was quenched with an aqueous solution (10 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 5 / 1) to give compound 345d (60.0 mg). MS m / z (ESI): 176.1 [M+1] + .

[0737] Fourth Step: Synthesis of compound 345e

[0738] Compound 146e (196.0 mg, 0.69 mmol), cuprous iodide (36.0 mg, 0.19 mmol), potassium carbonate (261.3 mg, 1.89 mmol) were added to a solution of compound 345d (110.0 mg, 0.63 mmol) in dimethyl sulfoxide (3 mL) at 25 °C under nitrogen atmosphere. The reaction mixture was stirred at 120 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 5 / 1) to give compound 345e (30.0 mg). MS m / z (ESI): 330.1 [M+1] + .

[0739] Fifth step: synthesis of compound 345

[0740] Compound 2d (29.2 mg, 0.08 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (6.2 mg, 0.007 mmol), potassium phosphate (48.4 mg, 0.23 mmol) were added to a solution of compound 345e (25.0 mg, 0.07 mmol) in dioxane (2 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 10 / 1) to give compound 345 (2.3 mg). MS m / z (ESI): 473.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.53 (s, 1H), 7.43 - 7.34 (m, 5H), 7.30 (s, 1H), 7.12 (d, J = 8.4 Hz, 2H), 4.35 (dd, J = 12.1, 4.9 Hz, 1H), 4.16 (t, J = 7.1 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 2.85 - 2.74 (m, 1H), 2.71 - 2.61 (m, 2H), 2.57 - 2.54 (m, 1H), 2.39 - 2.30 (m, 1H), 2.11 - 2.00 (m, 1H).

[0741] Example 36 (compound 405)

[0742] First Step: Synthesis of compound 405b

[0743] Compound 107a (4 g, 25.23 mmol) was dissolved in ethanol (50 mL) at room temperature, then compound 405a (piperidine) (6.45 g, 75.69 mmol) was added, and the reaction mixture was warmed to 70 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to obtain compound 405b (5.1 g). MS m / z (ESI): 208.1 [M+1] + .

[0744] Second Step: Synthesis of compound 405c

[0745] Compound 405b (5.1 g, 24.61 mmol) was dissolved in triethyl phosphite (40 mL) at room temperature, and the reaction mixture was warmed to 110 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10 / 1) to obtain compound 405c (830 mg). MS m / z (ESI): 174.1 [M+1] + .

[0746] Third Step: Synthesis of compound 405d

[0747] Compound 405c (830 mg, 4.79 mmol) was dissolved in dichloromethane (10 mL) under ice bath conditions, and m-chloroperoxybenzoic acid (1.65 g, 9.58 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10 / 1) to obtain compound 405d (700 mg). MS m / z (ESI): 190.1 [M+1] + .

[0748] Fourth Step: Synthesis of compound 405e

[0749] Compound 405d (700 mg, 3.7 mmol) was dissolved in acetic anhydride (5 mL) at room temperature, and the reaction mixture was warmed to 140 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10 / 1) to obtain compound 405e (364 mg). MS m / z (ESI): 190.1 [M+1] + .

[0750] Fifth Step: Synthesis of compound 405f

[0751] Compound 405e (100 mg, 0.53 mmol) was dissolved in dimethyl sulfoxide (2 mL) under nitrogen atmosphere, compound 146e (150 mg, 0.53 mmol), cuprous iodide (30 mg 0.16 mmol) and potassium carbonate (220 mg 1.59 mmol) were added, then the reaction mixture was warmed to 120 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10 / 1) to obtain compound 405f (70 mg). MS m / z (ESI): 343.9 [M+1] + .

[0752] Sixth step: synthesis of compound 405

[0753] Compound 405f (35 mg, 0.1 mmol) was dissolved in 1,4-dioxane (2 mL), compound 2d (50 mg, 0.1 mmol), potassium phosphate (64 mg, 0.3 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (7 mg, 0.01 mmol) were added in sequence. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 405 (22.9 mg). MS m / z (ESI): 486.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.58-7.48 (m, 5H), 7.47-7.36 (m, 3H), 6.71 (d, J = 7.3 Hz, 1H), 4.39 (dd, J = 12.3, 4.9 Hz, 1H), 4.10 (t, J = 5.7 Hz, 2H), 2.92 (t, J = 6.1 Hz, 2H), 2.87-2.75 (m, 1H), 2.54-2.61 (m, 1H), 2.30-2.42 (m, 1H), 2.11-1.98 (m, 3H), 1.88-1.97 (m, 2H).

[0754] Example 37 (compound 408)

[0755] First step: synthesis of compound 408a

[0756] Compound 312b (synthesis method refer to synthesis of compound 312, second step, compound 312b) (1 g, 6.92 mmol) was dissolved in N,N-dimethylformamide (15 mL) at room temperature, compound 146c (692.83 mg, 6.92 mmol), N-methylmorpholine (2.10 g, 20.76 mmol) were added successively, the reaction mixture was stirred at 115 °C for 16 hours. After the reaction was completed, the reaction liquid was poured into water (50 mL), extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by combi-Flash rapid preparation instrument (C18 reverse phase column, mobile phase: methanol-water; gradient: 0-100%) to obtain compound 408a (38 mg). MS m / z (ESI): 191.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 5.49 (s, 1H), 4.06-4.00 (m, 2H), 3.65-3.59 (m, 2H), 2.90-2.87 (m, 2H), 2.54-2.52 (m, 2H), 1.79-1.68 (m, 4H).

[0757] Second step: synthesis of compound 408b

[0758] Compound 408a (38 mg, 0.20 mmol) was dissolved in dimethyl sulfoxide (2 mL) at room temperature under nitrogen, compound 146e (84.87 mg, 0.30 mmol), cuprous iodide (7.62 mg, 0.04 mmol), potassium carbonate (82.93 mg, 0.6 mmol) were added successively, the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction liquid was poured into water (50 mL), extracted with ethyl acetate (30 ml x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-100%) to obtain compound 408b (14 mg) as a yellow solid. MS m / z (ESI): 344.9 [M+1] + .

[0759] Third step: synthesis of compound 408

[0760] Compound 2d (18.32 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL), followed by the addition of compound 408b (14 mg, 0.04 mmol), potassium phosphate (26.11 mg, 0.12 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (6 mg, 0.01 mmol). The reaction mixture was heated to 90 °C under nitrogen protection for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain the crude product. The residue was purified by combi-Flash rapid preparation instrument (C18 reverse phase column, mobile phase: methanol-water; gradient: 0-100%) to obtain compound 408 (1.37 mg). MS m / z (ESI): 488.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.46 - 7.39 (m, 5H), 7.37 - 7.32 (m, 2H), 6.75 (s, 1H), 4.35 (dd, J = 12.1, 5.0 Hz, 1H), 4.24 - 4.17 (m, 2H), 4.09 - 4.05 (m, 2H), 2.84 - 2.66 (m, 4H), 2.57 - 2.55 (m, 1H), 2.40 - 2.30 (m, 1H), 2.09 - 1.95 (m, 2H), 1.66 (s, 4H).

[0761] Example 38 (Compound 557)

[0762] First Step: Synthesis of compound 557

[0763] Compound 2d (87 mg, 0.25 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of compound 557a (7-bromo-2,3,4,5-tetrahydro-1H-benzo[C]azepin-1-one) (60 mg, 0.25 mmol), potassium phosphate (159 mg, 0.75 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (18 mg, 0.025 mmol). The reaction mixture was heated to 100 °C under nitrogen protection for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 70-100%) to obtain compound 557 (43 mg). MS m / z (ESI): 383.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.11 (t, J = 5.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.44 - 7.36 (m, 3H), 7.35 (dd, J = 6.8, 2.3 Hz, 1H), 7.31 (s, 1H), 4.36 (dd, J = 12.4, 5.2 Hz, 1H), 2.97 (dd, J = 12.4, 6.4 Hz, 2H), 2.86 - 2.75 (m, 3H), 2.59-2.57 m, 1H), 2.42 - 2.32 (m, 1H), 2.09 - 2.01 (m, 1H), 1.97 - 1.88 (m, 2H).

[0764] Example 39 (Compound 87)

[0765] First Step: Synthesis of compound 87a

[0766] Compound 88a (1.5 g, 6.7 mmol), thiourea (1.53 g, 20.1 mmol), iodine (1.87 g, 7.37 mmol) were dissolved in ethanol (15 mL). The reaction mixture was stirred in a sealed tube at 100 °C for 4 hours. The reaction solution was concentrated in vacuum, the residue was dissolved with 10% sodium hydroxide aqueous solution (40 mL), extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 1) again, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-50%) to give compound 87a (1.5 g). MS (ES, m / z): 281.0 [M+H] + .

[0767] Second Step: Synthesis of compound 87b

[0768] Compound 87a (350 mg, 1.24 mmol) was dissolved in tetrahydrofuran (15 mL), and isoamyl nitrite (583 mg, 4.97 mmol) was added. The reaction mixture was stirred at 45 °C for 3 hours. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 1) again, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-75%) to give compound 87b (140 mg). MS (ES, m / z): 266.0 [M+H] + .

[0769] Third Step: Synthesis of compound 87

[0770] Compound 87b (70 mg, 0.26 mmol) was dissolved in a mixture of 1,4-dioxane and water (10 / 1, 4.4 mL), compound 2d (91.9 mg, 0.26 mmol), potassium phosphate (111.6 mg, 0.52 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19.2 mg, 0.02 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 ml), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 48-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm / 254 nm) to give compound 87 (12.1 mg). MS m / z (ES): 409.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.04 (s, 1H), 7.92-7.86 (m, 1H), 7.43-7.33 (m, 5H), 4.35 (dd, J = 12.2, 5.0 Hz, 1H), 3.12-3.06 (m, 4H), 2.84-2.76 (m, 1H), 2.59-2.53 (m, 1H), 2.38-2.31 (m, 1H), 2.09-2.03 (m, 1H)

[0771] Example 40 (Compound 357)

[0772] First Step: Synthesis of compound 357a

[0773] Compound 91a (900.0 mg, 4.00 mmol) and L-proline (46.0 mg, 0.40 mmol) were dissolved in dimethyl sulfoxide (9 mL), and the mixture was stirred at 25 °C for 30 minutes, and then p-toluenesulfonyl azide (394.3 mg, 2.00 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was filtered and the filter cake was washed with ethanol, and the obtained filter cake was dried under reduced pressure to give compound 357a (480 mg). MS (ES, m / z): 404.0 [M+H] + .

[0774] Second Step: Synthesis of compound 357b

[0775] Compound 357a (480 mg, 1.18 mmol) was dissolved in tetrahydrofuran (12 mL), sodium hydroxide (236.8 mg, 5.92 mmol) was added. The reaction mixture was stirred at 30 °C for 16 hours. After the reaction was completed, 1M hydrochloric acid was added to adjust pH to 6, extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 357b (280 mg). MS (ES, m / z): 250.0 [M+H] + .

[0776] Step 3: Synthesis of compound 357c

[0777] Compound 357b (280 mg, 1.12 mmol) was dissolved in N,N-dimethylformamide (6 mL), sodium hydride (32.2 mg, 1.34 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 minutes, then iodomethane (476.8 mg, 3.36 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, water (50 mL) was added, extracted with ethyl acetate (50 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-100%) to give compound 357c (180 mg). MS (ES, m / z): 264.1 [M+H] + .

[0778] Step 4: Synthesis of compound 357

[0779] Compound 357c (40 mg, 0.15 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (20 / 1, 4.2 mL), compound 2d (52.9 mg, 0.15 mmol), potassium phosphate (64.3 mg, 0.30 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (11.1 mg, 0.015 mmol) were added in turn. The reaction mixture was heated to 80 °C and stirred for 4 hours under nitrogen protection. After the reaction was completed, the reaction was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by thin layer chromatography silica gel plate (petroleum ether / ethyl acetate = 0-80%) to give compound 357 (30.4 mg). MS m / z (ES): 407.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.42 - 7.32 (m, 5H), 4.35 (dd, J = 12.2, 4.9 Hz, 1H), 4.17 (s, 3H), 3.08 (t, J = 7.4 Hz, 2H), 2.96 - 2.90 (m, 2H), 2.86 - 2.74 (m, 1H), 2.59 - 2.52 (m, 1H), 2.37 - 2.31 (m, 1H), 2.08 - 2.02 (m, 1H).

[0780] Example 41 (Compound 376)

[0781] First Step: Synthesis of Compound 376a and 376b

[0782] Compound 404b (synthesis method refer to the synthesis of compound 404, second step 404b of example 33) (120.0 mg, 0.48 mmol) and cesium carbonate (313.9 mg, 0.96 mmol) were dissolved in N,N-dimethylformamide (2 mL), then 2,2,2-trifluoroethyl trifluoromethanesulfonate (145.3 mg, 0.63 mmol) was added to the mixture at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. After the reaction was completed, water (40 mL) was added, extracted with ethyl acetate (40 mL x 2), the combined organic phase was washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-30%) to obtain a mixture of compound 376a and compound 376b (130 mg). Compound 376a (80 mg) and compound 376b (30 mg) were obtained by supercritical fluid chromatography (SFC) (equipment: SFC AD-3, chromatographic column: CHIRALPAK AD-H 4.6mm*50mm, 3μm, mobile phase: 40% methanol / carbon dioxide (ammonia monohydrate 0.2%), total flow rate: 40g / min). MS (ES, m / z): 331.2 [M+H] + .

[0783] Compound 376a: MS m / z (ESI): 331.2 [M+1]+. Supercritical fluid chromatography: retention time = 0.524 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.50 - 7.37 (m, 3H), 5.10 (q, J = 9.2 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H).

[0784] Compound 376b: MS m / z (ESI): 331.2 [M+1]+. Supercritical fluid chromatography: Retention time = 1.186 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.43 (ddd, J = 10.1, 7.3, 1.8 Hz, 3H), 5.15 (q, J = 9.2 Hz, 2H), 3.01 - 2.96 (m, 2H), 2.90 (dd, J = 11.4, 4.7 Hz, 2H).

[0785] Second Step: Synthesis of compound 376

[0786] Compound 376a (30 mg, 0.091 mmol) was dissolved in a mixture of 1,4-dioxane and water (20 / 1, 3.15 mL), compound 2d (31.7 mg, 0.091 mmol), potassium phosphate (38.5 mg, 0.18 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (6.6 mg, 0.0091 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (20 ml), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2) again, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 0-70%) to give compound 376 (9.42 mg). MS m / z (ES): 474.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.21 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.40 - 7.24 (m, 5H), 5.12 (q, J = 9.0 Hz, 2H), 4.35 (dd, J = 12.0, 4.8 Hz, 1H), 3.00 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.3 Hz, 2H), 2.57 (s, 2H), 2.35 (dt, J = 21.6, 10.7 Hz, 1H), 2.08 - 2.02 (m, 1H).

[0787] Example 42 (Compound 394)

[0788] First Step: Synthesis of compound 376

[0789] Compound 376b (synthesis method refer to the first step of synthesis of compound 376b of example 41) (30 mg, 0.091 mmol) was dissolved in a mixture of 1,4-dioxane and water (20 / 1, 3.15 mL), compound 2d (31.7 mg, 0.091 mmol), potassium phosphate (38.5 mg, 0.18 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (6.6 mg, 0.0091 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (20 ml), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 0-70%) to give compound 394 (6.5 mg). MS m / z (ES): 474.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.02 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.41 - 7.25 (m, 5H), 5.17 (q, J = 9.1 Hz, 2H), 4.35 (dd, J = 12.1, 4.9 Hz, 1H), 3.06 - 2.95 (m, 4H), 2.83 - 2.75 (m, 1H), 2.56 (d, J = 3.6 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.08 - 2.03 (m, 1H).

[0790] Example 43 (compound 374)

[0791] First step: synthesis of compound 374a and compound 374b

[0792] Compound 404b (synthesis method refer to the synthesis of compound 404, second step 404b of compound 404) (300 mg, 1.20 mmol) was dissolved in N,N-dimethylformamide (12 mL), isopropyl bromide (296.2 mg, 2.41 mmol) and cesium carbonate (1961.9 mg, 6.02 mmol) were added, and the reaction mixture was stirred at 60 °C for 2 hours. After the reaction was completed, after waiting for the reaction to cool to room temperature, water (40 mL) was added for dilution, and the combined organic phase was washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to obtain a mixture of compound 374a and compound 374b (300 mg). The mixture (100 mg) was separated by supercritical fluid chiral chromatography (SFC) (chromatographic column: chiralpak-AD, mobile phase: 50-70 carbon dioxide / ethanol (diethanolamine), total flow rate: 40 g / min) to obtain compound 374a (60 mg) and compound 374b (30 mg).

[0793] Compound 374a: MS m / z (ESI): 291.1 [M+1] + . Super critical fluid chromatography: retention time = 0.722 min. 1 HNMR (400MHz, DMSO-d6) δ 8.12 (s, 1H), 7.43 (s, 1H), 7.36 (d, J = 1.1 Hz, 2H), 4.44 (dt, J = 13.3, 6.6 Hz, 1H), 2.92 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 1.43 (d, J = 6.7 Hz, 6H).

[0794] Compound 374b: MS m / z (ESI): 291.1 [M+1] + . Super critical fluid chromatography (SFC): retention time = 1.754 min. 1 H NMR (400MHz, DMSO-d6) δ 7.81 (s, 1H), 7.43 (s, 1H), 7.39 - 7.33 (m, 2H), 4.57 - 4.48 (m, 1H), 2.95 (d, J = 7.3 Hz, 2H), 2.88 (d, J = 7.6 Hz, 2H), 1.38 (d, J = 6.6 Hz, 6H).

[0795] Second step: synthesis of compound 374

[0796] Compound 374a (30.0 mg, 0.10 mmol) was dissolved in a mixture of 1,4-dioxane and water (20 / 1, 2.1 mL), compound 2d (36.0 mg, 0.10 mmol), potassium phosphate (43.7 mg, 0.21 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (7.5 mg, 0.01 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (20 ml), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to give compound 374 (29.07 mg). MS m / z (ES): 434.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 10.93 (s, 1H), 8.14 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.41 - 7.31 (m, 3H), 7.23 (dd, J = 12.5, 4.7 Hz, 2H), 4.46 (dq, J = 13.2, 6.6 Hz, 1H), 4.34 (dd, J = 12.1, 5.0 Hz, 1H), 2.96 (t, J = 7.4 Hz, 2H), 2.83 - 2.73 (m, 3H), 2.56 (d, J = 3.7 Hz, 1H), 2.34 (dt, J = 12.2, 8.5 Hz, 1H), 2.08 - 2.00 (m, 1H), 1.45 (d, J = 6.7 Hz, 6H).

[0797] Example 44 (Compound 391)

[0798] First Step: Synthesis of compound 391

[0799] Compound 374b (synthesis method refer to the synthesis of compound 374b in the first step of compound 374 in example 43) (20.0 mg, 0.07 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (20 / 1, 2.1 mL), compound 2d (24.0 mg, 0.7 mmol), potassium phosphate (29.2 mg, 0.14 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (5.0 mg, 0.01 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (20 ml), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to give compound 391 (4.99 mg). MS m / z (ES): 434.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.84 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.32 (dt, J = 7.3, 2.0 Hz, 2H), 7.26 (d, J = 1.4 Hz, 1H), 7.21 (dd, J = 7.8, 1.8 Hz, 1H), 4.61 - 4.50 (m, 1H), 4.34 (dd, J = 12.1, 5.0 Hz, 1H), 3.01 (t, J = 7.3 Hz, 2H), 2.92 (dd, J = 11.3, 4.6 Hz, 2H), 2.38 - 2.27 (m, 2H), 2.09 - 1.93 (m, 2H), 1.41 (d, J = 6.6 Hz, 6H).

[0800] Example 45 (compound 620)

[0801] First Step: Synthesis of compound 620b

[0802] Compound 329a (4 g, 25.2 mmol), compound 620a (4,4-dimethyltetrahydropyrrol-2-one) (2.86 g, 25.2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.92 g, 5.05 mmol), palladium acetate (1.13 g, 5.05 mmol) and cesium carbonate (24.66 g, 75.7 mmol) were added into 1,4-dioxane (5 mL), the reaction mixture was heated to 100 °C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-70%) to obtain compound 620b (3.6 g). MS m / z (ESI): 236.1 [M+1] + .

[0803] Second Step: Synthesis of compound 620c

[0804] Compound 620b (3.5 g, 14.88 mmol), iron powder (8.31 g, 148.78 mmol) and ammonium chloride (3.98 g, 74.39 mmol) were added into a mixture solution of ethanol (10 mL) and water (2 mL), the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the reaction solution was directly filtered, the filter cake was washed with methanol (50 mL), distilled under reduced pressure, and purified by silica gel column chromatography (methanol:dichloromethane = 0-30%) to obtain compound 620c (2.7 g). MS m / z (ESI): 206.1 [M+1] +

[0805] Third Step: Synthesis of compound 620d

[0806] Compound 620c (2.5 g, 12.18 mmol) was dissolved in acetic acid (20 mL), the reaction mixture was stirred at 110 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-30%) to obtain compound 620d (2.2 g). MS m / z (ESI): 188.1 [M+1] +

[0807] Fourth Step: Synthesis of compound 620e

[0808] Compound 620d (1.2 g, 6.41 mmol) was dissolved in dichloromethane (6 mL), and m-chloroperoxybenzoic acid (1.77 g, 7.69 mmol) was slowly added under ice bath. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, it was quenched with saturated sodium bisulfite (30 mL), extracted with dichloromethane (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 620e (600 mg) was obtained by purification with silica gel column chromatography (methanol:dichloromethane = 0-30%). MS m / z (ESI): 204.1 [M+1] +

[0809] Fifth step: synthesis of compound 620f

[0810] Compound 620e (400 mg, 1.97 mmol) was dissolved in acetic anhydride (10 mL), and the reaction mixture was stirred at 140°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and compound 620f (600 mg) was obtained by purification with silica gel column chromatography (methanol:dichloromethane = 0-30%). MS m / z (ESI): 246.2 [M+1] +

[0811] Sixth step: synthesis of compound 620g

[0812] Compound 620f (550 mg, 2.24 mmol) and potassium carbonate (309.89 mg, 2.24 mmol) were dissolved in methanol (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and compound 620g (300 mg) was obtained by purification with silica gel column chromatography (methanol:dichloromethane = 0-30%). MS m / z (ESI): 204.2 [M+1] +

[0813] Seventh step: synthesis of compound 620h

[0814] Compound 620g (250 mg, 1.23 mmol), compound 146e (347.9 mg, 1.23 mmol), cuprous iodide (78.8 mg, 0.25 mmol), and potassium carbonate (509.98 mg, 3.69 mmol) were added to dimethyl sulfoxide (5 mL), and the reaction mixture was stirred at 120°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was performed with ethyl acetate (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 620h (90 mg) was obtained by purification with silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%). MS m / z (ESI): 358.1 [M+1] +

[0815] Eighth Step: Synthesis of compound 620

[0816] Compound 620h (60 mg, 0.167 mmol), compound 2d (58.6 mg, 0.17 mmol), potassium carbonate (69.4 mg, 0.50 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (24.5 mg, 0.033 mmol) were added to a mixture of 1,4-dioxane (2 mL) and water (0.5 mL), the reaction mixture was heated to 90 °C under nitrogen protection, stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 620 (12 mg). MS m / z (ESI): 500.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.46 - 7.34 (m, 5H), 7.21 - 7.15 (m, 2H), 6.89 (d, J = 8.5 Hz, 1H), 4.36 (dd, J = 12.2, 5.1 Hz, 1H), 3.84 (s, 2H), 2.88 - 2.76 (m, 3H), 2.61 - 2.56 (m, 1H), 2.40 - 2.33 (m, 1H), 2.09 - 2.03 (m, 1H), 1.26 (s, 6H).

[0817] Example 46 (Compound 771)

[0818] First Step: Synthesis of compound 771b

[0819] Compound 771a (2,6-dibromoaniline) (0.5 g, 1.99 mmol) was dissolved in toluene (5 mL) at room temperature, then compound 303b (0.17 mL, 2.19 mmol), phosphorus oxychloride (0.28 mL, 2.99 mmol), triethylamine (0.42 mL, 2.99 mmol) were added. The reaction mixture was stirred at 120 °C under nitrogen protection for 3 hours. After the reaction was completed, ethyl acetate (200 mL) was added to the reaction solution, toluene was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-15%) to obtain compound 771b (210 mg). MS m / z (ESI): 318.8 [M+1] +

[0820] Second Step: Synthesis of compound 771c

[0821] Potassium carbonate (243.4 mg, 1.76 mmol), cuprous iodide (27.9 mg, 0.088 mmol), tetramethylethylenediamine (0.025 mL, 0.176 mmol) were added to compound 771b (560 mg, 1.76 mmol) in acetonitrile (5 mL) at room temperature. The reaction mixture was stirred at 100 °C for 2 hours under nitrogen. After the reaction was completed, the solid in the reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-15%) to obtain compound 771c (70 mg). MS m / z (ESI): 238.1 [M+1] +

[0822] Third Step: Synthesis of compound 771

[0823] Compound 2d (88.9 mg, 0.21 mmol), potassium phosphate (131.12 mg, 0.57 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (15.5 mg, 0.019 mmol) were added to compound 771c (45 mg, 0.19 mmol) in 1,4-dioxane (10 mL) at room temperature. The reaction mixture was heated to 100 °C and stirred for 16 hours under nitrogen. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain a crude product, which was further purified by thin layer chromatography preparation plate (dichloromethane / methanol = 20:1) to obtain compound 771 (2.62 mg). MS m / z (ESI): 455.9 [M+1] +

[0824] Example 47 (compound 903)

[0825] First Step: Synthesis of compound 903a

[0826] Compound 88a (1.0 g, 4.44 mmol) was added to a solution of N,N-dimethylformamide dimethyl acetal (5 mL, 37.64 mmol) and the reaction mixture was heated to 105 °C for 18 hours under nitrogen. After the reaction was completed, the reaction mixture was distilled under reduced pressure to obtain compound 903a (1.24 g).

[0827] Second Step: Synthesis of compound 903b

[0828] Hydrazine hydrate (0.43 mL, 7.52 mmol) was added to a solution of compound 903a (1.24 g, 4.43 mmol) in ethanol (5 mL) and the reaction mixture was stirred at 85 °C for 18 h. After completion of the reaction, the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%) to give compound 903b (1.0 g). MS m / z (ESI): 248.9 [M+1] +

[0829] Third Step: Synthesis of compound 903

[0830] Compound 2d (70.2 mg, 0.20 mmol) was added to a solution of compound 903b (50 mg, 0.20 mmol), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (16.4 mg, 0.02 mmol), potassium phosphate (138.7 mg, 0.60 mmol) in dioxane (2 mL) and the reaction mixture was heated to 90 °C under nitrogen atmosphere and stirred for 1 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-5%) to give compound 903 (20 mg). MS m / z (ESI): 391.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.32 - 12.72 (m, 1H), 11.00 (s, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7.63 (s, 1H), 7.51 - 7.31 (m, 5H), 4.41 (dd, J = 12.2, 5.1 Hz, 1H), 2.98 (d, J = 7.0 Hz, 2H), 2.93 - 2.75 (m, 3H), 2.63 (d, J = 3.8 Hz, 1H), 2.41 (dt, J = 12.3, 8.6 Hz, 1H), 2.18 - 2.08 (m, 1H).

[0831] Example 48 (Compound 363)

[0832] First Step: Synthesis of compound 363a

[0833] To a solution of compound 88a (1000.0 mg, 4.44 mmol) in dichloromethane (20.0 mL) was added p-toluenesulfonic acid (76.5 mg, 0.44 mmol) and N-bromosuccinimide (790.7 mg, 4.44 mmol), the reaction mixture was stirred at 40 °C for 4 hours. After the reaction was completed, the reaction was allowed to cool to room temperature, the reaction was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to give compound 363a (1000.0 mg). MS (ES, m / z): 304.0 [M+H] + .

[0834] Second Step: Synthesis of compound 363b

[0835] A solution of compound 363a (200.0 mg, 0.66 mmol) in formamide (2.0 mL) was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography on silica gel plate (ethyl acetate) to give compound 363b (7.0 mg). MS (ES, m / z): 250.0 [M+H] + .

[0836] Third Step: Synthesis of compound 363

[0837] Compound 363b (6.0 mg, 0.02 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (20 / 1, 0.50 mL), compound 2d (8.4 mg, 0.02 mmol), potassium phosphate (10.2 mg, 0.05 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (1.7 mg, 0.002 mmol) were added successively. Under nitrogen protection, the reaction mixture was heated to 80 °C and stirred for 4 hours. After the reaction was completed, the reaction was cooled to room temperature, the filtrate was concentrated under reduced pressure, purified by thin layer chromatography on silica gel plate (ethyl acetate) to give compound 363 (4.74 mg). MS m / z (ES): 393.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.39 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.40 - 7.29 (m, 5H), 4.34 (dd, J = 12.0, 5.1 Hz, 1H), 3.18 (dd, J = 10.7, 5.7 Hz, 2H), 3.04 (t, J = 8.3 Hz, 2H), 2.85 - 2.74 (m, 1H), 2.56-2.54 (m, 1H), 2.37 - 2.30 (m, 1H), 2.08 - 2.01 (m, 1H).

[0838] Example 49 (Compound 343)

[0839] First Step: Synthesis of compound 343b

[0840] Compound 343a (2-piperidinone) (1.23 g, 12.41 mmol), tris(dibenzylideneacetone)dipalladium (0.95 g, 1.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.20 g, 2.037 mmol), cesium carbonate (10.11 g, 31.02 mmol) were added to a solution of compound 345a (1.95 g, 10.34 mmol) in dioxane (20 mL) at 25 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 10 / 1) to give compound 343b (900.0 mg). MS m / z (ESI): 252.2 [M+1] + .

[0841] Second Step: Synthesis of compound 343c

[0842] Iron powder (199.3 mg, 3.57 mmol) was added to a solution of compound 343b (300.0 mg, 1.19 mmol) in acetic acid (10 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 5 / 1) to give compound 343c (150.0 mg). MS m / z (ESI): 204.2 [M+1]+ .

[0843] Step 3: Synthesis of compound 343d

[0844] Pyridine hydrochloride (355.0 mg, 3.10 mmol) was added to a solution of compound 343c (210.0 mg, 0.53 mmol) in N,N-dimethylformamide (10 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 18 h. After completion of the reaction, the reaction solution was quenched with an aqueous solution (30 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 5 / 1) to give compound 343d (170.0 mg). MS m / z (ESI): 190.2 [M+1] + .

[0845] Step 4: Synthesis of compound 343e

[0846] Compound 146e (246.7 mg, 0.87 mmol), cuprous iodide (75.4 mg, 0.23 mmol), and potassium carbonate (328.6 mg, 2.37 mmol) were added to a solution of compound 343d (150.0 mg, 0.79 mmol) in dimethyl sulfoxide (10 mL) at 25 °C under nitrogen protection, and the reaction mixture was stirred at 120 °C for 18 h. After completion of the reaction, the reaction solution was quenched with an aqueous solution (30 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 10 / 1) to give compound 343e (50.0 mg). MS m / z (ESI): 344.2 [M+1] + .

[0847] Step 5: Synthesis of compound 343

[0848] Compound 2d (50.2 mg, 0.14 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (10.6 mg, 0.013 mmol), potassium phosphate (90.3 mg, 0.39 mmol) were added to a solution of compound 7 (45.0 mg, 0.13 mmol) in dioxane (3 mL) at room temperature under nitrogen. The reaction mixture was stirred at 100 °C for 18 h. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 0 ~ 10 / 1) to give compound 343 (3.7 mg). MS m / z (ESI): 487.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.47 (s, 1H), 7.42-7.36 (m, 5H), 7.27 (s, 1H), 7.10 (d, J = 8.7 Hz, 2H), 4.36 (dd, J = 12.2, 5.1 Hz, 1H), 4.12 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 6.3 Hz, 2H), 2.83-2.76 (m, 1H), 2.59–2.56 (m, 1H), 2.38–2.30 (m, 1H), 2.08–1.93 (m, 5H).

[0849] Example 50 (Compound 354)

[0850] First Step: Synthesis of compound 354b

[0851] Compound 354a (3-chloro-4-nitropyridine) (2 g, 12.62 mmol), compound 303b (1.29 g, 15.14 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.46 g, 2.52 mmol) and palladium acetate (0.28 g, 1.26 mmol) were added to a solution of cesium carbonate (8.22 g, 25.24 mmol) in 1,4-dioxane (6 mL) at room temperature. The reaction mixture was stirred at 100 °C for 2 h. After completion, silica gel was added directly to the reaction mixture and concentrated under reduced pressure. Purification by column chromatography on silica gel (methanol: ethyl acetate = 10%) gave compound 354b (1 g). MS m / z (ESI): 208.1 [M+1] + .

[0852] Second Step: Synthesis of compound 354c

[0853] Compound 354b (1 g, 4.83 mmol) was added to a solution of iron powder (1.35 g, 24.15 mmol) and ammonium chloride (2.58 g, 48.3 mmol) in ethanol (30 mL) and water (10 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and silica gel was added to the filtrate, which was purified by column chromatography on silica gel (methanol:dichloromethane = 0-30%) to obtain compound 354c (700 mg). MS m / z (ESI): 178.1 [M+1] + .

[0854] Third Step: Synthesis of compound 354d

[0855] Compound 354c (0.6 g, 3.39 mmol) was added to a solution of acetic acid (10 mL) and concentrated sulfuric acid (0.5 mL) at room temperature, and the reaction mixture was stirred at 110 °C for 72 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the solvent was removed by concentration. The residue was added to water (100 mL), and the pH was adjusted to 7. The resulting solution was extracted with dichloromethane (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain compound 354d (300 mg). MS m / z (ESI): 160.1 [M+1] + .

[0856] Fourth Step: Synthesis of compound 354e

[0857] Compound 354d (350 mg, 2.20 mmol) and 3-chloroperbenzoic acid (607.45 mg, 2.64 mmol) were dissolved in dichloromethane, and the reaction mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bisulfite (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was purified by column chromatography on silica gel (methanol:dichloromethane = 0-30%) to obtain compound 354e (230 mg). MS m / z (ESI): 176.1 [M+1] + .

[0858] Fifth Step: Synthesis of compound 354f

[0859] Compound 354e (0.22 g, 1.26 mmol) was added to a solution of acetic anhydride (2 mL), and the reaction mixture was stirred at 140 °C for 2 hours. After the reaction was completed, silica gel was added directly to the reaction solution, which was purified by column chromatography on silica gel (methanol:dichloromethane = 0-30%) to obtain compound 354f (50 mg). MS m / z (ESI): 218.1 [M+1] + .

[0860] Step 6: Synthesis of compound 354g

[0861] Potassium carbonate (0.19 g, 1.38 mmol) was added to a solution of compound 354f (0.10 g, 0.46 mmol) in methanol (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was distilled under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane = 0-30%) to obtain compound 354g (40 mg). MS m / z (ESI): 176.1 [M+1] + .

[0862] Step 7: Synthesis of compound 354h

[0863] Compound 354g (40 mg, 0.23 mmol) was added to a solution of compound 146e (161.25 mg, 0.57 mmol), cuprous iodide (21.71 mg, 0.11 mmol), and potassium carbonate (236.34 mg, 1.71 mmol) in dimethyl sulfoxide (2 mL) at room temperature, and the reaction mixture was stirred at 120°C for 16 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), concentrated under reduced pressure, and purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 0-100%) to obtain compound 354h (24 mg). MS m / z (ESI): 330.0 [M+1] + .

[0864] Step 8: Synthesis of compound 354

[0865] Compound 354h (24 mg, 0.072 mmol), compound 2d (52.94 mg, 0.151 mmol), potassium phosphate (104.61 mg, 0.454 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (22.16 mg, 0.030 mmol) were added to a solution in 1,4-dioxane (2 mL), and the reaction mixture was stirred at 100°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was purified by a reverse column (methanol:water = 0-100) to obtain compound 354 (7.2 mg). MS m / z (ESI): 473.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.58 - 7.52 (m, 4H), 7.47 - 7.37 (m, 4H), 6.67 (d, J = 7.3 Hz, 1H), 4.39 (dd, J = 12.2, 5.0 Hz, 1H), 4.25 (t, J = 7.1 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 2.86 - 2.77 (m, 1H), 2.658 - 2.62 (m, 2H), 2.58 - 2.53 (m, 1H), 2.36 - 2.34 (m, 1H), 2.10 - 2.05 (m, 1H).

[0866] Example 51 (Compound 355)

[0867] Third Step: Synthesis of compound 355a and compound 355b

[0868] Compound 903b (600 mg, 2.41 mmol, synthesis method refer to synthesis of compound 903b in example 47, second step) was dissolved in N,N-dimethylformamide (2 mL), sodium hydride (115.6 mg, 2.89 mmol, 60% w) was added at 0 °C, the reaction mixture was stirred at 25 °C for 30 minutes. Iodomethane (68.38 mg, 4.82 mmol) was added to the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, water (80 mL) was added, extracted with ethyl acetate (80 mL x 2), the combined organic phase was washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-30%) to obtain a mixture of compound 355a and compound 355b (500 mg). The mixture (100 mg) was separated by supercritical fluid chiral chromatography (equipment: SFC AD-3, column: CHIRALPAK AD-H 4.6 mm*50 mm, 3 μm, mobile phase: 40% MeOH / CO2(NH4OH 0.2%), total flow rate: 40 g / min), Method Set: CS_20-40_B1_3ml_5min to obtain compound 355a (50 mg) and compound 355b (30 mg).

[0869] Compound 355a: MS m / z (ESI): 263.2 [M+1] + Supercritical fluid chromatography SFC: Retention time = 0.724 min, UV = 214 nm. 1H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 3.84 (s, 3H), 2.86 (t, J = 7.3 Hz, 2H), 2.67 (t, J = 7.3 Hz, 2H).

[0870] Compound 355b: MS m / z (ESI): 263.2 [M+1] + Supercritical fluid chromatography SFC: Retention time = 0.928 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (dd, J = 14.2, 5.0 Hz, 2H), 7.51 (dd, J = 8.3, 2.0 Hz, 1H), 7.30 (s, 1H), 4.06 (s, 3H), 2.84 (t, J = 7.3 Hz, 2H), 2.63 - 2.56 (m, 2H).

[0871] Second Step: Synthesis of compound 355

[0872] Compound 355a (30 mg, 0.11 mmol) was dissolved in a mixture solution of 1,4-dioxane and water (20 / 1, 3.15 mL), compound 2d (39.9 mg, 0.11 mmol), potassium phosphate (48.4 mg, 0.23 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8.3 mg, 0.011 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2) again, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 0~80%) to give compound 355 (17.8 mg). MS m / z (ES): 406.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.41 - 7.32 (m, 3H), 7.27 (dd, J = 10.9, 3.1 Hz, 2H), 4.35 (dd, J = 12.2, 5.0 Hz, 1H), 3.87 (s, 3H), 2.91 (t, J = 7.2 Hz, 2H), 2.84 - 2.70 (m, 3H), 2.56 (d, J = 3.7 Hz, 1H), 2.40 - 2.31 (m, 1H), 2.09 - 2.02 (m, 1H).

[0873] Example 52 (Compound 242)

[0874] First Step: Synthesis of compound 242b

[0875] Compound 242a (methyltriphenylphosphonium bromide) (4.76 g, 13.32 mmol) was dissolved in tetrahydrofuran (40 mL), and potassium tert-butoxide (16.7 mL, 1 mol / L tetrahydrofuran solution) was added dropwise at 0 °C under nitrogen protection. The reaction mixture was stirred at 0 °C for 30 min. Compound 88a (2.5 g, 11.1 mmol) was added, and the reaction was allowed to naturally warm to room temperature and stirred overnight. After the reaction was completed, the reaction solution was added to an aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (100 mL x 2), and the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-5%) to obtain compound 242b (1.9 g). 1 H NMR (400 MHz, CDCl3) δ 7.51 - 7.45 (m, 1H), 7.26 - 7.23 (m, 2H), 5.45 (s, 1H), 4.96 (s, 1H), 2.80 (t, J = 6.3 Hz, 2H), 2.55 - 2.47 (m, 2H), 1.89 - 1.80 (m, 2H).

[0876] Second Step: Synthesis of compound 242d

[0877] Compound 242b (1.9 g, 8.51 mmol) was dissolved in methanol (20 mL), and compound 242c ([hydroxy(p-toluenesulfonyloxy)iodo]benzene) (4 g, 10.21 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated in vacuo, and the residue was added to an aqueous solution (100 mL), extracted with dichloromethane (100 mL x 2), and the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 0-50%) to obtain compound 242d (1.13 g). 1 H NMR (400 MHz, CDCl3) δ 7.34-7.28 (m, 2H), 7.04-6.99 (m, 1H), 3.67 (s, 2H), 2.95-2.87 (m, 2H), 2.56 (t, J = 6.9 Hz, 2H), 2.04-1.94 (m, 2H).

[0878] Third step: synthesis of compound 242e

[0879] Compound 242d (1.1 g, 4.6 mmol) and p-toluenesulfonic acid monohydrate (175.02 mg, 0.92 mmol) were dissolved in N,N-dimethylformamide dimethyl acetal (5 mL). The reaction mixture was stirred at 40°C for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-100%) to obtain compound 242e (300 mg). MS (ES, m / z): 294.0 [M+H] + .

[0880] Fourth step: synthesis of compound 242f

[0881] Compound 242e (320 mg, 1.08 mmol) was dissolved in methanol (5 mL), and hydrazine hydrate (172 mg, 2.71 mmol, 80% mass fraction) was added. The reaction was stirred at 30°C overnight. After the reaction was completed, the reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-70%) to obtain compound 242f (220 mg). MS (ES, m / z): 263.0 [M+H] + .

[0882] Fifth step: synthesis of compound 242g

[0883] Compound 242f (220 mg, 0.83 mmol) was dissolved in N,N-dimethylformamide (2 mL), the reaction mixture was cooled to 0 °C under nitrogen protection, and stirred for 5 min, then sodium hydride (50.17 mg, 1.25 mmol, 60% mass fraction) was added, and stirred at 0 °C for 30 min. Compound iodomethane (178.09 mg, 1.25 mmol) was added. The reaction mixture was warmed to room temperature, and stirred for 2 h. After the reaction was completed, water (10 mL) was added to the reaction solution, and extracted with ethyl acetate (10 mL x 2), then the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-35%) to obtain a mixture (200 mg). The mixture was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 60-65%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm / 254 nm) to obtain compound 242g (50 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.42-7.34 (m, 3H), 3.80 (s, 3H), 2.83 (t, J = 6.9 Hz, 1H), 2.77-2.68 (m, 1H), 1.99-1.89 (m, 1H).

[0884] Sixth step: synthesis of compound 242

[0885] Compound 242g (40 mg, 0.14 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (10 / 1, 4.4 mL), and compound 2d (50.5 mg, 0.14 mmol), potassium phosphate (61.3 mg, 0.29 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (10.6 mg, 0.014 mmol) were added in sequence. The reaction mixture was heated to 80 °C under nitrogen protection, and stirred for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 40-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm / 254 nm) to obtain compound 242 (4.3 mg). MS m / z (ES): 420.1 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.07 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.39 - 7.31 (m, 3H), 7.24 - 7.19 (m, 2H), 4.36 - 4.32 (m, 1H), 3.82 (s, 3H), 2.88 (t, J = 6.8 Hz, 2H), 2.81 - 2.78 (m, 2H), 2.38 - 2.28 (m, 2H), 2.10 - 1.94 (m, 4H).

[0886] Example 53 (Compound 358)

[0887] First Step: Synthesis of compound 358a

[0888] Compound 357b (synthesis method refer to the synthesis of compound 357b in the second step of compound 357 in example 40) (280 mg, 1.12 mmol) was dissolved in N,N-dimethylformamide (6 mL), sodium hydride (32.2 mg, 1.34 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Then iodomethane (476.8 mg, 3.36 mmol) was added to the mixture at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, water (50 mL) was added, extracted with ethyl acetate (50 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-100%) to give compound 358a (50 mg). MS (ES, m / z): 264.1 [M+H] + .

[0889] Second Step: Synthesis of compound 358

[0890] Compound 358a (30 mg, 0.11 mmol) was dissolved in a mixture of 1,4-dioxane and water (20 / 1, 3.15 mL), compound 2d (30.7 mg, 0.11 mmol), potassium phosphate (48.2 mg, 0.23 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (8.3 mg, 0.011 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 4 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 5 / 4) to give compound 358 (4.4 mg). MS m / z (ES): 407.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.42 - 7.31 (m, 5H), 4.35 (dd, J = 12.3, 5.1 Hz, 1H), 4.00 (s, 3H), 3.10 (t, J = 7.3 Hz, 2H), 3.01 (t, J = 7.1 Hz, 2H), 2.86 - 2.75 (m, 1H), 2.56-2.53 (m, 1H), 2.38-2.29 (m, 1H), 2.10-2.06 (m, 1H).

[0891] Example 54 (Compound 367)

[0892] First Step: Synthesis of compound 367b

[0893] Compound 367a (5-bromo-2-indanone) (1 g, 4.74 mmol) was dissolved in chloroform (10 mL), N,N-dimethylformamide dimethyl acetal (564.6 mg, 4.74 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-100%) to give compound 367b (100 mg). MS m / z (ES): 266.0 [M+H] + .

[0894] Second Step: Synthesis of compound 367c

[0895] Compound 367b (100 mg, 0.38 mmol) was dissolved in methanol (3 mL), methylhydrazine sulfate (135.43 mg, 0.94 mmol) was added. The reaction mixture was heated to 40 °C and stirred for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 1 / 3) to give compound 367c (10 mg). 1 H NMR (400 MHz, CDC13) δ 7.57 (s, 1H), 7.44 - 7.37 (m, 2H), 7.29 (d, J = 8.1 Hz, 1H), 3.98 (s, 3H), 3.73 (s, 2H).

[0896] Third Step: Synthesis of compound 367

[0897] Compound 367c (10 mg, 0.04 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (10 / 1, 1.1 mL), compound 2d (14.02 mg, 0.04 mmol), potassium phosphate (17.02 mg, 0.08 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (2.93 mg, 0.004 mmol) were added successively. The reaction mixture was heated to 80 °C and stirred for 2 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / ethyl acetate = 1 / 3) to give compound 367 (3.63 mg). MS m / z (ES): 392.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.88 (s, 1H), 7.56 - 7.53 (m, 1H), 7.48 (s, 1H), 7.39 - 7.29 (m, 4H), 4.35 (dd, J = 12.1, 5.0 Hz, 1H), 3.93 (s, 3H), 3.72 (s, 2H), 2.87 - 2.72 (m, 1H), 2.59 - 2.55 (m, 1H), 2.36 - 2.32 (m, 1H), 2.08 - 2.03 (m, 1H).

[0898] Example 55 (Compound 375)

[0899] First Step: Synthesis of compound 375b and compound 375c

[0900] Compound 404b (300.0 mg, 1.20 mmol) was dissolved in acetonitrile (6.0 mL), potassium fluoride (139.9 mg, 2.41 mmol) and compound 375a (bromofluoromethyl diethyl phosphonate) (643.1 mg, 2.41 mmol) were added, and the reaction mixture was stirred at 50 °C for 4 h. After the reaction was completed, the reaction was allowed to cool to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to obtain a mixture of compound 375b and compound 375c (280.0 mg). The mixture (120.0 mg) was prepared by pre-HPLC (column: Gemini-C18-100 x 30 mm, 5 μm, mobile phase: acetonitrile-water (0.1% trifluoroacetic acid), gradient: 60-70) to obtain compound 375b (40.0 mg) and compound 3475c (50.0 mg).

[0901] Compound 375b: MS m / z (ESI): 299.0 [M+1] + HPLC: Ret Time = 5.286 min. 1 HNMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.78 (t, J = 59.4 Hz, 1H), 7.53 (dd, J = 9.8, 4.7 Hz, 2H), 7.47 - 7.40 (m, 1H), 2.98 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.3 Hz, 2H).

[0902] Compound 375c: MS m / z (ESI): 299.0 [M+1] + HPLC: Ret Time = 5.423 min. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.86 (t, J = 58.0 Hz, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.2 Hz, 1H), 3.04 (s, 4H).

[0903] Second Step: Synthesis of compound 375

[0904] Compound 375b (30.0 mg, 0.10 mmol) was dissolved in a mixture of 1,4-dioxane and water (20 / 1, 2.1 mL), compound 2d (35.1 mg, 0.10 mmol), potassium phosphate (42.6 mg, 0.20 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (7.3 mg, 0.01 mmol) were added successively. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography on silica gel plate (ethyl acetate: petroleum ether = 1:1) to obtain compound 375 (6.9 mg). MS m / z (ES): 442.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.62 (s, 1H), 7.87 (d, J = 59.5 Hz, 1H), 7.66 (t, J = 5.6 Hz, 1H), 7.42 - 7.28 (m, 5H), 4.35 (dd, J = 12.1, 5.0 Hz, 1H), 3.02 (d, J = 7.6 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 2.84 - 2.74 (m, 1H), 2.56-2.53 (m, 1H), 2.34-2.32 (m, 1H), 2.07 - 1.99 (m, 1H).

[0905] Example 56 (Compound 407)

[0906] First Step: Synthesis of compound 407a

[0907] Compound 405e (synthesis method refer to the synthesis of compound 405e in the fourth step of compound 405 in Example 36) (100 mg, 0.53 mmol) was dissolved in acetic acid (2 mL), then palladium on carbon (10 mg) was added, and then heated to 85 °C under hydrogen protection and stirred for 12 hours. After the reaction was completed, it was filtered, the filtrate was rotary evaporated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%-10%) to obtain compound 407a (60 mg). MS m / z (ESI): 192.1 [M+1] + .

[0908] Second Step: Synthesis of compound 407b

[0909] Compound 407a (60 mg, 0.31 mmol) was dissolved in dimethyl sulfoxide (2 mL) under nitrogen atmosphere, compound 146e (88 mg, 0.31 mmol), cuprous iodide (18 mg, 0.093 mmol) and potassium carbonate (129 mg, 0.93 mmol) were added, and then the reaction mixture was heated to 120 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-10 / 1) to obtain compound 407b (35 mg). MS m / z (ESI): 345.8 [M+1] + .

[0910] Step 3: Synthesis of compound 407

[0911] Compound 407b (35 mg, 0.1 mmol) was dissolved in 1,4-dioxane (2 mL), and compound 2d (50 mg, 0.1 mmol), potassium phosphate (64 mg, 0.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (7 mg, 0.01 mmol) were sequentially added. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain compound 407 (2.0 mg). MS m / z (ESI): 489.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.46-7.40 (m, 5H), 7.40-7.33 (m, 2H), 4.35 (dd, J = 12.1, 5.0 Hz, 1H), 4.06 (t, J = 6.8 Hz, 2H), 3.92 (t, J = 5.9 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H), 2.86-2.73 (m, 3H), 2.61-2.70 (m, 1H), 2.38-2.30 (m, 1H), 2.12-2.01 (m, 1H), 2.00-1.92 (m, 2H), 1.91-1.82 (m, 2H).

[0912] Example 57 (Compound 514)

[0913] Step 1: Synthesis of compound 514b and compound 514c

[0914] Compound 404b (350 mg, 1.41 mmol) and cesium carbonate (915.6 mg, 2.81 mmol) were dissolved in N,N-dimethylformamide (15 mL), then compound 514a (tert-butyl-(2-iodoethoxy)dimethylsilane) (603.2 mg, 2.11 mmol) was added to the mixture at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. After the reaction was completed, water (40 mL) was added, and the combined organic phases were extracted with ethyl acetate (40 mL x 2), washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-40%) to obtain a mixture of compound 514b and compound 514c (500 mg). MS m / z (ES): 407....

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z is CR 4 or N; R 1 and R 2 are the same or different and each is independently selected from H, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl and C 1-6 haloalkyl; or R 1 and R 2 with the atom to which they are attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein said C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, and C 1-6 alkyl; R 3 selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl and C 3-8 halocycloalkyl; R 4 and R 5 are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxyl, cyano, amino, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R 6 and R 7 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 8 and R 9 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 10 selected from 11-20 membered heterocyclyl, 11-20 membered heteroaryl and -K-R 0 , said 11-20 membered heterocyclyl and 11-20 membered heteroaryl being optionally substituted by one or more R 11 ; or R 10 and R 8 , R 10 and R 9 any one of the groups R 11 together with the phenyl ring to which it is attached form a fused ring group, said fused ring group being a 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl or 11-20 membered heteroaryl being optionally substituted with one or more R K is selected from O, S, NH and N-C 1-6 alkyl; R 0 is 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl and 11-20 membered heteroaryl being optionally substituted with one or more R 11 substituents; R 11 They may be the same or different, and each is independently selected from halogens, deuterium, thiocyanates, oxocyanates, and NR. j C 1-6 Alkyl, -C 1-6 alkylene-5-10 heteroaryl, -C 1-6 alkylene-3-8-membered heterocyclic group, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, hydroxyl, cyano, C(O)R a SF5, S(O) 0-2 R b NR j R k C(O)NR j R k -NR j C(O)R a C(O)OR g S(O)(=NR) j )R b S(O)2NR j R k C 3-8 Cycloalkyl, 3-8 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyloxy and 3-8 membered heterocyclic alkyloxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -C 1-6 alkylene-5-10 heteroaryl, -C 1-6 alkylene-3-8-membered heterocyclic groups, phenyl groups, 5-6-membered heteroaryl groups, C 3-8 Cycloalkyloxy and 3-8 membered heterocyclic alkyloxy groups are optionally surrounded by one or more R v replace; or two R 11 with the atom to which it is attached to form C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 one or more of alkyl, hydroxy, cyano and amino; or two R 11 with the atom to which it is attached to form R 20 and R 21 are the same or different and each is independently selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; R v are the same or different and each is independently selected from halogen, deuterium, C 1-6 alkyl, hydroxyl, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C(O)R a , S(O) 0-2 R b , NR j R k , C(O)NR j R k , -NR j C(O)R a , C(O)OR g , S(O)(=NR j )R b , S(O)2NR j R k , C 6-10 aryl and 5-10 membered heteroaryl; R a selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R b selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, cyano, NR j R k , C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R j and R k are the same or different and each is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; or R j and R k together with the nitrogen atom to which they are attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein said C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C 1-6 alkyl; R g selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 11 are the same or different, and each is independently selected from halogen, deuterium, oxo, =NR j , C 1-6 alkyl, -C 1-6 alkylene-5-10 membered heteroaryl, -C 1-6 alkylene-3-8 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, C(O)R a , SF5, S(O) 0-2 R b , NR j R k , C(O)NR j R k , -NR j C(O)R a , C(O)OR g , S(O)(=NR j )R b , S(O)2NR j R k , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy, and 3-8 membered heterocyclyloxy, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 1-6 alkylene-5-10 membered heteroaryl, and -C 1-6 alkylene-3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy, and 3-8 membered heterocyclyloxy are optionally substituted with one or more R v , R a , R b , R j , R k , R g , and R v are as defined in claim 1; R 20 and R 21 is selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound of Formula (I) is a compound of Formula (I-1) or Formula (I-2): ###0002### (I-1) (I-2) ​ wherein, R 1 , R 2 , R 3 , Z, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in claim 1.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 10 and R 9 together with the phenyl ring to which they are attached form a fused ring group, said fused ring group being an 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl or 11-20 membered heteroaryl being optionally substituted with one or more R 11 . Or, R 10 and R 8 Together with the benzene ring attached thereto, a fused ring group is formed, wherein the fused ring group is an 11-20 membered heterocyclic group or an 11-20 membered heteroaryl group, wherein the 11-20 membered heterocyclic group or the 11-20 membered heteroaryl group is optionally surrounded by one or more R 11 Replaced; R 11 As defined in claim 1.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein selected from: Preferably, selected from: is a single or double bond; X is CR X or CR X R Y ; R X and R Y are the same or different, each being independently selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; G1is selected from CR 11a , CR 11a R 11b , N and NR 11c ; R 11a and R 11b are the same or different, each being independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; or R 11a and R 11b together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; R 11c selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl and C 1-6 hydroxyalkyl; R N selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl and C 1-6 hydroxyalkyl; or R N and R X , R X and R 11a , R X and R 11c , R 11 form, together with the atoms to which they are attached, a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl; said 5-12 membered heterocyclyl and 5-12 membered heteroaryl are optionally substituted with one or more R L 1 and L 2 are the same or different and each is independently selected from a chemical bond, O, S, NR L , S(O), S(O)2, C(O), S(O)(=NR L ), C(O)NR L , S(O)2NR L , C 1-6 alkylene and C 2-6 alkenylene, one, two, three, four or five CH2in said C 1-6 alkylene and C 2-6 alkenylene being optionally the same or different replaced by one or more radicals selected from O, S, NR L , S(O), S(O)2, S(O)(=NR L ), C(O)NR L and S(O)2NR L , said C 1-6 alkylene and C 2-6 alkenylene being optionally substituted by one or more R u ; R u the same or different, and each independently selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or two R u with the atom to which it is attached to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; R L selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1- 6 hydroxyalkyl and C 3-8 cycloalkyl; Ring A is selected from phenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, and 5-10 membered heteroaryl; ring B is selected from 7-12 membered cycloalkyl, 7-12 membered heterocyclyl, and 7-12 membered heteroaryl; The ring C is selected from phenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups and 5-10 membered heteroaryl groups; n is 0, 1, 2, 3, or 4; R 6 , R 7 , R 8 , R 9 and R 11 are as defined in any one of claims 1 to 4.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein selected from is a single or double bond; W1and W2are the same or different, and each independently selected from the group consisting of -0-, -NR w1 -, -CR w2 R w3 -, -C(O)- and -S-; W3is selected from -NR w1 - and -CR w2 R w3 - and -C(O)-; R w1 H, C(O)R a , C 1-6 alkyl and -C 1-6 alkylene-5-10 membered heteroaryl, -C 1-6 alkylene-3-8 membered heterocyclyl, said C 1-6 alkyl, -C 1-6 alkylene-5-10 membered heteroaryl and -C 1-6 alkylene-3-8 membered heterocyclyl is optionally substituted with one or more R v ; R w2 and R W3 are the same or different, each independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; or R w2 and R W3 together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; or R w2 and R W3 together with the atom to which they are attached form R 11a and R 11b together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; R 11x , R 11y , R 11z , R 11u , R 11v , and R 11w are the same or different, each being independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; or R 11x and R 11y , R 11u and R 11v , R 11z and R 11w , taken together with the atom to which they are attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl being optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; or R 11u and R 11w together with the atom to which they are attached form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; or R 11x and R 11y , R 11u and R 11v , R 11z and R 11w any one of the groups R 20 and R 21 are the same or different and each is independently selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; H on NH can be replaced by R 11 ; R 6 , R 7 , R 8 , R 9 , R 11 , R v , R a and n are as defined in any one of claims 1 to 4.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Z is CR 4 ; R 4 as defined in claim 1.

8. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5 or 7, wherein selected from R Y selected from H, halogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, hydroxy, cyano, and amino; R N and R X together with the atom to which they are attached form a 5-12 membered heterocyclyl or 5-12 membered heteroaryl; said 5-12 membered heterocyclyl and 5-12 membered heteroaryl are optionally substituted with one or more R 11 ; G1, R 6 G1, R 7 G1, R 8 G1, R 9 G1, R 11 as defined in any one of claims 1 to 5.

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5 or 7, wherein is L 1 and L 2 are each independently selected from a bond, C 1-4 alkylene, C 2-4 alkenylene, C(O), NR L , O, C(O)NR L , S, S(O), S(O)2, S(O)(=NR L ), S(O)2NR L , a-C 1-3 alkylene-C(O)NR L , a-C(O)NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L C(O)-, a-NR L C(O)-C 1-3 alkylene, a-O-C 1-3 alkylene-, a-C 1-3 alkylene-O-, -O-C 1-3 alkylene-O-, -C 1-3 alkylene-O-C 1-3 alkylene, -C 1-3 alkylene-NR L -C 1-3 alkylene, a-NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L -, a-C(O)-C 1-3 alkylene, a-C 1-3 alkylene-C(O), a-C 1-3 alkylene-S(O) 0-2 , a-S(O) 0-2 -C 1-3 alkylene, -C 1-3 alkylene-S(O) 0-2 -C 1-3 alkylene, a-C 1-3 alkylene-S(O)(=NR L ), a-S(O)(=NR L )-C 1-3 alkylene, -C 1-3 alkylene-S(O)(=NR L )-C 1-3 alkylene, -C 1-3 alkylene-C(O)NR L -C 1-3 alkylene, -C 1-3 alkylene-C(O)-C 1-3 alkylene, a-C 1-3 alkylene-S(O)2NR L , a-S(O)2NR L -C 1-3 alkylene, a-C 1-3 alkylene-NR L S(O)2, a-NR L S(O)2-C 1-3 alkylene and -C 1-3 alkylene-S(O)2NR L -C 1-3 alkylene, a is attached to the phenyl ring, said C 1-4 alkylene, C 1-3 alkylene and C 2-4 alkenylene is optionally substituted by one or more R u ; Preferably, L 1 and L 2 are the same or different, each independently selected from a bond, C 1-3 alkylene, C(O), NH, N(CH3), O, a-O-C 1-3 alkylene-, a-C 1-3 alkylene-O-, a-NH-C 1-3 alkylene, a-C 1-3 alkylene-NH-, a-N(CH3)-C 1-3 alkylene, a-C 1-3 alkylene-N(CH3)-, a-C(O)-C 1-3 alkylene and a-C 1-3 alkylene-C(O), attached at the a-position to the phenyl ring, said C 1-3 alkylene is optionally substituted with one or more substituents selected from halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, cyano, and amino; ring A is selected from phenyl, 5-12 membered heterocyclyl, and 5-10 membered heteroaryl; Preferably, ring A is selected from tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyrimidinyl, dihydropyrimidinyl, pyrrolyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, oxazinyl, pyrazolyl, imidazolyl, imidazolidinyl, imidazolidinonyl, oxazolyl, oxazolidinyl, oxazolidinonyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and phenyl; R 6 , R 7 , R 8 , R 9 , R 11 , R L , R u and n are as defined in any one of claims 1 to 5.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R 10 is 11-20 membered heterocyclyl or 11-20 membered heteroaryl, said 11-20 membered heterocyclyl and 11-20 membered heteroaryl being optionally substituted with one or more R 11 ; R 11 is as defined in claim 1 or 2.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1, 2, 3, 9, 10, wherein R 10 selected from: G2is CR 11d or N; G3and G4are the same or different, each independently selected from the group consisting of CR 11e , CR 11e R 11f , N and NR 11g ; G7is selected from CR 11e R 11f , NR 11g , O and S; R 11d selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; R 11e and R 11f are the same or different, each being independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy, 3-8 membered heterocyclyloxy, SF5, S(O) 0-2 R b , NR j R k , C(O)NR j R k , -NR j C(O)R a , C(O)OR g , S(O)(=NR j )R b , and S(O)2NR j R k , wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyloxy, and 3-8 membered heterocyclyloxy are optionally substituted with one or more selected from halogen, oxo, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; or R 11e and R 11f together with the atom to which they are attached form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; R 11g selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl and C 1-6 hydroxyalkyl; R F selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; R D and R E , R D and R F , R D and R 11d , R E and R 11d , together with the atoms to which they are attached form a 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; said 4-12 membered cycloalkyl, 4-12 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl are optionally substituted with one or more R 11 ; Ring E is selected from phenyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; G5 is C or N; Ring F is selected from phenyl, C 5-8 cycloalkyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl; each R 12 the same or different, each independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; ring Q is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; each R 13 the same or different, each independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; or two R 13 with the atom to which it is attached to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more selected from halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; When R in R D and R F R is absent when the ring is formed E ​ G6 is CR 11h R 11i or NR 11j ; R 11h and R 11i are the same or different, each independently selected from H, halogen, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; R 11j selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl and C 1-6 hydroxyalkyl; m is 0, 1, 2, 3, or 4; f is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; R 11 , R a , R b , R g , R j and R k are as defined in any one of claims 1 to 5.

12. The compound of any one of claims 1, 2, 3, or a pharmaceutically acceptable salt thereof, wherein R 10 is -K-R 0 ; K is O; R 0 is selected from 11-, 12-, 13-, 14-, 15-, or 16-membered heterocyclyl and 11-, 12-, 13-, 14-, 15-, or 16-membered heteroaryl.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1, 2, 3, wherein R 0 selected from: G2is CR 11d or N; V4 is C or N; V1, V2, and V3 are selected from any combination of the following: (1) V1is selected from N, O, S, CR 11d and CR 11e R 11f ; V2is CR E ; V3is NR D ; (2) V1is selected from N, O, S, CR 11d and CR 11e R 11f ; V2is NR D ; V3is CR E ; (3) V1 is CR E ; V2 is NR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ; (4) V2 is CR E ; V1 is NR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ; (5) V1 is CR E ; V2 is selected from N, O, S, CR 11d and CR 11e R 11f ; V3 is NR D ; (6) V1 is NR D ; V2 is selected from N, O, S, CR 11d and CR 11e R 11f ; V3 is CR E ; (7) V1is selected from N, O, S, CR 11d and CR 11e R 11f ; V2is CR E ; V3is CR D ; (8) V1is selected from N, O, S, CR 11d and CR 11e R 11f ; V2is CR 11 R E ; V3is CR D ; (9) V1 is selected from N, O, S, CR 11d and CR 11e R 11f ; V2 is CR D ; V3 is CR 11 R E ; (10) V1 is CR E ; V2 is CR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ; (11) V1 is CR 11 R E ; V2 is CR D ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ; (12) V1 is CR D ; V2 is CR 11 R E ; V3 is selected from N, O, S, CR 11d and CR 11e R 11f ; R D and R E together with the atom to which they are attached form a 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl; said 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl optionally substituted with one or more R 11 . R 11 , R 11d , R 11e , R 11f As defined in claim 11.

14. The compound or pharmaceutically acceptable salt thereof of claim 11, wherein, ring E is selected from phenyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl; ring F is selected from phenyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl; ring Q is selected from 7-10 membered monocyclic cycloalkyl, 7-10 membered spiro cycloalkyl, 7-10 membered bridged cycloalkyl, 7-10 membered monocyclic heterocyclyl, 7-10 membered spiro heterocyclyl, and 7-10 membered bridged heterocyclyl.

15. The compound of any one of claims 1, 2, 10, 11, and 14, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from one or more groups of the following: (1) R 10 selected from the group consisting of: R D and R E the ring formed together with the atom to which it is attached is selected from Optionally, the H on NH can be replaced by R 11 ; G2, G3, G4, R 11e , R 11f , R 11 and m are as defined in any one of claims 1-9; (2) R 10 selected from the group consisting of: G6 is CR 11h R 11i or NR 11j ; T is selected from CR 11h R 11i , NR 11j , O and S; R 11h and R 11i are the same or different, each being independently selected from H, halo, deuterium, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, hydroxy, cyano, and amino; R 11j selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl and C 1-6 hydroxyalkyl; Y 1 and Y 2 are the same or different and each independently CR 11a or N; Y 3 selected from CR 11a R 11b , NR 11c , O and S; Y 4 selected from N or CR 11a ; p is 0, 1, 2, 3, or 4; R 11 , R 11a , R 11b and m are as defined in any one of claims 1 to 12; (3) R 10 selected from the group consisting of: Each R 12 Whether the elements are the same or different, they are each independently selected from H, halogens, deuterium, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, hydroxyl, cyano, and amino groups; each R 13 Whether the elements are the same or different, they are each independently selected from H, halogens, deuterium, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, hydroxyl, cyano, and amino groups; f is 0, 1, or 2; q is 0, 1, or 2.

16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein: R 1 is selected from H, deuterium, and halogen; preferably, R 1 is H.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-16, wherein: R 2 is halogen; preferably, R 2 is CI.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-17, wherein, R 3 , R 4 , and R 5 are the same or different and each is independently selected from the group consisting of H, halogen, and C 1-6 alkyl.

19. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-18, wherein, R 6 , R 7 , R 8 and R 9 are the same or different and each is independently selected from H, halogen and C 1-6 alkyl.

20. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from halogens, deuterium, oxometalates, and carbon. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, hydroxy, cyano, amino, -C 1-3 alkylene-5-6-membered heteroaryl, C(O)C 1-3 Alkyl, S(O)2C 1-3 Alkyl, NH(C) 1-3 Alkyl), N(C) 1-3 Alkyl)2, NHC(O)C 1-3 Alkyl, NHC(O)C 3-6 cycloalkyl, -SC 1-3 Alkyl, SF5, -S(O)C 1-3 Alkyl group, -S(O)2C 1-3 Alkyl group, S(O)2NH2, S(O)2NH(C 1-3 Alkyl), S(O)2N(C 1-3 Alkyl)2, C(O)NH2, C(O)NH(C 1-3 Alkyl), C(O)N(C 1-3 Alkyl)2, C(O)OC 1-3 Alkyl group, S(O)(=NH)C 1-3 Alkyl, S(O)(=NCH3)C 1-3 Alkyl, C 3- 8-cycloalkyl, 3-8-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C 3-8 Cycloalkyloxy and 3-8 membered heterocyclic alkyloxy, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-8 cycloalkyl, -C 1-3 alkylene-5-6-membered heteroaryl, 3-8-membered heterocyclic, phenyl, 5-6-membered heteroaryl, C 3-8 Cycloalkyloxy and 3-8 membered heterocyclic alkyloxy groups are optionally surrounded by one or more R v replace; or two R 11 with the atom to which it is attached to form a C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, said C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, oxo, C 1-6 alkyl and C 1-6 haloalkyl; R v selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, C(O)C 1-3 alkyl, S(O)2C 1-3 alkyl, NH(C 1-3 alkyl), N(C 1-3 alkyl)2, S(O)2NH2, S(O)2NH(C 1-3 alkyl), S(O)2N(C 1-3 alkyl)2, C(O)NH2, C(O)NH(C 1-3 alkyl), C(O)N(C 1-3 alkyl)2, C(O)OC 1-3 alkyl, S(O)(=NH)C 1-3 alkyl, S(O)(=NCH3)C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; Preferably, R 11 Selected from halogens, deuterium, oxometalates, and carbon. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 1-6 Hydroxyalkyl, C 1-3 Alkoxy, hydroxy, cyano, amino, C(O)C 1-3 Alkyl, C(O)NH(C) 1-3 Alkyl), C(O)N(C 1-3 Alkyl)2, S(O)2C 1-3 Alkyl and C 3-6 Cycloalkyl.

21. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-20, wherein, The compounds have the following structures:

22. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-21, wherein, The compound has the following structure:

23. A pharmaceutical composition comprising at least one prophylactically and / or therapeutically effective amount of a compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

24. Use of a compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 23, for the manufacture of a medicament for degrading VAV1 protein.

25. Use of a compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 23, for the manufacture of a medicament for mediating the interaction of VAV1 protein with an E3 ligase, thereby increasing the degradation of VAV1 protein; preferably, the compound interacts with the E3 ligase prior to the interaction of VAV1 protein with the E3 ligase.

26. Use of a compound according to any one of claims 1-22, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 23, for the manufacture of a medicament for preventing and / or treating a disease or disorder caused by or associated with a disorder in the development or activity of lymphocytes, preferably T cells.

27. Use of a compound, a pharmaceutically acceptable salt thereof according to any one of claims 1-22 or a pharmaceutical composition of claim 23 in the manufacture of a medicament for the prevention and / or treatment of an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease or a cancer; preferably, the autoimmune disease is selected from multiple sclerosis, rheumatoid arthritis, systemic lupus, thyroiditis, myasthenia gravis, type I diabetes, type II diabetes, vasculitis, pernicious anemia, dry eye, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata, allergic asthma, atopic dermatitis, allergic dermatitis, rhinitis, conjunctivitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

28. A method of preparing a compound of formula (I) comprising the steps of: The compound of formula (IA) is coupled with a compound of formula (IB) in the presence of a catalyst to give a compound of formula (I) wherein: R t for X is halogen; preferably, X is Br or I; R 1 , R 2 , R 3 , Z, R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in any one of claims 1-19.

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