Macrocyclic compound and preparation method therefor and use thereof

Abstract

The present disclosure relates to the field of medicine. Disclosed are a macrocyclic compound and a preparation method therefor and a use thereof. Specifically disclosed are a series of compounds or stable deuterated derivatives thereof or stereoisomers thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof. Also disclosed are pharmaceutical compositions comprising the described compounds and a use thereof in the preparation of a drug for preventing and / or treating diseases or conditions (such as cancer) related to the activity of the KRAS G12V mutant protein.

Description

Macrocycles, methods of making and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 202411386434X, filed on September 29, 2024, Chinese Patent Application No. 2025102204143, filed on February 26, 2025, and Chinese Patent Application No. 2025105783148, filed on April 30, 2025, the contents of all of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present disclosure belongs to the field of medicine, in particular to macrocycles capable of selectively inhibiting KRAS G12V protein activity, and methods of making and uses thereof. BACKGROUND

[0003] The RAS gene (Rat sarcoma viral oncogene homolog) encodes a family of small GTP-hydrolyzing enzymes with a molecular weight of approximately 21 kDa. The RAS family in mammals includes three members, HRAS, KRAS, and NRAS, which function as molecular switches in a variety of cellular signaling processes. When RAS is bound to GDP, it is in an inactive state of rest or off. When cells are exposed to certain growth-promoting stimuli, RAS is induced to exchange its bound GDP for GTP and is thereby activated, subsequently recruiting and activating other downstream target proteins (e.g., Raf and PI3K), which promotes cell proliferation. RAS proteins have intrinsic activity to hydrolyze GTP to GDP (thereby converting themselves to an inactive state), but the rate of conversion is low. However, when it binds to a GTPase-activating protein (GAP), the interaction between the two greatly accelerates the rate at which RAS proteins convert GTP to GDP, thereby rapidly restoring RAS to an inactive state and shutting down signal pathway transmission when cell stimulation ends.

[0004] RAS gene mutations can be found in approximately 30% of human tumors; among them, KRAS mutations are the most common, accounting for about 85%, and NRAS and HRAS account for only 12% and 3%, respectively. KRAS mutations predominate in pancreatic cancer (86%), colorectal cancer (41%), and lung cancer (32%). In tumors, KRAS gene mutations mainly occur through point mutations. More than 150 different KRAS point mutations have been found, among which mutations at positions G12 and G13 and Q61 are the most common. These pathogenic mutations often affect the interaction of RAS with GAP and the intrinsic GTPase activity of RAS, causing the mutated RAS protein to exist mainly in the activated form bound to GTP in cells, leaving the signal pathway mediated by it in a state of persistent activation, which in turn leads to uncontrolled cell proliferation and ultimately promotes tumor formation.

[0005] Currently, for KRAS G12C mutation, targeted drugs AMG510 and MRTX849 have been approved for the treatment of non-small cell lung cancer with KRAS G12C mutation. However, for KRAS G12V mutation which often occurs in pancreatic cancer and colorectal cancer, there is a lack of selective targeted drugs approved. RMC-6236 is a pan-RAS inhibitor in the clinical stage, which shows certain clinical response in non-small cell lung cancer and pancreatic cancer patients with KRAS G12V mutation, but due to its strong inhibition on wild-type RAS, it produces more obvious side effects in the clinic, such as skin rash, gastrointestinal reaction, etc. Therefore, it is of important clinical value to develop new KRAS G12V mutant selective inhibitors with higher activity, better selectivity and lower toxicity, and it is also a hot spot and difficulty in the field of new drug research and development. SUMMARY

[0006] The present disclosure provides a class of KRAS G12V selective inhibitors, which are expected to have good physicochemical properties and drug properties.

[0007] The first aspect of the present disclosure provides a compound represented by formula (I) or a stable deuterium derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

[0008] Case A: wherein,

[0009] R 40 is hydrogen or deuterium; R 41 is hydrogen or deuterium; or R 40 and R 41 are connected to form -CH2- or -CH2CH2-;

[0010] R1is hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 heteroalkyl;

[0011] R2is hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl;

[0012] R 42 is hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; R 43 is hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; or R 42 and R 43 together with the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl;

[0013] L1is -L2-substituted or unsubstituted C 6-10 aryl-, -L2-substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl-, or -L2-substituted or unsubstituted 3- to 8-membered heterocyclyl-;

[0014] each L2is independently a bond, -O-, -C 1-4 alkyl-, -N(R 00 )-, -C(=O)-, -CR 09 =CR 10 -, -N(R 00 )C(=O)-, or -N(R 00 )C(=S)-;

[0015] Ring A is wherein, is a single or double bond;

[0016] W6, W7, W8, W9and W 10 are each independently selected from CR 13 or N;

[0017] R3is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl; R 13 is hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-6 alkoxy;

[0018] or R 13 and R3together with the atoms to which they are attached form a substituted or unsubstituted nitrogen-containing 3- to 8-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; one ring atom of the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, or 3) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus;

[0019] X is

[0020] Y1is N or CH; wherein N can be oxidized (N + -O - );

[0021] Y2is N or CH; wherein N can be oxidized (N + -O - );

[0022] R 4a is substituted or unsubstituted C 1-6 alkyl;

[0023] R5is hydrogen, -NR 01 R 02 , -C(R 05 )R 03 R 04 , -C 2-4 alkynyl-NR 01 R 02 , -C 2-4 alkenyl-NR 01 R 02 or -C 2-4 alkynyl-C 1-4 alkyl-NR 01 R 02 ;

[0024] R 01 , R 02 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 1-6 acyl; or,

[0025] R 01 , R 02 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted 7- to 12-membered bicyclic heterocyclyl, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl;

[0026] R 03 , R 04 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, or substituted or unsubstituted C 2-6 alkynyl; wherein 2 hydrogen atoms on the same carbon atom of said C 1-6 alkyl or C 1-6 alkoxy are optionally simultaneously replaced with -(CH2) j - to form a cycloalkyl group, wherein j is 2, 3, 4, 5, or 6; or

[0027] R 03 R 04 Together with the attached carbon atom, they form substituted or unsubstituted 5- to 15-membered tricyclic heterocyclic groups, substituted or unsubstituted 7- to 12-membered bicyclic heterocyclic groups, substituted or unsubstituted 3- to 8-membered monocyclic heterocyclic groups, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl groups, or substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl groups.

[0028] R 05 Hydrogen, deuterium, halogen, deuterated C 1-6 Alkyl or C 1-6 alkyl;

[0029] R 12 For hydrogen, C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0030] Y3 is in, It can be a single or double bond; 'a' is selected from 1, 2, or 3;

[0031] R y1 Selected from hydrogen, halogen, cyano, -NR 01 R 02 C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic groups, or 5- or 6-membered monocyclic heteroaryl groups; R 01 R 02 Each custom definition is the same as before;

[0032] R6 is

[0033] Cy1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaromatic ring;

[0034] Cy2 rings are 3 to 8-membered heterocyclic rings;

[0035] R 61 Substituents at any position on the Cy1 or Cy2 ring, selected from hydrogen, deuterium, oxo groups, and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl group;

[0036] n is 0, 1, 2, or 3;

[0037] R 62 Substituents at any position on the Cy2 ring are

[0038] m is 1, 2, 3, or 4;

[0039] R 14 , R 15 each independently is selected from hydrogen, deuterium, or C 1-6 alkyl;

[0040] Cy3is a C 6-10 aromatic ring, a 5- to 14-membered heteroaromatic ring, a C 3-20 cycloalkyl ring, or a 3- to 20-membered heterocyclic ring;

[0041] R 2a is a substituent on any position of the Cy3ring;

[0042] p1is 0, 1, 2, or 3; R 2a each independently is selected from hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 alkyl, C 1-6 cycloalkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-O-, -(C=O)NR 01 R 02 , or -NR 01 R 02 ; R 01 , R 02 each is as previously defined; or

[0043] p1is 2; both R 2a are connected to form a -C 1-6 alkyl- or -C 1-8 heteroalkyl-;

[0044] R 2b is a substituent on any position of the Cy3ring, which is

[0045] p2is 1, 2, or 3;

[0046] Cy4is a C 6-10 aromatic ring, a 5- to 14-membered heteroaromatic ring, a C 3-20 cycloalkyl ring, or a 3- to 20-membered heterocyclic ring;

[0047] L3is a bond, -O-C 1-4 alkyl-, -O-, -C 1-4 alkyl-, -N(R 00 )-, -N(R00 )-C 1-4 alkyl-, -C(=O)-, -CR 09 =CR 10 - or -N(R 00 )C(=O)-; wherein said -C 1-4 alkyl- is optionally substituted with one or more groups selected from deuterium, halogen, C 1-4 alkyl, haloC 1-4 alkyl;

[0048] R 3a is a substituent on any position of the Cy4ring;

[0049] R 3a each is independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl;

[0050] t1 is 1, 2, 3, 4 or 5;

[0051] R 00 each is independently hydrogen or C 1-6 alkyl;

[0052] or one R 2a is attached to R 00 to form a -C 1-6 alkyl- or -C 1-8 heteroalkyl-;

[0053] R 09 each is independently hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; said substitution means substitution with one or more (e.g. 1, 2, 3 or 4) groups selected from the group of deuterium and halogen;

[0054] R 10 each is independently hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; said substitution means substitution with one or more (e.g. 1, 2, 3 or 4) groups selected from the group of deuterium and halogen;

[0055] in each of the above groups, said substitution each independently means that each of the above groups is independently substituted with 1, 2, 3, 4, 5 or 6 groups selected from the group S1; said groups of S1 are each independently selected from the group consisting of -SF5, deuterium, oxo (=0), thioxo (=S), =CR e Rf , =NR e , halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -O-C 3-20 cycloalkyl, -O-3- to 20-membered heterocyclyl, -O-C 6-14 aryl, -O-5- or 6-membered monocyclic heteroaryl, -O-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-O-C 3-20 cycloalkyl, -C 1-4 alkyl-3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3- to 20-membered heterocyclyl, -C 1-4 alkyl-C 6- 14 aryl, -C 1-4 alkyl-O-C 6-14 aryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, -O-C 1-4 alkyl-hydroxy, -O-C 1-4 alkyl-cyano, -O-C 1-4 alkyl-C 1-6 alkyl, -O-C 1-4 alkyl-C 1-6 alkoxy, -O-C 1-4 alkyl-C 3-20 cycloalkyl, -O-C 1-4 alkyl-O-C 3-20 cycloalkyl, -O-C 1-4 alkyl-3- to 20-membered heterocyclyl, -O-C 1-4 alkyl-O-3- to 20-membered heterocyclyl, -O-C 1-4 alkyl-C 6-14aryl, -C(=O)O-C 1-6 alkyl, -C(=O)O-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -C(=O)-5- or 6-membered monocyclic heteroaryl, -C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5- or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 and -P(=O)-(C 1-6 alkyl)2; wherein the C 1-6 alkyl, the C 1-6 alkoxy, the C 2-6 alkenyl, and the C 2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 groups selected from halogen, deuterium, cyano, or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 groups selected from S2; or, when the above groups are each independently substituted with 2, 3, 4, 5, or 6 groups selected from S1, optionally two S1groups are taken together with the atom(s) to which they are attached to form a bridged ring structure;

[0056] In each of the above groups, each R a1 , R b1 is each independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, -C 1-4alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenoC 1-6 alkyl, -C 1-4 alkyl-deuteroC 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenoC 1-6 alkoxy, -C 1-4 alkyl-deuteroC 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-O-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 monocyclic cycloalkyl or -C(=O)-3- to 6-membered monocyclic heterocyclyl; wherein said C 3-6 monocyclic cycloalkyl, said 3- to 6-membered monocyclic heterocyclyl, said phenyl, said 5- or 6-membered monocyclic heteroaryl, said 8- to 10-membered bicyclic heteroaryl is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxy, nitro, C 1-6 alkyl, halogenoC 1-6 alkyl, deuteroC 1-6 alkyl, C 1-6 alkoxy, halogenoC 1-6 alkoxy, deuteroC 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C 1-6 alkyl)2and -P(=O)-(C 1-6 alkyl)2; or

[0057] each R a1 and R b1together with the nitrogen atom to which they are attached form a 3- to 20-membered heterocyclyl; wherein said 3- to 20-membered heterocyclyl is each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxy, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuteratedC 1-6 alkyl, C 1- 6alkoxy, haloC 1-6 alkoxy, deuteratedC 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C 1-6 alkyl)2and -P(=O)-(C 1-6 alkyl)2;

[0058] each R c1 is each independently H, C 1-6 alkyl, haloC 1-6 alkyl, deuteratedC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuteratedC 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkyl, -C 1-4 alkyl-deuteratedC 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkoxy, -C 1-4 alkyl-deuteratedC 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-O-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; said C 3-6The monocyclic cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 or -P(=O)-(C 1-6 Alkyl)2;

[0059] Among the above groups, each group of S2 is independently selected from the following group: deuterium, oxo (=O), thio (=S), =CR e R f =NR e Halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-(C=O)-NHC 1-6 Alkyl, -(C=O)-N(C 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 Alkyl)2、-P(=O)-(C 1-6 Alkyl)2、-(C=O)C 1-6 Alkyl groups and -SF5;

[0060] Of the above groups, the -C 1-4 Alkyl group - is unsubstituted; or -C 1-4 The 1, 2, 3, or 4 hydrogen atoms on the alkyl group are each independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Substituted with alkyl, -CH2-hydroxy, -CH2-cyano, or phenyl groups; or C 1-4 Two hydrogen atoms on the same carbon atom of an alkyl group are simultaneously converted to -(CH2). j- Substitution further forms a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; or C 1-4 Two hydrogen atoms on the same carbon atom of an alkyl group are simultaneously converted to CR. e R f replace;

[0061] Of the above groups, R e Each is independently H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0062] Of the above groups, R f Each is independently H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0063] In the aforementioned groups, one or more (e.g., 1, 2, 3, or 4) ring atoms of the 3- to 8-membered heterocyclic group, 3- to 8-membered heterocycle, 3- to 6-membered monocyclic heterocyclic group, or 3- to 8-membered monocyclic heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; the C 1-6 One or more (e.g., 1, 2, 3, or 4) ring atoms of the heteroalkyl group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 7- to 12-membered bicyclic heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 3- to 20-membered heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 5- or 6-membered monocyclic heteroaromatic ring and the 5- or 6-membered monocyclic heteroaromatic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus. The heteroatom of phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 8- to 10-membered bicyclic heteroaryl group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, or 4) ring atoms of the 3- to 6-membered monocyclic heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 5- to 15-membered tricyclic heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 5- to 14-membered heteroaryl ring are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus.

[0064] When the ring atom is a sulfur atom, the sulfur atom is optionally replaced by one or two atoms selected from oxo and =NR. e Group substitution; R e Definitions are the same as before;

[0065] When the ring atom is a phosphorus atom, the phosphorus atom is optionally surrounded by one or two atoms selected from oxo and =NR. esubstituted with 1 to 3 groups independently selected from the group consisting of -OR e as previously defined;

[0066] or,

[0067] Case B: wherein

[0068] R 40 is hydrogen or deuterium; R 41 is hydrogen or deuterium; or R 40 and R 41 are joined to form -CH2- or -CH2CH2-;

[0069] R1is -NR 17 R 18 ; R 17 , R 18 and the nitrogen atom to which they are attached together form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted 6- to 12-membered bicyclic heterocyclyl, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl;

[0070] R2is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl;

[0071] R 42 is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl; R 43 is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl; or R 42 and R 43 together with the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl;

[0072] L1is -L2-substituted or unsubstituted C 6-10 aryl-, -L2-substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl-, or -L2-substituted or unsubstituted 3- to 8-membered heterocyclyl-;

[0073] L2is each independently -CR 09 =CR 10 -, -N(R 00 )C(=O)-, or -N(R 00 )C(=S)-;

[0074] Ring A is

[0075] W6is selected from CR 13 or N;

[0076] R3is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl;

[0077] R 13 is hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 alkoxy;

[0078] or R 13 and R3together with the atoms to which they are attached form a substituted or unsubstituted nitrogen-containing 3- to 8-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; one ring atom of the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, or 3) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus;

[0079] X is

[0080] Y1is N or CH; wherein N can be oxidized (N + -O - );

[0081] Y2is N or CH; wherein N can be oxidized (N + -O - );

[0082] R 4a is substituted or unsubstituted C 1-6 alkyl;

[0083] R5is hydrogen, -NR 01 R 02 , -C(R 05 )R 03 R 04 , -C 2-4 alkynyl-NR 01 R 02 , -C 2-4 alkenyl-NR 01 R 02 or -C 2-4 alkynyl-C 1-4 alkyl-NR 01 R 02 ;

[0084] R 01 , R 02 are each independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or substituted or unsubstituted C 1-6 acyl; or,

[0085] R 01 , R 02 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted 7- to 12-membered bicyclic heterocyclyl, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl;

[0086] R 03 , R 04 each independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl; wherein the C 1-6 alkyl or C 1-6 2 hydrogen atoms on the same carbon atom of the C j alkyl group are optionally and simultaneously replaced with -(CH2) 03 to form a cycloalkyl group, wherein j is 2, 3, 4, 5, or 6; or

[0087] R 04 , R 05 together with the carbon atom to which they are attached form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted 7- to 12-membered bicyclic heterocyclyl, a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl, a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or a substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl;

[0088] R 1-6 is hydrogen, deuterium, halogen, deuterated C 1-6 alkyl or C 12 alkyl;

[0089] R 1-6 is hydrogen, C 1-6 alkyl or deuterated C y1 alkyl;

[0090] Y3is wherein, is a single or double bond; a is selected from 1, 2, or 3;

[0091] R 01 is selected from hydrogen, halogen, cyano, -NR 02 R 1-6 , C 1-6alkyl, substituted or unsubstituted C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered monocyclic heteroaryl; 01 , R 02 each is as defined above;

[0092] R6is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered monocyclic heteroaryl; 6-10 aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl;

[0093] or

[0094] R6is

[0095] Cy1ring is a phenyl ring or a 5- or 6-membered monocyclic heteroaryl ring;

[0096] Cy2ring is a 3- to 8-membered heterocycle;

[0097] R 61 is a substituent on any position of the Cy1ring or the Cy2ring selected from hydrogen, deuterium, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, cyano, C 2-6 alkenyl, or C 2-6 alkynyl;

[0098] n is 0, 1, 2, or 3;

[0099] R 62 is a substituent on any position of the Cy2ring selected from hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, -cyano, (C=O)NR 01 R 02 ,

[0100] m is 1, 2, 3, or 4;

[0101] R 14 , R 15 each is independently selected from hydrogen, deuterium, or C 1-6 alkyl;

[0102] Cy3ring is C 6-10 aromatic ring, 5- to 14-membered heteroaromatic ring, C 3-20 cycloalkyl ring or 3- to 20-membered heterocyclic ring;

[0103] R 2a is a substituent on any position of the Cy3ring;

[0104] p1 is 0, 1, 2 or 3; R 2a each is independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-O-, -(C=O)NR 01 R 02 or -NR 01 R 02 ; R 01 , R 02 each is as defined above; or

[0105] p1 is 2; both R 2a are connected to form a -C 1-6 alkyl- or -C 1-8 heteroalkyl- group;

[0106] R 2b is a substituent on any position of the Cy3ring, which is

[0107] p2 is 1, 2 or 3;

[0108] Cy4ring is C 6-10 aromatic ring, 5- to 14-membered heteroaromatic ring, C 3-20 cycloalkyl ring or 3- to 20-membered heterocyclic ring;

[0109] L3 is a bond, -O-C 1-4 alkyl-, -O-, -C 1-4 alkyl-, -N(R 00 )-, -N(R 00 )-C 1-4 alkyl-, -C(=O)-, -CR 09 =CR 10 - or -N(R 00 )C(=O)-; wherein said -C 1-4 alkyl- is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, C 1-4alkyl, haloC 1-4 one or more groups in alkyl are substituted;

[0110] R 3a is a substituent on any position of the Cy4ring;

[0111] R 3a each independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl;

[0112] t1 is 1, 2, 3, 4 or 5;

[0113] R 00 each independently hydrogen or C 1-6 alkyl;

[0114] or one R 2a is attached to R 00 to form a -C 1-6 alkyl- or -C 1-8 heteroalkyl- group;

[0115] R 09 each independently hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; said substitution means substitution by one or more (e.g. 1, 2, 3 or 4) groups selected from the group consisting of deuterium and halogen;

[0116] R 10 each independently hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; said substitution means substitution by one or more (e.g. 1, 2, 3 or 4) groups selected from the group consisting of deuterium and halogen;

[0117] in each of the aforementioned groups, said substitution each independently means that each of the aforementioned groups is independently substituted by 1, 2, 3, 4, 5 or 6 groups selected from the group S1; said groups of the group S1 are each independently selected from the group consisting of -SF5, deuterium, oxo (=0), thioxo (=S), =CR e R f , =NR e , halogen, cyano, hydroxy, carboxy, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C 6-14aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -O-C 3-20 cycloalkyl, -O-3- to 20-membered heterocyclyl, -O-C 6-14 aryl, -O-5- or 6-membered monocyclic heteroaryl, -O-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-O-C 3-20 cycloalkyl, -C 1-4 alkyl-3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3- to 20-membered heterocyclyl, -C 1-4 alkyl-C 6- 14 aryl, -C 1-4 alkyl-O-C 6-14 aryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, -O-C 1-4 alkyl-hydroxy, -O-C 1-4 alkyl-cyano, -O-C 1-4 alkyl-C 1-6 alkyl, -O-C 1-4 alkyl-C 1-6 alkoxy, -O-C 1-4 alkyl-C 3-20 cycloalkyl, -O-C 1-4 alkyl-O-C 3-20 cycloalkyl, -O-C 1-4 alkyl-3- to 20-membered heterocyclyl, -O-C 1-4 alkyl-O-3- to 20-membered heterocyclyl, -O-C 1-4 alkyl-C 6-14 aryl, -C(=O)O-C 1-6 alkyl, -C(=O)O-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-C 6-14 aryl, -NR a1 R b1-C(=O)-NR a1 R b1 -C(=O)-5 or 6-membered monocyclic heteroaryl, -C(=O)-8 to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 Alkyl-C 3-20 Cycloalkyl, -C(=O)-C 1-6 Alkyl-3 to 20-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl-C 6-14 Aryl, -C(=O)-C 1-6 Alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 Alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-NR a1 R b1 -C 1-4 Alkyl-C(=O)-NR a1 R b1 -C 1-4 Alkyl-OR c1 and -P(=O)-(C 1-6 Alkyl)2; wherein, the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 2-6 alkenyl, the C 2-6 Each alkynyl group is independently and optionally replaced by one, two, or three groups selected from halogens, deuterium, cyano, or hydroxyl groups; the C 3-20 cycloalkyl, the 3 to 20 membered heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each optionally substituted by 1, 2, 3, or 4 groups selected from the S2 group; or, when the above groups are each optionally substituted by 2, 3, 4, 5, or 6 groups selected from the S1 group, two S1 group groups are connected to the atoms they are attached to to form a bridged ring structure.

[0118] In the above groups, each R a1 R b1 Each independently represents H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-deuterated C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4alkyl-haloC 1-6 alkoxy, -C 1-4 alkyl-deuteroC 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-O-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-6 monocyclic cycloalkyl or -C(=O)-3- to 6-membered monocyclic heterocyclyl; wherein said C 3-6 monocyclic cycloalkyl, said 3- to 6-membered monocyclic heterocyclyl, said phenyl, said 5- or 6-membered monocyclic heteroaryl, said 8- to 10-membered bicyclic heteroaryl is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxy, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuteroC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuteroC 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C 1-6 alkyl)2and -P(=O)-(C 1-6 alkyl)2; or

[0119] each R a1 and R b1 together with the nitrogen atom to which they are attached form a 3- to 20-membered heterocyclyl; wherein said 3- to 20-membered heterocyclyl is each independently optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxy, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuteroC 1-6 alkyl, C 1- 6alkoxy, haloC 1-6 alkoxy, deuteroC 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C 1-6 alkyl)2, and -P(=O)-(C 1-6 alkyl)2;

[0120] each R c1 is independently H, C 1-6 alkyl, haloC 1-6 alkyl, deuteratedC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuteratedC 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkyl, -C 1-4 alkyl-deuteratedC 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkoxy, -C 1-4 alkyl-deuteratedC 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-O-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; said C 3-6 monocyclic cycloalkyl, said 3- to 6-membered monocyclic heterocyclyl, said phenyl, said 5- or 6-membered monocyclic heteroaryl, said 8- to 10-membered bicyclic heteroaryl is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxy, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuteratedC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuteratedC 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C1-6 alkyl)2or -P(=0)-(C 1-6 alkyl)2;

[0121] In each of the above groups, the groups of each S2group are each independently selected from the group consisting of: deuterium, oxo (=0), thioxo (=S), =CR e R f , =NR e , halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -(C=0)-NHC 1-6 alkyl, -(C=0)-N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=0)-(C 1-6 alkyl)2, -P(=0)-(C 1-6 alkyl)2, -(C=0)C 1-6 alkyl and -SF5;

[0122] In each of the above groups, the -C 1-4 alkyl- is unsubstituted; or 1, 2, 3 or 4 hydrogen atoms on the -C 1-4 alkyl- are each independently replaced with a group selected from halogen, cyano, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, -CH2-hydroxyl, -CH2-cyano, phenyl; or 2 hydrogen atoms on the same carbon atom on the C 1-4 alkyl are simultaneously replaced with -(CH2) j - to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; or 2 hydrogen atoms on the same carbon atom on the C 1-4 alkyl are simultaneously replaced with =CR e R f ;

[0123] In each of the above groups, R e are each independently H, halogen, C 1-6 alkyl, haloC 1-6 alkyl or deuterated C 1-6 alkyl;

[0124] In each of the above groups, R f are each independently H, halogen, C1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0125] In the aforementioned groups, one or more (e.g., 1, 2, 3, or 4) ring atoms of the 3- to 8-membered heterocyclic group, 3- to 8-membered heterocycle, 3- to 6-membered monocyclic heterocyclic group, or 3- to 8-membered monocyclic heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; the C 1-6 One or more (e.g., 1, 2, 3, or 4) ring atoms of the heteroalkyl group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 7- to 12-membered bicyclic heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 3- to 20-membered heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 5- or 6-membered monocyclic heteroaromatic ring and the 5- or 6-membered monocyclic heteroaromatic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus. The heteroatom of phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 8- to 10-membered bicyclic heteroaryl group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, or 4) ring atoms of the 3- to 6-membered monocyclic heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 5- to 15-membered tricyclic heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 5- to 14-membered heteroaryl ring are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus.

[0126] When the ring atom is a sulfur atom, the sulfur atom is optionally replaced by one or two atoms selected from oxo and =NR. e Group substitution; R e Definitions are the same as before;

[0127] When the ring atom is a phosphorus atom, the phosphorus atom is optionally surrounded by one or two atoms selected from oxo and =NR. e Group substitution; R e The definition is the same as before.

[0128] In case A or case B Selected from

[0129] In case A, for Among them, R 13 X and R3 are each defined in any of the items disclosed herein.

[0130] In one embodiment, the compound represented by formula (I) is as follows:

[0131] In formula (A1), formula (A2), formula (A3), W6, W7, W8, W9, W 10 , R1, R2, R 42 , R 43 , R 4a , R5, R6 and L1 are each independently defined as in case A of the present disclosure.

[0132] In formula (A1), formula (A3), W6, W7, W8, W9, W 10 , R1, R2, R 42 , R 43 , R 4a , R5, R6 and L1 are each independently defined as in case B of the present disclosure.

[0133] In one embodiment, the compound of formula (I) is of the following formula:

[0134] In formula (B1), formula (B2), formula (B3), formula (B4), formula (B5), formula (B6), R1, R2, R 13 , R 42 , R 43 , R 4a , R5, R6 and L1 are each defined as in case A of the present disclosure; or

[0135] In formula (B1), formula (B2), formula (B3), formula (B4), R1, R2, R 13 , R 42 , R 43 , R 4a , R5, R6 and L1 are each independently defined as in case B of the present disclosure.

[0136] In one embodiment, the compound of formula (I) is of the following formula:

[0137] In formula (B7), formula (B8), W6, R3, R 42 , R 43 , R 4a , R5 and R6 are each defined as in case A of the present disclosure; in formula (B9), W6, R3, R 42 , R 43 , R 4a , R5, R6, R1, R2 are each defined as in case B of the present disclosure.

[0138] In one embodiment, R 40 is hydrogen; R 41 is hydrogen.

[0139] In one embodiment, R1is hydrogen; R2is hydrogen.

[0140] In one embodiment, R 42 is hydrogen; R 43 is hydrogen.

[0141] In one embodiment, L1is -L2-substituted or unsubstituted thiazolyl- or -L2-substituted or unsubstituted oxazolyl-; L2is as defined in any one of the present disclosure.

[0142] In one embodiment, L2is independently for each occurrence a bond or -CH=CH-.

[0143] In one embodiment, L1is wherein "*" indicates the point of attachment to ring A.

[0144] In one embodiment, L1is wherein "*" indicates the point of attachment to ring A.

[0145] In one embodiment, R 13 is hydrogen.

[0146] In one embodiment, R3is selected from the group consisting of -CH2CH2O-R 19 ; R 19 is substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, substituted or unsubstituted 6- to 12-membered bicyclic heterocyclyl, or substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl.

[0147] In one embodiment, R3is selected from the group consisting of: said groups are substituted or unsubstituted; said substitution means each of the above groups is independently substituted with 1, 2, 3, or 4 C 1-6 alkyl groups.

[0148] In one embodiment, R3is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 cycloalkyl-substituted C 1-6 alkyl, C 1-6 alkoxy-substituted C 1-6 alkyl, -O-3- to 20-membered heterocyclyl-substituted C 1-6 alkyl, or C 3-6 cycloalkyl.

[0149] In one embodiment, R3is hydrogen, C 1-3 alkyl, haloC 1-3 alkyl, C 3-6 cycloalkyl-substituted C 1-3 alkyl, C1-3 alkyl, -O-3 to 80 membered heterocyclyl-substituted C 1-3 alkyl, -O-3 to 80 membered heterocyclyl-substituted C 1-6 alkyl or deuterated C 1-3 alkyl.

[0150] In one embodiment, R3is ethyl, cyclopropyl-substituted methyl, cyclobutyl-substituted methyl, trifluoromethyl-substituted methyl,

[0151] In one embodiment, R3is ethyl, cyclopropyl-substituted methyl, cyclobutyl-substituted methyl.

[0152] In one embodiment, R3is

[0153] In one embodiment, Y1is N; Y2is CH.

[0154] In one embodiment, R 4a is -C 1-6 alkyl-C 1-6 alkoxy.

[0155] In one embodiment, R 4a is -C 1-3 alkyl-C 1-3 alkoxy.

[0156] In one embodiment, R 4a is -CH(CH3)-O-CH3.

[0157] In one embodiment, R 4a is

[0158] In one embodiment, R5is -NR 01 R 02 or -C(R 05 )R 03 R 04 ; wherein R 01 , R 02together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5- to 15-membered tricyclic nitrogen-containing heterocyclyl, a substituted or unsubstituted 7- to 12-membered bicyclic nitrogen-containing heterocyclyl, or a substituted or unsubstituted 3- to 8-membered monocyclic nitrogen-containing heterocyclyl; one ring atom of the 5- to 15-membered tricyclic nitrogen-containing heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, 3, or 4) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one ring atom of the 7- to 12-membered bicyclic nitrogen-containing heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, 3, or 4) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one ring atom of the 3- to 8-membered monocyclic nitrogen-containing heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, or 3) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus. 03 04 together with the carbon atom to which they are attached form a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl. 05 Definitions are as defined anywhere in the disclosure.

[0159] In one embodiment, the 5- or 6-membered monocyclic heteroaryl is pyrazolyl or pyridinyl.

[0160] In one embodiment, the 5- or 6-membered monocyclic heteroaryl is unsubstituted or substituted with C 1-3 alkyl-5- to 6-membered heterocyclyl.

[0161] In one embodiment, the R 01 02 together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3- to 8-membered monocyclic nitrogen-containing heterocyclyl.

[0162] In one embodiment, R5is -C 2-4 alkynyl-NR 01 R 02 or -C 2-4 alkynyl-C 1-4 alkyl-NR 01 R 02 ; wherein R 01 , R 02 ​​together with the nitrogen atom to which they are attached form a substituted or unsubstituted nitrogen-containing 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted nitrogen-containing 7- to 12-membered bicyclic heterocyclyl, or a substituted or unsubstituted nitrogen-containing 3- to 8-membered monocyclic heterocyclyl; one ring atom of the nitrogen-containing 5- to 15-membered tricyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, 3, or 4) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one ring atom of the 7- to 12-membered bicyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, 3, or 4) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one ring atom of the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, or 3) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus. In one embodiment, the R 01 , R 02 together with the nitrogen atom to which they are attached form a substituted or unsubstituted nitrogen-containing 3- to 8-membered monocyclic heterocyclyl.

[0163] In one embodiment, the substitution means that the nitrogen-containing 5- to 15-membered tricyclic heterocyclyl, the nitrogen-containing 7- to 12-membered bicyclic heterocyclyl, the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is substituted with 1, 2, 3, 4, 5, or 6 groups selected from Group S1; wherein when a ring atom is a sulfur atom, the sulfur atom is optionally substituted with one or two groups selected from oxo and =NR e ; when a ring atom is a phosphorus atom, the phosphorus atom is optionally substituted with one or two groups selected from oxo and =NR e ; R e is as previously defined R e each independently is H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, or deuterated C 1-6 alkyl.

[0164] In one embodiment, the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is selected from

[0165] In one embodiment, the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is unsubstituted or substituted with 1 or 2 groups selected from cyano, methyl, or cyclopropyl, or two of the methyl groups are joined to form -CH2CH2-.

[0166] In one embodiment, R5is selected from

[0167] In one embodiment, R5is selected from

[0168] In one embodiment, R 12 is hydrogen.

[0169] In one embodiment, X is For example,

[0170] In one embodiment, X is For example,

[0171] In one embodiment, X is

[0172] In one embodiment, Cy4is a phenyl ring, a naphthyl ring, a thiazole ring, an isothiazole ring, a thiophene ring, or a pyridine ring.

[0173] In one embodiment, R 3a is halogen or methyl.

[0174] In one embodiment, t1is 1.

[0175] In one embodiment, L3is a bond, -O-CH2-, -O-CH(CH3)-, -O-CH(CH2CH3)-, -O-(CH2)2-, -NH-CH2-, -NH-CH(CH3)-, or -CH2-.

[0176] In one embodiment, p2is 1.

[0177] In one embodiment, Cy3is a phenyl ring, a naphthyl ring, a pyridine ring,

[0178] In one embodiment, Cy3is a phenyl ring,

[0179] In one embodiment, R 2a is hydrogen, fluorine, chlorine, cyano, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, methyl, ethyl, cyclopropyl,

[0180] In one embodiment, R 2a is hydrogen, chlorine, ethynyl, methoxy, ethoxy.

[0181] In one embodiment, p1is 2.

[0182] In one embodiment, two R 2a are joined to form a -C 1-3 heteroalkyl-.

[0183] In one embodiment, two R 2a are joined to form a -O-CH2CH2-O- or -O-CH2CH2CH2-O-.

[0184] In an embodiment, m is 1.

[0185] In an embodiment, R6is each p3is independently 0 or 1 ; p4is 1 or 2; n, R 61 , R 62 each is defined as in any of the present disclosure.

[0186] In an embodiment, R 61 is hydrogen, oxo, or methyl.

[0187] In an embodiment, n is 1.

[0188] In an embodiment, R 62 is

[0189] In an embodiment, R 62 is

[0190] In an embodiment, R 62 is

[0191] In an embodiment, R 62 is

[0192] In an embodiment, R 2b is

[0193] In an embodiment, R 2b is

[0194] In an embodiment, R 09 is hydrogen.

[0195] In an embodiment, R 10 is hydrogen.

[0196] In an embodiment, R 00 is hydrogen.

[0197] In an embodiment, the C 1-6 alkyl is isopropyl, methyl, sec-butyl, isobutyl, n-propyl, ethyl, pentyl, neopentyl, or tert-pentyl.

[0198] In an embodiment, the -C 1-8 heteroalkyl- is -0-CH2-CH2-CH2-0-, -0-CH2-CH2-0-, or -0-CH2-0-.

[0199] In one embodiment, the C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl.

[0200] In one embodiment, the 3 to 8 membered heterocyclyl is azetidinyl, thietanyl, pyrrolidinyl, cyclopropyltetrahydrofuranyl, cyclopropyltetrahydropyrrolyl, cyclopropyltetrahydrothiophenyl,

[0201] In one embodiment, R6is:

[0202] In one embodiment, R6is:

[0203] In one embodiment, R6is:

[0204] In one embodiment, the compound is selected from Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, Z20, Z21, Z22, Z23, Z24, Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39, Z40, Z41, Z42, Z43, Z44, Z45, Z46, Z47, Z48, Z49, Z50, Z51, Z52, Z53, Z54, Z55, Z56, Z57, Z58, Z59, Z60, Z61, Z62, Z63, Z64, Z65, Z66, Z67, Z68, Z69, Z70, Z71, Z72, Z73, Z74, Z75, Z76, Z77, Z78, Z79, Z80, Z82, Z83, Z84, Z85, Z86, Z87, Z88, Z89, Z90, Z91, Z92, Z93, Z94, Z95, Z96, Z97, Z98, Z99, Z100, Z101, Z102.

[0205] In one embodiment, R1is -NR 17 R 18 ; wherein R 17 , R 18 and the nitrogen atom to which they are attached together form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted 6- to 12-membered bicyclic heterocyclyl, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl.

[0206] In one embodiment, R1is -NR 17 R 18 ; wherein R 17 , R 18 and the nitrogen atom to which they are attached together form a substituted or unsubstituted 4- to 6-membered monocyclic heterocyclyl, a substituted or unsubstituted 7- to 9-membered bicyclic heterocyclyl.

[0207] In one embodiment, R1is -NR 17 R 18 ; wherein R 17 , R 18 and the nitrogen atom to which they are attached together form a substituted or unsubstituted 7- to 9-membered bicyclic spiroheterocyclyl.

[0208] In one embodiment, R1is selected from the group consisting of:

[0209] and the aforementioned groups are substituted or unsubstituted;

[0210] each of said substitutions is independently that each of the aforementioned groups is independently substituted with 1, 2, 3, 4, 5, or 6 groups selected from the group S1.

[0211] In one embodiment, R1is hydrogen,

[0212] In one embodiment, R3is selected from the group consisting of -CH2CH2O-R 19 ; R 19 is a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted 6- to 12-membered bicyclic heterocyclyl, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl.

[0213] In one embodiment, R3is selected from the group consisting of: the aforementioned groups are substituted or unsubstituted; and the substitutions are that each of the aforementioned groups is independently substituted with 1, 2, 3, or 4 C 1-6 alkyl groups.

[0214] R3is selected from the group consisting of C 1-6 alkoxy-substituted C 1-6 alkyl, -O-3- to 20-membered heterocyclyl-substituted C 1-6 alkyl.

[0215] In one embodiment, R3is selected from the group consisting of C 1-3 alkoxy-substituted C 1-3 alkyl, -O-3- to 20-membered heterocyclyl-substituted C 1-3 alkyl.

[0216] In one embodiment, R3is selected from the group consisting of:

[0217] In one embodiment, R5is selected from the group consisting of:

[0218] In one embodiment, R5is selected from the group consisting of:

[0219] In one embodiment, the compound is selected from: Z103, Z104, Z105, Z106, Z107, Z108, Z109, Z110, Z111, Z112, Z113, Z114, Z115, Z116, Z117, Z118, Z119, Z120, Z121, Z122, Z123, Z124, Z125, Z126, Z127, Z128, Z129, Z130, Z131, Z132, Z133, Z134, Z135, Z136, Z137, Z138, Z139, Z140, Z141, Z142, Z143, Z144, Z145, Z146, Z147, Z148, Z149, Z150, Z151, Z152, Z153, Z154, Z155, Z156, Z157, Z158, Z159, Z160, Z161, Z162, Z163, Z164, Z165, Z166, Z167, Z168, Z169, Z170, Z171, Z172, Z173, Z174, Z175, Z176, Z177, Z178, Z179, Z180, Z181, Z182, Z183, Z184, Z185, Z186, Z187, Z188, Z189, Z190, Z191, Z192, Z193, Z194, Z195, Z196, Z197, Z198, Z199, Z200, Z201, Z202, Z203, Z204, Z205, Z206, Z207, Z208, Z209, Z210, Z211, Z212, Z213, Z214, Z215, Z216, Z217, Z218, Z219, Z220, Z221, Z222, Z223, Z224, Z225, Z226, Z227, Z228, Z229, Z230, Z231, Z232, Z233, Z234, Z235, Z236, Z237, Z238, Z239, Z240, Z241, Z242, Z243, Z244, Z245, Z246.

[0220] A pharmaceutical composition comprising a compound of the first aspect described above, or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable carrier is provided in a second aspect of the present disclosure.

[0221] The third aspect of the present disclosure provides the aforementioned compound as a medicament.

[0222] As used herein, the term "pharmaceutically acceptable carrier" means any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or subject, representative carriers include water, oils, vegetables and minerals, ointment bases, lotion bases, ointment bases, and the like. These bases include suspending agents, viscosity enhancers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the art of cosmetics or topical medicine.

[0223] In the embodiments of the present application, the pharmaceutical composition can be administered in any of the following ways: orally, spray inhalation, rectally, nasally, buccally, topically, parenterally, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an external implant reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred. The water suspension preparation is usually mixed with suitable emulsifying agents and suspending agents. If necessary, some sweeteners, fragrances or colorants can also be added to the above oral preparation forms. When used topically, especially for the treatment of local external application of easily accessible affected areas or organs, such as eyes, skin or lower intestinal nervous diseases, the compound of the present application can be prepared into different topical preparation forms according to different affected areas or organs. When applied topically to the eye, the compound of the present application can be formulated into a micronized suspension or solution preparation form, and the carrier used is isotonic sterile saline of a certain pH, and a preservative such as benzalkonium chloride can or can not be added. For eye use, the compound can also be prepared into an ointment form such as vaseline ointment. When applied topically to the skin, the compound of the present application can be prepared into a suitable ointment, lotion or cream preparation form, in which the active ingredient is suspended or dissolved in one or more carriers. The ointment preparation can use carriers including but not limited to: mineral oil, liquid vaseline, white vaseline, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; the lotion or cream can use carriers including but not limited to: mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, cetyl aralkyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compound of the present application can also be administered in the form of a sterile injection preparation, including sterile injection water or oil suspension or sterile injection solution. The carriers and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.

[0224] Another aspect of the present disclosure provides use of the compound of the first aspect described above, or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the pharmaceutical composition of the second aspect described above, in the manufacture of a medicament for the prevention and / or treatment of a disease or a disorder; the disease or disorder is a disease or disorder associated with KRAS G12V protein activity.

[0225] Another aspect of the present disclosure provides a method for the prevention and / or treatment of a disease or a disorder associated with KRAS G12V protein activity, the method comprising the step of: administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect described above, or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; or administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the second aspect described above.

[0226] Another aspect of the present disclosure provides the compound of the first aspect described above, or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the pharmaceutical composition of the second aspect described above, for use in the prevention and / or treatment of a disease or a disorder; the disease or disorder is a disease or disorder associated with KRAS G12V protein activity.

[0227] Another aspect of the present disclosure provides use of the compound of the first aspect described above, or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the pharmaceutical composition of the second aspect described above, in the manufacture of a medicament for the prevention and / or treatment of a disease or a disorder; the disease or disorder is a disease or disorder associated with KRAS G12V protein activity.

[0228] Herein, the disease or disorder associated with KRAS G12V protein activity is cancer, including but not limited to pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, squamous cell lung cancer, esophageal cancer, ovarian cancer, uterine cancer, melanoma, bladder cancer or head and neck cancer.

[0229] Herein, the use or method further comprises administering an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second RAS inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, a mTORCl inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, or a combination thereof.

[0230] Another aspect of the present disclosure provides a method for treating a cancer in a subject in need thereof, the method comprising:

[0231] (a) determining that the cancer is associated with KRAS G12V protein activity; and

[0232] (b) administering to the subject a therapeutically effective amount of a compound of the first aspect of the disclosure or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; or administering to the subject a therapeutically effective amount of a pharmaceutical composition of the second aspect of the disclosure.

[0233] In one embodiment, the administration is accomplished by a route selected from parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intraluminal, intrasynovial, intrathecal, intramuscular injection, intravitreal injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous, and topical administration.

[0234] Another aspect of the present disclosure provides a method of inhibiting KRAS G12V protein activity in a cell, the method comprising the step of: contacting the cell with a compound of the first aspect of the disclosure or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; or contacting the cell with a pharmaceutical composition of the second aspect of the disclosure. The cell can be in vivo or in vitro.

[0235] Another aspect of the present disclosure provides the use of a compound of the first aspect described above or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition as described above in the second aspect, in the manufacture of an inhibitor of KRAS G12V protein activity.

[0236] Definitions and Terminology

[0237] As used herein, the term "subject" refers to an animal, particularly a mammal. Preferably, a human.

[0238] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a drug or pharmaceutical agent that is sufficient to achieve an intended effect, without being toxic to the patient. In the context of the present application, the amount of a given drug will depend on factors such as the particular dosage form being used, the type and severity of the disease or condition, the identity of the recipient or host (e.g., weight), but the amount administered can be routinely determined by methods known in the art according to the particular circumstances, including, for example, the specific drug employed, the route of administration, the condition being treated, and the recipient or host being treated. In general, for dosage regimens in adults, the amount of drug administered will typically be in the range of 0.02-5000 mg / day, such as about 1-1500 mg / day. The desired dose can be conveniently presented in a dosage unit or a divided or unit daily dose, such as two, three, four or more sub-doses, administered simultaneously or at appropriate intervals, for example as one, two, three, four or more sub-doses per day. It will be appreciated by one skilled in the art that the specific effective amount will vary according to the patient's status and in conjunction with the diagnosis of the physician.

[0239] As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound of the present application which is pharmaceutically acceptable and which has the pharmacological activity of the parent compound. Such salts include acid addition salts with inorganic acids such as nitric acid, phosphoric acid, carbonic acid and the like; or with organic acids such as propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid and the like; or salts of metal ions such as alkali metal ions or alkaline earth metal ions which have replaced the acidic protons present on the parent compound; or coordination compounds with organic bases such as ethanolamine and the like. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains an acid or a base moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile, and the like, are preferred. In addition to salt forms, the compounds provided by the present application can also take the form of prodrugs. Prodrugs of the compounds described herein are readily converted by chemical or physiological action, or both, into the compounds of the present application. In addition, prodrugs can be converted to the compounds of the present application in the body by chemical or biochemical methods.

[0240] As used herein, the term "solvate" refers to a compound of the present application in combination with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid and the like. Solvates include stoichiometric and non-stoichiometric solvates. Certain compounds of the present application can exist in both solvated and unsolvated forms. In general, the solvated forms are equivalent in every respect to the unsolvated forms for the purposes of the present application.

[0241] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers include primarily cis-trans isomers and optical isomers. The compounds of the present application can exist in stereoisomeric forms and therefore encompass all possible stereoisomeric forms, including but not limited to, cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers, and the like, as well as any combination or mixture of any two or more of the foregoing. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compounds of the present application contain an olefinic double bond, unless specified otherwise, it is intended that the double bond contain only E isomers, only Z isomers, or any combination thereof. Atropisomers are stereoisomers based on restricted rotation within a molecule resulting in axial or planar chirality. And as a drug, the stereoisomer with superior activity is preferred. The compounds of the present application have optical isomers resulting from asymmetric carbons and the like, and individual isomers can be prepared by methods known in the art, for example, by crystallization or chiral chromatography, and the like, if desired.

[0242] As used herein, the =CR e R f substituted means that an atom of the molecule is attached to a CR e R f carbon atom (C) by a double bond. That is, an atom of the molecule is substituted with As used herein, the =NR e substituted means that an atom of the molecule is attached to a NR e nitrogen atom (N) by a double bond. That is, an atom of the molecule is substituted with As used herein, the oxo means that an atom of the molecule is attached to an oxygen atom (O) by a double bond. That is, an atom of the molecule is substituted with As used herein, the thioxo means that an atom of the molecule is attached to a sulfur atom (S) by a double bond. That is, an atom of the molecule is substituted with As used herein, the thioxo means that an atom of the molecule is attached to a sulfur atom (S) by a double bond. That is, an atom of the molecule is substituted with

[0243] As used herein, when an alkyl group or the like is positioned in the middle of a structural formula, the group is a radical. For example, an alkyl group is an alkyl radical and the like.

[0244] As used herein, the term "C 1-6 alkyl" means a straight or branched chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Preferably, C 1-4 alkyl. More preferably, C 1-3 alkyl. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof, and the like. The alkyl groups described herein can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described herein.

[0245] As used herein, the term "heteroalkyl" means an alkyl group in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom), wherein the definition of alkyl is as described above. The term "C 1-6 heteroalkyl" means a straight or branched chain heteroalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Preferably, C 1-4 heteroalkyl. More preferably, C 1-3 heteroalkyl. The heteroatom can be in the middle or at the end of the group. The heteroalkyl groups described herein can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described herein. Exemplary heteroalkyl groups can include alkoxy, alkylthio, and the like.

[0246] As used herein, the term "alkoxy" means a group having the structure -O-alkyl, wherein the definition of alkyl is as described above. The term "C 1-6 alkoxy" means an alkoxy group having 1 to 6 carbon atoms. Preferably, C 1-4 alkoxy. More preferably, C 1-3 alkoxy. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, n-pentoxy, and the like. The alkoxy groups described herein can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described herein.

[0247] As used herein, the term "alkylthio" means a group having the structure -S-alkyl, wherein the definition of alkyl is as described above. The term "C 1-6 alkylthio" means an alkylthio group having 1 to 6 carbon atoms. Preferably, C 1-4Alkylthio. More preferably C 1-3 Alkylthio. The alkylthio group can be substituted or unsubstituted, and when substituted, the substituent group(s) is preferably one or more of the substituent groups described herein.

[0248] As used herein, the term "alkenyl" refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position on the chain, the term "C 2-6 Alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. Preferably C 2-4 Alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. Preferably C

[0249] As used herein, the term "alkynyl" refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position on the chain, the term "C 2-6 Alkynyl refers to an alkynyl group having 2 to 6 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon triple bond. Preferably C 2-4 Alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. Preferably C

[0250] As used herein, the term "acyl" refers to an organic functional group (C=0) in which a carbon and an oxygen atom are connected by a double bond, the term "C 1-6 Acyi refers to an acyl group having 1 to 6 carbon atoms and at least one (C=0). Preferably C 1-3 Acyi. Specific examples include, but are not limited to, -(C=0)H, -(C=0)CH3, or -(C=0)CH2CH3, and the like. The acyl group can be substituted or unsubstituted, and when substituted, the substituent group(s) is preferably one or more of the substituent groups described herein.

[0251] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0252] As used herein, the term "halo" refers to fluoro, chloro, bromo, or iodo.

[0253] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5, etc.) hydrogen atoms have been replaced with a halogen atom, wherein alkyl is as described above. The term "haloC1-6 alkyl. More preferably, haloC 1-4 alkyl. More preferably, haloC 1-3 alkyl. Specific examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, 1,2-dichloroethyl, trichloroethyl, bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and the like. The haloalkyl group can be substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more of the substituent groups described herein.

[0254] As used herein, the term "haloalkoxy" means an alkoxy group in which one or more (e.g., 1, 2, 3, 4, or 5, etc.) hydrogen atoms are replaced by a halogen atom, wherein alkoxy is as defined above. The term "haloC 1-6 alkoxy. More preferably, haloC 1-4 alkoxy. More preferably, haloC 1-3 alkoxy. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, fluoromethoxy, fluoroethoxy, difluoromethoxy, difluoroethoxy, and the like. The haloalkoxy group can be substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more of the substituent groups described herein.

[0255] As used herein, the term "deuterated" means that one or more (e.g., 1, 2, 3, 4, or 5, etc.) hydrogen atoms in a group are replaced by deuterium atoms.

[0256] As used herein, the term "deuterated alkyl" means an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5, etc.) hydrogen atoms are replaced by deuterium atoms, wherein alkyl is as defined above. The term "deuterated C 1-6 alkyl. More preferably, deuterated C 1-4 alkyl. More preferably, deuterated C 1-3 alkyl. Specific examples include, but are not limited to, deuteromethyl, dideuteromethyl, trideuteromethyl, deuteromethyl, 1,2-dideuteromethyl, trideuteromethyl, and the like. The deuterated alkyl group can be substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more of the substituent groups described herein.

[0257] As used herein, the term "deuterated alkyl" means an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5, etc.) hydrogen atoms are replaced by deuterium atoms, wherein alkyl is as defined above. The term "deuterated C 1-6 alkoxy. More preferably, deuterated C 1-4 alkoxy. More preferably, deuterated C 1-3Alkoxy. Particular examples include, but are not limited to, trideuteromethoxy, trideuteromethoxy, monodeuteromethoxy, monodeuteromethoxy, dideuteromethoxy, dideuteromethoxy, and the like. The deuterated alkoxy group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described herein.

[0258] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon radical. The ring carbon atoms of the cycloalkyl group can optionally be substituted with one or more (e.g., 1, 2, 3, 4, 5, etc.) oxo groups to form a cyclic ketone structure. The term "3 to 20 membered cycloalkyl" or "C 3-20 Cycloalkyl refers to a cycloalkyl group having 3 to 20 ring carbon atoms. Monocyclic cycloalkyl, spiro cycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups can be included. Preferred are C 3-12 Cycloalkyl (e.g., C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, C 3-8 Monocyclic cycloalkyl, etc.), C 5-20 Spirocycloalkyl, C 5-20 Fused cycloalkyl, C 5-20 Bridged cycloalkyl, etc.

[0259] As used herein, the term "C 3-6 Cycloalkyl refers to a cycloalkyl group having 3 to 6 ring carbon atoms. It can be monocyclic (particular examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); it can also be bicyclic (particular examples include, but are not limited to, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, etc.).

[0260] As used herein, the term "cycloalkyl-substituted alkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5, etc.) hydrogen atoms have been replaced by a cycloalkyl group, wherein alkyl and cycloalkyl are as defined above. The term "C 3-6 Cycloalkyl-substituted C 1-6 Alkyl refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by a C 3-6 Cycloalkyl group. Where the C 3-6 Cycloalkyl is a monocyclic or bridged cycloalkyl group having 3 to 6 carbon atoms. The alkyl group can be straight-chained or branched, preferably C 1-4 Alkyl, more preferably C 1-3 Alkyl. Particular examples include, but are not limited to, cyclopropyl-substituted methyl, cyclobutyl-substituted methyl, etc. The "C 3-6 Cycloalkyl-substituted C 1-6 Alkyl" can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described herein.

[0261] As used herein, the term "bridged ring structure" refers to a structure formed by the connection of two or more rings through the sharing of two or more non-adjacent atoms. Included, but not limited to, are "bridged cycloalkyl" and "bridged heterocyclyl", among others.

[0262] As used herein, the term "C 3-8 "3 to 8 membered monocyclic cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group having from 3 to 8 ring carbon atoms. Preferred are C 3-6 "3 to 6 membered monocyclic cycloalkyl" or C 4-6 "4 to 6 membered monocyclic cycloalkyl". More preferred are C3, C4, C5, or C6monocyclic cycloalkyl groups. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0263] As used herein, the term "spirocycloalkyl" and "spirocycloalkyl ring" refers to a saturated or partially unsaturated polycyclic cyclic hydrocarbon group formed by the sharing of one carbon atom (termed a spiro atom) between two or more monocyclic rings. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups can be designated as mono-, bi-, and polyspirocycloalkyl groups. The term "5 to 20 membered spirocycloalkyl" or "C 5-20 "5 to 20 membered spirocycloalkyl" refers to a spirocycloalkyl group having from 5 to 20 ring carbon atoms. Preferred are 6 to 14 membered (i.e., C 6- 14 "6 to 14 membered spirocycloalkyl". More preferred are 6 to 14 membered monosprirocycloalkyl groups. More preferred are 7 to 11 membered (i.e., C 7-11 "7 to 11 membered spirocycloalkyl". More preferred are 7 to 11 membered monosprirocycloalkyl groups. More preferred are 7 membered, 8 membered, 9 membered, 10 membered, or 11 membered monosprirocycloalkyl groups. Specific examples of spirocycloalkyl groups include, but are not limited to: These spirocycloalkyl groups can be attached to the remainder of the molecule through any one of the ring atoms.

[0264] As used herein, the term "fused ring cycloalkyl" and "fused ring cycloalkyl ring" refers to a saturated or partially unsaturated polycyclic cyclic hydrocarbon group formed by the sharing of an adjacent pair of carbon atoms between two or more monocyclic rings. Depending on the number of rings formed, fused ring cycloalkyl groups can be designated as bi-, tri-, tetra-, or polycyclic. The term "5 to 20 membered fused ring cycloalkyl" or "C 5-20 "5 to 20 membered fused ring cycloalkyl" refers to a fused ring cycloalkyl group having from 5 to 20 ring carbon atoms. Preferred are 6 to 14 membered (i.e., C 6-14 "6 to 14 membered fused ring cycloalkyl". More preferred are 6 to 14 membered bicycloalkyl groups. More preferred are 7 to 10 membered (i.e., C 7-10 "7 to 10 membered fused ring cycloalkyl". More preferred are 7 to 10 membered bicycloalkyl groups. More preferred are 8 membered, 9 membered, or 10 membered bicycloalkyl groups. Specific examples of fused ring cycloalkyl groups include, but are not limited to: These fused ring cycloalkyl groups can be attached to the remainder of the molecule through any one of the ring atoms.

[0265] As used herein, the terms "bridged cycloalkyl" and "bridged cycloalkyl ring" mean a saturated or partially unsaturated polycyclic cyclic hydrocarbon group formed between two or more monocyclic rings by the sharing of two non-adjacent carbon atoms. Depending on the number of rings formed, the bridged cycloalkyl group can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group. The terms "5- to 20-membered bridged cycloalkyl" and "C 5-20 "bridged cycloalkyl" mean a bridged cycloalkyl group having 5 to 20 ring carbon atoms. Preferably, the bridged cycloalkyl group is a 6- to 14-membered (i.e., C 6-14 )bridged cycloalkyl group. More preferably, the bridged cycloalkyl group is a 7- to 10-membered (i.e., C 7-10 )bridged cycloalkyl group. Specific examples of bridged cycloalkyl groups include, but are not limited to: These bridged cycloalkyl groups can be attached to the remainder of the molecule through any one of the ring atoms.

[0266] Each of the above-mentioned cycloalkyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described herein.

[0267] As used herein, the terms "heterocyclyl" and "heterocyclyl ring" are used interchangeably to mean a saturated or partially unsaturated monocyclic or polycyclic ringed cyclic hydrocarbon group in which one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur, but excluding ring moieties of -0-0-, -0-S-, or -S-S-, with the remaining ring atoms being carbon. When a ring atom is a nitrogen atom, it can be substituted or unsubstituted (i.e., N or NR, R being hydrogen or other substituents as defined herein) and / or the nitrogen atom can form a quaternary ammonium salt. When a heteroatom is a sulfur atom, the sulfur atom can be optionally oxidized (e.g., S(=0) m , m' is an integer of 0 to 2). When a heteroatom is a phosphorus atom, the phosphorus atom can be optionally oxidized (e.g., P(=0) m ", m" is an integer of 0, 1 or 2). For example, monocyclic heterocyclyl, spiroheterocyclyl, fused heterocyclyl and bridged heterocyclyl groups are included. The ring carbon atoms of the heterocyclyl group can be optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5, etc.) oxo groups to form cyclic ketone, cyclic lactone or cyclic lactam structures. The term "3- to 20-membered heterocyclyl" means a heterocyclyl group having 3 to 20 ring atoms in which one or more (e.g., 1, 2, 3, 4, 5, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferably, the 3- to 20-membered heterocyclyl group is a 3- to 10-membered heterocyclyl group, a 3- to 12-membered monocyclic heterocyclyl group (e.g., 3- to 8-membered monocyclic heterocyclyl group), a 5- to 20-membered spiroheterocyclyl group, a 5- to 20-membered fused heterocyclyl group, a 5- to 20-membered bridged heterocyclyl group, etc.

[0268] The term "3 to 8 membered heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical having 3 to 8 ring atoms, one or more (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. The heterocyclyl group can be monocyclic (as in the specific examples described in the definition of 3 to 8 membered monocyclic heterocyclyl) or bicyclic (as in the specific examples including, but not limited to, cyclopropylcyclo-tetrahydro-pyrrolyl ring, cyclopropylcyclo-tetrahydro-furanyl ring, etc.).

[0269] As used herein, the terms "3 to 8 membered monocyclic heterocyclyl," "3 to 8 membered monocyclic heterocyclyl," and "3 to 8 membered monocyclic heterocyclyl ring" refer to a saturated or partially unsaturated monocyclic ring hydrocarbon radical having 3 to 8 ring atoms, one or more (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferred is 3 to 6 membered monocyclic heterocyclyl having 3 to 6 ring atoms, one or more (e.g., 1 or 2, etc.) of which are heteroatoms. More preferred is 4 to 6 membered monocyclic heterocyclyl having 4 to 6 ring atoms, one or more (e.g., 1 or 2, etc.) of which are heteroatoms. More preferred is 5 or 6 membered monocyclic heterocyclyl having 5 or 6 ring atoms, one or more (e.g., 1 or 2, etc.) of which are heteroatoms.Specific examples of monocyclic heterocyclyl groups include, but are not limited to, aziridine, oxirane, azetidine, azetidin-2-one, oxetane, oxetan-2-one, oxazolidine, pyrrolidine-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidin-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholine-3-one, morpholine-2-one, thiomorpholine-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydrooxetane, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxan-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydropyridin-2(1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrol-2-one, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, and the like.

[0270] As used herein, the term "nitrogen-containing 3- to 8-membered heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical having 3 to 8 ring atoms, one of which is a nitrogen atom, and the others (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. The term "nitrogen-containing 4- to 8-membered heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical having 4 to 8 ring atoms, one of which is a nitrogen atom, and the others (e.g., 1, 2, 3, 4, or 5) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. The heterocyclyl radical can be monocyclic or bicyclic. Specific examples include, but are not limited to, aziridinyl, azetidinyl, azapentadinyl (i.e., tetrahydropyrrole), azahexalinyl (i.e., hexahydropyridine), morpholinyl, piperazinyl, oxazolidinyl.

[0271] As used herein, the terms "spiroheterocyclyl" and "spiroheterocyclyl ring" refer to a polycyclic heterocyclyl radical formed by sharing one carbon atom (referred to as a spiro atom) between two or more saturated or partially unsaturated monocyclic rings, one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur, and the remainder of which are carbon. Each monocyclic ring can contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Depending on the number of spiro atoms shared between the rings, the spiroheterocyclyl radical can be a monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl. The term "5- to 20-membered spiroheterocyclyl" refers to a spiroheterocyclyl radical having 5 to 20 ring atoms, one or more (e.g., 1, 2, 3, 4, 5, etc.) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferably, the 6- to 14-membered spiroheterocyclyl radical has 6 to 14 ring atoms, one or more (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms. More preferably, the 7- to 11-membered spiroheterocyclyl radical has 7 to 11 ring atoms, one or more (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms. Most preferably, the 7-membered, 8-membered, or 10-membered monospiroheterocyclyl radical. Specific examples of spiroheterocyclyl radicals include, but are not limited to:

[0272] The spiroheterocyclyl radical can be attached to the remainder of the molecule through any one of the appropriate ring atoms.

[0273] As used herein, the terms "fused heterocyclyl" and "fused heterocyclyl ring" refer to a polycyclic heterocyclyl group formed from two or more saturated or partially unsaturated monocyclic rings through the sharing of adjacent pairs of ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur, and the remainder of the ring atoms are carbon. Each monocyclic ring can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The shared adjacent pairs of ring atoms can be C-C or N-C. Depending on the number of rings comprising the ring system, the fused heterocyclyl group can be bicyclic, tricyclic, tetracyclic, or polycyclic. The term "5- to 20-membered fused heterocyclyl" refers to a fused heterocyclyl group having 5 to 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferred are 6- to 14-membered fused heterocyclyl groups having 6 to 14 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5, etc.) ring atoms are heteroatoms. More preferred are 6- to 10-membered fused heterocyclyl groups having 6 to 10 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5, etc.) ring atoms are heteroatoms. More preferred are 8- to 10-membered fused heterocyclyl groups having 8 to 10 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5, etc.) ring atoms are heteroatoms. Most preferred are 8-membered, 9-membered, or 10-membered bicyclic fused heterocyclyl groups. Specific examples of fused heterocyclyl groups include, but are not limited to:

[0274] The fused heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.

[0275] As used herein, the terms "bridged heterocyclyl" and "bridged heterocyclyl ring" refer to a polycyclic heterocyclyl group formed from two or more saturated or partially unsaturated monocyclic rings through the sharing of two non-adjacent ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur, and the remainder of the ring atoms are carbon. Depending on the number of rings comprising the ring system, the bridged heterocyclyl group can be bicyclic, tricyclic, tetracyclic, or polycyclic. The term "5- to 20-membered bridged heterocyclyl" refers to a bridged heterocyclyl group having 5 to 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Each monocyclic ring can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferred are 6- to 14-membered bridged heterocyclyl groups. More preferred are 7- to 10-membered bridged heterocyclyl groups. Specific examples of bridged heterocyclyl groups include, but are not limited to:

[0276] The bridged heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.

[0277] The various heterocyclyl groups in the present application can be optionally substituted, and when substituted, the substituents are preferably one or more of the substituent groups recited herein.

[0278] The term "5- to 15-membered tricyclic heterocyclyl" refers to a tricyclic heterocyclyl group having 5 to 15 ring atoms, wherein the three rings can be connected by one or more means selected from spiro-attachment, fused attachment, and bridging. Particular examples can include, but are not limited to, a first monocyclic ring being a 6-membered monocyclic heterocyclyl, a second monocyclic ring being a 6-membered monocyclic heterocyclyl, and a third monocyclic ring being a 3- to 6-membered monocyclic heterocyclyl; and the first monocyclic ring and the second monocyclic ring are fused, and the third monocyclic ring is spiro-attached to the second monocyclic ring.

[0279] The term "6- to 12-membered bicyclic heterocyclyl" refers to a bicyclic heterocyclyl group having 6 to 12 ring atoms, wherein the two rings can be connected by one means selected from spiro-attachment, fused attachment, and bridging. The term "7- to 12-membered bicyclic heterocyclyl" refers to a bicyclic heterocyclyl group having 7 to 12 ring atoms, wherein the two rings can be connected by one means selected from spiro-attachment, fused attachment, and bridging. Particular examples can be selected from the particular examples of spiro-heterocyclyl groups, the particular examples of fused heterocyclyl groups, the particular examples of bridged heterocyclyl groups.

[0280] As used herein, the terms "aryl," "aryl ring," and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic, all-carbon polycyclic (rings connected by covalent bonds, non-fused), or all-carbon fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups, at least one ring of which is aromatic (i.e., having a planar ring of delocalized 6-10 The term "aryl" refers to an aromatic group having 6 to 10 ring atoms. Preferred are phenyl, naphthyl, and the like. The various aryl groups in the present application can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups recited herein.

[0281] As used herein, the terms "heteroaryl," "heteroaryl ring," and "heteroaromatic ring" are used interchangeably and refer to a monocyclic or fused polycyclic (i.e., sharing adjacent pairs of ring atoms, which can be C-C or N-C) group in which ring atoms are replaced, in whole or in part, by at least one heteroatom, independently selected from phosphorus, nitrogen, oxygen, or sulfur. The heteroaryl group has 6, 10, or 14 π electrons shared in common, and at least one ring is aromatic. When a ring atom is a nitrogen atom, it can be substituted or unsubstituted (i.e., N or NR, R being hydrogen or another substituent as defined herein) and / or the nitrogen atom can form a quaternary ammonium salt. When a heteroatom is a sulfur atom, the sulfur atom can be optionally oxidized (e.g., S(=O) m , m' is an integer from 0 to 2). When a heteroatom is a phosphorus atom, the phosphorus atom can be optionally oxidized (e.g., P(=O) mThe term "5- to 14-membered heteroaryl" refers to a heteroaryl group having 5 to 14 ring atoms, one or more (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferably, it is a 5- to 10-membered heteroaryl group having 5 to 10 ring atoms, one or more (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms. The 5- to 14-membered heteroaryl group can be a monocyclic heteroaryl group, a fused bicyclic heteroaryl group, a fused tricyclic heteroaryl group, etc. Specific examples of the 5- to 14-membered heteroaryl group can include, but are not limited to, a benzene ring-fused 5- or 6-membered monocyclic heteroaryl group, a benzene ring-fused 5- or 6-membered heterocycloalkyl group, a 5- or 6-membered monocyclic heteroaryl group-fused 5- or 6-membered heterocycloalkyl group, a 5- or 6-membered monocyclic heteroaryl group-fused 5- or 6-membered monocyclic heteroaryl group, etc.

[0282] The term "5- or 6-membered monocyclic heteroaryl" as used herein refers to a monocyclic heteroaryl group having 5 or 6 ring atoms, one or more (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Specific examples of the monocyclic heteroaryl group include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0283] The term "8- to 10-membered bicyclic heteroaryl" as used herein refers to a fused bicyclic heteroaryl group having 8 to 10 ring atoms, one or more (e.g., 1, 2, 3, 4, or 5, etc.) of which are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. The fused bicyclic heteroaryl group can be a monocyclic aryl ring (e.g., phenyl) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) fused to form a bicyclic group (preferably a 9- or 10-membered bicyclic heteroaryl ring), or a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) fused to form a bicyclic group.

[0284] Any two ring atoms of the above monocyclic heteroaryl ring that are connected can be fused to form a fused polycyclic ring with the monocyclic cycloalkyl ring, the monocyclic heterocyclyl ring, the monocyclic aryl ring, the 5- or 6-membered monocyclic heteroaryl ring, etc. defined herein. Preferably, the two ring atoms of the monocyclic heteroaryl ring that are connected to form a fused polycyclic ring are C-C, non-limitingly including the following forms:

[0285] The ring atom marked with is connected to the rest of the molecule.

[0286] Non-limiting examples of 8- to 10-membered bicyclic heteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H- benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazol, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2- d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8- naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, and the like.

[0287] Particular examples of bicyclic heteroaryl groups include, but are not limited to: These groups can be attached to the remainder of the molecule through any one of the appropriate ring atoms. The ring that is attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.

[0288] In some embodiments of the application, the fused bicyclic heteroaryl or fused tricyclic heteroaryl can be a polycyclic group formed by the fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) with one or more non-aromatic rings, wherein the ring that is attached to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. The non-aromatic rings include, but are not limited to, 3- to 6-membered monocyclic heterocyclyl rings (preferably 5- or 6-membered monocyclic heterocyclyl rings, which can be substituted with 1 to 2 oxo groups to form a cyclic amide or cyclic ester structure), 3- to 6-membered monocyclic cycloalkyl rings (preferably 5- or 6-membered monocyclic cycloalkyl rings, which can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure), and the like. The polycyclic group formed by the fusion of a monocyclic heteroaryl ring with one or more non-aromatic rings can be attached to other groups or the parent structure through a nitrogen atom or a carbon atom, and the ring that is attached to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.

[0289] The various heteroaryl groups of the application can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described herein.

[0290] As used herein, the term "hydroxy" means -OH.

[0291] As used herein, the term "cyano" means -CN.

[0292] As used herein, the term "nitro" means -NO2.

[0293] As used herein, the term "benzyl" means -CH2-phenyl.

[0294] As used herein, the term "oxo" refers to =0.

[0295] As used herein, the term "carboxyl" refers to -C(=0)OH.

[0296] As used herein, the term "acetyl" refers to -COCH3.

[0297] The above alkyl, heteroalkyl, alkoxy, alkynyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups recited in this application.

[0298] As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom is / are replaced with a substituent group, which can include heavy isotopes and variations of hydrogen, as long as the valency of the particular atom is not changed and the resulting compound is stable. When the substituent group is oxo (i.e., =0), it means that two hydrogen atoms are replaced. The term "optionally substituted" or "optionally substituted with" means that the group can or can not be substituted and that the nature and number of substituents, if present, are optional on a chemical basis.

[0299] or "*" indicates the position of the bond to the chemical group.

[0300] In the present disclosure, the following notations are used to indicate the absolute configuration of a stereogenic center. Unless otherwise indicated, the compounds are racemic mixtures or single enantiomers derived therefrom. including the possibility of being present as both, as structurally allowed.

[0301] When any variable (e.g., R) occurs more than one time in a compound or stereoisomer, its definition in each instance is independent of the definition of the other. Thus, for example, if a group is substituted with 0-2 R groups, then the group is optionally substituted with up to two R groups, and the R groups are selected independently of one another. In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0302] In any embodiment, any or all hydrogens present in a compound, or in a particular group or moiety within a compound, can be replaced by deuterium or tritium. One to the maximum number of hydrogens present in a compound can be replaced by deuterium. One to the maximum number of hydrogens present in any group in a general or specific compound can be replaced by deuterium. For example, where a group is described as ethyl, the ethyl group can be C2H5or C2H5in which x (1 to 5) hydrogens are replaced by deuterium, e.g., C2D5. x H 5-xWhen a group is described as being deuterated ethyl, the deuterated ethyl can be C2H5in which x (1 to 5) hydrogens are replaced by deuterium, e.g., C2D5 x H 5-x The stable deuterated derivatives of the present application are preferably stable deuterated isotopic derivatives of any of the formulae in which any hydrogen atom that can be deuterated is replaced by one to the maximum number of deuterium atoms (e.g., 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, etc.).

[0303] Unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, examples of isotopes that can be enriched in a compound of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 32 P、 33 P、 35 S、 18 F、 36 Cl、 123 I and 125 I. Isotopically labeled compounds (e.g., compounds labeled with 3 H and 14 C) can be used in compound or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C or 14 C-enriched carbon. Positron emitting isotopes such as 15 O、 13 N、 11 C and 18F can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically-labeled compounds is known to those of skill in the art. For example, an isotopically-labeled compound can generally be prepared by substituting an isotopically-labeled reagent for a non-isotopically labeled reagent in a procedure similar to those disclosed for the compounds of the application described herein. BRIEF DESCRIPTION OF DRAWINGS

[0304] FIG. 1 is an X-ray single crystal diffraction molecular stereoview of intermediate 51-7A.

[0305] FIG. 2 is an X-ray single crystal diffraction molecular stereoview of intermediate 118-12. DETAILED DESCRIPTION

[0306] The compounds of the present application can be prepared by a variety of synthetic processes known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments with other chemical synthetic processes known to those skilled in the art, and equivalents thereof known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0307] The present application is described in detail below by way of Examples, but not meant to be limited in any way by the Examples. The present application has been described in detail by specifically exemplifying the embodiments thereof, and it is apparent that those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present application. The specific conditions not mentioned in the Examples were carried out according to the conventional conditions or the conditions recommended by the manufacturers. The reagents or instruments not mentioned by the manufacturers were all conventional products available on the market.

[0308] The structure of the compounds was determined by nuclear magnetic resonance (NMR), mass spectrometry (MS), and the like.

[0309] NMR was measured using a Bruker Avance NEO 400 or a Bruker Avance NEO 500 nuclear magnetic resonance instrument, the chemical shift (δ) was measured in parts per million (ppm), the solvent was as indicated in each example, and tetramethylsilane (TMS) was used as an internal standard.

[0310] MS was measured using an Agilent 1100 liquid chromatograph.

[0311] High performance liquid chromatography (HPLC) analysis was performed using a Waters 2695 high performance liquid chromatograph.

[0312] High performance liquid preparation was performed using a Waters 2767 high performance liquid chromatograph.

[0313] Chiral HPLC analysis was performed on a Waters 2695 HPLC or a Waters Investigator SFC system.

[0314] Chiral prep was performed on a gilson gx-281 HPLC or a waters SFC-80 HPLC.

[0315] Thin layer chromatography silica gel plates were purchased from Qingdao GF254 or Yantai Huanghai HSGF254. The silica gel plates used in thin layer chromatography (TLC) were 0.15mm-0.2mm. The silica gel plates used in thin layer chromatography separation and purification of products were 0.4mm-0.5mm.

[0316] Column chromatography was generally performed on an ISCO CombiFlash NextGen 300 column chromatography system using Agela Flash Column Silica-Cs series silica gel columns.

[0317] Preparative HPLC used in the following examples, unless otherwise specified, can be used under the following conditions:

[0318] Preparative HPLC (ammonium bicarbonate method): Column: Welch Xtimate C18, 21.2*150mm, 5μm; mobile phase A: 5mmol / L ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 15mL / min; gradient: B% = 20%-100%; column temperature: room temperature.

[0319] Preparative HPLC (formic acid method 1): Column type: Waters XBridge C18, 19*250mm, 5μm; mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: analytical grade acetonitrile; flow rate: 15mL / min; gradient: B% = 20%-100%; column temperature: room temperature.

[0320] Preparative HPLC (trifluoroacetic acid method): Column: Welch Xtimate C18, 21.2*150mm, 5μm; mobile phase A: 0.1% trifluoroacetic acid-water; mobile phase B: acetonitrile; flow rate: 15mL / min; gradient: B% = 20%-100%; column temperature: room temperature.

[0321] Preparative HPLC (formic acid method 2): Column: Welch Xtimate C18, 21.2*150mm, 5μm; mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: acetonitrile; flow rate: 15mL / min; gradient: B% = 30%-70%; time: 25min; column temperature: room temperature.

[0322] The following retention time test method was used in the examples below, unless otherwise specified: Column: SunFire C18, 4.6*50mm, 3.5μιηL; Mobile phase A: water (0.05% trifluoroacetic acid); Mobile phase B: acetonitrile (0.05% trifluoroacetic acid); Gradient: 0-3 min, B% = 5%-95%; Flow rate: 1.7 mL / min; Column temperature: 40 °C.

[0323] Preparation Example 1 : Synthesis of intermediate 5-4

[0324] Step one: 3-bromo-l-Hpyrazole-4-carboxylic acid ethyl ester (5.0 g, 22.83 mmol) was dissolved in acetonitrile (50 mL), potassium carbonate (9.46 g, 68.48 mmol) and iodoethane (7.12 g, 45.65 mmol) were added at room temperature, the reaction was stirred at 85 °C for 18 hours. The reaction was concentrated, ethyl acetate (100 mL) was added, washed with water (25 mL), saturated brine (25 mL) successively, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-30%) to give compound 5-1 (1.6 g, yield 28.4%) as a colorless liquid. 1 H NMR (400 MHz, CDC13) δ 7.85 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H). ES-API: [M+H] + = 247.1, 249.1.

[0325] Step two: Compound 5-1 (1.35 g, 5.46 mmol) was dissolved in tetrahydrofuran (25 mL), 1.0 M diisobutylaluminum hydride (DIBAL H) in n-hexane (13.66 mL, 13.66 mmol) was added dropwise at 0 °C, the reaction was stirred at room temperature for 5 hours. The reaction was quenched with saturated potassium sodium tartrate solution (30 mL), stirred at room temperature for 1 hour, extracted with ethyl acetate (60 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-30%) to give compound 5-2 (1.0 g, yield 89.3%) as a white solid. ES-API: [M+H] + = 205.1, 207.1. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 4.92 (t, J = 5.4 Hz, 1H), 4.26 (d, J = 5.4 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).

[0326] Step three: Compound 5-2 (200 mg, 0.97 mmol) and triphenylphosphine (384 mg, 1.46 mmol) were dissolved in dichloromethane (5 mL), a solution of carbon tetrabromide (582 mg, 1.76 mmol) in dichloromethane (1 mL) was added at 0 °C, the reaction was stirred at room temperature for 18 hours. The reaction was concentrated, the crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-10%) to give compound 5-3 (175 mg, yield 67.0%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 4.38 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0327] Step four: Methyl isobutyrate (457 mg, 4.48 mmol) was dissolved in tetrahydrofuran (15 mL), 2.0 M diisopropylamino lithium in tetrahydrofuran / n-hexane (2.24 mL, 4.48 mmol) was added dropwise at -70 °C, the reaction was stirred at -70 °C for 1 hour. A solution of compound 5-3 (800 mg, 2.99 mmol) in tetrahydrofuran (8 mL) was added dropwise, the reaction was stirred at -70 °C for 1 hour, then slowly raised to room temperature and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (60 mL). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-20%) to give compound 5-4 (730 mg, yield 84.5%) as a light yellow liquid. 1 H NMR (400 MHz, CD3OD) 7.32 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.68 (s, 3H), 2.68 (s, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.18 (s, 6H). ES-API: [M+H] + = 289.1, 291.1.

[0328] Preparation example 2: synthesis of intermediate 51-12

[0329] Step one: Compound 5-4 (7500 mg, 25.936 mmol) was dissolved in toluene (90 mL), dioxane (30 mL) and water (30 mL). To the above solution was added (S)-2-(1-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10237.32 mg, 38.904 mmol), potassium phosphate (16515.72 mg, 77.809 mmol) and methanesulfonyloxy(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1888.86 mg, 2.594 mmol). After the addition was complete, the reaction was stirred at 110 °C in a microwave reactor for 5 hours. The reaction solution was added to water (100 mL) and extracted with water (100 mL*2). The separated organic phase was washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether: 0-60%) to obtain compound 51-1 (8700 mg, 25.185 mmol, 97.10% yield) as a light brown liquid. ES-API: [M+H] = 346.1. +

[0330] Step two: Compound 51-1 (9000 mg, 26.054 mmol) was dissolved in N,N-dimethylformamide, and N-bromosuccinimide (6955.95 mg, 39.081 mmol) was added to the above solution. After the addition was complete, the reaction was stirred at 80 °C for 1 hour. After the reaction was complete, water (300 mL) was added to the reaction solution and extracted with ethyl acetate (300 mL). The organic phase was separated and washed with saturated brine (400 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether: 0-40%) to obtain compound 51-2 (8200 mg, 19.233 mmol, 73.82% yield). ES-API: [M+H] = 424.1, 426.1. +

[0331] ​​Step three: Compound 51-2 (8000 mg, 18.853 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 °C. To the above solution was added diisobutylaluminum hydride (80 mL, 80.000 mmol, 1 M in n-hexane) slowly under nitrogen atmosphere. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for 1 hour. After the reaction was completed, the reaction was diluted with tetrahydrofuran (200 mL) and cooled to 0 °C. Water (3.2 mL), 15% aqueous sodium hydroxide (3.2 mL), and water (8 mL) were added slowly. The reaction was allowed to warm to room temperature and stirred for 15 minutes. Anhydrous sodium sulfate (50 g) was added and stirred for 15 minutes. The salt was removed by filtration. The filter cake was washed with ethyl acetate (1000 mL). The filtrate was concentrated to dryness to give a crude product. The crude product was purified by flash silica gel column (methanol / dichloromethane = 0-3%) to give compound 51-3 (5500 mg, 13.877 mmol, 73.61% yield) as a white solid. ES- API: [M+H] = 396.1, 398.1. + = 396.1, 398.1.

[0332] Step four: Compound 51-3 (5500 mg, 13.403 mmol), N,N-diisopropylethylamine (5370.52 mg, 41.632 mmol), and 4-dimethylaminopyridine (163.74 mg, 1.340 mmol) were dissolved in dichloromethane (100 mL). To the above solution was added acetic anhydride (1.955 mL, 20.816 mmol) slowly at 0 °C. After the addition was completed, the reaction was stirred at 0 °C for half an hour. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (100 mL*2). The organic phase was separated and washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-60%) to give compound 51-4 (5200 mg, 11.495 mmol, 85.76% yield) as a light yellow solid. ES-API: [M+H] + = 396.1, 398.1.

[0333] Step five: Compound 51-4 (4200 mg, 9.581 mmol), bis(pinacolato)diboron (4136.08 mg, 16.288 mmol), (1,5-cyclooctadiene)iridium(I) dimer (321.78 mg, 0.479 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (257.15 mg, 0.958 mmol) were dissolved in cyclohexane (100 mL). The reaction was stirred at 80 °C under nitrogen atmosphere for 17 hours. The reaction was concentrated to give compound 51-5 (4620 mg, crude) as a black oily liquid. ES-API: [M+H]+ = 482.1, 484.1.

[0334] Step six: Compound 51-5 (4620 mg, crude) was dissolved in acetonitrile (100 mL), 30% hydrogen peroxide (3.257 mL, 28.738 mmol) was added under ice bath, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with saturated sodium sulfite (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL) and dried to obtain the crude product. The crude product was purified by flash silica gel column chromatography (tetrahydrofuran / petroleum ether: 0-50%) to obtain compound 51-6 (3800 mg, 8.363 mmol, 87.29% yield of two steps), yellow oily liquid. ES-API: [M+H] + = 454.1, 456.1.

[0335] Step seven: Compound 51-6 (3500 mg, 7.703 mmol) was dissolved in methanol (10 mL), tetrahydrofuran (10 mL) and water (10 mL). Lithium hydroxide (1292.87 mg, 30.812 mmol) was added to the above solution. After the addition was completed, the reaction was stirred at room temperature for 17 hours. After the reaction was completed, the reaction liquid was acidified to weakly acidic (pH = about 6) with dilute hydrochloric acid (1M). The obtained solution was extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (100 mL) and dried to obtain the crude product. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-100%) to obtain two isomer compounds. The structure of one of the isomer compounds is (R a )-5-(3-bromo-1-ethyl-4-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-5-yl)-6-((S)-1-methoxyethyl)pyridin-3-ol (51-7A, 1800 mg, 4.365 mmol, yield 56.67%) (ethyl acetate, R f = 0.5), light yellow solid. ES-API: [M+H] + = 412.1, 414.1. 1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 2.8 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 4.13 - 4.06 (m, 1H), 3.98 - 3.83 (m, 2H), 3.19 (d, J = 10.8 Hz, 1H), 3.11 (d, J = 10.8 Hz, 1H), 3.06 (s, 3H), 2.43 (d, J = 14.4 Hz, 1H), 2.17 (d, J = 14.4 Hz, 1H), 1.49 (d, J = 6.4 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 0.78 (s, 3H), 0.65 (s, 3H). Another isomeric compound structure is (S a )-5-(3-bromo-1-ethyl-4-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-5-yl)-6-((S)-1- methoxyethyl)pyridin-3-ol (51-7B, 1000 mg, 2.425 mmol, yield 31.48%) (ethyl acetate, R f = 0.3), light yellow solid. ES-API: [M+H] + = 412.1, 414.1. 1 H NMR (400 MHz, MeOD) δ 8.30 (d, J = 2.8 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 4.10 - 4.03 (m, 1H), 3.94 - 3.84 (m, 1H), 3.82 - 3.73 (m, 1H), 3.27 (s, 3H), 3.21 (d, J = 10.8 Hz, 1H), 3.11 (d, J = 10.8 Hz, 1H), 2.46 (d, J = 14.4 Hz, 1H), 2.32 (d, J = 14.4 Hz, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H), 0.83 (s, 3H), 0.67 (s, 3H).

[0336] Step 8: Compound 51-7A (1800 mg, 4.365 mmol) was dissolved in toluene (30 mL), dioxane (10 mL), and water (10 mL). Potassium phosphate (2316.52 mg, 10.914 mmol), 1,1′-bis(di-tert-butylphosphine)ferrocene dichloropalladium(II) (426.28 mg, 0.655 mmol), (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)vinyl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (3604.63 mg, 6.548 mmol) was purged with nitrogen three times, and the reaction was stirred at 80 °C for 3 hours. The reaction mixture was added to ethyl acetate (100 mL) and water (50 mL). After separation of the organic phase, the mixture was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (tetrahydrofuran / petroleum ether: 0-60%) to give compound 51-8 (2800 mg, 3.704 mmol, yield 84.85%) as a white solid. ES-API: [M+H] + =756.3.

[0337] Step Nine: Compound 51-8 (2800 mg, 3.704 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL). Lithium hydroxide monohydrate (248.67 mg, 5.926 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 18 hours. The reaction solution was adjusted to pH 6 with 1 M dilute hydrochloric acid and extracted with ethyl acetate (30 mL * 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 51-9 (2700 mg, crude product), a pale yellow solid. ES-API: [M + H] + =742.3.

[0338] Step 10: Compound 51-9 (2700 mg, crude) was dissolved in dichloromethane (100 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19534 mg, 101.90 mmol), 1-hydroxybenzotriazole (2459 mg, 18.20 mmol), and diisopropylethylamine (19 mL, 109 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. Dichloromethane (100 mL) was added to the reaction mixture, and the solution was washed with dilute hydrochloric acid (0.5 M, 20 mL x 2) and saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (methanol / dichloromethane: 0-5%) to give compound 51-10 (1000 mg, 1.381 mmol, two-step yield 37.3%), a white solid. ES-API: [M+H] += 724.3.

[0339] Step eleven: Compound 51-10 (700 mg, 0.967 mmol) was dissolved in dichloromethane (20 mL), to the above solution was added triethylamine (0.403 mL, 2.901 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (518.18 mg, 1.450 mmol). After the addition was complete, the reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated to give a crude product. The crude product was purified by flash silica gel column (methanol / dichloromethane: 0%-3%) to give compound 51-11 (800 mg, 0.935 mmol, 96.65% yield) as a white solid. ES-API: [M+H] + = 856.3.

[0340] Step twelve: Compound 51-11 (750 mg, 0.876 mmol) was dissolved in acetonitrile (15 mL). To the above solution was added 4-(prop-2-yn-1-yl)thiomorpholine 1,1-dioxide (455.36 mg, 2.629 mmol), dichlorobis(triphenylphosphine)palladium (123.00 mg, 0.175 mmol), cuprous iodide (66.75 mg, 0.350 mmol), N,N'-diisopropylethylamine (339.75 mg, 2.629 mmol) and lithium chloride (148.57 mg, 3.505 mmol) at room temperature. After the addition was complete, the reaction was stirred at 80 °C for 1 hour under argon atmosphere. After the reaction was complete, water (30 mL) was added to the reaction and extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated brine (30 mL*2) and dried to give a crude product. The crude product was purified by flash silica gel column (methanol / dichloromethane: 0%-3%) to give compound 51-12 (700 mg, 0.794 mmol, 90.69% yield) as a white solid. ES-API: [M+H] + = 879.3.

[0341] Single crystal cultivation of intermediate 51-7A

[0342] 5-(3-bromo-1-ethyl-4-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-5-yl)-6-((S)-1- methoxyethyl)pyridin-3-ol

[0343] X-ray single crystal diffraction test was performed by a Bruker D8 Venture instrument. The results are shown in Table 1 below and Figure 1. Figure 1 is an ellipsoidal diagram of the molecular stereostructure, which contains one molecule of crystalline water.

[0344] Structure analysis and refinement process:

[0345] After the reduction of the diffraction data by integration, the data was empirically corrected for absorption using the SADABS program; the single crystal structure was solved by direct methods using SHELXT 2014, and the structure was refined by least squares, the hydrogen atoms were refined by isotropic calculation, the hydrogen atoms on N were obtained by residual electron density, the hydrogen atoms on C-H were obtained by calculation and refined by riding model. The Flack constant is 0.069(16), and C14 in Figure 1 is in S configuration. The C4-C5 axis chirality is R a configuration.

[0346] Table 1

[0347] Preparation Example 3: Synthesis of intermediate 118-13

[0348] Step one: methyl isobutyrate (14.67 g, 143.66 mmol) was dissolved in tetrahydrofuran (150 mL), and 2.0 M diisopropylaminolithium tetrahydrofuran / n-hexane solution (71.83 mL, 143.66 mmol) was added dropwise at -70°C, and the reaction was stirred at -70°C for 1 hour. A tetrahydrofuran solution (15 mL) of methyl 4-formyl-1H-pyrrole-2-carboxylate (10 g, 65.30 mmol) was added dropwise, and the reaction was stirred at -70°C for 1 hour, and then slowly raised to 0°C for 2 hours. The reaction was quenched with saturated ammonium chloride solution (50 mL) and water (30 mL), and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to obtain compound 118-1 (16.0 g, yield 96.0%), yellow liquid. ES-API: [M-18+H] = 238.1. + = 238.1.

[0349] Step 2: Compound 118-1 (9 g, 35.26 mmol) was dissolved in dichloromethane (120 mL), and trifluoroacetic acid (13.50 mL, 176.28 mmol) was added at 0 °C, followed by slow dropwise addition of triethylsilane (33.70 mL, 211.54 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate solution (50 mL) was slowly added. Extraction was performed with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (ethyl acetate / petroleum ether: 0-20%) to give compound 118-2 (5.7 g, yield 67.6%), a yellow liquid. ES-API: [M+H] + =240.2.

[0350] Step 3: Compound 118-2 (2.9 g, 12.12 mmol) was dissolved in acetonitrile (60 mL), and N-iodosuccinimide (3.55 g, 15.76 mmol) was added at 0 °C. The reaction mixture was stirred overnight at 10 °C. Ethyl acetate (150 mL) was added to the reaction solution, followed by washing with saturated sodium bicarbonate solution (80 mL) and saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (ethyl acetate / petroleum ether: 0-15%) to give compound 118-3 (2.9 g, yield 65.5%), a white solid. ES-API: [M+H] + =366.0.

[0351] Step 4: Compound 118-3 (2.7 g, 7.39 mmol) and 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (2.92 g, 11.09 mmol) were dissolved in 1,4-dioxane (50 mL) and water (25 mL). Potassium carbonate (2.25 g, 16.27 mmol) and 1,1′-bis(diphenylphosphine)ferrocene palladium(II) dichloride (0.54 g, 0.739 mmol) were added. The mixture was purged with nitrogen for 30 seconds, and the reaction was carried out in a microwave reactor at 90 °C with stirring for 8 hours. Ethyl acetate (100 mL) was added to the reaction solution, followed by washing with water (30 mL * 2) and saturated brine (30 mL) successively. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to give compound 118-4 (2.7 g, 97.5% yield), a pale brown liquid. ES-API: [M+H] + =375.1.

[0352] Step 5: Compound 118-4 (2.7 g, 6.95 mmol) was dissolved in acetonitrile (40 mL), and N-bromosuccinimide (1.67 g, 9.37 mmol) was added at room temperature. The reaction mixture was stirred at 40 °C for 1 hour. The reaction solution was cooled to room temperature, and water (5 mL) and concentrated ammonia (1.5 mL) were added. The mixture was stirred for another 15 minutes. Ethyl acetate (100 mL) was added to the reaction solution, and the mixture was washed with saturated brine (50 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to give compound 118-5 (3.2 g, 97.9% yield), a yellow liquid. ES-API: [M+H] + =453.1,455.1. 1 H NMR (400MHz, CDCl3) δ10.60(s,1H),8.61(dd,J=4.8,1.6Hz,1H),7.77(dd,J=8.0,1.6Hz,1H),7.34(dd,J=8.0,4.8Hz,1H),4.54(q,J=6.4Hz, 1H),3.89(s,3H),3.42(s,3H),3.13(s,3H),3.05(d,J=14.4Hz,1H),2.96(d,J=14.4Hz,1H),1.54(d,J=6.5Hz,3H),1.02(s,3H),0.96(s,3H).

[0353] Step Six: Compound 118-5 (2.6 g, 5.74 mmol) was dissolved in anhydrous ethanol (50 mL) and water (25 mL). Lithium hydroxide monohydrate (1.93 g, 45.88 mmol) was added at room temperature, and the reaction was stirred at 100 °C for 64 hours. The reaction solution was cooled to room temperature, and the ethanol solvent was concentrated under reduced pressure. The pH of the reaction solution was adjusted to 5 with 1 M dilute hydrochloric acid. The precipitated solid was filtered and dried under reduced pressure. The organic phase was dried over anhydrous sodium sulfate to obtain a crude product, which was purified by rapid silica gel column chromatography (methanol / dichloromethane: 0-5%) to give compound 118-6 (1.3 g, yield 59.5%) as a white solid. ES-API: [M+H] + =381.0,383.1.

[0354] Step seven: Compound 118-6 (600 mg, 1.57 mmol) was dissolved in N,N- dimethylformamide (10 mL), potassium carbonate (283 mg, 2.05 mmol) was added at room temperature, methyl iodide (268 mg, 1.89 mmol) was added, the reaction was stirred at room temperature for 2 hours. The reaction solution was added into ethyl acetate (100 mL), washed with saturated brine (30 mL*3). The organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain compound 118-7 (622 mg, yield 100%) as a light yellow liquid. ES-API: [M+H] + = 395.0, 397.0.

[0355] Step eight: Compound 118-7 (622 mg, 1.57 mmol) was dissolved in N,N- dimethylformamide (8 mL), cesium carbonate (1.02 g, 3.15 mmol) was added at room temperature, iodoethane (491 mg, 3.15 mmol) was added, the reaction was stirred at 60 °C for 1 hour. The reaction solution was added into ethyl acetate (100 mL), washed with saturated brine (30 mL*3). The organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-30%) to obtain two isomer compounds. One of the compounds with retention time of 1.96 min was arbitrarily assigned as compound 118-8 (350 mg, yield 52.5%) as a colorless liquid. ES-API: [M+H] + = 423.1, 425.1. The other compound with retention time of 1.82 min was arbitrarily assigned as compound 118-8-a (240 mg, yield 36.0%) as a colorless liquid. ES-API: [M+H] + = 423.1, 425.1.

[0356] Step nine: Compound 118-8 (retention time of 1.96 min) (350 mg, 0.83 mmol) was dissolved in dichloromethane (15 mL), 1.0 M diisobutylaluminum hydride in n-hexane (2.07 mL, 2.07 mmol) was added dropwise at -70 °C, the reaction was stirred at -70 °C for 1 hour, then was raised to room temperature and stirred for 2 hours. The reaction solution was cooled to 0 °C, water (0.10 mL), 15% sodium hydroxide solution (0.10 mL) and water (0.25 mL) were added slowly dropwise in turn to quench the reaction, stirred at room temperature for 15 minutes, dried with anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain compound 118-9 (326 mg, yield 99.7%) as a light yellow viscous liquid. ES-API: [M+H] + = 395.1, 397.1.

[0357] Step Ten: Compound 118-9 (326 mg, 0.83 mmol), diisopropylethylamine (320 mg, 2.47 mmol), and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were dissolved in dichloromethane (8 mL), acetic anhydride (168 mg, 1.65 mmol) was added at 0 °C, the reaction was stirred at 0 °C for 30 min. The reaction was concentrated, the crude was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-20%) to give compound 118-10 (320 mg, 88.7% yield) as a yellowish viscous liquid. ES-API: [M+H] = 437.1, 439.1. +

[0358] Step Eleven: Compound 118-10 (320 mg, 0.73 mmol), bis(pinacolato)diboron (334 mg, 1.32 mmol), (1,5-cyclooctadiene)iridium(I) dimer (59 mg, 0.088 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (39 mg, 0.146 mmol) were dissolved in cyclohexane (20 mL). The reaction was stirred at 85 °C under nitrogen atmosphere for 18 h. The reaction was concentrated to give compound 118-11 (352 mg, crude). ES-API: [M+H] = 481.1, 483.1. +

[0359] Step Twelve: Compound 118-11 (352 mg, crude) was dissolved in acetonitrile (6 mL), 30% hydrogen peroxide (248 mg, 2.19 mmol) was added under ice bath, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with saturated sodium sulfite (4 mL), extracted with ethyl acetate (25 mL*2), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. The crude was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-40%) to give compound 118-12 (200 mg, 60.3% yield over two steps) as a yellow liquid. ES-API: [M+H] = 453.1, 455.0. + 1 ​​​H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.13 (s, 1H), 7.00 (d, J = 2.8 Hz, 1H), 4.03 (dd, J = 12.2, 6.0 Hz, 1H), 3.62-3.55 (m, 3H), 3.43 (d, J = 10.8 Hz, 1H), 2.86 (s, 3H), 2.31 (d, J = 14.4 Hz, 1H), 2.11 (d, J = 14.4 Hz, 1H), 1.82 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H), 0.71 (s, 3H), 0.62 (s, 3H).

[0360] Step thirteen: Compound 118-12 (170 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL), diisopropylethylamine (145 mg, 1.13 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (201 mg, 0.56 mmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and the crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-20%) to give compound 118-13 (165 mg, yield 75.2%) as a colorless liquid. ES-API: [M+H] + = 585.0, 587.0.

[0361] Single crystal culture of intermediate 118-12

[0362] Acetic acid-3-(4-bromo-1-ethyl-(R a )-2-(5-hydroxy-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-pyrrol-3-yl)-2,2-dimethylpropyl ester

[0363] 5 mg of intermediate 118-12 was dissolved in 1 mL of methanol solution, slowly evaporated at room temperature for 24 h to get columnar crystals. X-ray single crystal diffraction test was performed by Bruker D8 Venture instrument. The results are shown in Table 2 and Figure 2 below. Figure 2 is the ellipsoidal diagram of the molecular stereostructure.

[0364] Structure analysis and refinement process:

[0365] The diffraction data was integrated and reduced by SAINT program, and then the data was empirically corrected by SADABS program. The single crystal structure was solved by direct method using SHELXT 2014, and the structure was refined by least square method. The hydrogen atoms were obtained by isotropic calculation in the refinement process. The hydrogen atoms on N were obtained by residual electron density, and the hydrogen atoms on C-H were obtained by calculation and refined by riding model. The Flack constant was 0.032 (19), and C8 in Figure 2 was S configuration. The C5-C9 axis chirality was R a configuration.

[0366] Crystal data:

[0367] Table 2

[0368] Preparation Example 4: synthesis of intermediate 49-6

[0369] Step one: compound 118-13 (180 mg, 0.307 mmol) was dissolved in acetonitrile (8 mL). To the above solution was added 1-(prop-2-yn-1-yl)piperidine-4-carbonitrile (91.14 mg, 0.615 mmol), dichlorobis(triphenylphosphine)palladium (32.37 mg, 0.046 mmol), cuprous iodide (17.57 mg, 0.092 mmol), N,N'-diisopropylethylamine (198.70 mg, 1.537 mmol) and lithium chloride (52.13 mg, 1.230 mmol) at room temperature. After the addition was completed, the reaction was stirred at 85 °C for 4 hours under an argon atmosphere. After the reaction was completed, water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0%-40%) to obtain compound 49-1 (150 mg, 0.257 mmol, 83.60% yield), light yellow solid. ES-API: [M+H] + = 583.1, 585.1.

[0370] Step two: Compound 49-1 (150 mg, 0.257 mmol) was dissolved in methanol (0.3 mL), tetrahydrofuran (3 mL) and water (3 mL). To the above solution was added lithium hydroxide (15.39 mg, 0.643 mmol). After the addition was complete, the reaction was stirred at room temperature for 10 hours. After the reaction was complete, the reaction was acidified to weakly acidic (pH = about 6) with dilute hydrochloric acid (1 M). The resulting solution was extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-4%) to give compound 49-2 (140 mg, 0.259 mmol, 100% yield), light yellow solid. ES-API: [M+H] = 541.2, 543.2. +

[0371] Step three: Compound 49-2 (120 mg, 0.222 mmol) was dissolved in toluene (1.5 mL), dioxane (4.5 mL) and water (1.5 mL). To the above solution was added compound 15-2 (243.97 mg, 0.443 mmol), potassium phosphate (117.59 mg, 0.554 mmol), 1,1'-bis (di-tert-butylphosphino) ferrocene palladium (II) dichloride (14.43 mg, 0.022 mmol), and the reaction was stirred at 80°C for 3 hours. The reaction was added with ethyl acetate (30 mL) and water (30 mL). The organic phase was separated and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-30%) to give compound 49-3 (170 mg, 0.192 mmol, 86.67% yield), gray solid. ES-API: [M+H] = 885.4. +

[0372] Step four: Compound 49-3 (170 mg, 0.192 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide (9.20 mg, 0.384 mmol) was added at 0°C. The reaction was stirred at room temperature for 18 hours. The reaction was adjusted to pH 6 with 1 M dilute hydrochloric acid, and extracted with ethyl acetate (30 mL*2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 49-4 (165 mg, 0.189 mmol, 98.62% yield), light yellow solid. ES-API: [M+H] = 871.3. +

[0373] ​​​Step five: Compound 49-4 (165 mg, 0.189 mmol) was dissolved in dichloromethane (40 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1072.05 mg, 5.592 mmol), 1-hydroxybenzotriazole (251.90 mg, 1.864 mmol), and diisopropylethylamine (1.136 mL, 6.524 mmol) were added at room temperature. The reaction was stirred at room temperature for 18 hours. The reaction was added to dichloromethane (50 mL), washed with dilute hydrochloric acid (0.5 M, 20 mL*2), saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether: 0-70%) to obtain compound 49-5 (100 mg, 0.117 mmol, 62.88% yield), a light yellow solid. ES-API: [M+H] = 853.3. +

[0374] Step six: Compound 49-5 (100 mg, 0.117 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated to remove the solvent. The residue was redissolved in dichloromethane (30 mL) and washed with saturated sodium bicarbonate solution (20 mL*2). The separated organic phase was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 49-6 (90 mg, crude), a light yellow solid. ES-API: [M+H] = 753.2. +

[0375] Preparation example 5: synthesis of intermediate 4-1

[0376] Step one: Compound 4a (60 g, 181.609 mmol) was dissolved in N,N-dimethylformamide (200 mL), sodium bicarbonate (45.77 g, 544.827 mmol) was added, and iodomethane (33.918 mL, 544.827 mmol) was added dropwise under nitrogen protection with an ice water bath. The reaction was stirred at room temperature overnight. Water (200 mL) was added, and ethyl acetate (200 mL*3) was extracted, washed with water (200 mL), and saturated brine (200 mL*3). After drying over anhydrous sodium sulfate, the crude product was concentrated under reduced pressure to obtain compound 4b (65 g, 188.729 mmol, 103.92% yield), an oily liquid. ES-API [M-156+H] = 189.1. +

[0377] ​​​Step two: Take the crude compound 4b (65 g, 188.729 mmol) and dissolve it in dichloromethane (200 mL), drop N-methylmorpholine (100 g, 996 mmol) under ice water bath and nitrogen protection, then add compound 4e (35 g, 99.655 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (38.07 g, 199.311 mmol), 1-hydroxybenzotriazole (4.04 g, 29.897 mmol) in sequence, and react at room temperature for 4 hours. Wash with water (200 mL) in sequence, 1N hydrochloric acid (80 mL), saturated brine (200 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain compound intermediate 4-1 (33 g, 69.129 mmol) by slurry (petroleum ether / ethyl acetate = 8 / 1). The mother liquor is further purified by flash silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound intermediate 4-1 (4 g, 8.34 mmol), and a total of 37 g (77.5 mmol, 78.7% yield) of intermediate 4-1 is obtained. White solid. ES-API M-56+H] + = 145.1.

[0378] Step three: Compound 4d (50 g, 136.896 mmol) is dissolved in tetrahydrofuran (300 mL) and water (75 mL), and lithium hydroxide monohydrate (9.38 g, 223.415 mmol) is added. React at room temperature for 4 hours, adjust pH to 3 with 1N hydrochloric acid, extract with ethyl acetate (200 mL*3), wash with water (200 mL*3), and saturated brine (200 mL). Dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain compound 4e (48 g, 136.670 mmol, 99.83% yield), colorless transparent oily liquid. ES-API M-56+H] + = 295.0.

[0379] Step four: Compound 4c in step two is dissolved in anhydrous dichloromethane (200 mL), drop N-methylmorpholine (100 g, 996 mmol) under ice water bath and nitrogen protection, then add compound 4e (35 g, 99.655 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (38.07 g, 199.311 mmol), 1-hydroxybenzotriazole (4.04 g, 29.897 mmol) in sequence, and react at room temperature for 4 hours. Wash with water (200 mL) in sequence, 1N hydrochloric acid (80 mL), saturated brine (200 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain compound intermediate 4-1 (33 g, 69.129 mmol) by slurry (petroleum ether / ethyl acetate = 8 / 1). The mother liquor is further purified by flash silica gel column (ethyl acetate: petroleum ether = 0-100%) to obtain compound intermediate 4-1 (4 g, 8.34 mmol), and a total of 37 g (77.5 mmol, 78.7% yield) of intermediate 4-1 is obtained. White solid. ES-API M-56+H] + = 477.1.

[0380] Preparation example 6: synthesis of intermediate 15-2

[0381] Step one: under nitrogen protection, compound intermediate 4-1 (1.0 g, 2.10 mmol), bis(triphenylphosphine)palladium dichloride (150 mg, 0.21 mmol), cuprous iodide (40 mg, 0.21 mmol), triethylamine (4.4 mL, 31.42 mmol) were dissolved in N,N-dimethylformamide (5 mL), trimethyl ethynylsilane (1.48 mL, 10.47 mmol) was added, the reaction was stirred in a microwave reactor at 80 °C for 1.5 hours. The reaction solution was added into ethyl acetate (60 mL), washed with water (30 mL*2) and saturated brine (30 mL*2) in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-60%) to give compound 4-2 (850 mg, yield 82.0%) as a light brown solid. ES-API: [M+H] = 495.1. +

[0382] Step two: compound 4-2 (850 mg, 1.718 mmol) was dissolved in methanol (12 mL), potassium carbonate (712 mg, 5.15 mmol) was added under ice bath, the reaction was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was poured into ice water, extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-80%) to give compound 15-a (425 mg, yield 58.5%) as a light yellow solid. ES-API: [M+H] = 423.1. +

[0383] Step three: under nitrogen protection, cuprous chloride (9 mg, 0.09 mmol), sodium tert-butoxide (17 mg, 0.18 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (51 mg, 0.09 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), the reaction was stirred at room temperature for 30 minutes, then pinacol diboronate (271 mg, 1.06 mmol) in tetrahydrofuran solution (2 mL) was added, the reaction was stirred at room temperature for 10 minutes, then compound 15-1 (375 mg, 0.89 mmol) and anhydrous methanol (57 mg, 1.78 mmol) in tetrahydrofuran solution (2 mL) was added, the reaction was continued to stir at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-60%) to give compound intermediate 15-2 (350 mg, yield 71.6%) as a white solid. ES-API: [M+H] = 551.2. +

[0384] Preparation example 7: synthesis of intermediate 70-6 ​​​

[0385] Step one: Compound 118-12 (150 mg, 0.33 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL), lithium hydroxide monohydrate (41 mg, 0.98 mmol) was added at 0 °C, the reaction was stirred at room temperature for 5 hours. The reaction was adjusted to pH 9 with 1M dilute hydrochloric acid, extracted with ethyl acetate (30 mL*2). The organic phase was dried with anhydrous sodium sulfate, concentrated. The crude product was purified by flash silica gel column (methanol / dichloromethane: 0-5%) to obtain compound 70-a (95 mg, yield 69.8%), white solid. ES-API: [M+H] + = 411.2, 413.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.10 (s, 1H), 6.99 (d, J = 2.8 Hz, 1H), 4.33 (t, J = 5.6 Hz, 1H), 4.01 (q, J = 6.4 Hz, 1H), 3.62-3.58 (m, 2H), 2.95-2.89 (m, 2H), 2.87 (s, 3H), 2.26 (d, J = 14.0 Hz, 1H), 1.99 (d, J = 14.0 Hz, 1H), 1.36 (d, J = 6.4 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H), 0.62 (s, 3H), 0.48 (s, 3H).

[0386] Step two: Compound 70-a (95 mg, 0.23 mmol) and compound intermediate 15-2 (191 mg, 0.35 mmol) were dissolved in toluene (1 mL), dioxane (3 mL) and water (1 mL), potassium phosphate (122 mg, 0.58 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium(II) dichloride (15 mg, 0.023 mmol) were added, replaced with nitrogen for 3 times, the reaction was stirred at 85 °C for 3 hours. The reaction was added with ethyl acetate (50 mL) and water (10 mL). The separated organic phase was washed with saturated brine (15 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-50%) to obtain compound 70-b (150 mg, yield 86.0%), light yellow solid. ES-API: [M+H] + = 755.3.

[0387] Step three: Compound 70-b (80 mg, 0.106 mmol) was dissolved in tetrahydrofuran (2.5 mL) and water (0.8 mL), lithium hydroxide monohydrate (7 mg, 0.16 mmol) was added at 0 °C, the reaction was stirred at room temperature for 1 hour. The reaction was adjusted to pH 6 with 1M dilute hydrochloric acid, extracted with ethyl acetate (10 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 70-c (74 mg, yield 94.3%) as a light yellow solid. ES- API: [M+H] = 741.3. +

[0388] Step four: Compound 70-c (74 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), diisopropylethylamine (39 mg, 3.0 mmol) and 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (53 mg, 0.15 mmol) were added, the reaction was stirred at room temperature for 18 hours. The reaction was added with dichloromethane (15 mL), washed with 0.5M dilute hydrochloric acid (2 mL*2), saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (methanol / dichloromethane: 0-30%) to give compound 70-d (70 mg, yield 80.3%) as a light yellow solid. ES-API: [M+H] = 873.3. +

[0389] Step five: Compound 70-d (130 mg, 0.149 mmol) was dissolved in dichloromethane (15 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (714 mg, 3.72 mmol), 1-hydroxybenzotriazole (101 mg, 0.745 mmol), and diisopropylethylamine (577 mg, 4.47 mmol) were added at room temperature, the reaction was stirred at room temperature for 64 hours. The reaction was added with dichloromethane (15 mL), washed with 0.5M dilute hydrochloric acid (4 mL*2), saturated sodium bicarbonate (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-35%) to give compound 70-e (55 mg, yield 43.2%) as a light pink solid. ES-API: [M+H] = 855.3. + 1 ​​​H NMR (400MHz, DMSO) δ8.90(d,J=2.8Hz,1H),8.07(d,J=2.4Hz,1H),7.49(s,1H),7.34(d,J=15.6Hz,1H),7.25(d,J=9.2Hz,1H),7.1 5(s,1H),6.84(d,J=15.6Hz,1H),5.18(t,J=4.8Hz,1H),5.01(d,J=12.2Hz,1H),4.31-4.19(m,2H),3.99(t,J=10.8Hz,1H),3.94- 3.81(m,2H),3.85-3.63(m,1H),3.52(d,J=10.8Hz,1H),3.26(s,3H),3.13-3.12(m,2H),2.82-2.59(m,2H),2.28-2.24(m,1H),1. 99(d,J=10.2Hz,1H),1.78-1.71(m,2H),1.46-1.43(m,1H),1.40-1.34(m,12H),1.03(t,J=7.2Hz,3H),0.73(s,3H),0.24(s,3H).

[0390] Step Six: Compound 70-e (55 mg, 0.064 mmol) was dissolved in anhydrous methanol (0.3 mL), and 1.5 mL of 4.0 M hydrogen chloride / dioxane solution was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give intermediate 70-6 (48 mg, 98.9% yield), a yellow solid. ES-API: [M+H] + =755.1.

[0391] Preparation Example 8: Synthesis of Intermediate 1

[0392] Step 1: Acetonitrile (5 mL) was added to a flask containing 2-(1-(tert-butyloxycarbonyl)piperidin-4-yl)propionic acid (150 mg, 0.583 mmol), followed by benzyl bromide (199.40 mg, 1.166 mmol) and potassium carbonate (241.67 mg, 1.749 mmol). The mixture was stirred overnight at room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (ethyl acetate / petroleum ether: 0-20%) to give tert-butyl 4-(1-benzyloxy)-1-oxopropane-2-yl)piperidin-1-carboxylate (160 mg, 0.432 mmol, yield 74.15%). The above compound was prepared chirally (column: Daicel). I.D. 250*4.6 mm*5 μm; mobile phase: n-hexane: ethanol = 95:5; flow rate: 1 mL / min; column temperature 35 °C) to give two isomeric compounds. One of the isomeric compounds with retention time 4.781 min was arbitrarily assigned the structure (S)-tert-butyl 4-(1-benzyloxy-1-oxopropan-2-yl)piperidin-1-ylcarbamate (1-a, 68 mg). ES-API: [M+Na] + = 370.1. The other isomeric compound with retention time 5.570 min was arbitrarily assigned the structure (R)-tert-butyl 4-(1-benzyloxy-1-oxopropan-2-yl)piperidin-1-ylcarbamate (1-b, 85 mg). ES-API: [M+Na] + = 370.1.

[0393] Step two: A mixture of compound 1-b (with retention time 5.570 min) (69 mg, 0.2 mmol) and 10% palladium on carbon (10 mg, 0.01 mmol) in methanol (5 mL) was stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction mixture was filtered and concentrated to give compound intermediate 1 (50 mg). ES-API: [M+Na] + = 280.1.

[0394] Preparation 9: Synthesis of intermediate 50-int-A, 50-int-B

[0395] Step one: 2,3-Dihydroxybenzaldehyde (8.5 g, 61.6 mmol) was added to 50 mL of dimethyl sulfoxide, then 60% sodium hydride (3.7 g, 92.4 mmol) was added to the above solution in portions. The reaction mixture was stirred at room temperature for 30 minutes. Then benzyl bromide (10.5 g, 61.6 mmol) was added and the stirring was continued for 2 hours. After the reaction was completed, 100 mL of water was added and the mixture was extracted with ethyl acetate (50 mL*3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by flash silica gel column (petroleum ether: ethyl acetate = 10:1) to give compound 50-a (4.7 g, yield 26%) as a white solid. LC-MS (ESI) m / z: [M+H] + = 229.2; retention time: 1.59 min.

[0396] Step two: Compound 50-a (4.7 g, 20.6 mmol) and sodium acetate (2.5 g, 30.9 mmol) were added into 40 mL acetic acid, and bromine (3.2 g, 20.6 mmol) was dissolved in 5 mL acetic acid, then slowly added into the reaction solution. After the addition was completed, the reaction solution was stirred at room temperature for 1 hour. 100 mL water was added, and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain yellow solid compound 50-b (4.9 g, yield 78%). LC-MS (ESI) m / z: [M+23] + = 329.0; 331.0; Retention time: 1.84 min.

[0397] Step three: Compound 50-b (4.9 g, 16.0 mmol) and potassium carbonate (4.4 g, 32.0 mmol) were added into 50 mL N,N-dimethylformamide, then dimethyl sulfate (3.0 g, 24.0 mmol) was added dropwise into the reaction solution. After the addition was completed, the reaction solution was stirred at room temperature for 16 hours. 100 mL water was added, and extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 10: 1) to obtain light yellow solid compound 50-c (4.4 g, yield 86%). LC-MS (ESI) m / z: [M+H] + = 321.1; 323.1; Retention time: 1.80 min.

[0398] Step four: Compound 50-c (4 g, 12.5 mmol) was dissolved in 20 mL tetrahydrofuran and 20 mL tert-butyl alcohol, then cooled to 0°C. Sodium chlorite (1.68 g, 18.75 mmol) and sodium dihydrogen phosphate (3 g, 25 mmol) were dissolved in 5 mL water, then the sodium chlorite buffer solution was added to the above low temperature solution. The reaction solution was warmed to room temperature and stirred for 1 hour. After the reaction was completed, 100 mL water was added, and extracted with ethyl acetate (80 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 4: 1) to obtain white solid compound 50-d (2.05 g, yield 49%). LC-MS (ESI) m / z: [M+H] + = 337.0; 339.0; Retention time: 1.76 min.

[0399] Step five: Compound 50-d (1 g, 2.97 mmol) was dissolved in 10 mL of N,N- dimethylformamide, then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.35 g, 3.57 mmol), N,N-diisopropylethylamine (1.15 g, 8.91 mmol) and ammonium chloride (315 mg, 5.94 mmol) were added. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, 100 mL of water was added, and the reaction was extracted with ethyl acetate (80 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 50-e (900 mg, yield 90%) as a yellow solid. LC-MS (ESI) m / z: [M+H] = 336.1; 338.2; Retention time: 1.72 min. + +

[0400] Step six: Compound 50-e (300 mg, 0.89 mmol) was added to 5 mL of dioxane and 1 mL of water, and palladium acetate (20 mg, 0.089 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (51 mg, 0.089 mmol) were added to the reaction solution, followed by the addition of triethylamine (270 mg, 2.67 mmol), and the reaction was stirred at 80°C under carbon monoxide for 16 hours. After the reaction was completed, the reaction was cooled to room temperature, and the reaction was dried by rotary evaporation, 50 mL of water was added, and the reaction was extracted with ethyl acetate (50 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by preparative HPLC (trifluoroacetic acid method) to obtain compound intermediate 50-int-A (108 mg, yield 40%) as a white solid. LC-MS (ESI) m / z: [M+H] = 302.1; Retention time: 1.27 min.1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 1.9 Hz, 2H), 7.49 (dd, J = 11.6, 4.5 Hz, 3H), 7.44-7.40 (m, 2H), 7.37-7.32 (m, 1H), 5.18 (s, 2H), 3.84 (s, 3H).

[0401] ​​Step seven: Compound 50-d (1 g, 2.97 mmol) was dissolved in 10 mL of N,N- dimethylformamide, then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluoro phosphate (1.35 g, 3.57 mmol), N,N-diisopropylethylamine (1.15 g, 8.91 mmol) and dimethylamine hydrochloride (481 mg, 5.94 mmol) were added. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, 100 mL of water was added, and the reaction was extracted with ethyl acetate (80 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound intermediate 50-int-B (865 mg, yield 80%) as a yellow solid. LC-MS (ESI) m / z: [M+H] = 364.0; 366.0; Retention time: 1.83 min. +

[0402] Preparation Example 10: Synthesis of intermediate 54-int

[0403] Step one: Methyl 3,5-dihydroxy-4-methoxybenzoate (3.10 g, 15.66 mmol) was dissolved in acetonitrile (50 mL), cooled to 0°C, and then potassium carbonate (4.32 g, 31.3 mmol) and benzyl bromide (2.68 g, 15.66 mmol) were sequentially added, and the reaction was stirred at room temperature overnight. The reaction was transferred to an ice water bath, and ice water (100 mL) was added, and the reaction was extracted with ethyl acetate (150 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 54-a (2.8 g, yield 62%) as a white solid. LC-MS (ESI) m / z: [M+H] + = 289.0; Retention time: 1.639 min.

[0404] Step two: Compound 54-a (1100 mg, 3.82 mmol), vinyl acetate (1315 mg, 15.3 mmol), sodium carbonate (242.9 mg, 2.29 mmol), and 1,5-cyclooctadiene iridium chloride dimer (256.5 mg, 0.38 mmol) were dissolved in dry toluene (20 mL), and nitrogen was replaced, and the reaction was carried out at 100°C overnight. After the reaction was completed, the solvent was evaporated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 88:12) to obtain compound 54-b (700 mg, yield 58%) as a colorless oil. LC-MS (ESI) m / z: [M+H] + = 315.3; Retention time: 1.999 min.​

[0405] Step three: Compound 54-b (400 mg, 1.27 mmol) and diiodomethane (682 mg, 2.55 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, and diethylzinc (2.55 ml, 1.0 M, 2.55 mmol) was added dropwise under nitrogen protection. The reaction was stirred at 0 °C for 2 h. The reaction was monitored by spotting on a plate. After the reaction was completed, the reaction was slowly added to saturated ammonium chloride, extracted with ethyl acetate, and the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by flash silica gel column (petroleum ether: ethyl acetate = 9: 1) to give compound 54-c (140 mg, yield 33.6%) as colorless oil. LC-MS (ESI) m / z: [M+H] + = 329.3; Retention time: 1.962 min.

[0406] Step four: Compound 54-c (140 mg, 0.43 mmol) was dissolved in methanol (5 mL) and water (1 mL), and then lithium hydroxide (179 mg, 4.27 mmol) was added. The reaction was stirred at 50 °C for 2 h. After the reaction was completed, the reaction was poured into water, acidified to PH = 4 with 1 N hydrochloric acid, and a white solid was precipitated. The solid was collected by filtration, washed with water, and dried to give white solid compound intermediate 54-int (115 mg, yield 85.8%). LC-MS (ESI) m / z: [M+H] + = 315.3; Retention time: 1.632 min. 1 H NMR (500 MHz, DMSO-d6) d 12.94 (s, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.33 (dd, J = 10.0, 4.5 Hz, 2H), 5.19 (d, J = 21.2 Hz, 2H), 3.93 (tt, J = 6.0, 2.9 Hz, 1H), 3.72 (s, 3H), 0.80 (q, J = 5.9 Hz, 2H), 0.73 - 0.65 (m, 2H).

[0407] Preparation Example 11: Synthesis of intermediate 56-int

[0408] Step one: Dissolve 5-bromovanillin (20 g, 86.5 mmol) in dichloromethane (100 mL), add aluminum chloride (12.6 g, 95.2 mmol) and pyridine (30 g, 380.9 mmol), heat the reaction solution to 45 degrees under nitrogen protection for 16 hours. After the reaction is completed, add 100 mL of water, extract with ethyl acetate (80 mL*3). Dry the combined organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrated solution with a flash silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain compound 56-a (19.2 g, yield 97.3%) as a yellow solid. LC-MS (ESI) m / z: 217.0; 219.0 [M+H] + ; Retention time: 1.30 min.

[0409] Step two: Dissolve compound 56-a (19 g, 87.96 mmol) in N,N-dimethylformamide (100 mL), add lithium carbonate (16.3 g, 219.9 mmol) and iodomethane (19.7 g, 131.9 mmol), heat the reaction solution to 45 degrees for 16 hours. After the reaction is completed, add 100 mL of water, extract with ethyl acetate (80 mL*3), dry the combined organic phase with anhydrous sodium sulfate, concentrate, and purify with a flash silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain compound 56-b (12.8 g, yield 63.3%) as a yellow solid. LC-MS (ESI) m / z: 231.0; 232.9 [M+H] + ; Retention time: 1.30 min.

[0410] Step three: Dissolve compound 56-b (10 g, 43.47 mmol) in N,N-dimethylformamide (50 mL), add potassium carbonate (18 g, 130.4 mmol) and benzyl bromide (8.2 g, 47.8 mmol), and stir the reaction solution at room temperature for 5 hours. After the reaction is completed, add water (100 mL) and extract with ethyl acetate (50 mL*3), wash the combined organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrated solution with a flash silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 56-c (12.2 g, yield 87.6%) as a yellow solid. LC-MS (ESI) m / z: 321.0.0; 323.0 [M+H] + ; Retention time: 1.88 min.

[0411] Step four: Compound 56-c (8 g, 25 mmol) was dissolved in potassium tert-butoxide (20 mL), sodium chlorite (2.25 g, 25 mmol) and sodium phosphate monobasic dihydrate (7.8 g, 50 mmol) were added, and the reaction was stirred at 0 °C for 2 hours. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL*3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain compound 56-d (4.8 g, yield 57.1%) as a yellow solid. LC-MS (ESI) m / z: 337.0; 339.0 [M+H] + ; Retention time: 1.92 min.

[0412] Step five: Compound 56-d (4.8 g, 14.3 mmol) was dissolved in methanol (20 mL), and sulfuric acid (2.1 g, 21.42 mmol) was added. The reaction was heated to 60 °C and stirred for 16 hours. After the reaction was completed, the reaction was slowly added dropwise into saturated aqueous sodium bicarbonate solution (100 mL), and the mixture was extracted with ethyl acetate (50 mL*3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain compound 56-e (4 g, yield 80%) as a yellow solid. LC-MS (ESI) m / z: 351.0; 353.0 [M+H] + ; Retention time: 2.03 min.

[0413] Step six: Compound 56-e (1 g, 2.86 mmol) and methylamine hydrochloride (110 mg, 1.71 mmol) were dissolved in 50 mL of anhydrous dioxane, and then cesium carbonate (2.8 g, 8.56 mmol) and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (130 mg, 0.14 mmol) were added. The reaction was stirred at 100 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction was directly applied to a flash silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain compound 56-f (760 mg, yield 80%) as a yellow solid. LC-MS (ESI) m / z: 302.3 [M+H] + ; Retention time: 1.91 min.

[0414] Step seven: Compound 56-f (350 mg, 1.16 mmol) was dissolved in 10 mL of N,N- dimethylformamide, then sodium hydride (93 mg, 2.32 mmol) was added at 0 °C, after the reaction was half an hour, iodomethane (330 mg, 2.32 mmol) was added dropwise into the reaction solution, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, 100 mL of water was added, and extracted with ethyl acetate (100 mL*3). The combined organic was dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 1: 1) to obtain compound 56-g (270 mg, yield 75%) as colorless oil. LCMS (ESI): m / z 316.4 [M+H] + ; Retention time: 1.46 min.

[0415] Step eight: Compound 56-g (270 mg, 0.86 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of water, then potassium hydroxide (240 mg, 4.3 mmol) was added, and the reaction was stirred at 70 °C for 12 hours. The reaction was spun dry at room temperature, 50 mL of dilute hydrochloric acid was added, and extracted with ethyl acetate (50 mL*3). The combined organic was dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by C18 reverse phase flash column (0.1% aqueous ammonium bicarbonate, 0-30% acetonitrile) to obtain compound intermediate 56-int (130 mg, yield 50%) as white solid. LC-MS (ESI) m / z: 302.1 [M+H] + ; Retention time: 1.12 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 7.52-7.30 (m, 5H), 7.27 (d, J = 1.7 Hz, 1H), 7.16 (d, J = 1.7 Hz, 1H), 5.14 (s, 2H), 3.75 (s, 3H), 2.77 (s, 6H).

[0416] Preparation 12: Synthesis of intermediate 76-int

[0417] Step one: Compound 56-e (300 mg, 0.86 mmol), trimethylsilylethynyl (126 mg, 1.29 mmol), dichlorobispalladium (120 mg, 0.17 mmol), cuprous iodide (32.6 mg, 0.17 mmol), dissolved in triethylamine (10 mL), nitrogen was replaced, the reaction was stirred at 90 °C overnight. After the reaction was completed, it was cooled to room temperature, ice water (30 mL) was added, and extracted with ethyl acetate (50 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the concentrated solution was purified by flash silica gel column (petroleum ether: ethyl acetate = 10: 1) to obtain white solid compound 76-a (165 mg, yield 52.3%). LC-MS (ESI) m / z: 369.3 [M+H] + ; Retention time: 1.99 min.

[0418] Step two: Compound 76-a (165 mg, 0.45 mmol) was dissolved in methanol (5 mL) and water (1 mL), then sodium hydroxide (179 mg, 4.48 mmol) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was adjusted to pH = 4 with 1N hydrochloric acid, purified by C18 reverse phase flash column (0.1% trifluoroacetic acid aqueous solution, 0-60% acetonitrile) and freeze-dried to obtain white solid compound intermediate 76-int (110 mg, yield 87.3%). LC-MS (ESI) m / z: 283.2 [M+H] + ; Retention time: 1.383 min. 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.52-7.46 (m, 2H), 7.45-7.39 (m, 2H), 7.36 (ddd, J = 7.2, 3.7, 1.4 Hz, 1H), 5.22 (s, 2H), 4.40 (s, 1H), 3.90 (s, 3H).

[0419] Preparation example 13: synthesis of intermediate 40-int

[0420] Step 1: Compound 56-f (350 mg, 1.16 mmol) was dissolved in 10 mL of tetrahydrofuran, then N,N-diisopropylethylamine (450 mg, 3.49 mmol) and acetic anhydride (180 mg, 1.74 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL * 3). The combined organic compounds were dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a colorless oily compound 40-a (270 mg, 70% yield). LCMS (ESI): m / z [M+H] + =344.2. Retention time =1.74 min.

[0421] Step 2: Compound 40-a (200 mg, 0.58 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of water, then potassium hydroxide (160 mg, 2.92 mmol) was added. The reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was then evaporated to dryness at room temperature, and 50 mL of dilute hydrochloric acid was added. Extraction was performed with ethyl acetate (50 mL * 3). The combined organic compounds were dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by C18 reversed-phase flash column chromatography (0.1% formic acid aqueous solution, 0-40% acetonitrile) to give a white solid intermediate 40-int (95 mg, 50% yield). LC-MS (ESI) m / z: [M+H] + =330.3. Retention time =1.48min. 1 H NMR (400MHz, DMSO-d6) δ13.10(s,1H),7.68(s,1H),7.50(t,J=7.5Hz,3H),7.43(t,J=7 .5Hz,2H),7.36(t,J=7.3Hz,1H),5.24(s,2H),3.86(s,3H),3.08(s,3H),1.70(s,3H).

[0422] Preparation Example 14: Synthesis of Intermediate INT-179

[0423] Step one: To a solution of compound 118-7 (2.4 g, 6.071 mmol) in N,N- dimethylformamide (50 mL) was added cesium carbonate (5.934 g, 18.214 mmol) and 4- methylbenzenesulfonic acid 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl ester (3.647 g, 12.143 mmol) sequentially under nitrogen atmosphere. The reaction mixture was heated to 60 °C and stirred overnight under nitrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by automatic flash chromatography on silica gel (tetrahydrofuran / petroleum ether = 0-60%) to give two isomers. One of them with retention time 1.78 min was arbitrarily assigned as compound 179-a-1 (1.843 g, yield: 58%) and ES-API: [M+H] = 523.1. The other one with retention time 1.69 min was arbitrarily assigned as compound 179-a-2 (569 mg, yield: 18%) and ES-API: [M+H] = 523.1. + +

[0424] Step two: To a solution of compound 179-a-1 (retention time 1.78 min) (1.558 g, 2.976 mmol) in dichloromethane (40 mL) was added diisobutylaluminum hydride (9.5 mL, 9.524 mmol, 1 M in cyclohexane) dropwise slowly at -70 °C under nitrogen atmosphere. The reaction mixture was stirred at -70 °C for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was slowly warmed to 0 °C and then 0.30 mL of water, 0.30 mL of 15% sodium hydroxide solution, 0.90 mL of water and a small amount of anhydrous sodium sulfate were added sequentially dropwise slowly. The mixture was then stirred at room temperature for 0.5 hours. The mixture was filtered and concentrated to give compound 179-b (1.0 g, yield: 68%) as a white solid. ES-API: [M+H] = 495.1. +

[0425] ​​​Step 3: Under ice-water bath conditions, acetic anhydride (0.38 mL, 4.037 mmol), N,N-diisopropylethylamine (0.35 mL, 2.018 mmol), and 4-dimethylaminopyridine (24.66 mg, 0.202 mmol) were added to a solution of compound 179-b (1.0 g, 2.018 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at 0 °C for 0.5 hours. LC-MS analysis confirmed the reaction was complete, and the solvent was removed by concentration under reduced pressure. 50 mL of dichloromethane was added to the residue, followed by washing with water (20 mL) and saturated brine (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The residue was purified by automated rapid chromatography on silica gel (tetrahydrofuran / petroleum ether = 0–20%) to obtain compound 179-c (788 mg, yield: 73%). ES-API: [M+H] + =537.2. 1 H NMR(400MHz,DMSO-d6)δ8.69(dd,J=4.7,1.6Hz,1H),7.80(dd,J=7.8,1.7Hz,1H),7.44- 7.41(m,1H),7.20(s,1H),4.17-4.12(m,1H),3.79-3.53(m,7H),3.43-3.38(m,2H),3.32 -3.27(m,2H),2.91(s,3H),2.35(d,J=14.2Hz,1H),2.11(d,J=14.2Hz,1H),1.83(s,3H) ,1.78-1.73(m,2H),1.44(d,J=6.3Hz,3H),1.37-1.29(m,2H),0.73(s,3H),0.63(s,3H).

[0426] Step 4: Under nitrogen protection, compound 179-c (765 mg, 1.423 mmol), pinacol diboronate (542 mg, 2.135 mmol), methoxy(cyclooctadiene)iridium dimer (93 mg, 0.142 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (67 mg, 0.285 mmol) were dissolved in cyclohexane (15 mL). The reaction mixture was heated in an oil bath to 45 °C and stirred for 3 hours. LC-MS analysis confirmed the reaction was complete. After cooling to room temperature, the mixture was concentrated under reduced pressure to give crude compound 179-d (827 mg, yield: 99%). ES-API: [M+H] + =581.2.

[0427] Step five: To a solution of compound 179-d (827 mg, 1.423 mmol) in acetonitrile (20 mL) was added hydrogen peroxide (0.44 mL, 4.268 mmol), the reaction mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was completed, the solvent was removed by reduced pressure. To the residue was added 50 mL of dichloromethane, then washed with water (20 mL) and saturated brine (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to give a crude, which was purified by automatic flash chromatography on silica gel (tetrahydrofuran / petroleum ether = 0-50%) to give compound 179-e (648 mg, yield: 82%). ES- API: [M+H] + = 553.2.

[0428] Step six: To a solution of compound 179-e (648 mg, 1.171 mmol) in tetrahydrofuran (6 mL), methanol (6 mL) and water (6 mL) was added lithium hydroxide (147 mg, 3.512 mmol) at 0 °C, the reaction mixture was stirred at 0 °C for 3 h. LCMS showed the reaction was completed, the solvent was removed by reduced pressure. The residue was added water (6 mL), the pH of the mixture was adjusted to about 6.0 by dilute hydrochloric acid (1.0 M), extracted with ethyl acetate (50 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to give compound intermediate INT-179 (548 mg, yield: 92%). ES-API: [M+H] + = 511.2.

[0429] Preparation 15: synthesis of intermediate 0012-c

[0430] Step one: Isobutyric acid ethyl ester (16.67 g, 143.66 mmol) was dissolved in tetrahydrofuran (150 mL), 2.0 M diisopropylamino lithium in tetrahydrofuran / n-hexane solution (71.83 mL, 143.66 mmol) was added dropwise at -70 °C, the reaction was stirred at -70 °C for 1 h. 4-Formyl-1H-pyrrole-2-carboxylic acid ethyl ester (10 g, 65.30 mmol) in tetrahydrofuran solution (15 mL) was added dropwise, the reaction was stirred at -70 °C for 1 h, then slowly raised to 0 °C and stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL) and water (30 mL), extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The crude was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to give compound 0012-a (16.0 g, yield 92.0%) as a yellow liquid. ES-API: [M-18+H] + = 252.1.

[0431] Step two: Compound 0012-a (9.5 g, 35.26 mmol) was dissolved in dichloromethane (120 mL), trifluoroacetic acid (13.50 mL, 176.28 mmol) was added at 0 °C, then triethylsilane (33.70 mL, 211.54 mmol) was added dropwise slowly, the reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution (50 mL) was added slowly, extracted with ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 0012-b (5.7 g, yield 64.6%) as a yellow liquid. ES-API: [M+H] + = 254.2.

[0432] Step three: Compound 0012-b (3.1 g, 12.12 mmol) was dissolved in acetonitrile (60 mL), N-iodosuccinimide (3.55 g, 15.76 mmol) was added at 0 °C, the reaction was stirred at 10 °C overnight. The reaction solution was added with ethyl acetate (150 mL), washed with saturated sodium bicarbonate solution (80 mL), saturated brine (80 mL) in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-15%) to give compound 0012-c (2.9 g, yield 63.5%) as a white solid. ES-API: [M+H] + = 380.0.

[0433] Preparation example 16: synthesis of intermediate INT-64

[0434] Step one: 5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-ol (2 g, 8.618 mmol, preparation method refer to intermediate 1 in WO2025 / 45233) was dissolved in N,N-dimethylformamide (30 mL), 4-methoxybenzyl chloride (2.70 g, 17.235 mmol) and potassium carbonate (3.57 g, 25.853 mmol) were added, the reaction was stirred at 65 °C for 3 hours. The reaction solution was added with water (80 mL), extracted with ethyl acetate (150 mL). The organic phase was washed with saturated brine (50 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 64-a (2.6 g, yield 85.6%) as a white solid. ES-API: [M+H] + = 352.0, 354.0.

[0435] Step two: Compound 64-a (2.35 g, 6.672 mmol) and isopropyl alcohol pinacol borate (2.23 g, 12.009 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), the reaction was cooled to -70 °C, 2.5 M n-butyllithium (5.34 mL, 13.344 mmol) was added dropwise slowly, the reaction was stirred at -70 °C for 1 hour, quenched with water (2.5 mL), the resulting reaction of compound 64-b was used directly in the next step.

[0436] Step three: To the reaction of compound 64-b above, 1,4-dioxane (20 mL), compound 0012-c (1.3 g, 3.428 mmol), potassium carbonate (1.18 g, 8.571 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.25 g, 0.343 mmol) were added, the reaction was stirred at 85 °C for 2 hours under nitrogen atmosphere. The reaction was added with ethyl acetate (150 mL), washed with water (50 mL), saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The crude was purified by flash silica gel column (methanol / methylene chloride: 0-2%) to give compound 64-c (1.75 g, yield 97.3%) as a colorless liquid. ES-API: [M+H] = 525.3. +

[0437] Step four: Compound 64-c (1.65 mg, 3.145 mmol) was dissolved in acetonitrile (25 mL), N-bromosuccinimide (672 mg, 3.774 mmol) was added portionwise under ice bath, the reaction was stirred at ice bath for 1 hour. The reaction was added with water (20 mL) and concentrated ammonia (2 mL), continued to stir for 15 minutes, extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The crude was purified by flash silica gel column (methanol / methylene chloride: 0-3%) to give compound 64-d (1.85 g, yield 97.5%) as a sticky solid. ES-API: [M+H] = 603.2, 605.2. +

[0438] ​​Step five: Compound 64-d (1.85 g, 3.065 mmol) was dissolved in n-propanol (30 mL) and water (15 mL), and lithium hydroxide monohydrate (1.29 g, 30.65 mmol) was added at room temperature. The reaction was stirred at 98 °C for 40 h. The reaction was cooled to room temperature, and the n-propanol solvent was concentrated under reduced pressure. The reaction was adjusted to pH 5 with 1M dilute hydrochloric acid and extracted with ethyl acetate (60 mL*2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (methanol / methylene chloride: 0-4%) to give compound 64-e (1.4 g, yield 88.3%) as a light orange solid. ES- API: [M+H] + = 517.1, 519.1.

[0439] Step six: Compound 64-e (1.35 g, 2.609 mmol) was dissolved in N,N- dimethylformamide (15 mL), and potassium carbonate (469 mg, 3.392 mmol) was added in an ice bath. Methyl iodide (444 mg, 3.131 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction was added to ethyl acetate (100 mL) and washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-35%) to give compound intermediate INT-64 (1.35 g, yield 97.4%) as a light brown solid. ES-API: [M+H] + = 531.1, 533.0.

[0440] Preparation example 17: synthesis of intermediate INT-58

[0441] Step one: Methyl 3-(benzyloxy)-5-hydroxy-4-methoxybenzoate (288 mg, 1 mmol, CAS: 135388-93-1), N,N-diisopropylethylamine (387 mg, 3 mmol) was dissolved in dichloromethane (10 mL), and N-phenyl bis(trifluoromethanesulfonyl)imide (372 mg, 1.04 mmol) was added. The reaction was stirred at room temperature for 2 h. After the reaction was completed, it was poured into 30 mL of dichloromethane, washed with 15 mL of water and 15 mL of saturated brine in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash silica gel column (0-80% petroleum ether / ethyl acetate) to give compound 58-a (320 mg, yield 76%). ES-API [M+Na] + = 443.0.

[0442] Step two: To a solution of compound 58-a (50 mg, 0.119 mmol) in dioxane (2 mL) was added tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 10.89 mg, 0.012 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 6.88 mg, 0.012 mmol) and cesium carbonate (116.26 mg, 0.357 mmol), and the reaction was stirred at 100 °C for 1 h. To the reaction was added ethyl acetate (20 mL). The reaction was washed with water (20 mL*2) and brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification was performed on a silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give compound intermediate INT-58 (25 mg, 0.076 mmol, 63.8% yield). ES-API: [M+H] = 330.1. +

[0443] Example 1: Synthesis of compound Z1

[0444] Step one: Methyl 3-hydroxy-4,5-dimethoxybenzoate (1.0 g, 4.713 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and potassium carbonate (1.95 g, 14.138 mmol) and benzyl bromide (1.1 mL, 9.425 mmol) were added successively. The reaction was stirred at room temperature for 3 h. After the reaction was completed, 30 mL of ethyl acetate and 10 mL of water were added to dilute the reaction, and the organic layer was separated and washed twice with 10 mL of saturated brine. After vacuum concentration, purification was performed on a silica gel column (tetrahydrofuran: petroleum ether = 5%-25%) to give compound 1-1 (1.34 g, 4.432 mmol, 94.05% yield). ES-API: [M+H] = 303.1. +

[0445] Step two: Compound 1-1 (1.34 g, 4.432 mmol) was dissolved in 8 mL of methanol and 2 mL of water, and lithium hydroxide monohydrate (0.93 g, 22.161 mmol) was added under ice bath. The reaction was stirred at room temperature for 18 h. After the reaction was completed, the methanol was rotary evaporated under vacuum, and the pH of the reaction was adjusted to 6-7 with 1M dilute hydrochloric acid. Filtration gave compound 1-2 (1.12 g, 3.885 mmol, 87.65% yield). ES-API: [M+H] = 289.1. +

[0446] ​​​Step three: Compound 51-12 (55 mg, 0.063 mmol) was dissolved in 0.5 mL of methanol, 4M hydrogen chloride in dioxane (1.5 mL) was added dropwise slowly under ice-bath, and stirred at room temperature for 1 hour. After the reaction was completed, it was rotary-evaporated to give compound 1-3 (47 mg, 0.060 mmol, 96.43% yield), which was used directly in the next step. ES-API: [M+H] = 779.2. +

[0447] Step four: Compound 1-3 (47 mg, 0.060 mmol) was dissolved in 1 mL of dichloromethane, 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (33 mg, 0.121 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.121 mmol) and N,N'-diisopropylethylamine (0.032 mL, 0.181 mmol) were added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated, water (4 mL) was added to the residue, and extracted with ethyl acetate (8 mL*2), the organic phase was washed with saturated brine (5 mL*3), dried and concentrated to give a crude product, which was purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 10%-100%) to give compound 1-4 (57 mg, 0.055 mmol, 91.00% yield). ES-API: [M+H] = 1038.3. +

[0448] Step five: Compound 1-4 (57 mg, 0.055 mmol) was dissolved in 0.5 mL of methanol, 4M hydrogen chloride in dioxane (1.5 mL) was added dropwise slowly under ice-bath, and stirred at room temperature for 1 hour. After the reaction was completed, it was rotary-evaporated to give compound 1-5 (51 mg, 0.054 mmol, 99.03% yield), which was used directly in the next step. ES-API: [M+H] = 938.2. +

[0449] ​​​Step six: Compound 1-5 (51 mg, 0.054 mmol) was dissolved in 3 mL of dichloromethane, compound 1-2 (31 mg, 0.109 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (41 mg, 0.109 mmol) and N,N'-diisopropylethylamine (0.028 mL, 0.163 mmol) were added, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the residue was added to water (4 mL) and extracted with ethyl acetate (8 mL*2), the organic phase was washed with saturated brine (5 mL*3), dried and concentrated, and purified by preparative HPLC (formic acid method 1) to obtain 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 5 -(R a )-(5-(3-(1,1-dioxidothiomorpholine)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazole-8(1,3)-pyridazine-1(3,4)-pyrazole ring trideca-2- ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z1 (21.5 mg, 0.018 mmol, yield 32.71%). ES-API: [M+H] = 1208.3. +

[0450] Example 2: Synthesis of compound Z2

[0451] ​Step one: Compound 49-6 (20 mg, 0.027 mmol), 2-(tert-butoxy carbonyl)-5- carboxy-1,2,3,4-tetrahydroisoquinoline (11.05 mg, 0.040 mmol) were dissolved in N,N- dimethylformamide (3 mL), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (13 mg, 0.035 mmol), N,N'-diisopropylethylamine (17.2 mg, 0.133 mmol) were added, after the addition was completed, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (10 mL) was added and extracted with ethyl acetate (15 mL*2). The organic phase was washed with saturated brine (10 mL*3) and dried and concentrated to obtain the crude product which was purified by flash silica gel column (methanol / methylene chloride: 0%-10%) to obtain compound 2-1 (15 mg, 0.015 mmol, 55.79% yield). White solid, ES-API: [M+H] = 1012.4. +

[0452] Step two: Compound 2-1 (15 mg, 0.015 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.3 mL) was added, the reaction was stirred at room temperature under nitrogen protection for 1 hour, concentrated to dryness under reduced pressure to obtain compound 2-2 (12 mg, 0.013 mmol, 88.78% yield), yellow oily liquid, ES-API: [M+H] = 912.3. +

[0453] Step three: Compound 2-2 (10 mg, 0.007 mmol), compound 1-2 (3.41 mg, 0.012 mmol) were dissolved in N,N-dimethylformamide (3 mL), 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (3.75 mg, 0.01 mmol), N,N'- diisopropylethylamine (2.55 mg, 0.02 mmol) were added, after the addition was completed, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (10 mL) was added and extracted with ethyl acetate (15 mL*2). The organic phase was washed with saturated brine (10 mL*3) and dried and concentrated to obtain the crude product which was purified by preparative HPLC (formic acid method 1) to obtain 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8​​1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - Hexahydro-1 1 H-8-oxa-4(4,2)-thiazole-8(1,3)-pyridazine-1(3,4)-pyrrole cyclotrideca-2- ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z2 (3.11 mg, 0.003 mmol, 39.9% yield), white solid, ES-API: [M+H] + = 1182.3.

[0454] Example 3: Synthesis of compound Z3

[0455] Step one: Compound 51-11 (100 mg, 0.117 mmol) and 1-(prop-2-yn-1-yl)piperidine-4- carbonitrile (60.60 mg, 0.409 mmol) were dissolved in 2 mL of acetonitrile, and then palladium dichloride bis-triphenylphosphine (32.76 mg, 0.047 mmol), cuprous iodide (13.46 mg, 0.070 mmol), N,N-diisopropylethylamine (0.083 mL, 0.467 mmol) and lithium chloride (19.63 mg, 0.467 mmol) were added under constant stirring. The reaction was stirred at 85 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction was concentrated, diluted with 30 mL of ethyl acetate and 20 mL of saturated ammonium chloride solution, the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 10%-100%) to obtain compound 3-1 (95 mg, 0.111 mmol, 95.21% yield). ES-API: [M+H] + = 854.3.

[0456] Step two: Compound 3-1 (95 mg, 0.111 mmol) was dissolved in 3 mL of dichloromethane, and then 1 mL of trifluoroacetic acid was slowly added dropwise under ice bath, and then stirred at room temperature for half an hour. After the reaction was completed, it was rotary evaporated to obtain the crude compound 3-2 (79 mg, 0.105 mmol, 99.43% yield), which was directly used in the next step. ES-API: [M+H] + = 754.3.

[0457] Step three: Compound 3-2 (79 mg, 0.105 mmol) was dissolved in 1 mL of dichloromethane, 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (58.24 mg, 0.210 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (79.85 mg, 0.210 mmol) and N,N'-diisopropylethylamine (0.055 mL, 0.315 mmol) were added, the reaction was stirred at room temperature for half an hour. After the reaction was completed, 4 mL of water was added to the mixture and extracted with ethyl acetate (8 mL*2), the organic phase was washed with saturated brine (5 mL*3), dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 10%-100%) to obtain compound 3-3 (97 mg, 0.096 mmol, 91.36% yield). ES-API: [M+H] = 1013.3. +

[0458] Step four: Compound 3-3 (20 mg, 0.020 mmol) was dissolved in 1 mL of dichloromethane, 0.5 mL of trifluoromethane was slowly added dropwise under ice bath, and stirred at room temperature for half an hour. After the reaction was completed, it was rotary evaporated to obtain compound 3-4 (18 mg, 0.020 mmol, 99.87% yield), which was directly used in the next step reaction. ES-API: [M+H] = 913.3. +

[0459] Step five: Compound 3-4 (18 mg, 0.020 mmol) was dissolved in 1 mL of dichloromethane, compound 1-2 (11.37 mg, 0.039 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (15.21 mg, 0.040 mmol) and N,N'-diisopropylethylamine (7.76 mg, 0.060 mmol) were added, the reaction was stirred at room temperature for half an hour. After the reaction was completed, 4 mL of water was added to the residue and extracted with ethyl acetate (8 mL*2), the organic phase was washed with saturated brine (5 mL*3), dried and concentrated, and the crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8​​2 ,8 3 ,8 4 ,8 5 ,8 6 - Hexahydro-1 1 H-10-oxa-4(4,2)-thiazole-8(1,3)-pyridazine-1(3,4)-pyrazole cyclo-trideca-2- ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z3 (10.97 mg, 0.009 mmol, 47.02% yield). ES-API: [M+H] = 1183.8. +

[0460] Example 4: Synthesis of compound Z4

[0461] Step one: Methyl 3,4,5-trihydroxybenzoate (500 mg, 2.715 mmol) was dissolved in 5 mL of N,N-dimethylformamide, potassium carbonate (750.48 mg, 5.430 mmol) and 1,2-dibromoethane (0.353 mL, 4.073 mmol) were added, and stirred at 90 °C for 18 hours. After the reaction was completed, 1M dilute hydrochloric acid was used to adjust pH = 6-7, then 20 mL of ethyl acetate and 5 mL of water were added, washed with 5 mL of saturated brine three times, and the organic phase was dried with sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 10%-30%) to obtain compound 4-1 (399 mg, 1.898 mmol, 69.91% yield). ES-API: [M+H] = 211.1. +

[0462] Step two: Compound 4-1 (399 mg, 1.898 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and potassium carbonate (1.05 g, 7.593 mmol) and benzyl bromide (0.5 mL, 3.797 mmol) were added in turn, and stirred at room temperature for 18 hours. After the reaction was completed, 30 mL of ethyl acetate and 10 mL of water were added to dilute the reaction solution, and the organic layer was separated and washed with 10 mL of saturated brine twice, concentrated under vacuum, and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 5%-25%) to obtain compound 4-2 (459 mg, 1.528 mmol, 80.52% yield). ES-API: [M+H] = 301.1. +

[0463] ​​​Step three: Dissolve 4-2 (459 mg, 1.528 mmol) in 10 mL of methanol and 2 mL of water, add lithium hydroxide monohydrate (320.66 mg, 7.642 mmol) under ice bath, stir the reaction at 50 °C for 18 hours, after the reaction is completed, spin dry the methanol under vacuum, adjust the pH of the reaction to 6-7 with 1M dilute hydrochloric acid, filter to obtain compound 4-3 (411 mg, 1.436 mmol, 93.93% yield). ES-API: [M+H] = 287.1. +

[0464] Step four: Dissolve compound 1-5 (18 mg, 0.019 mmol) in 1 mL of dichloromethane, add compound 4-3 (10.99 mg, 0.038 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14.59 mg, 0.038 mmol) and N,N'-diisopropylethylamine (7.44 mg, 0.058 mmol), stir the reaction at room temperature for half an hour. After the reaction is completed, concentrate, add water (4 mL) to the residue and extract with ethyl acetate (8 mL*2), wash the organic phase with saturated brine (5 mL*3), dry and concentrate, and purify with preparative HPLC (formic acid method 1) to obtain 2-(8-(benzyloxy)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(1,1-dioxidothiomorpholine)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazole-8(1,3)-pyridazine-1(3,4)-pyrazolecyclo-trideca-2- ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z4 (11.5 mg, 0.010 mmol, 49.68% yield). ES-API: [M+H] = 1206.2. +

[0465] Example 5: Synthesis of compound Z5

[0466] ​​Step one: To a flask containing methyl 3-hydroxy-4,5-dimethoxybenzoate (200 mg, 0.943 mmol) was added N,N-dimethylformamide (5 mL), followed by 1-(bromomethyl)-3-methylbenzene (348.84 mg, 1.885 mmol) and potassium carbonate (521.02 mg, 3.770 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 5-a (290 mg, 0.917 mmol, 97.26% yield). ES-API: [M+H] = 317.2. +

[0467] Step two: To a flask containing compound 5-a (290 mg, 0.917 mmol) was added methanol (5 mL) and water (1 mL), followed by lithium hydroxide (192.32 mg, 4.584 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a suspension of 2M hydrochloric acid added until pH = 3. The organic phase was separated, and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound 5-b (260 mg, 0.860 mmol, 93.81% yield). ES-API: [M+H] = 303.1. +

[0468] Step three: Compound 1-5 (20 mg, 0.021 mmol) was dissolved in dichloromethane (5 mL), followed by compound 5-b (9.52 mg, 0.032 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (11.98 mg, 0.032 mmol) and N,N'- diisopropylethylamine (8.27 mg, 0.064 mmol), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), and the organic phase was washed with saturated brine (5 mL*3) and dried and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to give 2-(3,4-dimethoxy-5-((3-methylbenzyl)oxy)benzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(1,1-dioxidothiomorpholino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 ​​-Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolyl-8(1,3)-pyridazine-1(3,4)-pyrazolium tridecane-2-en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z5 (7 mg, 0.006 mmol, yield 27.27%). ES-API: [M+H] + =1222.5. 1 HNMR (400MHz, DMSO-d6) δ = 8.73 (d, J = 4.0Hz, 1H), 8.69 (d, J = 8.0Hz, 1H), 7.74 (d, J = 4 .0Hz,1H),7.37(s,1H),7.33(s,1H),7.29(s,1H),7.28-7.15(m,6H),7.07-7.00(m, 1H),6.77(s,1H),6.70(s,1H),5.61-5.52(m,1H),5.11-5.06(m,3H),4.71-4.51(m, 2H),4.26-4.12(m,2H),4.06-4.02(m,1H),3.98-3.91(m,2H),3.75(s,3H),3.69(d,J =4.0Hz,6H),3.55-3.45(m,3H),3.25-3.20(m,1H)3.18(s,3H),3.16-3.07(m,4H),3 .01-2.96(m,4H),2.91(m,2H),2.81-2.73(m,1H),2.60-2.57(m,1H),2.23(s,3H),2. 10(d,J=12.0Hz,1H),1.97(d,J=8.0Hz,1H),1.75-1.60(m,2H),1.50-1.43(dm,1H), 1.29(d,J=4.0Hz,3H),1.17(s,1H),1.09(t,J=8.0Hz,3H),0.77(s,3H),0.24(s,3H).

[0469] Example 6: Synthesis of compound Z6

[0470] Step one: To a flask containing methyl 3-hydroxy-4,5-dimethoxybenzoate (300 mg, 1.414 mmol) was added N,N-dimethylformamide (5 mL), followed by 1-(bromomethyl)-3-fluorobenzene (534.58 mg, 2.828 mmol) and potassium carbonate (781.53 mg, 5.655 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 6-1 (450 mg, 1.405 mmol, 99.35% yield). ES-API: [M+H] = 321.2. +

[0471] Step two: To a flask containing compound 6-1 (450 mg, 1.405 mmol) was added methanol (5 mL) and water (1 mL), followed by lithium hydroxide (294.74 mg, 7.024 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a suspension of 2M hydrochloric acid added until pH = 3. The organic phase was separated and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 6-2 (430 mg, 1.404 mmol, 99.93% yield). ES-API: [M+H] = 307.1. +

[0472] Step three: Compound 1-5 (20 mg, 0.021 mmol) was dissolved in dichloromethane (5 mL), followed by compound 6-2 (9.65 mg, 0.032 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (11.98 mg, 0.032 mmol) and N,N'- diisopropylethylamine (8.27 mg, 0.064 mmol), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), and the organic phase was washed with saturated brine (5 mL*3) and dried and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to give N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(1,1-dioxidothiomorpholino)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8​​1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - Hexahydro-1 1 H-10-oxa-4(4,2)-thiazole-8(1,3)-pyridazine-1(3,4)-pyrazole cyclo-trideca-2- ene-6-yl)-2-(3-((3-fluorobenzyl)oxy)-4,5-dimethoxybenzoyl)-1,2,3,4- tetrahydroisoquinoline-5-carboxamide Z6 (8 mg, 0.007 mmol, 31.06% yield). ES-API: [M+H] = 1226.9. + = 1226.9. 1 H NMR (400 MHz, DMSO-d6) d = 8.73 (d, J = 4.0 Hz, 1H), 8.69 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.45 - 7.37 (m, 3H), 7.33 (s, 1H), 7.29 - 7.15 (m, 5H), 7.20 - 7.15 (m, 1H), 6.76 (s, 1H), 6.69 (s, 1H), 5.60 - 5.50 (m, 1H), 5.10 - 5.05 (m, 3H), 4.72 - 4.50 (m, 2H), 4.25 - 4.10 (m, 2H), 4.05 - 4.00 (m, 1H), 3.96 - 3.90 (m, 2H), 3.74 (s, 3H), 3.68 (d, J = 4.0 Hz, 6H), 3.55 - 3.45 (m, 3H), 3.25 - 3.20 (m, 1H), 3.18 (s, 3H), 3.15 - 3.08 (m, 4H), 3.00 - 2.95 (m, 4H), 2.90 - 2.85 (m, 2H), 2.80 - 2.72 (m, 1H), 2.59 - 2.55 (m, 1H), 2.10 (d, J = 12.0 Hz, 1H), 1.98 (d, J = 8.0 Hz, 1H), 1.76 - 1.61 (m, 2H), 1.51 - 1.43 (m, 1H), 1.30 (d, J = 4.0 Hz, 3H), 1.17 (s, 1H), 1.10 (t, J = 8.0 Hz, 3H), 0.78 (s, 3H), 0.25 (s, 3H).

[0473] Example 7: Synthesis of compound Z7

[0474] Step one: Dissolve 4-(methoxycarbonyl)isoindoline hydrochloride (88.93 mg, 0.416 mmol) in 2 mL of dichloromethane, add compound 1-2 (100 mg, 0.347 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (263.78 mg, 0.694 mmol) and N,N'-diisopropylethylamine (0.5 mL, 2.870 mmol), stir the reaction at room temperature for half an hour. After the reaction is completed, add water (4 mL) to the residue and extract with ethyl acetate (8 mL*2), wash the organic phase with saturated brine (5 mL*3), dry and concentrate, and purify by preparative HPLC (formic acid method 1) to obtain compound 7-1 (135 mg, 0.302 mmol, yield 86.97%). ES-API: [M+H] = 448.2. +

[0475] Step two: Dissolve compound 7-1 (135 mg, 0.302 mmol) in 6 mL of methanol and 2 mL of water, add lithium hydroxide monohydrate (63.29 mg, 1.508 mmol) under ice bath, stir the reaction at 50°C for 3 hours, after the reaction is completed, dry the methanol under vacuum, adjust the pH of the reaction to 6-7 with 1M dilute hydrochloric acid, and filter to obtain compound 7-2 (85 mg, 0.196 mmol, yield 64.94%). ES-API: [M+H] = 434.2. +

[0476] Step three: Dissolve compound 49-6 (24 mg, 0.032 mmol) in 1 mL of dichloromethane, add compound 7-2 (27.63 mg, 0.064 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.24 mg, 0.064 mmol) and N,N'-diisopropylethylamine (12.36 mg, 0.096 mmol), stir the reaction at room temperature for half an hour. After the reaction is completed, add water (4 mL) to the residue and extract with ethyl acetate (8 mL*2), wash the organic phase with saturated brine (5 mL*3), dry and concentrate, and purify the crude product by preparative HPLC (ammonium bicarbonate method) to obtain 2-(3-benzyloxy-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8​​2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolyl-8(1,3)-pyridazine-1(3,4)-pyrrolocyclotridecane-2-en-6-yl)isoindoline-4-carboxamide Z7 (7.85 mg, 0.007 mmol, yield 21.08%). ES-API: [M+H + =1168.3.

[0477] Example 8: Synthesis of compound Z8

[0478] Step 1: Compound 3-4 (10 mg, 0.011 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of compound 5-b (4.97 mg, 0.016 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (6.25 mg, 0.016 mmol), and N,N′-diisopropylethylamine (4.25 mg, 0.033 mmol). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the residue was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (5 mL * 3), dried, and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolyl-8(1,3)-pyridazine-1(3,4)-pyrazolium tridecane-2-en-6-yl)-2-(3,4-dimethoxy-5-((3-methylbenzyl)oxy)benzoyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z8 (2 mg, 0.002 mmol, yield 15.25%). ES-API: [M+H + =1197.5.

[0479] Example 9: Synthesis of compound Z9

[0480] Step 1: Compound 3-4 (10 mg, 0.011 mmol) was dissolved in dichloromethane (5 mL), then compound 6-2 (7.46 mg, 0.025 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (6.25 mg, 0.016 mmol), and N,N′-diisopropylethylamine (4.25 mg, 0.033 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the residue was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (5 mL * 3), dried, and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain N-((4) 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolyl-8(1,3)-pyridazine-1(3,4)-pyrazolium tridecane-2-en-6-yl)-2-(3-((3-fluorobenzyl)oxy)-4,5-dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z9 (2 mg, 0.002 mmol, yield 15.20%). ES-API: [M+H + =1201.5.

[0481] Example 10: Synthesis of compound Z10

[0482] Step 1: N,N-dimethylformamide (5 mL) was added to a flask containing methyl 3-hydroxy-4,5-dimethoxybenzoate (200 mg, 0.943 mmol), followed by 1-(bromomethyl)-4-fluorobenzene (356.32 mg, 1.885 mmol) and potassium carbonate (521.02 mg, 3.770 mmol). The mixture was stirred overnight at room temperature. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (ethyl acetate / petroleum ether: 0-20%) to give compound 10-1 (300 mg, 0.937 mmol, 99.37% yield). ES-API: [M+H] + =321.2.

[0483] Step 2: Add methanol (5 mL) and water (1 mL) to a flask containing compound 10⁻¹ (300 mg, 0.937 mmol), then add lithium hydroxide (196.49 mg, 4.683 mmol), and stir the mixture at room temperature for 3 hours. Add 2 M hydrochloric acid to the reaction mixture until pH = 3. Extract the aqueous layer three times with ethyl acetate. Wash the combined organic extracts with water and brine, dry with anhydrous sodium sulfate, filter and concentrate to give crude compound 10⁻² (280 mg, 0.914 mmol, yield 97.61%). ES-API: [M+H] + =307.1.

[0484] Step 3: Compound 2-2 (18 mg, 0.020 mmol) was dissolved in dichloromethane (5 mL), then compound 10-2 (7.85 mg, 0.026 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (9.74 mg, 0.026 mmol), and N,N′-diisopropylethylamine (7.64 mg, 0.059 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the residue was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (5 mL * 3), dried, and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 82 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolyl-8(1,3)-pyridazine-1(3,4)-pyrrolocyclotridecane-2-en-6-yl)-2-(3-((4-fluorobenzyl)oxy)-4,5-dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z10 (5 mg, 0.004 mmol, yield 21.13%). ES-API: [M+H + =1200.3. 1 H NMR (400MHz, DMSO-d6) δ = 8.75-8.73 (m, 2H), 7.70 (d, J = 4.0Hz, 1H), 7.52-7.48 (m, 2H) ,7.46(s,1H),7.39(s,1H),7.35-7.31(m,2H),7.29-7.21(m,2H),7.19-7.10(m,1H), 6.90-6.80(m,2H),6.78(s,1H),5.61-5.52(m,1H),5.12-5.07(m,3H),4.734.51(m,2 H),4.26-4.13(m,2H),4.08-4.01(m,1H),3.98-3.92(m,2H),3.76(s,3H),3.69(d,J=4 .0Hz,6H),3.55-3.45(m,3H),3.25-3.20(m,1H)3.19(s,3H),3.15-3.09(m,4H),3.03 -2.97(m,4H),2.91-2.85(m,2H),2.80-2.72(m,1H),2.61-2.57(m,1H),2.55-2.47(m ,2H),2.12(d,J=12.0,1H),1.99(d,J=8.0,1H),1.79-1.62(m,2H),1.55-1.44(m,1H) ,1.32(d,J=4.0Hz,3H),1.19(s,1H),1.13(t,J=8.0Hz,3H),0.79(s,3H),0.24(s,3H).

[0485] Example 11: Synthesis of compound Z11

[0486] Step one: To a flask containing methyl 3-hydroxy-4,5-dimethoxybenzoate (100 mg, 0.471 mmol) was added N,N-dimethylformamide (5 mL), followed by (1-bromoethyl)benzene (174.42 mg, 0.943 mmol) and potassium carbonate (260.51 mg, 1.885 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 11-1 (120 mg, 0.379 mmol, 80.49% yield). ES-API: [M+H] = 317.2. +

[0487] Step two: To a flask containing compound 11-1 (120 mg, 0.379 mmol) was added methanol (5 mL) and water (1 mL), followed by lithium hydroxide (79.58 mg, 1.897 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 2M HCl until pH = 3. The aqueous layer was extracted with ethyl acetate three times. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound 11-2 (99 mg, 0.327 mmol, 86.33% yield). ES-API: [M+H] = 303.1. +

[0488] Step three: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (5 mL), followed by compound 11-2 (6.46 mg, 0.021 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (8.12 mg, 0.021 mmol) and N,N'- diisopropylethylamine (6.37 mg, 0.049 mmol), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the residue was concentrated, water (5 mL) was added and extracted with dichloromethane (10 mL*2), and the organic phase was washed with saturated brine (5 mL*3), dried and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to give N-((4 2 Z, 8 3 S, 2E, 6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8​​2 ,8 3 ,8 4 ,8 5 ,8 6 - Hexahydro-1 1 H-10-oxa-4(4,2)-thiazole-8(1,3)-pyridazine-1(3,4)-pyrrole cyclotrideca-2- ene-6-yl)-2-(3,4-dimethoxy-5-(1-phenylethoxy)benzoyl)-1,2,3,4- tetrahydroisoquinoline-5-carboxamide Z11 (3 mg, 0.003 mmol, 15.67% yield). ES-API: [M+H] = 1196.5. + = 1196.5.

[0489] Example 12: Synthesis of compound Z12

[0490] Step one: 3-ethoxy-4-hydroxybenzoic acid (950 mg, 5.215 mmol) was dissolved in tetrahydrofuran (15 mL), N-bromosuccinimide (1299.41 mg, 7.300 mmol) was added slowly at 0 degree, stirred at room temperature for 1 h. After the reaction was completed, 30 mL of ethyl acetate was poured, washed with 15 mL of water and 15 mL of saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 12-1. ES-API [M+H] + = 260.9.

[0491] Step two: the crude compound 12-1, iodomethane (3692.00 mg, 26.000 mmol) and potassium carbonate (3588.00 mg, 26.000 mmol) were mixed in N,N- dimethylformamide (10 mL), stirred at 20 degrees for 4 h. After the reaction was completed, 30 mL of ethyl acetate was poured, washed with 15 mL of water and 15 mL of saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by flash silica gel column (0-20% petroleum ether / ethyl acetate) to give compound 12-2 (750 mg, 2.594 mmol, two-step yield: 49.7%), ES-API [M+H] + = 289.0.

[0492] Step three: Compound 12-2 (750 mg, 2.594 mmol), bis(pinacolato)diboron (1646.80 mg, 6.485 mmol), potassium acetate (508.42 mg, 5.188 mmol) and palladium tetrakis(triphenylphosphine) (189.36 mg, 0.259 mmol) were mixed in toluene (10 mL) and stirred at 100 °C for 18 h. After reaction, the mixture was poured into 30 mL of ethyl acetate, washed with 15 mL of water and 15 mL of saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20%) to give the crude compound 12-3, which was used directly in the next step.

[0493] Step four: The crude compound 12-3 was mixed with 30% hydrogen peroxide solution (5 mL) in dioxane (5 mL) and stirred at 20 °C for 3 h. After reaction, the mixture was poured into 30 mL of ethyl acetate, washed with 15 mL of water, 15 mL of sodium thiosulfate solution and 15 mL of saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 12-4, which was used directly in the next step.

[0494] Step five: The crude compound 12-4, benzyl bromide (1778.82 mg, 10.400 mmol) and cesium carbonate (114.04 mg, 0.350 mmol) were mixed in N,N-dimethylformamide (3 mL) and stirred at 20 °C for 1 h. After reaction, the mixture was poured into 30 mL of ethyl acetate, washed with 15 mL of water and 15 mL of saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 15%) to give compound 12-5 (0.3 g, 0.948 mmol, 36.5% yield over three steps), ES-API [M+H] + = 317.2.

[0495] Step six: Compound 12-5 (30 mg, 0.095 mmol), water (1 mL) and lithium hydroxide (7.97 mg, 0.190 mmol) were mixed in tetrahydrofuran (4 mL) and stirred at 20 °C for 18 h. After reaction, the mixture was poured into 30 mL of ethyl acetate, washed with 15 mL of water and 15 mL of saturated brine successively after adjusting pH to acidic. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 12-6.

[0496] Step 7: Under nitrogen protection, compound 2-2 (12 mg, 0.013 mmol), crude compound 12-6, 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (5.00 mg, 0.013 mmol), and N,N-diisopropylethylamine (1.70 mg, 0.013 mmol) were mixed in dichloromethane (5 mL) and stirred at 20°C for 1 h. The mixture was concentrated and purified by preparative HPLC (ammonium bicarbonate method) to obtain 2-(3-(benzyloxy)-5-ethoxy-4-methoxybenzoyl)-N-((4-) 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolyl-8(1,3)-pyridazine-1(3,4)-pyrrolocyclotridecane-2-en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide Z12 (0.5 mg, yield 3.18%), ES-API [M+H] + =1196.5.

[0497] Example 13: Synthesis of compound Z25

[0498] Step 1: Methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (900 mg, 4.386 mmol) was dissolved in 5 mL of dichloromethane solution. Then, Boc-anhydride (2.015 mL, 8.772 mmol), 4-dimethylaminopyridine (53.58 mg, 0.439 mmol), and N,N-diisopropylethylamine (2.292 mL, 13.157 mmol) were added, and the mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was diluted with 10 mL of ethyl acetate and 5 mL of water. The organic layer was separated, washed twice with 10 mL of saturated sodium chloride solution, concentrated, and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 1%-5%) to obtain compound 25-1 (1.284 g, 4.205 mmol, yield 95.89%). ES-API: [M-56+H] + =250.1.

[0499] Step 2: Compound 25-1 (1.284 g, 4.205 mmol) was dissolved in 10 mL of cyclohexane. Pinaryl diborate (2.14 g, 8.411 mmol), methoxy(cyclooctadiene)iridium dimer (33.03 mg, 0.050 mmol), and 4,4′-di-tert-butyl-2,2′-dipyridine (0.18 g, 0.673 mmol) were added, and the mixture was stirred at 85 °C for 18 hours. After the reaction was complete, the reaction solution was diluted with 10 mL of ethyl acetate and 5 mL of water. The organic layer was separated, washed twice with 10 mL of saturated sodium chloride solution, concentrated, and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 0%-3%) to obtain compound 25-2 (1.343 g, 3.114 mmol, yield 74.05%). ES-API: [M-56+H] + =376.1.

[0500] Step 3: Compound 25-2 (1.3 g, 3.014 mmol) was dissolved in 1 mL of methanol and 0.2 mL of water. Copper(II) dibromide (2.02 g, 9.043 mmol) was added, and the mixture was stirred at 80 °C for 18 hours. After the reaction was complete, the reaction solution was diluted with 10 mL of ethyl acetate and 5 mL of water. The organic layer was separated, washed twice with 10 mL of saturated sodium chloride solution, concentrated, and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 20%-70%) to obtain compound 25-3 (760 mg, 2.675 mmol, yield 88.75%). ES-API: [M+H] + =284.0.

[0501] Step 4: Compound 25-3 (760 mg, 2.675 mmol) was dissolved in 10 mL of dioxane and 2 mL of water. Potassium carbonate (778.29 mg, 5.632 mmol), trimethylcycloborane (0.787 mL, 5.632 mmol), and 1,1′-bis(diphenylphosphine)ferrocene palladium(II) dichloride (206.04 mg, 0.282 mmol) were added. The mixture was stirred at 110 °C for 18 hours. After the reaction was complete, the reaction solution was diluted with 10 mL of ethyl acetate and 5 mL of water. The organic layer was separated, washed twice with 10 mL of saturated sodium chloride solution, concentrated, and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 20%-80%) to obtain compound 25-4 (356 mg, 1.624 mmol, yield 60.71%). ES-API: [M+H] + =220.1.

[0502] Step five: Compound 25-4 (336 mg, 1.533 mmol) was dissolved in 10 mL of tetrahydrofuran, borane tetrahydrofuran (16.858 mL, 252.870 mmol) was added, and the reaction was stirred at 70 °C for 18 hours. After the reaction was completed, 5 mL of 1 M hydrochloric acid solution was added to the reaction at 0 °C, stirred at 70 °C for 1 hour, concentrated and 10 mL of ethyl acetate was added, filtered and concentrated to obtain compound 25-5 (269 mg, 1.311 mmol, 85.51% yield). ES-API: [M+H] + = 206.2.

[0503] Step six: Compound 25-5 (269 mg, 1.311 mmol) was dissolved in 4 mL of dichloromethane, N,N-diisopropylethylamine (508.16 mg, 3.932 mmol) and Boc anhydride (0.602 mL, 2.621 mmol) were added, and the reaction was stirred at room temperature for 20 minutes. After the reaction was completed, the reaction was diluted with 10 mL of ethyl acetate and 5 mL of water, the organic layer was separated, washed twice with 10 mL of saturated sodium chloride solution, concentrated and purified by silica gel column chromatography (tetrahydrofuran: petroleum ether = 0%-15%) to obtain compound 25-6 (330 mg, 1.081 mmol, 82.46% yield). ES-API: [M-56+H] + = 250.1.

[0504] Step seven: Compound 25-6 (330 mg, 1.081 mmol) was dissolved in 4 mL of methanol and 1 mL of water, lithium hydroxide (226.72 mg, 5.403 mmol) was added, and the reaction was stirred at 50 °C for 18 hours. After the reaction was completed, the pH was adjusted to 6-7 with 1 M dilute hydrochloric acid in an ice bath, and concentrated to obtain compound 25-7 (194 mg, 0.666 mmol, 61.62% yield). ES-API: [M-55] + = 236.1.

[0505] Step eight: Compound 49-6 (17 mg, 0.023 mmol) was dissolved in 1 mL of dichloromethane, 2-(7-azobenzenetriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17.17 mg, 0.045 mmol), N,N-diisopropylethylamine (8.75 mg, 0.068 mmol) and compound 25-7 (13.16 mg, 0.045 mmol) were added, and the reaction was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction was diluted with 10 mL of ethyl acetate and 5 mL of water, the organic layer was separated, washed twice with 10 mL of saturated sodium chloride solution, concentrated and purified by silica gel column chromatography (methanol:dichloromethane = 2%-6%) to obtain compound 25-8 (23 mg, 0.022 mmol, 97.44% yield). ES-API: [M+H]+ = 1026.3.

[0506] Step nine: Compound 25-8 (23 mg, 0.022 mmol) was dissolved in 1 mL of dichloromethane, trifluoroacetic acid (0.5 mL, 0.022 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated to obtain compound 25-9 (20 mg, 0.022 mmol, yield 96.36%). ES-API: [M+H] + = 926.3.

[0507] Step ten: Compound 25-9 (20 mg, 0.022 mmol) was dissolved in 1 mL of dichloromethane, N,N-diisopropylethylamine (8.37 mg, 0.065 mmol), compound 1-2 (12.45 mg, 0.043 mmol), and 2-(7-azobenzo triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.42 mg, 0.043 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was diluted with 10 mL of ethyl acetate and 5 mL of water, the organic layer was separated, washed twice with 10 mL of saturated sodium chloride solution, and concentrated to obtain 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 5 -(R a )-(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolocyclotridec-2-en-6-yl)-7-methyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z25, 5.44 mg, 0.005 mmol, yield 20.67%). ES-API: [M+H] + = 1196.4.

[0508] Example 14: Synthesis of compound Z26

[0509] Step one: To a flask containing methyl 3-bromo-4-hydroxy-5-methoxybenzoate (1 g, 3.830 mmol) was added N,N-dimethylformamide (5 mL), followed by iodoethane (1.79 g, 11.491 mmol) and potassium carbonate (1.59 g, 11.491 mmol) and the mixture was stirred at room temperature for 3 h. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 26-1 (1.1 g, 3.805 mmol, 99.3% yield). ES-API: [M+H] = 289.2. +

[0510] Step two: To a flask containing compound 26-1 (800 mg, 2.767 mmol) was added 1,4-dioxane (5 mL), followed by bis(pinacolato)diboron (1405.26 mg, 5.534 mmol), potassium acetate (813.47 mg, 8.301 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (403.97 mg, 0.553 mmol), nitrogen was replaced for three times, stirred at 90 °C for 6 h. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to give compound 26-2 (805 mg, 2.394 mmol, 86.5% yield). ES-API: [M+H] = 255.3. +

[0511] Step three: To a flask containing compound 26-2 (1 g, 3.830 mmol) was added 1,4-dioxane (5 mL), followed by hydrogen peroxide (6 mL) and the mixture was stirred at room temperature for 3 h. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-60%) to give compound 26-3 (300 mg, 1.326 mmol, 55.7% yield). ES-API: [M+H] = 227.2. +

[0512] ​​​Step four: To the flask containing compound 26-3 (300 mg, 1.326 mmol) was added N,N-dimethylformamide (5 mL), then benzyl bromide (453.63 mg, 2.652 mmol) and potassium carbonate (549.79 mg, 3.978 mmol) were added and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 26-4 (200 mg, 0.632 mmol, 47.68% yield). ES-API: [M+H] = 317.2. +

[0513] Step five: To the flask containing compound 26-4 (200 mg, 0.632 mmol) was added methanol (5 mL) and water (1 mL), then lithium hydroxide (79.58 mg, 1.897 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 2M hydrochloric acid suspension until pH = 3. The organic phase was separated and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound 26-5 (180 mg, 0.595 mmol, 94.17% yield). ES-API: [M+H] = 302.1. +

[0514] Step six: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (5 mL), then compound 26-5 (6.46 mg, 0.021 mmol), 2-(7-azabenzotriazol-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.13 mg, 0.021 mmol) and N,N'-diisopropylethylamine (6.38 mg, 0.049 mmol) were added and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), the organic phase was washed with saturated brine (5 mL*3) and dried and concentrated, the crude product was purified by preparative HPLC (ammonium bicarbonate method) to give 2-(3-(benzyloxy)-4-ethoxy-5-methoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-(R a )-1 1 ​​- Ethyl-12,12-dimethyl-7,9-dioxy-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - Hexahydro-1 1 H-10-oxa-4(4,2)-thiazole-8(1,3)-pyridazine-1(3,4-)-pyrrolidine cyclo-trideca-2- ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z26, 7 mg, 0.006 mmol, 35.57% yield). ES-API: [M+H] + = 1196.4.

[0515] Example 15: Synthesis of compound Z27

[0516] Step one: Compound 49-6 (18 mg, 0.024 mmol) was dissolved in dichloromethane (5 mL), then 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxylic acid (8.26 mg, 0.031 mmol, CAS: 1363380-86-2), 2-(7-azabenzotriazolyl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (11.80 mg, 0.031 mmol) and N,N'-diisopropylethylamine (9.26 mg, 0.072 mmol) were added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), and the organic phase was washed with saturated brine (5 mL*3) and dried and concentrated, and the crude product was purified by silica gel column (methanol / dichloromethane: 0-20%) to obtain compound 27-1 (23 mg, 0.023 mmol, 96.23% yield). ES-API: [M+H] + = 1001.3.

[0517] Step two: Compound 27-1 (8 mg, 0.007 mmol) was added to a flask containing dichloromethane (1 mL), then trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour, and the reaction was concentrated to obtain compound 27-2 (23 mg, 0.026 mmol, 111.11% yield). ES-API: [M+H] + = 901.3.

[0518] Step 3: Compound 27-2 (23 mg, 0.026 mmol), compound 1-2 (9.57 mg, 0.033 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (12.62 mg, 0.033 mmol), and N,N′-diisopropylethylamine (9.90 mg, 0.077 mmol) were reacted at room temperature with stirring for 2 hours. After the reaction was complete, the residue was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (5 mL * 3), dried, and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-(R a )-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazo-8(1,3)-pyridazin-1(3,4)-pyrrolocyclotriacont-2-en-6-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-carboxamide (Z27, 8 mg, 0.007 mmol, yield 26.76%). ES-API: [M+H + =1171.4.

[0519] Example 16: Synthesis of compound Z28

[0520] Step one: To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5- carboxylic acid (211 mg, 0.76 mmol, CAS: 872001-50-8) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (0.33 mL, 1.9 mmol) and 2-(7-azabenzotriazol- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (290 mg, 0.76 mmol), after 5 min, compound 70-6 (480 mg, crude) was added, and the reaction was stirred at room temperature for 30 min. To the reaction was added ethyl acetate (20 mL). The mixture was washed with water (20 mL*2) and brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification using silica gel column chromatography (dichloromethane / methanol = 20 / 1) afforded compound 28-1 (520 mg, 0.513 mmol, 87.7% yield over two steps). ES-API: [M+H] = 1014.4. +

[0521] Step two: To a solution of compound 28-1 (520 mg, 0.513 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3 mL, 0.585 mmol). The mixture was stirred at room temperature for 1 h, and the reaction was complete. The mixture was concentrated to afford compound 28-2, trifluoroacetate salt (490 mg, crude). ES-API: [M+H] = 914.3. +

[0522] Step three: To a solution of compound 1-2 (211 mg, 0.76 mmol) in N,N-dimethylformamide (5 mL) was added diisopropylethylamine (0.643 mL, 3.687 mmol) and 2-(7-azabenzotriazol-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (210.31 mg, 0.553 mmol), after 5 min, compound 28-2 trifluoroacetate salt (490 mg, crude) was added, and the reaction was stirred at room temperature for 30 min. To the reaction was added ethyl acetate (20 mL). The mixture was washed with water (20 mL*2) and brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification using silica gel column chromatography (dichloromethane / methanol = 20 / 1) afforded compound 28-3 (460 mg, 0.388 mmol, 75.6% yield over two steps). ES-API: [M+H] = 1184.4. +

[0523] ​​​Step four: To a solution of compound 28-3 (100 mg, 0.084 mmol) in acetonitrile (5 mL) were added tert-butyldimethyl(2-propynoxy)silane (71.91 mg, 0.422 mmol), palladium dichloride (5.93 mg, 0.008 mmol), cuprous iodide (1.61 mg, 0.008 mmol), lithium chloride (17.90 mg, 0.422 mmol) and diisopropylethylamine (54.57 mg, 0.422 mmol) sequentially. The reaction was stirred at 85 °C for 1 h. To the reaction was added ethyl acetate (20 mL). The mixture was washed with water (20 mL*2) and brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography (dichloromethane / methanol = 20 / 1) afforded compound 28-4 (75 mg, 0.062 mmol, 73.7% yield). ES-API: [M+H] = 1204.6. +

[0524] Step five: To a solution of compound 28-4 (220 mg, 0.183 mmol) in tetrahydrofuran (2 mL) was added a solution of tetrabutylammonium fluoride (2 mL, 1.0 M in tetrahydrofuran) under ice water bath. The mixture was stirred at room temperature for 1 h. LCMS showed the reaction was completed. To the reaction was added 20 mL of ethyl acetate to dilute, then washed with saturated brine (15 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 28-5 (180 mg, crude). ES-API: [M+H] = 1090.5. +

[0525] Step six: To a solution of compound 28-5 (180 mg, crude) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (172.89 mg, 1.338 mmol) and methylsulfonic anhydride (116.50 mg, 0.669 mmol) sequentially under ice water bath. The reaction mixture was stirred at room temperature for 1 h. LCMS showed the reaction was completed. To the reaction was added 20 mL of dichloromethane to dilute, then washed with water (10 mL) and saturated brine (15 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by automatic flash chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 28-6 (190 mg, 0.163 mmol, 89% yield over two steps). ES-API: [M+H] = 1168.4 +

[0526] ​​​Step seven: To the solution of compound 28-6 (15 mg, 0.013 mmol) in acetonitrile (5 mL) was added morpholine (5.59 mg, 0.064 mmol), the reaction was stirred at 60 degree for 1 hour, LCMS showed the reaction was completed, concentrated, the crude product was purified by HPLC (Formic acid method 1) to give the final product 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 1 -ethyl-(Ra)-1 5 -(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolocyclotridec-2-en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z28, 8.21 mg, yield 54.4%). ES-API: [M+H] + = 1159.5.

[0527] Example 17: Synthesis of compound Z29

[0528] Step one: 3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester (240 mg, 1.199 mmol) was dissolved in 5 mL of N,N-dimethylformamide, potassium carbonate (497.10 mg, 3.597 mmol) and benzyl bromide (0.285 mL, 2.398 mmol) were added successively, the reaction was stirred at room temperature for 3 hours. After the reaction was completed, 10 mL of ethyl acetate and 5 mL of water were added to dilute the reaction, the organic layer was separated, washed with 10 mL of saturated brine twice, concentrated under vacuum, and purified using a silica gel column (tetrahydrofuran: petroleum ether = 1% to 15% elution) to give compound 29-1 (291 mg, 1.002 mmol, yield 83.61%). ES-API: [M+H] + = 291.1.

[0529] Step two: Compound 29-1 (291 mg, 1.002 mmol) was dissolved in 4 mL of methanol and 1 mL of water, and lithium hydroxide monohydrate (210.31 mg, 5.012 mmol) was added under ice bath. The reaction was stirred at 50 °C for 3 hours. After the reaction was completed, the methanol was removed by vacuum evaporation, and the pH of the reaction was adjusted to 6-7 with 1M dilute hydrochloric acid. Filtration gave compound 29-2 (256 mg, 0.927 mmol, 92.44% yield). ES-API: [M+H] + = 277.1.

[0530] Step three: Compound 2-2 (20 mg, 0.022 mmol) was dissolved in 1 mL of dichloromethane, and compound 29-2 (12.11 mg, 0.044 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol), and N,N'-diisopropylethylamine (8.50 mg, 0.066 mmol) were added. The reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the residue was concentrated, water (4 mL) was added, and extraction was performed with ethyl acetate (8 mL*2). The organic phase was washed with saturated brine (5 mL*3), dried, and concentrated. Purification by preparative HPLC (ammonium bicarbonate method) gave 2-(3-(benzyloxy)-5-fluoro-4-methoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 5 -(R a )-(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolocyclotrideca-2-ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z29, 4.92 mg, 0.004 mmol, 19.17% yield). ES-API: [M+H] + = 1170.3.

[0531] Example 18: Synthesis of compound Z30

[0532] Step one: Methyl 3-(benzyloxy)-4,5-dihydroxybenzoate (236 mg, 0.860 mmol) was dissolved in 5 mL of N,N-dimethylformamide, potassium carbonate (475.67 mg, 3.442 mmol) and 1,3-dibromo-propane (0.105 mL, 1.033 mmol) were added, stirred at 100 °C for 24 hours. After the reaction was completed, 20 mL of ethyl acetate was added, washed twice with 5 mL of water, and once with 5 mL of saturated brine, the organic phase was dried over sodium sulfate, filtered and concentrated, and purified by silica gel column (tetrahydrofuran: petroleum ether = 10%-32%) to obtain compound 30-1 (200 mg, 0.636 mmol, 73.94% yield). ES-API: [M+H] = 315.1. +

[0533] Step two: Compound 30-1 (200 mg, 0.636 mmol) was dissolved in 4 mL of methanol and 1 mL of water, lithium hydroxide monohydrate (133.49 mg, 3.181 mmol) was added under ice bath, stirred at 45 °C for 3 hours. After the reaction was completed, the methanol was rotary evaporated under vacuum, the pH of the reaction was adjusted to 6-7 with 1M dilute hydrochloric acid, filtered to obtain compound 30-2 (124 mg, 0.413 mmol, 64.90% yield). ES-API: [M+H] = 301.1. +

[0534] Step three: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in 1 mL of dichloromethane, compound 30-2 (12.11 mg, 0.044 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (12.51 mg, 0.033 mmol) and N,N'-diisopropylethylamine (6.38 mg, 0.049 mmol) were added, stirred at room temperature for half an hour. After the reaction was completed, the residue was concentrated, water (4 mL) was added and extracted with ethyl acetate (8 mL*2), the organic phase was washed with saturated brine (5 mL*3), dried and concentrated, and purified by preparative HPLC (ammonium bicarbonate method) to obtain 2-(9-(benzyloxy)-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carbonyl)-N-((4 2 Z,8 3 S,2E,6S)-1 5 -(R a )-(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ​​,8 4 ,8 5 ,8 6 - Hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolo-cyclotridecin-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z30, 6.55 mg, 0.005 mmol, 33.35% yield). ES-API: [M+H] + = 1194.3.

[0535] Example 19: Synthesis of compound Z31

[0536] Step one: 3-chloro-5-hydroxy-4-methoxybenzaldehyde (230 mg, 1.233 mmol) was dissolved in 5 mL of N,N-dimethylformamide, potassium carbonate (511.06 mg, 3.698 mmol) and benzyl bromide (0.293 mL, 2.465 mmol) were added successively, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, 10 mL of ethyl acetate and 5 mL of water were added to dilute the reaction, the organic layer was separated and washed with 10 mL of saturated brine twice, concentrated under vacuum, and purified using a silica gel column (tetrahydrofuran: petroleum ether = 10%-30% elution) to obtain compound 31-1 (80 mg, 0.289 mmol, 23.45% yield). ES-API: [M+H] + = 277.2.

[0537] Step two: Compound 31-1 (80 mg, 0.289 mmol) was dissolved in 2 mL of dioxane and 1 mL of water, and aminosulfonic acid (178.28 mg, 0.636 mmol) and sodium chlorite (57.52 mg, 0.636 mmol) were added successively under ice bath, and the reaction was stirred at 0°C for 0.5 hours. After the reaction was completed, sodium bisulfite was quenched under ice bath, extracted with 10 mL of ethyl acetate, and the organic phase was washed with 5 mL of saturated brine twice, dried, filtered and concentrated to obtain compound 31-2 (70 mg, 0.239 mmol, 82.72% yield). ES-API: [M+H] + = 293.1.

[0538] Step three: compound 2-2 (15 mg, 0.016 mmol) was dissolved in 1 mL of dichloromethane, compound 31-2 (9.37 mg, 0.032 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.51 mg, 0.033 mmol) and N,N'-diisopropylethylamine (6.38 mg, 0.049 mmol) were added, the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the residue was added to water (4 mL) and extracted with ethyl acetate (8 mL*2), the organic phase was washed with saturated brine (5 mL*3), dried and concentrated, and purified by preparative HPLC (formic acid method 1) to obtain 2-(3-(benzyloxy)-5-chloro-4-methoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 5 -(R a )-(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolocyclotrideca-2-ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z31, 8.56 mg, 0.007 mmol, yield 45.08%). ES-API: [M+H] = 1187.1. +

[0539] Example 20: Synthesis of compound Z32

[0540] ​Step one: In a round-bottom flask, methyl 3-hydroxy-4,5-dimethoxybenzoate (500 mg, 2.356 mmol), phenethyl alcohol (575.73 mg, 4.713 mmol) and triphenylphosphine (1236.05 mg, 4.713 mmol) were dissolved in 5 mL of tetrahydrofuran, cooled to 0-5 °C, and diethyl azodicarboxylate (0.742 mL, 4.713 mmol) was added dropwise under ice bath, stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with 5 mL of water and extracted with ethyl acetate (10 mL*3), the organic layer was washed with 5 mL of saturated brine, dried, filtered and concentrated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-20% elution) to give compound 32-1 (712 mg, 2.251 mmol, 95.53% yield). ES-API: [M+H] = 317.2. +

[0541] Step two: Compound 32-1 (712 mg, 2.251 mmol) was dissolved in 10 mL of methanol and 3 mL of water, and lithium hydroxide monohydrate (472.19 mg, 11.253 mmol) was added under ice bath, and stirred at 90 °C for 18 hours. After the reaction was completed, the methanol was rotary evaporated under vacuum, and the pH of the reaction was adjusted to 6-7 with 1M dilute hydrochloric acid, and filtered to give compound 32-2 (652 mg, 2.157 mmol, 95.82% yield). ES-API: [M+H] = 303.1. +

[0542] Step three: Compound 2-2 (20 mg, 0.022 mmol) was dissolved in 1 mL of dichloromethane, and compound 32-2 (13.26 mg, 0.044 mmol), 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (16.67 mg, 0.044 mmol) and N,N'-diisopropylethylamine (8.50 mg, 0.066 mmol) were added, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the residue was added with water (4 mL) and extracted with ethyl acetate (8 mL*2), and the organic phase was washed with saturated brine (5 mL*3), dried and concentrated, and purified by preparative HPLC (ammonium bicarbonate method) to give N-((4 2 Z,8 3 S,2E,6S)-1 5 -(R a )-(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8​​3 ,8 4 ,8 5 ,8 6 - hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)- pyridazino-1(3,4)-pyrrololotricyclo- dec-2-ene-6-yl)-2-(3,4-dimethoxy-5- phenethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline- 5-carboxamide (Z32, 4.77 mg, 0.004 mmol, 18.19% yield). ES-API: [M+H] = 1196.4. +

[0543] Example 21: Synthesis of compound Z33

[0544] Step one: To a solution of compound 28-6 (15 mg, 0.013 mmol) in acetonitrile (5 mL) was added N-methylpiperazine (6.43 mg, 0.064 mmol), the reaction was stirred at 60 degree for 1 hour, LCMS showed the reaction was complete, concentrated, the crude was purified by prep-HPLC (Formic acid method 1) to give 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 1 -ethyl-(Ra)-1 5 -(2-((S)-1-methoxyethyl)-5-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)- pyridazino-1(3,4)-pyrrololotricyclo- dec-2-ene-6-yl)-1,2,3,4-tetrahydroisoquinoline- 5-carboxamide (Z33, 8.23 mg, 54.68% yield). ES-API: [M+H] = 1172.6. +

[0545] Example 22: Synthesis of compound Z34

[0546] ​​Step one: To a solution of compound 28-6 (20 mg, 0.017 mmol) in acetonitrile (2 mL) was added aziridine (4.89 mg, 0.086 mmol), the reaction was stirred at 60 degree for 1 hour, LCMS showed the reaction was complete, concentrated, the crude was purified by prep-HPLC (Formic acid method 1) to give 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 1 -ethyl-(R a )-1 5 -(2-((S)-1-methoxyethyl)-5-(3-(azetidin-1-yl)prop-1-yn-1-yl)-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolocyclotridec-2-en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z34, 5.75 mg, yield 28.7%). ES-API: [M+H] + = 1129.6.

[0547] Example 23: Synthesis of compound Z35

[0548] Step one: To a flask containing 5-(tert-butoxycarbonyl)-1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazole-3-carboxylic acid (650 mg, 2.567 mmol) was added N,N-dimethylformamide (5 mL), followed by iodomethane (1.79 g, 11.491 mmol) and potassium carbonate (1064.08 mg, 7.700 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL), extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 35-1 (350 mg, 1.244 mmol, yield 48.5%). ES-API: [M+1] + = 282.1.

[0549] Step two: To a flask containing compound 35-1 (350 mg, 1.244 mmol) was added methanol (3 mL), tetrahydrofuran (3 mL) and water (1 mL), then lithium hydroxide (67.12 mg, 1.600 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a suspension of 2M hydrochloric acid added until pH = 3. The organic phase was separated, the aqueous layer was extracted with another portion of ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give compound 35-2 (120 mg, 0.449 mmol, 84.20% yield). ES-API: [M+1] = 268.1. +

[0550] Step three: Compound 49-6 (30 mg, 0.040 mmol) was dissolved in dichloromethane (5 mL), then compound 35-2 (13.90 mg, 0.052 mmol), 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19.69 mg, 0.052 mmol) and N,N'-diisopropylethylamine (15.45 mg, 0.120 mmol) were added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), the organic phase was washed with saturated brine (5 mL*3) and dried and concentrated, the crude product was purified by silica gel column (methanol / dichloromethane: 0-20%) to give compound 35-3 (35 mg, 0.035 mmol, 87.30% yield). ES-API: [M+1] = 1002.3. +

[0551] Step four: To a flask containing compound 35-3 (35 mg, 0.035 mmol) was added dichloromethane (1 mL), then trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour, and the reaction was concentrated to give compound 35-4 (30 mg, 0.033 mmol, 95.23% yield). ES-API: [M+1] = 902.3. +

[0552] ​​​Step 5: Compound 35-4 (30 mg, 0.033 mmol), compound 1-2 (12.38 mg, 0.043 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (12.46 mg, 0.043 mmol), and N,N′-diisopropylethylamine (9.90 mg, 0.077 mmol) were reacted at room temperature with stirring for 2 hours. After the reaction was complete, the residue was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (5 mL * 3), dried, and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain 5-(3-benzyloxy-4,5-dimethoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-(R a )-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazo-8(1,3)-pyridazin-1(3,4)-pyrrolocyclotriacont-2-en-6-yl)-2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide (Z35, 9 mg, 0.008 mmol, yield 23.08%). ES-API: [M+1 + =1172.4.

[0553] Example 24: Synthesis of compounds Z36, Z43, and Z44

[0554] Step one: To a flask of compound 49-6 (25 mg, 0.033 mmol) was added dichloromethane (5 mL), then 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (11.11 mg, 0.043 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16.41 mg, 0.043 mmol) and N,N'-diisopropylethylamine (12.87 mg, 0.100 mmol), the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the residue was concentrated, water (5 mL) was added and extracted with dichloromethane (10 mL*2), the organic phase was washed with saturated brine (5 mL*3), dried and concentrated, the crude product was purified by silica gel column (methanol / dichloromethane: 0-20%) to give compound 36-1 (25 mg, 0.025 mmol, 75.87% yield). ES-API: [M+H] = 992.3. +

[0555] Step two: To a flask of compound 36-1 (25 mg, 0.025 mmol) was added dichloromethane (1 mL), then trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hour, the reaction was concentrated to give crude compound 36-2 (23 mg, 0.026 mmol, 102.32% yield). ES-API: [M+H] = 892.3. +

[0556] Step three: Compound 36-2 (23 mg, 0.026 mmol), compound 1-2 (13.01 mg, 0.045 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.62 mg, 0.033 mmol) and N,N'-diisopropylethylamine (9.90 mg, 0.077 mmol), the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the residue was concentrated, water (5 mL) was added and extracted with dichloromethane (10 mL*2), the organic phase was washed with saturated brine (5 mL*3), dried and concentrated, the crude product was purified by HPLC (ammonium bicarbonate method) to give 2-(1-(3-(benzyloxy)-4,5-dimethoxybenzoyl)piperidin-4-yl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8​​2 ,8 3 ,8 4 ,8 5 ,8 6 - hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)- pyridazino-1(3,4)-pyrrolotricyclo dec-2-ene-6-yl)propanamide (Z36, 8 mg, 0.007 mmol, 26.76% yield). ES-API: [M+H] = 1162.5. +

[0557] Step four: The above compound Z36 was subjected to chiral preparation (column: Daicel Chiralpak® AD-H 250*1.2mm*5pm; mobile phase: hexane: ethanol = 80:20; flow rate: 1 mL / min; column temperature 30 °C) to give two isomer compounds. One of the isomer compounds has a retention time of 8.125 min, and its structure is arbitrarily assigned as (2R)-2-(1-(3-(benzyloxy)-4,5-dimethoxybenzoyl)piperidin-4-yl)-N-((4 IE 250*1.2mm*5pm; mobile phase: acetonitrile: isopropanol = 50:50; flow rate: 1 mL / min; column temperature 30 °C) to give two isomer compounds. One of the isomer compounds has a retention time of 8.125 min, and its structure is arbitrarily assigned as (2R)-2-(1-(3-(benzyloxy)-4,5-dimethoxybenzoyl)piperidin-4-yl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)- pyridazino-1(3,4)-pyrrolotricyclo dec-2-ene-6-yl)propanamide (Z43, 3 mg). ES-API: [M+H] = 1162.5. The other isomer compound has a retention time of 9.265 min, and its structure is arbitrarily assigned as: (2S)-2-(1-(3-(benzyloxy)-4,5-dimethoxybenzoyl)piperidin-4-yl)-N-((4 + IE 250*1.2mm*5pm; mobile phase: acetonitrile: isopropanol = 50:50; flow rate: 1 mL / min; column temperature 30 °C) to give two isomer compounds. One of the isomer compounds has a retention time of 8.125 min, and its structure is arbitrarily assigned as (2R)-2-(1-(3-(benzyloxy)-4,5-dimethoxybenzoyl)piperidin-4-yl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 ​- Ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - Hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)- pyrrolocyclotrideca-2-ene-6-yl)propanamide (Z44, 3 mg). ES-API: [M+H] + = 1162.5.

[0558] Example 25: Synthesis of compound Z37

[0559] Step one: To a flask containing methyl 3-hydroxy-4,5-dimethoxybenzoate (100 mg, 0.471 mmol) was added N,N-dimethylformamide (5 mL), followed by (1- bromoethyl)benzene (174.42 mg, 0.943 mmol) and potassium carbonate (260.51 mg, 1.885 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 11-1 (120 mg, 0.379 mmol, 80.49% yield). ES-API: [M+H] + = 317.2.

[0560] Step two: To a flask containing compound 11-1 (120 mg, 0.379 mmol) was added methanol (5 mL) and water (1 mL), followed by lithium hydroxide (79.58 mg, 1.897 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a suspension of 2M hydrochloric acid added until pH = 3. The organic phase was separated and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound 11-2 (99 mg, 0.327 mmol, 86.33% yield). ES-API: [M+H] + = 302.2.

[0561] Step three: Compound 11-2 was prepared chiral (Chromatography column: Daicel Chiralpak IC-U (250 x 4.6 mm, 5 µm), eluted with 10% i-PrOH in hexane at a flow rate of 1 mL / min). The fractions containing the pure enantiomer were combined and concentrated to give compound Z37 (10 mg, 0.033 mmol, 10.06% yield). ES-API: [M+H] (IH column 250*1.2mm*5μm; mobile phase: n-hexane:ethanol = 90:10; flow rate: 1mL / min; column temperature 30℃) yielded two isomers. One isomer had a retention time of 6.219 min and its structure was arbitrarily designated as (R)-3,4-dimethoxy-5-(1-phenylethoxy)benzoic acid (11-2A, 30 mg). The other isomer had a retention time of 6.817 min and its structure was arbitrarily designated as (S)-3,4-dimethoxy-5-(1-phenylethoxy)benzoic acid (11-2B, 33 mg).

[0562] Step 4: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (5 mL), then compound 11-2A (retention time 6.219 min) (6.46 mg, 0.021 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (8.12 mg, 0.021 mmol), and N,N′-diisopropylethylamine (6.37 mg, 0.049 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the residue was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (5 mL * 3), dried, and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazo-8(1,3)-pyrazino-1(3,4)-pyrazolocyclotridecan-2-en-6-yl)-2-(3,4-dimethoxy-5-((R)-1-phenylethoxy)benzoyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z37, 6 mg, 0.005 mmol, yield 31.35%). ES-API: [M+H + =1197.3.

[0563] Example 26: Synthesis of compound Z38

[0564] Step 1: Under nitrogen protection, methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (200 mg, 1.04 mmol), benzyl bromide (266 mg, 1.55 mmol), and potassium carbonate (429 mg, 3.11 mmol) were mixed in N,N-dimethylformamide (5 mL) and stirred at 20 °C for 2 hours. After the reaction was complete, 30 mL of ethyl acetate was added, followed by washing with 15 mL of water and 15 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid silica gel column chromatography (0-20% petroleum ether / ethyl acetate) to give compound 38-1 (270 mg, 92% yield). ES-API: [M+H] + =284.2.

[0565] Step 2: Compound 38-1 (270 mg, 0.95 mmol) was dissolved in methanol (5 mL), and sodium hydroxide solution (1 mL, 6 mmol) was added. The mixture was stirred at 60 °C for 2 hours. After the reaction, the mixture was concentrated and diluted with 10 mL of water, and acidified with 1 M hydrochloric acid to pH 5. It was then extracted three times with 10 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid, compound 38-2 (230 mg, 90% yield). ES-API: [M+H] + =270.2.

[0566] Step 3: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (2 mL), and compound 38-2 (6.46 mg, 0.024 mmol), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (9 mg, 0.025 mmol), and N,N-diisopropylethylamine (11 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 hour, then concentrated and purified by preparative HPLC (ammonium bicarbonate method) to obtain a white solid 2-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 --(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolo-cyclotridec-2-en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z38, 10.48 mg, purity 100%, yield 55%). ES-API: [M+H] + = 1163.6.

[0567] Example 27: Synthesis of compound Z39

[0568] Step one: Methyl 3-ethyl-4-methoxybenzoate (440 mg, 2.265 mmol), N-bromosuccinimide (59.57 mg, 0.335 mmol) and sulfuric acid (0.014 mL, 0.257 mmol) were mixed in acetonitrile (10 mL) and stirred at 20 degrees for 4 h. After the reaction was completed, it was poured into 30 mL of ethyl acetate, washed with 15 mL of water and 15 mL of saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by flash silica gel column (0-20% petroleum ether / ethyl acetate) to obtain compound 39-1 (400 mg, 1.465 mmol, yield 64.65%), ES-API [M+H] + = 273.0.

[0569] Step two: Compound 39-1 (400 mg, 1.465 mmol), pinacol diboron (743.8 mg, 2.929 mmol), potassium acetate (287.04 mg, 2.929 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (106.91 mg, 0.146 mmol) were mixed in dioxane (10 mL) and stirred at 100 degrees for 18 h. After the reaction was completed, it was poured into 30 mL of ethyl acetate, washed with 15 mL of water and 15 mL of saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column (EA / PE = 20%) to obtain compound 39-2 (400 mg, 1249 mmol, yield 85.3%). ES-API [M-82] + = 239.2.

[0570] Step three: Compound 39-2 (400 mg, 1.249 mmol) and hydrogen peroxide (3 mL) were mixed in dioxane (5 mL) and stirred at 20 degrees for 3 h. After the reaction was completed, it was poured into 30 mL of ethyl acetate, washed with 15 mL of water, 15 mL of sodium thiosulfate aqueous solution and 15 mL of saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 39-3 (300 mg, crude), which was directly used in the next step. ES-API [M-82] += 211.2.

[0571] Step four: Compound 39-3 (300 mg, 1.427 mmol), benzyl bromide (1220.38 mg, 7.135 mmol) and potassium carbonate (788.85 mg, 5.708 mmol) were mixed in N,N-dimethylformamide (9 mL) and stirred at 20 °C for 2 h. After the reaction was completed, it was poured into 30 mL of ethyl acetate, washed with 15 mL of water and 15 mL of saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by flash silica gel column (0-20% petroleum ether / ethyl acetate) to give compound 39-4 (200 mg, 0.666 mmol, two-step yield: 53%).

[0572] Step five: Compound 39-4 (30 mg, 0.100 mmol), tetrahydrofuran (2 mL), lithium hydroxide monohydrate (33.56 mg, 0.799 mmol) and water (1 mL) were mixed in methanol (2 mL) and stirred at 60 °C for 18 h. After the reaction was completed, it was poured into 30 mL of ethyl acetate, washed with 15 mL of water and 15 mL of saturated brine in turn. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 39-5 (20 mg), ES-API [M+H] + = 287.1.

[0573] Step six: Compound 2-2 (15 mg, 0.016 mmol), compound 39-5 (14.13 mg, 0.049 mmol), N,N-diisopropylethylamine (10.61 mg, 0.082 mmol) and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (12.50 mg, 0.033 mmol) were mixed in dichloromethane (5 mL) and stirred at 20 °C for 1 h. After the reaction was completed, it was concentrated and purified by preparative HPLC (Formic acid method 1) to give 2-(3-(benzyloxy)-5-ethyl-4-methoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-(R a )-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolo-cyclotridecin-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z39, 10 mg, 0.008 mmol, 51.52% yield), ES-API [M+H] + = 1180.4.

[0574] Example 28: Synthesis of compound Z40

[0575] Step one: To a solution of compound intermediate 40-int (15 mg, crude) in dichloromethane (2 mL) was added N,N-diisopropylethylamine (10.63 mg, 0.082 mmol) and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (8.13 mg, 0.021 mmol), after 5 min, compound 2-2 (15 mg, 0.016 mmol) was added and the reaction was stirred at room temperature for 30 min, the reaction was checked by LCMS and was complete, concentrated, the crude was purified by preparative HPLC (Formic acid method 1) to give the final product 2-(3-(benzyloxy)-4-methoxy-5-(N-methylacetamido)benzoyl)-N-((4 2 Z,8 3 S,2E,6S)-1 1 -ethyl-(R a )-1 5 -(2-((S)-1-methoxyethyl)-5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-12,12-dimethyl-7,9- dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolo-cyclotridecin-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z40, 11.8 mg, 58.6% yield). ES-API: [M+H] + = 1223.6.

[0576] Example 29: Synthesis of compound Z41

[0577] Step one: Compound 41-1 (30 mg, 0.039 mmol, for the preparation method, refer to WO2024153208, example 135) was dissolved in dichloromethane (5 mL), then 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (13.92 mg, 0.050 mmol, CAS:872001-50-8), 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19.07 mg, 0.050 mmol) and N,N'-diisopropylethylamine (14.97 mg, 0.116 mmol) were added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), and the organic phase was washed with saturated brine (5 mL*3), then dried and concentrated, and the crude product was purified by silica gel column (methanol / dichloromethane: 0-20%) to obtain compound 41-2 (25 mg, 0.024 mmol, yield 62.48%). ES-API: [M+H] = 1036.3. +

[0578] Step two: Compound 41-2 (25 mg, 0.024 mmol) was added to a flask containing dichloromethane (1 mL), then trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was concentrated to obtain compound 41-3 (22 mg, 0.023 mmol, yield 97.41%). ES-API: [M+H] = 936.5. +

[0579] Step three: Compound 41-3 (22 mg, 0.023 mmol), 5-(benzyloxy)-3,4-dimethoxybenzoic acid (8.81 mg, 0.031 mmol), 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (11.62 mg, 0.031 mmol) and N,N'-diisopropylethylamine (9.11 mg, 0.070 mmol) were added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), and the organic phase was washed with saturated brine (5 mL*3), then dried and concentrated, and the crude product was purified by HPLC (ammonium bicarbonate method) to obtain 2-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-6​​1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - Hexahydro-1 1 H-8-oxa-2(4,2)-thiazolo-1(5,3)-indolo-6(1,3)- pyridazinocycloundecan-4-yl)-1,2,3,4-tetrahydroisoquinoline-5- carboxamide (Z41, 9 mg, 0.007 mmol, 31.75% yield). ES-API: [M+H] = 1206.3. +

[0580] Example 30: Synthesis of compound Z42

[0581] Step one: To a flask containing methyl 3-hydroxy-4,5-dimethoxybenzoate (255.80 mg, 1.205 mmol) was added N,N-dimethylformamide (10 mL), followed by (1-bromopropyl)benzene (400 mg, 2.009 mmol) and potassium carbonate (555.33 mg, 4.018 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 42-1 (500 mg, 1.513 mmol, 75.33% yield). ES-API: [M+H] = 331.1. +

[0582] Step two: To a flask containing compound 42-1 (500 mg, 1.513 mmol) was added methanol (5 mL) and water (1 mL), followed by lithium hydroxide (181.61 mg, 7.567 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a suspension of 2M hydrochloric acid added until pH = 3. The organic phase was separated and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give compound 42-2 (400 mg, 1.264 mmol, 83.55% yield). ES-API: [M+H] = 317.1. +

[0583] ​​​Step 3: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (5 mL), and then compound 42-2 (6.58 mg, 0.021 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (8.12 mg, 0.021 mmol), and N,N′-diisopropylethylamine (6.37 mg, 0.049 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the residue was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (5 mL * 3), dried, and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain N-((4 2 Z,8 3 S,2E,6S)-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazo-8(1,3)-pyrazino-1(3,4)-pyrazolocyclotridecan-2-en-6-yl)-2-(3,4-dimethoxy-5-(1-phenylpropoxy)benzoyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z42, 2 mg, 0.002 mmol, yield 10.33%). ES-API: [M+1 + =1210.3.

[0584] Example 31: Synthesis of compound Z45

[0585] Step 1: A mixture of tert-butyl 2-(diethoxyphosphoryl)propionate (2080 mg, 9.948 mmol) and triethyl phosphite (1652.96 mg, 9.948 mmol) was heated to 105 °C and stirred for 17 hours. After the reaction was complete, the reaction solution was concentrated to give compound 45-1 (2649 mg, 10.140 mmol, 100% yield), a colorless, transparent liquid. ES-API: [2M + Na] + =555.2.

[0586] Step two: Compound 45-1 (1176.00 mg, 4.417 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 °C. To the above solution was added sodium hydride (208.78 mg, 60 wt%, 5.220 mmol) under nitrogen atmosphere and stirred for 1 hour. Then to the reaction was added tert-butyl 4-oxopiperidine-1-carboxylate (800 mg, 4.015 mmol) in tetrahydrofuran (20 mL). The reaction was allowed to warm to room temperature and stirred for another hour. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated brine (10 mL*3) and dried to give the crude product. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-30%) to give compound 45-2 (800 mg, 2.569 mmol, 63.98% yield) as a colorless transparent liquid. ES- API: [M+Na] = 334.1. + 1 H NMR (400 MHz, CDC13) δ 3.49 - 3.39 (m, 4H), 2.56 (t, J = 5.6 Hz, 2H), 2.31 (t, J = 5.6 Hz, 2H), 1.84 (s, 3H), 1.49 (s, 9H), 1.46 (s, 9H).

[0587] Step three: Compound 45-2 (300 mg, 0.963 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added to the above solution. After the addition was completed, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated to give compound 45-3 (150 mg, 0.963 mmol, 100% yield) as a colorless transparent liquid. ES-API: [M+H] +

[0588] Step four: Compound 45-3 (150 mg, 0.963 mmol) was dissolved in dichloromethane (5 mL). To the above solution was added triethylamine (0.403 mL, 2.898 mmol) and di-tert-butyl dicarbonate (0.444 mL, 1.932 mmol). After the addition was completed, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with dichloromethane (20 mL*2). The organic phase was washed with saturated brine (20 mL*2) and dried to give the crude product. The crude product was purified by flash silica gel column (methanol / dichloromethane: 0-4%) to give compound 45-4 (150 mg, 0.588 mmol, 60.79% yield) as a white solid. ES-API: [M+Na] + 1 ​​​H NMR (400 MHz, CDC13) δ 3.50 (t, J = 6.0 Hz, 2H), 3.45 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.41 (t, J = 5.6 Hz, 2H), 1.92 (s, 3H), 1.47 (s, 9H).

[0589] Step five: Compound 49-6 (15 mg, 0.020 mmol) was dissolved in dichloromethane (3 mL), to the above solution was added compound 45-4 (10.17 mg, 0.040 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.88 mg, 0.034 mmol) and N,N'-diisopropylethylamine (7.72 mg, 0.060 mmol). After the addition was complete, the reaction was stirred at room temperature for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction and extracted with dichloromethane (10 mL*2). The organic phase was washed with saturated brine (20 mL*2) and dried and concentrated to give a crude product. The crude product was purified by flash silica gel column (methanol / dichloromethane: 0%-5%) to give compound 45-5 (12 mg, 0.012 mmol, 60.82% yield), light yellow solid. ES-API: [M+H] + = 990.2.

[0590] Step six: Compound 45-5 (10 mg, 0.010 mmol) was dissolved in dichloromethane (0.5 mL), to the above solution was added trifluoroacetic acid (0.6 mL). After the addition was complete, the reaction was stirred at room temperature for one hour. After the reaction was complete, the reaction was concentrated to give compound 45-6 (10 mg, crude), light yellow oily liquid. ES-API: [M+H] + = 890.2.

[0591] Step seven: Compound 45-6 (10 mg, crude) was dissolved in dichloromethane (2 mL). To the above solution was added compound 1-2 (4.21 mg, 0.015 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.41 mg, 0.017 mmol) and N,N'-diisopropylethylamine (4.36 mg, 0.034 mmol). After the addition was complete, the reaction was stirred at room temperature for one hour. After the reaction was complete, the reaction was concentrated to remove the solvent, and the residue was purified by preparative HPLC (Formic acid method 1) to give 2-(1-(3-(benzyloxy)-4,5-dimethoxybenzoyl)piperidin-4-ylmethyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-15 - (5-(3-(4-cyanopiperidin-l-yl)prop-l-y n-2-((S)-l-methoxyethyl)pyridin-3-yl)-l 1 - ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - hexahydro-l 1 H-10-oxa-4(4,2)-thiazolo-8(l,3)-pyridazino-l(3,4)-pyrrolo-cyclotrideca-2- en-6-yl)propanamide (Z45, 4.75 mg, 0.004 mmol, 40% yield for two steps), white solid. ES-API: [M+H] + = 1160.4.

[0592] Example 32: Synthesis of compound Z46

[0593] Step one: Methyl 8-methoxy-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-carboxylate (200 mg, 0.896 mmol) (preparation method reference to WO2021 / 249475 Example 77) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (371.46 mg, 2.688 mmol) and benzyl bromide (0.170 mL, 1.433 mmol) were added to the above solution. After the addition was completed, the reaction was stirred at 40 °C for 5 hours. After the reaction was completed, the reaction liquid was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated brine and dried to obtain the crude product. The crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-30%) to obtain compound 46-1 (200 mg, 0.638 mmol, 71.24% yield), white solid. ES-API: [M+H] + = 314.2.

[0594] Step two: Compound 46-1 (50 mg, 0.160 mmol) was dissolved in tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL). Lithium hydroxide monohydrate (26.85 mg, 0.640 mmol) was added to the above solution. After the addition was completed, the reaction liquid was stirred at room temperature for 17 hours. After the reaction was completed, the pH value of the reaction liquid was adjusted to acidic with dilute hydrochloric acid (1 M) and extracted with dichloromethane (10 mL*2). The organic phase was washed with saturated brine and dried to obtain compound 46-2 (45 mg, 0.150 mmol, 94.22% yield), white solid. ES-API: [M+H]+ = 300.1.

[0595] Step three: Compound 2-2 (10 mg, 0.011 mmol) was dissolved in dichloromethane (2 mL). To the above solution was added compound 46-2 (4.92 mg, 0.016 mmol), 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.37 mg, 0.022 mmol) and N,N'-diisopropylethylamine (4.27 mg, 0.033 mmol). After the addition was complete, the reaction was stirred at room temperature for one hour. After the reaction was complete, the reaction was concentrated to remove the solvent and the residue was subjected to preparative HPLC (Formic Acid Method 1) to give 2-(4-benzyl-8-methoxy-3,4-dihydro-2H- benzo[b][l,4]oxazine-6-carbonyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-l-yl)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-l 1 H-10-oxa-4(4,2)-thiazolo-8(l,3)-pyridazino-l(3,4)-pyrrolocyclotrideca-2- en-6-yl)-l,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z46, 5.5 mg, 0.005 mmol, 42.05% yield), white solid. ES-API: [M+H] + = 1193.5.

[0596] Example 32: Synthesis of compound Z47

[0597] Step one: under nitrogen protection, 5-hydroxy-3,4-dimethoxybenzoic acid methyl ester (71.87 mg, 0.339 mmol), 1,2-thiazol-4-ylmethanol (30 mg, 0.261 mmol), triphenylphosphine (102.50 mg, 0.391 mmol) and diisopropyl azodicarboxylate (79.02 mg, 0.391 mmol) were mixed in tetrahydrofuran (5 mL) and stirred at 20 °C for 2 h. After the reaction was completed, the crude compound 47-1 (90 mg) was obtained by rotary evaporation and column purification (petroleum ether / ethyl acetate = 70:30). ES- API: [M+H] + = 310.0.

[0598] Step two: crude compound 47-1 (80 mg), lithium hydroxide (108.51 mg, 2.586 mmol), water (3 mL) and methanol (3 mL) were mixed in tetrahydrofuran (6 mL) and stirred at 60 °C for 1 h. After the reaction was completed, 1M hydrochloric acid was added to adjust the pH value to acidic, 30 mL of ethyl acetate was added, and then 15 mL of water and 15 mL of saturated brine were added in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude compound 47-2 (60 mg). ES-API: [M-82] + = 296.1.

[0599] Step three: under nitrogen protection, compound 2-2 (15 mg, 0.016 mmol), compound 47-2 (10 mg, 0.034 mmol), N,N-diisopropyl ethylamine (20 mg, 0.155 mmol) and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10 mg, 0.026 mmol) were mixed in dichloromethane (3 mL) and stirred at 20 °C for 1 h. After the reaction was completed, rotary evaporation was performed and preparative HPLC (formic acid method 1) was used to purify to obtain N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolotricyclo- dec-2-ene-6-yl)-2-(3-(isothiazol-4-ylmethoxy)-4,5-dimethoxybenzoyl)-1,2,3,4- tetrahydroisoquinoline-5-carboxamide (Z47, 6 mg, 0.005 mmol, 30.67% yield), ES- API: [M+H] + = 1189.4.

[0600] Example 34: Synthesis of compound Z48

[0601] Step one: Compound 2-2 (15 mg, 0.016 mmol), 4-(benzyloxy)-2-naphthoic acid (10 mg, 0.036 mmol, refer to WO2020 / 157491, page 189 for preparation method), 2-(7- azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10 mg, 0.026 mmol) and N,N-diisopropylethylamine (20 mg, 0.155 mmol) were mixed in dichloromethane (5 mL) and stirred at 20 degrees for 1 h. After the reaction was completed, it was rotary evaporated and purified by preparative HPLC (Formic acid method 1) to give 2-(4-(benzyloxy)-2- naphthoyl)-N-((4 2 Z,8 3 (S)-2-((S)-1 -methoxyethyl)pyridin-3-yl)-1 a -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolotricyclo- dec-2-ene-6-yl)-2-(3-(isothiazol-4-ylmethoxy)-4,5-dimethoxybenzoyl)-1,2,3,4- tetrahydroisoquinoline-5-carboxamide (Z47, 6 mg, 0.005 mmol, 30.67% yield), ES- API: [M+H] + = 1172.4.

[0602] Example 35: Synthesis of compound Z49

[0603] Step one: To a solution of compound 1-2 (150 mg, 0.520 mmol) in dichloromethane (3 mL) was added N, N-diisopropylethylamine (0.272 mL, 1.561 mmol) and 2-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (237.40 mg, 0.624 mmol), after 5 min, piperazin-2-one (52.09 mg, 0.520 mmol) was added, and the reaction was stirred at room temperature for 30 min. To the reaction was added ethyl acetate (20 mL). The organic phase was washed with water (20 mL*2) and brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification was performed on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to give compound 49-a (180 mg, 0.486 mmol, 93.5% yield). ES-API: [M+H] = 371.2. +

[0604] Step two: Compound 49-a (50 mg, 0.135 mmol) was dissolved in N, N-dimethylformamide (2 mL) under ice water bath condition, 60% sodium hydride (8.10 mg, 0.202 mmol) was added, and the reaction was protected by nitrogen, and stirred at room temperature for 0.5 h. Then, 2-bromopropionic acid methyl ester (45.09 mg, 0.270 mmol) was added, and the reaction was stirred at room temperature for 1 h. Then, water (3 mL) was added, and the reaction was stirred at room temperature for 1 h. Dilute hydrochloric acid was added dropwise until the pH was 4-6. The organic phase was extracted with ethyl acetate (10 mL*3), washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification was performed on a silica gel column (dichloromethane / methanol = 10 / 1) to give compound 49-b (15 mg, 0.034 mmol, 25%). ES-API: [M+H] = 443.2. +

[0605] Step three: To a solution of compound 49-b (9 mg, 0.020 mmol) in dichloromethane (2 mL) was added N, N-diisopropylethylamine (8.40 mg, 0.065 mmol) and 2-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (6.06 mg, 0.016 mmol), after 5 min, compound 49-6 (10 mg, 0.013 mmol) was added, and the reaction was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. Purification was performed by HPLC (Formic acid method 1) to give the final product 2-(4-(3-(benzyloxy)-4,5-dimethoxybenzoyl)-2-oxopiperazin-1-yl)-N-((4 2 Z,8 3 S,2E,6S)-1 1 -ethyl-(Ra)-1 5 ​​- (2-((S)-1 -methoxyethyl)-5-(3-(4-cyanopiperidin- 1 -yl)prop- 1 -yn- 1 -yl)-12,12- dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - hexahydro- 1 1 H- 10-oxa-4(4,2)-thiazolo-8( 1,3)-pyridazino- 1 (3,4)- pyrrolo-cyclotrideca-2-ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5- carboxamide (Z49, 2.2 mg, yield 14%). ES-API: [M+H] + = 1177.5.

[0606] Example 36: Synthesis of compound Z50

[0607] Step one: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (2 mL), compound 50-int-A (6.27 mg, 0.021 mmol), 2-(7-azobenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate (9 mg, 0.025 mmol) and N,N- diisopropylethylamine (11 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 hour, then concentrated and purified by preparative HPLC (ammonium bicarbonate method) to give 2-(3-(benzyloxy)-5- aminocarbonyl-4-methoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin- 1 -yl)prop- 1 -yn- 1 -yl)-2-((S)- 1 -methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 - hexahydro- 1 1 H- 10-oxa-4(4,2)-thiazolo-8( 1,3)-pyridazino- 1 (3,4)- pyrrolo-cyclotrideca-2-ene-6-yl)-1,2,3,4-tetrahydroisoquinoline-5- carboxamide (Z50, 4.3.mg, purity 100%, yield 23%). ES-API: [M+H] + = 1195.6.

[0608] Example 37: Synthesis of compound Z51

[0609] Step one: To a flask containing methyl 3,5-dihydroxy-4-methoxybenzoate (300 mg, 1.514 mmol) was added N,N-dimethylformamide (10 mL), followed by 1,1,1-trifluoro-2-iodoethane (476.73 mg, 2.271 mmol) and potassium carbonate (627.64 mg, 4.542 mmol) and the mixture was stirred at 90 °C overnight. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-40%) to give compound 51-a (424 mg, 1.071 mmol, 70.72% yield). ES-API: [M+H] + = 281.1.

[0610] Step two: To a flask containing compound 51-a (280 mg, 0.999 mmol) was added N,N-dimethylformamide (10 mL), followed by benzyl bromide (341.84 mg, 2.0 mmol) and potassium carbonate (1046.07 mg, 7.569 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 51-b (260 mg, 0.702 mmol, 70.26% yield). ES-API: [M+H] + = 371.1.

[0611] Step three: To a flask containing compound 51-b (260 mg, 0.702 mmol) was added methanol (5 mL) and water (1 mL), followed by lithium hydroxide (147.30 mg, 3.510 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a suspension of 2M hydrochloric acid added until pH = 3. The organic phase was separated and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give compound 51-c (210 mg, 0.589 mmol, 83.95% yield). ES-API: [M+H] + = 357.1.

[0612] Step four: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (5 mL), then compound 51-c (7.62 mg, 0.021 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.12 mg, 0.021 mmol) and N,N'-diisopropylethylamine (6.37 mg, 0.049 mmol) were added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), and the organic phase was washed with saturated brine (5 mL*3), dried and concentrated, and the crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain 2-(3-(benzyloxy)-4-methoxy-5-(2,2,2-trifluoroethoxy)benzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrazolo-cyclotrideca-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z51, 3 mg, 0.002 mmol, yield 14.99%). ES-API: [M+H] = 1251.3. + = 1251.3.

[0613] Example 38: Synthesis of compounds Z52, Z105

[0614] Step 1: Compound 36-2 (220 mg, 0.247 mmol) was dissolved in dichloromethane (10 mL). Compound 46-2 (95.95 mg, 0.321 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (140.64 mg, 0.370 mmol), and N,N′-diisopropylethylamine (0.129 mL, 0.740 mmol) were added to the above solution. After the addition was complete, the reaction was stirred at room temperature for one hour. After the reaction was complete, the reaction solution was concentrated to remove the solvent, and the residue was subjected to preparative HPLC (ammonium bicarbonate method) to obtain two isomers. One of the isomers had a retention time of 6.741 min, and its structure was arbitrarily designated as (2R)-2-(1-(4-benzyl-8-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)piperidin-4-yl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazo-8(1,3)-pyridazine-1(3,4)-pyrrolocyclotridecane-2-en-6-yl)propionamide (Z52, 58 mg, 0.049 mmol, yield 20.01%), white solid, ES-API: [M / 2+H] + =587.5. Another isomer has a retention time of 6.846 min, and its structure is arbitrarily designated as (2S)-2-(1-(4-benzyl-8-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)piperidin-4-yl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 83 ,8 4 ,8 5 ,8 6 - Hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)- pyridazino-1(3,4)-pyrrolo-cyclotridec-2- en-6-yl)propanamide (Z105, 58 mg, 0.049 mmol, 20.01% yield), white solid, ES- API: [M / 2+H] = 587.5. + = 587.5.

[0615] Example 39: Synthesis of compound Z53

[0616] Step one: To a flask containing methyl 3,5-dihydroxy-4-methoxybenzoate (500 mg, 2.523 mmol) was added N,N-dimethylformamide (10 mL), followed by 2- iodopropane (643.35 mg, 3.785 mmol) and potassium carbonate (1046.07 mg, 7.569 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL), extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-40%) to give compound 53-1 (280 mg, 1.165 mmol, 46.19% yield). ES-API: [M+H] + = 303.1.

[0617] Step two: To a flask containing compound 53-1 (280 mg, 1.165 mmol) was added N,N-dimethylformamide (10 mL), followed by benzyl bromide (398.68 mg, 2.331 mmol) and potassium carbonate (322.13 mg, 2.331 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20 mL), extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-20%) to give compound 53-2 (280 mg, 0.848 mmol, 72.72% yield). ES-API: [M+H] + = 331.1.

[0618] Step three: To a flask containing compound 53-2 (280 mg, 0.848 mmol) was added methanol (5 mL) and water (1 mL), then lithium hydroxide (355.6 mg, 8.48 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a suspension of 2M hydrochloric acid added until pH = 3. The organic phase was separated, the aqueous layer was extracted with another portion of ethyl acetate. The combined organic extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give compound 53-3 (200 mg, 0.632 mmol, 74.60% yield). ES-API: [M+H] + = 317.1.

[0619] Step four: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (5 mL), then compound 53-3 (6.76 mg, 0.021 mmol), 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.12 mg, 0.021 mmol) and N,N'-diisopropylethylamine (6.37 mg, 0.049 mmol) were added, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to the residue and extracted with dichloromethane (10 mL*2), the organic phase was washed with saturated brine (5 mL*3) and dried and concentrated, the crude product was purified by preparative HPLC (ammonium bicarbonate method) to give 3-(benzyloxy)-5-isopropoxy-4-methoxybenzyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrazolo-cyclotrideca-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z53, 3 mg, 0.002 mmol, 15.07% yield). ES-API: [M+H] + = 1211.4.

[0620] Example 40: Synthesis of compound Z54

[0621] Step 1: Compound 3-4 (15 mg, 0.016 mmol) was dissolved in dichloromethane (5 mL), then compound 54-int (5.82 mg, 0.019 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (8.12 mg, 0.021 mmol), and N,N′-diisopropylethylamine (6.37 mg, 0.049 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the residue was concentrated, water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (5 mL * 3), dried, and concentrated. The crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain 3-(benzyloxy)-5-cyclopropoxy-4-methoxybenzyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-12,12-dimethyl-7,9-dioxo-8 1 8 2 8 3 8 4 8 5 8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazo-8(1,3)-pyridazin-1(3,4)-pyrazolocyclotridecan-2-en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z54, 3 mg, 0.002 mmol, yield 17.42%). ES-API: [M+1 + =1208.4.

[0622] Example 41: Synthesis of compound Z55

[0623] Step one: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (2 mL), 3-(benzyloxy)-5-cyano-4-methoxybenzoic acid (5.95 mg, 0.021 mmol, prepared according to Journal of Medicinal Chemistry, 2019, vol. 62, #20, p. 8996-9007), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (9 mg, 0.025 mmol) and N,N-diisopropylethylamine (11 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 h, then concentrated and purified by preparative HPLC (ammonium bicarbonate method) to give compound 2-(3-benzyloxy-5-cyano-4-methoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolocyclotridec-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z55, 3.47 mg, purity 100%, yield 18%). ES-API: [M+H] = 1178.3. + = 1178.3.

[0624] Example 42: Synthesis of compound Z56

[0625] Step one: Compound 2-2 (10 mg, 0.011 mmol), compound 56-int (6.63 mg, 0.022 mmol), triethylamine (0.005 mL, 0.033 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (8.34 mg, 0.022 mmol) were mixed in dichloromethane (5 mL) and stirred at 20 °C for 0.5 h. After the reaction was completed, it was concentrated and purified by preparative HPLC (formic acid method 1) to give 2-(3-benzyloxy)-5-dimethylamino-4-methoxybenzoyl)-N-((4 2 Z,83 (S)-2-((S)-1 -methoxyethyl)pyridin-3-yl)-1 a -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1 H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1 (3,4)-pyrrolocyclotrideca-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z56, 5 mg, 0.004 mmol, 38.02% yield), ES-API [M+H] = 1195.6. + = 1195.6.

[0626] Example 43: Synthesis of compound Z57

[0627] Step one: Compound 2-2 (10 mg, 0.011 mmol), 76-int (6.21 mg, 0.022 mmol), triethylamine (0.005 mL, 0.033 mmol) and 2-(7-azabenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate (8.34 mg, 0.022 mmol) were mixed in dichloromethane (5 mL) and stirred at 20 degree for 0.5 h. After the reaction was completed, concentrated and purified by prep-HPLC (Formic acid method 1) to give 2-(3-benzyloxy)-5- ethynyl-4-methoxybenzoyl)-N-((4 2 Z,8 3 (S)-2-((S)-1 -methoxyethyl)pyridin-3-yl)-1 a -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolocyclotrideca-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z57, 5 mg, 0.004 mmol, 38.64% yield), ES-API [M+H] + = 1176.5.

[0628] Example 44: Synthesis of compound Z58

[0629] Step one: Compound INT-58 (30 mg, 0.09 mmol) was dissolved in methanol (1 mL) and water (0.2 mL), lithium hydroxide monohydrate (38 mg, 0.91 mmol) was added, stirred at 60 °C for 2 hours. The reaction was concentrated, 2 mL water was added, 1 M aqueous hydrochloric acid was added to form white solid. Filtered, the filter cake was washed with 1 mL water, dried to give white solid compound 58-1 (20 mg, 70% yield). ES-API: [M+H] + = 316.1.

[0630] Step two: Compound 2-2 (15 mg, 0.016 mmol) was dissolved in dichloromethane (2 mL), compound 58-1 (6.62 mg, 0.021 mmol), 2-(7-azobenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate (9 mg, 0.025 mmol) and N,N- diisopropylethylamine (11 mg, 0.082 mmol) were added. The mixture was stirred at room temperature for 1 hour, then concentrated and purified by preparative HPLC (ammonium bicarbonate method) to give white solid compound 2-(3-acetylamino-5- benzyloxy-4-methoxybenzoyl)-N-((4 2 Z,8 3 S,2E,6S)-(R a )-1 5 -(5-(3-(4-cyanopiperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-12,12-dimethyl-7,9-dioxo-8 1 ,8 2 ,8 3 ,8 4 ,8 5 ,8 6 -hexahydro-1 1H-10-oxa-4(4,2)-thiazolo-8(1,3)-pyridazino-1(3,4)-pyrrolocyclotrideca-2- en-6-yl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Z58, 1.94 mg, purity 100%, yield 15%). ES-API: [M+H] + = 1210.2.

[0631] Example 45: Synthesis of compounds Z59, Z60, Z61

[0632] Step one: 8-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester (200 mg, 0.896 mmol) [ref. WO2021 / 249475] was dissolved in N,N-dimethylformamide (5 mL), to the above solution was added potassium carbonate (371.46 mg, 2.688 mmol), potassium iodide (148.73 mg, 0.896 mmol) and (1-bromoethyl)benzene (265.28 mg, 1.433 mmol). After the addition was complete, the reaction was stirred at 40 °C for 5 hours. After the reaction was completed, the reaction liquid was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated brine and dried to obtain a crude product. The crude product was purified by flash silica gel column (tetrahydrofuran / petroleum ether: 0-30%) to obtain compound 59-1 (200 mg, 0.611 mmol, yield 68.19%), white solid. ES-API: [M+H] + = 328.1.

[0633] Step two: Compound 59-1 (100 mg, 0.305 mmol) was dissolved in tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL). To the above solution was added lithium hydroxide monohydrate (51.27 mg, 1.222 mmol). After the addition was complete, the reaction liquid was stirred at room temperature for 17 hours. After the reaction was completed, the pH value of the reaction liquid was adjusted to acidic with dilute hydrochloric acid (1M) and extracted with dichloromethane (10 mL*2). The organic phase was washed with saturated brine and dried to obtain compound 59-2 (180 mg, 0.601 mmol, yield 94.22%), white solid. ES-API: [M+H] + = 314.2.

[0634] Step 3: Dissolve compound 2-2 (25 mg, 0.027 mmol) in dichloromethane (2 mL). Add 8-methoxy-4-(1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (8.59 mg, 0.027 mmol), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (20.84 mg, 0.055 mmol), and N,N′-diisopropylethylamine (10.63 mg, 0.082 mmol) to the above solution. After the addition is complete, the reaction is stirred at room temperature for one hour. After the reaction is complete, the reaction solution is concentrated to remo...

Claims

1. A compound represented by Formula (I) or a stable deuterium derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: Case A: wherein R 40 is hydrogen or deuterium; R 41 is hydrogen or deuterium; or R 40 and R 41 are joined to form -CH2- or -CH2CH2-; R1is hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1-6 heteroalkyl; R2is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl; R 42 is hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; R 43 is hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; or R 42 and R 43 together with the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl; L1is -L2-substituted or unsubstituted C 6-10 aryl-, -L2-substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl-, or -L2-substituted or unsubstituted 3- to 8-membered heterocyclyl-; L2is each independently a chemical bond, -O-, -C 1-4 alkyl-, -N(R 00 )-, -C(=O)-, -CR 09 =CR 10 -, -N(R 00 )C(=O)- or -N(R 00 )C(=S)-; Ring A is wherein is a single or double bond; W6, W7, W8, W9, and W 10 each independently selected from CR 13 or N; R3is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl; R 13 halogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-6 alkoxy; or R 13 and R3together with the atoms to which they are attached form a substituted or unsubstituted nitrogen-containing 3- to 8-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; one ring atom of the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, or 3) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; X is Y1is N or CH; wherein N can be oxidized (N + -O - ); Y2is N or CH; wherein N can be oxidized (N + -O - ); R 4a substituted or unsubstituted C 1-6 alkyl; R5is hydrogen, -NR 01 R 02 , -C(R 05 )R 03 R 04 , -C 2-4 alkyl-NR 01 R 02 , -C 2-4 alkenyl-NR 01 R 02 or -C 2-4 alkynyl-C 1-4 alkyl-NR 01 R 02 ; R 01 , R 02 each independently is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or substituted or unsubstituted C 1-6 acyl; or, R 01 , R 02 and the nitrogen atom to which they are attached join to form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, substituted or unsubstituted 7- to 12-membered bicyclic heterocyclyl, or substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl; R 03 , R 04 each independently is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl; wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally simultaneously replaced by -(CH2) j -j- with j being 2, 3, 4, 5 or 6; or R 03 , R 04 together with the carbon atom to which they are attached form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, substituted or unsubstituted 7- to 12-membered bicyclic heterocyclyl, substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl; R 05 is hydrogen, deuterium, halogen, deuterated C 1-6 alkyl or C 1-6 alkyl; R 12 is hydrogen, C 1-6 alkyl or deuterated C 1-6 alkyl; Y3 is wherein is a single or double bond; a is selected from 1, 2, or 3; R y1 selected from hydrogen, halogen, cyano, -NR 01 R 02 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered monocyclic heteroaryl; R 01 , R 02 are each as previously defined; R6 is Cy1ring is a phenyl ring or a 5- or 6-membered monocyclic heteroaromatic ring; Cy2ring is a 3- to 8-membered heterocyclic ring; R 61 for a Cy1ring or a Cy2ring at any position is selected from hydrogen, deuterium, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl; n is 0, 1, 2, or 3; R 62 for any available valence, which is m is 1, 2, 3, or 4; R 14 , R 15 are each independently selected from hydrogen, deuterium or C 1-6 alkyl; Cy3ring is C 6-10 aromatic ring, 5- to 14-membered heteroaromatic ring, C 3-20 cycloalkyl ring or 3- to 20-membered heterocyclic ring; R 2a for a substituent on any available carbon of Cy3; p1 is 0, 1, 2, or 3; R 2a each independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-O-, -(C=O)NR 01 R 02 or -NR 01 R 02 ; R 01 , R 02 each is as previously defined; or p1 is 2; both R 2a is connected to form -C 1-6 alkyl- or -C 1-8 heteroalkyl-; R 2b for any position on the Cy3ring, which is p2is 1, 2, or 3; Cy4ring is C 6-10 aromatic ring, 5- to 14-membered heteroaromatic ring, C 3-20 cycloalkyl ring or 3- to 20-membered heterocyclic ring; L3is a bond, -O-C 1-4 alkyl-, -O-, -C 1-4 alkyl-, -N(R 00 )-, -N(R 00 )-C 1-4 alkyl-, -C(=O)-, -CR 09 =CR 10 - or -N(R 00 )C(=O)-; wherein said -C 1-4 alkyl- is optionally substituted with one or more groups selected from deuterium, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl; R 3a for any position on the Cy4ring; R 3a each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl; t1is 1, 2, 3, 4, or 5; R 00 each independently is hydrogen or C 1-6 alkyl; or one R 2a with R 00 to form -C 1-6 alkyl- or -C 1-8 heteroalkyl-; R 09 each independently is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl; said substitution is with one or more (e.g. 1, 2, 3, or 4) groups selected from the group consisting of deuterium and halogen; R 10 each independently is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl; said substitution is with one or more (e.g. 1, 2, 3, or 4) groups selected from the group consisting of deuterium and halogen; In the above groups, the substituents are each independently 1, 2, 3, 4, 5 or 6 groups selected from the group S1; the groups of the group S1 are each independently selected from the group consisting of -SF5, deuterium, oxo (=0), thioxo (=S), =CR e R f , =NR e , halogen, cyano, hydroxy, carboxy, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -O-C 3-20 cycloalkyl, -O-3- to 20-membered heterocyclyl, -O-C 6-14 aryl, -O-5- or 6-membered monocyclic heteroaryl, -O-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-O-C 3-20 cycloalkyl, -C 1-4 alkyl-3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3- to 20-membered heterocyclyl, -C 1-4 alkyl-C 6- 14 aryl, -C 1-4 alkyl-O-C 6-14 aryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, -O-C 1-4 alkyl-hydroxy, -O-C 1-4 alkyl-cyano, -O-C 1-4 alkyl-C 1-6 alkyl, -O-C 1-4 alkyl-C 1-6 alkoxy, -O-C 1-4 alkyl-C 3-20 cycloalkyl, -O-C 1-4 alkyl-O-C 3-20 cycloalkyl, -O-C 1-4 alkyl-3 to 20 membered heterocyclyl, -O-C 1-4 alkyl-O-3 to 20 membered heterocyclyl, -O-C 1-4 alkyl-C 6-14 aryl, -C(=O)O-C 1-6 alkyl, -C(=O)O-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -C(=O)-5 or 6 membered monocyclic heteroaryl, -C(=O)-8 to 10 membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3 to 20 membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5 or 6 membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8 to 10 membered bicyclic heteroaryl, -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 and -P(=O)-(C 1-6 alkyl)2; wherein, the C 1-6 alkyl, the C 1-6 alkoxy, the C 2-6 alkenyl, the C 2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 groups selected from halogen, deuterium, cyano, or hydroxyl; the C 3-20 cycloalkyl, the 3 to 20 membered heterocyclyl, the C 6-14 aryl, the 5 or 6 membered monocyclic heteroaryl, the 8 to 10 membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 groups selected from S2; or, when the above groups are each independently substituted with 2, 3, 4, 5, or 6 groups selected from S1, optionally two S1groups are taken together with the atom to which they are attached to form a bridged ring structure; In the above groups, each R a1 R b1 Each independently represents H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-deuterated C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-deuterated C 1-6 Alkoxy, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkyl-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkyl-OC 3-6 Monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclic groups, -C 1-4 Alkyl-3 to 6-membered monocyclic heterocyclic groups, -C 1-4 Alkyl-O-3 to 6-membered monocyclic heterocyclic groups, phenyl, -C 1-4 Alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Monocyclic cycloalkyl or -C(=O)-3 to 6-membered monocyclic heterocyclic groups; wherein, the C 3-6 The monocyclic cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 and -P(=O)-(C 1-6 Alkyl)2; or each R a1 and R b1 together with the nitrogen atom to which they are attached form a 3- to 20-membered heterocyclyl; wherein said 3- to 20-membered heterocyclyl is each independently optionally substituted with 1 or 2 groups selected from halo, hydroxy, carboxy, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 1- 6alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C 1-6 alkyl)2, and -P(=O)-(C 1-6 alkyl)2; each R c1 is independently H, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkoxy, -C 1-4 alkyl-deuterated C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-O-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; said C 3-6 monocyclic cycloalkyl, said 3- to 6-membered monocyclic heterocyclyl, said phenyl, said 5- or 6-membered monocyclic heteroaryl, said 8- to 10-membered bicyclic heteroaryl is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxy, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C 1-6 alkyl)2, or -P(=O)-(C 1-6 alkyl)2; In each of the above groups, the groups of each S2group are each independently selected from the group consisting of: deuterium, oxo (=0), thioxo (=S), =CR e R f , =NR e , halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -(C=0)-NHC 1-6 alkyl, -(C=0)-N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=0)-(C 1-6 alkyl)2, -P(=0)-(C 1-6 alkyl)2, -(C=0)C 1-6 alkyl and -SF5; In the above groups, the -C 1-4 alkyl- is unsubstituted; or -C 1-4 1, 2, 3 or 4 hydrogen atoms on the alkyl- group are each independently replaced by a member selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, -CH2-hydroxy, -CH2-cyano, phenyl; or C 1-4 2 hydrogen atoms on the same carbon atom on the alkyl group are simultaneously replaced by -(CH2) j to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; or C 1-4 2 hydrogen atoms on the same carbon atom on the alkyl group are simultaneously replaced by =CR e R f substituted; In the above groups, R e each independently H, halogen, C 1-6 alkyl, haloC 1-6 alkyl or deuterated C 1-6 alkyl; In the above groups, R f each independently H, halogen, C 1-6 alkyl, haloC 1-6 alkyl or deuterated C 1-6 alkyl; one or more (such as 1, 2, 3, or 4) ring atoms of said 3- to 8-membered heterocyclyl, 3- to 8-membered heterocycle, 3- to 6-membered monocyclic heterocyclyl, or 3- to 8-membered monocyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 7- to 12-membered bicyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 3- to 20-membered heterocycle, said 3- to 20-membered heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, or 4) ring atoms of said 5- or 6-membered monocyclic heteroaromatic ring, said 5- or 6-membered monocyclic heteroaryl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 8- to 10-membered bicyclic heteroaryl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, or 4) ring atoms of said 3- to 6-membered monocyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 5- to 15-membered tricyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 5- to 14-membered heteroaromatic ring is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; 1-6 one or more (such as 1, 2, 3, or 4) ring atoms of said 3- to 8-membered heterocyclyl, 3- to 8-membered heterocycle, 3- to 6-membered monocyclic heterocyclyl, or 3- to 8-membered monocyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, or 4) ring atoms of said 3- to 8-membered heterocyclyl, 3- to 8-membered heterocycle, 3- to 6-membered monocyclic heterocyclyl, or 3- to 8-membered monocyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; wherein when the ring atom is a sulfur atom, the sulfur atom is optionally substituted with one or two groups selected from oxo and =NR e R e is as previously defined; wherein when the ring atom is a phosphorus atom, the phosphorus atom is optionally substituted with one or two groups selected from oxo and =NR e R e is as previously defined; or Case B: wherein R 40 is hydrogen or deuterium; R 41 is hydrogen or deuterium; or R 40 and R 41 are joined to form -CH2- or -CH2CH2-; R1is -NR 17 R 18 ; R 17 , R 18 and the nitrogen atom to which they are attached together form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, substituted or unsubstituted 6- to 12-membered bicyclic heterocyclyl, or substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl; R2is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl; R 42 is hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; R 43 is hydrogen, deuterium, halogen or substituted or unsubstituted C 1-6 alkyl; or R 42 and R 43 together with the carbon atom to which they are attached form a substituted or unsubstituted cyclopropyl; L1is -L2-substituted or unsubstituted C 6-10 aryl-, -L2-substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl-, or -L2-substituted or unsubstituted 3- to 8-membered heterocyclyl-; L2is each independently -CR 09 =CR 10 -, -N(R 00 )C(=O)- or -N(R 00 )C(=S)-; Ring A is W6is selected from CR 13 or N; R3is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl; R 13 halogen, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-6 alkoxy; or R 13 and R3together with the atoms to which they are attached form a substituted or unsubstituted nitrogen-containing 3- to 8-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; one ring atom of the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, or 3) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; X is Y1is N or CH; wherein N can be oxidized (N + -O - ); Y2is N or CH; wherein N can be oxidized (N + -O - ); R 4a R is hydrogen, substituted or unsubstituted C 1-6 alkyl; R5 represents hydrogen, -NR 01 R 02 -C(R) 05 )R 03 R 04 -C 2-4 alkynyl-NR 01 R 02 -C 2-4 alkenyl-NR 01 R 02 or -C 2-4 alkynyl-C 1-4 Alkyl-NR 01 R 02 ; R 01 , R 02 each independently is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl or substituted or unsubstituted C 1-6 acyl; or, R 01 , R 02 and the nitrogen atom to which they are attached together form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, substituted or unsubstituted 7- to 12-membered bicyclic heterocyclyl, or substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl; R 03 , R 04 each independently is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl; wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with -(CH2) j -j-; wherein j is 1, 2, 3, 4, 5 or 6; or R 03 , R 04 together with the carbon atom to which they are attached form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, substituted or unsubstituted 7- to 12-membered bicyclic heterocyclyl, substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl; R 05 is hydrogen, deuterium, halogen, deuterated C 1-6 alkyl or C 1-6 alkyl; R 12 is hydrogen, C 1-6 alkyl or deuterated C 1-6 alkyl; Y3 is wherein, is a single or double bond; a is selected from 1, 2, or 3; R y1 selected from hydrogen, halogen, cyano, -NR 01 R 02 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or 5- or 6-membered monocyclic heteroaryl; R 01 , R 02 each are as previously defined; R6is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, or substituted or unsubstituted 8- to 10-membered bicyclic heteroaryl; or R6 is Cy1ring is a phenyl ring or a 5- or 6-membered monocyclic heteroaromatic ring; Cy2ring is a 3- to 8-membered heterocyclic ring; R 61 for a substituent on any position of the Cy1ring or Cy2ring selected from hydrogen, deuterium, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl; n is 0, 1, 2, or 3; R 62 for any available position on the Cy2ring, which is hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -cyano, (C=0)NR 01 R 02 、 m is 1, 2, 3, or 4; R 14 , R 15 are each independently selected from hydrogen, deuterium or C 1-6 alkyl; Cy3ring is C 6-10 aromatic ring, 5- to 14-membered heteroaromatic ring, C 3-20 cycloalkyl ring or 3- to 20-membered heterocyclic ring; R 2a for a substituent on any available carbon of Cy3; p1 is 0, 1, 2, or 3; R 2a each is independently selected from hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl-O-, -(C=0)NR 01 R 02 or -NR 01 R 02 ; R 01 , R 02 each is as previously defined; or p1 is 2; both R 2a linked to form -C 1-6 alkyl- or -C 1-8 heteroalkyl-; R 2b for Cy3is, independently at each occurrence, a substituent on any position of the ring and is p2is 1, 2, or 3; Cy4ring is C 6-10 aromatic ring, 5- to 14-membered heteroaromatic ring, C 3-20 cycloalkyl ring or 3- to 20-membered heterocyclic ring; L3is a bond, -O-C 1-4 alkyl-, -O-, -C 1-4 alkyl-, -N(R 00 )-, -N(R 00 )-C 1-4 alkyl-, -C(=O)-, -CR 09 =CR 10 - or -N(R 00 )C(=O)-; wherein said -C 1-4 alkyl- is optionally substituted with one or more groups selected from deuterium, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl; R 3a for any position on the Cy4ring; R 3a each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, halogenated 1-6 alkyl, C 1-6 alkoxy, halogenated 1-6 alkoxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl; t1is 1, 2, 3, 4, or 5; R 00 each independently is hydrogen or C 1-6 alkyl; or one R 2a with R 00 to form -C 1-6 alkyl- or -C 1-8 heteroalkyl-; R 09 each independently is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl; said substitution is with one or more (e.g. 1, 2, 3, or 4) groups selected from the group consisting of deuterium and halogen; R 10 each independently is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-6 alkyl; said substitution is with one or more (e.g. 1, 2, 3, or 4) groups selected from the group consisting of deuterium and halogen; In the above groups, the substituents are each independently 1, 2, 3, 4, 5 or 6 groups selected from the group S1 ; the groups of the group S1 are each independently selected from the group consisting of -SF5, deuterium, oxo (=0), thioxo (=S), =CR e R f , =NR e , halogen, cyano, hydroxy, carboxy, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl, C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -O-C 3-20 cycloalkyl, -O-3- to 20-membered heterocyclyl, -O-C 6-14 aryl, -O-5- or 6-membered monocyclic heteroaryl, -O-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-C 3-20 cycloalkyl, -C 1-4 alkyl-O-C 3-20 cycloalkyl, -C 1-4 alkyl-3- to 20-membered heterocyclyl, -C 1-4 alkyl-O-3- to 20-membered heterocyclyl, -C 1-4 alkyl-C 6- 14 aryl, -C 1-4 alkyl-O-C 6-14 aryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-O-5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-O-8- to 10-membered bicyclic heteroaryl, -O-C 1-4 alkyl-hydroxy, -O-C 1-4 alkyl-cyano, -O-C 1-4 alkyl-C 1-6 alkyl, -O-C 1-4 alkyl-C 1-6 alkoxy, -O-C 1-4 alkyl-C 3-20 cycloalkyl, -O-C 1-4 alkyl-O-C 3-20 cycloalkyl, -O-C 1-4 alkyl-3- to 20-membered heterocyclyl, -O-C 1-4 alkyl-O-3- to 20-membered heterocyclyl, -O-C 1-4 alkyl-C 6-14 aryl, -C(=O)O-C 1-6 alkyl, -C(=O)O-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 3-20 cycloalkyl, -C(=O)-C 6-14 aryl, -NR a1 R b1 , -C(=O)-NR a1 R b1 , -C(=O)-5- or 6-membered monocyclic heteroaryl, -C(=O)-8- to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 alkyl-C 3-20 cycloalkyl, -C(=O)-C 1-6 alkyl-3- to 20-membered heterocyclyl, -C(=O)-C 1-6 alkyl-C 6-14 aryl, -C(=O)-C 1-6 alkyl-5- or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 alkyl-8- to 10-membered bicyclic heteroaryl, -C 1-4 alkyl-NR a1 R b1 , -C 1-4 alkyl-C(=O)-NR a1 R b1 , -C 1-4 alkyl-OR c1 and -P(=O)-(C 1-6 alkyl)2; wherein the C 1-6 alkyl, the C 1-6 alkoxy, the C 2-6 alkenyl, and the C 2-6 alkynyl are each independently optionally substituted with 1, 2, or 3 groups selected from halogen, deuterium, cyano, or hydroxyl; the C 3-20 cycloalkyl, the 3- to 20-membered heterocyclyl, the C 6-14 aryl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 groups selected from S2; or, when the above groups are each independently substituted with 2, 3, 4, 5, or 6 groups selected from S1, optionally two of the groups of S1 are taken together with the atom(s) to which they are attached to form a bridged ring structure; In the above groups, each R a1 R b1 Each independently represents H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-deuterated C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-deuterated C 1-6 Alkoxy, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkyl-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkyl-OC 3-6 Monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclic groups, -C 1-4 Alkyl-3 to 6-membered monocyclic heterocyclic groups, -C 1-4 Alkyl-O-3 to 6-membered monocyclic heterocyclic groups, phenyl, -C 1-4 Alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Monocyclic cycloalkyl or -C(=O)-3 to 6-membered monocyclic heterocyclic groups; wherein, the C 3-6 The monocyclic cycloalkyl group, the 3- to 6-membered monocyclic heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 and -P(=O)-(C 1-6 Alkyl)2; or each R a1 and R b1 together with the nitrogen atom to which they are attached form a 3- to 20-membered heterocyclyl; wherein said 3- to 20-membered heterocyclyl is each independently optionally substituted with 1 or 2 groups selected from halo, hydroxy, carboxy, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 1- 6alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C 1-6 alkyl)2, and -P(=O)-(C 1-6 alkyl)2; each R c1 is independently H, C 1-6 alkyl, haloC 1-6 alkyl, deuteratedC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuteratedC 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkyl, -C 1-4 alkyl-deuteratedC 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-haloC 1-6 alkoxy, -C 1-4 alkyl-deuteratedC 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-O-C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-3- to 6-membered monocyclic heterocyclyl, -C 1-4 alkyl-O-3- to 6-membered monocyclic heterocyclyl, phenyl, -C 1-4 alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 alkyl-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, or -C 1-4 alkyl-8- to 10-membered bicyclic heteroaryl; said C 3-6 monocyclic cycloalkyl, said 3- to 6-membered monocyclic heterocyclyl, said phenyl, said 5- or 6-membered monocyclic heteroaryl, said 8- to 10-membered bicyclic heteroaryl is optionally substituted with 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxy, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuteratedC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuteratedC 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=O)-(C 1-6 alkyl)2, or -P(=O)-(C 1-6 alkyl)2; In each of the above groups, the groups of each S2group are each independently selected from the group consisting of: deuterium, oxo (=0), thioxo (=S), =CR e R f , =NR e , halogen, hydroxyl, carboxyl, nitro, C 1-6 alkyl, haloC 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, deuterated C 1-6 alkoxy, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -(C=0)-NHC 1-6 alkyl, -(C=0)-N(C 1-6 alkyl)2, -C 1-4 alkyl-P(=0)-(C 1-6 alkyl)2, -P(=0)-(C 1-6 alkyl)2, -(C=0)C 1-6 alkyl and -SF5; In the above groups, the -C 1-4 alkyl- is unsubstituted; or -C 1-4 1, 2, 3 or 4 hydrogen atoms on the alkyl- group are each independently replaced by a member selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl-, haloC 1-6 alkyl-, deuterioC 1-6 alkyl-, -CH2-hydroxy, -CH2-cyano, phenyl; or C 1-4 2 hydrogen atoms on the same carbon atom of the alkyl group are simultaneously replaced by -(CH2) j to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; or C 1-4 2 hydrogen atoms on the same carbon atom of the alkyl group are simultaneously replaced by =CR e R f substituted; In the above groups, R e each independently H, halogen, C 1-6 alkyl, haloC 1-6 alkyl or deuterated C 1-6 alkyl; In the above groups, R f each independently H, halogen, C 1-6 alkyl, haloC 1-6 alkyl or deuterated C 1-6 alkyl; one or more (such as 1, 2, 3, or 4) ring atoms of said 3- to 8-membered heterocyclyl, 3- to 8-membered heterocycle, 3- to 6-membered monocyclic heterocyclyl, or 3- to 8-membered monocyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 7- to 12-membered bicyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 3- to 20-membered heterocycle, said 3- to 20-membered heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, or 4) ring atoms of said 5- or 6-membered monocyclic heteroaromatic ring, said 5- or 6-membered monocyclic heteroaryl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 8- to 10-membered bicyclic heteroaryl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, or 4) ring atoms of said 3- to 6-membered monocyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 5- to 15-membered tricyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, 4, or 5) ring atoms of said 5- to 14-membered heteroaromatic ring is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; 1-6 one or more (such as 1, 2, 3, or 4) ring atoms of said 3- to 8-membered heterocyclyl, 3- to 8-membered heterocycle, 3- to 6-membered monocyclic heterocyclyl, or 3- to 8-membered monocyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (such as 1, 2, 3, or 4) ring atoms of said 3- to 8-membered heterocyclyl, 3- to 8-membered heterocycle, 3- to 6-membered monocyclic heterocyclyl, or 3- to 8-membered monocyclic heterocyclyl is a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; wherein when the ring atom is a sulfur atom, the sulfur atom is optionally substituted with one or two groups selected from oxo and =NR e R e is as previously defined; wherein when the ring atom is a phosphorus atom, the phosphorus atom is optionally substituted with one or two groups selected from oxo and =NR e R e is as previously defined.

2. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: Case A or Case B, selected from the group consisting of Case A, For wherein, R 13 , X and R3 are each defined as in claim 1.

3. The compound of claim 1 or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: a compound of Formula (I) as shown below: In formula (A1), formula (A2), formula (A3), W6, W7, W8, W9, W 10 , R1, R2, R 42 , R 43 , R 4a , R5, R6and L1are each independently defined as in case A of claim 1 ; or in formula (A1), formula (A3), W6, W7, W8, W9, W 10 , R1, R2, R 42 , R 43 , R 4a , R5, R6and L1are each independently defined as in case B of claim 1.

4. The compound of claim 1 or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: a compound of Formula (I) as shown below: In formula (B1), formula (B2), formula (B3), formula (B4), formula (B5), formula (B6), R1, R2, R3, R 13 , R 42 , R 43 , R 4a , R5, R6and L1are each independently defined as in case A of claim 1; or In formula (B1), formula (B2), formula (B3), formula (B4), R1, R2, R3, R 13 , R 42 , R 43 , R 4a , R5, R6and L1are each independently defined as in case B of claim 1.

5. The compound of claim 1 or its stable deuterated derivative or its stereoisomer, or its pharmaceutically acceptable salt, solvate or prodrug: the compound of formula (I) is shown in the following formula: in which W6, R3, R 42 , R 43 , R 4a , R5and R6are each as defined in case A of claim 1 ; in formula (B9) W6, R3, R 42 , R 43 , R 4a , R5, R6, R1, R2are each as defined in case B of claim 1.

6. The compound of claim 1 or 2, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 40 is hydrogen; R 41 is hydrogen.

7. The compound of any one of claims 1-4, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R1is hydrogen; R2is hydrogen.

8. The compound of any one of claims 1-5, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 42 is methyl; R 43 is methyl.

9. The compound of any one of claims 1-4, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: L1is -L2-substituted or unsubstituted thiazolyl- or -L2-substituted or unsubstituted oxazolyl-; L2is as defined in claim 1.

10. The compound of claim 9, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: each L2is independently a bond or -CH=CH-.

11. The compound of claim 9, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: L1is wherein, " " indicates the point of attachment to ring A.

12. The compound of any one of claims 1-5, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 13 is hydrogen.

13. The compound of any one of claims 1-5, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R3 is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, deuteratedC 1-6 alkyl, C 3-6 cycloalkyl-substituted C 1-6 alkyl or C 3-6 cycloalkyl.

14. The compound of claim 13, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R3 is hydrogen, C 1-3 alkyl, haloC 1-3 alkyl, C 3-6 cycloalkyl-substituted C 1-3 alkyl or deuterated C 1-3 alkyl.

15. The compound of claim 13, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R3is ethyl, cyclopropyl-substituted methyl, cyclobutyl-substituted methyl, or trifluoromethyl-substituted methyl.

16. The compound of claim 1 or 2, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: Y1is N; Y2is CH.

17. The compound of any one of claims 1-5, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 4a -C 1-6 alkyl-C 1-6 alkoxy.

18. The compound of any one of claims 1-5, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 4a -C 1-3 alkyl-C 1-3 alkoxy.

19. The compound of claim 18, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 4a is -CH(CH3)-0-CH3.

20. The compound of claim 18, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 4a To 21. The compound of any one of claims 1-5, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R5is -NR 01 R 02 or -C(R 05 )R 03 R 04 ; R 01 , R 02 and the nitrogen atom to which they are attached collectively form a substituted or unsubstituted nitrogen-containing 3- to 8-membered monocyclic heterocyclyl; one ring atom of the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, or 3) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus; R 03 , R 04 and the carbon atom to which they are attached collectively form a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; R 05 is as defined in claim 1. Preferably, the 5- or 6-membered monocyclic heteroaryl is pyrazolyl or pyridinyl; Preferably, said 5 or 6 membered monocyclic heteroaryl is unsubstituted or substituted by C 1-3 alkyl-5 to 6 membered heterocyclyl.

22. The compound of any one of claims 1-5, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R5is -C 2-4 alkynyl-NR 01 R 02 or -C 2-4 alkynyl-C 1-4 alkyl-NR 01 R 02 ; R 01 , R 02 and the nitrogen atom to which they are attached together form a substituted or unsubstituted nitrogen-containing 3- to 8-membered monocyclic heterocyclyl; one ring atom of the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is a nitrogen atom and optionally one or more (e.g., 1, 2, or 3) ring atoms are a heteroatom selected from nitrogen, oxygen, sulfur, or phosphorus.

23. The compound of claim 22, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is selected from Preferably, the nitrogen-containing 3- to 8-membered monocyclic heterocyclyl is unsubstituted or substituted with one or two groups selected from cyano, methyl, or cyclopropyl, or two of the methyl groups are joined to form -CH2CH2-.

24. The compound of claim 21 or 22, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R5is selected from 25. The compound of claim 1 or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 12 is hydrogen.

26. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: Cy4ring is a phenyl ring, a naphthalene ring, a thiazole ring, an isothiazole ring, a thiophene ring, or a pyridine ring.

27. The compound of claim 1 or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 3a is halogen or methyl.

28. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: t1is 1.

29. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: L3 is a bond, -O-CH2-, -O-CH(CH3)-, -O-CH(CH2CH3)-, -O-(CH2)2-, -NH-CH2-, -NH-CH(CH3)-, or -CH2-.

30. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: p2 is 1.

31. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: Cy3ring is a phenyl ring, naphthalene ring, pyridine ring, 32. The compound of claim 1 or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 2a is hydrogen, fluoro, chloro, cyano, methoxy, ethoxy, isopropoxy, cyclopropoxy, methyl, ethyl, cyclopropyl, 33. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: p1 is 2.

34. The compound of claim 1 or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: two R 2a is linked to form -C 1-3 heteroalkyl-.

35. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: m is 1.

36. The compound of any one of claims 1-5, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R6is each p3is independently 0 or 1; p4is 1 or 2; n, R 61 , R 62 are each as defined in claim 1.

37. The compound of claim 1 or 36, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 61 is hydrogen, oxo, or methyl.

38. The compound of claim 1 or 36, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: n is 1.

39. The compound of claim 1 or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 09 is hydrogen.

40. The compound of claim 1 or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 10 is hydrogen.

41. The compound of claim 1 or a stable deuterated derivative thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R 00 is hydrogen.

42. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: the compound is selected from Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, Z20, Z21, Z22, Z23, Z24, Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39, Z40, Z41, Z42, Z43, Z44, Z45, Z46, Z47, Z48, Z49, Z50, Z51, Z52, Z53, Z54, Z55, Z56, Z57, Z58, Z59, Z60, Z61, Z62, Z63, Z64, Z65, Z66, Z67, Z68, Z69, Z70, Z71, Z72, Z73, Z74, Z75, Z76, Z77, Z78, Z79, Z80, Z82, Z83, Z84, Z85, Z86, Z87, Z88, Z89, Z90, Z91, Z92, Z93, Z94, Z95, Z96, Z97, Z98, Z99, Z100, Z101, Z102.

43. The compound of any one of claims 1-4, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R1is -NR 17 R 18 ; wherein R 17 R 18 and the nitrogen atom to which they are attached join to form a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted 6- to 12-membered bicyclic heterocyclyl, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl; Preferably, R1is -NR 17 R 18 ; Among them, R 17 R 18 Together with the attached nitrogen atom, they form substituted or unsubstituted 4- to 6-membered monocyclic heterocyclic groups and substituted or unsubstituted 7- to 9-membered bicyclic heterocyclic groups; R1is -NR 17 R 18 ; wherein R 17 , R 18 and the nitrogen atom to which they are attached together form a substituted or unsubstituted 7- to 9-membered bicyclic spiro heterocyclyl group; Preferably, R1is selected from the group consisting of: and the above groups are substituted or unsubstituted; each of said substitutions is independently that each of the above groups is independently substituted with 1, 2, 3, 4, 5, or 6 groups selected from S1.

44. The compound of any one of claims 1-4, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R3is selected from the group consisting of -CH2CH2O-R 19 ; R 19 is a substituted or unsubstituted 5- to 15-membered tricyclic heterocyclyl, a substituted or unsubstituted 6- to 12-membered bicyclic heterocyclyl, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocyclyl; Preferably, R3is selected from the group consisting of: said groups are substituted or unsubstituted; said substitution means that each of the above groups is independently substituted with 1, 2, 3, or 4 C 1-6 alkyl groups; R3is selected from the group consisting of C 1-6 alkoxy-substituted C 1-6 alkyl, -O-3 to 20 membered heterocyclyl-substituted C 1-6 alkyl; R3is selected from the group consisting of C 1-3 alkoxy-substituted C 1-3 alkyl, -O-3 to 20 membered heterocyclyl-substituted C 1-3 alkyl; Preferably, R3is selected from the group consisting of:

45. The compound of any one of claims 1-4, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: R5 is selected from the group consisting of Preferably, R5is selected from the group consisting of:

46. The compound of claim 1, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: the compound is selected from Z103, Z104, Z105, Z106, Z107, Z108, Z109, Z110, Z111, Z112, Z113, Z114, Z115, Z116, Z117, Z118, Z119, Z120, Z121, Z122, Z123, Z124, Z125, Z126, Z127, Z128, Z129, Z130, Z131, Z132, Z133, Z134, Z135, Z136, Z137, Z138, Z139, Z140, Z141, Z142, Z143, Z144, Z145, Z146, Z147, Z148, Z149, Z150, Z151, Z152, Z153, Z154, Z155, Z156, Z157, Z158, Z159, Z160, Z161, Z162, Z163, Z164, Z165, Z166, Z167, Z168, Z169, Z170, Z171, Z172, Z173, Z174, Z175, Z176, Z177, Z178, Z179, Z180, Z181, Z182, Z183, Z184, Z185, Z186, Z187, Z188, Z189, Z190, Z191, Z192, Z193, Z194, Z195, Z196, Z197, Z198, Z199, Z200, Z201, Z202, Z203, Z204, Z205, Z206, Z207, Z208, Z209, Z210, Z211, Z212, Z213, Z214, Z215, Z216, Z217, Z218, Z219, Z220, Z221, Z222, Z223, Z224, Z225, Z226, Z227, Z228, Z229, Z230, Z231, Z232, Z233, Z234, Z235, Z236, Z237, Z238, Z239, Z240, Z241, Z242, Z243, Z244, Z245, Z246, for use in the prevention and / or treatment of a disease or disorder associated with KRAS G12V protein activity.

47. A pharmaceutical composition comprising a compound of any one of claims 1-46, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier.

48. Use of a compound of any one of claims 1-46, or a stable deuterated derivative thereof or stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of claim 47, for the manufacture of a medicament for the prevention and / or treatment of a disease or disorder associated with KRAS G12V protein activity.

49. The use of claim 48, wherein, The disease or disorder associated with KRAS G12V protein activity is cancer.

50. The use of claim 49, wherein, The cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, squamous cell lung cancer, esophageal cancer, ovarian cancer, uterine cancer, melanoma, bladder cancer, or head and neck cancer.

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