Kras inhibitor compound

Abstract

A compound of formula (A) and a pharmaceutical composition comprising the compound, and use of the compound of formula (A) in preventing and / or treating cancers, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

Description

A KRAS inhibitor compound Technical Field

[0001] This invention relates to a compound, and more particularly to a highly active KRAS inhibitor and its uses. Background Technology

[0002] RAS is one of the most frequently mutated genes in human tumors, occurring in approximately 30% of cancer patients, with KRAS accounting for about 85% of RAS mutations. KRAS mutations are found in 88% of pancreatic cancers, 50% of colorectal adenocarcinomas, and 32% of lung adenocarcinomas, making the development of KRAS-targeting inhibitors of great clinical significance and value.

[0003] KRAS is a membrane-bound protein with GTPase activity. It acts as a "molecular switch" by cycling between the GDP-binding inactive conformation and the GTP-binding active conformation through nucleotide exchange. In its GTP-bound state, KRAS can activate multiple downstream signaling pathways, including RAF-MEK-ERK and PI3K-AKT, to regulate life processes such as cell growth, proliferation, differentiation, and apoptosis.

[0004] KRAS mutations (such as G12C, G12D, G12V, G13D, etc.) affect GTP hydrolysis mediated by GTPase activating proteins (GAPs), increasing the number of KRAS in a GTP-bound activated state, overactivating downstream signaling pathways, and ultimately leading to tumorigenesis and development. However, because the KRAS protein lacks a corresponding hydrophobic pocket suitable for drug binding, and its affinity for GTP and GDP is in the picomolar range (~20 pM), the development of inhibitors that competitively bind to KRAS is extremely difficult. For decades, KRAS has been considered an untreatable target.

[0005] In May 2021, AMG510 was approved by the FDA for the treatment of patients with KRAS. G12C Locally advanced or metastatic non-small cell lung cancer with mutations has broken the historical barrier that KRAS was "untreatable." However, G12C mutations only account for a small fraction of KRAS mutations. For mutations at other sites in KRAS, there is currently a lack of satisfactory and effective inhibitory compounds, leaving a large unmet clinical need. Therefore, developing effective KRAS inhibitory compounds targeting other mutations is a necessary step in the current technological landscape. Summary of the Invention

[0006] This invention provides a KRAS inhibitor. This structure functions by mediating the formation of a ternary complex between KRAS protein and a ubiquitous intracellular chaperone protein (such as Cyclophilin A). This mechanism was previously reported by Revolution Medicines (Tanaka et al., 2021, Cancer discovery, 11(8), 1913–1922). The formation of the ternary complex can sterically block the binding of KRAS to its downstream effector molecules (such as RAF), inhibiting the activation of MAPK and PI3K-AKT signaling pathways, thereby inhibiting tumor development and progression, and playing a therapeutic role in diseases such as cancer.

[0007] In one aspect, the present invention provides a compound having the structure of formula (A), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0008] in:

[0009] Cy a express or It may optionally be selected from 0, 1, 2 or 3 halogens or C 1 -C 3 Alkyl substituents;

[0010] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. xA replace;

[0011] B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace;

[0012] W represents H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a '、CN、-C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a'、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a '; or W represents expression (D), where * represents connection to L2:

[0013] E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace;

[0014] X represents O or N-R8;

[0015] L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S;

[0016] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0017] Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0018] R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR aOr -NR a R a ';

[0019] R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a '、-(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be independently replaced by a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0020] R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a-OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl);

[0021] R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace;

[0022] R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace;

[0023] R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace;

[0024] R 10 Indicates hydrogen or C1-C3 alkyl;

[0025] R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0026] Cy0 represents a 5-12 bivalent aromatic ring or a heterocyclic aromatic ring;

[0027] R A Each is independently selected from H, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a '、-(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene, C1-C6 alkyl, or C1-C6 haloalkyl group can be replaced with a carbonyl group, -NR a-, -O-, or -S-, and optionally, each of the C0-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of the C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O-, -O-, -S-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0028] And optionally, R on two adjacent or non-adjacent atoms on Cy0 A Together with the CyO ring atoms, a 6-10 membered ring can be formed, which can be further substituted by 0, 1, 2, 3, or 4 substituents selected from the following: halogen, C1-C3 alkyl, -OR. a -SR a Or -NR a R a ';

[0029] L0 is selected from single bonds, C1-C6 alkylene groups, and C2-C6 alkenyl groups, wherein any methylene group on the C1-C6 alkylene or C2-C6 alkenyl group can be replaced by a carbonyl group or -NR. a-, -O- or -S-, and the C1-C6 alkylene or C2-C6 alkenylene may optionally be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl;

[0030] R C Selected from H, halogens, C1-C6 alkyl groups, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a Or -(C0-C6 alkylene)-NR a R a ';

[0031] R D Selected from H, C1-C6 alkyl, -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a ';

[0032] R E R F Each is independently selected from H, C1-C6 alkyl, halogen, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a Or -(C0-C6 alkylene)-NR a R a '; and optionally, R E R F It can form 3-6 membered rings with the C atoms attached to them, and the 3-6 membered rings can also contain 0, 1 or 2 heteroatoms selected from N, O or S;

[0033] Z represents N or CR3, Z' represents N or CR3', where R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN;

[0034] m, n, and q each independently represent 0, 1, 2, or 3;

[0035] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0036] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0037] In one aspect, the present invention provides a compound having the structure of formula (B), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0038] in:

[0039] --- indicates a single or double bond;

[0040] X1 and X2 can each independently represent C or N;

[0041] Y1, Y2, and Y3 independently represent non-bonded, single-bonded, and CR bonds, respectively. A 、N、NR1'、O、S;

[0042] Wherein, R1 and R1' independently represent C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), and -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a ', any methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently replaced by a carbonyl group or -NR group. a -, -O-, or -S-, and optionally, the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl and 4-8 membered heterocycloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl groups, -OR-, -O ... a -SR a -NR a R a', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0043] Where Y3 is CR A Optionally, R1 can be connected to R of Y3. A The substituent, together with the attached N, X1, and C atoms, forms a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3, or 4 substituents selected from: halogens, C1-C3 alkyl groups, -OR groups. a -SR a Or -NR a R a ';

[0044] t is selected from 0, 1, 2, or 3;

[0045] W, Cy a ,Cy1,Cy2,L1,L2,m,n,A,B,E,X,R A R C R D R E R F ,Z,Z',R2,R4,R5,R6,R7,R7',R9,R9',R 10 The definitions of and are as described in equation (A).

[0046] In one aspect, the present invention provides a compound having the structure of formula (C), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0047] in,

[0048] Cy a express or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups;

[0049] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. xA replace;

[0050] B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace;

[0051] E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace;

[0052] X represents O or N-R8;

[0053] L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S;

[0054] W represents H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a '、CN、-C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NRa C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a '; or W represents expression (D), where * represents connection to L2:

[0055] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0056] Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0057] R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocyclic alkyl), -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a ', any methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently replaced by a carbonyl group or -NR group. a -, -O-, or -S-, and optionally, the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl and 4-8 membered heterocycloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl groups, -OR-, -O ... a -SR a -NR a R a', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0058] R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a ';

[0059] R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN;

[0060] R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a '、-(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be independently replaced by a carbonyl group, -NR a-, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0061] R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2Ra -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl);

[0062] R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace;

[0063] R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace;

[0064] R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace;

[0065] R 10 Indicates hydrogen or C1-C3 alkyl;

[0066] R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -ORa -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0067] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0068] m and n can each independently represent 0, 1, 2 or 3;

[0069] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0070] In one aspect, the present invention provides a compound having the structure of formula (I), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0071] in:

[0072] Cy a express or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups;

[0073] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. xA replace;

[0074] B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace;

[0075] E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace;

[0076] X represents O or N-R8;

[0077] L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S;

[0078] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0079] Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0080] R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocyclic alkyl), -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a 'The methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, or C1-C6 haloalkyl group can be replaced with a carbonyl group or -NR group.' a-, -O-, or -S-, and optionally, each of the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of the C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl, -OR-, -O-, -O-, -S-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0081] R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a ';

[0082] R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN;

[0083] R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SRa -(C0-C6 alkylene)-NR a R a ', -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be replaced with a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0084] R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a-C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl);

[0085] R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace;

[0086] R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace;

[0087] R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace;

[0088] R 10 Indicates hydrogen or C1-C3 alkyl;

[0089] R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0090] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0091] m and n can each independently represent 0, 1, 2 or 3;

[0092] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0093] In one aspect, the present invention provides a compound having the structure of formula (II), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0094] in:

[0095] Cya said or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups;

[0096] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5-membered heteroaryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, and the 5-membered heteroaryl group can be independently represented by 0, 1, or 2 R's. xA replace;

[0097] B represents a 5-membered heteroaryl group, which may optionally contain 0, 1, or 2 R groups. xB replace;

[0098] X represents O or NR 8 ;

[0099] L1 and L2 each independently represent a single bond or a -(C1-C3)alkylene group, wherein any methylene group can be replaced by a carbonyl group or -NR. a -、-O- or -S-;

[0100] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl or 4-12 membered heterocyclic alkyl groups can be spirocyclic, bridged, or fused.

[0101] Cy2 represents a C3-C4 cycloalkyl or a 4-membered heterocyclic alkyl;

[0102] Q can independently represent -CH2-, -O-, -S-, or -NH-;

[0103] a, b, c, and d each independently represent 1, 2, or 3;

[0104] p and q can each independently represent 0, 1, or 2;

[0105] R xE Each is independently selected from oxo, C1-C3 alkyl groups.

[0106] R1 represents a C1-C6 alkyl or a C1-C6 haloalkyl;

[0107] R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and -OR. a -SR a -NR a R a ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0108] R7 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl);

[0109] R8 represents hydrogen, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl or C3-C6 cycloalkyl;

[0110] R9 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0111] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0112] m and n can each independently represent 0, 1, or 2;

[0113] R xB Each is independently selected from hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0114] R xA Each is independently selected from hydrogen, hydroxyl, halogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0115] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0116] In one aspect, the present invention provides a compound having the structure of formula (III), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0117] in,

[0118] Cya said or

[0119] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5-membered heteroaryl group, wherein the phenylene group may be substituted with 0, 1, or 2 hydroxyl groups, halogens, C1-C3 alkyl groups, or C1-C3 haloalkyl groups;

[0120] B indicates or

[0121] Cy1 represents a 4-8 membered heterocyclic alkyl group, wherein the ring can be a spirocyclic, bridged, or fused ring.

[0122] Cy2 represents a 4-membered heterocyclic alkyl group;

[0123] Q can represent -CH2- or -O- independently;

[0124] a, b, c, and d each independently represent 1, 2, or 3; R1 represents ethyl or trifluoroethyl;

[0125] R5 and R6 each independently represent hydrogen, halogen, -OH, -NH2, and C1-C3 alkyl groups;

[0126] R7 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0127] R8 represents hydrogen, -C(O)R a -S(O)2R a methyl or cyclopropyl;

[0128] R9 represents hydrogen, methyl, or cyclopropyl;

[0129] R a R a Each can independently represent either hydrogen or a C1-C3 alkyl group;

[0130] m and n each independently represent 0 or 1;

[0131] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0132] In one aspect, the present invention also provides a pharmaceutical composition comprising the compound described herein, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0133] In one aspect, the present invention also provides the use of the compounds described herein, their isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described herein, in the preparation of medicaments for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

[0134] In one aspect, the present invention provides methods for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases, comprising administering to mammals in need of such treatment the compounds of the present invention, their isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof.

[0135] It is particularly noteworthy that, in this article, when referring to a “compound” of a structure, the term generally also includes its stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives.

[0136] As is known to those skilled in the art, the salts, solvates, and hydrates of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noteworthy that when referring to a compound with a certain structure herein, its pharmaceutically acceptable salts are generally also included, and further included, its solvates and hydrates.

[0137] Similarly, when referring to a compound in this article, its prodrug, metabolites, and nitrogen oxides are generally also included. Detailed Implementation

[0138] Terminology Definition

[0139] Chemical terminology

[0140] Unless otherwise stated, the terms used in this application, including those in the specification and claims, are defined as follows.

[0141] In this application, unless the context clearly indicates otherwise, the term "a (one)" means "one or more". As used herein, "another" means at least a second or more.

[0142] Although this disclosure supports the definition of "and / or" only, the term "or" is used to mean "and / or" unless it is explicitly stated that it refers only to an option or that the options are mutually exclusive.

[0143] Unless the context clearly indicates otherwise, the terms “comprising” or “including” should be understood to encompass the listed components or steps, whether the components or steps are presented alone or in combination with one or more additional components or steps.

[0144] As used herein, endpoints are included when providing a range.

[0145] As used herein, the term "about" is used to refer to a numerical value that includes the standard deviation of the error of the means or method used to determine that value. In some embodiments, the term "about" refers to a range of a numerical value along any direction (greater or less than) within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or a lower percentage of that value, unless otherwise specified or otherwise apparent from the context (e.g., when the number would exceed 100% of the possible value).

[0146] In this invention, when the connection direction of the listed linking groups is not specified, the connection direction is arbitrary, for example... In this case, L stands for -C(O)NH-. -C(O)NH- can be formed by connecting the phenyl group and the cyclohexyl group in a left-to-right reading order. Alternatively, the phenyl and cyclohexyl groups can be connected in the reverse reading order from left to right to form the structure. The combination of the linking group and the linked group is only permitted if it results in a stable compound. In some preferred embodiments of the invention, the order is read from left to right.

[0147] Unless otherwise defined, the substituents in this invention are independent of each other and not related to each other, for example (enumerating rather than exhaustively listing), in one aspect, for R in the substituents a (or R) a Regarding R, it is independent of the definitions of different substituents. Specifically, for R a (or R) a Choosing a meaning among substituents does not mean that R a (or R) a The same meaning applies to all other substituents. More specifically, for example (not exhaustive list only) for NR... a R a In 'middle, when R a (or R) a When the meaning of ') is taken from hydrogen, it does not mean that in -OR a Or -C(O)-NR a R a R in ' a (or R) a ') must be hydrogen, and they can each independently represent those selected from R a (or R) aOther substituents in the definition of '). In another aspect, when a substituent contains more than one R... a (or R) a When '), these R a (or R) a ') are also independent. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n In the case where m+n is greater than or equal to 2, there are m+n R values. a (or R) a ') are independent and can represent selections from R a (or R) a The same or different substituents in the definition of ').

[0148] Unless otherwise defined, the meaning of "substituted by x A substituents or B substituents" as described in this invention is the same as "substituted by x substituents selected from A and B," and when the number of substituents is greater than 1, the x substituents may be the same or different. For example, "R1 may be substituted by 0, 1, or 2 R..." x "Replace" means that R1 can be optionally selected from R1 by 0, 1, or 2. x Substituents are substituted, and when the number of substituents is greater than one, these substituents can be derived from R. x Refers to the same or different substituents. For example, "R1 may be substituted with 0, 1 or 2 H, C1-C3 alkyl or C3-C6 cycloalkyl" means that R1 may optionally be substituted with 0, 1 or 2 substituents selected from H, C1-C3 alkyl or C3-C6 cycloalkyl, and when the number of substituents is greater than 1, these substituents may be the same or different. For example, when the number of substituents is 2, these 2 substituents may be, for example, 2 H, may be, for example, 2 C1-C3 alkyl, may be, for example, one is H and the other is C1-C3 alkyl, may be, for example, one is C1-C3 alkyl and the other is C3-C6 cycloalkyl.

[0149] Unless otherwise defined, the phrase "and the two substituents form a ring" as described in this invention means that two monovalent or polyvalent residues derived from the removal of one or more H atoms from each of the two substituents or any group form one or more covalent bonds, which can be single, double, or triple bonds, thereby forming a cyclic structure together with the same atom attached to them, or together with different atoms attached to them and the atoms between them. This description is a description of the structure, without regard to whether the two substituents can form a ring through a chemical reaction or what kind of chemical reaction is required to form a ring. All stable or chemically feasible cyclic structures formed by the above description are included within the scope of this invention. If further characteristic descriptions are provided (e.g., "forming a 4-12 membered heterocycle", "the ring comprises a monocyclic, bridged, or spirocyclic ring", "the ring may also contain one or two heteroatoms selected from N, O, or S", or "the ring may also be substituted by one or two substituents selected from Rz"), then the above-described cyclic structure may additionally have the features described therein.

[0150] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl group is optionally substituted”). It is not intended that the characteristic “X” (e.g., alkyl) itself is optional. As described herein, certain compounds may contain one or more “optionally substituted” moieties. Generally, the term “substituted”, whether preceded by the terms “optionally” or “arbitrarily”, means that one or more hydrogens of the specified moiety are replaced by suitable substituents, such as any of the substituents or groups described herein. Unless otherwise indicated, a “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. For example, in the term “optionally substituted C1-C6 alkyl-C5-C6 heteroaryl,” the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The combinations of substituents contemplated in this disclosure are preferably combinations that form stable or chemically viable compounds. As used herein, the term "stable" means that a compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and, in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein. In this document, "any substitution" has the same meaning as "optional substitution." Unless otherwise defined, "optional substitution" can refer to substitution by a monovalent substituent and / or a divalent substituent.For example, the monovalent substituent is selected from the following substituents, such as hydrogen, alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylanoylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylanoylamino, thio, alkylthio, arylthiothio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl (e.g., -SO2NH2), substituted sulfonylamino, nitro, cyano, carboxyl, ammonia The substituents may be alkyl, such as -CONH2; substituted carbamoyl, such as -CONHalkyl, -CONHaryl, -CONHarylalkyl; or have two substituents selected from alkyl, aryl, or arylalkyl on nitrogen; alkoxycarbonyl; aryl; substituted aryl; guanidine; heterocyclic, such as indolyl; imidazolyl; furanyl; thiophene; thiazolyl; pyrrolyl; pyridyl; pyrimidinyl; pyrrolyl; piperidinyl; morpholinyl; piperazinyl; homopiperazinyl; and substituted heterocyclic groups; for example, divalent substituents may be selected from the following substituents: =O, =S, =NNRr2, =NNHC(O)Rr, =NNHC(O)ORr, =NNHS(O)2Rr, =NRr, =NORr, and alkylene (e.g., -(C(Rr2)). 2-3 -、-(C(Rr2)) 2-3 O-、-O(C(Rr2)) 2-3 -、-O(C(Rr2)) 2-3 O-, -S(C(Rr2))2-3S-), etc., where Rr can represent hydrogen, alkyl, heteroalkyl, aromatic group, heteroaryl, etc.

[0151] Unless otherwise defined, the terms “single bond” or “bond” or “direct bond” as used herein refer to two atoms connected by a single saturated covalent bond. For example, when L represents a single bond, “ALB” means that A and B are connected by a single saturated covalent bond, i.e., “AB”; as another example, when L represents a single bond, “-CH2-L-NH-” means that -CH2- and -NH- are connected by a single saturated covalent bond, i.e., “-CH2-NH-”.

[0152] As used herein, the term "alkyl" or "alkylene" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). Alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable link, preferably from one or more of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In this document, alkyl is an alkyl group having 1 to 12 carbon atoms, preferably having 1 to 10, 1 to 8, 1 to 6, 1 to 4, and more preferably having 1 to 4 carbon atoms.

[0153] As used herein, the term "alkylene" is intended to include branched, straight-chain, saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, comprising or not comprising cyclic alkyl groups, which are residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. For example, "C0-C6 alkylene" means an alkylene having 0 (i.e., bond), 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (e.g., -(CH2)3-, -(CHCH3)CH2-, -(CHCH2CH)-), butylene (e.g., -(CH2)4-, -CH2CH(CH2CH3)-, -CH2(CHCH2CH)-, etc.), and pentylene (e.g., -(CH2)5-, -CH2CH(CH(CH3)2)-, -CH2(CH... (e.g., CH2CH)CH2-), hexanediol (e.g., -(CH2)6-, -CH2CH2CH(CH(CH3)2)-, -CH2(CHCH(CH3)CH)CH2-, etc.). In this document, alkylene groups are preferably alkylene groups having 0-6, 0-4, 0-3, 0-2, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-3 carbon atoms. In this document, alkylene groups are preferably alkylene groups that do not contain cyclic alkyl groups.

[0154] Similarly, the term "X-subgroup" or "X-subgroup" as used herein is intended to include divalent residues derived by removing two hydrogen atoms from the same atom or two different atoms of the parent compound X. The parent compound X is defined as in other paragraphs herein. For example, X can be alkyl, cycloalkyl, heterocycloalkyl, or phenyl, and correspondingly, X-subgroup represents alkylene, cycloalkylene, heterocycloalkylene, or phenylene.

[0155] The term "cycloalkyl" refers to monocyclic, polycyclic, or branched cycloalkyl groups. For example, C3-C 12 Cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". In this invention, cycloalkyl groups are preferably saturated carbocyclic. Polycyclic cycloalkyl groups, such as bicyclic and tricyclic cycloalkyl groups, include bridged rings, spirocyclic, or fused ring cycloalkyl groups. In this invention, cycloalkyl groups are preferably C3-C6. 12 Cycloalkyl, C3-C8 cycloalkyl, C8-C 12 Cycloalkyl, C3-C7 cycloalkyl, C8-C 12 Cycloalkyl, C4-C8 cycloalkyl, C5-C 10 Cycloalkyl, C3-C6 cycloalkyl. For example, in some embodiments, the cycloalkyl group in monocyclic form is C3-C8, C3-C6, or C5-C6. In some embodiments, the cycloalkyl group in bicyclic form is C7-C6. 12 In some embodiments, the cycloalkyl group in spirocyclic form is C5-C6. 12 Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridging bicyclic cycloalkyl groups include, but are not limited to, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The cycloalkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0156] The term “heteroalkyl” refers to an alkyl group as defined herein, wherein one or more carbon atoms in the chain are replaced by heteroatoms selected from O, S and N.

[0157] Similarly, the term "heterocyclic alkyl" refers to a cyclic structure in which at least one carbon atom in the cycloalkyl ring is replaced by a heteroatom selected from N, O, S, and P. The N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, SO, and SO2). It includes monocyclic, bicyclic, and tricyclic heterocyclic systems, wherein bicyclic and tricyclic heterocyclic systems include spirocyclic, fused, and bridged heterocyclic rings. Heterocyclic alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable junction. The substituents are preferably one or more selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, alkyl groups, alkoxy groups, haloalkyl groups, cycloalkyl groups, heterocyclic alkyl groups, aryl groups, and heteroaryl groups. In this invention, the heterocyclic alkyl group is preferably a 4-12 membered heterocyclic alkyl group, more preferably a 4-8 membered heterocyclic alkyl group.

[0158] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds and typically having a length of 2 to 20 carbon atoms, and includes groups having "cis" and "trans" orientations, or optionally "E" and "Z" orientations. For example, "C2-C6 alkenyl" is an alkenyl group containing two to six carbon atoms and having one, two, or three carbon-carbon double bonds. In some instances, the alkenyl group is C2-C... 18 alkenyl, C2-C 16 alkenyl, C2-C 14 alkenyl, C2-C 12 alkenyl, C2-C 10 The alkenyl group can be C2-C8, C2-C6, C2-C4, or C2-C3. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, and 1-methyl-2-buten-1-yl. In this invention, the alkenyl group is preferably C2-C6. In this invention, the alkenyl group preferably contains one or two double bonds, more preferably one double bond.

[0159] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more carbon-carbon triple bonds and typically ranging from 2 to 20 carbon atoms in length. For example, "C2-C6 alkynyl" is an alkynyl group containing two to six carbon atoms and having one, two, or three carbon-carbon triple bonds. In some instances, the alkenyl group is C2-C... 18 alkynyl group, C2-C 16 alkynyl group, C2-C 14 alkynyl group, C2-C 12 alkynyl group, C2-C 10The alkynyl group can be C2-C8, C2-C6, C2-C4, or C2-C3. Representative alkynyl groups include, but are not limited to, ethynyl, propynyl-1-yl (-C≡C-CH2), propynyl-2-yl (propynyl, -CH2-C≡CH), butynyl-1-yl, butynyl-2-yl, and butynyl-3-yl. In this document, the alkynyl group is preferably C2-C6 alkynyl.

[0160] The term "cycloalkenyl" refers to a non-aromatic hydrocarbon cyclic group having at least one carbon-carbon double bond. Cycloalkenyl encompasses monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged cyclic systems. Examples include C3-C8 cyclic alkenyl groups, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norcamphenyl. Examples of monocyclic cycloalkenyl groups include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohexen-3-enyl, and cyclohexadienyl. Exemplary arrangements of bicyclic cycloalkenyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] cyclic systems. Exemplary bridging bicyclic cycloalkenyl groups include, but are not limited to, bicyclic [2.2.1]heptene, bicyclic [2.2.2]octene, and bicyclic [3.2.2]nonene. Examples of spirocycloalkyl groups include spiro[2.2]pentene, spiro[2.3]hexene, spiro[2.4]heptene, spiro[2.5]octene, and spiro[4.5]decene. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are also included in the definition of "cycloalkenyl". In some embodiments of the invention, the cycloalkenyl group is C3-C5 cycloalkenyl, C3-C6 cycloalkenyl, C3-C7 cycloalkenyl, C3-C8 cycloalkenyl, C3-C9 cycloalkenyl, C3-C 10 Cycloalkenyl, C3-C 11 Cycloalkenyl, C3-C 12 Cycloalkenyl.

[0161] Similarly, "cycloalkynyl" refers to a non-aromatic hydrocarbon cyclic group having at least one carbon-carbon triple bond. Cycloalkynyl groups encompass monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged ring systems. In some embodiments of the present invention, the cycloalkynyl group is C3-C5 cycloalkynyl, C3-C6 cycloalkynyl, C3-C7 cycloalkynyl, C3-C8 cycloalkynyl, C3-C9 cycloalkynyl, C3-C... 10 Cycloalkynyl, C3-C 11 Cycloalkynyl, C3-C 12 Cycloacetic group.

[0162] Similarly, the term "heterocyclic alkenyl" refers to a non-aromatic heterocyclic group having at least one carbon-carbon double bond. Heterocyclic alkenyls encompass monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged ring systems.

[0163] Similarly, the term "heterocyclic ynyl" refers to a non-aromatic heterocyclic group having at least one carbon-carbon triple bond. Heterocyclic ynyl encompasses monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged ring systems.

[0164] The term "aryl" or "aromatic ring" refers to a carbocyclic aromatic group having a specified number of carbon atoms. If the number of carbon atoms is not specified, it is at most 14 carbon atoms. The aryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable junction. The substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some embodiments of the invention, the aryl group includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, 2-naphthyl, etc.

[0165] The term "heteroaryl" refers to an aromatic heterocycle having at least one monocyclic or fused polycyclic ring selected from oxygen, nitrogen, and sulfur. Suitable heteroaryl groups do not include ring systems such as pyranium that must be charged to be aromatic. Heteroaryl groups can be stable 5-, 6-, or 7-membered aromatic monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocycles. A suitable 5-membered heteroaryl ring (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) has one oxygen, sulfur, or nitrogen ring atom, or one nitrogen plus one oxygen or sulfur, or 2, 3, or 4 nitrogen ring atoms. A suitable 6-membered heteroaryl ring (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) has 1, 2, or 3 nitrogen ring atoms. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. The heteroaryl group can be unsubstituted or substituted, and if the resulting compound is stable, the heterocyclic group described herein can be substituted at any usable connection point, wherein the substituent is preferably one or more of halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indoleyl, benzimidazolyl, benzofuranyl, cenolinyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, pteridinyl, purine, oxadiazolyl, triazolyl, thiazolyl, furazanyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, and furopyridyl. The term "heteroaryl" may also include biaryl structures formed by an "aryl" as defined above and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridinyl-", "-phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", and "-pyrimidinylbiphenyl-"; wherein the present invention also includes fused-ring and spirocyclic compounds containing, for example, the rings described above.

[0166] The term "heterocyclic" or "heterocyclic group" refers to any monocyclic, bicyclic, polycyclic, fused, spirocyclic, or bridged non-aromatic ring system that is fully saturated, partially unsaturated, or fully unsaturated, having, for example, 3 to 20 ring atoms, wherein the ring atoms are carbon, and at least one carbon atom is replaced by a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the cyclic system is a heteroatom, the system is a heterocyclic system, regardless of the connection points between the cyclic system and the rest of the molecule. In one example, a heterocyclic group comprises 3-11 ring atoms ("members") and includes monocyclic, bicyclic, tricyclic, spirocyclic, and bridged ring systems, wherein the ring atoms are carbon, and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclic group comprises 4-10 or 5-10 ring atoms. In one example, a heterocyclic group comprises 1 to 4 heteroatoms. In one example, a heterocyclic group comprises 1 to 3 heteroatoms. In another example, the heterocyclic group comprises a 3- to 7-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, the heterocyclic group comprises a 4- to 6-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, the heterocyclic group comprises a 3-membered monocyclic ring. In another example, the heterocyclic group comprises a 4-membered monocyclic ring. In another example, the heterocyclic group comprises a 5- to 6-membered monocyclic ring. In some embodiments, the heterocyclic alkyl group comprises at least one nitrogen atom. In one example, the heterocyclic group comprises 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4+]Cl-, [NR4+]OH-).Examples of heterocycles include ethylene oxide, aziridinyl, thiohexacyclopropane, aziridinyl, oxetane, thiohexacyclobutane, 1,2-dithiohexacyclobutane, 1,3-dithiohexacyclobutane, pyrrolyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazoalkyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thioxanyl, homopiperazinyl, and homopiperidinyl. ridinyl), azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazaphene, triazaphene, thiazepanyl, tetrahydrothiaranyl, oxazolyl, thiazolyl, isothiazolyl, 1,1-dioxoisothiazolinyl, 1,1-dioxoisothiazolyl, oxazolidinyl, imidazolinone, 4,5,6,7-tetrahydro[2H]inzolyl, tetrahydrobenzo[2H]-benzyl Imidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxahiazinyl, thiatriazinyl, oxtriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, indololinyl, thiaranyl, 2H-pyranyl, 4H-pyranyl, dioxalyl, 1,3-dioxolanecycloyl, pyrazolinyl, pyrazolylalkyl, dithiopheneyl, dithiohexacyclopentyl, pyrimidinone, pyrimidinedione, pyrimidin-2,4-dicarboxyl, piperazinoneyl, piperazinedioneyl, pyrazolylalkyliminoimidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0] 1] Heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]dec-2-yl, azaspiro[5.5]undecane, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindolyl, 1,1-dioxahexahydrothiopyranyl.

[0167] Similarly, the terms "carbocyclic" or "carbocyclic group" or "cyclic hydrocarbon group" refer to any monocyclic, bicyclic, polycyclic, fused, spirocyclic, or bridged non-aromatic ring system that is fully saturated, partially unsaturated, or fully unsaturated, having, for example, 3 to 20 ring atoms, wherein said ring atoms are carbon.

[0168] In a specific embodiment, the heterocyclic group or the heteroaryl group is attached at a carbon atom of the heterocyclic group or the heteroaryl group. By way of example, carbon-bonded heterocyclic groups include the following bonding arrangements: at positions 2, 3, 4, 5, or 6 of the pyridine ring; at positions 3, 4, 5, or 6 of the pyridazine ring; at positions 2, 4, 5, or 6 of the pyrazine ring; at positions 2, 3, 5, or 6 of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole rings; at positions 2, 4, or 5 of the oxazole, imidazole, or thiazole rings; at positions 3, 4, or 5 of the isoxazole, pyrazole, or isothiazole rings; at positions 2 or 3 of the aziridine ring; at positions 2, 3, or 4 of the azacyclic butane ring; at positions 2, 3, 4, 5, 6, 7, or 8 of the quinoline ring; or at positions 1, 3, 4, 5, 6, 7, or 8 of the isoquinoline ring.

[0169] In some embodiments, the heterocyclic or heteroaryl group is N-linked. By way of example, nitrogen-bonded heterocyclic or heteroaryl groups include the following bonding arrangements: at the 1 position of aziridine, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrrololine, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, 1H-indazole, at the 2 position of isoindole or isodihydroindole, at the 4 position of morpholine, and at the 9 position of carbazole or β-carboline.

[0170] In this invention, the term "fused ring" or "fused ring" refers to a polycyclic group formed by two or more ring structures sharing two adjacent atoms.

[0171] In this invention, the term "bridged ring" refers to a polycyclic group in which two rings in the system share two or more ring atoms.

[0172] In this invention, the term "spirocyclic" refers to a polycyclic group in which single rings share a single carbon atom (called a spiro atom).

[0173] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. For example, "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. In this document, alkoxy groups are preferably alkoxy groups having 1 to 6, more preferably 1 to 4, carbon atoms. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above that is bridging a sulfur group and has a specified number of carbon atoms; for example, -S-methyl and -S-ethyl. Alkoxy groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable connection point, wherein the substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0174] In this invention, "halogenated" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" / "haloalkylene" is intended to include branched and straight-chain saturated alkyl / alkylene groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Similarly, "halocycloalkyl" / "haloheterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having a specified number of carbon atoms and substituted with one or more halogens. In this invention, the halogen atom is preferably fluorine or chlorine, more preferably fluorine. In this document, unless specifically stated that a certain alkyl, cycloalkyl, heterocycloalkyl, or alkylene group cannot be substituted with a halogen, or can be inferred from the context that the group cannot be halogenated, or is considered unsuitable for halogenation based on common knowledge in the art, then these groups are considered to be halogenated, for example, substituted with one, two, three, or four halogens; for example, substituted with one, two, or three halogens; for example, substituted with one or two halogens; for example, substituted with one halogen; in some other preferred embodiments of the invention, these groups are not halogenated.

[0175] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above that is oxygen-bridged and has a specified number of carbon atoms. For example, "haloC1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above that is sulfur-bridged and has a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0176] In this text, "oxo" means that at least two hydrogen atoms or bonding electrons on at least one atom of a specified group are replaced by the =O atom. Oxidation can occur on carbon atoms and / or heteroatoms. For example, oxoation on a C atom can oxidize -CH2- to -C(=O)-; oxoation on a S atom can oxidize -S- to -S(=O)- or -S(=O)2-. A specified group can have 0, 1, 2, 3, 4, or even more atoms oxidized.

[0177] In this paper, the lines drawn from the ring system indicate that the bond can be attached to any suitable ring atom. If the ring is a bicyclic fused ring system, the substituent can be attached to any position on either ring in the bicyclic system.

[0178] In this document, wavy lines intersecting with bonds in a chemical structure represent the connection points between atoms or groups connected to wavy bonds in the chemical structure and the remainder of the molecule or molecular segment. When a chemical structure contains two wavy lines intersecting with bonds, the structure can be connected to the remainder of the molecule or molecular segment in either orientation.

[0179] As used herein, in the context of describing adjacent atoms, the term "adjacent" refers to two atoms directly connected by a covalent bond.

[0180] In some embodiments, the divalent group generally described does not have a specific bonding configuration. It should be understood that, unless otherwise stated, the general description is intended to include two bonding structures. For example, in the group R1-R2-R3, if group R2 is described as -CH2C(O)-, it should be understood that the group can be bonded as R1-CH2C(O)-R3 and R1-C(O)CH2-R3, unless otherwise stated.

[0181] As used herein, the term "substitution" means the replacement of at least one hydrogen atom with a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. The cyclic double bond used herein refers to a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0182] The term "substitution" as used in this article refers to the replacement of an existing group in a molecule or substituent by another segment. Substitution can occur at one end or in the middle of the substituent. For example, "any methylene group on a C1-C6 alkylene group can be replaced by a carbonyl group, -NR..." a -, -O- or -S-", if the methylene group on the C1 alkylene group is replaced with -NR a -, then the entire group is -NR a -; If the methylene group of -CH(CH3)- is replaced with -O-, then the entire group is -CH(OH)-. Similarly, -C(O)-, -C(O)NRa -, -C(O)O-, -O-, -CH2CH(NMe2)-, etc. are all included in this range.

[0183] In this disclosure, C is used when referring to certain substituent groups. x1 -C x2 The expression indicates that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C3-C8 indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms; C4-C8 indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms; C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0184] In this disclosure, when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), the expression "x1-x2 membered ring" is used, indicating that the number of ring atoms in the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, and its number of ring atoms can be 3, 4, 5, or 6; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, or 8; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; 8 or 9; 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, and its number of ring atoms can be 4, 5, 6, or 7; 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 5, 6, 7, or 8; 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 5, 6, 7, 8, 9, 10, 11, or 12; 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cyclic heteroatoms, for example heteroatoms selected from N, O and S.

[0185] In cases where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxides to obtain derivatives of the present invention.

[0186] When any variable appears more than once in any composition or formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Thus, for example, if a substituent group is shown to have 0-3 R groups, the substituent group may optionally be substituted with up to three R groups, and each occurrence of R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce a stable compound.

[0187] Unless otherwise stated, the terms “compound(s) of the invention” and “compound(s) of the present invention” include compounds of general formula and compounds listed in the specific list, including their stereoisomers, tautomers, solvates, precursors, metabolites, isotope derivatives and salts (e.g., pharmaceutically acceptable salts).

[0188] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism (i.e., geometric isomerism) and optical isomerism (also called enantiomerism). Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration exhibit different spatial arrangements of atoms or atomic groups due to the rotation or twisting of carbon atoms or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations in cyclohexane. Cis-trans isomers are isomers caused by the presence of C=C double bonds, C=N double bonds, or ring systems, which make rotation difficult, and are usually represented by Z and E. Optical isomers, also called enantiomers, refer to two stereoisomers of a compound that are non-overlapping mirror images of each other. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotational sign of a compound with respect to plane-polarized light, where (-) or 1 indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Mixtures of enantiomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in a chemical reaction or process without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomer species. The compounds of the present invention may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist in the form of diastereomers, enantiomers, or mixtures thereof.

[0189] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that interconvert through low-barrier transformations. For example, proton tautomers (also known as proton-transformed tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions that occur through the recombination of some bonded electrons. The compounds described in this invention can exist in tautomer forms, having different hydrogen bonding sites through one or more double bond shifts.

[0190] The term "chirality" refers to a molecule that does not overlap with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0191] The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical procedures (such as electrophoresis) and chromatographic methods (such as HPLC).

[0192] The stereochemical definitions and conventions used in this article generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0193] All enantiomers, diastereomers, racemates, mesoomers, cis-trans isomers, trans-blocked isomers, tautomers, and mixtures thereof are included within the scope of this invention. All methods for preparing the compounds of this invention and the intermediates therein are considered part of this invention. When preparing enantiomers or diastereomers, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). The free forms and salts of these end products are within the scope of this invention. If desired, one form of the compound can be converted to another. Free bases or acids can be converted to salts; salts can be converted to free compounds or another salt; mixtures of isomers of this invention can be separated into individual isomers. The compounds of this invention, their free forms, and salts can exist in various tautomer forms, wherein hydrogen atoms are transposed to other parts of the molecule and thus the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all possible tautomer forms are included within this invention.

[0194] In the structures shown herein, where the stereochemistry of any specific chiral atom is not specified, all stereoisomers are considered as and included in the compound of the invention. When the stereochemistry is specified by a solid wedge or dashed line indicating a specific configuration, the stereoisomer is specified and defined. Unless otherwise stated, the use of a solid wedge or dashed line signifies relative stereochemistry.

[0195] In this invention, the term "pharmaceutical-acceptable salt" or "pharmaceutically acceptable salt" means that, within a reasonable medical judgment, it is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. The salt can be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent, as outlined below. For example, the free base functional group can react with a suitable acid, which can be an organic or inorganic acid; the free acid functional group can react with a suitable base, which can be an organic or inorganic base. Examples of pharmaceutically acceptable inorganic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, hernisulfate, heptaate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salts, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically usable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0196] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example by dissolving the compounds of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile), adding an excess of an aqueous solution of an organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid, and then separating the precipitated salt.

[0197] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form compounds. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism, or through N-demethylation of the compounds of this invention.

[0198] The term "solvate" as used in this invention refers to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0199] The term "isotope derivative" in this invention refers to molecules in which the compounds described herein are isotopically labeled. Commonly used isotopes for isotopic labeling are hydrogen isotopes. 2 H and 3 H; Carbon isotopes: 11 C, 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Tritium, in particular. 3 H and carbon 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2Substitution with H can enhance metabolic stability and prolong the half-life, thereby reducing the dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0200] As used herein, the terms "patient," "subject," or "patient" refer to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., rodents, apes, monkeys, horses, cattle, pigs, dogs, cats, etc.), and most preferably, humans.

[0201] As used herein, the term "effective amount" means the amount of a drug or agent (i.e., the compound of the present invention) that will elicit a biological or medical response in a tissue, system, animal, or human, as sought by, for example, a researcher or clinician. Furthermore, the term "therapeutic effective amount" means an amount that, compared to a corresponding subject who did not receive the aforementioned amount, results in improved treatment, cure, prevention, or reduction of disease, symptom, or side effects, or a slower rate of progression of disease or symptom. An effective amount may be administered, applied, or dosed in one or more ways and is not intended to be limited to a particular formulation or route of administration. The term also includes effective amounts that enhance normal physiological function within its scope. For cancer treatment, efficacy may be measured, for example, by assessing time to progression (TTP) or determining the response rate (RR).

[0202] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndrome; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; mitigating a disease or symptom; reducing complications arising from a disease or symptom, or preventing and / or treating signs arising from a disease or symptom.

[0203] The term "pharmaceutical" as used herein refers to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, and / or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0204] The term "pharmaceutically acceptable," as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for the general therapeutic goal, and does not produce adverse, allergic, or other adverse reactions.

[0205] The term "pharmaceutically acceptable carrier" or "pharmaceutical carrier" refers to media generally accepted in the art for the delivery of bioactive agents to animals (specifically mammals), including (i) adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on...

[0206] The term "pharmaceutical composition" means a composition comprising the compounds of the present invention and at least one other pharmaceutically acceptable carrier.

[0207] The term "combined administration" or similar terms, as used herein, refers to the administration of two or more selected therapeutic agents to a patient such that both formulations and / or their metabolites are present in the animal. Co-administration includes simultaneous administration of a single composition, administration of a single composition at different times, or administration of a composition in which both formulations are present.

[0208] The terms “enhancement” or “potential enhancement,” as used herein, refer to the expected increase or prolongation of either efficacy or duration of effect. Therefore, in the context of enhancing the therapeutic effect of a drug, the term “potential enhancement” refers to the ability of a drug in a system to increase or prolong its efficacy or duration. The term “synergistic value,” as used herein, refers to the ability of an ideal system to maximally enhance the efficacy of another therapeutic agent.

[0209] The terms “inhibition” or “reduction”, or any variations thereof, including any measurable reduction or complete inhibition, to achieve the desired result. For example, an activity may be reduced by about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range thereof, compared to normal.

[0210] The term "wildtype" refers to an entity that has the structure or activity seen in nature in a "normal" state or condition (as opposed to mutation, disease, alteration, etc.). Those skilled in the art will understand that wildtype genes and polypeptides often exist in many different forms (e.g., alleles).

[0211] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to compounds that have the biological function of inhibiting a target protein by inhibiting the activity or expression of proteins such as K-Ras, H-Ras, or N-Ras G12C. Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological function of the target protein. While the antagonists preferred herein interact specifically with the target (e.g., bind), compounds that inhibit the biological activity of a target protein by interacting with other members of the signal transduction pathway in which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are associated with tumor occurrence, growth, or spread.

[0212] As used herein, the term "agonist" refers to a compound that initiates or enhances the biological function of a target protein by inhibiting its activity or expression. Therefore, the term "agonist" is defined in the context of the biological action of the target peptide. While the preferred agonists herein interact specifically with the target (e.g., bind), compounds that initiate or enhance the biological activity of a target peptide by interacting with other members of the signal transduction pathway in which the target peptide is a member are also specifically included within this definition.

[0213] The term "immune disease" refers to a disease or symptom that results from an adverse or harmful reaction to endogenous or exogenous antigens. The result is often impaired cell function, or damage to cells leading to dysfunction, or damage to organs or tissues that may produce immune symptoms.

[0214] The terms “cancer” and “cancerous,” “vesicle” and “tumor,” along with related terms, describe a physiological condition in mammals characterized by the uncontrolled, abnormal growth of cells that can metastasize (spread) under certain conditions. A “tumor” contains one or more cancer cells, including, for example, solid tumors and hematologic malignancies. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer, including small cell lung cancer, non-small cell lung cancer (“NSCLC”), lung adenocarcinoma, and lung squamous cell carcinoma. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral cavity), lips, tongue, mouth, salivary glands, esophagus, larynx, hepatocellular carcinoma, stomach, gastrointestinal tract, small intestine, large intestine, pancreas, cervix, ovary, liver, bladder, hepatocellular carcinoma, breast, colon, rectum, colorectal, genitourinary system, biliary tract, thyroid gland, mastoid process, hepatic, endometrium, uterus, salivary glands, kidneys or renal tract cancers, prostate, testes, vulva, peritoneum, anus, penis, bone, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system cancer, brain, head and neck cancer, Hodgkin's disease, and related metastases. Examples of myeloproliferative disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis such as primary myelofibrosis, and chronic myeloid leukemia (CML).

[0215] As used herein, the term "therapeutic effect" encompasses the therapeutic and / or preventative benefits described above. Preventative effects include delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of symptoms of a disease or symptom, slowing, stopping, or reversing the progression of a disease or symptom, or any combination thereof.

[0216] "Chemotherapy agent" is a preparation that can be used to treat a pre-existing condition, such as cancer or an inflammatory condition. Examples of chemotherapeutic agents are well known in the art and include, for example, those disclosed in U.S. Publication No. 2010 / 0048557, which is incorporated herein by reference. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any chemotherapeutic agent, and combinations of two or more of them.

[0217] The terms "reagent kit" and "product packaging" are synonyms.

[0218] In particular, it is considered that any limitations discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention.

[0219] The titles used in this article are for compilation purposes only.

[0220] compound

[0221] In a first aspect, the present invention provides a compound having the structure of formula (A), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0222] in:

[0223] Cy a express or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups;

[0224] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. xA replace;

[0225] B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace;

[0226] W represents H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a '、CN、-C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a'; or W represents expression (D), where * represents connection to L2:

[0227] E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace;

[0228] X represents O or N-R8;

[0229] L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S;

[0230] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0231] Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0232] R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a ';

[0233] R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a'、-(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be independently replaced by a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0234] R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)Ra '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl);

[0235] R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace;

[0236] R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace;

[0237] R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace;

[0238] R 10 Indicates hydrogen or C1-C3 alkyl;

[0239] R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0240] Cy0 represents a 5-12 bivalent aromatic ring or a heterocyclic aromatic ring;

[0241] R A Each is independently selected from H, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a '、-(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene, C1-C6 alkyl, or C1-C6 haloalkyl group can be replaced with a carbonyl group, -NR a -, -O-, or -S-, and optionally, each of the C0-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of the C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O-, -O-, -S-, -O ... a -SR a -NR a Ra ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0242] And optionally, R on two adjacent or non-adjacent atoms on Cy0 A Together with the CyO ring atoms, a 6-10 membered ring can be formed, which can be further substituted by 0, 1, 2, 3, or 4 substituents selected from the following: halogen, C1-C3 alkyl, -OR. a -SR a Or -NR a R a ';

[0243] L0 is selected from single bonds, C1-C6 alkylene groups, and C2-C6 alkenyl groups, wherein any methylene group on the C1-C6 alkylene or C2-C6 alkenyl group can be replaced by a carbonyl group or -NR. a -, -O- or -S-, and the C1-C6 alkylene or C2-C6 alkenylene may optionally be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl;

[0244] R C Selected from H, halogens, C1-C6 alkyl groups, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a Or -(C0-C6 alkylene)-NR a R a ';

[0245] R D Selected from H, C1-C6 alkyl, -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SRa Or -(C1-C6 alkylene)-NR a R a ';

[0246] R E R F Each is independently selected from H, C1-C6 alkyl, halogen, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a Or -(C0-C6 alkylene)-NR a R a '; and optionally, R E R F It can form 3-6 membered rings with the C atoms attached to them, and the 3-6 membered rings can also contain 0, 1 or 2 heteroatoms selected from N, O or S;

[0247] Z represents N or CR3, Z' represents N or CR3', where R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN;

[0248] m, n, and q each independently represent 0, 1, 2, or 3;

[0249] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0250] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0251] In some implementations, R C R D For H.

[0252] In some implementations, Z represents CR3, and Z' represents CR3'.

[0253] In some embodiments, L0 is a vinylidene, a -(C1-C3)alkylene, or a single bond; more preferably, L0 is a single bond.

[0254] In some implementations, R E R F Each is independently selected from H, C1-C6 alkyl groups, and optionally, R E R F It can form 3-6 membered rings with the C atoms bonded to it, and the rings may additionally contain 0, 1, or 2 heteroatoms selected from N, O, and S; more preferably, R E R F Each is independently selected from C1-C3 alkyl groups.

[0255] In a second aspect, the present invention provides a compound having the structure of formula (B), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0256] in:

[0257] --- indicates a single or double bond;

[0258] X1 and X2 can each independently represent C or N;

[0259] Y1, Y2, and Y3 independently represent non-bonded, single-bonded, and CR bonds, respectively. A 、N、NR1'、O、S;

[0260] Wherein, R1 and R1' independently represent C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), and -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a ', any methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently replaced by a carbonyl group or -NR group. a -, -O-, or -S-, and optionally, the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl and 4-8 membered heterocycloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl groups, -OR-, -O ... a -SR a -NRa R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0261] Where Y3 is CR A Optionally, R1 can be connected to R of Y3. A The substituent, together with the attached N, X1, and C atoms, forms a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3, or 4 substituents selected from: halogens, C1-C3 alkyl groups, -OR groups. a -SR a Or -NR a R a ';

[0262] t is selected from 0, 1, 2, or 3;

[0263] W, Cy a ,Cy1,Cy2,L1,L2,m,n,A,B,E,X,R A R C R D R E R F ,Z,Z',R2,R4,R5,R6,R7,R7',R9,R9',R 10 The definition is as stated in equation (A).

[0264] In some implementations, X1 and X2 each independently represent C.

[0265] In some implementations... Selected from Where Q represents CR AAlternatively, N and T represent NR1', O, or S, and optionally, when Y3 is CR A At that time, R1 can be connected to R on Y3. A The substituents, together with the ring atoms on Cy0, form a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl, -ORa, -SRa or -NRaRa'.

[0266] In some implementations... express And optionally, R1 can be connected to R of Y3. A The substituent, together with the N, X1, and C atoms attached thereto, forms a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3, or 4 substituents selected from the following: halogen, C1-C3 alkyl, -OH.

[0267] In some implementations... express

[0268] In some implementations, R A Each is independently selected from H, halogen, CN, and C1-C3 alkyl; more preferably, R A Each can be represented independently as H or F.

[0269] In a third aspect, the present invention provides a compound having the structure of formula (C), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0270] in,

[0271] Cy a express or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups;

[0272] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. xA replace;

[0273] B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace;

[0274] E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace;

[0275] X represents O or N-R8;

[0276] L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S;

[0277] W represents H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a '、CN、-C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a '; or W represents expression (D), where * represents connection to L2:

[0278] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0279] Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0280] R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocyclic alkyl), -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a ', any methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently replaced by a carbonyl group or -NR group. a -, -O-, or -S-, and optionally, the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl and 4-8 membered heterocycloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl groups, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R aSubstituents of ';

[0281] R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a ';

[0282] R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN;

[0283] R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a '、-(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be independently replaced by a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a'、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0284] R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl);

[0285] R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace;

[0286] R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NRa R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace;

[0287] R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace;

[0288] R 10 Indicates hydrogen or C1-C3 alkyl;

[0289] R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0290] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0291] m and n can each independently represent 0, 1, 2 or 3;

[0292] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0293] In some embodiments of the present invention, W represents formula (D), H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a 'or -CN; W represents (D), H, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a 'Or -CN; preferably, W represents expression (D).

[0294] In a fourth aspect, the present invention provides a compound having the structure of formula (I), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof:

[0295] in:

[0296] Cy a express or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups;

[0297] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. xA replace;

[0298] B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace;

[0299] E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace;

[0300] X represents O or N-R8;

[0301] L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S;

[0302] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0303] Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused.

[0304] R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocyclic alkyl), -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a 'The methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, or C1-C6 haloalkyl group can be replaced with a carbonyl group or -NR group.' a-, -O-, or -S-, and optionally, each of the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of the C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl, -OR-, -O-, -O-, -S-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0305] R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a ';

[0306] R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN;

[0307] R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SRa -(C0-C6 alkylene)-NR a R a ', -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be replaced with a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0308] R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a-C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl);

[0309] R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace;

[0310] R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace;

[0311] R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace;

[0312] R 10 Indicates hydrogen or C1-C3 alkyl;

[0313] R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0314] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0315] m and n can each independently represent 0, 1, 2 or 3;

[0316] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0317] In some implementations, Cya represents or It may optionally be substituted with 0, 1, 2, or 3 substituents selected from halogens or C1-C3 alkyl groups; preferably, Cya represents or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups; more preferably, Cya is preferred. or

[0318] In some embodiments, A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5-membered heterocyclic aryl group can be independently represented by 0, 1, or 2 R groups. xA Replacement; preferably, R xA Each is independently selected from hydroxyl, halogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted; more preferably, R xA The number of them is 0.

[0319] In some embodiments, B represents a 5-membered heteroaryl group, which may optionally be 0, 1, or 2 R groups. xB Replacement; preferably, B indicates or The structure can be 0, 1, or 2 Rs. xB Replacement; preferably, R xB Each is independently selected from hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, B represents or

[0320] In some embodiments, E represents a 6- to 14-membered heterocyclic alkyl group, which can be monocyclic, spirocyclic, bridged, or fused, and can have 0, 1, or 2 R's. xE Replacement; preferred, R xE Each is independently selected from oxo, C1-C3 alkyl; more preferably, R xE The number of substituents is 0.

[0321] In some implementations, E has the structure shown in equation (e):

[0322] In this context, Q can independently represent -CH2-, -O-, -S-, or -NH-.

[0323] a, b, c, and d each independently represent 0, 1, 2, 3, 4, and 5;

[0324] p and q each independently represent 0, 1, 2, 3, and 4;

[0325] Preferably, Q independently represents -CH2- or -O-, and / or R. xE Each can be independently represented as either oxo or C1-C3 alkyl;

[0326] Preferably, a, b, c, and d each independently represent 1, 2, and 3, and / or p and q each independently represent 0, 1, and 2.

[0327] In some implementations, X represents NR. 8 .

[0328] In some embodiments, L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, and any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; preferably, L1 and L2 each independently represent a single bond or a C1-C3 alkylene group, and any methylene group on the C1-C3 alkylene group may be replaced with a carbonyl group or -NR. a -, -O-, or -S-; preferably, L1 and L2 independently represent single bonds, -CH2-, -(CH2)2-, -(CH2)3-, -C(O)-, and -NR-, respectively. a -, -O-, or -S-; preferably, L1 and L2 independently represent a single bond, -CH2-, -C(O)-, or -NR. a -, -O-, or -S-; more preferably, L1 and L2 each independently represent a single bond.

[0329] In some embodiments, Cy1 represents a 4-12 membered heterocyclic alkyl group, which can be a monocyclic, spirocyclic, bridged, or fused ring; preferably, Cy1 represents a 4-8 membered heterocyclic alkyl group, which can be a monocyclic, spirocyclic, bridged, or fused ring.

[0330] In some embodiments, Cy2 represents C3-C4 cycloalkyl, C5-C6 cycloalkyl, C7-C6 cycloalkyl, or C7-C6 cycloalkyl. 12 Cycloalkyl, 4-membered heterocycloalkyl, 5-6-membered heterocycloalkyl, or 7-12-membered heterocycloalkyl, wherein the C3-C4 cycloalkyl, C5-C6 cycloalkyl, C7-C 12 Cycloalkyl, 4-membered heterocyclic alkyl, 5-6-membered heterocyclic alkyl and 7-12-membered heterocyclic alkyl can be monocyclic, spirocyclic, bridged, or fused; preferably, Cy2 represents C3-C4 cycloalkyl or 4-membered heterocyclic alkyl.

[0331] In some embodiments, R1 represents a C4-C8 cycloalkyl, a 4-12 membered heterocycloalkyl, -(C1-C6 alkylene)-Cyx, or -(C1-C6 alkylene)-het-Cyx, wherein het represents O, S, or NR. a Cyx represents a C3-C8 cycloalkyl or a 4-12-membered heterocycloalkyl, wherein the C4-C8 cycloalkyl, 4-12-membered heterocycloalkyl, and Cyx in R1 may optionally be 0, 1, 2, or 3 selected from halogen, oxo, -OR a -SR a -NR a R a Substitution with ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic alkyl groups.

[0332] In some embodiments, R1 represents: ethyl, -CH2CF3, or

[0333] In some embodiments, R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a Preferably, R1 represents a C1-C6 alkyl, a C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl); more preferably, R1 represents a C1-C6 alkyl or a C1-C6 haloalkyl; more preferably, R1 represents an ethyl or -CH2CF3.

[0334] In some embodiments, R2 represents a C1-C6 alkyl group, which may be substituted with 0 or 1 -ORa; preferably, R2 represents 1-methoxyethyl; more preferably, R2 represents Where * indicates the site where R2 is connected to the part connected to it in equation (I).

[0335] In some embodiments, R3 and R3' each independently represent hydrogen, halogen, and C1-C6 alkyl; preferably, R3 and R3' are H.

[0336] In some embodiments, R4 represents H, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a Or -(C0-C6 alkylene)-NR a R a ', wherein any methylene group on the C0-C6 alkylene group can be replaced with a carbonyl group, -NR a -, -O-, or -S-; wherein, the C3-C8 cycloalkyl and 4-12 membered heterocycloalkyl groups are each independently selectable by 0, 1, 2, 3, or 4 groups selected from halogen, oxo, -OR a -SR a -NR a R a Substituents such as cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl) are used; preferably, R4 represents H, -O-(C2-C3 alkylene)-(C3-C8 cycloalkyl), or -NR. a -(C2-C3 alkylene)-(C3-C8 cycloalkyl), -O-(C2-C3 alkylene)-(4-8 membered heterocyclic alkyl), -NR a -(C2-C3 alkylene)-(4-8 membered heterocyclic alkylene), OR a -SR a Or NR a R a The C3-C8 cycloalkyl and 4-8 heterocyclic alkyl groups can each be independently selected from halogen, oxo, -OR by 0, 1, 2 or 3. a -SR a -NR a R a Substitution with cyano, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; more preferably, R4 represents H, -O-(C2-C3 alkylene)-(C3-C8 cycloalkyl), -O-(C2-C3 alkylene)-(4-8 membered heterocyclic alkyl), OR a Or NR a R a Each of the C3-C8 cycloalkyl groups and 4-8 heterocyclic alkyl groups can be independently substituted by 0, 1 or 2 substituents selected from halogens, oxo groups, and C1-C6 alkyl groups.

[0337] In some implementations, R4 represents: H,

[0338] In some embodiments, R4 represents hydrogen, -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a Or -(C0-C6 alkylene)NR a R a ', 3-8 membered cycloalkyl or 4-12 membered heterocycloalkyl, wherein each of the C0-C6 alkylene, 3-8 membered cycloalkyl or 4-12 membered heterocycloalkyl can be independently selected from 0, 1, 2, 3 or 4 alkyl groups selected from halogen, oxo, -OR a -SR a -NR a R a Substituents of cyano, C1-C6 alkyl, -(C0-C3 alkylene)-C3-C8 cycloalkyl, or -(C0-C3 alkylene)-4-8 heterocyclic alkyl; R4 represents hydrogen, -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a Or -(C0-C6 alkylene)NR a R a Preferably, R4 represents hydrogen, -OR a -SR a Or -NR a R a More preferably, R4 represents H.

[0339] In some implementations, R5 independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; preferably, R5 independently represents hydrogen, halogen, oxo, -OR a -SR a -NR a Ra ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic alkyl; preferably, R5 independently represents hydrogen, halogen, oxo, -OR a -NR a R a ', cyano, C1-C6 alkyl; more preferably, R5 independently represents hydrogen, halogen, C1-C3 alkyl.

[0340] In some implementations, R6 independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; preferably, R6 independently represents hydrogen, halogen, oxo, -OR a -SR a -NR a R a ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 heterocyclic alkyl; preferably, R6 independently represents hydrogen, halogen, C1-C3 alkyl.

[0341] In some embodiments, R7 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein each of the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), and -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can be independently represented by 0, 1, 2, 3, or 4 Rs. x7 Substitution, R7' represents hydrogen; preferably, R x7 Each is independently selected from hydrogen, halogen, and C1-C6 alkyl; preferably, R x7R7 represents hydrogen; more preferably, R7 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic alkyl, and R7' represents hydrogen; even more preferably, R7 represents C1-C6 alkyl or C3-C8 cycloalkyl, and R7' represents hydrogen.

[0342] In some implementations, R8 represents hydrogen, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic alkyl; preferably, R8 represents hydrogen, -C(O)R a -S(O)2R a Methyl or cyclopropyl.

[0343] In some embodiments, R8 represents hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 Substitution; preferably, R8 represents hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl or 4-6 heterocyclic alkyl; preferably, R8 represents hydrogen, methyl or cyclopropyl.

[0344] In some embodiments, R9 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic alkyl, and R9' represents hydrogen; preferably, R9 represents hydrogen, methyl or cyclopropyl, and R9' represents hydrogen.

[0345] In some implementations, R 10 It represents hydrogen.

[0346] In some implementations, R a R a Each of the following can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; preferably, R a R a Each can independently represent hydrogen or C1-C6 alkyl; more preferably, R a R a Each can be used independently to represent either hydrogen or a C1-C3 alkyl group.

[0347] In some implementations, m and n each independently represent 0, 1, or 2; preferably, m and n each independently represent 0 or 1.

[0348] In some preferred embodiments, the alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, or 3 halogen atoms.

[0349] In some embodiments, the above compound has the structure of formula (II):

[0350] in:

[0351] Cya said or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups;

[0352] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5-membered heteroaryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, and the 5-membered heteroaryl group can be independently represented by 0, 1, or 2 R's. xA replace;

[0353] B represents a 5-membered heteroaryl group, which may optionally contain 0, 1, or 2 R groups. xB replace;

[0354] X represents O or NR 8 ;

[0355] L1 and L2 each independently represent a single bond or a -(C1-C3)alkylene group, wherein any methylene group can be replaced by a carbonyl group or -NR. a -、-O- or -S-;

[0356] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl or 4-12 membered heterocyclic alkyl groups can be spirocyclic, bridged, or fused.

[0357] Cy2 represents a C3-C4 cycloalkyl or a 4-membered heterocyclic alkyl;

[0358] Q can independently represent -CH2-, -O-, -S-, or -NH-;

[0359] a, b, c, and d each independently represent 1, 2, or 3;

[0360] p and q can each independently represent 0, 1, or 2;

[0361] R xA Each is independently selected from hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0362] R xB Each is independently selected from hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl;

[0363] R xE Each is independently selected from oxo, C1-C3 alkyl groups.

[0364] R1 represents a C1-C6 alkyl or a C1-C6 haloalkyl;

[0365] R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and -OR. a -SR a -NR a R a ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0366] R7 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl);

[0367] R8 represents hydrogen, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl or C3-C6 cycloalkyl;;

[0368] R9 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0369] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0370] m and n can each independently represent 0, 1, or 2;

[0371] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0372] In some preferred embodiments, Cya represents or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups; more preferably, Cya is preferred. or

[0373] In some preferred embodiments, R xA Each is independently selected from hydroxyl, halogen, C1-C3 alkyl, or C1-C3 haloalkyl substituted; more preferably, R xA The number of them is 0.

[0374] In some preferred embodiments, B represents or The structure can be 0, 1, or 2 Rs. xB Replacement; preferably, B indicates or

[0375] In some preferred embodiments, L1 and L2 independently represent a single bond, -CH2-, -C(O)-, and -NR, respectively. a -, -O-, or -S-; more preferably, L1 and L2 each independently represent a single bond.

[0376] In some preferred embodiments, Cy1 represents a 4-12 membered heterocyclic alkyl group, which can be a monocyclic, spirocyclic, bridged, or fused ring; preferably, Cy1 represents a 4-8 membered heterocyclic alkyl group, which can be a monocyclic, spirocyclic, bridged, or fused ring.

[0377] In some preferred embodiments, Q independently represents either -CH2- or -O-.

[0378] In some preferred embodiments, R1 represents ethyl or -CH2CF3.

[0379] In some preferred embodiments, R5 independently represents hydrogen, halogen, oxo, -OR a -NR a R a ', cyano, C1-C6 alkyl; more preferably, R5 independently represents hydrogen, halogen, C1-C3 alkyl.

[0380] In some preferred embodiments, R6 independently represents hydrogen, halogen, or C1-C3 alkyl.

[0381] In some preferred embodiments, R7 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 heterocyclic alkyl; more preferably, R7 represents hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl.

[0382] In some preferred embodiments, R8 represents hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl; preferably, R8 represents hydrogen, methyl, or cyclopropyl.

[0383] In some preferred embodiments, R9 represents hydrogen, methyl, or cyclopropyl.

[0384] In some preferred embodiments, R a R a Each of the following can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; more preferably, R a R a Each can independently represent hydrogen or a C1-C6 alkyl group; more preferably, R a R a Each can be used independently to represent either hydrogen or a C1-C3 alkyl group.

[0385] In some preferred embodiments, m and n each independently represent 0 or 1.

[0386] In some preferred embodiments, the alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, or 3 halogen atoms.

[0387] In some embodiments, the above compound has the structure of formula (III):

[0388] in:

[0389] Cya said or

[0390] A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5-membered heteroaryl group, wherein the phenylene group may be substituted with 0, 1, or 2 hydroxyl groups, halogens, C1-C3 alkyl groups, or C1-C3 haloalkyl groups;

[0391] B indicates or

[0392] Cy1 represents a 4-8 membered heterocyclic alkyl group, wherein the ring can be a spirocyclic, bridged, or fused ring.

[0393] Cy2 represents a 4-membered heterocyclic alkyl group;

[0394] Q can represent -CH2- or -O- independently;

[0395] a, b, c, and d each independently represent 1, 2, or 3;

[0396] R1 represents ethyl or trifluoroethyl;

[0397] R5 and R6 each independently represent hydrogen, halogen, -OH, -NH2, and C1-C3 alkyl groups;

[0398] R7 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0399] R8 represents hydrogen, -C(O)R a -S(O)2R a methyl or cyclopropyl;

[0400] R9 represents hydrogen, methyl, or cyclopropyl;

[0401] R a R a Each can independently represent either hydrogen or a C1-C3 alkyl group;

[0402] m and n each independently represent 0 or 1;

[0403] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0404] In some preferred embodiments, R5 independently represents hydrogen, halogen, and C1-C3 alkyl.

[0405] In some preferred embodiments, R6 independently represents hydrogen, halogen, and C1-C3 alkyl.

[0406] In some preferred embodiments, R7 represents hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl.

[0407] In some preferred embodiments, R8 represents hydrogen, methyl, or cyclopropyl.

[0408] In some preferred embodiments, the alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, or 3 halogen atoms.

[0409] In one aspect, the present invention also provides compounds, isotopic derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof having the following structures:

[0410] 49.

[0411] In some embodiments, the compounds of the present invention exhibit significantly higher binding affinity to specific KRAS mutant proteins than to other RAS mutants or wild-type RAS compared to compounds known in the art. This results in better antiproliferative effects of the compounds of the present invention in tumor cell lines with the KRAS mutation, while showing good selectivity for other cell types. On the other hand, compared to another class of selective compounds known in the art, the compounds of the present invention show significantly enhanced antiproliferative activity in tumor cell lines with specific KRAS mutations. Methods for measuring such efficacy are known in the art, such as the SPR test, a cell antiproliferative activity assay, as provided in the following examples.

[0412] synthesis

[0413] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0414] The compounds of the present invention can be prepared by a variety of methods well known to those skilled in organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described in the following embodiments, as well as synthetic methods known in synthetic organic chemistry or modifications thereof as understood by those skilled in the art. These methods include, but are not limited to, those described in the following embodiments.

[0415] For illustrative purposes, the following reaction schemes provide pathways for the synthesis of the compounds of this invention and key intermediates. Detailed descriptions of each reaction step are provided in the following examples section. Those skilled in the art will understand that other synthetic routes can be used. Although certain specific starting materials and reagents are described in the process and discussed below, other starting materials and reagents can be substituted to provide various derivatives or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified using conventional chemical methods well known to those skilled in the art, based on this disclosure.

[0416] If necessary, starting materials and intermediates for the synthetic reaction can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. Conventional methods can be used to characterize these materials, including physical constants and spectral data.

[0417] Unless otherwise stated, the reactions described herein are preferably carried out under an inert atmosphere, at atmospheric pressure, in a temperature range of about -78°C to about 150°C, more preferably in a temperature range of about 0°C to about 125°C, and most preferably and conveniently at about room temperature (or ambient temperature) or about 20°C.

[0418] Certain substituents in some compounds of the following schemes may be replaced with broader substituents; however, those skilled in the art will readily recognize that the nature of the substituents can be varied to provide the various compounds contemplated in this invention. Furthermore, the reaction conditions are exemplary and alternative conditions are well known. The reaction sequences in the following examples are not intended to limit the scope of the invention as described in the claims.

[0419] Synthetic scheme 1 for macrocyclic lactones:

[0420] Synthesis scheme two for macrocyclic lactone compounds:

[0421] By using the synthesis schemes 1 and 2 disclosed in this invention, combined with the preparation methods of similar compounds known at the time of filing this application and common knowledge in the field, those skilled in the art can select appropriate solvents, temperatures, intermediates, and other reaction conditions and synthesis steps to obtain other compounds disclosed in this invention.

[0422] Drug description

[0423] Drug composition and dosage

[0424] The compounds involved in this invention are KRAS mutation inhibitors and can be used to treat cancer. Therefore, one embodiment of this invention provides a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and a method for preparing such compositions using the compound of the invention.

[0425] For use as a treatment for subjects, the compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as pharmaceutical compositions. Depending on the subject to be treated, the mode of administration, and the desired type of treatment, such as prevention, treatment, or therapy, the compounds or pharmaceutically acceptable salts thereof are formulated in a manner consistent with the parameters described herein. An overview of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0426] The compositions can be prepared according to commonly used mixing, granulation, or coating methods, and the pharmaceutical compositions of the present invention may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the compounds of the present invention or pharmaceutically acceptable salts thereof. In some embodiments, the amount of the compounds described herein or pharmaceutically acceptable salts thereof may be, by weight, 1-95% of the total amount of the pharmaceutical composition.

[0427] The composition may be provided in dosage forms suitable for administration such as intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intracystic, intraurethral, ​​intrathecal, epidural, ocular, or by injection, inhalation, or direct contact with the nasal, genitourinary, genital, or oral mucosa. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, solutions, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoresis delivery, or aerosols. The composition may be formulated according to common pharmaceutical practices.

[0428] As used herein, the term "administration" means administering a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system. Administration to animal subjects (e.g., to humans) can be performed via any suitable route. For example, in some embodiments, administration can be via bronchial (including bronchial infusion), buccal, intestinal, intradermal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, mucosal, nasal, oral, rectal, subcutaneous, sublingual, surface, tracheal (including intratracheal infusion), percutaneous, vaginal, or vitreous administration.

[0429] Formulations can be prepared for systemic or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous) or those prepared for transdermal, transmucosal, or oral administration. Formulations will generally include diluents and, in some cases, adjuvants, buffers, preservatives, etc. Compounds or pharmaceutically acceptable salts thereof may also be administered as liposome compositions or as microemulsions.

[0430] For injection, formulations can be prepared in commonly used forms, such as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in emulsion forms. Suitable excipients include, for example, water, saline, dextrose, glycerol, etc. These compositions may also contain a certain amount of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, etc.

[0431] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. It will be understood in the art that suitable forms include syrups, capsules, and tablets.

[0432] Each compound described herein, or its pharmaceutically acceptable salt, can be formulated in a variety of ways known in the art. For example, the first and second agents in a combination therapy can be formulated together or separately. Other modalities of combination therapy are also described herein.

[0433] Individually or separately formulated pharmaceutical preparations may be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, suppositories, or liquids in vials, two topical creams, etc. The kit may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstitution of the powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit dose kit may contain instructions for the preparation and administration of the composition. The kit may be manufactured as a single-use unit dose for one subject, for multiple uses for a specific subject (constant dose, or in which the potency of individual compounds or their pharmaceutically acceptable salts may vary with treatment progression); or the kit may contain multiple doses suitable for administration to multiple subjects (“integral package”). The kit components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0434] Formulations for oral use include tablets containing a mixture of an active ingredient and a non-toxic, pharmaceutically acceptable excipient. The excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0435] Two or more compounds may be mixed together in tablets, capsules or other media, or they may be separated. In one example, the first compound is contained on the inside of the tablet, while the second compound is on the outside, thereby allowing the majority of the second compound to be released before the first compound is released.

[0436] Formulations for oral use may also be provided as chewable tablets or as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or as soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets may be prepared using the ingredients mentioned above for tablets and capsules, in a conventional manner, using, for example, a mixer, a fluid bed apparatus, or a spray dryer.

[0437] Controlled release through dissolution or diffusion can be achieved by appropriately coating the compound with tablets, capsules, pellets, or granules, or by incorporating the compound or a pharmaceutically acceptable salt thereof into a suitable matrix. Controlled release coatings may include one or more of the coating substances mentioned above, such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogels, 1,3-butanediol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene or halogenated fluorocarbons.

[0438] Liquid forms of compounds or pharmaceutically acceptable salts and compositions thereof that can be incorporated into the present invention for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical mediators.

[0439] Generally, when administered to humans, the oral dose of any compound of the present invention or a pharmaceutically acceptable salt thereof will depend on the nature of the compound and can be readily determined by those skilled in the art. The dose can be, for example, from about 0.001 mg to about 2000 mg daily, from about 1 mg to about 1000 mg daily, from about 5 mg to about 500 mg daily, from about 100 mg to about 1500 mg daily, from about 500 mg to about 1500 mg daily, from about 500 mg to about 2000 mg daily, or any range derived therefrom. In some embodiments, the daily dose for oral administration may, for example, be in the range of from about 0.001 mg to about 2000 mg per kilogram of human body weight, administered in a single dose or divided doses. On the other hand, in some cases, doses outside the stated limits may be necessary.

[0440] In some embodiments, the pharmaceutical composition may additionally contain an additional compound having antiproliferative activity. Depending on the administration regimen, the compound or a pharmaceutically acceptable salt thereof will be formulated to suit the composition for delivery. Each compound or a pharmaceutically acceptable salt thereof in the combination therapy may be formulated in a variety of ways known in the art. For example, the first and second agents in the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for simultaneous or near-simultaneous administration of these agents.

[0441] It should be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated together with one or more other desired therapeutic agents or medical procedures, or administered concurrently with, before, or after the administration of such one or more other desired therapeutic agents or medical procedures. The specific combination of the therapies (therapeutic agents or procedures) used in the combination regimen should take into account the compatibility of the desired therapeutic agent or procedure with the desired therapeutic effect to be achieved. It should also be understood that the therapies used may achieve the desired effect for the same condition, or they may achieve different effects (e.g., controlling any adverse effects).

[0442] As described in this article, the individual drugs in the combination therapy can be administered independently, once to four times daily, for one day to one year, and even for the subject's lifetime. Chronic / long-term administration is also applicable.

[0443] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0444] How to use

[0445] In some embodiments, the present invention discloses a method for treating malignant tumors or cancers caused by KRAS mutants.

[0446] In some implementations, the disease or condition is an inflammatory disease, an autoimmune disease, or an immune-mediated disease. Representative examples may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other inflammatory joint conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, and urticaria (rubella). Multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0447] In some implementations, the disease or condition is cancer or a tumor. Representative examples of cancer or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral thyroid cancer. Neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

[0448] When the compounds of the present invention or their pharmaceutically acceptable salts are administered in combination with other therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compounds of the present invention or their pharmaceutically acceptable salts may provide enhanced therapeutic effects.

[0449] The present invention also provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. A method for treating KRAS mutant protein-related disease in a subject in need is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0450] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compounds of the present invention or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods include, but are not limited to, tumor types such as astrocytoma, breast, cervix, colorectal, endometrial, esophagus, stomach, head and neck, hepatocellular, larynx, lung, oral cavity, ovary, prostate and thyroid cancers and sarcomas.

[0451] A method for inhibiting KRAS mutant protein in cells is also provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The compound or a pharmaceutically acceptable salt thereof inhibits KRAS mutant protein in cells. The cells may be cancer cells. The cancer cells may belong to any type of cancer described herein. The cells may be in vivo or in vitro.

[0452] Combination therapy

[0453] The methods of the present invention may include the compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). When administered alone, the dose of one or more of the additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced relative to a standard dose. For example, the dose may be determined empirically based on the combination and arrangement of drugs or inferred by isoradiometric analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0454] The compounds of the present invention may be administered before, after, or simultaneously with one or more of the additional therapies. When combined, the dose of the compounds of the present invention provides a therapeutic effect (e.g., synergistic or additive therapeutic effect) in conjunction with the dose of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). The compounds of the present invention and additional therapies, such as anticancer agents, may be administered together, for example, as a single pharmaceutical composition, or separately, and when administered separately, the administration may occur simultaneously or sequentially. Such sequential administration may be close in time or distant in time.

[0455] In some embodiments, the additional therapy is the administration of a side effect limiter (e.g., an agent intended to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of the present invention may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0456] In some embodiments, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies include therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, the one or more additional therapies include two therapeutic agents. In still other embodiments, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0457] In this section on combination therapies, all references are incorporated by way of citation for the pharmaceutical agents described, or for their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers, whether or not so explicitly stated.

[0458] Examples of non-pharmacological treatments include, but are not limited to, radiotherapy, cryotherapy, hyperthermia, surgery (e.g., surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0459] In some embodiments, the compounds of the present invention can be used as postoperative adjuvant therapy. In some embodiments, the compounds of the present invention can be used as preoperative neoadjuvant therapy.

[0460] In some embodiments, the compounds of the present invention can sensitize abnormal cells to radiotherapy, thereby killing or inhibiting the growth of such cells. Therefore, the present invention further relates to a method for sensitizing abnormal cells in a mammal to radiotherapy, the method comprising administering to the mammal a quantity of the compounds of the present invention, the quantity of which effectively sensitizes the abnormal cells to radiotherapy. The amount of the compound in this method may be determined according to the manner used to determine the effective amount of such compounds described herein. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0461] In some embodiments, the non-pharmacological treatment is adoptive T-cell transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The source of the T cells is obtained from the subject before the T cells are expanded and genetically modified. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of the invention, a variety of T cell lines available in the art may be used.

[0462] Therapeutic agents can be compounds used to treat cancer or its related symptoms.

[0463] For example, the therapeutic agent may be a steroid. Therefore, in some embodiments, the one or more additional therapies include steroids. Suitable steroids may include, but are not limited to, acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, and cortisol. sone, cortivazol, deflazacort, desonide, deoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortinbutyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasolPropionate, halometasone, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, 25-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone Triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0464] Therapeutic agents can be biological agents (e.g., cytokines such as interferon or leukocyte-stimulating factors such as IL-2) used to treat cancer or related symptoms. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that activates a target to stimulate an anticancer response or antagonizes an antigen important for cancer. Antibody-drug conjugates are also included.

[0465] The therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L2 inhibitor or antagonist (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or... Checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0466] Therapeutic agents can be anti-TIGIT antibodies, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0467] Therapeutic agents can be drugs used to treat cancer or related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapy agents or targeted therapy agents.

[0468] Anticancer agents include mitosis inhibitors, insertional antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted urea, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, the one or more additional therapies comprise two or more anticancer agents. The two or more anticancer agents can be used in a mixture for combined or separate administration.

[0469] Other non-limiting representative examples of anticancer agents may include cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dextrin, doxorubicin, epirubicin, doxorubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixaprone, and tamoxifen. Flutamide, Gonarelin analogues, Megestrol acetate, Prednisone, Dexamethasone, Methylprednisolone, Thalidomide, Interferon Alpha, Leucovorin, Sirolimus, Sirolimus esters, Everolimus, Afatinib, Alisertib, Amuvatinib, Apatinib, Axitinib, Bortezomib, Bosutinib, Brinib, Cabozantinib, Sildenafil, Crenolanib, Crizotinib, Dabrafenib, Dacomitinib, Danusertib, Dasatinib, Dovitinib, Erlotinib, Foretinib, Ganetespib, Gefitinib, Ibrutinib, Icotinib, Imatinib, i Niparib, Lapatinib, Lenvatinib, Linifanib, Linsitinib, Masatinib, Momelotinib, Motishanib, Lenatinib, Nilotinib, Niraparib, Oprozomib, Olaparib, Pazopanib, Pictilisib, Ponatinib, Quizartinib, Regorafenib, Rigosertib, Rucaparib, Ruxolitinib, Secatinib, Saridegib, Sorafenib, Sunitinib, Tilatinib, Vtivantinib, Tivolitinib Zanil, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vemodega, volasertib, alenumab, bevacizumab, belentoumab, vedotin, caputuzumab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, oflamumab, panitumab, rituximab, tosimomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.

[0470] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0471] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. They can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by variations thereof understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and suitable for the transformation achieved. Those skilled in the art of organic synthesis will understand that the functionalities present on the molecule are consistent with the proposed transformation. This sometimes necessitates determining whether to change the order of synthetic steps or the starting materials to obtain the desired compound of the present invention.

[0472] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0473] Example

[0474] General process

[0475] When the preparation method is not specified, all raw materials and reagents used in this invention are known products that can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents used require further purification. Room temperature refers to 20-30°C.

[0476] Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere. A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon of approximately 1L.

[0477] Hydrogenation reactions are typically carried out under vacuum, filled with hydrogen gas, and repeated three times. A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon of approximately 1L.

[0478] Microwave reaction use Initiator + Microwave Reactor.

[0479] The structure of the compounds of this invention was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) were expressed in terms of 10⁻¹⁰. -6 The measurements are given in units of (ppm). NMR determinations are performed using (Bruker Ascend) TMA Model 500 NMR spectrometer was used. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). The following abbreviations are used for NMR signal multiplicity: s = singlet, brs = broad peak, d = doublet, t = triplet, m = multiplet. Coupling constants are listed in J values ​​and measured in Hz.

[0480] Reversed-phase preparative chromatography was performed using a Thermo (UltiMate 3000) reversed-phase preparative chromatograph. Rapid column chromatography was performed using an Agilent (FS-9200T) automated column press, and pre-packed silica gel columns were obtained from Sante. Pre-packed column. Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The thickness used for thin-layer chromatography separation and purification of products is 0.4mm to 0.5mm.

[0481] The LC-MS analysis method is as follows:

[0482] 1) Mass spectrometry method: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameters: drying gas temperature 350℃; drying gas flow rate 10L / min; MS range: 120-1000. 2) Liquid chromatography conditions: Column: Waters XBridge (3.5μm, 50mm×4.6mm); mobile phase A was an aqueous solution containing 0.1% ammonium bicarbonate, mobile phase B was acetonitrile solution, linear gradient elution was performed according to Table 1; flow rate: 2mL / min; column temperature: 30℃; UV detection wavelengths: 214nm, 254nm, 280nm; injection volume: 2μL.

[0483] Table 1. Gradient elution conditions

[0484] The HPLC analysis method is as follows:

[0485] Chromatographic column: Waters XBridge phenyl (3.5 μm, 150 mm × 4.6 mm); mobile phase A was an aqueous solution containing 0.1% ammonium bicarbonate, and mobile phase B was an acetonitrile solution, with linear gradient elution performed according to Table 2; flow rate: 1 mL / min; column temperature: 30 ℃; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0486] Table 2. Gradient elution conditions

[0487] The synthesis methods of some intermediates in the invention are as follows:

[0488] Intermediate 1

[0489] Intermediate 1 is prepared by the following steps:

[0490] Step 1: Methyl 2,2-dimethyl-3-hydroxypropionate INT-1a (100 g, 756.67 mmol) was dissolved in N,N-dimethylformamide (1 L), and imidazole (128.8 g, 1.89 mol) was added. The mixture was stirred until dissolved, and tert-butyldiphenylchlorosilane (228.8 g, 832.34 mmol) was added dropwise at 20 °C. After the addition was complete, the mixture was stirred for 4 hours. After the reaction was complete, the reaction solution was poured into 3 L of ice water. The suspension was extracted with ethyl acetate (1 L * 2). The organic phase was washed three times with water and concentrated under reduced pressure to obtain a colorless oily substance, INT-1b, which did not require purification and was used directly in the next step. ESI-MS (m / z): 371.2 [M+H] + ;

[0491] Step 2: Add the residual INT-1b obtained in the previous step to methanol (2L), then add 360g of a prepared 33% sodium hydroxide aqueous solution, and stir at 20°C for 17 hours. After the reaction is complete, add water (1L), remove methanol under reduced pressure, and extract the residual liquid with petroleum ether (1L*5). After extraction, adjust the pH of the aqueous phase to 4-5 with hydrochloric acid, and a large amount of white solid precipitates. Continue stirring for 30 minutes, filter, and dry to obtain white solid INT-1c (269g, yield 90%). ESI-MS (m / z): 357.8 [M+H] + ;

[0492] Step 3: Dissolve INT-1c (130g, 364.63mmol) in dichloromethane (500mL), add thionyl chloride (130.1g, 1.09mol, 79.35mL) at room temperature, add N,N-dimethylformamide (0.05mL) dropwise, stir at 60℃ for 3 hours. After the reaction is complete, remove dichloromethane and the remaining thionyl chloride under reduced pressure. Add petroleum ether (300mL) to the residue and continue distillation until no fraction is distilled off. Repeat 2-3 times to finally obtain a pale yellow oily substance INT-1d. Without purification, add dichloromethane (200mL) for later use.

[0493] Step 4: Dissolve 5-bromoindole INT-1e (64.8 g, 331 mmol) in dichloromethane (400 mL), and add diethylaluminum chloride solution (198 mL, 396 mmol, 2 M in hexanes) at 0 °C. After the addition is complete, stir for 30 minutes. Add the dichloromethane solution of INT-1d obtained above to the reaction flask. After the addition is complete, continue stirring for 2 hours. After the reaction is complete, slowly pour the reaction solution into 1 L of ice-cold potassium sodium tartrate (3 eq) aqueous solution and stir for 5 hours. After the system stabilizes, concentrate under reduced pressure to remove dichloromethane. Extract the residue with ethyl acetate (1 L * 2), wash with water, and rotary evaporate the organic phase to obtain a brown oil. Add the oil to a mixed solution of petroleum ether / ethyl acetate = 10 / 1 (2 L), stir at 20 °C to precipitate a solid, filter, and obtain a yellow solid INT-1f (139 g, yield 78%). ESI-MS (m / z): 534.8 [M+H] + ;

[0494] Step 5: Dissolve INT-1f (100g, 187.07mmol) in tetrahydrofuran (500mL), add lithium borohydride (12.23g, 561.21mmol) under ice bath conditions, stir for 20 minutes after the addition is complete, and after the system is stable, heat to 60℃ and stir overnight. After the starting material disappeared, the reaction solution was slowly added to ice water (200 mL) for quenching. Extraction was performed with ethyl acetate (500 mL * 3). The organic phase was washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL), and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (28.43 g, 112.24 mmol) and p-toluenesulfonic acid (21.35 g, 112.24 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the dichloromethane. The residue was dissolved in methanol (500 mL), and a pre-prepared 14% lithium hydroxide aqueous solution (100 mL) was added. The mixture was stirred at room temperature for 3 hours, filtered, and dried at room temperature to give a yellow solid INT-1 g (84 g, yield 86.26%). ESI-MS (m / z): 520.2 [M+H] + ;

[0495] Step 6: Dissolve INT-1 g (50 g, 96 mmol) in tetrahydrofuran (250 mL), add tetrabutylammonium fluoride (197 mL, 1 M in THF), stir overnight at 60 °C. After the reaction is complete, add the reaction solution to water (300 mL), extract with ethyl acetate (200 mL * 3), wash with water, concentrate under reduced pressure to obtain a brown oil. Dissolve the residue in methanol (40 mL), add water (20 mL), wash the mixture with petroleum ether (40 mL * 5), concentrate under reduced pressure to remove methanol, extract the residue with ethyl acetate (50 mL * 2), wash the organic phase with water, dry to obtain a pale yellow oil INT-1h (25 g, yield 90.40%). ESI-MS (m / z): 282.8 [M+H] + ;

[0496] Step 7: Dissolve compound INT-1h (25 g, 88.7 mmol) in dioxane (250 mL), add potassium acetate (21.7 g, 221.8 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (3.24 g, 4.4 mmol), and neopentyl glycol diboronate (24.1 g, 106.4 mmol). React at 90 °C for 4 hours under nitrogen protection. LCMS monitoring showed that the reaction proceeded to completion. Diatomaceous earth was filtered, and the filtrate was concentrated. Dichloromethane (200 mL) was added to the concentrate, followed by a 15% sodium hydroxide aqueous solution (17.7 g, 3548 mmol). Concentration under reduced pressure continued until the aqueous phase was clear. The solution was filtered, and the aqueous phase was extracted once with dichloromethane. The pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid under ice bath conditions, resulting in the precipitation of a large amount of yellow solid. Stirring was continued for 30 minutes, and the mixture was filtered to obtain a yellow solid compound INT-1i (17.96 g, yield 82.1%). ESI-MS (m / z): 248.4 [M+H] + ;

[0497] Step 8: Compound INT-1i (35 g, 142 mmol) and compound INT-1k (51.8 g, 142 mmol) were dissolved in dioxane (350 mL) and water (17.5 mL). Potassium carbonate (39.2 g, 284 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (5.2 g, 7.1 mmol) were added. The reaction was carried out at 90 °C for 17 hours under nitrogen protection. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (300 mL). After washing with water, the residue was evaporated to dryness to obtain a brown oily compound INT-1j, which was used directly in the next step without further processing. ESI-MS (m / z): 488.4 [M+H] + ;

[0498] Step 9: Dissolve the crude compound INT-1j in dichloromethane (700 mL). Add 4-dimethylaminopyridine (866 mg, 7.1 mmol) and triethylamine (43.0 g, 426 mmol). Add acetic anhydride (14.5 g, 142 mmol) dropwise at 0 °C. After the addition is complete, remove the ice bath and allow the temperature to rise naturally. Stir for 1-2 hours until the reaction is complete. Wash the reaction solution with water, dry, and concentrate to obtain a brown oil. Purify by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain a pale yellow oil INT-1l (62.3 g, yield 83.2%). ESI-MS (m / z): 530.5 [M+H] + ;

[0499] Step 10: Compound INT-1l (62.3 g, 117.9 mmol) was dissolved in N,N-dimethylformamide (620 mL), and N-iodosuccinimide (26.5 g, 117.9 mmol) was added. The mixture was reacted overnight at 10 °C. LCMS was used to monitor the reaction until complete. The reaction solution was slowly poured into ice water (3000 mL), and a solid precipitated upon stirring. The solid was filtered, washed with water, and dried to obtain a yellow solid compound INT-1m (64.2 g, 87% yield). ESI-MS (m / z): 656.3 [M+H] + ;

[0500] Step 11: Compound INT-1m (64 g, 99.1 mmol) was dissolved in tetrahydrofuran (640 mL) and water (128 mL). Lithium hydroxide monohydrate (11.86 g, 282.4 mmol) was added, and the mixture was stirred at 70 °C for 1 hour. The reaction mixture was monitored by LCMS until the starting material was completely reacted. Water (300 mL) was added to the reaction mixture, and the solution was concentrated under reduced pressure. Then, methyltetrahydrofuran (200 mL) was added, and the pH was adjusted to 4–5 with 4 M hydrochloric acid. The mixture was then extracted with methyltetrahydrofuran (200 mL * 3). The organic phases were combined, washed three times with brine, and evaporated thoroughly to dryness to obtain a yellow solid compound INT-1n (56.5 g, 95% yield). ESI-MS (m / z): 600.5 [M + H] + ;

[0501] Step 12: INT-1n (57 g, 95.0 mmol), 1-methylimidazole (38.9 g, 475 mmol), and (S)-hexahydropyridazine-3-carboxylic acid methyl ester trifluoroacetate (52.7 g, 142.5 mmol) were dissolved in acetonitrile (800 mL). A solution of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (40.0 g, 142.5 mmol) in acetonitrile (400 mL) was added at 0 °C. After the addition was complete, the mixture was stirred for 1 hour. LC-MS was used to monitor the reaction until complete. Water (1000 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (1000 mL * 3). The extract was evaporated to dryness to give a yellow solid, INT-1o (56.5 g, 95% yield). ESI-MS (m / z): 726.3 [M+H] + ;

[0502] Step 13: Compound INT-1o (56.5 g, 77.8 mmol) was dissolved in tetrahydrofuran (560 mL) and water (112 mL). Lithium hydroxide (4.66 g, 194.7 mmol) was added, and the mixture was reacted at 10 °C for 2 hours. LC-MS was used to monitor the reaction until complete. Water (300 mL) was added, and the pH was adjusted to 5-6 with 4 M hydrochloric acid. The mixture was concentrated, extracted with methyltetrahydrofuran, washed with brine, and after thorough separation, the solvent was completely removed by rotary evaporation to obtain a yellow solid compound INT-1p (55.4 g, yield 88.16%). ESI-MS (m / z): 712.6 [M+H] + ;

[0503] Step 14: N,N,N',N'-Tetramethylchloromethanesulfonamide hexafluorophosphate (59.1 g, 210.8 mmol) and 1-methylimidazole (26.5 g, 323.2 mmol) were added to acetonitrile (2000 mL), stirred until dissolved, and a THF solution of compound INT-1p (100 g / 1000 mL, 140.5 mmol) was added dropwise at 10-20 °C. After the addition was complete, the mixture was stirred for 1-2 hours. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting material. The solvent was removed by rotary evaporation, and the residue was extracted with water (1000 mL) and dichloromethane (1000 mL * 3). The pH was adjusted to 3-4 with hydrochloric acid, and the organic phase was evaporated to dryness to give a yellow solid. Recrystallization from isopropanol gave compound INT-1q (59 g, 60% yield). ESI-MS (m / z): 694.6 [M+H] + ;

[0504] Step 15: Compound INT-1q (37 g, 53.35 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (6.6 g, 16.0 mmol), tris(dibenzylacetone)dipalladium (5.86 g, 6.40 mmol), and potassium acetate (18.3 g, 186.7 mmol) were dissolved in toluene (370 mL). Pinara-borane (34.1 g, 266.7 mmol, 38.7 mL) was added under nitrogen protection. After the addition was complete, the reaction was carried out at 50 °C for 3 hours under nitrogen protection. The reaction mixture was monitored by LCMS to ensure complete reaction. The reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow solid compound INT-1 (31 g, yield 82%). ESI-MS (m / z): 694.8 [M+H] + .

[0505] Intermediate 2

[0506] Intermediate 2 is prepared by the following steps:

[0507] Step 1: Compound INT-2a (43 g, 199 mmol), pinacol diboronate (55.6 g, 219 mmol), methoxy(cyclooctadiene)iridium dimer (1.30 g, 1.99 mmol), and 4,4-di-tert-butylbipyridine (2.67 g, 9.95 mmol) were added to tetrahydrofuran (500 mL). The mixture was heated to 75 °C under nitrogen atmosphere and stirred for 16 hours. LCMS monitoring showed complete conversion of the starting material. Excess tetrahydrofuran was removed by rotary evaporation, yielding a brown residue, INT-2b, which was used directly in the next reaction without purification. ESI-MS (m / z): 358.3 [M+H] + .

[0508] Step 2: The residual liquid INT-2b obtained in the previous step was added to methanol (200 mL), followed by concentrated hydrochloric acid (100 mL). The reaction solution was refluxed for 3 hours. LCMS monitoring showed the disappearance of the starting material. Methanol was removed by rotary evaporation. The residual liquid was added to water (200 mL), and the pH was adjusted to 13 with 30% sodium hydroxide solution. Extraction with dichloromethane was performed to remove impurities. The aqueous phase was cooled to 0-5℃, and the pH was adjusted to 6-7 with hydrochloric acid. Stirring continued to wash out the solid, which was then filtered and dried to obtain a white solid compound INT-2c (41.3 g, yield 80%). ESI-MS (m / z): 276.3 [M+H] + .

[0509] Step 3: Compound INT-2c (41.3 g, 159 mmol) was dissolved in acetonitrile (400 mL), and N-iodosuccinimide (35.8 g, 239 mmol) was added. The mixture was heated to 80 °C and stirred overnight. LC-MS showed that the starting material disappeared. Acetonitrile was removed by rotary evaporation of the reaction solution. The residue was added to ethyl acetate (300 mL), washed with water, dried, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid compound INT-2d (45.6 g, yield 85%). ESI-MS (m / z): 358.1 [M+H] + .

[0510] Step 4: Compound INT-2d (5 g, 14.6 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of zinc cyanide (1.03 g, 8.8 mmol) and tetrakis(triphenylphosphine)palladium (1.69 g, 1.46 mmol). The mixture was stirred overnight at 100 °C under nitrogen protection. The reaction was monitored by LCMS until complete. The reaction was quenched with ammonia (5 mL), and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give a colorless oily compound INT-2e (2.1 g, yield 59.6%). ESI-MS (m / z): 241.2 [M+H] + .

[0511] Step 5: Compound INT-2e (2.1 g, 8.7 mmol) was dissolved in a mixed solution of ethanol (20 mL) and water (4 mL). Potassium hydroxide (0.54 g, 9.6 mmol) was added, and the reaction mixture was refluxed for 16 hours. LC-MS monitoring showed the starting material had disappeared. The reaction solution was concentrated to give a white solid compound INT-2f (2.26 g, 100% yield). ESI-MS (m / z): 259.3 [M+H] + .

[0512] Step 6: Dissolve compound INT-2f (770 mg, 2.96 mmol) in methanol (10 mL), and add thionyl chloride (1.06 g, 8.9 mmol). Stir the reaction mixture at 70 °C for 3 hours. LCMS monitoring showed complete reaction of the starting material. Concentrate the reaction mixture to give a pale yellow solid compound INT-2g (800 mg, yield 98.6%). ESI-MS (m / z): 274.1 [M+H] + .

[0513] Step 7: Dissolve compound INT-2 g (600 mg, 2.19 mmol) in ethanol (6 mL), and add hydrazine hydrate (329 mg, 6.57 mmol). Stir the reaction mixture at 90 °C for 16 hours. Monitor the reaction progress using LC-MS until complete. Concentrate the reaction mixture. Purify the residue by column chromatography (dichloromethane / methanol = 20:1) to obtain a colorless oily compound INT-2h (550 mg, yield 91.7%). ESI-MS (m / z): 274.2 [M+H] + .

[0514] Step 8: Compound INT-2h (300 mg, 1.09 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the sequential addition of INT-2i (376 mg, 1.64 mmol), 1-hydroxybenzotriazole (222 mg, 1.64 mmol), N,N-diisopropylethylamine (424 mg, 3.28 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.64 mmol). The reaction mixture was stirred at room temperature for 16 hours. LCMS was used to monitor the reaction until complete. Water was added to the system, and the mixture was extracted with dichloromethane. The organic phase was dried, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by column chromatography (dichloromethane / methanol = 10:1) to give a pale yellow oily compound INT-2j (480 mg, yield 90.4%). ESI-MS (m / z): 485.3 [M+H] + .

[0515] Step 9: Compound INT-2j (480 mg, 0.99 mmol) was dissolved in tetrahydrofuran (5 mL), and Burgess reagent (354 mg, 1.48 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was monitored by LCMS until the starting material was completely reacted, and the reaction mixture was concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 20:1) to give a colorless oily compound INT-2 (320 mg, yield 69.2%). ESI-MS (m / z): 467.2 [M+H] + .

[0516] Intermediate 3

[0517] Intermediate 3 is prepared by the following steps:

[0518] Step 1: Dissolve INT-3a (663 mg, 2.92 mmol) in ethanol (8 mL), add sodium ethoxide (199 mg, 2.92 mmol) at room temperature, and stir for 30 minutes at room temperature. Filter to remove the solid, then add an ethanol solution of INT-2h (400 mg, 1.46 mmol) to the filtrate. Stir the reaction mixture at 85 °C for 16 hours. After the reaction is complete, concentrate under reduced pressure. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 20:1) to give a pale yellow solid compound INT-3b (516 mg, yield 75.8%). ESI-MS (m / z): 466.3 [M+H] + .

[0519] Step 2: INT-3b (516 mg, 1.11 mmol) was dissolved in acetonitrile (8 mL). Potassium carbonate (459 mg, 3.33 mmol) and iodomethane (236 mg, 1.66 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated by filtration. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give a colorless oily compound INT-3 (382 mg, yield 71.9%). ESI-MS (m / z): 480.3 [M+H] + .

[0520] Intermediate 4

[0521] Intermediate 4 is prepared by the following steps:

[0522] Step 1: Compound INT-4a (1 g, 7.93 mmol) was dissolved in ethanol (10 mL) and water (5 mL), followed by the addition of hydroxylamine hydrochloride (2.2 g, 31.7 mmol) and sodium carbonate (2.52 g, 23.8 mmol). The reaction mixture was stirred overnight at 90 °C. The reaction proceeds were monitored by LCMS until complete. The reaction mixture was concentrated, and the residue was purified by column chromatography (dichloromethane / methanol = 10:1) to give a white solid compound INT-4b (901 mg, yield 71.4%). ESI-MS (m / z): 160.2 [M+H] + .

[0523] Step 2: Compound INT-2f (409 mg, 1.40 mmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the sequential addition of INT-4b (202 mg, 1.68 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (639 mg, 1.68 mmol), and N,N-diisopropylethylamine (543 mg, 4.20 mmol). The reaction mixture was stirred at room temperature for 4 hours. LCMS was used to monitor the reaction until complete. Water was added to the system, and the mixture was extracted with dichloromethane. The organic phase was dried, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give a colorless oily compound INT-4c (407 mg, yield 59.9%). ESI-MS (m / z): 485.4 [M+H] + .

[0524] Step 3: Compound INT-4c (407 mg, 0.84 mmol) was dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (325 mg, 2.52 mmol) was added. The reaction mixture was stirred at 90 °C for 16 hours. LCMS was used to monitor the reaction until complete. Water was added to the system, and the mixture was extracted with dichloromethane. The organic phase was dried, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:3) to give a colorless oily compound INT-4 (149 mg, yield 38.0%). ESI-MS (m / z): 467.4 [M+H] + .

[0525] Intermediate 5

[0526] By replacing intermediate INT-2i in the synthetic step of INT-2 with (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid, and using a similar method and reaction steps, compound INT-5 can be obtained. ESI-MS (m / z): 453.2 [M+H] + .

[0527] Intermediate 6

[0528] By replacing intermediate INT-2i in the synthetic step of INT-2 with (R)-1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid, and using a similar method and reaction steps, compound INT-6 can be obtained. ESI-MS (m / z): 467.2 [M+H] + .

[0529] Intermediate 7

[0530] By replacing intermediate INT-2i in the synthetic step of INT-2 with (R)-1-(tert-butyloxycarbonyl)piperidine-2-carboxylic acid, and using a similar method and reaction steps, compound INT-7 can be obtained. ESI-MS (m / z): 467.2 [M+H] + .

[0531] Intermediate 8

[0532] By replacing intermediate INT-2i in the synthetic step of INT-2 with (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid, and using a similar method and reaction steps, compound INT-8 can be obtained. ESI-MS (m / z): 453.2 [M+H] + .

[0533] Intermediate 9

[0534] Intermediate 9 is prepared by the following steps:

[0535] Step 1: Compound INT-2e (150 mg, 0.62 mmol) was dissolved in ethanol (6 mL), followed by the addition of hydroxylamine hydrochloride (86 mg, 1.24 mmol) and triethylamine (126 mg, 1.24 mmol). The reaction mixture was stirred at 80 °C for 3 hours. LCMS was used to monitor the reaction until complete. The reaction mixture was concentrated to obtain a crude, colorless oily compound INT-9a, which was used directly in the next step without purification. ESI-MS (m / z): 274.2 [M+H] + .

[0536] Step 2: Compound INT-9a (350 mg, 1.28 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the sequential addition of INT-2i (293 mg, 1.28 mmol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (533 mg, 1.40 mmol), and N,N-diisopropylethylamine (495 mg, 3.83 mmol). The reaction mixture was stirred at 100 °C for 16 hours. LC-MS was used to monitor the reaction until complete. Water was added to the system, and the mixture was extracted with dichloromethane. The organic phase was dried, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give a colorless oily compound INT-9 (315 mg, yield 52.8%). ESI-MS (m / z): 467.4 [M+H] + .

[0537] Intermediate 10

[0538] By replacing intermediate INT-2i in the synthetic step of INT-2 with (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid, and using a similar method and reaction steps, compound INT-10 can be obtained. ESI-MS (m / z): 453.2 [M+H] + .

[0539] Intermediate 11

[0540] By replacing intermediate INT-2i in the synthetic step of INT-2 with (2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid, and using a similar method and reaction steps, compound INT-11 can be obtained. ESI-MS (m / z): 453.2 [M+H] + .

[0541] Intermediate 12

[0542] Intermediate 12 is prepared by the following steps:

[0543] Step 1: Compound INT-12a (5.0 g, 39.0 mmol) was dissolved in dichloromethane (50 mL) and methanol (10 mL). Trimethylsilyldiazomethane (2 M, 29.3 mL) was added dropwise at 0 °C. After the addition was complete, the mixture was stirred for 1 hour, and the reaction was monitored by TLC until the starting material was fully reacted. The solution was concentrated to obtain a colorless oily compound INT-12b (5.6 g, 100% yield). ESI-MS (m / z): 143.4 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ3.70(s,3H),3.32–3.20(m,2H),2.87–2.77(m,3H),2.68–2.60(m,2H).

[0544] Step 2: Compound INT-12b (5.6 g, 39.4 mmol) was dissolved in n-heptane (60 mL), and tert-butyl hydrazide formate (5.5 g, 41.4 mmol) was added. The reaction mixture was heated to 70 °C and stirred for 16 hours. LC-MS was used to monitor the reaction until complete. The reaction solution was concentrated, and the residue was recrystallized from n-heptane / isopropanol = 30 / 1 to give a white solid compound INT-12c (9.0 g, yield 89.1%). ESI-MS (m / z): 257.3 [M+H] + .

[0545] Step 3: Compound INT-12c (3.0 g, 11.7 mmol) was dissolved in methanol (30 mL), and platinum dioxide (300 mg, 10% wt) was added. The reaction mixture was stirred for 16 hours under a hydrogen atmosphere, and the reaction was monitored by LC-MS to ensure complete reaction of the starting materials. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a colorless oily compound INT-12d (3.0 g, yield 99.2%). ESI-MS (m / z): 259.3 [M+H] + .

[0546] Step 4: Compound INT-12d (3.0 g, 11.6 mmol) was dissolved in tetrahydrofuran (30 mL). Di-tert-butyl dicarbonate (3.0 g, 14.0 mmol), triethylamine (3.5 g, 34.8 mmol), and 4-dimethylaminopyridine (0.14 g, 1.2 mmol) were added sequentially at 0 °C. The reaction was stirred at room temperature for 2 hours, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a colorless oily compound INT-12e (3.2 g, yield 75.7%). ESI-MS (m / z): 359.2 [M+H] + .

[0547] Step 5: Compound INT-12e (2.0 g, 5.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Lithium bis(trimethylsilylamino) (1 M, 16.7 mL) was added dropwise at -70 °C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at this temperature for 30 minutes. Then, trimethylchlorosilane (1.8 g, 16.7 mmol) was added, and stirring continued for 1 hour. N-bromosuccinimide (3.0 g, 16.7 mmol) was then added, and the reaction mixture was heated to room temperature and stirred for 16 hours. LC-MS was used to monitor the reaction until complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product INT-12f was used directly in the next step of the reaction. ESI-MS (m / z): 509.3 [M+H] + .

[0548] Step 6: The crude compound INT-12f was dissolved in methanol (20 mL). Potassium carbonate (1.5 g, 11.2 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until the starting material was completely reacted. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a colorless oily compound INT-12g (1.4 g, yield 57.4%). ESI-MS (m / z): 437.2 [M+H] + .

[0549] Step 7: Compound INT-12 g (1.4 g, 3.2 mmol) was dissolved in acetonitrile (140 mL), and cesium carbonate (3.1 g, 9.6 mmol) was added. The reaction was heated to 60 °C and stirred for 16 hours. The reaction was monitored by LCMS to ensure complete reaction of the starting material. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography and SFC to obtain a white solid compound INT-12 (0.21 g, yield 18.4%). ESI-MS (m / z): 357.2 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ5.24–4.93(m,1H),4.52–4.42(m,1H),3.78–3.71(m,3H),2.93 –2.84(m,1H),2.42–2.35(m,1H),2.17–2.09(m,1H),1.61–1.55(m,2H),1.55–1.46(m,18H).

[0550] Intermediate 13

[0551] Intermediate 13 is prepared by the following steps:

[0552] Step 1: Compound INT-1k (1.0 g, 2.7 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide monohydrate (230 mg, 5.5 mmol) was added at 0 °C, and the mixture was stirred for 2 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water, adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid compound INT-13a (900 mg, yield 93.6%). ESI-MS (m / z): 350.8 [M+H] + .

[0553] Step 2: Compound INT-12 (100 mg, 0.24 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added to it under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated to give a colorless oily trifluoroacetate of compound INT-13b (91 mg, 100% yield). ESI-MS (m / z): 157.3 [M+H] + .

[0554] Step 3: Compound INT-13b (91 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL). Diisopropylethylamine (118 mg, 0.91 mmol), compound INT-13a (80 mg, 0.23 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (104 mg, 0.27 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours, and the reaction proceeded to completion as monitored by LC-MS. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a colorless oily compound INT-13 (100 mg, yield 89.7%). ESI-MS (m / z): 489.2 [M+H] + .

[0555] Intermediate 14

[0556] Intermediate 14 is prepared by the following steps:

[0557] Step 1: Compound INT-2 (10 g, 21.4 mmol) was dissolved in 1,4-dioxane (300 mL), followed by the addition of potassium acetate (4.2 g, 42.8 mmol), neopentyl glycol diboronate (7.3 g, 32.1 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (1.4 g, 2.14 mmol). The mixture was stirred at 85 °C for 16 hours under a nitrogen atmosphere, and the reaction was monitored for completeness by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude INT-14a, a brown oil. This crude product was used directly in the next reaction without purification. ESI-MS (m / z): 501.2 [M+H] + .

[0558] Step 2: The crude compound INT-14a obtained above was dissolved in 1,4-dioxane (150 mL) and water (15 mL). Then, INT-14b (8.5 g, 13.2 mmol), potassium carbonate (5.5 g, 39.4 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.96 g, 1.3 mmol) were added sequentially. The reaction mixture was stirred at 85 °C under a nitrogen atmosphere for 16 hours, and the reaction was monitored to be complete by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a colorless oily compound INT-14c (4.1 g, yield 20.5%). ESI-MS (m / z): 906.7 [M+H] + .

[0559] Step 3: Compound INT-14c (1.4 g, 1.5 mmol) was dissolved in N,N-dimethylformamide (15 mL), and cesium carbonate (1.5 g, 4.5 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.0 g, 4.5 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (150 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a pale yellow solid compound INT-14d (770 mg, yield 51.3%). ESI-MS (m / z): 988.7 [M+H] + .

[0560] Step 4: Compound INT-14d (770 mg, 0.78 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1 M, 3.9 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give a pale yellow solid compound INT-14e (526 mg, yield 90.0%). ESI-MS (m / z): 750.6 [M + H] + .

[0561] Step 5: Compound INT-14e (400 mg, 0.54 mmol) was dissolved in acetonitrile (4 mL), and trimethyliodosilane (190 mg, 0.8 mmol) was added to it under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. After the reaction was complete, sodium bicarbonate aqueous solution (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a pale yellow solid compound INT-14f (325 mg, yield 93.8%). ESI-MS (m / z): 650.6 [M + H] + .

[0562] Step 6: Compound INT-14f (325 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL), and 3-oxetane (72 mg, 1.0 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (318 mg, 1.5 mmol) was added, followed by stirring for 2 hours. After the reaction was complete, sodium bicarbonate aqueous solution (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-14 (225 mg, yield 77.9%). ESI-MS (m / z): 706.6 [M+H] + .

[0563] Intermediate 15

[0564] Intermediate 15 is prepared by the following steps:

[0565] Step 1: Compound INT-14 (220 mg, 0.31 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of potassium acetate (92 mg, 0.94 mmol), pinacol diborate (118 mg, 0.47 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (20 mg, 0.031 mmol). The mixture was stirred at 70 °C for 16 hours under a nitrogen atmosphere, and the reaction was monitored for completeness by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-15a (173 mg, yield 73.9%). ESI-MS (m / z): 754.6 [M+H] + .

[0566] Step 2: INT-13 (66 mg, 0.13 mmol), potassium carbonate (46 mg, 0.34 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (8.7 mg, 0.013 mmol) were added sequentially to a mixture of compound INT-15a (101 mg, 0.13 mmol), 1,4-dioxane (3 mL), and water (0.3 mL). The reaction mixture was stirred at 70 °C under a nitrogen atmosphere for 16 hours, and the reaction was monitored for completeness by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-15b (118 mg, yield 85.0%). ESI-MS (m / z): 1036.7 [M+H] + .

[0567] Step 3: Compound INT-15b (118 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL). Lithium hydroxide monohydrate (14 mg, 0.33 mmol) was added at 0 °C, and the mixture was stirred for 1 hour. LC-MS was used to monitor the reaction until complete. The solution was diluted with water, adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid, compound INT-15c (101 mg, 90.0% yield). ESI-MS (m / z): 1022.7 [M+H] + .

[0568] Step 4: N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (56 mg, 0.2 mmol) and 1-methylimidazole (41 mg, 0.5 mmol) were added to acetonitrile (3 mL), stirred until dissolved, and then a THF solution of compound INT-15c (101 mg, 0.1 mmol) in 1 mL was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 hour, and the reaction was monitored by LCMS to ensure complete reaction of the starting material. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-15d (72 mg, yield 65.0%). ESI-MS (m / z): 1004.7 [M+H] + .

[0569] Step 5: Dissolve compound INT-15d (30 mg, 0.03 mmol) in dichloromethane (2 mL), and add trifluoroacetic acid (1 mL) under ice bath conditions. Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, adjust the pH to 8 by adding saturated sodium bicarbonate solution under ice bath conditions. Extract with dichloromethane (20 mL * 2), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a pale yellow solid compound INT-15 (25 mg, yield 92.6%). ESI-MS (m / z): 904.7 [M+H] + .

[0570] Intermediate 16

[0571] By replacing intermediate INT-13 in the synthetic step INT-15 with methyl (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylate, and using a similar method and reaction steps, compound INT-16 can be obtained. ESI-MS (m / z): 892.7 [M+H] + .

[0572] Intermediate 17

[0573] Intermediate 17 is prepared by the following steps:

[0574] Step 1: Compound INT-2 (300 mg, 0.64 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice bath conditions to adjust the pH to 8. The mixture was extracted with dichloromethane (30 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid compound INT-17a (230 mg, yield 97.6%). ESI-MS (m / z): 367.2 [M + H] + .

[0575] Step 2: Compound INT-17a (150 mg, 0.41 mmol) was dissolved in methanol (3 mL), and 1-ethoxy-1-trimethoxycyclopropane (356 mg, 2.05 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 10 min. Then, sodium cyanoborohydride (77 mg, 1.23 mmol) was added, and the reaction mixture was stirred at 60 °C for 3 h. The reaction was confirmed to be complete by LC-MS. The reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted with dichloromethane, and the combined organic phases were concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give a colorless oily compound INT-17 (95 mg, yield 57.1%). ESI-MS (m / z): 407.3 [M+H] + .

[0576] Intermediate 18

[0577] By replacing INT-1k in the intermediate INT-1 synthesis step with methyl (S)-3-(2-bromopyridin-4-yl)-2-(tert-butoxycarbonyl)amino)propionate, compound INT-18 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 688.7 [M+H] + .

[0578] Intermediate 19

[0579] By replacing INT-1k in the intermediate INT-1 synthesis step with methyl (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionate, compound INT-19 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 687.7 [M+H] + .

[0580] Intermediate 20

[0581] Intermediate 20 is prepared by the following steps:

[0582] Step 1: Compound INT-20a (2.0 g, 13.9 mmol) was dissolved in acetonitrile (20 mL), and tetrabutylammonium iodide (256 mg, 0.69 mmol), potassium carbonate (5.75 g, 41.6 mmol), and benzyl bromide (2.60 g, 15.3 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a colorless oily substance INT-20b (2.5 g, yield 76.9%). ESI-MS (m / z): 235.3 [M+H] + .

[0583] Step 2: Compound INT-20b (1.6 g, 6.9 mmol) was dissolved in dichloromethane (20 mL). Trifluoromethanesulfonic anhydride (2.32 g, 8.25 mmol) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane = 4 / 1) to give a colorless oily substance INT-20c (2.09 g, yield 83.0%). ESI-MS (m / z): 367.2 [M+H] + .

[0584] Step 3: Compound INT-20d (1.0 g, 4.4 mmol) was dissolved in tetrahydrofuran (10 mL). Cesium carbonate (4.32 g, 13.3 mmol) and INT-20c (1.78 g, 4.86 mmol) were added under ice bath conditions. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to obtain a yellow oily substance INT-20e (1.70 g, yield 86.9%). ESI-MS (m / z): 443.3 [M+H] + .

[0585] Step 4: Compound INT-20e (531 mg, 1.20 mmol) was dissolved in methanol (10 mL), and palladium on carbon (53 mg, 10% w / w, 50% water content) was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was slurried with methyl tert-butyl ether to obtain a white solid compound INT-20 (250 mg, yield 59.1%). ESI-MS (m / z): 353.4 [M+H] + .

[0586] Intermediate 21

[0587] Intermediate 21 is prepared by the following steps:

[0588] Step 1: Compound INT-21a (11.8 g, 165.0 mmol) was dissolved in dichloromethane (100 mL), followed by the addition of INT-21b (10.0 g, 82.5 mmol) and copper sulfate (39.5 g, 247.5 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, and the residue was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a colorless oily compound INT-21c (13.0 g, yield 90.9%). ESI-MS (m / z): 174.3 [M+H] + .

[0589] Step 2: Ethyl bromoacetate (9.6 g, 57.7 mmol) was dissolved in tetrahydrofuran (100 mL), and lithium bis(trimethylsilylamino)hydroxide (57.7 mL, 1 mmol / L) was added dropwise at -78 °C. The mixture was stirred for 1 hour after the addition was complete. Then, a tetrahydrofuran solution of INT-21c (5.0 g, 28.9 mmol) was added dropwise at the same temperature, and the reaction was continued with stirring for 2 hours. After the reaction was complete, the reaction was quenched with a water-saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give a pale yellow oily compound INT-21d (4.0 g, yield 53.5%). ESI-MS (m / z): 260.3 [M+H] + .

[0590] Step 3: Compound INT-21d (3.0 g, 11.6 mmol) was dissolved in methanol (30 mL), and dioxane hydrochloride (8.7 mL, 34.7 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred at this temperature for ten minutes. After the reaction was complete, the pH was adjusted to 8 with sodium bicarbonate, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a pale yellow oily compound INT-21e (1.10 g, yield 61.3%). ESI-MS (m / z): 156.3 [M+H] + .

[0591] Step 4: Compound INT-21e (500 mg, 3.22 mmol) was dissolved in 1,2-dichloroethane (10 mL), and methylboric acid (964 mg, 16.1 mmol), copper acetate (585 mg, 3.22 mmol), 2,2'-bipyridine (503 mg, 3.22 mmol), and sodium carbonate (1.02 g, 9.67 mmol) were added sequentially. The reaction mixture was stirred at 50 °C for 24 hours under an oxygen atmosphere. After the reaction was complete, water and ethyl acetate were added, and the reaction solution was filtered through diatomaceous earth. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a pale yellow oily compound INT-21f (300 mg, yield 55.0%). ESI-MS (m / z): 170.2 [M+H] + .

[0592] Step 5: Compound INT-21f (50 mg, 0.3 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL). Lithium hydroxide monohydrate (25 mg, 0.6 mmol) was added at 0 °C, and the mixture was stirred for 3 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water, adjusted to pH 8 with dilute hydrochloric acid, and lyophilized to give a white solid, INT-21 (40 mg, yield 95.9%). ESI-MS (m / z): 142.3 [M+H] + .

[0593] Intermediate 22

[0594] Intermediate 22 is prepared by the following steps:

[0595] Step 1: Compound INT-22a (500 mg, 1.18 mmol) was dissolved in tetrahydrofuran (5 mL) and water (2 mL). Lithium hydroxide monohydrate (75 mg, 1.78 mmol) was added at 0 °C, and the mixture was stirred for 2 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water, adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid, compound INT-22b (480 mg, 99.3% yield). ESI-MS (m / z): 409.3 [M+H] + .

[0596] Step 2: Compound (S)-hexahydropyridazine-3-carboxylic acid methyl ester trifluoroacetate (870 mg, 2.36 mmol) was dissolved in acetonitrile (10 mL). At room temperature, N-methylimidazolium (482 mg, 5.88 mmol), compound INT-22b (480 mg, 1.18 mmol), and N,N,N',N'-tetramethylchloromethamine hexafluorophosphate (396 mg, 1.41 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours, and the reaction proceeded to completion as monitored by LC-MS. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a colorless oily compound INT-22c (500 mg, yield 79.6%). ESI-MS (m / z): 535.3 [M+H] + .

[0597] Step 3: Compound INT-22c (500 mg, 0.94 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice bath conditions to adjust the pH to 8. The mixture was extracted with dichloromethane (30 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid compound INT-22 (310 mg, yield 76.0%). ESI-MS (m / z): 435.3 [M + H] + .

[0598] Intermediate 23

[0599] Intermediate 23 is prepared by the following steps:

[0600] Step 1: Compound INT-14d (2.2 g, 2.22 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 2 hours. After the reaction was complete, sodium bicarbonate aqueous solution was added to the reaction system to adjust the pH to 8, and the mixture was extracted with dichloromethane (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid compound INT-23a (1.9 g, yield 96.1%). ESI-MS (m / z): 888.6 [M + H] + .

[0601] Step 2: Compound INT-23a (1.9 g, 2.14 mmol) was dissolved in dichloromethane (20 mL), and 3-oxetane (462 mg, 6.41 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (1.36 g, 6.41 mmol) was added, and stirring continued for 2 hours. After the reaction was complete, sodium bicarbonate aqueous solution (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-23b (1.9 g, yield 99.4%). ESI-MS (m / z): 944.6 [M + H] + .

[0602] Step 3: Compound INT-23b (500 mg, 0.53 mmol) was dissolved in 1,4-dioxane (8 mL), followed by the addition of INT-22 (276 mg, 0.63 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (49 mg, 0.11 mmol), (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) chloride (41 mg, 0.053 mmol), and cesium carbonate (345 mg, 1.06 mmol). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 16 hours, and the reaction was monitored for completeness by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-23c (341 mg, yield 49.6%). ESI-MS (m / z): 1298.7 [M+H] + .

[0603] Step 4: Compound INT-23c (341 mg, 0.26 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1 M, 0.52 mL) was added. The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-23d (250 mg, yield 90.0%). ESI-MS (m / z): 1060.6 [M + H] + .

[0604] Step 5: Compound INT-23d (250 mg, 0.24 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added at 0 °C, and the mixture was stirred for 2 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water, adjusted to pH 5 with dilute hydrochloric acid, extracted with 2-methyltetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid compound INT-23e (150 mg, yield 59.8%). ESI-MS (m / z): 1046.7 [M+H] + .

[0605] Step 6: N,N,N',N'-Tetramethylchloromethanesulfonyl hexafluorophosphate (59 mg, 0.21 mmol) and 1-methylimidazole (57 mg, 0.7 mmol) were added to acetonitrile (3 mL), stirred until dissolved, and a THF solution of compound INT-23e (150 mg, 0.14 mmol) in 1 mL was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 hour, and the reaction was monitored by LCMS to ensure complete reaction of the starting material. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-23f (72 mg, yield 50.0%). ESI-MS (m / z): 1028.7 [M+H] + .

[0606] Step 7: Compound INT-23f (72 mg, 0.07 mmol) was dissolved in methanol (5 mL), and palladium on carbon (14 mg, 10% on carbon) was added. The mixture was stirred under a hydrogen atmosphere for 16 hours, and the reaction was monitored by LCMS to ensure complete reaction of the starting material. The reaction solution was filtered through diatomaceous earth and concentrated to obtain a pale yellow solid compound INT-23 (50 mg, yield 79.8%). ESI-MS (m / z): 895.7 [M+H] +.

[0607] Intermediate 24

[0608] By replacing INT-1k in the synthetic step of intermediate INT-13 with methyl (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionate, and replacing INT-13b with methyl (S)-hexahydropyridazine-3-carboxylic acid trifluoroacetate, compound INT-24 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 470.3 [M+H] + .

[0609] Intermediate 25

[0610] By replacing INT-13 in the synthesis of intermediate INT-15 with INT-24, and using a similar method and reaction steps, compound INT-25 can be obtained. ESI-MS (m / z): 885.8 [M+H] + .

[0611] Intermediate 26

[0612] Intermediate 26 is prepared by the following steps:

[0613] Step 1: Diethyl methylphosphonoacetate (7.2 g, 34.2 mmol) was dissolved in acetonitrile (30 mL). 1,8-diazacyclo[5,4,0]undecene-7 (5.21 g, 34.2 mmol), lithium chloride (1.81 g, 42.8 mmol), and INT-26a (2.0 g, 28.5 mmol) were added sequentially under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (40 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give a colorless oily compound INT-26b (2.24 g, yield 62.2%).

[0614] Step 2: Potassium ferricyanide (7.83 g, 23.78 mmol), potassium carbonate (3.29 g, 23.78 mmol), sodium bicarbonate (2.0 g, 23.78 mmol), and methanesulfonamide (754 mg, 7.93 mmol) were added to a mixed solution of tert-butanol (30 mL) and water (20 mL). After stirring the reaction mixture at room temperature for 10 minutes, potassium osmium tetroxide dihydrate (49 mg, 0.158 mmol) and quinidine 1,4-(2,3-diazanaphthalene) diether (62 mg, 0.079 mmol) were added sequentially. The mixture was stirred at room temperature for another 30 minutes. Then, an INT-26b solution (1.0 g, 7.93 mmol) in tert-butanol (10 mL) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 16 hours. After the reaction was complete, an aqueous solution of sodium thiosulfate was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a white solid INT-26c (679 mg, yield 53.5%).

[0615] Step 3: Compound INT-26c (250 mg, 1.56 mmol) and triethylamine (237 mg, 2.34 mmol) were dissolved in dichloromethane (6 mL), and p-nitrobenzenesulfonyl chloride (381 mg, 1.72 mmol) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (30 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a colorless oily compound INT-26d (276 mg, yield 51.2%). ESI-MS (m / z): 363.9 [M + NH4] + .

[0616] Step 4: Compound INT-26d (386 mg, 1.12 mmol) and potassium carbonate (309 mg, 2.24 mmol) were added to ethanol (6 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a colorless oily compound INT-26e (138 mg, yield 79.0%). ESI-MS (m / z): 157.3 [M+H] + .

[0617] Step 5: Dissolve compound INT-26e (81 mg, 0.519 mmol) in tetrahydrofuran (2 mL) and water (1 mL), add lithium hydroxide monohydrate (24 mg, 0.57 mmol) at 0 °C, and continue stirring for 3 hours. Monitor the reaction of the starting material by LCMS until complete. Dilute with water and lyophilize to obtain a white solid compound INT-26.

[0618] Intermediate 27

[0619] Intermediate 27 is prepared by the following steps:

[0620] Step 1: Compound INT-27a (100 mg, 0.425 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL). Lithium hydroxide monohydrate (20 mg, 0.46 mmol) was added at 0 °C, and the mixture was stirred for 3 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water, adjusted to pH 8 with dilute hydrochloric acid, and lyophilized to obtain a white solid, INT-27a. ESI-MS (m / z): 220.4 [MH] - .

[0621] Intermediate 28

[0622] By replacing INT-1k in the synthetic step of intermediate INT-13 with methyl (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionate, compound INT-28 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 482.3 [M+H] + .

[0623] Intermediate 29

[0624] By replacing INT-13 in the synthesis step of intermediate INT-15 with INT-28, and using a similar method and reaction steps, compound INT-29 can be obtained. ESI-MS (m / z): 897.8 [M+H] + .

[0625] Intermediate 30

[0626] By replacing methylboric acid in the synthesis step of intermediate INT-21 with cyclopropylboric acid, and using a similar method and reaction steps, compound INT-30 can be obtained. ESI-MS (m / z): 168.3 [M+H] + .

[0627] Intermediate 31

[0628] By replacing intermediate INT-20a in the synthetic step of INT-20 with (2R)-3-methyl-2-hydroxybutyric acid, compound INT-31 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 327.3 [M+H] + .

[0629] Intermediate 32

[0630] By replacing intermediate INT-20d in the synthetic step of INT-20 with 5-oxa-2,8-diazaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester, compound INT-32 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 355.3 [M+H] + .

[0631] Intermediate 33

[0632] By replacing intermediate INT-20d in the synthesis step of INT-20 with tert-butyl 2,7-diazaspiro[4.5]decane-2-carboxylic acid, compound INT-33 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 367.3 [M+H] + .

[0633] Intermediate 34

[0634] Intermediate 34 is prepared by the following steps:

[0635] Step 1: Compound INT-21e (30 mg, 0.19 mmol) was dissolved in tetrahydrofuran (1 mL) and water (1 mL). Lithium hydroxide monohydrate (16 mg, 0.38 mmol) was added at 0 °C, and the mixture was stirred for 3 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water, adjusted to pH 8 with dilute hydrochloric acid, and lyophilized to give a white solid compound INT-34 (25 mg, 100% yield). ESI-MS (m / z): 128.3 [M+H] + .

[0636] Intermediate 35

[0637] By replacing the (S)-hexahydropyridazine-3-carboxylic acid methyl ester trifluoroacetate in the synthesis step of intermediate INT-22 with INT-13b, compound INT-35 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 447.3 [M+H] + .

[0638] Intermediate 36

[0639] By replacing INT-22 in the synthesis step of intermediate INT-23 with INT-35, and using a similar method and reaction steps, compound INT-36 can be obtained. ESI-MS (m / z): 906.8 [M+H] + .

[0640] Intermediate 37

[0641] Intermediate 37 is prepared by the following steps:

[0642] Step 1: Compound INT-37a (5.0 g, 21.81 mmol) was dissolved in tetrahydrofuran (50 mL). Bistrimethylsilylaminolithium (32.71 mL, 1 M in THF) was added at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Subsequently, an allyl bromide (3.96 g, 32.71 mmol) solution in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred at -78 °C for 2 hours. The reaction was monitored by LCMS to ensure complete reaction of the starting material. A saturated ammonium chloride solution (60 mL) was added to the reaction mixture, and the mixture was stirred for 5 minutes. The mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give a colorless oily compound INT-37b (5.3 g, yield 90.2%). ESI-MS (m / z): 270.2 [M+H] + .

[0643] Step 2: Compound INT-37b (4.0 g, 14.85 mmol) and 2,6-dimethylpyridine (3.18 g, 29.70 mmol) were dissolved in 1,4-dioxane (40 mL) and water (4 mL). Potassium osmium tetroxide dihydrate (340 mg, 8.10 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 15 minutes. Then, sodium periodate (273.6 mg, 742.6 μmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS to ensure the starting material was completely reacted. Saturated sodium sulfite solution (60 mL) was added to the reaction mixture, and the mixture was stirred for 5 minutes. The mixture was extracted with ethyl acetate (60 mL * 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a colorless oily compound INT-37c (2.6 g, yield 64.5%). ESI-MS (m / z): 272.1 [M+H] + .

[0644] Step 3: Compound INT-37d (4.0 g, 16.44 mmol) was dissolved in acetonitrile (40 mL), and tetrabutylammonium iodide (340 mg, 8.10 mmol), potassium carbonate (6.82 g, 49.32 mmol), and benzyl bromide (3.37 g, 19.73 mmol) were added. The mixture was stirred at room temperature for 16 hours, and the reaction mixture was monitored by LCMS to ensure complete reaction. The reaction solution was extracted with ethyl acetate (30 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a colorless oily compound INT-37e (4.0 g, yield 73.0%). ESI-MS (m / z): 334.4 [M+H] + .

[0645] Step 4: Compound INT-37e (3.0 g, 9.00 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was added at 0 °C. The mixture was stirred at room temperature for 4 hours, and the reaction was monitored by LCMS until the starting material was fully reacted. The solution was diluted with water, adjusted to pH 7 with saturated sodium bicarbonate, extracted with dichloromethane (20 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid compound INT-37f (2.0 g, yield 95.3%). ESI-MS (m / z): 234.3 [M+H] + .

[0646] Step 5: Compounds INT-37f (2.0 g, 7.37 mmol) and INT-37c (2.58 g, 11.06 mmol) were dissolved in methanol (40 mL). Zinc chloride (1.51 g, 11.06 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 15 minutes. Then, sodium cyanoborohydride (926.5 mg, 14.74 mmol) was added to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting materials. Saturated ammonium chloride (30 mL) was added to the reaction mixture, and the mixture was stirred for 5 minutes. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a colorless oily compound INT-37g (1.5 g, yield 41.6%). ESI-MS (m / z): 489.0 [M+H] + .

[0647] Step 6: Dissolve compound INT-37 g (1.3 g, 2.66 mmol) in toluene (20 mL), add N,N-diisopropylethylamine (3.44 g, 26.61 mmol) and 4-dimethylaminopyridine (325 mg, 2.66 mmol), and stir the reaction solution at 60 °C for 48 hours. LC-MS was used to monitor the reaction until complete. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a colorless oily compound INT-37 (970 mg, yield 79.9%). ESI-MS (m / z): 457.3 [M+H] + .

[0648] Intermediate 38

[0649] Intermediate 38 is prepared by the following steps:

[0650] Step 1: Compound INT-38a (50.0 g, 499.4 mmol) was dissolved in toluene (250 mL), and ethylene glycol (31.0 g, 499.4 mmol) and p-toluenesulfonic acid (8.6 g, 49.94 mmol) were added at room temperature. The reaction mixture was stirred at 105 °C for 16 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (200 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (200 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oily compound INT-38b (38.6 g, yield 53.6%). 1 H NMR(500MHz,Chloroform-d)δ3.91(s,4H),3.76–3.66(m,4H),1.70–1.63(m,4H).

[0651] Step 2: Compound INT-38b (10.0 g, 69.36 mmol) was dissolved in tetrahydrofuran (100 mL). Under a nitrogen atmosphere, dimethyl sulfide borane (41.62 mL, 83.42 mmol, 2 M in THF) was added at -78 °C, followed by the dropwise addition of trimethylsilyl trifluoromethanesulfonate (770.8 mg, 3.47 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, methanol (100 mL) was added to the reaction system under an ice bath to quench the reaction, and the mixture was concentrated to give a brown oily compound INT-38c (10.1 g, 100.0% yield). 1H NMR (500MHz, Chloroform-d) δ3.99–3.90(m,2H),3.78–3.69(m,2H),3.63–3.49(m,3H),3.49–3.39(m,3H),1.97–1.88(m,2H),1.67–1.52(m,2H).

[0652] Step 3: Compound INT-38c (10.0 g, 68.41 mmol) was dissolved in dichloromethane (100 mL). p-Toluenesulfonyl chloride (19.56 g, 102.61 mmol), triethylamine (20.77 g, 205.22 mmol), and 4-dimethylaminopyridine (835.8 mg, 6.84 mmol) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (100 mL) was added to the reaction system under ice bath conditions. The pH was adjusted to 7 with dilute hydrochloric acid. The mixture was extracted with dichloromethane (100 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a pale yellow oily compound INT-38 (16.0 g, yield 77.9%). ESI-MS (m / z): 301.1 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ7.85–7.78(m,2H),7.39–7.31(m,2H),4.19–4.15(m,2H),3.93–3.84(m,2H),3 .71–3.62(m,2H),3.50–3.44(m,1H),3.44–3.35(m,2H),2.46(s,3H),1.87–1.76(m,2H),1.57–1.46(m,2H).

[0653] Intermediate 39

[0654] Intermediate 39 is prepared by the following steps:

[0655] Step 1: Compound INT-14c (5.0 g, 5.51 mmol) was dissolved in N,N-dimethylformamide (50 mL), and cesium carbonate (4.49 g, 13.78 mmol) and INT-38 (2.48 g, 8.27 mmol) were added at room temperature. The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, water (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow solid compound INT-39a (4.2 g, yield 73.6%). ESI-MS (m / z): 1034.8 [M+H] + .

[0656] Step 2: Compound INT-39a (4.2 g, 4.06 mmol) was dissolved in dichloromethane (40 mL), and trifluoroacetic acid (5 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice bath conditions to adjust the pH to 8. The mixture was extracted with dichloromethane (80 mL * 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid compound INT-39b (3.3 g, yield 86.9%). ESI-MS (m / z): 934.6 [M + H] + .

[0657] Step 3: Compound INT-39b (3.0 g, 3.21 mmol) was dissolved in dichloromethane (30 mL), and 3-oxetane (0.69 g, 9.63 mmol) was added at room temperature. Ten minutes later, sodium triacetoxyborohydride (3.4 g, 16.04 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (80 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give a white solid compound INT-39c (0.7 g, yield 22.0%). ESI-MS (m / z): 990.8 [M+H] + .

[0658] Step 4: Compound INT-39c (0.7 g, 0.71 mmol) was dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (7 mL, 1 M in THF). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (60 mL) was added to the reaction system, and the mixture was extracted with methyl tert-butyl ether (40 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give a yellow solid compound INT-39 (0.48 g, yield 90.3%). ESI-MS (m / z): 752.5 [M + H] + .

[0659] Intermediate 40

[0660] By replacing INT-14 in the synthesis step of intermediate INT-15 with INT-39, and using a similar method and reaction steps, compound INT-40 can be obtained. ESI-MS (m / z): 950.7 [M+H] + .

[0661] Intermediate 41

[0662] Intermediate 41 is prepared by the following steps:

[0663] Step 1: Compound INT-23b (1 g, 1.06 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). Then, 1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (491 mg, 1.59 mmol), potassium carbonate (366 mg, 2.65 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (77 mg, 0.106 mmol) were added sequentially. The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours, and the reaction was monitored to be complete by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a brown solid compound INT-41a (1.08 g, 97.5% yield). ESI-MS (m / z): 1047.7 [M+H] + .

[0664] Step 2: Compound INT-41a (1.08 g, 1.04 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added under ice bath conditions. The reaction mixture was stirred under these conditions for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice bath conditions to adjust the pH to 8. The mixture was extracted with dichloromethane (40 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid compound INT-41b (909 mg, yield 92.4%). ESI-MS (m / z): 947.8 [M + H] + .

[0665] Step 3: Compound INT-41b (909 mg, 0.960 mmol) and N,N-diisopropylethylamine (248 mg, 1.92 mmol) were dissolved in acetonitrile (10 mL), and (S)-N-(tert-butoxycarbonyl)-3-amino-2-propanoate propyl ester (171 mg, 0.912 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred for 2 hours under these conditions. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a pale yellow solid compound INT-41c (841 mg, yield 77.3%). ESI-MS (m / z): 1134.9 [M+H] + .

[0666] Step 4: Compound INT-41c (741 mg, 0.653 mmol) was dissolved in tetrahydrofuran (6 mL), and tetrabutylammonium fluoride (2.61 mL, 1 M in THF) was added. The reaction mixture was stirred at 60 °C for 20 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (acetonitrile / water = 3 / 7) to give a white solid compound INT-41d (370 mg, yield 63.2%). ESI-MS (m / z): 896.8 [M+H] + .

[0667] Step 5: Compounds INT-41d (370 mg, 0.41 mmol) and INT-13b (122 mg, 0.454 mmol) were dissolved in acetonitrile (20 mL), and 1-methylimidazole (170 mg, 2.06 mmol) was added. N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (174 mg, 0.62 mmol) was added under ice bath conditions, and the mixture was stirred at 0 °C for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was quenched with water (30 mL), extracted with ethyl acetate (20 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound INT-41e (400 mg, yield 93.7%). ESI-MS (m / z): 1034.8 [M+H] + .

[0668] Step 6: Compound INT-41e (400 mg, 0.39 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL). Lithium hydroxide monohydrate (24.4 mg, 0.58 mmol) was added at 0 °C, and the mixture was stirred for 1 hour. The reaction was monitored by LC-MS until complete. The solution was diluted with water, adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude compound. This crude compound was then purified by preparative liquid chromatography to obtain compound INT-41f (230 mg, yield 58.3%). ESI-MS (m / z): 1020.8 [M+H] + .

[0669] Step 7: N,N,N',N'-Tetramethylchloromethanesulfonamide hexafluorophosphate (126.5 mg, 0.45 mmol) and 1-methylimidazole (92.6 mg, 1.13 mmol) were added to acetonitrile (18 mL), stirred until dissolved, and a tetrahydrofuran (6 mL) solution of compound INT-41f (230 mg, 0.23 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 hour, and the reaction was monitored by LCMS to ensure complete reaction of the starting material. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a pale yellow solid compound INT-41g (110 mg, yield 48.7%). ESI-MS (m / z): 1002.6 [M+H] + .

[0670] Step 8: Dissolve compound INT-41 g (110 mg, 0.11 mmol) in dichloromethane (5 mL), and add trifluoroacetic acid (1 mL) under ice bath conditions. Stir the reaction mixture at room temperature for 1 hour. After the reaction is complete, adjust the pH to 8 by adding saturated sodium bicarbonate solution under ice bath conditions. Extract with dichloromethane (20 mL * 2), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate to obtain a pale yellow solid compound INT-41 (73 mg, yield 73.7%). ESI-MS (m / z): 902.7 [M+H] + .

[0671] Intermediate 42

[0672] Intermediate 42 is prepared by the following steps:

[0673] Step 1: Compound INT-27a (300 mg, 1.28 mmol) was dissolved in tetrahydrofuran (5 mL), and palladium on carbon (30 mg, 10% on carbon) was added. The mixture was stirred under a hydrogen atmosphere for 2 hours, and the reaction was monitored by LCMS to ensure complete reaction of the starting materials. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (2 mL). The filtrate was used directly for the next step of the reaction.

[0674] Step 2: Compound INT-42a (128 mg, 1.27 mmol) and N,N-diisopropylethylamine (490.9 mg, 3.8 mmol) were dissolved in tetrahydrofuran (7 mL), and cyclopropylsulfonyl chloride (267.0 mg, 1.9 mmol) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily compound INT-42b (250 mg, yield 96.0%). ESI-MS (m / z): 206.2 [M+H] + .

[0675] Step 3: Compound INT-42b (250 mg, 1.22 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide monohydrate (204.5 mg, 4.87 mmol) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 2). The aqueous phase was adjusted to pH = 1 with dilute hydrochloric acid (4 M), and then extracted with dichloromethane (30 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily compound INT-42 (150 mg, yield 64.0%). ESI-MS (m / z): 190.2 [MH] - .

[0676] Intermediate 43

[0677] By replacing 2,2,2-trifluoroethyltrifluoromethane sulfonate in the synthesis step of intermediate INT-14 with iodoethane, and using a similar method and reaction steps, compound INT-43 can be obtained. ESI-MS (m / z): 652.3 [M+H] + .

[0678] Intermediate 44

[0679] By replacing INT-14 in the synthesis of intermediate INT-15 with INT-43, and using a similar method and reaction steps, compound INT-44 can be obtained. ESI-MS (m / z): 850.8 [M+H] + .

[0680] Intermediate 45

[0681] Intermediate 45 is prepared by the following steps:

[0682] Step 1: Compound INT-45a (4.5 g, 29.0 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of cyclopropylformaldehyde (2.03 g, 29.0 mmol) and tetrahydropyrrole (0.16 g, 2.3 mmol). The reaction mixture was stirred at 50 °C for 5 hours, and then cyclopropylformaldehyde (2.03 g, 29.0 mmol) was added, with stirring continuing for another 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give a white solid INT-45b (4.45 g, yield 74.1%). ESI-MS (m / z): 208.1 [M+H] + .

[0683] Step 2: Benzyl bromoacetate (8.29 g, 36.2 mmol) and INT-45b (4.17 g, 20.1 mmol) were dissolved in tetrahydrofuran (60 mL), and bis(trimethylsilylaminolithium) (30.2 mL, 1 M in THF) was added dropwise at -78 °C. The temperature was raised to -50 °C, and the reaction was continued with stirring for 2 hours. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give a pale yellow oily compound INT-45c (6.81 g, yield 95.2%). ESI-MS (m / z): 356.3 [M+H] + .

[0684] Step 3: Compound INT-45c (2.0 g, 5.6 mmol) was dissolved in a mixed solvent of acetone (20 mL) and water (10 mL), and trifluoroacetic acid (2.15 mL, 28.1 mmol) was added dropwise at -15 °C. The reaction mixture was stirred at this temperature for 2 hours. After the reaction was complete, ammonia (5.52 g, 39.4 mmol, 25%) was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a pale yellow oily compound INT-45d (612 mg, yield 50.2%). ESI-MS (m / z): 218.3 [M+H] + .

[0685] Step 4: Compound INT-45d (50 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (89 mg, 0.69 mmol) and methanesulfonic anhydride (120 mg, 0.70 mmol) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction system under ice bath conditions, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow oily compound INT-45e (65 mg, yield 95.6%). ESI-MS (m / z): 296.1 [M+H] + .

[0686] Step 5: Compound INT-45e (65 mg, 0.22 mmol) was dissolved in tetrahydrofuran (0.9 mL) and water (0.3 mL). Lithium hydroxide monohydrate (18 mg, 0.44 mmol) was added at room temperature, and the mixture was stirred for 2 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water and lyophilized to obtain a white solid, INT-45. ESI-MS (m / z): 206.1 [M+H] + .

[0687] Intermediate 46

[0688] Intermediate 46 is prepared by the following steps:

[0689] Step 1: Compounds INT-46a (2.0 g, 8.09 mmol) and INT-46b (1.62 g, 8.9 mmol) were dissolved in N,N-dimethylformamide (20 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (3.08 g, 8.09 mmol) and N,N-diisopropylethylamine (2.60 g, 20.22 mmol) were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution (80 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily substance, INT-46c (3.0 g, 99% yield). ESI-MS (m / z): 375.3 [M+H] + .

[0690] Step 2: Compound INT-46c (1.90 g, 5.07 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL). Lithium hydroxide monohydrate (319.4 mg, 7.61 mmol) was added at 0 °C, and the mixture was stirred for 1 hour. LC-MS was used to monitor the reaction until complete. The solution was diluted with water, adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a colorless oily compound INT-46 (1.7 g, 93.0% yield). ESI-MS (m / z): 361.3 [M+H] + .

[0691] Intermediate 47

[0692] By replacing intermediate INT-46b in the synthetic step of INT-46 with methyl(2S)-2-cyclopentyl-2-(methylamino)acetic acid, compound INT-47 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 387.2 [M+H] + .

[0693] Intermediate 48

[0694] By replacing intermediate INT-46b in the synthetic step of INT-46 with 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid, compound INT-48 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 329.2 [M+H] + .

[0695] Intermediate 49

[0696] Intermediate 49 is prepared by the following steps:

[0697] Step 1: Compound INT-23a (1 g, 1.12 mmol) was dissolved in 1,2-dichloroethane (10 mL), followed by the addition of 3-oxetane (324.3 mg, 4.50 mmol) and acetic acid (675.5 mg, 11.25 mmol). The mixture was stirred at 0 °C for 1 hour. Then, trimethylsilylacetonitrile (1.12 g, 11.25 mmol) was added to the reaction mixture, and the mixture was stirred at 60 °C for 5 hours. The reaction was monitored by LC-MS until complete. Water was added to the system, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-49a (873 mg, yield 80.0%). ESI-MS (m / z): 969.7 [M+H] + .

[0698] Step 2: Compound INT-49a (664 mg, 0.68 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of potassium acetate (202 mg, 2.06 mmol), pinacol diborate (261 mg, 1.03 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (50.14 mg, 0.068 mmol). The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere, and the reaction was monitored for completeness by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-49b (550 mg, yield 78.9%). ESI-MS (m / z): 1017.8 [M+H] + .

[0699] Step 3: Compound INT-49b (550 mg, 0.54 mmol), 1,4-dioxane (5 mL), and water (0.5 mL) were mixed with INT-13 (264 mg, 0.54 mmol), potassium carbonate (224 mg, 1.62 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (35 mg, 0.054 mmol). The reaction mixture was stirred at 60 °C under a nitrogen atmosphere for 20 hours, and the reaction was monitored to be complete by LC-MS. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-49c (423 mg, yield 60.2%). ESI-MS (m / z): 1299.8 [M+H] + .

[0700] Step 4: Compound INT-49c (148 mg, 0.12 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1.15 mL, 1 M in THF) was added. The reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by preparative liquid chromatography (acetonitrile / water = 3 / 7) to give a white solid compound INT-49d (95 mg, yield 78.6%). ESI-MS (m / z): 1047.8 [M+H] + .

[0701] Step 5: N,N,N',N'-Tetramethylchloromethanesulfonamide hexafluorophosphate (51 mg, 0.18 mmol) and 1-methylimidazole (37 mg, 0.45 mmol) were added to acetonitrile (12 mL), stirred until dissolved, and a THF solution of compound INT-49d (95 mg, 0.09 mmol) in 4 mL was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 hour, and the reaction was monitored by LCMS to ensure complete reaction of the starting material. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-49e (72 mg, yield 65.0%). ESI-MS (m / z): 1029.7 [M+H] + .

[0702] Step 6: Dissolve compound INT-49e (42 mg, 0.04 mmol) in dichloromethane (2 mL), and add trifluoroacetic acid (0.5 mL) under ice bath conditions. Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, adjust the pH to 8 by adding saturated sodium bicarbonate solution under ice bath conditions. Extract with dichloromethane (20 mL * 2), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate to obtain a pale yellow solid compound INT-49 (36 mg, yield 94.9%). ESI-MS (m / z): 929.7 [M+H] + .

[0703] Intermediate 50

[0704] Intermediate 50 is prepared by the following steps:

[0705] Step 1: Compounds INT-23a (2.4 g, 2.70 mmol) and INT-50a (1.66 g, 8.10 mmol) were dissolved in dichloromethane (40 mL) and stirred at room temperature for 15 minutes. Then, sodium triacetoxyborohydride (2.86 g, 13.50 mmol) was added to the reaction solution at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting materials. A saturated sodium bicarbonate solution (30 mL) was added to the reaction solution and stirred for 5 minutes. The mixture was extracted with dichloromethane (30 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a colorless oily compound INT-50b (2.8 g, yield 96.2%). ESI-MS (m / z): 1077.8 [M+H] + .

[0706] Step 2: Compound INT-50b (3.0 g, 2.78 mmol) was dissolved in tetrabutylammonium fluoride (27.8 mL, 1 M in THF). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with methyl tert-butyl ether (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-50 (2.3 g, yield 98.4%). ESI-MS (m / z): 839.5 [M + H] + .

[0707] Intermediate 51

[0708] By replacing INT-14 in the synthesis step of intermediate INT-15 with INT-50, and using a similar method and reaction steps, compound INT-51 can be obtained. ESI-MS (m / z): 1137.8 [M+H] + .

[0709] Intermediate 52

[0710] Intermediate 52 is prepared by the following steps:

[0711] Step 1: Compound INT-51 (90 mg, 79.14 μmol) was dissolved in isopropanol (3 mL), and palladium on carbon (15.0 mg, 10% on carbon) and palladium hydroxide / carbon (15.0 mg, 10% on carbon) were added. The reaction mixture was stirred at 70 °C for 16 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and concentrated to give a pale yellow solid compound INT-52a (73 mg, yield 92.0%). ESI-MS (m / z): 1003.8 [M+H] + .

[0712] Step 2: Compound INT-52a (73 mg, 58.22 μmol) was dissolved in dichloromethane (4 mL), and acetone (3.6 mg, 58.22 μmol) was added. The mixture was stirred at room temperature for 15 minutes. Then, sodium triacetoxyborohydride (61.7 mg, 291.09 μmol) was added to the reaction solution at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was monitored by LCMS to ensure complete reaction of the starting material. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution and stirred for 5 minutes. The mixture was extracted with dichloromethane (10 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 8 / 1) to obtain a colorless oily compound INT-52b (53 mg, yield 83.8%). ESI-MS (m / z): 1045.7 [M + H] + .

[0713] Step 3: Compound INT-52b (51 mg, 48.79 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.3 mL) was added at 0 °C. The mixture was stirred at 0 °C for 2 hours, and the reaction was monitored by LCMS to ensure complete reaction of the starting material. The solution was diluted with water, adjusted to pH 7 with saturated sodium bicarbonate, extracted with dichloromethane (10 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid compound INT-52 (43 mg, yield 93.3%). ESI-MS (m / z): 945.8 [M+H] + .

[0714] Intermediate 53

[0715] Intermediate 53 is prepared by the following steps:

[0716] Step 1: Compound INT-45d (50 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (127 mg, 0.92 mmol) and 2-bromo-N,N-dimethylacetamide (76 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system under ice bath conditions, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with water (30 mL x 3) and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give a colorless oily compound INT-53a (49 mg, yield 70.4%). ESI-MS (m / z): 303.5 [M+H] + .

[0717] Step 2: Compound INT-53a (49 mg, 0.16 mmol) was dissolved in tetrahydrofuran (0.9 mL) and water (0.3 mL). Lithium hydroxide monohydrate (13 mg, 0.32 mmol) was added at room temperature, and the mixture was stirred for 2 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water and lyophilized to obtain a white solid, INT-53. ESI-MS (m / z): 213.2 [M+H] + .

[0718] Intermediate 54

[0719] Intermediate 54 is prepared by the following steps:

[0720] Step 1: Compound INT-45d (80 mg, 368.22 μmol) and (2-bromoethoxy)-tert-butyldimethylsilane (440.43 mg, 1.84 mmol) were dissolved in N,N-dimethylacetamide (3 mL), and potassium carbonate (203.6 mg, 1.47 mmol) was added. The mixture was stirred at 75 °C for 16 hours, and the reaction mixture was monitored by LCMS to ensure complete reaction. The reaction solution was extracted with ethyl acetate (20 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a colorless oily compound INT-54a (100 mg, yield 72.3%). ESI-MS (m / z): 376.6 [M+H] + .

[0721] Step 2: Compound INT-54a (50 mg, 133.13 μmol) was dissolved in tetrahydrofuran (1 mL) and water (0.5 mL). Lithium hydroxide monohydrate (22.3 mg, 532.52 μmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. LC-MS was used to monitor the reaction until complete. The reaction solution was adjusted to pH 8 with dilute hydrochloric acid and lyophilized to obtain a white solid compound INT-54 (21 mg, yield 92.1%). ESI-MS (m / z): 172.2 [M+H] +

[0722] Intermediate 55

[0723] By replacing (2-bromoethoxy)-tert-butyldimethylsilane in the synthesis of intermediate INT-54 with 3-iodomethyloxetane, compound INT-55 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 198.2 [M+H] + .

[0724] Intermediate 56

[0725] Intermediate 56 is prepared by the following steps:

[0726] Step 1: INT-14f (3.60 g, 6.33 mmol) was dissolved in dichloromethane (40 mL), and 3-oxetane (1.37 g, 19.00 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (4.03 g, 19.00 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL), extracted with dichloromethane (50 mL * 3), and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain INT-56a (3.80 g, yield 96.1%). ESI-MS (m / z): 624.2 [M+H] + .

[0727] Step 2: Dissolve compounds INT-56a (3.30 g, 5.28 mmol), INT-56b (7.48 g, 26.42 mmol), and cesium carbonate (8.61 g, 26.42 mmol) in N,N-dimethylformamide (30 mL), and stir the reaction solution at 80 °C under nitrogen protection for 12 hours. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was dried and concentrated to obtain the crude product. The crude product was subjected to reversed-phase column chromatography (column: Welch Ultimate XB-C18 (10 μm, 250 mm × 21.2 mm); mobile phase A was 10 mM ammonium bicarbonate solution, mobile phase B was acetonitrile, linear gradient elution was performed according to Table 3; flow rate: 20 mL / min; UV detection wavelength: 214 nm, 254 nm, 280 nm, 320 nm; injection volume: 500 μL) to obtain the target product INT-56 (1.50 g, INT-56 retention time in 3 min LCMS: 1.94 min [byproduct retention time: 1.89 min], yield 36.4%). ESI-MS (m / z): 779.4 [M + H] + .

[0728] Table 3. Gradient elution conditions

[0729] Step 3: Compound INT-56c (670 mg, 0.86 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added to the reaction solution at 0 °C. After the reaction was complete, a saturated sodium bicarbonate aqueous solution (20 mL) was added to quench the reaction. Extraction was performed with dichloromethane (20 mL * 3). The organic phase was dried and concentrated to obtain crude INT-56d (580 mg, yield 99.3%), which was directly used in the next step. ESI-MS (m / z): 775.6 [M+H] + .

[0730] Step 4: Dissolve INT-56d (580 mg, 0.75 mmol) in methanol (10 mL), add potassium carbonate (516.7 mg, 3.74 mmol) to the above reaction solution, and stir the reaction solution at room temperature for 4 hours. After the reaction is complete, quench the reaction with water (40 mL), extract with dichloromethane (50 mL * 3), dry and concentrate the organic phase to obtain crude INT-56e (508.2 mg, yield 100%). ESI-MS (m / z): 679.5 [M+H] + .

[0731] Step 5: Dissolve INT-56e (600 mg, 0.88 mmol) in 1,2-dichloroethane (8 mL). Add formaldehyde solution (406.33 mg, 4.41 mmol, 37%) to the above reaction solution and stir the reaction solution at room temperature for 1 hour. Then add sodium triacetoxyborohydride (935.5 mg, 4.41 mmol) and stir the reaction solution at room temperature for 12 hours. After the reaction is complete, quench the reaction with saturated sodium bicarbonate aqueous solution (50 mL), extract with dichloromethane (50 mL * 3), and dry and concentrate the organic phase to obtain the crude product. The crude product is purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain INT-56 (580 mg, yield 94.7%). ESI-MS (m / z): 693.3 [M+H] + .

[0732] Intermediate 57

[0733] By replacing INT-14 in the synthesis step of intermediate INT-15 with INT-56, and using a similar method and reaction steps, compound INT-57 can be obtained. ESI-MS (m / z): 891.8 [M+H] + .

[0734] Intermediate 58

[0735] Intermediate 58 is prepared by the following steps:

[0736] Step 1: Compound INT-45a (2 g, 12.89 mmol) was dissolved in dichloromethane (50 mL), and INT-58a (1.11 g, 12.89 mmol) and tetrahydropyrrole (91.64 mg, 1.29 mmol) were added. The reaction mixture was stirred at 50 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give a white solid INT-58b (760 mg, yield 26.7%). ESI-MS (m / z): 224.1 [M+H] + .

[0737] Step 2: Benzyl bromoacetate (1.40 g, 6.13 mmol) and INT-58b (760 mg, 3.40 mmol) were dissolved in tetrahydrofuran (10 mL), and bis(trimethylsilylaminolithium) (5.1 mL, 1 M in THF) was added dropwise at -78 °C. The temperature was raised to -50 °C, and the reaction was continued with stirring for 2 hours. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give a pale yellow oily compound INT-58c (550 mg, yield 43.4%). ESI-MS (m / z): 372.2 [M+H] + .

[0738] Step 3: Compound INT-58c (550 mg, 1.48 mmol) was dissolved in a mixed solvent of acetonitrile (20 mL) and water (10 mL), and trifluoroacetic acid (844.1 mg, 7.40 mmol) was added dropwise at -10 °C. The reaction mixture was stirred at this temperature for 2 hours. After the reaction was complete, ammonia was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a pale yellow oily compound INT-58d (100 mg, yield 28.9%). ESI-MS (m / z): 234.5 [M+H] + .

[0739] Step 4: Compound INT-58d (100 mg, 428.70 μmol) was dissolved in 1,2-dichloroethane (5 mL), and methylboric acid (128.3 mg, 2.14 mmol), copper acetate (77.9 mg, 428.70 μmol), 2,2'-bipyridine (67.0 mg, 428.70 μmol), and sodium carbonate (136.3 mg, 1.29 mmol) were added sequentially. The reaction mixture was stirred at 50 °C for 24 hours under an oxygen atmosphere. After the reaction was complete, water and ethyl acetate were added, and the reaction solution was filtered through diatomaceous earth. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give a pale yellow solid compound INT-58e (5 mg, yield 4.7%). ESI-MS (m / z): 248.3 [M+H] + .

[0740] Step 5: Compound INT-58e (5 mg, 20.2 μmol) was dissolved in tetrahydrofuran (0.3 mL) and water (0.1 mL). Lithium hydroxide monohydrate (1.4 mg, 40.4 μmol) was added at room temperature, and the mixture was stirred for 2 hours. LC-MS was used to monitor the reaction until complete. The solution was diluted with water and lyophilized to obtain a white solid, INT-58. ESI-MS (m / z): 158.1 [M+H] + .

[0741] Intermediate 59

[0742] Intermediate 59 is prepared by the following steps:

[0743] Step 1: Compound INT-23a (3.1 g, 3.49 mmol), 1-ethoxy-1-trimethoxycyclopropane (1.52 g, 8.72 mmol), and acetic acid (0.63 g, 10.46 mmol) were dissolved in methanol (40 mL). Sodium cyanoborohydride (1.1 g, 17.44 mmol) was then added to the reaction solution at room temperature, and the mixture was stirred at 50 °C for 16 hours. LC-MS was used to monitor the reaction until complete. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was stirred for 5 minutes. Extraction was performed with dichloromethane (60 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain a colorless oily compound INT-59a (1.88 g, yield 58.0%). ESI-MS (m / z): 928.8 [M+H] + .

[0744] Step 2: Compound INT-59a (2.49 g, 2.69 mmol) was dissolved in tetrabutylammonium fluoride (26.8 mL, 1 M in THF). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (60 mL) was added to the reaction system, and the mixture was extracted with methyl tert-butyl ether (60 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-59 (1.01 g, yield 54.6%). ESI-MS (m / z): 690.7 [M + H] + .

[0745] Intermediate 60

[0746] By replacing INT-14 in the synthesis step of intermediate INT-15 with INT-59, and using a similar method and reaction steps, compound INT-60 can be obtained. ESI-MS (m / z): 888.8 [M+H] + .

[0747] Intermediate 61

[0748] By replacing (2-bromoethoxy)-tert-butyldimethylsilane in the synthesis of intermediate INT-54 with 2-iodopropane, and using a similar method and reaction steps, compound INT-61 can be obtained. ESI-MS (m / z): 170.3 [M+H] + .

[0749] Intermediate 62

[0750] Intermediate 62 is prepared by the following steps:

[0751] Step 1: Dissolve INT-2h (300 mg, 1.09 mmol) in dichloromethane (10 mL), and add N,N-diisopropylethylamine (283 mg, 2.18 mmol) and triphosgene (130 mg, 0.44 mmol) under ice bath conditions. Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to obtain a white solid compound INT-62a (240 mg, yield 73.1%). ESI-MS (m / z): 300.1 [M+H] + .

[0752] Step 2: INT-62a (11 g, 36.65 mmol) was dissolved in N,N-dimethylformamide (100 mL). N,N-diisopropylethylamine (9.47 g, 73.31 mmol), 1-(tert-butyloxycarbonyl)piperazine (13.65 mg, 73.31 mmol), and Carter's condensing agent (17.83 g, 40.32 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (80 mL) was added, and the mixture was extracted with ethyl acetate (80 mL * 3). The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give a colorless oily compound INT-62 (4.17 g, yield 24.3%). ESI-MS (m / z): 468.8 [M+H] + .

[0753] Intermediate 63

[0754] By replacing INT-2 in the synthesis step of intermediate INT-14d with INT-62, and using a similar method and reaction steps, compound INT-63 can be obtained. ESI-MS (m / z): 989.6 [M+H] + .

[0755] Intermediate 64

[0756] Intermediate 64 is prepared by the following steps:

[0757] Step 1: Compound INT-63 (1.37 g, 1.39 mmol) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 2 hours. After the reaction was complete, sodium bicarbonate aqueous solution was added to the reaction system to adjust the pH to 8. The mixture was extracted with dichloromethane (40 mL * 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid compound INT-64a (1.2 g, yield 97.6%). ESI-MS (m / z): 889.7 [M + H] + .

[0758] Step 2: Compound INT-64a (600 mg, 0.674 mmol) was dissolved in dichloromethane (6 mL), and 3-oxetane (146 mg, 2.02 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (714 mg, 3.37 mmol) was added, and stirring continued for 16 hours. After the reaction was complete, sodium bicarbonate aqueous solution (30 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (40 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-64b (531 mg, yield 83.3%). ESI-MS (m / z): 945.9 [M+H] + .

[0759] Step 3: Compound INT-64b (531 mg, 0.561 mmol) was dissolved in tetrabutylammonium fluoride (5.61 mL, 1 M in THF). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (40 mL) was added to the reaction system, and the mixture was extracted with methyl tert-butyl ether (40 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-64 (330 mg, yield 83.1%). ESI-MS (m / z): 707.9 [M+H] + .

[0760] Intermediate 65

[0761] Intermediate 65 is prepared by the following steps:

[0762] Step 1: Compound INT-64a (740 mg, 0.831 mmol), 1-ethoxy-1-trimethoxycyclopropane (362 mg, 2.08 mmol), and acetic acid (150 mg, 2.49 mmol) were dissolved in methanol (8 mL). Sodium cyanoborohydride (261 mg, 4.16 mmol) was then added to the reaction solution at room temperature, and the mixture was stirred at 50 °C for 16 hours. LC-MS was used to monitor the reaction until complete. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was stirred for 5 minutes. The mixture was extracted with dichloromethane (60 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a colorless oily compound INT-65a (589 mg, yield 76.2%). ESI-MS (m / z): 929.8 [M+H]+ .

[0763] Step 2: Compound INT-65a (589 mg, 0.633 mmol) was dissolved in tetrabutylammonium fluoride (6.33 mL, 1 M in THF). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (60 mL) was added to the reaction system, and the mixture was extracted with methyl tert-butyl ether (60 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a pale yellow solid compound INT-65 (351 mg, yield 80.1%). ESI-MS (m / z): 691.9 [M+H] + .

[0764] Intermediate 66

[0765] By replacing INT-14 in the synthesis step of intermediate INT-15 with INT-64, and using a similar method and reaction steps, compound INT-66 can be obtained. ESI-MS (m / z): 905.8 [M+H] + .

[0766] Intermediate 67

[0767] By replacing INT-14 in the synthesis step of intermediate INT-15 with INT-65, and using a similar method and reaction steps, compound INT-67 can be obtained. ESI-MS (m / z): 889.8 [M+H] + .

[0768] Intermediate 68

[0769] Intermediate 68 is prepared by the following steps:

[0770] Step 1: Dissolve INT-68a (500 mg, 3.96 mmol) in dichloromethane (3 mL), cool to 0 °C, add bromine (696.74 mg, 4.36 mmol), and stir for 1 hour. Monitor the reaction mixture by TLC until complete. Add saturated sodium bicarbonate solution (10 mL) to the reaction mixture and stir for 5 minutes. Extract with dichloromethane (60 mL * 3). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a colorless oily compound INT-68b.

[0771] Step 2: Weigh INT-68b (200 mg, 666.70 μmol) and dissolve it in ethanol (10 mL). Add 3-oxacyclobutamine (487.31 mg, 6.67 mmol). Stir the mixture at 80 °C for 2 hours. Monitor the reaction mixture by LC-MS to ensure complete reaction. Concentrate the reaction solution, and purify the residue by preparative l...

Claims

A compound having the structure of formula (A), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof: in: Cy a express or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups; A represents 4- to 6-membered heterocycloalkylene, 4- to 6-membered heterocycloalkenylene, phenylene or 5- to 6-membered heteroarylene, each independently of the other, unsubstituted or substituted by 0, 1, 2, 3 or 4 R xA substituents; B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace; W represents H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a '、CN、-C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a '; or W represents expression (D), where * represents connection to L2: E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace; X represents O or N-R8; L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused. Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused. R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a '; R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a '、-(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be independently replaced by a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of '; R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl); R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace; R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace; R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace; R 10 Indicates hydrogen or C1-C3 alkyl; R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; Cy0 represents a 5-12 bivalent aromatic ring or a heterocyclic aromatic ring; R A Each is independently selected from H, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a '、-(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene, C1-C6 alkyl, or C1-C6 haloalkyl group can be replaced with a carbonyl group, -NR a -, -O-, or -S-, and optionally, each of the C0-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of the C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O-, -O-, -S-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of '; And optionally, R on two adjacent or non-adjacent atoms on Cy0 A Together with the CyO ring atoms, a 6-10 membered ring can be formed, which can be further substituted by 0, 1, 2, 3, or 4 substituents selected from the following: halogen, C1-C3 alkyl, -OR. a -SR a Or -NR a R a '; L0 is selected from single bonds, C1-C6 alkylene groups, and C2-C6 alkenyl groups, wherein any methylene group on the C1-C6 alkylene or C2-C6 alkenyl group can be replaced by a carbonyl group or -NR. a -, -O- or -S-, and the C1-C6 alkylene or C2-C6 alkenylene may optionally be substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1-C3 alkyl; R C Selected from H, halogens, C1-C6 alkyl groups, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a Or -(C0-C6 alkylene)-NR a R a '; R D Selected from H, C1-C6 alkyl, -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a '; R E R F Each is independently selected from H, C1-C6 alkyl, halogen, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a Or -(C0-C6 alkylene)-NR a R a '; and optionally, R E R F It can form 3-6 membered rings with the C atoms attached to them, and the 3-6 membered rings can also contain 0, 1 or 2 heteroatoms selected from N, O or S; Z represents N or CR3, Z' represents N or CR3', where R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN; m, n, and q each independently represent 0, 1, 2, or 3; R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S; The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene groups can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms. The compound of claim 1, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R C R D For H. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... Z represents CR3, and Z' represents CR3'. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... L0 is a vinylidene, a C1-C3 alkylidene, or a single bond; more preferably, L0 is a single bond. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... R E R F Each is independently selected from H, C1-C6 alkyl groups, and optionally, R E R F It can form 3-6 membered rings with the C atoms bonded to it, and the rings may additionally contain 0, 1, or 2 heteroatoms selected from N, O, and S; more preferably, R E R F Each is independently selected from C1-C3 alkyl groups. The compound, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, as described in any of the preceding claims, have the structure shown in formula (B): in: Indicates a single or double bond; X1 and X2 can each independently represent C or N; Y1, Y2, and Y3 independently represent non-bonded, single-bonded, and CR bonds, respectively. A 、N、NR1'、O、S; Wherein, R1 and R1' independently represent C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), and -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a ', any methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently replaced by a carbonyl group or -NR group. a -, -O-, or -S-, and optionally, the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl and 4-8 membered heterocycloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl groups, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of '; Where Y3 is CR A Optionally, R1 can be connected to R of Y3. A The substituent, together with the attached N, X1, and C atoms, forms a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3, or 4 substituents selected from: halogens, C1-C3 alkyl groups, -OR groups. a -SR a Or -NR a R a '; t is selected from 0, 1, 2, or 3; W, Cy a ,Cy1,Cy2,L1,L2,m,n,A,B,E,X,R A R C R D R E R F ,Z,Z',R2,R4,R5,R6,R7,R7',R9,R9',R 10 The definition is as described in any of the preceding claims. The compound of claim 6, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein, X1 and X2 each represent C independently. The compound, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, as described in any one of claims 6-7, wherein, Selected from Where Q represents CR A Alternatively, N and T represent NR1', O, or S, and optionally, when Y3 is CR A At that time, R1 can be connected to R on Y3. A The substituents, together with the ring atoms on CyO, form a 6-10 membered ring, which can be further substituted by 0, 1, 2, 3, or 4 substituents selected from: halogens, C1-C3 alkyl groups, -OR groups. a -SR a Or -NR a R a '. The compound, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, as described in any one of claims 6-8, wherein, express And optionally, R1 can be connected to R of Y3. A The substituent, together with the N, X1, and C atoms attached thereto, forms a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3, or 4 substituents selected from the following: halogen, C1-C3 alkyl, -OH. The compound, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, as described in any one of claims 6-9, wherein, express The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... R A Each is independently selected from H, halogen, CN, and C1-C3 alkyl; more preferably, R A Each can be represented independently as H or F. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... The compound has the structure shown in formula (C): in, Cy a express or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups; A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. xA replace; B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace; E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace; X represents O or N-R8; L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; W represents H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a '、CN、-C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a '; or W represents expression (D), where * represents connection to L2: Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused. Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused. R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocyclic alkyl), -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a ', any methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently replaced by a carbonyl group or -NR group. a -, -O-, or -S-, and optionally, the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C3-C8 cycloalkyl and 4-8 membered heterocycloalkyl groups can each be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl groups, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of '; R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a '; R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN; R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a '、-(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be independently replaced by a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of '; R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl); R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace; R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace; R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace; R 10 Indicates hydrogen or C1-C3 alkyl; R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S; m and n can each independently represent 0, 1, 2 or 3; The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... W represents (D), H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a 'or -CN; W represents (D), H, C1-C6 alkyl, C1-C6 haloalkyl, -OR a -SR a -NR a R a 'Or -CN; preferably, W represents expression (D). A compound having the structure of formula (I), its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof: in: Cy a express or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups; A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, or the 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. xA replace; B represents a 5-6 membered heteroaryl or phenylene group, wherein each of the 5-6 membered heteroaryl or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. xB replace; E represents a 6- to 14-membered heterocyclic alkyl group or a 6- to 14-membered heterocyclic alkenyl group, wherein the 6- to 14-membered heterocyclic alkyl group or the 6- to 14-membered heterocyclic alkenyl group can be monocyclic, spirocyclic, bridged, or fused, and can be independently bounded by 0, 1, 2, 3, or 4 R groups. xE replace; X represents O or N-R8; L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused. Cy2 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl and 4-12 membered heterocyclic alkyl groups can be monocyclic, spirocyclic, bridged, or fused. R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocyclic alkyl), -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a 'The methylene group on the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, or C1-C6 haloalkyl group can be replaced with a carbonyl group or -NR group.' a -, -O-, or -S-, and optionally, each of the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of the C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl, -OR-, -O-, -O-, -S-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of '; R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a '; R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN; R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a ', -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be replaced with a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of '; R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a '、-NR a S(O)2R a ', C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl); R7 and R7' each independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can each be represented by 0, 1, 2, 3, or 4 R's. x7 replace; R8 represents hydrogen, cyano group, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace; R9 and R9' each independently represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl can be independently represented by 0, 1, 2, 3, or 4 R's. x9 replace; R 10 Indicates hydrogen or C1-C3 alkyl; R xA R xB R xE R x7 R x8 R x9 Each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S; m and n can each independently represent 0, 1, 2 or 3; The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms. The compound, its isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof as described in any of the preceding claims, wherein Cya represents or It may optionally be substituted with 0, 1, 2, or 3 substituents selected from halogens or C1-C3 alkyl groups; preferably, Cya represents or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups; more preferably, Cya is preferred. or The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5-membered heteroaryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, and the 5-membered heteroaryl group can be independently represented by 0, 1, or 2 R's. xA Replacement; preferably, R xA Each is independently selected from hydroxyl, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, R xA The number of them is 0. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... B represents a 5-membered heteroaryl group, which may optionally contain 0, 1, or 2 R groups. xB Replacement; preferably, B indicates or The structure can be 0, 1, or 2 Rs. xB Replacement; preferably, R xB Each is independently selected from hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, B represents or The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... E represents a 6- to 14-membered heterocyclic alkyl group, which can be monocyclic, spirocyclic, bridged, or fused, and can have 0, 1, or 2 R's. xE Replacement; preferred, R xE Each is independently selected from oxo, C1-C3 alkyl; more preferably, R xE The number of substituents is 0. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... E has the structure shown in equation (e): In this context, Q can independently represent -CH2-, -O-, -S-, or -NH-. a, b, c, and d each independently represent 0, 1, 2, 3, 4, and 5; p and q each independently represent 0, 1, 2, 3, and 4; Preferably, Q independently represents -CH2- or -O-, and / or R. xE Each can be independently represented as either oxo or C1-C3 alkyl; Preferably, a, b, c, and d each independently represent 1, 2, and 3, and / or p and q each independently represent 0, 1, and 2. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... X represents N-R8. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... L1 and L2 each independently represent a single bond or a C1-C6 alkylene group, wherein any methylene group on the C1-C6 alkylene group can be replaced by a carbonyl group or -NR. a -, -O-, or -S-, and optionally, the C1-C6 alkylene group may be substituted with 0, 1, 2, 3, or 4 substituents selected from C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; preferably, L1 and L2 each independently represent a single bond or a C1-C3 alkylene group, and any methylene group on the C1-C3 alkylene group may be replaced with a carbonyl group or -NR. a -, -O-, or -S-; preferably, L1 and L2 independently represent single bonds, -CH2-, -(CH2)2-, -(CH2)3-, -C(O)-, and -NR-, respectively. a -, -O-, or -S-; preferably, L1 and L2 independently represent a single bond, -CH2-, -C(O)-, or -NR. a -, -O-, or -S-; more preferably, L1 and L2 each independently represent a single bond. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... Cy1 represents a 4-12 membered heterocyclic alkyl group, which can be a monocyclic, spirocyclic, bridged, or fused ring. Preferably, Cy1 represents a 4-8 membered heterocyclic alkyl group, which can be a monocyclic, spirocyclic, bridged, or fused ring. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... Cy2 represents C3-C4 cycloalkyl, C5-C6 cycloalkyl, C7-C 12 Cycloalkyl, 4-membered heterocycloalkyl, 5-6-membered heterocycloalkyl, or 7-12-membered heterocycloalkyl, wherein the C3-C4 cycloalkyl, C5-C6 cycloalkyl, C7-C 12 Cycloalkyl, 4-membered heterocyclic alkyl, 5-6-membered heterocyclic alkyl and 7-12-membered heterocyclic alkyl can be monocyclic, spirocyclic, bridged, or fused; preferably, Cy2 represents C3-C4 cycloalkyl or 4-membered heterocyclic alkyl. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... R1 represents C4-C8 cycloalkyl, 4-12 membered heterocycloalkyl, -(C1-C6 alkylene)-Cyx, or -(C1-C6 alkylene)-het-Cyx, where het represents O, S, or NR. a Cyx represents a C3-C8 cycloalkyl or a 4-12-membered heterocycloalkyl, wherein the C4-C8 cycloalkyl, 4-12-membered heterocycloalkyl, and Cyx in R1 may optionally be 0, 1, 2, or 3 selected from halogen, oxo, -OR a -SR a -NR a R a Substitution with ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic alkyl groups. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... R1 indicates: ethyl group, -CH2CF3, or The compound, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, as claimed in any one of claims 1-23, wherein, R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocyclic alkyl), -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-SR a Or -(C1-C6 alkylene)-NR a R a Preferably, R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 heterocyclic alkyl); preferably, R1 represents C1-C6 alkyl or C1-C6 haloalkyl; more preferably, R1 represents ethyl or -CH2CF3. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... R4 represents H, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-12 membered heterocyclic alkyl), -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a Or -(C0-C6 alkylene)-NR a R a ', wherein any methylene group on the C0-C6 alkylene group can be replaced with a carbonyl group, -NR a -, -O-, or -S-; wherein, the C3-C8 cycloalkyl and 4-12 membered heterocycloalkyl groups are each independently selectable by 0, 1, 2, 3, or 4 groups selected from halogen, oxo, -OR a -SR a -NR a R a Substituents such as cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl), or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl) are used; preferably, R4 represents H, -O-(C2-C3 alkylene)-(C3-C8 cycloalkyl), or -NR. a -(C2-C3 alkylene)-(C3-C8 cycloalkyl), -O-(C2-C3 alkylene)-(4-8 membered heterocyclic alkyl), -NR a -(C2-C3 alkylene)-(4-8 membered heterocyclic alkylene), OR a -SR a Or NR a R a The C3-C8 cycloalkyl and 4-8 heterocyclic alkyl groups can each be independently selected from halogen, oxo, -OR by 0, 1, 2 or 3. a -SR a -NR a R a Substitution with cyano, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; more preferably, R4 represents H, -O-(C2-C3 alkylene)-(C3-C8 cycloalkyl), -O-(C2-C3 alkylene)-(4-8 membered heterocyclic alkyl), OR a Or NR a R a Each of the C3-C8 cycloalkyl groups and 4-8 heterocyclic alkyl groups can be independently substituted by 0, 1 or 2 substituents selected from halogens, oxo groups, and C1-C6 alkyl groups. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... R4 represents: H, The compound, or its isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-26, wherein, R4 represents hydrogen, -(C0-C6 alkylene) OR a -(C0-C6 alkylene)SR a Or -(C0-C6 alkylene)NR a R a ', 3-8 membered cycloalkyl or 4-12 membered heterocycloalkyl, wherein each of the C0-C6 alkylene, 3-8 membered cycloalkyl or 4-12 membered heterocycloalkyl can be independently selected from 0, 1, 2, 3 or 4 alkyl groups selected from halogen, oxo, -OR a -SR a -NR a R a Substituents of cyano, C1-C6 alkyl, -(C0-C3 alkylene)-C3-C8 cycloalkyl, or -(C0-C3 alkylene)-4-8 heterocyclic alkyl; R4 represents hydrogen, -(C0-C6 alkylene)OR a -(C0-C6 alkylene)SR a Or -(C0-C6 alkylene)NR a R a Preferably, R4 represents hydrogen, -OR a -SR a Or -NR a R a More preferably, R4 represents H. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R2 represents a C1-C6 alkyl group, wherein the C1-C6 alkyl group may be substituted with 0 or 1 -ORa; preferably, R2 represents 1-methoxyethyl; more preferably, R2 represents Where * indicates the site where R2 is connected to the part connected to it in equation (I). The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R3 and R3' each independently represent hydrogen, halogen, and C1-C6 alkyl; preferably, R3 and R3' are H. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R5 independently represents hydrogen, halogen, oxo, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; preferably, R5 independently represents hydrogen, halogen, oxo, -OR a -SR a -NR a R a ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic alkyl; preferably, R5 independently represents hydrogen, halogen, oxo, -OR a -NR a R a ', cyano, C1-C6 alkyl; more preferably, R5 independently represents hydrogen, halogen, C1-C3 alkyl. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R6 can independently represent hydrogen, halogen, oxo, and =NR. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-NR a C(O)R a '、-NR a C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; preferably, R6 independently represents hydrogen, halogen, oxo, -OR a -SR a -NR a R a ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 heterocyclic alkyl; preferably, R6 independently represents hydrogen, halogen, C1-C3 alkyl. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R7 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), wherein each of the C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), and -(C0-C6 alkylene)-(4-8 heterocyclic alkyl) can be independently represented by 0, 1, 2, 3, or 4 Rs. x7 Substitution, R7' represents hydrogen; preferably, R x7 Each is independently selected from hydrogen, halogen, and C1-C6 alkyl; preferably, R x7 R7 represents hydrogen; more preferably, R7 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic alkyl, and R7' represents hydrogen; even more preferably, R7 represents hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, and R7' represents hydrogen. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R8 represents hydrogen, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic alkyl; preferably, R8 represents hydrogen, -C(O)R a -S(O)2R a Methyl or cyclopropyl. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R8 represents hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl, wherein each of the C1-C3 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic alkyl can be independently represented by 0, 1, or 2 R's. x8 replace. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R8 represents hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic alkyl; preferably, R8 represents hydrogen, methyl, or cyclopropyl. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R9 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocyclic alkyl, and R9' represents hydrogen; preferably, R9 represents hydrogen, methyl or cyclopropyl, and R9' represents hydrogen. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R 10 It represents hydrogen. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R a R a Each of the following can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; preferably, R a R a Each can independently represent hydrogen or C1-C6 alkyl; more preferably, R a R a Each can be used independently to represent either hydrogen or a C1-C3 alkyl group. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... m and n each independently represent 0, 1, or 2; preferably, m and n each independently represent 0 or 1. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... Compounds with structure (I) have structure (II): in: Cya said or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups; A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5-membered heteroaryl group, wherein each of the 4- to 6-membered heterocyclic alkyl group, the 4- to 6-membered heterocyclic alkenyl group, the phenylene group, and the 5-membered heteroaryl group can be independently represented by 0, 1, or 2 R's. xA replace; B represents a 5-membered heteroaryl group, which may optionally contain 0, 1, or 2 R groups. xB replace; X represents O or N-R8; L1 and L2 each independently represent a single bond or a C1-C3 alkylene group, wherein any of the above-mentioned methylene groups can be replaced by a carbonyl group or -NR. a -、-O- or -S-; Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, wherein C3-C 12 Cycloalkyl or 4-12 membered heterocyclic alkyl groups can be spirocyclic, bridged, or fused. Cy2 represents a C3-C4 cycloalkyl or a 4-membered heterocyclic alkyl; Q can independently represent -CH2-, -O-, -S-, or -NH-; a, b, c, and d each independently represent 1, 2, or 3; p and q can each independently represent 0, 1, or 2; R xA Each is independently selected from hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R xB Each is independently selected from hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R xE Each is independently selected from oxo, C1-C3 alkyl groups. R1 represents a C1-C6 alkyl or a C1-C6 haloalkyl; R5 and R6 independently represent hydrogen, halogen, oxidative oxidation, and -OR. a -SR a -NR a R a ', cyano, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; R7 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl); R8 represents hydrogen, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C3 alkyl or C3-C6 cycloalkyl; R9 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S; m and n can each independently represent 0, 1, or 2; The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof as described in any of the preceding claims, wherein... R8 represents hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl; preferably, R8 represents hydrogen, methyl, or cyclopropyl. Compounds having the structure of formula (III) as described in any of the preceding claims, their isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein: in: Cya said or A represents a 4- to 6-membered heterocyclic alkyl group, a 4- to 6-membered heterocyclic alkenyl group, a phenylene group, or a 5-membered heteroaryl group, wherein the phenylene group may be substituted with 0, 1, or 2 hydroxyl groups, halogens, C1-C3 alkyl groups, or C1-C3 haloalkyl groups; B indicates or Cy1 represents a 4-8 membered heterocyclic alkyl group, wherein the ring can be a spirocyclic, bridged, or fused ring. Cy2 represents a 4-membered heterocyclic alkyl group; Q can represent -CH2- or -O- independently; a, b, c, and d each independently represent 1, 2, or 3; R1 represents ethyl or trifluoroethyl; R5 and R6 each independently represent hydrogen, halogen, -OH, -NH2, and C1-C3 alkyl groups; R7 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; R8 represents hydrogen, -C(O)R a -S(O)2R a methyl or cyclopropyl; R9 represents hydrogen, methyl, or cyclopropyl; m and n each independently represent 0 or 1; The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms. The compound as described in any of the preceding claims, or its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, wherein... R8 represents hydrogen, methyl, or cyclopropyl. The compound, its isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, having the following structure: Pharmaceutical compositions comprising the compounds of any of the preceding claims, their isotopic derivatives, stereoisomers, or pharmaceutically acceptable salts thereof. Use of the compound, its isotope derivative, stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 47, in the preparation of a medicament for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

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