Compound having triple bond structure, and pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a compound having a triple bond structure, and a pharmaceutical composition thereof and the use thereof. Provided in the present invention is a compound having a triple bond structure as represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of the pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope compound thereof. As a highly selective inhibitor, the compound having the triple bond structure of the present invention can not only meet the requirements of tumor treatment, but also helps to reduce adverse reactions caused by the inhibition of PARP-2.

Description

A triple bond structure compound, its pharmaceutical composition and its application Technical Field

[0001] The present invention relates to a triple-bond structure compound, a pharmaceutical composition thereof and application thereof. Background Art

[0002] The poly(ADPribose) polymerase family (PARP) consists of 17 members that primarily mediate the phosphorylation of target proteins. The increased negative charge caused by phosphorylation alters the structure of the target protein and the interaction between PARP and the target protein. Consequently, PARPs influence numerous biological processes, including the regulation of chromatin structure, transcription, cell cycle progression, apoptosis, and DNA replication and repair. The most intensively studied of these is the role of PARP-1 and PARP-2 in repairing single-strand DNA damage.

[0003] Studies have shown that PARP is overexpressed in diseases such as tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, and metabolic stress. Among them, the role of PARP in tumors has been studied most intensively. Inhibiting PARP activity in tumor cells can reduce DNA repair in tumor cells, thereby promoting tumor cell death. Therefore, PARP has become an important target for the development of tumor drugs. PARP inhibitors have a synergistic lethal effect on tumors with breast cancer susceptibility gene (BRCA) mutations. They can target tumor cells with homologous recombination repair (HRR) defects, thereby killing tumor cells more effectively. BRCA mutations were first discovered in ovarian cancer and breast cancer, and prostate cancer and pancreatic cancer are also related to BRCA gene mutations.

[0004] PARP inhibitors are expected to become ideal drugs for cancer treatment and have broad research significance. In recent years, several PARP inhibitors have been approved by the FDA for the treatment of tumors. These marketed PARP inhibitors have low selectivity. While inhibiting PARP-1, they also affect PARP-2, and all have significant adverse reactions. Studies have found that the loss of PARP-2 shortens the lifespan of mouse red blood cells and impairs the differentiation of erythroid progenitor cells, leading to chronic anemia. Ischemic damage can cause neuronal damage, and chemical damage makes pancreatitis more likely to occur. In addition, spermatogenesis, adipogenesis, and thymogenesis are also impaired in PARP-2 single knockout mice.

[0005] Since the first PARP inhibitor was launched in 2014, six PARP inhibitors have been released worldwide, all of which are non-selective. Low-toxicity, highly selective inhibitors not only meet the requirements of cancer treatment but also help reduce the adverse reactions caused by PARP-2 inhibition. The successful development of PARP inhibitors has revolutionized some cancer drug treatment options, particularly in the field of ovarian cancer, ushering in the era of precision medicine for the treatment of recurrent ovarian cancer. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a highly selective inhibitor that not only meets the requirements of tumor treatment but also helps to reduce the adverse reactions caused by the inhibition of PARP-2.

[0007] The present invention provides a triple-bond structure compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof:

[0008] Among them, ring D is

[0009] is a single bond or a double bond;

[0010] M is -C(R 1 )=、-C(R 1 R 2 )-or-NR a -;

[0011] D1 is CL D1 -R 6 , N, NR or S;

[0012] D2 does not exist, CL D2 -R 7 or N, wherein when D1 is S or NR, D2 is absent;

[0013] D3 is CL D3 -R 8 or N;

[0014] D4 is absent, O, S, N, NR 4 or -C(R 4 R 5 );

[0015] D5 is CL D5 -R 9 or N;

[0016] or D1 and D4 and the atoms to which they are attached form a "5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S";

[0017] when When there is a double bond, any of the following conditions (1), (2), (3) and (4) apply:

[0018] (1)M is -C(R 1 )=, D4 is N; R 1 For hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl;

[0019] (2)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 The carbon atom to which it is attached forms Ring A is phenyl, "3-8 membered cycloalkenyl", "3-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S" or "5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S";

[0020] (3)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 Alkyl; or, R 4 and L D1 -R 6 Together with the carbon atom to which it is attached, it forms an optionally substituted phenyl group or a 5-6 membered aryl group containing 1 to 4 heteroatoms independently selected from O, N and S;

[0021] (4)M is -NR a -, R 5 and R a Does not exist, R 4 For hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl;

[0022] when For a single bond, either of the following conditions (5) and (6) applies:

[0023] (5) D4 is NR4 ,M is -C(R 1 )=,R 1 Does not exist, M and R 4 The “3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S” or “6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S”; the “3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S” and “6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S” are optionally substituted by any of the following groups: C 1-6 Alkyl, Halogen, -CN, -OR, -SR, -N(R)2, -NO2, -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O) 2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2 or -SON(R)2;

[0024] (6)M is -C(R 1 R 2 )-or-N(R a )-, D4 is absent, O, S or -C(R 4 R 5 );R 1 and R 2 are independently hydrogen, halogen, C 1-6 -C(O)N(R)2, -CN, -OR, -SR, -N(R)2, -NO2, -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O)2R', -SON(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, or -SON(R)2, or is optionally substituted by any of the following groups: C1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S"; or, R 1 and R 2 The carbon atom to which it is attached forms a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, a 6-10 membered saturated or partially unsaturated bicyclic carbocyclic group, a "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", a "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S"; or

[0025] R 2 and R 4 The carbon atom to which it is attached forms Ring A' is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from O, N and S;

[0026] R a For hydrogen or

[0027] L R3 is a connecting key or C 1-6 alkylene;

[0028] R 3 is hydrogen or any substituted C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, "8-10 membered bicyclic aryl", "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from O, N and S", "6-10 membered saturated or partially unsaturated bicyclic heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S", "5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S" or "8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected from O, N and S";

[0029] R 4 and R 5and -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R), -NRC(O)N(R), -NRS(O)N(R), -NRS(O)R', -NRS(O)N(R), or -SON(R). 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic ring, "3-7 membered saturated or partially unsaturated monoheterocyclic ring containing 1-3 heteroatoms, which are independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic ring containing 1-4 heteroatoms, which are independently selected from O, N and S"; or

[0030] R 4 and R 5 The carbon atom connected to it forms -C=O-, -C=S-, -C=NR L -, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, a 6-10 membered saturated or partially unsaturated bicyclic carbocyclic group, a "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", a "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S"; or

[0031] R L is hydrogen, -CN, -OR L1 or any substituted C 1-6 alkyl;

[0032] R L1 For hydrogen, C 1-6 Alkyl or halogen substituted C 1-6 alkyl;

[0033] Each L is independently a connecting bond, C 1-6 Alkylene or C substituted by one or more halogen 1-6 alkylene;

[0034] Each R A1 are independently halogen, -CN, -OR, -SR, -N(R)2, -N +(R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R ', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR', ​​-C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R' or -P(O)(R)2, or optionally substituted by any of the following groups: C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S";

[0035] L D1 、L D2 , L D3 and L D5 is independently a connecting bond or an optionally substituted C 1-6 alkylene;

[0036] R 6 、R 7 、R 8 and R 9 are independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R ', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR', ​​-C(=NR m)N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R' or -P(O)(R)2, or optionally substituted by any of the following groups: C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", or "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S";

[0037] X is a connecting bond, -C(O)-, O or NR x ;

[0038] R x For hydrogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl or C 3-8 Cycloalkyl;

[0039] Ring C is C 6-10 Aryl, "3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, N and S", "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S", "9-10 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S" or dihydropyridyl;

[0040] R C -L C -R C1 ; When R C When there are multiple R C Same or different;

[0041] Each L C Independently for the connecting bond, C 1-6 Alkylene or C substituted by one or more halogen 1-6 alkylene;

[0042] Each R C1 are independently hydrogen, oxo, halogen, -CN, -OR, -SR, -N(R)2, -N +(R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R ', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR'、-C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R', -P(O)(R)2, "a 5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S", or the above groups are arbitrarily substituted by any of the following groups: halogen, C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", or "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S";

[0043] Each R is independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S" or "4-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", the C 1-6 Alkyl, -OC 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S" or "4-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S" any deuterated, halogen, hydroxyl, cyano, C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, -OC 1-6Alkyl, C 3-8 Cycloalkyl and hydroxy substituted C 1-6 is substituted by one or more substituents in the alkyl group; or

[0044] Two Rs and the N atom to which they are connected form a "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S";

[0045] Each R' is independently an optionally substituted or unsubstituted C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-10 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, N and S", or "8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms, which are independently selected from O, N and S", or

[0046] Two R's and the N atom to which they are connected form a "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S";

[0047] Each R m are independently -OH, -CN or R;

[0048] m is 0, 1, 2, 3 or 4;

[0049] p and n are independently 0, 1, 2 or 3;

[0050] q is 0, 1, 2, 3, 4 or 5.

[0051] In a certain embodiment, among the triple bond structure compounds shown in Formula I, the specific compound

[0052] Ring D is

[0053] is a single bond or a double bond;

[0054] M is -C(R 1 )=、-C(R 1 R 2 )-or-NR a -;

[0055] D1 is CL D1 -R 6 or N

[0056] D2 is CL D2 -R 7 ,;

[0057] D3 is CL D3 -R 8 or N;

[0058] D4 is absent, O, S, N, NR 4 or -C(R 4 R 5 );

[0059] or D1 and D4 and the atoms to which they are attached form a "5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S";

[0060] when When there is a double bond, any of the following conditions (1), (2), (3) and (4) apply:

[0061] (1)M is -C(R 1 )=, D4 is N; R 1 For hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl;

[0062] (2)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 The carbon atom to which it is attached forms Ring A is phenyl, "3-8 membered cycloalkenyl", "3-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S" or "5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S";

[0063] (3)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 Alkyl; or, R 4 and L D1 -R 6 Together with the carbon atom to which it is attached, it forms an optionally substituted phenyl group or a 5-6 membered aryl group containing 1 to 4 heteroatoms independently selected from O, N and S;

[0064] (4)M is -NRa -, R 5 and R a Does not exist, R 4 For hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl;

[0065] when For a single bond, either of the following conditions (5) and (6) applies:

[0066] (5) D4 is NR 4 ,M is -C(R 1 )=,R 1 Does not exist, M and R 4 Forming a "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S"; the "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S" is optionally substituted by any of the following groups: C 1-6 Alkyl or halogen;

[0067] (6)M is -C(R 1 R 2 )-or-N(R a )-, D4 is absent, O, S or -C(R 4 R 5 ), R 1 and R 2 are independently hydrogen, halogen or C 1- 6 alkyl; or

[0068] R 2 and R 4 The carbon atom to which it is attached forms Ring A' is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from O, N and S;

[0069] L is a connecting bond or C 1-6 alkylene;

[0070] R A1 C 1-6 Alkyl, halogen or C substituted by one or more halogens 1-6 alkyl;

[0071] R a for

[0072] L R3is a connecting key or C 1-6 alkylene;

[0073] R 3 is hydrogen, arbitrarily substituted C 1-6 Alkyl or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group;

[0074] R 4 and R 5 are independently hydrogen;

[0075] L D1 、L D2 and L D3 independently a connecting bond;

[0076] R 6 、R 7 and R 8 are independently hydrogen or halogen;

[0077] X is a connecting bond, -C(O)-, O or NR x ;

[0078] R x For hydrogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl or C 3-8 Cycloalkyl;

[0079] Ring C is C 6-10 Aryl, "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S" or dihydropyridyl;

[0080] R C -L C -R C1 ;

[0081] Each L C Independently for the connecting bond, C 1-6 Alkylene or C substituted by one or more halogen 1-6 alkylene;

[0082] Each R C1 are independently hydrogen, oxo, halogen, -CN, -N(R)2, -OC 1-6 Alkyl, -C(O)N(R)2, C substituted by one or more halogens 1-6 Alkyl, "5-12 membered heteroaryl containing 1-3 heteroatoms, which are independently selected from O, N and S", or the above groups are optionally substituted by any of the following groups: C 1-6 alkyl;

[0083] Each R is independently hydrogen, C 1-6 Alkyl, C6-10 Aryl, -OC 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", "4-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", the C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl, 3-7 membered saturated or partially unsaturated monocyclic carbon ring, optionally substituted by deuterium, halogen, hydroxyl, cyano, C 1- 6-alkyl, cyano-substituted C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl and hydroxy substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0084] m is 0, 1, or 2;

[0085] p and n are independently 0, 1 or 2;

[0086] q is 0, 1, 2, or 3.

[0087] In a certain embodiment, among the triple bond structure compounds shown in Formula I, there are

[0088] Ring D is

[0089] is a single bond or a double bond;

[0090] M is -C(R 1 )=、-C(R 1 R 2 )-or-NR a -;

[0091] D1 is CL D1 -R 6 or N;

[0092] D2 is CL D2 -R 7 or N;

[0093] D3 is CL D3 -R 8 ;

[0094] D4 is absent, O, S, N, NR 4 or -C(R 4 R 5 );

[0095] or D1 and D4 and the atoms to which they are attached form a "5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S";

[0096] when When there is a double bond, any of the following conditions (1), (2), (3) and (4) apply:

[0097] (1)M is -C(R 1 )=, D4 is N; R 1 C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl;

[0098] (2)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 The carbon atom to which it is attached forms Ring A is phenyl, "3-8 membered cycloalkenyl" or "5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; m is 0, 1 or 2, L is a connecting bond or C 1-6 Alkylene, R A1 C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl or halogen;

[0099] (3)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 are independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl;

[0100] (4)M is -NR a -, R 5 and R a Does not exist, R 4 C 1-6 alkyl;

[0101] when For a single bond, either of the following conditions (5) and (6) applies:

[0102] (5) D4 is NR 4 ,M is -C(R 1 )=,R 1 Does not exist, M and R 4Forming a "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S"; the "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S" is optionally substituted by any of the following groups: C 1-6 Alkyl or halogen;

[0103] (6)M is -C(R 1 R 2 )-or-N(R a )-, D4 is O or -C(R 4 R 5 );R 1 and R 2 are independently hydrogen or C 1-6 Alkyl; R a C 3-8 Cycloalkyl; R 4 and R 5 are independently hydrogen;

[0104] L D1 , L D and L D3 independently a connecting bond;

[0105] R 6 、R 7 and R 8 are independently hydrogen or halogen;

[0106] X is a connecting bond, -C(O)-, O or NR x ;

[0107] R x For hydrogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl or C 3-8 Cycloalkyl;

[0108] Ring C is C 6-10 Aryl, "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S" or dihydropyridyl;

[0109] R C -L C -R C1 ;

[0110] Each L C Independently for the connecting bond, C 1-6 Alkylene or C substituted by one or more halogen 1-6 alkylene;

[0111] Each R C1independently hydrogen, oxo, halogen, -CN, -N(R)2, -C(O)N(R)2, "5-12 membered heteroaryl containing 1-3 heteroatoms, which are independently selected from O, N and S", or the above groups are optionally substituted by any of the following groups: C 1-6 alkyl;

[0112] Each R is independently hydrogen, C 1-6 Alkyl, C 6-20 Aryl, -OC 1-6 Alkyl or 3-7 membered saturated monocyclic carbocyclic group; the C 1-6 Alkyl, C 6-20 Aryl or 3-7 membered saturated monocyclic carbocyclic group is optionally substituted with deuterium, halogen, -OC 1-6 Alkyl and C 3-8 substituted by one or more substituents in the cycloalkane;

[0113] p and n are independently 0 or 1;

[0114] q is 0, 1, 2, or 3.

[0115] In one embodiment, M is -N(R a )-, is a single bond, and D1 and D4 and the atoms to which they are attached form a "5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S".

[0116] In one embodiment, M is -N(R a )-, D1 is CL D1 -R 6 , D4 is -C(R 4 R 5 ), D1 and D4 and the atoms to which they are attached form a "5-6 membered heteroaromatic ring containing 1-3 heteroatoms, which are independently selected from O, N and S", for example, a 6-membered heteroaromatic ring containing two heteroatoms N.

[0117] In one plan, middle, is a double bond, M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 The carbon atom to which it is attached forms Ring A is phenyl, "3-8 membered cycloalkenyl", "3-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S" or "5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S".

[0118] In one plan, middle, is a single bond, M is -C(R 1 R 2 ), D4 is -C(R 4 R 5 ), R 2 and R 4 The carbon atom to which it is attached forms When Ring A' is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from O, N and S, D5 is CL D5 -R 9 or N, R 1 and R 5 are independently hydrogen.

[0119] In one plan, middle, is a double bond, M is -C(R 1 )=, D4 is N; R 1 For hydrogen, halogen, C 1- 6 alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 Alkyl; D1, D2 and D3 are as defined above, preferably D1 is CL D1 -R 6 or N, D2 is CL D2 -R 7 or N, D3 is CL D3 -R 8 or N.

[0120] In one embodiment, when ring D is When ring D is The definitions of D1, D2 and D3 are as described above, preferably D1 is CL D1 -R 6 or N, D2 is CL D2 -R 7 or N, D3 is CL D3 -R 8 or N.

[0121] In one plan, middle, is a double bond, M is -C(R 1 )=, D4 is N or -C(R 4 R 5 );R 1 and R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen1-6 Alkyl; R 5 Not present; D1, D2 and D3 are as defined above, preferably D1 is CL D1 -R 6 or N, D2 is CL D2 -R 7 or N, D3 is CL D3 -R 8 or N.

[0122] In a certain embodiment, when Ring C is a "5-12 membered heteroaryl group containing 1-3 heteroatoms independently selected from O, N and S", Ring C is a pyridyl group, an isoquinolyl group or an imidazolyl group.

[0123] In a certain scheme, when R C1 When it is a "5-12 membered heteroaryl group containing 1-3 heteroatoms independently selected from O, N and S", the R C1 It is pyrazolyl.

[0124] In one plan, for

[0125] In one embodiment, X is a linker, O, NCH3, or NH.

[0126] In one plan, for

[0127] In one embodiment, ring C is pyridyl, phenyl, imidazolyl, isoquinolinyl, 1H-indazolyl, 1,2-dihydropyridyl,

[0128] In one plan, for

[0129] In one embodiment, the triple bond structure compound as shown in Formula I is any of the following compounds:

[0130] The present invention also provides a compound, the structure of which is shown below:

[0131] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the triple-bond structure compound as described above as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0132] The present invention also provides a use of the aforementioned triple-bond structure compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its solvate of a pharmaceutically acceptable salt, its crystal form, its stereoisomer, its tautomer or its isotope compound in the preparation of PARP inhibitor drugs.

[0133] The present invention also provides a triple-bond structure compound as described above as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its solvate of a pharmaceutically acceptable salt, its crystal form, its stereoisomer, its tautomer or its isotope compound for use in the preparation of a drug for treating cancer, ischemic disease or neurodegenerative disease; preferably, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

[0134] In the present invention, when referring to C 1-6 When alkyl, the C 1-6 The alkyl group can be C 1-4 Alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0135] In one embodiment, when a halogen is mentioned, the halogen is fluorine, chlorine, bromine or iodine.

[0136] In a certain scheme, when C 3-8 When cycloalkyl, the C 3-8 Cycloalkyl can be C 3-6 Cycloalkyl, for example, cyclopropyl, cyclobutane, cyclopentane or cyclohexane.

[0137] The positive progress of the present invention is that the triple-bond structure compound shown in Formula I provided by the present invention can serve as a highly selective inhibitor that not only meets the requirements of tumor treatment but also helps to reduce the adverse reactions caused by PARP-2 inhibition. DETAILED DESCRIPTION

[0138] The present invention is further illustrated by way of examples below, but the invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications. The solvents involved in the following examples were all analytically pure or chromatographically pure. When the solvents involved in the following examples are mixed solvents, unless otherwise stated, all are by volume ratios.

[0139] Synthesis of key intermediates:

[0140] Synthesis route of intermediate 1

[0141] Synthesis of compound YL230769-262

[0142] To a 250 mL three-necked flask, ethyl 5-nitro-6-methylnicotinate (7880 mg, 37.490 mmol), selenium dioxide (6240.38 mg, 56.235 mmol), and 1,4-dioxane (70 mL) were added in sequence. Under nitrogen protection, the reaction was carried out at 110°C for 18 hours. LCMS showed that the reaction was complete. The filtrate was filtered and concentrated by column chromatography to obtain YL230769-262 (7000 mg, 31.226 mmol, 83.29%). LC-MS (ESI): m / z 225.0 (M+H) + .

[0143] Synthesis of compound YL230769-269

[0144] To a 250 mL three-necked flask, sodium hydride (2997.72 mg, 74.943 mmol) and tetrahydrofuran (40 mL) were added sequentially. Under nitrogen, the mixture was cooled to 0°C, followed by the slow addition of triethyl 2-butyl acrylate (18904.40 mg, 74.943 mmol). The reaction was allowed to proceed at 0°C for 10 minutes, then the temperature was slowly raised to room temperature and the reaction continued for 10 minutes. The temperature was then raised to 40°C and the reaction continued for 5 minutes. The reaction solution was then cooled to -78°C, and YL230769-262 (7000 mg, 31.226 mmol) was added. The reaction was continued at this temperature for 1 hour. LCMS indicated the reaction was complete. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic phase was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 40:1-30:1) to yield YL230769-269 (8300 mg, 25.751 mmol, 82.47%). LC-MS (ESI): m / z 323.2 (M+H) + .

[0145] Synthesis of compound YL230769-270

[0146] To a 250 mL three-necked flask were added YL230769-269 (8300 mg, 25.751 mmol), 10% palladium on carbon (4100 mg, 38.527 mmol), and ethanol (60 mL). The mixture was allowed to react at room temperature for 18 hours under hydrogen protection. LCMS indicated the reaction was complete. The reaction solution was filtered and the filtrate was concentrated to obtain YL230769-270 (4800 mg, 16.307 mmol, 63.33%). LC-MS (ESI): m / z 295.3 (M+H) + .

[0147] Synthesis of compound YL230769-272

[0148] To a 100 mL three-necked flask, YL230769-270 (4800 mg, 16.307 mmol) and a 4 mol / L 1,4-dioxane hydrochloride solution (35 mL) were added sequentially. Under nitrogen protection, the mixture was allowed to react at room temperature for 1 hour. LCMS indicated the reaction was complete. A large amount of ether was added, the reaction mixture was filtered, and the filter cake was dried to obtain YL230769-272 (3914 mg, 15.764 mmol, 96.67%). LC-MS (ESI): m / z 249.2 (M+H) + .

[0149] Synthesis of compound YL230769-274

[0150] To a 250 mL three-necked flask, YL230769-272 (3900 mg, 15.708 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (4278.88 mg, 18.850 mmol), and 1,4-dioxane (65 mL) were added in sequence. Under nitrogen protection, the mixture was reacted at 110°C for 3 hours. LCMS showed that the reaction was complete, the reaction solution was concentrated, and then a saturated aqueous sodium bicarbonate solution was added thereto, filtered, and the filter cake was dried to obtain YL230769-274 (2440 mg, 9.908 mmol, 63.07%). LC-MS (ESI): m / z 247.2 (M+H) + .

[0151] Synthesis of compound YL230769-275

[0152] To a 250 mL three-necked flask, YL230769-274 (2440 mg, 9.908 mmol) and tetrahydrofuran (50 mL) were added sequentially. Under nitrogen protection, the mixture was cooled to 0°C, and then lithium aluminum tetrahydride solution (19.816 mL, 19.816 mmol) was slowly added dropwise. The reaction was continued at this temperature for 1 hour. LCMS showed that the reaction was complete. Ethyl acetate was slowly added dropwise to the reaction solution, and the reaction solution was directly concentrated and column chromatography (dichloromethane:methanol = 20:1-10:1) was performed to obtain YL230769-275 (1550 mg, 7.589 mmol, 76.60%). LC-MS (ESI): m / z 205.1 (M+H) + .

[0153] Synthesis of compound YL230769-283

[0154] To a 50 mL three-necked flask, YL230769-275 (408 mg, 1.998 mmol), dichloromethane (10 mL), and N,N-dimethylformamide (0.016 mL, 0.200 mmol) were added sequentially. Under nitrogen protection, the mixture was cooled to 0°C, and then thionyl chloride (1425.91 mg, 11.986 mmol) was slowly added. The temperature was then raised to room temperature and the reaction was continued for 3 hours. LCMS indicated that the reaction was complete. Saturated sodium bicarbonate solution and dichloromethane were slowly added to the reaction solution. The organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 30:1-20:1) to obtain YL230769-283 (254 mg, 1.141 mmol, 57.10%). LC-MS (ESI): m / z 223.1 (M+H) + .

[0155] Synthesis route of intermediate 2

[0156] Synthesis of compound YL230783-167-A

[0157] Dissolve 1-bromo-2,4-difluoro-3-nitrobenzene (45 g, 189.084 mmol) and L-alanine methyl ester hydrochloride (26.39 g, 189.084 mmol) in DMF (180 mL). Slowly add N,N-diisopropylethylamine (73.32 g, 567.251 mmol). Continue the reaction at room temperature overnight. After the reaction is complete, remove most of the reaction solvent and dilute with ethyl acetate and water. Separate the organic phase, and extract the aqueous phase with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The resulting crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 4 to 100 / 8) to give compound YL230783-167-A (33.5 g, 103.807 mmol, 54.90%), ESI: (m / z) = 320.9 / .322.9 [M+H] + , 1 H NMR (400MHz, Chloroform-d) δ7.47 (dd, J=9.3, 6.9Hz, 1H), 7.23 (s, 1H), 6.40 (dd, J=9.4, 1.8Hz, 1H), 4.20 (p, J=7.0Hz, 1H), 3.78 (s, 3H), 1.57 (d, J=7.0Hz, 3H).

[0158] Synthesis of compound YL230783-170-A

[0159] Zinc powder (54.57 g, 834.631 mmol), YL230783-167-A (33.5 g, 104.329 mmol), and ammonium chloride (44.64 g, 834.631 mmol) were dissolved in a mixture of methanol (360 mL) and water (18 mL) under ice conditions and allowed to react overnight at room temperature. After completion, the remaining solid residue was filtered and rinsed with a large amount of methanol:dichloromethane (1:5) solution. The filtrate was concentrated and then diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to yield the mixed compound YL230783-170-A (31.8 g, 86.294 mmol, 82.71%), ESI: (m / z) = 291.0 / 293.0 [M+H] + , some of the products have been ring-closed to generate the product required for the next step.

[0160] Synthesis of compound YL230783-171-A

[0161] YL230783-170-A (31.8 g, 109.233 mmol) was dissolved in a mixture of ethyl acetate (170 mL) and methanol (170 mL). A 4 M hydrochloric acid-1,4-dioxane solution (25 mL) was then added and the reaction continued at room temperature for 1 hour. Upon completion, the solvent was removed by rotary evaporation to yield the crude target compound YL230783-171-A (29.5 g, 74.012 mmol, 67.76%). ESI: (m / z) = 259.1 [M+H] + .

[0162] Synthesis of compound YL230783-172-A

[0163] YL230783-171-A (29.5 g, 113.864 mmol) was dissolved in dichloromethane (1100 mL), and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (31.02 g, 136.637 mmol) was added all at once. The reaction was continued at room temperature for 2 hours. After the reaction was completed, the solvent was removed by evaporation, and a large amount of saturated sodium bicarbonate was added to quench the reaction. The mixture was stirred at room temperature overnight and filtered. The filter cake was rinsed with a large amount of water and then with diethyl ether. The filter cake was evaporated to dryness to directly obtain compound YL230783-172-A (16.7 g, 40.928 mmol, 35.94%). ESI: (m / z) = 257.0 / 259.0 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.62 (s, 1H), 7.53–7.45 (m, 2H), 2.40 (s, 3H).

[0164] Synthesis of compound YL230783-173-A

[0165] YL230783-172-A (10 g, 38.901 mmol) and XPhos Pd G2 (1.53 g, 1.945 mmol) were dissolved in 1,2-dioxane (200 mL) at room temperature and replaced with nitrogen. (tributyltin)methanol (14.99 g, 46.682 mmol) was then added and replaced with nitrogen again. The temperature was then raised to 80°C and the reaction was allowed to proceed for 11 hours. After the reaction was complete, the solvent was removed by rotary evaporation. The crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 8 to 100 / 12) to give compound YL230783-173-A (4.5 g, 19.453 mmol, 50.01%), ESI: (m / z) = 209.1 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ12.42 (s, 1H), 7.51 (dd, J=8.3, 1.1Hz, 1H), 7.37–7.28 (m, 1H), 5.41 (t, J=5.8Hz, 1H), 4.63 (dd, J=5.6, 1.4Hz, 2H), 2.40 (s, 3H).

[0166] Synthesis of compound YL230783-174-A

[0167] YL230783-173-A (3.05 g, 14.650 mmol) was dissolved in HBr-H2O (48%, 600 mL) at room temperature and then heated to 80°C for 3 days. After the reaction, the remaining reaction solvent was removed by swirl, ethyl acetate and water were added to dilute, and the mixture was filtered. The filtrate was extracted again with a large amount of ethyl acetate. The organic phases were combined, washed with water and saturated NaCl, and the organic layer solvent was dried. The residue was re-added with a large amount of ethyl acetate and acetonitrile, sonicated, and filtered. The filtrate was concentrated to directly obtain compound YL230783-174-A (2.65 g, 7.869 mmol, 53.71%), ESI: (m / z) = 271.0 / 273.0 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.54 (s, 1H), 7.50 (d, J=8.3Hz, 1H), 7.35 (t, J=7.8Hz, 1H), 4.86–4.72 (m, 2H), 2.41 (s, 3H).

[0168] Synthesis route of intermediate 3

[0169] Synthesis of compound YL230774-420

[0170] 4-Bromo-2,6-difluorobenzonitrile (5.00 g, 22.94 mmol) was added to a mixture of aqueous ammonia (28 mL) and isopropanol (10 mL) and heated to 80°C for 5 hours. The reaction mixture was cooled to room temperature and poured into water. After stirring for 10 minutes, it was filtered and the filter cake was dried under vacuum at 40°C to obtain YL230774-420 (3.50 g, 70.99% yield). 1 H NMR (400MHz, CDCl3) δ6.72 (t, J = 1.4Hz, 1H), 6.67 (dd, J = 8.4, 1.6Hz, 1H), 4.62 (s, 2H).

[0171] Synthesis of compound YL230774-430

[0172] 98% concentrated sulfuric acid (6 mL) was slowly added to formic acid (48 mL), stirred at room temperature for 10 minutes, then YL230774-420 (4.00 g, 18.60 mmol) was added portionwise and heated to 100°C for 2 hours. The reaction solution was cooled to 0°C, diluted with water (10 mL), stirred for half an hour, filtered, and the filter cake was rinsed with water and isopropanol (v / v = 1:1). The filter cake was taken and vacuum dried at low temperature to obtain YL230774-430 (3.00 g, yield 66.37%). (ESI): m / z 243.0, 245.0 [M+H] + .

[0173] Synthesis of compound YL230774-433

[0174] p-Methoxybenzylamine (8.47 g, 61.72 mmol) was added to a solution of YL230774-430 (3.00 g, 12.34 mmol) in DMSO (20 mL) and heated to 80°C for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to obtain YL230774-433 (3.00 g, yield 67.42%). (ESI): m / z 360.0, 362.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),9.05(t,J=5.0Hz,1H),7.97(s,1H),7.29(d,J=8.5Hz,2H),7 .04–6.88(m,2H),6.84(d,J=1.8Hz,1H),6.64(d,J=1.8Hz,1H),4.37(d,J=5.6Hz,2H),3.74(s,3H).

[0175] Synthesis of compound YL230774-453

[0176] DBU (CAS: 6674-22-2) (1.81 g, 11.91 mmol) and Carter condensation agent (CAS: 56602-33-6) (4.79 g, 10.83 mmol) were added to a solution of YL230774-433 (1.3 g, 3.61 mmol) in DMF (13 mL). The mixture was stirred at room temperature for 15 minutes, followed by the addition of methylamine (0.56 g, 18.05 mmol) and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by reverse phase chromatography (C18, NH4HCO3) to afford YL230774-453 (90 mg, 6.67% yield). (ESI): m / z 373.1, 375.1 [M+H] + .

[0177] Synthesis of compound YL230774-461

[0178] Triphosgene (72 mg, 0.24 mmol) in dichloromethane (1.5 mL) was added dropwise to a solution of YL230774-453 (90 mg, 0.24 mmol) and DIEA (312 mg, 2.41 mmol) in dichloromethane (3 mL) at 0°C in an ice-water bath. The mixture was allowed to warm to room temperature and allowed to react for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford YL230774-461 (30 mg, 31.16% yield). (ESI): m / z 399.0, 401.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.79 (s, 1H), 7.65 (d, J = 1.4Hz, 1H), 7.31–7.27 (m, 2H), 7. 02(d,J=1.4Hz,1H),6.92–6.86(m,2H),5.23(s,2H),3.79(s,3H),3.69(s,3H).

[0179] Synthesis route of intermediate 4 (YL230774-454)

[0180] Synthesis of compound YL230804-108-A1

[0181] 3-Bromo-2-fluoroaniline (1 g, 6.723 mmol) was dissolved in dichloromethane (15 mL), pyridine (0.766 mL, 9.473 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. (E)-3-ethoxyacryloyl chloride (1.06 g, 7.894 mmol) was added. The mixture was reacted at room temperature for 2 hours. Ethyl acetate and water were added to dilute the mixture, and the organic phase was washed twice with saturated sodium chloride. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and slurried with petroleum ether / ethyl acetate = 10 / 1 to obtain compound YL230804-108-A1 (1.5 g, 98.93%), ESI: (m / z) = 288.0 / 290.0 [M+H] + .

[0182] Synthesis of compound YL230774-451

[0183] YL230804-108-A1 (1.40 g, 4.86 mmol) was added to a concentrated H2SO4 solution (15 mL) and allowed to react at room temperature for 2 hours. The reaction solution was cooled to 0°C, and then the aqueous solution was slowly added dropwise. A white solid precipitated, which was filtered and the filter cake was vacuum dried to obtain YL230774-451 (1.00 g, yield 85.02%). (ESI): m / z 242.0, 244.0 [M+H] + .

[0184] Synthesis of compound YL230774-454

[0185] At room temperature, sodium difluoromethanesulfinate (1.14 g, 8.26 mmol) and potassium persulfate (4.47 g, 16.53 mmol) were added to a mixture of YL230774-451 (1.00 g, 4.13 mmol) in acetonitrile (20 mL) and water (6 mL). The mixture was then heated to 100°C for 16 hours. The reaction mixture was diluted with water and ethyl acetate, and the organic phase was separated. After concentration, the organic phase was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-2%) to obtain YL230774-454 (100 mg, yield 8.26%). (ESI): m / z 292.0, 294.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),8.36(s,1H),7.64(d,J=8.6Hz,1H),7.53(dd,J=8.5,6.1Hz,1H),6.96(t,J=54.5Hz,1H).

[0186] Synthesis route of intermediate 5 (YL230774-428)

[0187] Synthesis of compound YL230774-407

[0188] Under nitrogen, triphenylphosphine (0.29 g, 1.09 mmol) and Pd(Ph3P)2Cl2 (0.43 g, 0.55 mmol) were added to a mixture of YL230774-405 (5.00 g, 18.23 mmol), pinacol diboron (5.09 g, 20.06 mmol), and potassium carbonate (3.78 g, 27.35 mmol) in 1,4-dioxane (100 mL). The mixture was heated to 80°C for 5 hours. The reaction mixture was filtered through a celite filter cake, and the filtrate was concentrated and dried in vacuo to yield YL230774-407 (5.00 g, crude product).

[0189] Synthesis of compound YL230774-410

[0190] Under nitrogen, Pd(dtbpf)Cl2 (26 mg, 0.04 mmol) was added to a mixture of YL230774-407 (100 mg, 0.397 mmol), methyl 6-chloro-5-nitronicotinate (86 mg, 0.40 mmol), and triethylamine (0.17 mL, 1.19 mmol) in N,N-dimethylformamide (3 mL) and water (0.6 mL). The mixture was heated to 100°C for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford YL230774-410 (30 mg, 25.00% yield). (ESI): m / z 307.1 [M+H] + .

[0191] Synthesis of compound YL230774-416

[0192] Under nitrogen, iron powder (27 mg, 0.49 mmol) and ammonium chloride (16 mg, 0.29 mmol) were added to a mixture of YL230774-410 (30 mg, 0.098 mmol) in ethanol (2 mL) and water (0.2 mL). The mixture was heated to 80°C for 2 hours. The reaction mixture was filtered through celite, and the filter cake was rinsed with tetrahydrofuran several times. The filtrate was concentrated and purified by reverse phase chromatography (C18, 1.0 mmol HCl) to afford YL230774-416 (15 mg, 54.53% yield). (ESI): m / z 245.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),8.91(d,J=1.8Hz,1H),8.20(d,J=1.8Hz,1H) ,3.92(s,3H),3.19(t,J=7.8Hz,2H),2.84(t,J=7.6Hz,2H),2.13(p,J=7.6Hz,2H).

[0193] Synthesis of compound YL230774-425

[0194] In a 0°C ice-water bath, a 1M solution of lithium aluminum hydride in tetrahydrofuran (1.6 mL, 1.6 mmol) was added dropwise to a mixture of YL230774-416 (200 mg, 0.82 mmol) in tetrahydrofuran (8 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched with water (1 drop) at 0°C, followed by the addition of sodium hydroxide solution (3 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.1 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filter cake was rinsed with tetrahydrofuran several times. The filtrate was concentrated to obtain the crude product, which was purified by slurrying with dichloromethane and petroleum ether (v / v = 1:1) to obtain YL230774-425 (100 mg, 55.56% yield). (ESI): m / z 217.2 [M+H] + .

[0195] Synthesis of compound YL230774-428

[0196] Thionyl chloride (550 mg, 4.6 mmol) was added to a mixture of YL230774-425 (100 mg, 0.46 mmol) in dichloromethane (10 mL) and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution until neutral, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield YL230774-428 (70 mg, crude product). (ESI): m / z 235.1 [M+H] + .

[0197] Synthesis route of intermediate 6

[0198] Synthesis of compound YL230774-405

[0199] Trifluoromethanesulfonic anhydride (10.92 g, 38.69 mmol) was slowly added to a solution of methyl 2-oxocyclopentane-1-carboxylate (5.00 g, 35.17 mmol) and DIEA (6.82 g, 52.76 mmol) in dichloromethane (70 mL) at -78°C. The mixture was stirred for 0.5 hours, then warmed to room temperature and reacted for 1.5 hours. The reaction mixture was quenched with water, and the organic phase was separated, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:3) to afford YL230774-405 (9.00 g, 93.26% yield). 1 H NMR (400MHz, CDCl3) δ3.87 (d, J = 51.6Hz, 3H), 3.11–2.52 (m, 4H), 2.27–1.90 (m, 2H).

[0200] Synthesis of compound YL230774-406

[0201] Under nitrogen, XPhos Pd G2 (1.15 g, 1.46 mmol) was added to a mixture of YL230774-405 (4.00 g, 14.59 mmol), (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid (3.94 g, 17.50 mmol), and cesium carbonate (9.51 g, 29.17 mmol) in 1,4-dioxane (80 mL). The mixture was heated to 80°C for 4 hours. The reaction mixture was filtered through a celite filter cake, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to obtain YL230774-406 (3.30 g, yield 74.16%). (ESI): m / z 306.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.71(d,J=1.6Hz,1H),8.24(dd,J=8.0,1.7Hz,1H),7.31(d,J=8.0Hz,1H),3.98 (s,3H),3.50(s,3H),2.89(tt,J=7.7,2.4Hz,2H),2.82(tt,J=7.7,2.5Hz,2H),2.13(p,J=7.6Hz,2H).

[0202] Synthesis of compound YL230774-411

[0203] Under nitrogen, iron powder (1.19 g, 21.29 mmol) and ammonium chloride (0.68 g, 12.78 mmol) were added to a mixture of YL230774-406 (1.30 g, 4.26 mmol) in ethanol (40 mL) and water (8 mL). The mixture was heated to 80°C for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude solid. The crude product was purified by slurrying with acetonitrile and water (v / v = 1:5), filtered, and the filter cake was dried under low-temperature vacuum to obtain YL230774-411 (0.60 g, yield 57.69%). (ESI): m / z 244.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ11.09(s,1H),7.96(d,J=73.9Hz,2H),7.59(s,1H),4.00(s,3H),3.54–2.92(m,4H),2.29(s,2H).

[0204] Synthesis of compound YL230774-412

[0205] Lithium aluminum hydride (1.6 mL, 1 M) in tetrahydrofuran (THF) was added dropwise to a solution of YL230774-411 (200 mg, 0.82 mmol) in THF (10 mL) in an ice-water bath at 0°C. The reaction was allowed to react for 1.5 hours, maintaining the temperature at 0°C. The reaction mixture was quenched with water (1 drop) at 0°C, followed by the addition of sodium hydroxide solution (3 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.1 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filter cake was rinsed with THF several times. The filtrate was concentrated to yield the crude product, which was purified by slurrying with acetonitrile and water (v / v = 1:1) to afford YL230774-412 (80 mg, 45.21% yield). (ESI): m / z 216.2 [M+H] + .

[0206] Synthesis of compound YL230774-414

[0207] Thionyl chloride (442 mg, 3.72 mmol) was added to a mixture of YL230774-412 (80 mg, 0.37 mmol) in dichloromethane (2 mL) and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution until neutral, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield YL230774-414 (70 mg, crude product). (ESI): m / z 234.1 [M+H] + .

[0208] Synthesis route of intermediate 7

[0209] Synthesis of compound YL230804-038-A

[0210] 3-Bromo-2-chloro-6-methyl-5-nitropyridine (25 g, 99.419 mmol) was dissolved in methanol (140 mL). The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Sodium methoxide (19.7 g, 109.361 mmol) was added and allowed to react at room temperature for 1 hour. The reaction mixture was spin-dried to dryness, ethyl acetate and water were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to yield compound YL230804-038-A (24.1 g, 98.12%). 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),4.04(s,3H),2.69(s,3H).

[0211] Synthesis of compound YL230804-039-A

[0212] YL230804-038-A (24.1 g, 97.551 mmol) was dissolved in DMF (100 mL) and N,N-dimethylformamide dimethyl acetal (100 mL) was added. The atmosphere was replaced with N2 and the reaction was carried out at 100°C for 2 hours. Most of the DMF was removed by swirl, and ethyl acetate and water were added. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain compound YL230804-039-A (29.3 g, 99.42%). ESI: (m / z) = 302.0 [M+H] + ;

[0213] Synthesis of compound YL230804-045-A

[0214] YL230804-039-A (29.3 g, 96.978 mmol) was dissolved in tetrahydrofuran (120 mL) and water (120 mL). The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Sodium periodate (45.63 mL, 213.352 mmol) was added and allowed to react at room temperature for 2 hours. The reaction mixture was quenched with aqueous sodium thiosulfate, diluted with water, and extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to yield compound YL230804-045-A (25.2 g, 99.57%).

[0215] Synthesis of compound YL230804-046-A

[0216] YL230804-045-A (25.2 g, 96.541 mmol) was dissolved in ethanol (250 mL), and ethyl 3,3-diethoxypropionate (73.46 g, 386.163 mmol) and stannous chloride (91.53 g, 482.703 mmol) were added. The mixture was allowed to react at 80°C overnight. The reaction solution was spin-dried and poured into aqueous sodium bicarbonate solution. Extraction was performed with ethyl acetate. The organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound YL230804-046-A (19.3 g, 64.25%). ESI: (m / z) = 311.1 [M+H] + .

[0217] Synthesis of compound YL230804-048-A

[0218] YL230804-046-A (1.9 g, 6.107 mmol) was dissolved in 1,4-dioxane (20 mL), and (tributyltin)methanol (2.16 g, 6.717 mmol) and XPhos Pd G2 (38 mg, 0.048 mmol) were added. The atmosphere was purged with N2 and the reaction was allowed to proceed overnight at 80°C. The reaction solution was extracted with ethyl acetate and water. The organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to afford compound YL230804-048-A (840 mg, 52.45%). ESI: (m / z) = 263.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.18(d,J=2.1Hz,1H),8.53(dd,J=2.0,0.8Hz,1H),8.25(q,J=1.4Hz,1H),5.6 7(d,J=69.6Hz,1H),4.62(d,J=1.5Hz,2H),4.40(q,J=7.1Hz,2H),4.05(s,3H),1.38(t,J=7.1Hz,3H).

[0219] Synthesis of compound YL230804-051-A

[0220] YL230804-048-A (0.84 g, 3.203 mmol) was dissolved in dichloromethane (20 mL). Dess-Martin periodinane (1.63 g, 3.884 mmol) was added at 0°C and allowed to react at room temperature for 1 hour. The reaction mixture was quenched with aqueous sodium thiosulfate and extracted with dichloromethane. The organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified on a normal phase column (petroleum ether / ethyl acetate = 4 / 1) to obtain compound YL230804-051-A (1 g). ESI: (m / z) = 261.1 [MH] + ;1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.29(d,J=2.0Hz,1H),8.67(s,1H),8 .63–8.60(m,1H),4.43(q,J=7.1Hz,2H),4.17(s,3H),1.40(t,J=7.1Hz,3H).

[0221] Synthesis of compound YL230804-053-A

[0222] YL230804-051-A (0.8 g, 3.074 mmol) was dissolved in tetrahydrofuran (15 mL) and bis(2-methoxyethyl)aminosulfur trifluoride (2.72 g, 12.296 mmol) was added at 0°C. The mixture was allowed to react at 50°C for 2 hours. The reaction solution was diluted with saturated aqueous ammonium chloride and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified on a normal phase column (petroleum ether / ethyl acetate = 4 / 1) to give compound YL230804-053-A (310 mg, 35.73%). ESI: (m / z) = 283.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.29(d,J=2.0Hz,1H),8.65(d,J=2.0Hz,1H),8.57(s,1H), 7.25(t,J=54.0Hz,1H),4.43(q,J=7.1Hz,2H),4.13(s,3H),1.40(t,J=7.1Hz,3H).

[0223] Synthesis of compound YL230804-054-A

[0224] YL230804-053-A (310 mg, 1.098 mmol) was dissolved in acetonitrile (8 mL) and trimethylsilyl iodide (879 mg, 4.393 mmol) was added. The mixture was allowed to react at 50°C for 5 hours. The reaction solution was diluted with ethyl acetate and water. The organic phase was washed with aqueous sodium chloride solution, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound YL230804-054-A (250 mg, 86.21%). ESI: (m / z) = 269.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),8.98(d,J=1.9Hz,1H),8.22(dq,J=1.7 ,0.8Hz,2H),7.21–6.77(m,1H),4.40(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0225] Synthesis of compound YL230804-055-A

[0226] YL230804-054-A (250 mg, 0.932 mmol) was dissolved in tetrahydrofuran (5 mL) and lithium aluminum hydride (1.86 mL, 1.864 mmol) was added at 0°C. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was quenched with ethyl acetate, evaporated to dryness, and purified by normal phase column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound YL230804-055-A (60 mg, 28.57%). ESI: (m / z) = 227.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.49(d,J=1.8Hz,1H),8.15(d,J=1.7Hz,1H),7.70(d d,J=1.9,0.9Hz,1H),6.97(t,J=54.5Hz,1H),5.57(t,J=5.5Hz,1H),4.67(d,J=4.1Hz,2H).

[0227] Synthesis of compound YL230804-056-A

[0228] YL230804-055-A (52 mg, 0.230 mmol) was dissolved in dichloromethane (5 mL), and triphenylphosphine (90 mg, 0.345 mmol) was added. Carbon tetrabromide (114 mg, 0.345 mmol) was then added at 0°C. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was spin-dried and purified on a normal phase column (dichloromethane / methanol = 10 / 1) to obtain compound YL230804-056-A (50 mg).

[0229] Synthesis route of intermediate 8

[0230] Synthesis of compound YL230783-189-A

[0231] Dissolve methyl 2-bromobenzoate (3 g, 13.950 mmol), methyl 3-amino-4-(dihydroxyboryl)benzoate hydrochloride (3.23 g, 13.950 mmol), and potassium carbonate (9.64 g, 69.751 mmol) in 1,4-dioxane (180 mL) and water (18 mL). Then add 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (1.41 g, 1.932 mmol). Nitrogen is purged and the mixture is reacted at 100°C for 2 hours. Dilute with ethyl acetate and water. Separate the organic phase, and extract the aqueous phase with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The resulting crude product was purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 12) to give solid compound YL230783-189-A (2.9 g, 11.107 mmol, 79.62%), LC-MS (ESI): m / z 254.1 (M+H)+, 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.55(dd,J=16.9,8.3Hz,2H),8.35(dd,J=8.0,1.4Hz,1H),7.99 (d,J=1.7Hz,1H),7.94–7.89(m,1H),7.78(dd,J=8.4,1.7Hz,1H),7.73(d,J=7.6Hz,1H),3.90(s,3H).

[0232] Synthesis of compound YL230783-192-A

[0233] YL230783-189-A (1.6 g, 6.318 mmol) and anhydrous tetrahydrofuran (340 mL) were added to the reaction flask, and the mixture was cooled to 0°C. Subsequently, lithium aluminum hydride tetrahydrofuran solution (1 M) (15.8 mL, 15.794 mmol) was slowly added. The mixture was stirred at 0°C for 1.5 hours. Upon completion of the reaction, the mixture was quenched with 20 mL of ethyl acetate, followed by the addition of 5 mL of water. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 6 to 100 / 8) to obtain compound YL230783-192-A (1.25 g, 5.549 mmol, 87.84%). LC-MS (ESI): m / z 224.0 (MH). - , 1 H NMR(400MHz, DMSO-d6)δ11.69(s,1H),8.47(d,J=8.1Hz,1H),8.36–8.27(m,2H),7.83(ddd,J=8.4,7.2,1.5Hz,1H), 7.66–7.56(m,1H),7.36(d,J=1.5Hz,1H),7.19(dd,J=8.2,1.6Hz,1H),5.36(t,J=5.7Hz,1H),4.59(d,J=5.7Hz,2H).

[0234] Synthesis of compound YL230783-198-A

[0235] YL230783-192-A (500 mg, 2.220 mmol), dichloromethane (110 mL), and DMF (0.018 mL, 0.222 mmol) were added to the reaction flask. The atmosphere was purged with nitrogen and the temperature was lowered to 0°C. Thionyl chloride (1584.37 mg, 13.319 mmol) was then slowly added dropwise. After the addition, the mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure and purified by Biotage column chromatography (mobile phase: petroleum ether / ethyl acetate 100 / 30 to 100 / 40) to obtain YL230783-198-A (170 mg, 0.565 mmol, 25.46%) as an off-white solid. LC-MS (ESI): m / z 244.0 (M+H). + , 1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.54–8.30(m,3H),7.92–7.81(m,1H),7.66 (t,J=7.5Hz,1H),7.41(d,J=1.8Hz,1H),7.32(dd,J=8.3,1.8Hz,1H),4.86(s,2H).

[0236] Synthesis route of intermediate 9

[0237] Synthesis of compound YL230804-145-A1

[0238] 7-Bromo-2(1H)-quinoxalinone (5 g, 22.218 mmol) was dissolved in dimethyl sulfoxide (50 mL), and sodium difluoromethanesulfinate (6.22 g, 44.437 mmol) and 2,3-butanedione (9.8 mL, 111.091 mmol) were added. The mixture was irradiated with blue light and allowed to react at room temperature for 7 days. Ethyl acetate and water were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1) to obtain compound YL230804-145-A1 (3 g, 49.1%). ESI: (m / z) = 275.1 / 277.1 [M+H] + ;

[0239] Synthesis of compound YL230804-153-A

[0240] YL230804-145-A1 (1 g, 3.636 mmol) was dissolved in 1,4-dioxane (15 mL), and (tributyltin)methanol (1.28 g, 3.999 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G2) (0.14 g, 0.182 mmol) were added. The atmosphere was purged with nitrogen and the reaction was allowed to proceed overnight at 80°C. Ethyl acetate and water were added, the layers separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified via normal phase column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to yield compound YL230804-153-A (300 mg, 36.59%). ESI: (m / z) = 227.0 [M+H] + ;

[0241] Synthesis of compound YL230804-156-A

[0242] YL230804-153-A (100 mg, 0.444 mmol) was dissolved in dichloromethane (8 mL), and 1 drop of DMF was added. The mixture was replaced with nitrogen and cooled to 0°C. Thionyl chloride (315 mg, 2.653 mmol) was added and allowed to react at room temperature overnight. The reaction solution was cooled to 0°C, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane / methanol = 10 / 1. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified on a normal phase column (dichloromethane / methanol = 20 / 1) to obtain compound YL230804-156-A (60 mg, 54.55%). ESI: (m / z) = 245.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),7.89(d,J=8.4Hz,1H),7.42(d,J=7.4Hz,2H),7.05(t,J=53.2Hz,1H),4.91(s,2H).

[0243] Synthesis route of intermediate 10

[0244] Synthesis of compound YL230769-371

[0245] To a 50 mL three-necked flask, 5-methyl-2H-pyrazole-3-carboxylic acid (4000 mg, 31.718 mmol) and thionyl chloride (40 mL) were added sequentially. Under nitrogen protection, the reaction was allowed to proceed at 80°C for 18 hours. LCMS indicated a successful reaction. The reaction solution was cooled to room temperature and slowly poured into a saturated sodium bicarbonate solution. Dichloromethane was added, and the organic phase was concentrated to yield YL230769-371 (2440 mg, 11.286 mmol, 35.58%). LC-MS (ESI): m / z 217.2 (M+H) + .

[0246] Synthesis of compound YL230769-377

[0247] To a 250 mL three-necked flask were added YL230769-371 (2162 mg, 10.000 mmol), 3-bromo-2,6-difluoroaniline (4160.20 mg, 20.000 mmol), and tetrahydrofuran (80 mL). The mixture was cooled to -10°C under nitrogen, and then sodium bis(trimethylsilyl)amide (25.000 mL) was slowly added. The reaction was continued at this temperature for 2 hours. LCMS indicated a successful reaction. Acetic acid was added to the reaction solution to a pH of 7, followed by ethyl acetate. The organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-377 (3130 mg, 9.902 mmol, 99.02%). LC-MS (ESI): m / z 318.0 (M+H). + .

[0248] Synthesis of compound YL230769-378

[0249] To a 50 mL three-necked flask, YL230769-377 (3130 mg, 9.902 mmol), sodium hydroxide (594.10 mg, 14.852 mmol), and N,N-dimethylacetamide (30 mL) were added sequentially. Under nitrogen, the mixture was allowed to react at room temperature for 1 hour. The temperature was then raised to 120°C and the reaction was continued for 18 hours. LCMS indicated the reaction was complete. Saturated ammonium chloride and ethyl acetate were added, and the organic phase was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to afford YL230769-378 (560 mg, 1.891 mmol, 19.10%). LC-MS (ESI): m / z 296.0 (M+H). + .

[0250] Synthesis of compound YL230769-380

[0251] To a 50 mL three-necked flask were added YL230769-378 (355 mg, 1.199 mmol), (tributyltin)methanol (461.95 mg, 1.439 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (94.21 mg, 0.120 mmol), and 1,4-dioxane (25 mL). The mixture was reacted at 80°C for 18 hours under nitrogen. LCMS indicated the reaction was complete. The reaction solution was then concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-380 (206 mg, 0.833 mmol, 69.50%). LC-MS (ESI): m / z 248.1 (M+H) + .

[0252] Synthesis of compound YL230769-384

[0253] To a 50 mL three-necked flask were added YL230769-380 (124 mg, 0.502 mmol), N,N-dimethylformamide (0.006 mL, 0.068 mmol), and dichloromethane (10 mL) in sequence. Under nitrogen, thionyl chloride (357.99 mg, 3.009 mmol) was slowly added. The reaction was continued at room temperature for 18 hours. LCMS indicated the reaction was complete. Saturated sodium bicarbonate solution and dichloromethane were added, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 30:1-20:1) to afford YL230769-384 (120 mg, 0.452 mmol, 90.06%). LC-MS (ESI): m / z 266.1 (M+H). + .

[0254] Synthesis route of intermediate 11

[0255] Synthesis of compound YL230769-405

[0256] To a 250 mL three-necked flask were added 3-amino-5-bromopyridine-2-carboxylic acid (5000 mg, 23.039 mmol) and dichloromethane (100 mL). The mixture was cooled to -78°C under nitrogen, followed by the addition of diisobutylaluminum hydride (46.079 mL, 46.079 mmol). The reaction was continued for 2 hours. LCMS indicated the reaction was complete. Slowly add 5 mL of water to the reaction solution, followed by 5 mL of 15% sodium hydroxide, and then add 15 mL of water. The mixture was then dried over a small amount of magnesium sulfate. The reaction solution was filtered, and the filtrate was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to afford YL230769-405 (220 mg, 1.094 mmol, 4.75%). MS (ESI): m / z 201.1 (M+H). + .

[0257] Synthesis of compound YL230769-406

[0258] To a 50 mL three-necked flask, methyl cyclopropylacetate (210.41 mg, 1.642 mmol) and tetrahydrofuran (10 mL) were added sequentially. Under nitrogen, the mixture was cooled to -78°C, followed by the addition of lithium bis(trimethylsilyl)amide (3.830 mL). The reaction was continued at this temperature for 30 minutes, followed by the addition of YL230769-405 (220 mg, 1.094 mmol). The reaction was continued at -78°C for 30 minutes, then the temperature was slowly raised to room temperature and the reaction continued for 18 hours. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated and subjected to column chromatography (dichloromethane:methanol = 50:1-20:1) to afford YL230769-406 (160 mg, 0.604 mmol, 55.15%). MS (ESI): m / z 265.0 (M+H). + .

[0259] Synthesis of compound YL230769-409

[0260] To a 50 mL three-necked flask were added YL230769-406 (150 mg, 0.566 mmol), tributyltin carbinol (218.01 mg, 0.679 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (44.46 mg, 0.057 mmol), and 1,4-dioxane (10 mL). The mixture was reacted at 80°C for 18 hours under nitrogen. LCMS indicated the reaction was complete. The reaction solution was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-409 (96 mg, 0.444 mmol, 78.46%). MS (ESI): m / z 217.2 (M+H). + .

[0261] Synthesis of compound YL230769-410

[0262] To a 50 mL three-necked flask were added YL230769-409 (96 mg, 0.444 mmol), N,N-dimethylformamide (0.004 mL, 0.044 mmol), and dichloromethane (10 mL). The mixture was cooled to 0°C under nitrogen, followed by the addition of thionyl chloride (316.87 mg, 2.664 mmol). The reaction was continued for 30 minutes, then the temperature was raised to room temperature and the reaction continued for 6 hours. LCMS indicated the reaction was complete. Saturated aqueous sodium bicarbonate and dichloromethane were added to the reaction solution, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 40:1-20:1) to afford YL230769-410 (86 mg, 0.366 mmol, 82.54%). MS (ESI): m / z 235.1 (M+H).+ .

[0263] Synthesis route of intermediate 12

[0264] Synthesis of compound YL230783-140-A

[0265] To the reaction flask, methyl 2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (1 g, 4.521 mmol) and anhydrous tetrahydrofuran (75 mL) were added. The atmosphere was purged with nitrogen and the mixture was cooled to 0°C. LiAlH4 (10 mL, 1 M, 113.015 mmol) was then slowly added. The mixture was stirred at 0°C for 1 hour. After completion of the reaction, the mixture was quenched with 15 mL of ethyl acetate, followed by the addition of 5 mL of water. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 10 to 100 / 15) to yield compound YL230783-140-A (360 mg, 1.694 mmol, 37.47%). LC-MS (ESI): m / z 192.1 (M+H). + .

[0266] Synthesis of compound YL230783-142

[0267] To a two-necked flask containing YL230783-140 (360 mg, 1.863 mmol) at zero degrees Celsius, phosphine oxide (35 mL) and N,N-diisopropylethylamine (240.84 mg, 1.863 mmol) were added. The reaction mixture was stirred at 90°C under nitrogen for 4 hours, then dried by vortexing. The residue was diluted with ice water (100 mL) and ethyl acetate, and the layers were separated. The organic phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: dichloromethane / methanol 3% to 5%) to obtain compound YL230783-142 (175 mg, 0.571 mmol, 30.62%). LC-MS (ESI): m / z 212.1 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),6.99(dd,J=8.0,2.1Hz,1H),6.97–6.91(m,2H),4.70(s,2H),4.66(t,J=6.8Hz,1H),1.41(d,J=6.7Hz,3H).

[0268] Synthesis route of intermediate 13

[0269] Synthesis of compound YL230774-375

[0270] Under nitrogen, NBS (14.52 g, 81.58 mmol) was added to a solution of 2,3,6-trifluoroaniline (10.00 g, 67.98 mmol) in N,N-dimethylformamide (120 mL) and allowed to react at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to afford YL230774-375 (9.0 g, 58.59% yield). (ESI): m / z 223.9 [MH] - .

[0271] Synthesis of compound YL230774-384

[0272] Under nitrogen, sodium perborate (54.46 g, 353.98 mmol) was added to a solution of YL230774-375 (8.00 g, 35.40 mmol) in acetic acid (40 mL). The mixture was heated to 60°C and allowed to react for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution until neutral, extracted with ethyl acetate, and the organic phase was separated. After concentration, the organic phase was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-5%) to afford YL230774-384 (3.0 g, 33.11% yield). 1 H NMR(400MHz,DMSO-d6)δ8.27–7.90(m,1H).

[0273] Synthesis of compound YL230774-385

[0274] YL230774-384 (1.50 g, 5.86 mmol) was added to an amine solution in 1,4-dioxane (35 mL, 0.4 M) and allowed to react at room temperature for 16 hours. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain YL230774-385 (0.60 g, 40.54% yield). (ESI): m / z 251.0 [MH] - .

[0275] Synthesis of compound YL230774-386

[0276] Under nitrogen, iron powder (0.66 g, 11.86 mmol) was added to a solution of YL230774-385 (0.60 g, 2.37 mmol) in ethanol (2 mL), acetic acid (2 mL), and water (1 mL). The mixture was heated to 90°C for 2 hours. The reaction solution was filtered through celite, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%, 0.1% NH3 dissolved in ethyl acetate) to afford YL230774-386 (300 mg, 56.72% yield). (ESI): m / z 221.0 [MH] - .

[0277] Synthesis of compound YL230774-387

[0278] Under nitrogen, methyl 2-oxopropanoate (137 mg, 1.35 mmol) was added to a mixture of YL230774-386 (300 mg, 1.35 mmol) in toluene (3 mL). The mixture was heated to 100°C and reacted for 16 hours. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain the mixture YL230774-387 (250 mg, yield 67.57%). (ESI): m / z 273.0 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ12.77(s,1H),7.72(ddd,J=111.5,9.7,5.5Hz,1H),2.44(d,J=12.5Hz,3H).

[0279] Synthesis of compound YL230774-393

[0280] Under nitrogen, XPhos Pd G2 (Cas: 1310584-14-5, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)) (72 mg, 0.091 mmol) was added to a solution of YL230774-387 (250 mg, 0.909 mmol) and (tributyltin)methanol (350 mg, 1.09 mmol) in 1,4-dioxane (5 mL). The mixture was heated to 80°C for 2 hours. The reaction mixture was filtered through a celite filter cake, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) to afford YL230774-393 (120 mg, 58.37% yield). (ESI): m / z 227.1[M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.52 (s, 1H), 7.27 (ddd, J = 110.3, 10.9, 5.7Hz, 1H), 5. 48(dt,J=37.9,5.8Hz,1H), 4.61(dd,J=12.4,5.1Hz,2H), 2.43(d,J=3.7Hz,3H).

[0281] Synthesis of compound YL230774-398

[0282] DESS-MARTIN (56 mg, 0.13 mmol) was added to a solution of YL230774-393 (20 mg, 0.088 mmol) in tetrahydrofuran (1 mL) and reacted at room temperature for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give YL230774-398 (15 mg, crude product).

[0283] Synthesis route of intermediate 14

[0284] Synthesis of compound YL230769-476-A

[0285] Methyl 2-pyrrolidine (2 g, 15.984 mmol), 1-bromo-2,4-difluoro-3-nitrobenzene (4.18 g, 17.582 mmol), and cesium carbonate (11.46 g, 35.164 mmol) were dissolved in DMF (60 mL) at room temperature and reacted for 5 hours. The mixture was diluted with ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by automatic column chromatography (mobile phase: petroleum ether / ethyl acetate 100 / 8 to 100 / 10) to give compound YL230769-476-A (5.2 g, 10.609 mmol, 66.37%), LC-MS (ESI): m / z = 342.9 / 344.9 (M+H) +

[0286] Synthesis of compound YL230804-244-A

[0287] YL230769-476-A (1.4 g, 4.080 mmol) was dissolved in acetic acid (15 mL), and iron powder (1.14 g, 20.402 mmol) was added. The atmosphere was replaced with nitrogen and the reaction was carried out at 75°C for 3 hours. The reaction solution was filtered through celite, rinsed with methanol, and dried by spin drying. The product was purified by normal phase column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to obtain compound YL230804-244-A (1.1 g, 95.65%). ESI: (m / z) = 281.0 [M+H] + ;

[0288] Synthesis of compound YL230804-254-A

[0289] YL230804-244-A (500 mg, 1.779 mmol) was dissolved in 1,4-dioxane (10 mL), and (tributyltin)methanol (685 mg, 2.135 mmol) and Xphos Pd G2 (140 mg, 0.178 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 80°C overnight. The reaction solution was spin-dried and purified by normal phase column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to obtain compound YL230804-254-A (370 mg, 85.37%). ESI: (m / z) = 231.3 [M+H] + ;

[0290] Synthesis of compound YL230804-264-A

[0291] YL230804-254-A (370 mg, 1.593 mmol) was dissolved in dichloromethane (10 mL), and 1 drop of DMF was added. The mixture was replaced with nitrogen and cooled to 0°C. Thionyl chloride (1.13 g, 9.560 mmol) was added and allowed to react at room temperature overnight. The reaction mixture was cooled to 0°C, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane / methanol = 10 / 1. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude compound YL230804-264-A (370 mg, 92.5%). ESI: (m / z) = 251.0 [M+H] + ;

[0292] Synthesis route of intermediate 15

[0293] Synthesis of compound YL230784-484-C1

[0294] To a 50 mL three-necked flask were added ethyl 3-fluoro-1H-pyrrole-2-carboxylate (2000 mg, 12.727 mmol), N,N-dimethylformamide (20 mL), 4-bromo-1-fluoro-2-nitrobenzene (4199 mg, 19.091 mmol), and potassium carbonate (3517 mg, 25.454 mmol) in sequence. The mixture was heated to 100°C under nitrogen and reacted for 2 hours. Water and ethyl acetate were added for dilution, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic phases were combined, washed three times with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / petroleum ether = 0-8%) afforded YL230784-484-C1 (4.05 g, 11.340 mmol, 89.10%). LC-MS (ESI): m / z 357.1, 359.1 (M+H)+

[0295] Synthesis of compound YL230784-485-C1

[0296] To a 50 mL three-necked flask, YL230784-484-C1 (2000 mg, 5.600 mmol), acetic acid (20 mL), and iron powder (1563 mg, 28.001 mmol) were added in sequence. The mixture was heated to 75°C under nitrogen and reacted for 3 hours. The mixture was filtered, rinsed with a large amount of methanol, and the filter cake was slurried with methanol. The mixture was filtered, the filtrates were combined, concentrated to dryness under reduced pressure, slurried with methanol, filtered, and dried under vacuum to obtain YL230784-485-C1 (1.3 g, 4.625 mmol, 82.59%). LC-MS (ESI): m / z 323.2 (M+H) +

[0297] Synthesis of compound YL230784-492-C1

[0298] To a 50 mL three-necked flask were added YL230784-485-C1 (500 mg, 1.779 mmol), dioxane (10 mL), (tributyltin)methanol (685 mg, 2.135 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (140 mg, 0.178 mmol) in sequence. The mixture was heated to 80°C under nitrogen and reacted overnight. The mixture was concentrated under reduced pressure and purified by column chromatography (methanol / dichloromethane = 0-10%) to give YL230784-492-C1 (290 mg, 1.249 mmol, 70.21%). LC-MS (ESI): m / z 233.3 (M+H). +

[0299] Synthesis of compound YL230784-494-C1

[0300] To a 50 mL three-necked flask, YL230784-492-C1 (50 mg, 0.215 mmol), dichloromethane (5 mL), and N,N-dimethylformamide (0.05 mL) were added in sequence. The temperature was lowered to 0°C under nitrogen protection, and thionyl chloride (153 mg, 1.292 mmol) was added dropwise. The temperature was then raised to room temperature and the reaction was allowed to react overnight. Saturated sodium bicarbonate was added to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain YL230784-494-C1 (58 mg, 0.197 mmol, 91.35%). LC-MS (ESI): m / z 251.2 (M+H) + .

[0301] Example 1 Synthesis route of compound 1

[0302] Synthesis of compound YL230769-290

[0303] To a 50 mL three-necked flask, YL230769-283 (111 mg, 0.498 mmol), N-methylpropargylamine (41.34 mg, 0.598 mmol), potassium iodide (16.55 mg, 0.100 mmol), N,N-diisopropylethylamine (322.15 mg, 2.492 mmol), and acetonitrile (10 mL) were added in sequence. Under nitrogen, the mixture was reacted at 80°C for 2 hours. LCMS indicated a successful reaction. The reaction solution was directly concentrated and subjected to column chromatography (dichloromethane:methanol = 40:1-20:1) to afford YL230769-290 (120 mg, 0.470 mmol, 94.28%); LC-MS (ESI): m / z 256.2 (M+H). + .

[0304] Synthesis of compound YL230769-291 (compound 1)

[0305] To a 50 mL three-necked flask, YL230769-290 (120 mg, 0.470 mmol), N-methyl-5-bromopicolinamide (111.18 mg, 0.517 mmol), cuprous iodide (179.02 mg, 0.940 mmol), potassium iodide (78.02 mg, 0.470 mmol), N,N-diisopropylethylamine (303.74 mg, 2.350 mmol), tetrakistriphenylphosphine palladium (108.63 mg, 0.094 mmol), and N,N-dimethylformamide (15 mL) were added in sequence. The mixture was reacted at 100°C under nitrogen protection for 3 hours. LCMS showed the reaction was successful. Water and ethyl acetate were added to the reaction solution, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to obtain YL230769-291 (compound 1) (85 mg, 0.218 mmol, 46.44%); LC-MS (ESI): m / z 390.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.80 (d, J=5.6Hz, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 8.12-7.97 (m, 2H), 7.74 (s, 1H), 7. 63 (s, 1H), 3.72 (s, 2H), 3.63 (s, 2H), 2.82 (d, J = 4.8Hz, 3H), 2.50 (s, 2H), 2.33 (s, 3H), 1.17 (t, J = 7.4Hz, 3H).

[0306] Example 2 Synthesis route of compound 2

[0307] Synthesis of compound YL230769-312

[0308] To a 50 mL three-necked flask were added N-methyl-5-bromopicolinamide (645 mg, 2.999 mmol), N-tert-butoxycarbonylaminopropyne (558.59 mg, 3.599 mmol), cuprous iodide (1142.43 mg, 5.999 mmol), potassium iodide (497.88 mg, 2.999 mmol), N,N-diisopropylethylamine (1938.30 mg, 14.997 mmol), tetrakistriphenylphosphine palladium (693.19 mg, 0.600 mmol), and N,N-dimethylformamide (20 mL). The mixture was reacted at 100°C for 3 hours under nitrogen protection. LCMS showed the reaction was successful. Water and ethyl acetate were added, and the organic phase was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 5:1-2:1) to obtain YL230769-312 (375 mg, 1.296 mmol, 43.21%); LC-MS (ESI): m / z 290.2 (M+H) + .

[0309] Synthesis of compound YL230769-315

[0310] To a 50 mL three-necked flask, YL230769-312 (500 mg, 1.728 mmol), dichloromethane (15 mL), and trifluoroacetic acid (1.5 mL, 19.589 mmol) were added in sequence. Under nitrogen protection, the mixture was allowed to react at room temperature for 2 hours. LCMS indicated a successful reaction. Saturated sodium bicarbonate, dichloromethane, and isopropanol were added, and the organic phase was concentrated to yield YL230769-315 (206 mg, 1.089 mmol, 63.00%); LC-MS (ESI): m / z 190.1 (M+H) + .

[0311] Synthesis of compound YL230769-318 (compound 2)

[0312] To a 10 mL microwave tube were added YL230769-315 (45.87 mg, 0.2424 mmol), YL230769-283 (45 mg, 0.202 mmol), N,N-diisopropylethylamine (52.22 mg, 0.404 mmol), potassium iodide (6.71 mg, 0.040 mmol), and acetonitrile (3 mL). The mixture was reacted at 80°C for 40 minutes under nitrogen. LCMS indicated a successful reaction. The reaction solution was directly concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-318 (compound 2) (12 mg, 0.032 mmol, 15.82%); LC-MS (ESI): m / z 376.2 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ8.83-8.74 (m, 1H), 8.64 (d, J = 1.8Hz, 1H), 8.44 (d, J = 1.9Hz, 1H), 7.99 (d, J = 1.5Hz, 2H), 7.72 (s, 1 H), 7.65 (d, J=1.9Hz, 1H), 3.93 (s, 2H), 3.63 (s, 2H), 2.81 (d, J=4.8Hz, 3H), 2.54 (d, J=7.2Hz, 2H), 1.17 (t, J=7.4Hz, 3H).

[0313] Example 3 Synthesis route of compound 3

[0314] Synthesis of compound YL230769-316

[0315] To a 25 mL microwave tube were added YL230769-283 (111 mg, 0.498 mmol), 2,2,2-trifluoroethylamine (493.81 mg, 4.985 mmol), potassium iodide (16.55 mg, 0.100 mmol), N,N-diisopropylethylamine (128.86 mg, 0.997 mmol), and acetonitrile (10 mL). Under nitrogen, the mixture was reacted at 80°C for 2 hours. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-316 (140 mg, 0.491 mmol, 98.45%); LC-MS (ESI): m / z 286.1 (M+H). + .

[0316] Synthesis of compound YL230769-317

[0317] To a 25 mL microwave tube were added YL230769-316 (140 mg, 0.491 mmol), 3-bromopropyne (70.06 mg, 0.589 mmol), potassium carbonate (101.74 mg, 0.736 mmol), potassium iodide (16.29 mg, 0.098 mmol), and acetonitrile (10 mL). Under nitrogen, the mixture was reacted at 80°C for 2 hours. LCMS indicated a successful reaction. The reaction solution was directly concentrated and subjected to column chromatography (dichloromethane:methanol = 30:1-20:1) to afford YL230769-317 (64 mg, 0.198 mmol, 40.33%); LC-MS (ESI): m / z 324.1 (M+H). + .

[0318] Synthesis of compound YL230769-319 (compound 3)

[0319] To a 50 mL three-necked flask, YL230769-317 (47 mg, 0.145 mmol), N-methyl-5-bromopicolinamide (37.51 mg, 0.174 mmol), cuprous iodide (55.37 mg, 0.291 mmol), potassium iodide (24.13 mg, 0.145 mmol), N,N-diisopropylethylamine (93.94 mg, 0.727 mmol), tetrakistriphenylphosphine palladium (33.60 mg, 0.029 mmol), and N,N-dimethylformamide (5 mL) were added in sequence. The mixture was reacted at 100°C under nitrogen protection for 1.5 hours. LCMS showed the reaction was complete. Water and ethyl acetate were added, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol=20:1-10:1) to give YL230769-319 (compound 3) (15 mg, 0.033 mmol, 22.56%); LC-MS (ESI): m / z 458.3 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.78 (q, J=4.7Hz, 1H), 8.62 (d, J=1.9Hz, 1H), 8.53 (d, J=1.6Hz, 1H), 8.08 (s, 1H), 8.02-7.91 (m, 2H), 7.83 (s , 1H), 5.44 (s, 2H), 4.00 (d, J=4.5Hz, 2H), 3.23 (t, J=8.8Hz, 2H), 2.79 (d, J=4.8Hz, 3H), 2.61 (q, J=7.4Hz, 2H), 1.21 (t, J=7.3Hz, 3H).

[0320] Example 4 Synthesis route of compound 4

[0321] Synthesis of compound YL230774-347

[0322] Under nitrogen, cuprous iodide (89 mg, 0.47 mmol) and Pd(Ph3P)2Cl2 (181 mg, 0.23 mmol) were added to a solution of 5-bromo-N-methylpicolinamide (500 mg, 2.33 mmol) and prop-2-en-1-ol (0.15 mL, 2.56 mmol) in triethylamine (5 mL). The mixture was heated to 70°C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford YL230774-347 (250 mg, 56.53% yield). (ESI): m / z 191.1 [M+H] + .

[0323] Synthesis of compound 4

[0324] Sodium hydride (13 mg, 0.34 mmol) was added to a solution of YL230774-347 (85 mg, 0.45 mmol) in tetrahydrofuran (10 mL) in an ice-water bath at 0°C. After stirring for 0.5 hours, YL230769-310 (50 mg, 0.23 mmol) was added and the mixture was allowed to warm to room temperature for 16 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by preparative HPLC (NH4HCO3) to give compound 4 (25 mg, yield 29.58%). (ESI): m / z 191.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.93 (s, 1H), 8.86–8.80 (m, 1H), 8.71 (dd, J=2.1, 0.9Hz, 1H), 8.46 (d, J=1.9Hz, 1H), 8.07 (dd, J=8.1, 2.1Hz, 1H), 8.01 (dd, J= 8.1, 0.9Hz, 1H), 7.75 (q, J=1.0Hz, 1H), 7.68–7.63 (m, 1H), 4.77 (s, 2H), 4. 58(s, 2H), 2.82(d, J=4.8Hz, 3H), 2.58–2.53(m, 2H), 1.18(t, J=7.4Hz, 3H).

[0325] Example 5 Synthesis route of compound 5

[0326] Synthesis of compound YL230804-031-A

[0327] YL230769-283 (100 mg, 0.449 mmol), cyclopropylamine (256 mg, 4.491 mmol), DIEA (116.1 mg, 0.898 mmol), and potassium iodide (15 mg, 0.09 mmol) were added to a reaction flask. Acetonitrile (2 mL) was added, the atmosphere was replaced with nitrogen, and the reaction was carried out at 80°C for 2 hours. The reaction solution was spin-dried and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to obtain YL230804-031-A (90 mg, 82.36%); LCMS (ESI): m / z 244.1 (M+H) + ;

[0328] Synthesis of compound YL230804-033-1

[0329] YL230804-031-A (90 mg, 0.370 mmol), 3-bromopropyne (44 mg, 0.370 mmol), and potassium carbonate (102 mg, 0.740 mmol) were added to a reaction flask, and DMF (3 mL) was added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at room temperature for 4 hours. The reaction solution was spin-dried and purified by a normal phase column (dichloromethane / methanol = 20 / 1) to obtain YL230804-033-1 (60 mg, 57.65%); LCMS (ESI): m / z 282.2 (M+H) + ;

[0330] Synthesis of compound YL230804-035-A (compound 5)

[0331] YL230804-033-1 (55 mg, 0.195 mmol), N-methyl-5-bromopicolinamide (46.1 mg, 0.215 mmol), cuprous iodide (74.5 mg, 0.391 mmol), DIEA (126.3 mg, 0.977 mmol) and tetrakis(triphenylphosphine)palladium (45.2 mg, 0.039 mmol) were added to a reaction flask, and DMF (5 mL) was added. The atmosphere was replaced with nitrogen and the mixture was reacted at 100° C. for 1.5 hours. The reaction solution was filtered and dried to obtain YL230804-035-A (compound 5) (7.5 mg, 9.23%). LCMS (ESI): m / z 416.3 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ11.81 (s, 1H), 8.79 (d, J=5.0Hz, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 8.10–7.96 (m, 2H), 7.72 (s, 1H), 7.60 (d, J=1.8Hz, 1H), 3.95 (s, 2H), 3.5 9(s, 2H), 2.82(d, J=4.8Hz, 3H), 2.56–2.52(m, 2H), 2.19(dt, J=6.5, 3.1Hz, 1H) , 1.16 (t, J=7.4Hz, 3H), 0.54 (dt, J=6.2, 3.0Hz, 2H), 0.43 (q, J=3.4, 3.0Hz, 2H).

[0332] Example 6 Synthesis route of compound 6

[0333] Synthesis of compound YL230774-359

[0334] Potassium iodide (6 mg, 0.038 mmol) was added to a solution of YL230783-142 (40 mg, 0.19 mmol), N-methyl-2-propyn-1-amine (16 mg, 0.23 mmol) and DIEA (N-ethyl-N-isopropylpropan-2-amine) (73 mg, 0.57 mmol) in acetonitrile (4 mL), and the mixture was heated to 80°C for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%, the methanol phase contained 0.1% (v / v) NH3 . H2O) to give YL230774-359 (40 mg, yield 86.64%). (ESI): m / z 245.3 [M+H] + .

[0335] Synthesis of compound YL230774-363

[0336] Under nitrogen, Pd(Ph3P)2Cl2 (25 mg, 0.033 mmol) and cuprous iodide (12 mg, 0.065 mmol) were added to a solution of YL230774-359 (40 mg, 0.164 mmol) and 5-bromo-N-methylpicolinamide (35 mg, 0.16 mmol) in triethylamine (5 mL). The mixture was heated to 70°C for 2 hours. The reaction solution was diluted with dichloromethane and filtered through a celite filter cake. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford YL230774-363 (20 mg, 32.28% yield). (ESI): m / z 379.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.65 (s, 1H), 8.81 (q, J=4.7Hz, 1H), 8.70 (dd, J=2.1, 0 .9Hz, 1H), 8.08 (dd, J=8.1, 2.1Hz, 1H), 8.02 (dd, J=8.1, 0.9Hz, 1H), 6.91 (d, J=5 .5Hz, 1H), 6.90 (s, 1H), 6.87 (dd, J=8.3, 1.7Hz, 1H), 4.64 (q, J=6.8Hz, 1H), 3.56 (s, 2H), 3.51 (s, 2H), 2.82 (d, J = 4.9Hz, 3H), 2.29 (s, 3H), 1.41 (d, J = 6.8Hz, 3H).

[0337] Example 7 Synthesis of Compound 7

[0338] Synthesis of compound YL230783-175-A

[0339] YL230783-174-A (550 mg, 2.029 mmol) and potassium iodide (168.39 mg, 1.014 mmol) were dissolved in acetonitrile (120 mL) and replaced with nitrogen. N,N-diisopropylethylamine (1311.14 mg, 10.144 mmol) and N-methylpropargylamine (280.43 mg, 4.058 mmol) were added and replaced with nitrogen again. The temperature was then raised to 80°C for 1.5 hours. After the reaction, the solvent was removed by rotary evaporation. The crude product was purified by Biotage column chromatography (mobile phase: dichloromethane / methanol 100 / 6 to 100 / 10) to give compound YL230783-175-A (710 mg, 2.355 mmol, 116.07%), ESI: (m / z) = 260.1 [M+H] + , 1 H NMR (400MHz, Deuterium Oxide) δ8.17 (s, 1H), 7.57–7.19 (m, 1H), 3.64 (td, J=6.5, 3.2Hz, 2H), 3.15 ( qd, J=7.4, 3.4Hz, 2H), 2.40(s, 1H), 2.22(s, 1H), 1.27(s, 3H), 1.24(s, 3H).

[0340] Synthesis of compound 7

[0341] YL230783-175-A (200 mg, 0.771 mmol), YL230774-364-A1 (197.74 mg, 0.849 mmol), copper iodide (293.81 mg, 1.543 mmol), potassium iodide (128.05 mg, 0.771 mmol), and tetrakistriphenylphosphine palladium (178.28 mg, 0.154 mmol) were dissolved in DMF (20 mL) at room temperature and purged with nitrogen. N,N-diisopropylethylamine (498.50 mg, 3.857 mmol) was then added, and the atmosphere was purged with nitrogen again. The temperature was then raised to 100°C and the reaction was allowed to react for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified (Welch Xtimate C18, 21.2*250mm, 10um, water (10mM trifluoroacetic acid) / acetonitrile, flow rate 30mL / min, column temperature 25°C, detection wavelength 254nm) to give compound 7 (compound 7 (1.6mg, 0.003mmol, 0.45%), ESI: (m / z) = 412.2[M+H] + .

[0342] Example 8 Synthesis route of compound 8

[0343] YL230783-175-A (150 mg, 0.579 mmol), 4-iodobenzene-1-carbonitrile (158.99 mg, 0.694 mmol), copper iodide (220.36 mg, 1.157 mmol), potassium carbonate (319.81 mg, 2.314 mmol), potassium iodide (128.05 mg, 0.771 mmol), and allylpalladium(II) chloride dimer (42.34 mg, 0.116 mmol) were dissolved in DMF (30 mL) at room temperature. The atmosphere was purged with nitrogen and the temperature was then raised to 130°C for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified (Welch Xtimate C18, 21.2*250mm, 10um, water (10mM trifluoroacetic acid) / acetonitrile, flow rate 30mL / min, column temperature 25°C, detection wavelength 254nm), neutralized with saturated sodium bicarbonate under ice bath, and then extracted with ethyl acetate. The organic phase was removed, acetonitrile and water were added again, and lyophilized to obtain compound YL230783-178-A (compound 8), (33mg, 0.091mmol, 15.67%), ESI: (m / z) = 361.1 [M+H] +, 1 H NMR (400MHz, DMSO-d6) δ10.57 (s, 1H), 8.98 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 6.43 (s, 1H), 4.15 (d, J = 8.5Hz, 2H), 3.94 (t, J = 8.6Hz, 2H), 3.08 (d, J = 7.9Hz, 3H), 2.81 (d, J = 63.3Hz, 3H).

[0344] Example 9 Synthesis of Compound 9

[0345] Synthesis of compound YL230783-180-A

[0346] 2-Bromo-5-fluoropyridine (1 g, 5.682 mmol), tert-butyl methyl(prop-2-yn-1-yl)carbamate (1.44 g, 8.523 mmol), copper iodide (1.08 g, 5.682 mmol), potassium iodide (0.94 g, 5.682 mmol), and tetrakistriphenylphosphine palladium (1.31 g, 1.136 mmol) were dissolved in DMF (50 mL) at room temperature and purged with nitrogen. N,N-diisopropylethylamine (3.67 g, 28.411 mmol) was then added, and the atmosphere was purged with nitrogen again. The temperature was then raised to 100°C and the reaction was allowed to react for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The resulting crude product was purified by automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 6 to 100 / 10) to give compound YL230783-180-A (300 mg, 0.946 mmol, 16.64%), ESI: (m / z) = 265.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.56 (d, J=3.0Hz, 1H), 7.76 (td, J=8.6, 3.0Hz, 1H), 7.61 (dd, J=8.7, 4.5Hz, 1H), 4.28 (s, 2H), 2.88 (s, 3H), 1.42 (s, 9H).

[0347] Synthesis of compound YL230783-183-A

[0348] Under ice-bath conditions, YL230783-180-A (300 mg, 1.135 mmol), dichloromethane (30 mL), and trifluoroacetic acid (1.5 mL) were added to the reaction flask and stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and water and extracted. Since the target product had good water solubility and was almost completely dissolved in the aqueous layer, the aqueous phase was lyophilized to directly obtain the target compound YL230783-183-A as an oil. LC-MS (ESI): m / z 165.1 (M+H) + .

[0349] Synthesis of compound YL230783-184-A

[0350] YL230783-174-A (120 mg, 0.443 mmol), YL230783-183-A (72.68 mg, 0.443 mmol), and potassium iodide (73.48 mg, 0.443 mmol) were dissolved in acetonitrile (20 mL), and N,N-diisopropylethylamine (286.07 mg, 2.213 mmol) was added. The temperature was then raised to 80°C for 1.5 hours. After the reaction, the solvent was removed by rotary evaporation. The crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 5) to give compound YL230783-184-A (100 mg, 0.268 mmol, 60.56%), ESI: (m / z) = 355.2 [M+H] + .

[0351] Example 10 Synthesis route of compound 10

[0352] Synthesis of compound YL230774-366

[0353] Dess-Martin (306 mg, 0.72 mmol) was added to a solution of 8-fluoro-7-hydroxymethyl-3-methylquinoxalin-2(1H)-one (100 mg, 0.48 mmol) in dichloromethane (5 mL) and allowed to react at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to obtain YL230774-366 (40 mg, yield 40.39%). (ESI): m / z 207.0 [M+H] + .

[0354] Synthesis of compound YL230774-374

[0355] Under nitrogen, Pd(Ph3P)2Cl2 (80 mg, 0.11 mmol) and CuI (43 mg, 0.23 mmol) were added to a solution of 5-bromo-2-fluoropyridine (200 mg, 1.14 mmol) and tert-butyl methyl(prop-2-en-1-yl)carbamate (192 mg, 1.14 mmol) in triethylamine (5 mL) and dimethyl sulfoxide (1 mL). The mixture was heated to 70°C for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-30%) to afford YL230774-374 (200 mg, 66.59% yield). (ESI): m / z 265.0 [M+H] + .

[0356] Synthesis of compound YL230774-376

[0357] YL230774-374 (200 mg, 0.76 mmol) was added to a 1,4-dioxane hydrochloride solution (4 M, 5 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain YL230774-376 (150 mg, yield 98.76%). (ESI): m / z 165.1 [M+H] + .

[0358] Synthesis of compound 10 (YL230774-377)

[0359] Tetraethoxytitanium (44 mg, 0.19 mmol) was added to a mixture of YL230774-376 (40 mg, 0.19 mmol) and YL230774-366 (47 mg, 0.23 mmol) in tetrahydrofuran (3 mL), stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (164 mg, 0.78 mmol) was added and reacted at room temperature for 16 hours. The reaction solution was quenched with methanol, concentrated under reduced pressure, and purified by preparative HPLC (NH4HCO3) to give YL230774-377 (15 mg, yield 21.82%). (ESI): m / z 355.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.33 (s, 1H), 8.37 (d, J=2.4Hz, 1H), 8.08 (td, J=8.1, 2.4Hz, 1H), 7. 50(d, J=8.3Hz, 1H), 7.30–7.21(m, 2H), 3.74(s, 2H), 3.58(s, 2H), 2.41(s, 3H), 2.32(s, 3H).

[0360] Example 11 Synthesis route of compound 11

[0361] Synthesis of compound YL230784-300-C1

[0362] To a 50 mL three-necked flask were added YL230769-274 (100 mg, 0.449 mmol), acetonitrile (5 mL), N-methylpropargylamine (46 mg, 0.674 mmol), potassium iodide (15 mg, 0.090 mmol) and N,N-diisopropylethylamine (290 mg, 2.245 mmol) in sequence. Under nitrogen protection, the temperature was raised to 80°C and the reaction was allowed to react for 2 hours. The mixture was diluted with water and ethyl acetate, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried, and concentrated under reduced pressure. Purification by column chromatography (methanol / dichloromethane = 0-2%) gave YL230784-300-C1 (96 mg, 0.376 mmol, 83.73%). LC-MS (ESI): m / z 256.2 (M+H) + .

[0363] Synthesis of compound YL230784-306-C1

[0364] 1-Chloro-6-bromoisoquinoline (300 mg, 1.237 mmol) and methylamine ethanol solution (6 mL) were added to a 20 mL flask, the atmosphere was replaced with nitrogen, and the temperature was raised to 80°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain YL230784-300-C1 (260 mg, 1.097 mmol, 88.64%). LC-MS (ESI): m / z 237.1, 239.1 (M+H) + .

[0365] Synthesis of compound YL230784-310-C1

[0366] To a 50 mL three-necked flask were added YL230784-300-C1 (100 mg, 0.422 mmol), dioxane (5 mL), di-tert-butyl dicarbonate (276 mg, 1.265 mmol) and 4-dimethylaminopyridine (10 mg, 0.084 mmol), replaced with nitrogen three times, and heated to 100 ° C for overnight reaction. Ethyl acetate and water were added to dilute. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with brine, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain YL230784-310-C1 (115 mg, 0.341 mmol, 80.85%), LC-MS (ESI): m / z 337.0, 339.0 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ8.41 (d, J=5.7Hz, 1H), 8.34 (d, J=2.1Hz, 1H), 7.84 (d , J=1.8Hz, 1H), 7.83 (s, 1H), 7.77 (d, J=5.7Hz, 1H), 3.29 (s, 3H), 1.25 (s, 9H).

[0367] Synthesis of compound YL230784-318-C1

[0368] To a 50 mL three-necked flask were added YL230784-310-C1 (110 mg, 0.326 mmol), triethylamine (6 mL), dimethyl sulfoxide (1 mL), YL230784-300-C1 (83 mg, 0.326 mmol), cuprous iodide (12 mg, 0.065 mmol), and bistriphenylphosphine palladium dichloride (22 mg, 0.033 mmol). The mixture was heated to 70°C under nitrogen and reacted for 1 hour. Ethyl acetate and water were added for dilution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (methanol / dichloromethane = 0-5%) to obtain YL230784-318-C1 (60 mg, 0.117 mmol, 35.95%). LC-MS (ESI): m / z 512.3 (M+H) + .

[0369] Synthesis of compound 11

[0370] To a 50 mL three-necked flask, YL230784-318-C1 (50 mg, 0.098 mmol), DCM (5 mL), and trifluoroacetic acid (1.5 mL) were added sequentially and stirred at room temperature under nitrogen for 1 hour. The mixture was concentrated under reduced pressure, methanol was added, and ammonia methanol solution was added dropwise to adjust the mixture to neutral. The mixture was concentrated under reduced pressure and sent to the preparation to obtain compound 11 (25 mg, 0.061 mmol, 62.16%); LC-MS (ESI): m / z 412.3 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ11.95 (s, 1H), 8.46 (s, 1H), 8.06 (d, J=1.7Hz, 1H) , 7.82–7.76(m, 1H), 7.76–7.73(m, 1H), 7.68(s, 1H), 7.35(s, 1H), 7.22(s, 1H), 7.17(d, J=6.9Hz, 1H), 7.09(s, 1H), 3.87(s, 2H), 3.77(s, 2H), 3.12(d , J=4.3Hz, 3H), 2.55 (d, J=7.3Hz, 2H), 2.44 (s, 3H), 1.17 (t, J=7.4Hz, 3H).

[0371] Example 12 Synthesis route of compound 12

[0372] Synthesis of compound YL230784-294-C1

[0373] To a 100 mL three-necked flask, 4-bromo-5-fluoro-2-methylbenzamide (4 g, 17.238 mmol), tetrahydrofuran (60 mL) and N,N-dimethylformamide dimethyl acetal (2.26 g, 18.961 mmol) were added in sequence, and the temperature was raised to 65 ° C under nitrogen protection to react overnight. Ethyl acetate and water were added to dilute. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to obtain crude product YL230784-294-C1 (6.15 g, 21.419 mmol, 124.26%), LC-MS (ESI): m / z 287.1, 289.1 (M+H) + .

[0374] Synthesis of compound YL230784-298-C1

[0375] To a 100 mL three-necked flask, YL230784-294-C1 (6.15 g, 21.419 mmol), tetrahydrofuran (30 mL), and potassium tert-butoxide (2.64 g, 23.561 mmol) were added sequentially. The mixture was heated to 60°C under nitrogen and reacted for 2 days. The reaction solution was quenched by adding 1 M citric acid solution, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether = 0-70%) to obtain YL230784-298-C1 (830 mg, 3.429 mmol, 16.01%); LC-MS (ESI): m / z 242.0, 244.0 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ 11.49 (s, 1H), 8.16 (d, J=6.7Hz, 1H), 7.94 (d, J=9.2Hz, 1H), 7.22 (dd, J=7.1, 5.7Hz, 7H), 6.57 (d, J=7.2Hz, 6H).

[0376] Synthesis of compound YL230784-308-C1

[0377] To a 50 mL three-necked flask, YL230784-298-C1 (200 mg, 0.826 mmol) and toluene (5 mL) were added in sequence. N,N-diisopropylethylamine (320 mg, 2.479 mmol) was added dropwise. Phosphorus oxychloride (380 mg, 2.479 mmol) was added dropwise under nitrogen protection, and the temperature was raised to 130°C to react overnight. Ethyl acetate and water were added for dilution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain YL230784-308-C1 (76 mg, 0.292 mmol, 35.31%); LC-MS (ESI): m / z 260.0, 262.0 (M+H) + .

[0378] Synthesis of compound YL230784-313-C1

[0379] To a 10 mL pressure tube, YL230784-308-C1 (76 mg, 0.292 mmol) and methylamine ethanol solution (2 mL) were added sequentially. The temperature was raised to 80°C under nitrogen protection and the reaction was allowed to proceed for 1 hour. The mixture was concentrated under reduced pressure to obtain YL230784-313-C1 (35 mg, 0.137 mmol, 47.03%); LC-MS (ESI): m / z 255.0, 257.0 (M+H) + .

[0380] Synthesis of compound YL230784-327-C1

[0381] To a 50 mL three-necked flask, YL230784-313-C1 (50 mg, 0.196 mmol), dioxane (5 mL), di-tert-butyl dicarbonate (128 mg, 0.588 mmol) and 4-dimethylaminopyridine (5 mg, 0.039 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times and the temperature was raised to 100°C for overnight reaction. Ethyl acetate and water were added for dilution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain YL230784-327-C1 (60 mg, 0.169 mmol, 86.18%); LC-MS (ESI): m / z 355.1, 357.1 (M+H) + .

[0382] Synthesis of compound YL230784-329-C1

[0383] To a 50 mL three-necked flask were added YL230784-327-C1 (55 mg, 0.155 mmol), triethylamine (3 mL), dimethyl sulfoxide (0.5 mL), YL230784-300-C1 (59 mg, 0.232 mmol), cuprous iodide (6 mg, 0.031 mmol), and bistriphenylphosphine palladium dichloride (12 mg, 0.015 mmol). The mixture was heated to 70°C under nitrogen for 1 hour. Ethyl acetate and water were added for dilution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (methanol / dichloromethane = 0-5%) to obtain YL230784-329-C1 (55 mg, 0.104 mmol, 67.06%); LC-MS (ESI): m / z 530.3 (M+H) + .

[0384] Synthesis of compound 12

[0385] To a 50 mL three-necked flask, YL230784-329-C1 (45 mg, 0.085 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added sequentially and reacted at room temperature under nitrogen for 1 hour. The mixture was concentrated under reduced pressure, dissolved in methanol, and neutralized by dropwise addition of ammonia methanol solution under an ice-water bath. The mixture was concentrated under reduced pressure to obtain 12 (24 mg, 0.055 mmol, 55.05%); LC-MS (ESI): m / z 430.3 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.89 (s, 1H), 8.42 (d, J = 1.8Hz, 1H), 8.10 (d, J = 11.2Hz, 1 H), 7.97 (d, J = 7.3Hz, 1H), 7.90 (d, J = 5.8Hz, 1H), 7.74 (s, 1H), 7.64 (d, J = 1.8Hz, 1 H), 7.45 (q, J=4.5Hz, 1H), 6.90 (d, J=5.8Hz, 1H), 3.75 (s, 2H), 3.67 (s, 2H), 2.96 ( d, J=4.4Hz, 3H), 2.55 (dd, J=7.4, 1.2Hz, 2H), 2.35 (s, 3H), 1.18 (t, J=7.4Hz, 3H).

[0386] Example 13 Synthesis route of compound 13

[0387] Synthesis of compound YL230784-336-C1

[0388] To a 50 mL three-necked flask were added 4-bromo-3-fluoro-N-methylbenzamide (1000 mg, 4.309 mmol), DMF (10 mL), tert-butyl methyl(prop-2-yn-1-yl)carbamate (1458 mg, 8.619 mmol), cuprous iodide (1641 mg, 8.619 mmol), potassium iodide (715 mg, 4.309 mmol), and N,N-diisopropylethylamine (2784 mg, 21.547 mmol). Tetrakistriphenylphosphine palladium (995 mg, 0.862 mmol) was added under nitrogen. The mixture was heated to 100°C under nitrogen and allowed to react for 10 hours. Ethyl acetate and water were added to dilute the mixture. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (EA / PE = 0-40%) to give YL230784-336-C1 (350 mg, 1.093 mmol, 25.35%); LC-MS (ESI): m / z 321.0 (M+H) + .

[0389] Synthesis of compound YL230784-337-C1

[0390] To a 50 mL three-necked flask, YL230784-336-C1 (350 mg, 1.093 mmol), DCM (5 mL), and trifluoroacetic acid (1.5 mL) were added sequentially and reacted at room temperature under nitrogen for 1 hour. The mixture was concentrated under reduced pressure, dissolved in methanol, and neutralized by dropwise addition of ammonia methanol solution under an ice-water bath. The mixture was concentrated under reduced pressure and purified by column chromatography (methanol / dichloromethane = 0-4%) to give YL230784-337-C1 (235 mg, 1.067 mmol, 97.66%); LC-MS (ESI): m / z 221.2 (M+H) + .

[0391] Synthesis of compound 13

[0392] To a 50 mL three-necked flask were added YL230784-337-C1 (28 mg, 0.127 mmol), ACN (5 mL), YL230769-274 (22 mg, 0.102 mmol), potassium iodide (4 mg, 0.025 mmol), and N,N-diisopropylethylamine (82 mg, 0.636 mmol). The atmosphere was purged with nitrogen three times and the temperature was raised to 80°C for 4 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (methanol / dichloromethane = 0-3%) to give compound 13 (18 mg, 0.044 mmol, 34.84%); LC-MS (ESI): m / z 407.3 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ11.89 (s, 1H), 8.61 (d, J = 4.9Hz, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 7.74 (d, J = 4.9Hz, 1H), 7.71–7.65 (m, 2H) , 7.63 (s, 1H), 3.72 (s, 2H), 3.65–3.63 (m, 2H), 2.79 (d, J = 4.5Hz, 3H), 2.56 (d, J = 7.5Hz, 2H), 2.33 (s, 3H), 1.18 (t, J = 7.4Hz, 3H).

[0393] Example 14 Synthesis route of compound 14

[0394] Synthesis of compound YL230784-345-C1

[0395] To a 50 mL three-necked flask were added 4-bromo-N-methylbenzamide (1000 mg, 4.672 mmol), DMF (10 mL), tert-butyl methyl(prop-2-yn-1-yl)carbamate (1581 mg, 9.344 mmol), cuprous iodide (1779 mg, 9.344 mmol), potassium iodide (775 mg, 4.672 mmol), and N,N-diisopropylethylamine (3019 mg, 23.358 mmol). Tetrakistriphenylphosphine palladium (1079 mg, 0.934 mmol) was added under nitrogen. The mixture was heated to 100°C under nitrogen and allowed to react for 4 hours. Ethyl acetate and water were added to dilute the mixture. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (EA / PE = 0-40%) to give YL230784-345-C1 (578 mg, 1.912 mmol, 40.92%); LC-MS (ESI): m / z 303.2 (M+H) + .

[0396] Synthesis of compound YL230784-348-C1

[0397] YL230784-345-C1 (578 mg, 1.912 mmol), DCM (5 mL), and trifluoroacetic acid (1.5 mL) were added to a 50 mL three-necked flask in sequence and reacted at room temperature under nitrogen for 1 hour. The mixture was concentrated under reduced pressure, dissolved in methanol, and neutralized by dropwise addition of ammonia methanol solution under an ice-water bath. The mixture was concentrated under reduced pressure to obtain the crude product YL230784-348-C1 (1060 mg, 1.310 mmol, 68.54%) with a content of approximately 28%. LC-MS (ESI): m / z 203.2 (M+H) + .

[0398] Synthesis of compound 14

[0399] To a 50 mL three-necked flask were added YL230784-348-C1 (42 mg, 0.208 mmol), ACN (5 mL), YL230769-274 (37 mg, 0.166 mmol), potassium iodide (7 mg, 0.042 mmol), and N,N-diisopropylethylamine (134 mg, 1.038 mmol). The atmosphere was purged with nitrogen three times and the temperature was raised to 80°C for 2 hours. The mixture was concentrated under reduced pressure and purified by reverse phase column to obtain compound 14 (16 mg, 0.041 mmol, 19.83%); LC-MS (ESI): m / z 407.3 (M+H). + . 1H NMR (400MHz, DMSO-d6) δ11.89 (s, 1H), 8.52 (q, J=4.4Hz, 1H), 8.41 (d, J=1.8Hz, 1H), 7.84 (d, J=8.3Hz, 2H), 7.75 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.3Hz, 2H), 3.71 (s, 2H), 3.59 (s, 2H), 2.79 (d, J=4.5Hz, 3H), 2.59–2.51 (m, 2H), 2.32 (s, 3H), 1.18 (t, J=7.4Hz, 3H).

[0400] Example 15 Synthesis route of compound 15

[0401] Synthesis of compound YL230804-031-A

[0402] YL230769-310-A ​​(100 mg, 0.449 mmol), cyclopropylamine (256 mg, 4.491 mmol), DIEA (116.1 mg, 0.898 mmol), and potassium iodide (15 mg, 0.09 mmol) were added to a reaction flask. Acetonitrile (2 mL) was added, the atmosphere was replaced with nitrogen, and the reaction was carried out at 80°C for 2 hours. The reaction solution was spin-dried and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to obtain YL230804-031-A (90 mg, 82.36%); LCMS (ESI): m / z 244.1 (M+H) + .

[0403] Synthesis of compound YL230804-033-1

[0404] YL230804-031-A (90 mg, 0.370 mmol), 3-bromopropyne (44 mg, 0.370 mmol), and potassium carbonate (102 mg, 0.740 mmol) were added to a reaction flask, and DMF (3 mL) was added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at room temperature for 4 hours. The reaction solution was spin-dried and purified by a normal phase column (dichloromethane / methanol = 20 / 1) to obtain YL230804-033-1 (60 mg, 57.65%); LCMS (ESI): m / z 282.2 (M+H) + ;

[0405] Synthesis of compound 15

[0406] YL230804-033-1 (55 mg, 0.195 mmol), N-methyl-5-bromopicolinamide (46.1 mg, 0.215 mmol), cuprous iodide (74.5 mg, 0.391 mmol), DIEA (126.3 mg, 0.977 mmol) and tetrakis(triphenylphosphine)palladium (45.2 mg, 0.039 mmol) were added to a reaction flask, and DMF (5 mL) was added. The atmosphere was replaced with nitrogen and the mixture was reacted at 100° C. for 1.5 hours. The reaction solution was filtered and dried to give compound 15 (7.5 mg, 9.23%); LCMS (ESI): m / z 416.3 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.79(d,J=5.0Hz,1H),8.69(s,1H),8.40 (s,1H),8.10–7.96(m,2H),7.72(s,1H),7.60(d,J=1.8Hz,1H),3.95(s,2H),3.5 9(s,2H),2.82(d,J=4.8Hz,3H),2.56–2.52(m,2H),2.19(dt,J=6.5,3.1Hz,1H) ,1.16(t,J=7.4Hz,3H),0.54(dt,J=6.2,3.0Hz,2H),0.43(q,J=3.4,3.0Hz,2H).

[0407] Example 16 Synthesis route of compound 16

[0408] Synthesis of compound YL230804-062-A

[0409] YL230804-056-A (50 mg, 0.173 mmol) was dissolved in acetonitrile (2 mL), and N-methylpropargylamine (12 mg, 0.173 mmol), N,N-diisopropylethylamine (67 mg, 0.519 mmol), and potassium iodide (2.87 mg, 0.017 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was spin-dried and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound YL230804-062-A (30 mg, 60%). ESI: (m / z) = 278.1 [M+H] + .

[0410] Synthesis of compound 16 (YL230804-064-A)

[0411] YL230804-062-A (30 mg, 0.108 mmol) was dissolved in DMF (1 mL), and 4-iodobenzene-1-carbonitrile (27 mg, 0.119 mmol), N,N-diisopropylethylamine (70 mg, 0.541 mmol), cuprous iodide (41 mg, 0.216 mmol), and tetrakistriphenylphosphine palladium (25 mg, 0.022 mmol) were added. The mixture was reacted at 100°C for 1.5 hours. The reaction mixture was acidified to yield compound YL230804-064-A (YL-27032) (15 mg, 36.64%). ESI: (m / z) = 379.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.59(s,1H),8.66(d,J=1.8Hz,1H),8.17(s,1H),7.95–7.89(m,2H),7.8 7(d,J=1.8Hz,1H),7.76–7.69(m,2H),7.15–6.81(m,1H),4.43(s,2H),4.24(s,2H),2.78(s,3H).

[0412] Example 17 Synthesis route of compound 17

[0413] Synthesis of compound YL230804-082-A

[0414] YL230804-055-A (55 mg, 0.230 mmol) was dissolved in dichloromethane (8 mL), and triphenylphosphine (128 mg, 0.486 mmol) was added. Carbon tetrabromide (161 mg, 0.486 mmol) was then added at 0°C and allowed to react at room temperature for 5 hours. The reaction solution was spin-dried and purified on a normal phase column (dichloromethane / methanol = 10 / 1) to obtain compound YL230804-082-A (55 mg, 47.1%). ESI: (m / z) = 289.0 [M+H] + .

[0415] Synthesis of compound YL230804-085-A

[0416] YL230804-082-A (20 mg, 0.069 mmol) was dissolved in acetonitrile (2 mL), and YL230774-417-A (21 mg, 0.104 mmol), N,N-diisopropylethylamine (45 mg, 0.346 mmol), and potassium iodide (1.15 mg, 0.007 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried to obtain compound YL230804-085-A (5.8 mg). ESI: (m / z) = 412.3 [M+H]+ ; 1 H NMR (400MHz, DMSO-d6) δ11.73(s,1H),8.80(q,J=4.7Hz,1H),8.73–8.68(m,1H),8.54(d,J=1.8Hz,1H),8.15(d,J=1.9Hz,1H),8.08(dd,J=8.1,2.1 Hz,1H),8.02(dd,J=8.1,0.9Hz,1H),7.71(d,J=1.8Hz,1H),6.98(t,J=54 .5Hz,1H),3.78(s,2H),3.66(s,2H),2.82(d,J=4.8Hz,3H),2.34(s,3H).

[0417] Example 18 Synthesis route of compound 18

[0418] Synthesis of compound YL230804-066-A

[0419] 3-Fluoro-4-bromo-acetophenone (500 mg, 2.304 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-dimethylformamide dimethyl acetal (330 mg, 2.764 mmol) was added. The mixture was allowed to react at 80°C overnight. The reaction mixture was dried by rotary evaporation, ethyl acetate and water were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain crude compound YL230804-066-A (620 mg, 98.89%). ESI: (m / z) = 272.0 [M+H] + ;

[0420] Synthesis of compound YL230804-068-A

[0421] YL230804-066-A (620 mg, 2.278 mmol) was dissolved in ethanol (8 mL), and hydrazine hydrate (402 mg, 6.835 mmol, 85%) was added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 70°C for 2 hours. The reaction solution was cooled to room temperature and poured into ice water. A white solid precipitated. The solid was filtered, washed with water, filtered again, and evaporated to dryness to obtain compound YL230804-068-A (500 mg, 89.22%). ESI: (m / z) = 241.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ13.06(s,1H),7.84–7.75(m,2H),7.71(t,J=7.8Hz,1H),7.63(dd,J=8.4,1.9Hz,1H),6.83(d,J=2.3Hz,1H).

[0422] Synthesis of compound YL230804-084-A

[0423] YL230804-068-A (500 mg, 2.074 mmol) was dissolved in tetrahydrofuran (10 mL), replaced with N2, cooled to 0°C, and sodium hydride (125 mg, 3.111 mmol) was added. The reaction mixture was allowed to react at room temperature for 0.5 hours. 2-(Trimethylsilyl)ethoxymethyl chloride (520 mg, 3.111 mmol) was added and allowed to react at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified on a normal phase column (petroleum ether / ethyl acetate = 7 / 1) to obtain compound YL230804-084-A (620 mg, 80.5%). ESI: (m / z) = 371.0 [M+H] + ;

[0424] Synthesis of compound YL230804-086-A

[0425] YL230804-084-A (620 mg, 1.675 mmol) was dissolved in N,N-dimethylformamide (10 mL), and tert-butyl methyl(prop-2-yn-1-yl)carbamate (425 mg, 2.513 mmol), cuprous iodide (638 mg, 3.35 mmol), N,N-diisopropylethylamine (1.08 g, 8.375 mmol), tetrakistriphenylphosphine palladium (387 mg, 0.335 mmol), and sodium iodide (50 mg, 0.335 mmol) were added. The mixture was reacted at 120°C for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified on a normal phase column (petroleum ether / ethyl acetate = 7 / 1) to afford compound YL230804-086-A (150 mg, 15.43%). ESI: (m / z) = 460.0 [M+H] + ;

[0426] Synthesis of compound YL230804-089-A

[0427] YL230804-086-A (90 mg, 0.202 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was spin-dried and adjusted to alkalinity by adding 7 M amine methanol solution under ice bath. The mixture was spin-dried to obtain compound YL230804-089-A (40 mg, 92.02%). ESI: (m / z) = 230.0 [M+H] + .

[0428] Synthesis of compound YL230804-092-A

[0429] YL230804-089-A (40 mg, 0.173 mmol) was dissolved in acetonitrile (4 mL), and YL230784-293-C3 (39 mg, 0.180 mmol), N,N-diisopropylethylamine (116 mg, 0.898 mmol), and potassium iodide (2.98 mg, 0.018 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was spin-dried to obtain compound YL230804-092-A (12 mg). ESI: (m / z) = 416.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.10(s,1H),11.89(s,1H),8.40(d,J=1.8Hz,1H),7.78–7.65(m,4H),7.63(d,J=1.8Hz,1H),7.56(t,J =7.8Hz,1H),6.85(d,J=2.3Hz,1H),3.71(s,2H),3.62(s,2H),2.54(td,J=7.4,1.2Hz,2H),2.32(s,3H),1.17(t,J=7.4Hz,3H).

[0430] Example 19 Synthesis route of compound 19

[0431] Synthesis of compound YL230804-117-A

[0432] Dissolve 7-bromo-2-methoxyquinoline (3 g, 12.601 mmol) in tetrahydrofuran (15 mL), add 3N dilute hydrochloric acid (15 mL), and react at 70°C for 24 hours. The reaction solution was added dropwise to ice water, stirred, filtered, and the solid was dried to give compound YL230804-117-A (2.6 g, 92.09%). ESI: (m / z) = 224.1 / 226.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),7.94–7.86(m,1H),7.62(d,J=8.4Hz,1 H),7.47(d,J=1.9Hz,1H),7.33(dd,J=8.3,1.9Hz,1H),6.52(d,J=9.6Hz,1H).

[0433] Synthesis of compound YL230804-125-A

[0434] YL230804-117-A (2.4 g, 10.711 mmol) was dissolved in acetonitrile (20 mL) and water (6 mL). Sodium difluoromethanesulfinate (3 g, 21.423 mmol) and potassium persulfate (11.58 g, 42.846 mmol) were added and the mixture was allowed to react at 100°C overnight. The reaction solution was added dropwise to water and stirred. Ethyl acetate was added and filtered. The solid was used as the starting material. The filtrate was dried and purified by normal phase column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound YL230804-125-A (200 mg, 6.81%). ESI: (m / z) = 274.1 [M+H] + .

[0435] Synthesis of compound YL230804-130-A

[0436] YL230804-125-A (40 mg, 0.146 mmol) was dissolved in 1,4-dioxane (0.5 mL) and water (0.1 mL). YL230774-467-A1 (21 mg, 0.104 mmol), cesium carbonate (143 mg, 0.438 mmol), XPHOS (14 mg, 0.029 mmol), and palladium acetate (3.3 mg, 0.015 mmol) were added and reacted at 100°C for 1 hour. The reaction solution was dried and purified by normal phase column chromatography to obtain compound YL230804-130-A (YL-27054) (3.2 mg). ESI: (m / z) = 411.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.80(d,J=4.9Hz,1H),8.71(dd,J=2.1, 0.9Hz,1H),8.27(s,1H),8.08(dd,J=8.1,2.1Hz,1H),8.02(dd,J=8.1,0.8Hz, 1H),7.79(d,J=8.1Hz,1H),7.36(s,1H),7.24(dd,J=8.0,1.5Hz,1H),6.94(t, J=54.9Hz,1H),3.70(s,2H),3.62(s,2H),2.82(d,J=4.8Hz,3H),2.33(s,3H).

[0437] Example 20 Synthesis route of compound 20

[0438] Synthesis of compound 20

[0439] YL230804-125-A (40 mg, 0.146 mmol) was dissolved in 1,4-dioxane (0.5 mL) and water (0.1 mL). YL230774-473-A1 (189 mg, 0.438 mmol, 79%), cesium carbonate (143 mg, 0.438 mmol), XPHOS (14 mg, 0.029 mmol), and palladium acetate (3.3 mg, 0.015 mmol) were added and reacted at 100°C for 1 hour. The reaction solution was dried and purified by normal phase column chromatography to obtain compound 20 (5.3 mg). ESI: (m / z) = 429.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.73(d,J=5.1Hz,1H),8.35–8.22(m,2H),7.96(dd,J=7.7,1.6Hz,1H),7.79(d,J=8.1Hz,1H ),7.36(s,1H),7.22(dd,J=8.1,1.5Hz,1H),6.94(t,J=54.9Hz,1H),3.70(s,2H),3.65(s,2H),2.80(d,J=4.8Hz,3H),2.33(s,3H).

[0440] Example 21 Synthesis route of compound 21

[0441] Synthesis of compound YL230804-137-A

[0442] YL230804-125-A (400 mg, 1.022 mmol, 70% purity) was dissolved in 1,4-dioxane (8 mL), and (tributyltin)methanol (360 mg, 1.124 mmol) and XPhos Pd G2 (11.5 mg, 0.015 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 80°C overnight. The reaction solution was extracted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to afford compound YL230804-137-A (150 mg, 65.20%). ESI: (m / z) = 226.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.25(d,J=1.6Hz,1H),7.76(d,J=8.1Hz,1H),7.38–7.32(m,1H ),7.16(dd,J=8.1,1.5Hz,1H),6.94(t,J=54.9Hz,1H),5.43(t,J=5.7Hz,1H),4.60(d,J=5.6Hz,2H).

[0443] Synthesis of compound YL230804-141-A

[0444] YL230804-137-A (150 mg, 0.666 mmol) was dissolved in dichloromethane (8 mL), and one drop of DMF was added. The mixture was replaced with nitrogen and cooled to 0°C. Thionyl chloride (475 mg, 3.997 mmol) was added and allowed to react at room temperature overnight. The reaction mixture was cooled to 0°C and saturated sodium bicarbonate aqueous solution was added dropwise. After stirring, extraction was performed with dichloromethane / methanol = 10 / 1. The organic phase was washed with water, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound YL230804-141-A (130 mg, 81.25%). ESI: (m / z) = 244.1 [M+H] + .

[0445] Synthesis of compound 21

[0446] YL230804-082-A (20 mg, 0.082 mmol), YL230783-234-A (19 mg, 0.086 mmol), N,N-diisopropylethylamine (32 mg, 0.246 mmol) and potassium iodide (1.3 mg, 0.008 mmol) were added to a reaction flask, acetonitrile (2 mL) was added, the atmosphere was replaced with nitrogen, and the reaction was carried out at 80° C. for 2 hours. The reaction solution was spin-dried and purified by normal phase column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 21 (15 mg, 37%); LCMS (ESI): m / z 428.3 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.61(d,J=4.7Hz,1H),8.27(s,1H),7.79(d,J=8.0Hz,1H),7.75–7.64(m,3H),7.35( s,1H),7.22(dd,J=8.0,1.4Hz,1H),6.94(t,J=54.9Hz,1H),3.69(s,2H),3.63(s,2H),2.79(d,J=4.5Hz,3H),2.31(s,3H).

[0447] Example 22 Synthesis route of compound 22

[0448] Synthesis of compound YL230804-145-A1

[0449] 7-Bromo-2(1H)-quinoxalinone (5 g, 22.218 mmol) was dissolved in dimethyl sulfoxide (50 mL), and sodium difluoromethanesulfinate (6.22 g, 44.437 mmol) and 2,3-butanedione (9.8 mL, 111.091 mmol) were added. The mixture was irradiated with blue light and allowed to react at room temperature for 7 days. Ethyl acetate and water were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1) to obtain compound YL230804-145-A1 (3 g, 49.1%). ESI: (m / z) = 275.1 / 277.1 [M+H] + ;

[0450] Synthesis of compound YL230804-153-A

[0451] YL230804-145-A1 (1 g, 3.636 mmol) was dissolved in 1,4-dioxane (15 mL), and (tributyltin)methanol (1.28 g, 3.999 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G2) (0.14 g, 0.182 mmol) were added. The atmosphere was purged with nitrogen and the reaction was allowed to proceed overnight at 80°C. Ethyl acetate and water were added, the layers separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified via normal phase column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to yield compound YL230804-153-A (300 mg, 36.59%). ESI: (m / z) = 227.0 [M+H] + ;

[0452] Synthesis of compound YL230804-156-A

[0453] YL230804-153-A (100 mg, 0.444 mmol) was dissolved in dichloromethane (8 mL), and 1 drop of DMF was added. The mixture was replaced with nitrogen and cooled to 0°C. Thionyl chloride (315 mg, 2.653 mmol) was added and allowed to react at room temperature overnight. The reaction solution was cooled to 0°C, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane / methanol = 10 / 1. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified on a normal phase column (dichloromethane / methanol = 20 / 1) to obtain compound YL230804-156-A (60 mg, 54.55%). ESI: (m / z) = 245.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),7.89(d,J=8.4Hz,1H),7.42(d,J=7.4Hz,2H),7.05(t,J=53.2Hz,1H),4.91(s,2H).

[0454] Synthesis of compound 22

[0455] YL230804-156-A (12 mg, 0.049 mmol) was dissolved in acetonitrile (2 mL), and 6-fluoro-N-methyl-5-(3-(methylamino)prop-1-yn-1-yl)picolinamide (12 mg, 0.054 mmol), N,N-diisopropylethylamine (19 mg, 0.147 mmol), and potassium iodide (0.8 mg, 0.005 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried to obtain compound 22 (3.5 mg). ESI: (m / z) = 430.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),8.73(d,J=5.0Hz,1H),8.29(dd,J=9.2,7.6Hz,1H),7.96(dd,J=7.7,1.6Hz,1H),7.84 (d,J=8.1Hz,1H),7.40–7.28(m,2H),7.04(t,J=53.4Hz,1H),3.73(s,2H),3.67(s,2H),2.80(d,J=4.8Hz,3H),2.34(s,3H).

[0456] Example 23 Synthesis route of compound 23

[0457] Synthesis of compound YL230784-362

[0458] To a 50 mL three-necked flask were added triethylamine (12 mL), 5-iodo-1H-indazole (500 mg, 2.049 mmol), dimethyl sulfoxide (2 mL), methyl(prop-2-yn-1-yl)carbamic acid tert-butyl ester (520 mg, 3.073 mmol), cuprous iodide (78 mg, 0.410 mmol), and bistriphenylphosphine palladium dichloride (143 mg, 0.205 mmol). The mixture was heated to 70°C under nitrogen for 1 hour. Ethyl acetate and water were added for dilution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl solution, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain YL230784-362 (296 mg, 1.037 mmol, 50.63%). LC-MS (ESI): m / z 286.2 (M+H) + .

[0459] Synthesis of compound YL230784-366-C1

[0460] To a 50 mL three-necked flask, YL230784-362 (290 mg, 1.016 mmol), dioxane (2.5 mL), and dioxane hydrochloride solution (2.5 mL) were added sequentially and reacted at room temperature under nitrogen for 1 hour. The reaction solution was concentrated under reduced pressure, neutralized by adding ammonia methanol solution, and concentrated under reduced pressure to obtain the crude product YL230784-366-C1 (296 mg, 1.598 mmol, 157.24%); LC-MS (ESI): m / z 186.2 (M+H) + .

[0461] Synthesis of compound YL230804-152-A

[0462] 7-Bromo-1,5-naphthyridin-2(1H)-one (1.2 g, 5.332 mmol) was dissolved in acetonitrile (10 mL) and water (3 mL). Sodium difluoromethanesulfinate (1.66 g, 10.665 mmol) and potassium persulfate (4.32 g, 15.997 mmol) were added and reacted at 100°C for 24 hours. Ethyl acetate and water were added to the reaction solution, filtered, and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1) to obtain compound YL230804-152-A (310 mg, 21.14%). ESI: (m / z) = 275.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.66(d,J=2.1Hz,1H),8.15(d,J=1.9Hz,1H),7.90(d,J=2.0Hz,1H),6.97(t,J=54.2Hz,1H).

[0463] Synthesis of compound YL230804-161-A

[0464] YL230804-152-A (200 mg, 0.727 mmol) was dissolved in 1,4-dioxane (10 mL), and (tributyltin)methanol (257 mg, 0.800 mmol) and Xphos Pd G2 (28.5 mg, 0.036 mmol) were added. The atmosphere was replaced with N2 and the reaction was allowed to proceed at 80°C overnight. Ethyl acetate and water were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to obtain compound YL230804-161-A (100 mg, 60.80%). ESI: (m / z) = 227.1 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.49(d,J=1.8Hz,1H),8.15(d,J=1.5Hz,1H),7.70(d d,J=1.9,0.9Hz,1H),6.97(t,J=54.5Hz,1H),5.56(t,J=5.6Hz,1H),4.67(d,J=5.6Hz,2H).

[0465] Synthesis of compound YL230804-163-A

[0466] YL230804-161-A (100 mg, 0.444 mmol) was dissolved in dichloromethane (8 mL), 1 drop of DMF was added, the mixture was replaced with N2, the temperature was lowered to 0°C, thionyl chloride (315 mg, 2.653 mmol) was added, and the mixture was allowed to react at room temperature overnight. The reaction solution was cooled to 0°C, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane / methanol = 10 / 1. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified on a normal phase column (dichloromethane / methanol = 20 / 1) to obtain compound YL230804-163-A (80 mg, 72.73%). ESI: (m / z) = 245.1 [M+H] + ;

[0467] Synthesis of compound 23

[0468] YL230804-163-A (20 mg, 0.069 mmol) was dissolved in acetonitrile (2 mL), and YL230784-366-C1 (36 mg, 0.123 mmol), N,N-diisopropylethylamine (32 mg, 0.245 mmol), and potassium iodide (1.4 mg, 0.008 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried to obtain compound 23 (22 mg). ESI: (m / z) = 394.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),12.25(s,1H),8.54(d,J=1.8Hz,1H),8.15(d,J=1.9Hz,1H),8.09(s,1H),7.92(d,J=1.3Hz,1H),7 .72(d,J=1.7Hz,1H),7.54(d,J=8.6Hz,1H),7.39(dd,J=8.6,1.5Hz,1H),6.97(t,J=54.5Hz,1H),3.77(s,2H),3.58(s,2H),2.34(s,3H).

[0469] Example 24 Synthesis route of compound 24

[0470] Synthesis of compound YL230784-361

[0471] To a 50 mL three-necked flask were added triethylamine (12 mL), 5-iodo-1H-indazole (400 mg, 1.550 mmol), dimethyl sulfoxide (2 mL), tert-butyl methyl(prop-2-yn-1-yl)carbamate (393 mg, 2.325 mmol), cuprous iodide (59 mg, 0.310 mmol), and bistriphenylphosphine palladium dichloride (108 mg, 0.155 mmol). The mixture was heated to 70°C under nitrogen for 1 hour. Ethyl acetate and water were added for dilution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl solution, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain YL230784-361 (400 mg, 1.336 mmol, 86.2%); LC-MS (ESI): m / z 300.1 (M+H). + ;

[0472] Synthesis of compound YL230784-367-C1

[0473] To a 50 mL three-necked flask, YL230784-361 (500 mg, 1.670 mmol), dioxane (5 mL), and dioxane hydrochloride solution (5 mL) were added sequentially and reacted at room temperature under nitrogen for 1 hour. The reaction solution was concentrated under reduced pressure, neutralized by adding ammonia methanol solution, and concentrated under reduced pressure to obtain the crude product YL230784-367-C1 (465 mg, 2.334 mmol, 139.72%); LC-MS (ESI): m / z 200.2 (M+H) + ;

[0474] Synthesis of compound YL230804-165-A

[0475] YL230804-163-A (20 mg, 0.069 mmol) was dissolved in acetonitrile (2 mL), and YL230784-367-C1 (36 mg, 0.123 mmol), N,N-diisopropylethylamine (32 mg, 0.245 mmol), and potassium iodide (1.4 mg, 0.008 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried to obtain compound 24 (18 mg). ESI: (m / z) = 408.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.55(d,J=1.8Hz,1H),8.15(d,J=1.9Hz,1H),8.06(d,J=0.9Hz,1H),7.91(t,J=1.0Hz,1H),7.73(d,J= 1.7Hz,1H),7.65(d,J=8.7Hz,1H),7.44(dd,J=8.7,1.5Hz,1H),6.97(t,J=54.5Hz,1H),4.05(s,3H),3.77(s,2H),3.59(s,2H),2.34(s,3H).

[0476] Example 25 Synthesis route of compound 25

[0477] Synthesis of compound YL230804-167-A

[0478] Methyl 5-bromo-6-fluoropicolinate (500 mg, 2.137 mmol) was dissolved in a solution of methanol (10 mL) and water (10 mL). Potassium hydroxide (240 mg, 4.273 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3-4 by adding dilute hydrochloric acid (2 M). The solution was extracted several times with a mixture of dichloromethane and methanol. The organic phase was separated, concentrated, and dried under vacuum to obtain compound YL230804-167-A (520 mg, crude product); LC-MS (ESI): m / z 218.0 (M+H) + ;

[0479] Synthesis of compound YL230804-168-A

[0480] YL230804-167-A (520 mg, 2.364 mmol) was dissolved in DMF (10 mL), and DIEA (916 mg, 7.091 mmol), HATU (1.35 g, 3.545 mmol), and cyclopropylamine (150 mg, 2.60 mmol) were added. The mixture was reacted at room temperature for 1 hour, quenched with water, extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain YL230804-168-A (450 mg, 73.48%); LC-MS (ESI): m / z 261.1 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ8.73(d,J=4.9Hz,1H),8.46(dd,J=8.9,7.9Hz,1H),7.85(dd,J=7.9,1.4Hz,1H),2.97–2.78(m,1H),0.74–0.60(m,4H).

[0481] Synthesis of compound YL230804-170-A

[0482] YL230804-168-A (200 mg, 0.772 mmol) was dissolved in triethylamine (5 mL) and dimethyl sulfoxide (1 mL). Pd(Ph3P)2Cl2 (54.2 mg, 0.077 mmol), cuprous iodide (29 mg, 0.154 mmol), and tert-butyl methyl(propan-2-yl)carbamate (144 mg, 0.849 mmol) were added and heated to 70°C for 2 hours. The mixture was extracted with ethyl acetate and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain YL230804-170-A (200 mg, 74.07%). LC-MS (ESI): m / z 348.3 (M+H) + ;

[0483] Synthesis of compound YL230804-172-A

[0484] YL230804-170-A (50 mg, 0.144 mmol) was added to a 1,4-dioxane hydrochloride solution (2 mL, 4 M) and allowed to react at room temperature for 1 hour. The reaction mixture was concentrated to yield YL230804-172-A (40 mg, crude product). LC-MS (ESI): m / z 225.1 (M+H) + ;

[0485] Synthesis of compound 25

[0486] YL230804-172-A (34 mg, 0.123 mmol) was dissolved in acetonitrile, DIEA (53 mg, 0.410 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. YL230804-141-A (20 mg, 0.082 mmol) and potassium iodide (1.4 mg, 0.008 mmol) were then added, and the mixture was stirred at 80°C for 2 hours. Compound 25 (21 mg, 52.5%) was obtained; LC-MS (ESI): m / z 455.2 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.72(d,J=5.0Hz,1H),8.33–8.22(m,2H),7.95(dd,J=7.8,1.5Hz,1H),7.79(d,J=8.0Hz,1H),7.35(s, 1H),7.22(dd,J=8.1,1.5Hz,1H),6.94(t,J=54.9Hz,1H),3.67(d,J=18.0Hz,4H),2.89(h,J=5.6Hz,1H),2.32(s,3H),0.69(d,J=5.7Hz,4H).

[0487] Example 26 Synthesis route of compound 26

[0488] Synthesis of compound YL230804-166-A

[0489] 7-Bromo-2(1H)-quinolinone (24 g, 107.11 mmol) (600 mg*10*4) was dissolved in acetonitrile (10 mL) and water (3 mL). Sodium difluoromethanesulfinate (30 g, 214.23 mmol) and potassium persulfate (86.87 g, 321.34 mmol) were added and reacted at 100°C overnight. Ethyl acetate and water were added to the reaction solution, which was filtered and the solid was used as the starting material. The filtrate was dried and purified by normal phase column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound YL230804-166-A (1.1 g, 3.75%). ESI: (m / z) = 274.1 [M+H] + ;

[0490] Synthesis of compound YL230804-169-A

[0491] YL230804-166-A (200 mg, 0.730 mmol) was dissolved in DMF (5 mL) and methanol (5 mL), and triethylamine (0.3 mL, 2.189 mmol) and Pd(dppf)Cl2 (107 mg, 0.146 mmol) were added. The mixture was reacted at 80°C for 30 hours under a carbon monoxide atmosphere. The mixture was then extracted with ethyl acetate and water, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain YL230804-169-A (120 mg, 66.67%); LC-MS (ESI): m / z 254.1 (M+H). + ; 1H NMR (400MHz, DMSO-d6) δ12.37(s,1H),8.38(s,1H),7.97(t,J=4.0Hz,2H),7.76(dd,J=8.4,1.5Hz,1H),6.97(t,J=54.5Hz,1H),3.90(s,3H).

[0492] Synthesis of compound YL230804-175-A

[0493] YL230804-169-A (100 mg, 0.395 mmol) was dissolved in methanol (3 mL) and water (3 mL). Potassium hydroxide (44 mg, 0.790 mmol) was added and the mixture was heated to 50°C for 2 hours. 1N dilute hydrochloric acid was added to adjust the pH to 4-5. The mixture was extracted with dichloromethane / methanol = 10 / 1. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain YL230804-175-A (180 mg, crude product). LC-MS (ESI): m / z 239.9 (M+H) + ;

[0494] Synthesis of compound 26

[0495] YL230804-175-A (25 mg, 0.084 mmol) was dissolved in DMF (3 mL), and DIEA (32 mg, 0.251 mmol) and HATU (48 mg, 0.125 mmol) were added. The mixture was stirred at room temperature for 20 minutes, and then YL230769-421-A (28 mg, 0.125 mmol) was added. The mixture was reacted at room temperature for 1 hour. Compound 26 (17 mg, 42.5%) was obtained; LC-MS (ESI): m / z 443.2 (M+H) + ; 1 H NMR(400MHz, DMSO-d6)δ12.30(s,1H),8.76(d,J=5.3Hz,1H),8.39–8.22(m,2H),8.02–7.87(m,2H),7.38(d,J=1.4Hz,1H),7 .31(dd,J=8.1,1.5Hz,1H),6.97(t,J=54.7Hz,1H),4.68(s,1H),4.37(s,1H),3.07(d,J=29.0Hz,3H),2.80(d,J=4.8Hz,3H).

[0496] Example 27 Synthesis route of compound 27

[0497] Synthesis of compound YL230769-363

[0498] To a 50 mL three-necked flask, methyl 5-bromo-6-methylpicolinate (460 mg, 1.999 mmol) and a solution of methylamine in ethanol (5 mL) were added sequentially. The mixture was allowed to react at room temperature under nitrogen for 18 hours. LCMS indicated a successful reaction, and the reaction solution was directly dried to yield YL230769-363 (458 mg, 1.999 mmol, 99.99%); LC-MS (ESI): m / z 231.0 (M+H). + .

[0499] Synthesis of compound YL230769-376

[0500] To a 100 mL three-necked flask, add YL230769-363 (458 mg, 1.999 mmol), tert-butyl methyl(prop-2-ynyl)carbamate (507.48 mg, 2.999 mmol), cuprous iodide (761.53 mg, 3.999 mmol), potassium iodide (331.88 mg, 1.999 mmol), N,N-diisopropylethylamine (1292.05 mg, 9.997 mmol), tetrakistriphenylphosphine palladium (462.07 mg, 0.400 mmol), and N,N-dimethylformamide (20 mL). The mixture was reacted at 100°C for 3 hours under nitrogen protection. LCMS showed the reaction was complete. Water and ethyl acetate were added to the reaction solution, and the organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate - 5:1-2:1) to obtain YL230769-376 (312 mg, 0.983 mmol, 49.17%); LC-MS (ESI): m / z 318.6 (M+H) + .

[0501] Synthesis of compound YL230769-385

[0502] To a 25 mL three-necked flask, YL230769-376 (100 mg, 0.315 mmol) and dichloromethane (10 mL) were added sequentially. Under nitrogen, trifluoroacetic acid (1 mL, 13.059 mmol) was slowly added. The reaction was continued at room temperature for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated, and then ammonia methanol solution was added. After stirring for 30 minutes, the solution was concentrated to yield YL230769-385 (68 mg, 0.313 mmol, 99.34%). LC-MS (ESI): m / z 218.3 (M+H). + .

[0503] Synthesis of compound 27

[0504] To a 50 mL three-necked flask were added YL230769-385 (26 mg, 0.120 mmol), YL230769-384 (31.79 mg, 0.120 mmol), potassium iodide (3.97 mg, 0.024 mmol), N,N-diisopropylethylamine (77.33 mg, 0.598 mmol), and acetonitrile (10 mL). The mixture was reacted at 80°C for 2 hours under nitrogen. LCMS indicated a successful reaction. The reaction solution was concentrated and then subjected to an alkaline method to obtain compound 27 (22 mg, 0.049 mmol, 41.18%). LC-MS (ESI): m / z 447.2 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),8.64(q,J=4.8Hz,1H),7.94(d,J=7.9Hz,1H),7.87-7.77(m,2H),7.31(dd,J=8 .5,6.9Hz,1H),6.95(s,1H),3.75(s,2H),3.67(s,2H),2.83(d,J=4.9Hz,3H),2.68(s,3H),2.41(s,3H),2.35(s,3H).

[0505] Example 28 Synthesis route of compound 28

[0506] Synthesis of compound 28

[0507] To a 50 mL three-necked flask were added YL230769-378 (59 mg, 0.199 mmol), YL230774-462 (96.54 mg, 0.299 mmol), cesium carbonate (194.77 mg, 0.598 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (19.00 mg, 0.040 mmol), palladium acetate (4.47 mg, 0.020 mmol), 1,4-dioxane (10 mL), and water (2 mL). The mixture was reacted at 100°C for 2 hours under nitrogen. LCMS indicated the reaction was complete, and the reaction solution was concentrated and reverse-phase purified to yield compound 28 (11 mg, 0.025 mmol, 12.77%); LC-MS (ESI): m / z 433.2 (M+H). + . 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.79(d,J=4.9Hz,1H),8.68(dd,J=2.1,0.9Hz,1H),8.11-7.95(m,2H),7.85(dd,J=8.5,1 .1Hz,1H),7.32(dd,J=8.5,6.9Hz,1H),6.96(s,1H),3.74(s,2H),3.63(s,2H),2.82(d,J=4.8Hz,3H),2.42(s,3H),2.34(s,3H).

[0508] Example 29 Synthesis route of compound 29

[0509] Synthesis of compound YL230769-379

[0510] To a 50 mL three-necked flask were added 1-(4-bromo-2,3-difluorophenyl)ethan-1-one (470 mg, 2.000 mmol), hydrazine hydrate (149.98 mg, 2.400 mmol), and ethanol (8 mL). The mixture was reacted at room temperature under nitrogen for 18 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 20:1-5:1) to afford YL230769-379 (410 mg, 1.646 mmol, 82.32%); LC-MS (ESI): m / z 249.1 (M+H). + .

[0511] Synthesis of compound YL230769-381

[0512] YL230769-379 (250 mg, 1.004 mmol) and ethylene glycol (10 mL) were added to a 25 mL microwave tube. The mixture was reacted at 165°C for 3 hours under nitrogen. LCMS indicated a successful reaction. Water and ethyl acetate were added to the reaction solution, and the organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to afford YL230769-381 (190 mg, 0.830 mmol, 82.64%). LC-MS (ESI): m / z 231.1 (M+H). + .

[0513] Synthesis of compound 29

[0514] To a 50 mL three-necked flask were added YL230769-381 (23 mg, 0.100 mmol), YL230774-469 (48.65 mg, 0.151 mmol), cesium carbonate (98.15 mg, 0.301 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (9.57 mg, 0.020 mmol), palladium acetate (2.25 mg, 0.010 mmol), 1,4-dioxane (10 mL), and water (2 mL). The mixture was reacted at 100°C for 2 hours under nitrogen. LCMS indicated a successful reaction. The reaction solution was directly concentrated and subjected to the reverse alkaline method to obtain compound 29 (3.8 mg, 0.010 mmol, 10.36%); LC-MS (ESI): m / z 366.3 (M+H). + .

[0515] Example 30 Synthesis route of compound 30

[0516] Synthesis of compound 30

[0517] To a 50 mL three-necked flask were added YL230784-293 (50 mg, 0.225 mmol), YL230774-470 (59.61 mg, 0.269 mmol), potassium iodide (7.45 mg, 0.045 mmol), N,N-diisopropylethylamine (145.11 mg, 1.123 mmol), and acetonitrile (10 mL). The mixture was reacted at 80°C for 4 hours under nitrogen. LCMS indicated a successful reaction. The reaction solution was concentrated and subjected to reverse phase column chromatography (alkaline method) to afford compound 30 (32.6 mg, 0.080 mmol, 35.63%); LC-MS (ESI): m / z 408.3 (M+H). + . 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.73(d,J=4.9Hz,1H),8.40(d,J=1.8Hz,1H),8.28(dd,J=9.2,7.7Hz,1H),7.96(dd,J=7.7,1.6Hz,1H),7.74(d, J=1.2Hz,1H),7.62(d,J=1.8Hz,1H),3.72(s,2H),3.66(s,2H),2.80(d,J=4 .8Hz,3H),2.54(td,J=7.4,1.2Hz,2H),2.33(s,3H),1.17(t,J=7.4Hz,3H).

[0518] Example 31 Synthesis route of compound 31

[0519] Synthesis of compound YL230769-405

[0520] To a 250 mL three-necked flask were added 3-amino-5-bromopyridine-2-carboxylic acid (5000 mg, 23.039 mmol) and dichloromethane (100 mL). The mixture was cooled to -78°C under nitrogen, followed by the addition of diisobutylaluminum hydride (46.079 mL, 46.079 mmol). The reaction was continued for 2 hours. LCMS indicated the reaction was complete. Slowly add 5 mL of water to the reaction solution, followed by 5 mL of 15% sodium hydroxide, and then add 15 mL of water. The mixture was then dried over a small amount of magnesium sulfate. The reaction solution was filtered, and the filtrate was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to afford YL230769-405 (220 mg, 1.094 mmol, 4.75%). MS (ESI): m / z 201.1 (M+H). + .

[0521] Synthesis of compound YL230769-406

[0522] To a 50 mL three-necked flask, methyl cyclopropylacetate (210.41 mg, 1.642 mmol) and tetrahydrofuran (10 mL) were added sequentially. Under nitrogen, the mixture was cooled to -78°C, followed by the addition of lithium bis(trimethylsilyl)amide (3.830 mL). The reaction was continued at this temperature for 30 minutes, followed by the addition of YL230769-405 (220 mg, 1.094 mmol). The reaction was continued at -78°C for 30 minutes, then the temperature was slowly raised to room temperature and the reaction continued for 18 hours. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated and subjected to column chromatography (dichloromethane:methanol = 50:1-20:1) to afford YL230769-406 (160 mg, 0.604 mmol, 55.15%). MS (ESI): m / z 265.0 (M+H). + .

[0523] Synthesis of compound YL230769-409

[0524] To a 50 mL three-necked flask were added YL230769-406 (150 mg, 0.566 mmol), tributyltin carbinol (218.01 mg, 0.679 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (44.46 mg, 0.057 mmol), and 1,4-dioxane (10 mL). The mixture was reacted at 80°C for 18 hours under nitrogen. LCMS indicated the reaction was complete. The reaction solution was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-409 (96 mg, 0.444 mmol, 78.46%). MS (ESI): m / z 217.2 (M+H). + .

[0525] Synthesis of compound YL230769-410

[0526] To a 50 mL three-necked flask were added YL230769-409 (96 mg, 0.444 mmol), N,N-dimethylformamide (0.004 mL, 0.044 mmol), and dichloromethane (10 mL). The mixture was cooled to 0°C under nitrogen, followed by the addition of thionyl chloride (316.87 mg, 2.664 mmol). The reaction was continued for 30 minutes, then the temperature was raised to room temperature and the reaction continued for 6 hours. LCMS indicated the reaction was complete. Saturated aqueous sodium bicarbonate and dichloromethane were added to the reaction solution, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 40:1-20:1) to afford YL230769-410 (86 mg, 0.366 mmol, 82.54%). MS (ESI): m / z 235.1 (M+H). + .

[0527] Synthesis of compound 31

[0528] To a 50 mL three-necked flask were added YL230769-410 (23.5 mg, 0.100 mmol), YL230774-470 (33.23 mg, 0.150 mmol), potassium iodide (3.32 mg, 0.020 mmol), N,N-diisopropylethylamine (64.71 mg, 0.501 mmol), and acetonitrile (10 mL). Under nitrogen, the mixture was reacted at 80°C for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford compound 31 (17 mg, 0.041 mmol, 40.47%); LC-MS (ESI): m / z 420.3 (M+H). + . 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),8.73(d,J=5.4Hz,1H),8.37(s,1H),8.28(t,J=8.5Hz,1H),7.95(d,J=7.8Hz,1H),7.60(s,1H) ,7.40(s,1H),3.68(d,J=21.2Hz,4H),2.80(d,J=4.8Hz,3H),2.32(s,3H),2.13(s,1H),0.96(d,J=8.1Hz,2H),0.81(d,J=5.3Hz,2H).

[0529] Example 32 Synthesis route of compound 32

[0530] Synthesis of compound YL230769-422

[0531] To a 100mL three-necked flask, add ethyl butyrate (866.78mg, 7.462mmol) and tetrahydrofuran (40mL) in sequence. Cool to -78°C under nitrogen, then slowly add lithium bistrimethylsilylamide (17.411mL). Continue the reaction at this temperature for 30 minutes, then add a solution of 3-amino-5-bromopyridinaldehyde (1000mg, 4.975mmol) in tetrahydrofuran (10mL). Continue the reaction at -78°C for 30 minutes, then warm to room temperature and continue the reaction for 18 hours. Then, add 10mL of methanol and continue the reaction for 6 hours. LCMS showed the reaction was successful. The reaction solution was directly concentrated and column chromatography (dichloromethane:methanol = 20:1-10:1) was performed to obtain YL230769-422 (560 mg, 2.213 mmol, 44.48%); LC-MS (ESI): m / z 255.0 (M+H) + .

[0532] Synthesis of compound YL230769-424

[0533] To a 50 mL three-necked flask were added YL230769-422 (200 mg, 0.790 mmol), triethylamine (0.330 mL, 2.371 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (115.64 mg, 0.158 mmol), methanol (8 mL), and N,N-dimethylformamide (8 mL). The mixture was reacted at 80°C for 6 hours under carbon monoxide protection. LCMS indicated the reaction was complete. The reaction solution was concentrated, and water and ethyl acetate were added. The organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-424 (160 mg, 0.689 mmol, 87.19%). LC-MS (ESI): m / z 231.3 (M+H). - .

[0534] Synthesis of compound YL230769-427

[0535] To a 50 mL three-necked flask were added YL230769-424 (160 mg, 0.689 mmol), lithium hydroxide (49.60 mg, 2.067 mmol), methanol (20 mL), and water (10 mL) in sequence. Under nitrogen protection, the reaction was allowed to proceed at room temperature for 3 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated, and 1 M hydrochloric acid was added to adjust the pH to 5. The reaction solution was filtered, and the filter cake was washed with water and dried to yield YL230769-427 (130 mg, 0.596 mmol, 86.47%); LC-MS (ESI): m / z 217.2 (M+H). - .

[0536] Synthesis of compound YL230769-408

[0537] To a 100 mL three-necked flask were added 1H-pyrazole-3-boronic acid pinacol ester (1940 mg, 9.998 mmol), 25 mL of dichloromethane, N,N-diisopropylethylamine (2584.47 mg, 19.996 mmol), and 2-(trimethylsilyl)ethoxymethyl chloride (1833.54 mg, 10.998 mmol). The reaction was allowed to proceed at room temperature for 18 hours. LCMS indicated the reaction was complete. Water and dichloromethane were added, and the organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 40:1-20:1) to afford YL230769-408 (1300 mg, 4.009 mmol, 40.09%); LC-MS (ESI): m / z 243.2 (M+H). + .

[0538] Synthesis of compound YL230769-418

[0539] To a 100 mL three-necked flask were added 3-bromo-2-fluoro-6-iodopyridine (990 mg, 3.279 mmol), YL230769-408 (1063.53 mg, 3.279 mmol), potassium carbonate (1359.66 mg, 9.838 mmol), tetrakistriphenylphosphine palladium (378.97 mg, 0.328 mmol), 1,4-dioxane (30 mL), and water (6 mL). The mixture was reacted at 80°C for 2 hours under nitrogen. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 20:1-10:1) to afford YL230769-418 (860 mg, 2.310 mmol, 70.44%); LC-MS (ESI): m / z 374.0 (M+H). + .

[0540] Synthesis of compound YL230769-420

[0541] To a 100 mL three-necked flask were added YL230769-418 (843 mg, 2.264 mmol), tert-butyl methyl(prop-2-yn-1-yl)carbamate (574.73 mg, 3.396 mmol), cuprous iodide (862.45 mg, 4.528 mmol), potassium iodide (375.86 mg, 2.264 mmol), N,N-diisopropylethylamine (1463.27 mg, 11.321 mmol), tetrakistriphenylphosphine palladium (523.31 mg, 0.453 mmol), and N,N-dimethylformamide (30 mL). The reaction was continued at 100°C under nitrogen protection for 4 hours. LCMS showed the reaction was complete. Water and ethyl acetate were added to the reaction solution, and the organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to obtain YL230769-420 (780 mg, 1.693 mmol, 74.79%); LC-MS (ESI): m / z 461.5 (M+H) + .

[0542] Synthesis of compound YL230769-429

[0543] To a 25 mL three-necked flask, YL230769-420 (92 mg, 0.200 mmol), dichloromethane (1 mL), and trifluoroacetic acid (1 mL, 13.059 mmol) were added sequentially and allowed to react at room temperature for 1 hour. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated to yield YL230769-429 (45.6 mg, 0.195 mmol, 99.35%); LC-MS (ESI): m / z 231.2 (M+H) + .

[0544] Synthesis of compound 32

[0545] To a 25 mL three-necked flask were added YL230769-427 (36 mg, 0.165 mmol), YL230769-429 (45.58 mg, 0.198 mmol), N,N-diisopropylethylamine (63.97 mg, 0.495 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (94.10 mg, 0.247 mmol), and N,N-dimethylformamide (5 mL). The mixture was reacted at room temperature for 2 hours under nitrogen protection. LCMS indicated the reaction was complete. Water and ethyl acetate were added to the reaction solution, and the organic phase was concentrated. Compound 32 (15.7 mg, 0.036 mmol, 22.11%) was prepared by alkaline method; LC-MS (ESI): m / z 431.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),12.01(s,1H),8.53(d,J=1.9Hz,1H),8.15(s,1H),7.90(d,J=12.1Hz,2H),7.81(s ,1H),7.70(d,J=1.9Hz,1H),6.83(s,1H),4.54(d,J=99.4Hz,2H),3.11(s,3H),2.61-2.53(m,2H),1.19(t,J=7.4Hz,3H).

[0546] Example 33 Synthesis route of compound 33

[0547] Synthesis of compound 33

[0548] To a 50 mL three-necked flask were added YL230769-283 (37 mg, 0.166 mmol), YL230769-429 (45.91 mg, 0.199 mmol), potassium iodide (5.52 mg, 0.033 mmol), N,N-diisopropylethylamine (107.38 mg, 0.831 mmol), and acetonitrile (10 mL). The mixture was reacted at 80°C under nitrogen for 2 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated and subjected to an alkaline reverse phase reaction to afford compound 33 (13.7 mg, 0.033 mmol, 19.80%); LC-MS (ESI): m / z 417.3 (M+H)+. 1H NMR (400MHz, DMSO-d6) δ13.27(s,1H),11.88(s,1H),8.40(d,J=1.8Hz,1H),8.11(t,J=8.7Hz,1H),7.89(d,J=13.6Hz,2H),7.74(q ,J=1.0Hz,1H),7.67-7.54(m,1H),6.82(s,1H),3.72(s,2H),3.64(s,2H),2.60-2.49(m,2H),2.33(s,3H),1.17(t,J=7.4Hz,3H).

[0549] Example 34 Synthesis of Compound 34

[0550] Synthesis of compound YL230783-190-A

[0551] To the reaction flask, methyl 5-bromo-6-fluoropicolinate (7.8 g, 33.330 mmol), potassium hydroxide (3.74 g, 66.661 mmol), methanol (280 mL), and water (280 mL) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the methanol was removed by vortexing, and the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to directly obtain solid compound YL230783-190-A (7.25 g, 31.307 mmol, 93.93%). LC-MS (ESI): m / z 221.1 (M+H) + .

[0552] Synthesis of compound YL230783-191-A

[0553] Dissolve YL230783-190-A (7.25 g, 32.955 mmol), methylamine hydrochloride (4.45 g, 65.909 mmol), and HATU (18.80 g, 49.432 mmol) in DMF (140 mL). Then add N,N-diisopropylethylamine (12.78 g, 98.864 mmol) and continue the reaction at room temperature overnight. Dilute with ethyl acetate and water, separate the organic phase, and extract the aqueous phase with ethyl acetate. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vortexing. The resulting crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 0 to 100 / 4) to obtain compound YL230783-191-A (5.9 g, 23.419 mmol, 71.06%). ESI: (m / z) = 233.0 / 235.0 [M+H] + ,1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=4.8Hz,1H),8.46(dd,J=8.9,7.9Hz,1H),7.86(dd,J=7.9,1.5Hz,1H),2.78(d,J=4.9Hz,3H).

[0554] Synthesis of compound YL230783-195-A

[0555] YL230783-191-A (1.14 g, 6.758 mmol), cuprous iodide (0.86 g, 4.506 mmol), potassium iodide (0.75 g, 4.506 mmol), and tetrakistriphenylphosphine palladium (1.04 g, 0.901 mmol) were dissolved in DMF (75 mL) at room temperature and replaced with nitrogen. N,N-diisopropylethylamine (2.91 g, 22.528 mmol) was then added and replaced with nitrogen again. The temperature was then raised to 100°C for 1 hour. After the reaction, the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The resulting crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 5) to give compound YL230783-195-A (1.7 g, 3.306 mmol, 73.38%), ESI: (m / z) = 322.2 [M+H] + .

[0556] Synthesis of compound YL230783-199-A

[0557] Under ice bath conditions, YL230783-195-A (700 mg, 2.178 mmol), dichloromethane (25 mL), and trifluoroacetic acid (2.5 mL, 32.648 mmol) were added to the reaction flask and stirred at room temperature for 2 hours. After the reaction, sodium hydroxide solution (1 M) was added to neutralize the excess trifluoroacetic acid, and then the mixture was diluted with dichloromethane and water. Extraction was performed and the organic solvent was completely removed to directly obtain the target compound YL230783-199-A (700 mg, 1.266 mmol, 58.10%). LC-MS (ESI): m / z 222.1 (M+H) + .

[0558] Synthesis of compound 34

[0559] YL230783-198-A (80 mg, 0.328 mmol), YL230783-199-A (87.16 mg, 0.394 mmol), and potassium iodide (54.50 mg, 0.328 mmol) were dissolved in acetonitrile (30 mL) at room temperature. N,N-diisopropylethylamine (212.15 mg, 1.641 mmol) was then added, and the reaction was continued at 80°C for 1.5 hours. The mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 12 to 100 / 15) to obtain compound YL210743-203. Preparative purification (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) gave compound 34 (10 mg, 0.022 mmol, 6.82%), ESI: (m / z) = 429.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.75(d,J=5.1Hz,1H),8.48(d,J=8.4Hz,1H),8.35(d,J=8.2Hz,1H),8.30(s,1H),7.96(d,J=7.5Hz,1H),7.85(t,J=7.8 Hz,1H),7.63(t,J=7.6Hz,1H),7.37(s,1H),7.24(d,J=8.4Hz,1H),6.06(s,2H),3.69(s,2H),3.66(s,2H),2.80(d,J=4.8Hz,3H),2.35(s,3H).

[0560] Example 35 Synthesis of Compound 35

[0561] YL230783-198-A (89 mg, 0.365 mmol), YL230783-234-A (96.53 mg, 0.438 mmol), and KI (60.63 mg, 0.365 mmol) were dissolved in acetonitrile (60 mL). DIEA (236.02 mg, 1.826 mmol) was then added and the reaction continued at 80°C for 1.5 hours. The mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 12 to 100 / 15) to afford 120 mg of compound YL210743-235. Preparative purification (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) afforded compound 35 (28 mg, 0.065 mmol, 17.76%), ESI: (m / z) = 428.3 [M+H]+, 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.61(d,J=5.1Hz,1H),8.48(d,J=8.2Hz,1H),8.38–8.29(m,2H),7.88–7.81(m,1H),7.7 5–7.61(m,4H),7.37(d,J=1.6Hz,1H),7.23(dd,J=8.2,1.7Hz,1H),3.66(d,J=19.0Hz,4H),2.79(d,J=4.5Hz,3H),2.34(s,3H).

[0562] Example 36 Synthesis route of compound 36

[0563] Synthesis of compound YL230783-244-A

[0564] 2-Amino-4-methoxycarbonylphenyl boronate hydrochloride (2.5 g, 10.802 mmol), methyl 2-bromonicotinate (2.57 g, 11.882 mmol), and potassium carbonate (4.48 g, 32.406 mmol) were dissolved in 1,4-dioxane (50 mL) and water (5 mL), and then tetrakistriphenylphosphine palladium (1.25 g, 1.080 mmol) was added, nitrogen was replaced for protection, and then the reaction was carried out at 100 ° C for 5 hours. The mixture was diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting crude product was purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 7) to obtain solid compound YL230783-244-A (2.6 g, 10.226 mmol, 94.67%), LC-MS (ESI): m / z 255.2 (M+H)+, 1 H NMR (400MHz, DMSO-d6) δ12.05(s,1H),9.09(dd,J=4.5,1.8Hz,1H),8.70(d,J=8.3Hz,1H),8.62(dd,J=8.0 ,1.8Hz,1H),8.00(d,J=1.6Hz,1H),7.83(dd,J=8.3,1.6Hz,1H),7.74(dd,J=8.0,4.6Hz,1H),3.91(s,3H).

[0565] Synthesis of compound YL230783-248-A

[0566] YL230783-244-A (1.5 g, 5.900 mmol) and anhydrous tetrahydrofuran (55 mL) were added to the reaction flask. The mixture was cooled to 0°C, and then lithium aluminum hydride tetrahydrofuran solution (1 M) (11.8 mL) was slowly added. The mixture was stirred at 0°C for 2 hours. After the reaction was completed, it was quenched with 20 mL of ethyl acetate and then 5 mL of water was added. The resulting mixture was spin-dried. The remaining residue was purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 6 to 100 / 8) to obtain compound YL230783-248-A (730 mg, 2.636 mmol, 44.68%). LC-MS (ESI): m / z 225.1 (MH) - , 1H NMR (400MHz, DMSO-d6) δ11.88(s,1H),9.03(dd,J=4.6,1.9Hz,1H),8.63–8.48(m,2H),7.64(dd,J=8.0,4. 6Hz, 1H), 7.39 (d, J = 1.4Hz, 1H), 7.23 (dd, J = 8.2, 1.5Hz, 1H), 5.40 (t, J = 5.7Hz, 1H), 4.61 (d, J = 5.6Hz, 2H).

[0567] Synthesis of compound YL230783-251-A

[0568] YL230783-248-A (720 mg, 3.182 mmol), dichloromethane (60 mL), and DMF (0.018 mL, 0.222 mmol) were added to the reaction flask. The atmosphere was purged with nitrogen and the temperature was lowered to 0°C. Thionyl chloride (5678.78 mg, 47.737 mmol) was then slowly added dropwise. After the addition, the mixture was allowed to rise to room temperature and stirred for 4 hours. The mixture was concentrated under reduced pressure to obtain a solid compound YL230783-251-A (1 g, 2.943 mmol, 92.46%). LC-MS (ESI): m / z 245.1 (M+H). + .

[0569] Synthesis of compound YL230783-250-A

[0570] Under ice bath conditions, YL230783-195-A (1 g, 3.112 mmol), dichloromethane (30 mL), and trifluoroacetic acid (3 mL, 39.177 mmol) were added to the reaction flask and stirred at room temperature for 2 hours. After the reaction, ammonia methanol (7 M) solution was added to neutralize the excess trifluoroacetic acid, and then the mixture was diluted with dichloromethane and water, extracted, and the organic solvent was vortexed to obtain the target compound YL230783-250-A (5.5 g, 1.539 mmol, 49.46%) in the form of a salt. LC-MS (ESI): m / z 222.2 (M+H) + .

[0571] Synthesis of compound 36

[0572] YL230783-251-A (250 mg, 1.022 mmol), YL230783-250-A (2448.88 mg, 1.328 mmol), and potassium iodide (169.61 mg, 1.022 mmol) were dissolved in acetonitrile (120 mL) at room temperature, and then N,N-diisopropylethylamine (132.06 mg, 1.022 mmol) was added, and the reaction was continued at 80°C for 5 hours. The mixture was diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 4 to 100 / 6) to give compound 36 (16 mg, 0.036 mmol, 3.54%), ESI: (m / z) = 430.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),9.05(dd,J=4.6,1.9Hz,1H),8.73(d,J=5.0Hz,1H),8.63–8.55(m,2H),8.30(t,J=8.4Hz,1H),7. 96(dd,J=7.7,1.5Hz,1H),7.66(dd,J=8.0,4.6Hz,1H),7.45–7.27(m,2H),3.70(d,J=16.9Hz,4H),2.80(d,J=4.8Hz,3H),2.37(s,3H).

[0573] Example 37 Synthesis of Compound 37

[0574] Synthesis of compound YL230783-249-A

[0575] Methyl 6-chloro-5-nitropyridine-3-carboxylate (3.4 g, 15.699 mmol) was dissolved in ethanol (330 mL) and saturated aqueous ammonium chloride (110 mL) at room temperature. Iron powder (5.26 g, 94.192 mmol) was then added and the temperature was raised to 80°C for 3 hours. After the reaction, the solvent was removed by vortexing, the mixture was diluted with ethyl acetate and water, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to directly obtain compound YL230783-249-A (3.2 g, 15.263 mmol, 97.23%). ESI: (m / z) = 187.2 [M+H] + .

[0576] Synthesis of compound YL230783-254-A

[0577] YL230783-249-A (3.2 g, 17.150 mmol), 2-(methoxycarbonyl)phenylboronic acid (6.17 g, 34.300 mmol), SPhos Pd G2 (1.24 g, 1.715 mmol) and potassium phosphate (10.92 g, 51.450 mmol) were dissolved in 1,4-dioxane (370 mL) and then heated to 100°C for overnight reaction. After completion of the reaction, the reaction solution was vortexed and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by automatic column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 20 to 100 / 34) to obtain compound YL230783-254-A (82 mg, 0.306 mmol, 1.79%), ESI: (m / z) = 255.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),9.00(d,J=1.9Hz,1H),8.80(d,J=8.1Hz,1H),8.39–8.30( m,1H),8.23(d,J=1.9Hz,1H),7.98(td,J=8.2,7.7,1.3Hz,1H),7.88–7.79(m,1H),3.94(s,3H).

[0578] Synthesis of compound YL230783-258-A1

[0579] YL230783-254-A (80 mg, 0.315 mmol) and tetrahydrofuran (25 mL) were added to the reaction flask. The mixture was cooled to 0°C, and then lithium aluminum hydride tetrahydrofuran solution (1 M) (15.8 mL, 15.794 mmol) was slowly added. The mixture was then stirred at room temperature for 1 hour. After the reaction was completed, it was quenched with 10 mL of ethyl acetate and then 3 mL of water was added. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 10 to 100 / 12) to obtain compound YL230783-258-A1 (55 mg, 0.243 mmol, 77.26%). LC-MS (ESI): m / z 227.2 (M+H). + .

[0580] Synthesis of compound YL230783-259-A

[0581] YL230783-258-A1 (55 mg, 0.243 mmol), dichloromethane (40 mL), and DMF (0.004 mL, 0.049 mmol) were added to the reaction flask. The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Thionyl chloride (433.80 mg, 3.647 mmol) was then slowly added dropwise. After the addition, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was evaporated to give solid compound YL230783-259-A (60 mg, 0.150 mmol, 61.53%). LC-MS (ESI): m / z 245.1 (M+H) + .

[0582] Synthesis of compound 37

[0583] YL230783-259-A (60 mg, 0.245 mmol), YL230783-250-A (434.02 mg, 0.294 mmol), and potassium iodide (40.71 mg, 0.245 mmol) were dissolved in acetonitrile (60 mL) at room temperature, and then N,N-diisopropylethylamine (158.47 mg, 1.226 mmol) was added, and the reaction was continued at 80°C overnight. The mixture was diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 5) to obtain compound 37 (12 mg, 0.028 mmol, 11.28%), ESI: (m / z) = 430.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.78–8.70(m,2H),8.50(d,J=1.8Hz,1H),8.29(t,J=7.9Hz,2H),7.93(dd,J =16.9,8.0Hz,2H),7.77–7.69(m,2H),3.76(s,2H),3.69(s,2H),2.80(d,J=4.8Hz,3H),2.36(s,3H).

[0584] Example 38 Synthesis of Compound 38

[0585] Synthesis of compound YL230783-255-A

[0586] Methyl 4-amino-2-picolinate (3.6 g, 23.661 mmol) and N-bromosuccinimide (4.21 g, 23.661 mmol) were dissolved in 1,2-dichloroethane (120 mL), and the reaction was continued at room temperature for 2 hours. After the reaction, the solvent was evaporated and the residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 7) to obtain compound YL230783-255-A (5.5 g, 22.376 mmol, 94.57%), ESI: (m / z) = 231.1 / 233.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.40(s,1H),6.63(s,2H),3.81(s,3H).

[0587] Synthesis of compound YL230783-257-A

[0588] YL230783-255-A (5.5 g, 23.804 mmol), 2-(methoxycarbonyl)phenylboronic acid (8.57 g, 47.609 mmol), SPhos Pd G2 (3.43 g, 4.761 mmol) and potassium phosphate (15.16 g, 71.413 mmol) were dissolved in 1,4-dioxane (620 mL) and then heated to 100°C for overnight reaction. After completion of the reaction, the reaction solution was vortexed and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by automatic column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 35 to 100 / 45) to obtain compound YL230783-257-A (90 mg, 0.336 mmol, 1.41%), ESI: (m / z) = 255.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),9.67(s,1H),8.74(d,J=8.1Hz,1H),8. 35(dd,J=7.9,1.4Hz,1H),8.04–7.93(m,2H),7.82–7.74(m,1H),3.92(s,3H).

[0589] Synthesis of compound YL230783-261-A

[0590] YL230783-257-A (90 mg, 0.354 mmol) and tetrahydrofuran (50 mL) were added to the reaction flask. The mixture was cooled to 0°C, and then lithium aluminum hydride tetrahydrofuran solution (1 M) (2.85 mL) was slowly added. The mixture was then stirred at room temperature for 4 hours. After the reaction was completed, it was quenched with 12 mL of ethyl acetate and then 5 mL of water was added. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 8 to 100 / 10) to obtain compound YL230783-261-A (70 mg, 0.305 mmol, 86.18%). LC-MS (ESI): m / z 227.2 (M+H). + .

[0591] Synthesis of compound YL230783-262-A

[0592] YL230783-261-A (70 mg, 0.309 mmol), dichloromethane (50 mL), and DMF (0.010 mL, 0.124 mmol) were added to the reaction flask. The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Thionyl chloride (552.10 mg, 4.641 mmol) was then slowly added dropwise. After the addition, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was evaporated to give solid compound YL230783-262-A (75 mg, 0.222 mmol, 71.82%). LC-MS (ESI): m / z 245.1 (M+H) + .

[0593] Synthesis of compound 38

[0594] YL230783-262-A (75 mg, 0.307 mmol), YL230783-250-A (678.15 mg, 0.460 mmol), and potassium iodide (50.88 mg, 0.307 mmol) were dissolved in acetonitrile (60 mL) at room temperature, and then N,N-diisopropylethylamine (396.18 mg, 3.065 mmol) was added, and the reaction was continued at 80°C overnight. After completion, the mixture was diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting crude product was purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 4 to 100 / 6) to give compound 38 (4 mg, 0.009 mmol, 2.94%), ESI: (m / z) = 430.2 [M+H] + .

[0595] Example 39 Synthesis route of compound 39

[0596] Synthesis of compound 39

[0597] Potassium iodide (4.26 mg, 0.026 mmol) was added to a mixture of YL230774-479 (30 mg, 0.128 mmol), YL230774-234 (31.10 mg, 0.141 mmol), and DIE Acetylide (49.78 mg, 0.385 mmol) in ACN (2 mL). The mixture was heated to 70°C for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford YL230774-480 (13 mg, 26.00% yield). (ESI): m / z 418.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),8.61(d,J=4.7Hz,1H),7.76–7.62(m,3H),7.50(d,J=8.0Hz,1H),7.33(d,J=1.5Hz,1H),7.16(dd,J=8.1, 1.5Hz,1H),3.66(s,2H),3.61(s,2H),3.08(t,J=7.6Hz,2H),2.79(d,J=4.5Hz,3H),2.75(t,J=7.4Hz,2H),2.31(s,3H),2.10(p,J=7.7Hz,2H).

[0598] Example 40 Synthesis route of compound 40

[0599] Synthesis of compound YL230774-468

[0600] Under nitrogen, Pd(dppf)Cl2 (CAS: 72287-26-4) (0.55 g, 0.75 mmol) was added to a mixture of methyl 3-amino-4-bromo-2,6-difluorobenzoate (2.00 g, 7.52 mmol), pinacol diboron (CAS: 73183-34-3) (2.10 g, 8.27 mmol), and potassium acetate (2.21 g, 22.55 mmol) in N,N-dimethylformamide (20 mL). The mixture was heated to 100°C for 2 hours. LCMS monitoring revealed the desired product. The mixture was cooled to room temperature, and Pd(dppf)Cl2 (0.55 g, 0.75 mmol), methyl 2-iodobenzoate (0.55 g, 0.75 mmol), potassium carbonate (3.12 g, 22.55 mmol), and water (4 mL) were added. The reaction mixture was then heated to 100°C and reacted for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to obtain YL230774-468 ​​(500 mg, yield 23.04%). (ESI): m / z 290.1 ​​[M+H] + . 1 H NMR(400MHz, DMSO-d6)δ11.87(s,1H),8.58(d,J=8.1Hz,1H),8.42–8.31(m,2H),7 .93(ddd,J=8.3,7.2,1.5Hz,1H),7.79(ddd,J=8.1,7.2,1.1Hz,1H),3.95(s,3H).

[0601] Synthesis of compound YL230774-474

[0602] LAH (CAS: 16853-85-3) (2 mL, 1 M, 2.07 mmol) was added dropwise to a mixture of YL230774-468 ​​(300 mg, 1.04 mmol) in tetrahydrofuran (10 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched with water (0.1 mL) at 0°C, followed by sodium hydroxide solution (0.1 mL). After stirring for 10 minutes, anhydrous sodium sulfate (0.1 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filter cake was rinsed several times with a mixture of tetrahydrofuran and methanol (v / v = 5:1). The filtrate was concentrated to obtain the crude product, which was purified by slurrying with dichloromethane and petroleum ether (v / v = 1:1) to obtain YL230774-474 (220 mg, 81.20% yield). (ESI): m / z 262.2[M+H] + .

[0603] Synthesis of compound YL230774-475

[0604] Thionyl chloride (683 mg, 5.74 mmol) was added to a mixture of YL230774-474 (150 mg, 0.57 mmol) in dichloromethane (20 mL) and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution until neutral, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield YL230774-475 (70 mg, 43.75% yield). (ESI): m / z 280.1 [M+H] + .

[0605] Synthesis of compound 40

[0606] Potassium iodide (4 mg, 0.025 mmol) was added to a mixture of YL230774-475 (66 mg, 0.30 mmol) and DIE Acetylide (97 mg, 0.75 mmol) in acetonitrile (5 mL). The mixture was heated to 70°C for 2 hours. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phase was separated, concentrated, and purified by preparative HPLC (NH4HCO3) to afford compound 40 (13 mg, 11.22% yield). (ESI): m / z 464.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),8.58(q,J=4.4Hz,1H),8.51(d,J=8.1Hz,1H),8.35(dd,J=8.0,1.4Hz,1H),8.18(dd,J=10.9,1.6Hz,1H),7 .94–7.84(m,1H),7.72(d,J=7.5Hz,1H),7.70–7.63(m,2H),7.59(t,J=7 .5Hz,1H),3.80(s,2H),3.68(s,2H),2.79(d,J=4.5Hz,3H),2.33(s,3H)

[0607] Example 41 Synthesis route of compound 41

[0608] Synthesis of compound YL230774-470

[0609] 4M HCl in 1,4-dioxane (30 mL) was slowly added to a solution of YL230774-466 (4.00 g, 12.447 mmol) in 1,4-dioxane (20 mL) at 0°C in an ice-water bath. The mixture was then allowed to react at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution until weakly alkaline. The mixture was then extracted with a mixed solvent of dichloromethane and methanol (v / v = 5:1), and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield YL230774-470 (2.50 g, 90.91% yield). (ESI): m / z 222.2 [M+H] + .

[0610] Synthesis of compound YL230774-473

[0611] YL230774-470 (2.18 g, 9.860 mmol) was added to a mixture of potassium bromomethyl trifluoroborate (1.80 g, 8.964 mmol) and potassium iodide (0.07 g, 0.448 mmol) in ACN (50 mL) and heated to 70°C for 16 hours. The reaction solution was concentrated to remove acetonitrile and washed with methyl tert-butyl ether to obtain YL230774-473 (3.9 g, crude product). (ESI): m / z 304.2 [MH] - .

[0612] Synthesis of compound 41

[0613] Under nitrogen, XPhos Pd G2 (CAS: 1310584-14-5) (8.07 mg, 0.010 mmol) was added to a mixture of YL230774-460 (30 mg, 0.10 mmol), YL230774-473 (88.97 mg, 0.206 mmol), and cesium carbonate (100.68 mg, 0.309 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL). The mixture was heated to 100°C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-3%) to obtain the crude product. Compound 41 (4 mg, 8.70% yield) was then purified by preparative HPLC (NH4HCO3). (ESI):m / z 447.2[M+H] + .

[0614] Example 42 Synthesis route of compound 42

[0615] Synthesis of compound YL230774-420

[0616] 4-Bromo-2,6-difluorobenzonitrile (5.00 g, 22.94 mmol) was added to a mixed solution of ammonia (28 mL) and isopropanol (10 mL), and the mixture was heated to 80°C for 5 hours. The reaction solution was cooled to room temperature and poured into water, stirred for 10 minutes, and then filtered. The filter cake solid was taken and vacuum dried at 40°C to obtain YL230774-420 (3.50 g, yield 70.99%). 1 HNMR reference standard YL230774-409): 1 H NMR (400MHz, CDCl3) δ6.72 (t, J = 1.4Hz, 1H), 6.67 (dd, J = 8.4, 1.6Hz, 1H), 4.62 (s, 2H).

[0617] Synthesis of compound YL230774-430

[0618] 98% concentrated sulfuric acid (6 mL) was slowly added to formic acid (48 mL), stirred at room temperature for 10 minutes, then YL230774-420 (4.00 g, 18.60 mmol) was added portionwise and heated to 100°C for 2 hours. The reaction solution was cooled to 0°C, diluted with water (10 mL), stirred for half an hour, filtered, and the filter cake was rinsed with water and isopropanol (v / v = 1:1). The filter cake was taken and vacuum dried at low temperature to obtain YL230774-430 (3.00 g, yield 66.37%). (ESI): m / z 243.0, 245.0 [M+H] + .

[0619] Synthesis of compound YL230774-433

[0620] p-Methoxybenzylamine (8.47 g, 61.72 mmol) was added to a solution of YL230774-430 (3.00 g, 12.34 mmol) in DMSO (20 mL) and heated to 80°C for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to obtain YL230774-433 (3.00 g, yield 67.42%). (ESI): m / z 360.0, 362.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.19(s,1H),9.05(t,J=5.0Hz,1H),7.97(s,1H),7.29(d,J=8.5Hz,2H),7 .04–6.88(m,2H),6.84(d,J=1.8Hz,1H),6.64(d,J=1.8Hz,1H),4.37(d,J=5.6Hz,2H),3.74(s,3H).

[0621] Synthesis of compound YL230774-453

[0622] DBU (CAS: 6674-22-2) (1.81 g, 11.91 mmol) and Carter condensation agent (4.79 g, 10.83 mmol) were added to a solution of YL230774-433 (1.3 g, 3.61 mmol) in DMF (13 mL). The mixture was stirred at room temperature for 15 minutes, followed by the addition of methylamine (0.56 g, 18.05 mmol) and the reaction was allowed to proceed at room temperature for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by reverse phase chromatography (C18, NH4HCO3) to afford YL230774-453 (90 mg, 6.67% yield). (ESI): m / z 373.1, 375.1 [M+H] + .

[0623] Synthesis of compound YL230774-461

[0624] Triphosgene (72 mg, 0.24 mmol) in dichloromethane (1.5 mL) was added dropwise to a solution of YL230774-453 (90 mg, 0.24 mmol) and DIE Acetylide (312 mg, 2.41 mmol) in dichloromethane (3 mL) at 0°C in an ice-water bath. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford YL230774-461 (30 mg, 31.16% yield). (ESI): m / z 399.0, 401.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.79 (s, 1H), 7.65 (d, J = 1.4Hz, 1H), 7.31–7.27 (m, 2H), 7. 02(d,J=1.4Hz,1H),6.92–6.86(m,2H),5.23(s,2H),3.79(s,3H),3.69(s,3H).

[0625] Synthesis of compound YL230774-464

[0626] Under nitrogen, palladium acetate (3 mg, 0.014 mmol) was added to a mixture of YL230774-461 (27 mg, 0.068 mmol), YL230774-469 (10 mg, 0.030 mmol), cesium carbonate (66 mg, 0.20 mmol), and XPHOS (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, CAS: 564483-18-7) (13 mg, 0.027 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was heated to 100°C for 4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford YL230774-464 (5 mg, 13.73% yield). (ESI): m / z 536.5[M+H] + .

[0627] Synthesis of compound 42

[0628] YL230774-464 (5 mg, 0.009 mmol) was added to trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL) and heated to 100°C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution until weakly alkaline, extracted with dichloromethane, and the organic phase was separated. After concentration, the organic phase was purified by reverse phase chromatography (C18, NH4HCO3) to afford 42 (0.5 mg, 13.37% yield). (ESI): m / z 416.3 [M+H] + .

[0629] Example 43 Synthesis route of compound 43

[0630] Synthesis of compound YL230774-463

[0631] Under nitrogen, Pd(Ph3P)2Cl2 (0.65 g, 0.93 mmol) and CuI (0.18 g, 0.93 mmol) were added to 5-bromo-N-methylpicolinamide (2.00 g, 9.30 mmol) and tert-butyl methyl(prop-2-yn-1-yl)carbamate (1.57 g, 9.30 mmol) in triethylamine (12 mL) and DMSO (2 mL). The mixture was heated to 70°C for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford YL230774-463 (2.50 g, 88.65% yield). (ESI): m / z 304.6 [M+H] + .

[0632] Synthesis of compound YL230774-465

[0633] YL230774-463 (2.50 g, 8.24 mmol) was dissolved in dioxane hydrochloride (20 mL, 4 M) and allowed to react at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution in an ice-water bath at 0°C until weakly alkaline. The mixture was extracted with a mixed solvent of dichloromethane and methanol (v / v = 5:1), and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield YL230774-465 (1.50 g, 89.82% yield). (ESI): m / z 204.3 [M+H] + .

[0634] Synthesis of compound YL230774-469

[0635] A mixture of YL230774-465 (1.10 g, 5.48 mmol) and potassium iodide (0.09 g, 0.55 mmol) in acetonitrile (30 mL) was heated to 70°C for 16 hours. The reaction solution was concentrated to remove acetonitrile to obtain YL230774-469 (2.50 g, crude product). (ESI): m / z 284.2 [MH] - .

[0636] Synthesis of compound YL230774-451

[0637] YL230804-108 (1.40 g, 4.86 mmol) was added to a concentrated H2SO4 solution (15 mL) and allowed to react at room temperature for 2 hours. The reaction solution was cooled to 0°C, and then the aqueous solution was slowly added dropwise. A white solid precipitated, which was filtered and the filter cake was vacuum dried to obtain YL230774-451 (1.00 g, yield 85.02%). (ESI): m / z 242.0, 244.0 [M+H] + .

[0638] Synthesis of compound YL230774-454

[0639] At room temperature, sodium difluoromethanesulfinate (1.14 g, 8.26 mmol) and potassium persulfate (4.47 g, 16.53 mmol) were added to a mixture of YL230774-451 (1.00 g, 4.13 mmol) in acetonitrile (20 mL) and water (6 mL). The mixture was then heated to 100°C for 16 hours. The reaction mixture was diluted with water and ethyl acetate, and the organic phase was separated. After concentration, the organic phase was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-2%) to obtain YL230774-454 (100 mg, yield 8.26%). (ESI): m / z 292.0, 294.0 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),8.36(s,1H),7.64(d,J=8.6Hz,1H),7.53(dd,J=8.5,6.1Hz,1H),6.96(t,J=54.5Hz,1H).

[0640] Synthesis of compound 43

[0641] Under nitrogen, XPhos Pd G2 (CAS: 1310584-14-5) (8.07 mg, 0.010 mmol) was added to a mixture of YL230774-454 (30 mg, 0.10 mmol), YL230774-469 (115.81 mg, 0.308 mmol), and cesium carbonate (167 mg, 0.51 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL). The mixture was heated to 80°C for 1 hour. The reaction solution was diluted with acetonitrile and filtered through celite. The filtrate was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford the crude product (12 mg). Compound 43 was further purified by reverse phase chromatography (C18, NH4HCO3) to afford compound 43 (5 mg, 11.36% yield). (ESI): m / z 429.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=5.0Hz,1H),8.69(dd,J=2.0,0.9Hz,1H),8.32(s,1H),8.06(dd,J=8.1,2.0Hz,1H),8.01(dd,J=8.2,0.9Hz, 1H),7.66(d,J=8.2Hz,1H),7.30(dd,J=8.1,6.4Hz,1H),6.97(t,J=52.0Hz,1H),3.78(s,2H),3.64(s,2H),2.82(d,J=4.8Hz,3H),2.33(s,3H).

[0642] Example 44 Synthesis route of compound 44

[0643] Synthesis of compound 44

[0644] Potassium iodide (5 mg, 0.030 mmol) was added to a mixture of YL230774-428 (70 mg, 0.30 mmol), YL230774-417 (107 mg, 0.45 mmol), and DIEA (N-ethyl-N-isopropylpropan-2-amine) (193 mg, 1.49 mmol) in acetonitrile (3 mL). The mixture was heated to 70°C for 2 hours. The reaction mixture was concentrated and purified by reverse phase chromatography (C18, NH4HCO3) to afford compound 44 (10 mg, 8.33% yield). (ESI): m / z 402.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=5.0Hz,1H),8.69(dd,J=2.1,0.9Hz,1H),8.41(d,J=1.8Hz,1H),8.06(dd,J=8.1,2.1Hz,1H),8.00(dd,J=8.1,0.9Hz,1 H),7.65(d,J=1.9Hz,1H),3.72(s,2H),3.61(s,2H),3.14(t,J=7.6Hz,2H),2 .81(d,J=4.9Hz,3H),2.81–2.74(m,2H),2.32(s,3H),2.09(p,J=7.6Hz,2H).

[0645] Example 45 Synthesis route of compound 45

[0646] Potassium iodide (6 mg, 0.037 mmol) was added to a solution of YL230783-174 (100 mg, 0.37 mmol), YL230774-426 (143 mg, 0.55 mmol), and DIEA (N-ethyl-N-isopropylpropan-2-amine) (238 mg, 1.84 mmol) in acetonitrile (4 mL). The mixture was heated to 70°C for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by preparative HPLC (NH4HCO3) to give compound 45 (53 mg, 34.92% yield). (ESI): m / z 412.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.74(q,J=4.4Hz,1H),8.26(dd,J=9.3,7.7Hz,1H),7.95(dd,J=7.7,1.6Hz,1H),7 .48(d,J=8.3Hz,1H),7.23(t,J=7.7Hz,1H),3.75(s,2H),3.66(s,2H),2.80(d,J=4.8Hz,3H),2.39(s,3H),2.33(s,3H).

[0647] Example 46 Synthesis of Compound 46

[0648] Potassium iodide (3 mg, 0.017 mmol) was added to a mixture of YL230774-414 (20 mg, 0.086 mmol), YL230774-417 (38 mg, 0.13 mmol), and DIEA (N-ethyl-N-isopropylpropane-2-amine) (55 mg, 0.43 mmol) in acetonitrile (2 mL). The mixture was heated to 70°C for 2 hours. The reaction mixture was concentrated and purified by reverse phase chromatography (C18, NH4HCO3) to afford compound 46 (6 mg, 20.00% yield). (ESI): m / z 401.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.58(s,1H),8.81(d,J=5.1Hz,1H),8.71(d,J=1.9Hz,1 H),8.08(dd,J=8.1,2.1Hz,1H),8.02(d,J=8.1Hz,1H),7.50(d,J=8.0Hz,1H),7. 34(s,1H),7.20–7.14(m,1H),3.67(s,2H),3.60(s,2H),3.08(t,J=7.6Hz,2H),2 .83(d,J=4.8Hz,3H),2.76(t,J=7.5Hz,2H),2.32(s,3H),2.10(p,J=7.6Hz,2H).

[0649] Example 47 Synthesis of Compound 47

[0650] Tetraisopropoxytitanium (CAS: 546-68-9) (57 mg, 0.20 mmol) was added to a mixture of YL230774-398 (90 mg, 0.20 mmol) and YL230774-400 (44 mg, 0.20 mmol) in tetrahydrofuran (1 mL) and stirred at room temperature for 0.5 hours. Sodium triacetylborohydride (212 mg, 1.00 mmol) was then added and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with methanol, filtered through celite, and the filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford P1 (28 mg, ~85% purity) and YL230774-404-P2 (20 mg, 23.20% yield). P1 (28 mg, 85% purity) was then purified by secondary preparative HPLC (CF3COOH) to give compound 47 (TFA salt) (13 mg, yield 11.92%). (ESI): m / z 430.2 [M+H] + .YL230774-404-P1(TFA salt): 1 H NMR (400MHz, DMSO-d6) δ12.79(s,1H),8.76(p,J=4.1,3.4Hz,1H),8.32(dd,J=9.2,7.7Hz,1H),7.99(dd,J=7.7,1 .5Hz,1H),7.59(dd,J=10.8,5.4Hz,1H),4.28(d,J=16.0Hz,4H),2.81(d,J=4.8Hz,3H),2.73(s,3H),2.44(s,3H).

[0651] YL230774-404-P2:1H NMR(400MHz, DMSO-d6)δ9.26(s,1H),8.80–8.70(m,1H),8.25(dd,J=9.2,7.7Hz,1H),7.95(dd,J=7.7,1.5Hz, 1H),7.10(dd,J=10.7,5.4Hz,1H),3.74(s,2H),3.69(s,2H),2.80(d,J=4.8Hz,3H),2.41(s,3H),2.33(s,3H).

[0652] Example 48 Synthesis route of compound 48

[0653] Synthesis of compound YL230774-348

[0654] Under nitrogen, AIBN (0.86 g, 5.26 mmol) was added to a mixture of 3-bromo-2-fluoro-6-methylpyridine (5.00 g, 26.31 mmol) and NBS (7.03 g, 39.47 mmol) in carbon tetrachloride (60 mL). The mixture was heated to 80°C for 16 hours. The reaction mixture was filtered through filter paper, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:40) to obtain YL230774-348 (5.00 g, 70.62% yield). (ESI): m / z 269.9 [M+H] + .

[0655] Synthesis of compound YL230774-354

[0656] Under nitrogen, NMMO (87 mg, 0.74 mmol) was added to a solution of YL230774-348 (200 mg, 0.74 mmol) in acetonitrile (4 mL) and allowed to react at room temperature for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic phase was separated, concentrated, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-5%) to afford YL230774-354 (50 mg, 33.33% yield). 1 H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 8.58 (t, J = 8.3Hz, 1H), 7.84 (dd, J = 7.8, 1.6Hz, 1H).

[0657] Synthesis of compound YL230774-355

[0658] DAST (0.1 mL, 0.49 mmol) was slowly added dropwise to a solution of YL230774-390 (50 mg, 0.25 mmol) in dichloromethane (1 mL) at -20°C under nitrogen atmosphere. The mixture was then allowed to react at room temperature for 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution until weakly alkaline, extracted with dichloromethane, and the organic phase was separated and filtered through a flash silica gel filter cake. The filtrate was concentrated to yield YL230774-355 (20 mg, 33.33% yield). 1 H NMR (400MHz, DMSO-d6) δ8.53(t,J=8.3Hz,1H),7.64(dd,J=7.9,1.5Hz,1H),6.99(t,J=54.3Hz,1H). 19 F NMR(377MHz,DMSO-d6)δ-65.46,-116.67.

[0659] Synthesis of compound YL230774-391

[0660] DIEA (N-ethyl-N-isopropylpropan-2-amine) (238 mg, 1.84 mmol) was added to a mixture of YL230783-174 (100 mg, 0.37 mmol), N-methyl-2-propyn-1-amine (127 mg, 1.84 mmol), and potassium iodide (12 mg, 0.074 mmol). The mixture was heated to 80°C for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to obtain YL230774-391 (80 mg, yield 83.65%). (ESI): m / z 260.1 [M+H] + .

[0661] Synthesis of compound 48

[0662] Under nitrogen, Pd(Ph3P)2Cl2 (22 mg, 0.031 mmol) and cuprous iodide (12 mg, 0.062 mmol) were added to YL230774-391 (80 mg, 0.31 mmol) and YL230774-355 (84 mg, 0.37 mmol) in triethylamine (3 mL) and DMSO (0.5 mL). The mixture was heated to 70°C for 1 hour. The reaction solution was diluted with acetonitrile and filtered through a nylon syringe filter (NY 0.22 μm). The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford compound 48 (10 mg, 8.01% yield). (ESI): m / z 405.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.31(t,J=8.4Hz,1H),7.69(dd,J=7.7,1.5Hz,1H),7.56–7.42(m,1H),7.28–7 .17(m,1H),6.99(t,J=54.4Hz,1H),6.11(s,1H),3.75(s,2H),3.66(s,2H),2.40(s,3H),2.33(s,3H). 19 F NMR(377MHz,DMSO-d6)δ-65.35,-116.86,-135.59.

[0663] Example 49 Synthesis route of compound 49

[0664] Synthesis of compound YL230804-189-A

[0665] YL240807-039-A (60 mg, 0.160 mmol) was added to a 1,4-dioxane hydrochloride solution (2 mL, 4 M) and allowed to react at room temperature for 1 hour. The reaction mixture was concentrated to yield YL230804-189-A (45 mg, crude product). LC-MS (ESI): m / z 290.2 (M+H) + ;

[0666] Synthesis of compound YL230804-183-A

[0667] Ethyl 2-cyclopropylacetate (0.96 g, 7.462 mmol) was dissolved in tetrahydrofuran (15 mL), replaced with nitrogen, and cooled to -78°C. LiHMDS (17.5 mL, 1 M) was slowly added dropwise and stirred at -78°C for 1 hour. 3-Amino-5-bromopicolinaldehyde (1 g, 4.975 mmol) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the reaction system at -78°C. The reaction solution was allowed to warm to room temperature and stirred overnight. Methanol (5 mL) was added at room temperature and allowed to react at room temperature for 8 hours. The reaction solution was dried under vacuum and purified on a normal phase column (mobile phase: dichloromethane / methanol = 20 / 1) to obtain compound YL230804-183-A (600 mg, 45.5%). ESI: (m / z) = 263.2 [M+H] + ;

[0668] Synthesis of compound YL230804-185-A

[0669] YL230804-183-A (510 mg, 1.942 mmol) was dissolved in 1,4-dioxane (15 mL), and (tributyltin)methanol (803 mg, 2.501 mmol) and Xphos Pd G2 (88.9 mg, 0.113 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 80°C overnight. The reaction solution was dried under vacuum and purified by normal phase column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to obtain compound YL230804-185-A (310 mg, 74.51%). ESI: (m / z) = 215.2 [M+H] + ;

[0670] Synthesis of compound YL230804-188-A

[0671] YL230804-161-A (300 mg, 1.387 mmol) was dissolved in dichloromethane (8 mL), and 1 drop of DMF was added. The mixture was replaced with nitrogen and cooled to 0°C. Thionyl chloride (990 mg, 8.324 mmol) was added and allowed to react at room temperature overnight. The reaction solution was cooled to 0°C, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane / methanol = 10 / 1. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified on a normal phase column (dichloromethane / methanol = 20 / 1) to obtain compound YL230804-188-A (270 mg, 82.93%). ESI: (m / z) = 235.1 [M+H] + ;

[0672] Synthesis of compound YL230804-189-A

[0673] YL240807-039-A (60 mg, 0.160 mmol) was dissolved in a hydrochloric acid-dioxane solution (2 mL) and reacted at room temperature for 1 hour. The reaction solution was dried under vacuum to obtain compound YL230804-189-A (45 mg, 90.33%). ESI: (m / z) = 290.2 [M+H] + ;

[0674] Synthesis of compound YL230804-190-A (compound 49)

[0675] YL230804-188-A (25 mg, 0.107 mmol) was dissolved in acetonitrile (2 mL), and YL230804-189-A (45 mg, 0.123 mmol), N,N-diisopropylethylamine (69 mg, 0.533 mmol), and potassium iodide (1.8 mg, 0.011 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried and purified by normal phase column chromatography to obtain compound YL230804-190-A (Compound 49) (32 mg). ESI: (m / z) = 488.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.88(s,1H),9.33(t,J=6.5Hz,1H),8.37(d,J=1.9Hz ,1H),8.32(dd,J=9.2,7.7Hz,1H),8.01(dd,J=7.7,1.5Hz,1H),7.60(d,J=1.9 Hz,1H),7.40(s,1H),4.06(qd,J=9.6,6.5Hz,2H),3.71(s,2H),3.66(s,2H),2 .32(s,3H),2.13(tt,J=8.4,5.3Hz,1H),1.01–0.90(m,2H),0.85–0.77(m,2H).

[0676] Example 50 Synthesis route of compound 50

[0677] YL240807-045-A was obtained by replacing cis-3-methoxycyclobutylamine with cyclopropylamine using the method for synthesizing YL230804-172-A in Example 25;

[0678] Synthesis of compound YL230804-191-A (compound 50)

[0679] YL230804-188-A (20 mg, 0.085 mmol) was dissolved in acetonitrile (2 mL), and YL240807-045-A (44 mg, 0.160 mmol), N,N-diisopropylethylamine (33 mg, 0.256 mmol), and potassium iodide (1.4 mg, 0.009 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried and purified by normal phase column chromatography to obtain compound YL230804-191-A (Compound 50) (20 mg). ESI: (m / z) = 490.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.94(d,J=8.0Hz,1H),8.37(d,J=1.8Hz,1H),8.2 7(dd,J=9.2,7.7Hz,1H),7.93(dd,J=7.7,1.6Hz,1H),7.60(d,J=1.8Hz,1H),7.40(s,1H) ,4.07–3.96(m,1H),3.70(s,2H),3.65(s,2H),3.63–3.56(m,1H),3.14(s,3H),2.54(q,J =5.4,3.9Hz,2H),2.32(s,3H),2.18–2.02(m,3H),1.00–0.92(m,2H),0.85–0.76(m,2H).

[0680] Example 51 Synthesis route of compound 51

[0681] Synthesis of compound YL230769-434

[0682] To a 100 mL three-necked flask, methyl cyclopropylacetate (961.13 mg, 7.499 mmol) and tetrahydrofuran (40 mL) were added sequentially. Under nitrogen, the mixture was cooled to -78°C, and then lithium bis(trimethylsilyl)amide (17.497 mL) was slowly added. The reaction was continued for 30 minutes, followed by the slow addition of a 5 mL tetrahydrofuran solution of 2-amino-4-bromobenzaldehyde (1000 mg, 4.999 mmol). The reaction was continued for another 30 minutes, and the mixture was warmed to room temperature and allowed to react for 18 hours. LCMS indicated the reaction was complete. The reaction mixture was directly concentrated and subjected to column chromatography (dichloromethane:methanol = 40:1-20:1) to afford YL230769-434 (1100 mg, 4.165 mmol, 83.31%). LC-MS (ESI): m / z 264.2 (M+H). - .

[0683] Synthesis of compound YL230769-436

[0684] To a 100 mL three-necked flask were added YL230769-434 (1023 mg, 3.873 mmol), (tributyltin)methanol (1492.39 mg, 4.648 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (304.44 mg, 0.387 mmol), and 1,4-dioxane (30 mL). The mixture was reacted at 80°C for 12 hours under nitrogen. LCMS indicated the reaction was complete. The reaction solution was then concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-436 (760 mg, 3.531 mmol, 91.16%). LC-MS (ESI): m / z 216.2 (M+H) + .

[0685] Synthesis of compound YL230769-437

[0686] To a 100 mL three-necked flask were added YL230769-436 (538 mg, 2.499 mmol), dichloromethane (30 mL), and N,N-dimethylformamide (0.010 mL, 0.125 mmol) in sequence. Under nitrogen, the mixture was cooled to 0°C, and then thionyl chloride (1783.99 mg, 14.997 mmol) was slowly added. The reaction was continued for 1 hour, then the temperature was raised to room temperature and the reaction was continued for 11 hours. LCMS indicated the reaction was complete. Saturated sodium bicarbonate and dichloromethane were slowly added to the reaction solution. The organic phase was concentrated and subjected to column chromatography (dichloromethane:methanol = 20:1-10:1) to afford YL230769-437 (500 mg, 2.140 mmol, 85.60%). LC-MS (ESI): m / z 234.2 (M+H). + .

[0687] Synthesis of compound YL230769-439

[0688] To a 50 mL three-necked flask, add YL230804-170-A (43 mg, 0.124 mmol), 1,4-dioxane (2 mL), and a 1,4-dioxane solution of hydrochloric acid (4 mL, 16.000 mmol). The mixture was allowed to react at room temperature for 3 hours. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated to yield YL230769-439 (30 mg, 0.121 mmol, 98.02%). LC-MS (ESI): m / z 248.2 (M+H). + .

[0689] Synthesis of Compound YL230769-440 (Compound 51): To a 50 mL three-necked flask were added YL230769-437 (23.4 mg, 0.100 mmol), YL230769-439 (29.71 mg, 0.120 mmol), potassium iodide (3.32 mg, 0.020 mmol), N,N-diisopropylethylamine (64.71 mg, 0.501 mmol), and acetonitrile (10 mL). Under nitrogen protection, the mixture was reacted at 80°C for 2 hours. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated and prepared using an alkaline method to obtain Compound YL230769-440 (Compound 51) (32 mg, 0.072 mmol, 71.89%). LC-MS (ESI): m / z 445.7 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.72(d,J=5.0Hz,1H),8.27(dd,J=9.2,7. 7Hz,1H),7.95(dd,J=7.7,1.6Hz,1H),7.50(d,J=8.0Hz,1H),7.40(s,1H),7.25( d,J=1.5Hz,1H),7.09(dd,J=8.0,1.5Hz,1H),3.63(d,J=8.0Hz,4H),2.89(h,J=5 .6Hz,1H),2.30(s,3H),2.17-1.98(m,1H),1.05-0.83(m,2H),0.77-0.47(m,6H).

[0690] Example 52 Synthesis route of compound 52

[0691] Synthesis of compound YL230769-443 (compound 52)

[0692] To a 50 mL three-necked flask were added YL230769-437 (23.4 mg, 0.100 mmol), YL240807-045-A (35.01 mg, 0.120 mmol), potassium iodide (3.32 mg, 0.020 mmol), N,N-diisopropylethylamine (64.71 mg, 0.501 mmol), and acetonitrile (10 mL). Under nitrogen protection, the reaction was allowed to proceed at 80°C for 3 hours. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated and prepared using a reverse-phase alkaline method to obtain compound YL230769-443 (compound 52) (31 mg, 0.063 mmol, 63.37%). LC-MS (ESI): m / z 489.3 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.94(d,J=8.1Hz,1H),8.27(dd,J=9.2,7.7Hz,1 H),7.93(dd,J=7.7,1.5Hz,1H),7.51(d,J=8.0Hz,1H),7.40(s,1H),7.26(s,1H),7.09 (dd,J=8.0,1.5Hz,1H),4.01(h,J=8.2Hz,1H),3.62(t,J=7.5Hz,6H),3.14(s,3H),2.6 6-2.51(m,1H),2.31(s,3H),2.19-1.92(m,3H),1.01-0.80(m,2H),0.79-0.50(m,2H);

[0693] Example 53 The method of Example 37 was used to obtain the following compounds 53, 54 and 55:

[0694] Example 54 Synthesis route of compound 56

[0695] Synthesis of compound YL240807-049

[0696] Under nitrogen, Pd(dtbpf)Cl2 (cas: 95408-45-0) (0.22 g, 0.335 mmol) was added to a mixture of methyl 6-chloro-5-nitronicotinate (0.73 g, 3.355 mmol), methyl 4,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.00 g, 3.355 mmol), and triethylamine (1.399 mL, 10.065 mmol) in N,N-dimethylformamide (25 mL) and water (5 mL). The mixture was heated to 100°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5% to 30%) to obtain YL240807-049 (560 mg, yield 47.46%). (ESI): m / z 353.1 [M+H] + .

[0697] Synthesis of compound YL240807-055

[0698] Under nitrogen, iron powder (356.68 mg, 6.388 mmol) and ammonium chloride (205.00 mg, 3.833 mmol) were added to a mixture of YL240807-049 (450 mg, 1.278 mmol) in ethanol (15 mL) and water (2 mL). The mixture was heated to 80°C for 4 hours. The reaction solution was filtered through celite, and the filter cake was rinsed with tetrahydrofuran several times. The filtrate was concentrated to obtain a crude product (300 mg), which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10) to obtain YL240807-055 (100 mg, yield 26.97%). (ESI): m / z 291.2 [M+H] + .

[0699] Synthesis of compound YL240807-063

[0700] Lithium aluminum hydride (1M) in tetrahydrofuran (0.69 mL, 0.689 mmol) was added dropwise to a mixture of YL240807-055 (100 mg, 0.345 mmol) in tetrahydrofuran (4 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched with water (1 drop) at 0°C, followed by the addition of sodium hydroxide solution (3 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.05 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered and the filtrate was concentrated to obtain the crude product, which was slurried with dichloromethane to obtain YL240807-063 (80 mg, 88.54% yield). (ESI): m / z 263.2 [M+H] + .

[0701] Synthesis of compound YL240807-066

[0702] Thionyl chloride (362.93 mg, 3.051 mmol) was added to a mixture of YL240807-063 (80 mg, 0.305 mmol) in dichloromethane (10 mL) and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution until neutral, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield YL240807-066 (80 mg, crude product). (ESI): m / z 281.2 [M+H] + .

[0703] Synthesis of compound 56

[0704] Under nitrogen, potassium iodide (2.37 mg, 0.014 mmol) was added to a mixture of YL240807-066 (40 mg, 0.152 mmol), YL240807-061 (44.48 mg, 0.157 mmol), and DIEA (92.10 mg, 0.713 mmol) in acetonitrile (3 mL). The mixture was heated to 80°C for 4 hours. The reaction solution was diluted with acetonitrile and filtered through celite. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to give compound 56 (4.5 mg, 6.42% yield). (ESI): m / z 492.1 [M+H] + .

[0705] Synthesis route of Example Compound 57

[0706] Synthesis of compound YL230804-193-A

[0707] 7-Chloro-1,6-naphthyridin-2(1H)-one (2.8 g, 15.505 mmol) was dissolved in acetonitrile (40 mL) and water (9 mL). Sodium difluoromethanesulfinate (6.52 g, 46.514 mmol) and potassium persulfate (12.57 g, 46.514 mmol) were added and reacted at 100°C for 30 hours. Ethyl acetate and water were added to the reaction solution, filtered, and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by normal phase column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1) to obtain compound YL230804-193-A (230 mg, 5.2%). ESI: (m / z) = 231.2 [M+H] + ;

[0708] Synthesis of compound YL230804-209-A

[0709] YL230804-193-A (230 mg, 0.997 mmol) was dissolved in 1,4-dioxane (5 mL), and (tributyltin)methanol (960 mg, 2.992 mmol) and Xphos Pd G2 (72 mg, 0.091 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 80°C overnight. The reaction solution was spin-dried and purified by normal phase column chromatography (mobile phase: dichloromethane / methanol = 20 / 1) to obtain compound YL230804-209-A (30 mg, 13.30%). ESI: (m / z) = 227.2 [M+H] + ;

[0710] Synthesis of compound YL230804-215-A

[0711] YL230804-209-A (30 mg, 0.133 mmol) was dissolved in dichloromethane (5 mL), 1 drop of DMF was added, the mixture was replaced with N2, the temperature was lowered to 0°C, thionyl chloride (95 mg, 0.796 mmol) was added, and the mixture was allowed to react at room temperature for 8 hours. The reaction solution was cooled to 0°C, neutralized with saturated aqueous sodium bicarbonate, and extracted with dichloromethane / methanol = 10 / 1. The organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain crude compound YL230804-215-A (30 mg). ESI: (m / z) = 245.2 [M+H] + ;

[0712] Synthesis of compound 57

[0713] YL230804-215-A (30 mg, 0.123 mmol) was dissolved in acetonitrile (2 mL), and YL230804-170-A (39 mg, 0.159 mmol), N,N-diisopropylethylamine (80 mg, 0.613 mmol), and potassium iodide (2.0 mg, 0.012 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried to obtain compound 57 (19 mg). ESI: (m / z) = 456.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.92(s,1H),8.71(d,J=5.0Hz,1H),8.37(s,1H),8.25(dd,J=9.2,7.7Hz,1H),7.94(dd,J=7.7 ,1.6Hz,1H),7.36(s,1H),6.94(t,J=54.6Hz,1H),3.80(s,2H),3.74(s,2H),2.94–2.83(m,1H),2.36(s,3H),0.68(d,J=5.1Hz,4H).

[0714] Example. Synthesis route of compound 58

[0715] Synthesis of compound YL240807-065

[0716] Under nitrogen, Pd(dppf)Cl2 (cas: 72287-26-4) (0.77 g, 1.048 mmol) was added to a mixture of methyl 2-bromo-6-methylbenzoate (4.00 g, 17.462 mmol), pinacol diboron (4.88 g, 19.208 mmol), and potassium acetate (5.14 g, 52.386 mmol) in 1,4-dioxane (50 mL). The mixture was heated to 100°C for 18 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain YL240807-065 (2.50 g, 51.87% yield). 1 H NMR (400MHz, Chloroform-d) δ7.58–7.52(m,1H),7.31(t,J=7.4Hz,1H),7.28–7.24(m,1H),3.88(s,3H),2.38(s,3H),1.33(s,12H).

[0717] Synthesis of compound YL240807-067

[0718] Under nitrogen, Pd(dtbpf)Cl2 (cas: 95408-45-0) (0.30 g, 0.462 mmol) was added to a mixture of methyl 6-chloro-5-nitronicotinate (1.00 g, 4.617 mmol), YL240807-065 (1.66 g, 6.002 mmol), and triethylamine (1.925 mL, 13.852 mmol) in N,N-dimethylformamide (50 mL) and water (10 mL). The mixture was heated to 100°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5% to 30%) to afford YL240807-067 (500 mg, 32.79% yield). (ESI): m / z 331.1[M+H] + .

[0719] Synthesis of compound YL240807-070

[0720] Under nitrogen, iron powder (422.65 mg, 7.569 mmol) and ammonium chloride (242.92 mg, 4.541 mmol) were added to a mixture of YL240807-067 (500 mg, 1.514 mmol) in ethanol (10 mL) and water (1 mL). The mixture was heated to 80°C for 4 hours. The reaction solution was filtered through celite, and the filter cake was rinsed with tetrahydrofuran several times. The filtrate was concentrated and purified by slurrying with dichloromethane and petroleum ether (v / v = 1:1) to obtain YL240807-070 (270 mg, yield 65.85%). (ESI): m / z 269.0 [M+H] + .

[0721] Synthesis of compound YL240807-073

[0722] Lithium aluminum hydride (1M) in tetrahydrofuran (2.0 mL, 2.013 mmol) was added dropwise to a mixture of YL240807-070 (270 mg, 1.006 mmol) in tetrahydrofuran (10 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched with water (3 drops) at 0°C, followed by the addition of sodium hydroxide solution (9 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.1 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield YL240807-073 (220 mg, 91.67% yield). (ESI): m / z 241.0 [M+H] + .

[0723] Synthesis of compound YL240807-074

[0724] Thionyl chloride (1089.29 mg, 9.157 mmol) was slowly added to a mixture of YL240807-073 (220 mg, 0.916 mmol) in dichloromethane (15 mL) and allowed to react at room temperature for 16 hours. The reaction solution was concentrated, excess solvent removed, dissolved in methanol, and concentrated again to yield YL240807-074 (175 mg, crude). (ESI): m / z 259.2 [M+H] + .

[0725] Synthesis of compound 58

[0726] Potassium iodide (5.45 mg, 0.033 mmol) was added to a mixture of YL240807-074 (85 mg, 0.329 mmol), YL240807-061 (102.54 mg, 0.361 mmol), and DIEA (127.40 mg, 0.986 mmol) in acetonitrile (3 mL). The mixture was heated to 80°C for 1 hour. The reaction mixture was diluted with acetonitrile and filtered through celite. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to give compound 58 (7.5 mg, 4.86% yield). (ESI): m / z 470.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),8.69(dd,J=10.5,6.5Hz,2H),8.44(d,J=1.9Hz,1H),8.28(t,J=8.5Hz,1H),7.94(d,J=7.8Hz,1H),7.73(t,J=7. 7Hz,1H),7.64(d,J=1.9Hz,1H),7.49(d,J=7.4Hz,1H),3.74(s,2H),3.68( s,2H),2.94–2.89(m,1H),2.86(s,3H),2.36(s,3H),0.70(d,J=7.6Hz,4H).

[0727] Synthesis route of Example Compound 59

[0728] Synthesis of compound YL240807-064

[0729] Under nitrogen, Pd(dtbpf)Cl2 (0.47 g, 0.724 mmol) was added to a mixture of methyl 2-bromo-6-methylbenzoate (2.00 g, 7.245 mmol), pinacol diboron (2.21 g, 8.693 mmol), and triethylamine (3.021 mL, 21.734 mmol) in N,N-dimethylformamide (5 mL). The mixture was heated to 100°C for 2 hours. The reaction mixture was diluted with water and ethyl acetate, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0% to 5%) to obtain YL240807-064 (1.00 g, 49.99% yield). (ESI): m / z 277.5 [M+H] + .

[0730] Synthesis of compound YL240807-069

[0731] Under nitrogen, Pd(dtbpf)Cl2 was added to a mixture of methyl 6-chloro-5-nitronicotinate (0.78 g, 3.621 mmol), YL240807-064 (1.00 g, 3.621 mmol), and triethylamine (1.510 mL, 10.864 mmol) in N,N-dimethylformamide (25 mL) and water (5 mL). The mixture was heated to 100°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5% to 30%) to afford YL240807-069 (350 mg, 29.17% yield). (ESI): m / z 331.1 [M+H] + .

[0732] Synthesis of compound YL240807-072

[0733] Under nitrogen, iron powder (295.85 mg, 5.298 mmol) and ammonium chloride (170.04 mg, 3.179 mmol) were added to a mixture of YL240807-069 (350 mg, 1.060 mmol) in ethanol (7 mL) and water (0.7 mL). The mixture was heated to 80°C and reacted for 4 hours. The reaction solution was filtered through celite, and the filter cake was rinsed with tetrahydrofuran several times. The filtrate was concentrated and purified by slurrying with dichloromethane and petroleum ether (v / v = 1:1) to obtain YL240807-072 (180 mg, yield 63.32%). (ESI): m / z 269.1 [M+H] + .

[0734] Synthesis of compound YL240807-075

[0735] Lithium aluminum hydride (1M) in tetrahydrofuran (1.3 mL, 1.342 mmol) was added dropwise to a mixture of YL240807-072 (170 mg, 0.634 mmol) in tetrahydrofuran (6 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched by the addition of water (3 drops) at 0°C, followed by the addition of sodium hydroxide solution (9 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.05 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield YL240807-075 (110 mg, 72.25% yield). (ESI): m / z 241.0 [M+H] + .

[0736] Synthesis of compound YL240807-076

[0737] Thionyl chloride (544.64 mg, 4.578 mmol) was slowly added to a mixture of YL240807-075 (110 mg, 0.458 mmol) in dichloromethane (10 mL) and allowed to react at room temperature for 16 hours. The reaction solution was concentrated, excess solvent removed, dissolved in methanol, and concentrated again to yield YL240807-076 (130 mg, crude). (ESI): m / z 259.2 [M+H] + .

[0738] Synthesis of compound 59

[0739] Potassium iodide (3.85 mg, 0.023 mmol) was added to a mixture of YL240807-074 (65 mg, 0.232 mmol), YL240807-061 (72.37 mg, 0.255 mmol), and DIEA (89.92 mg, 0.696 mmol) in acetonitrile (3 mL). The mixture was heated to 80°C for 1 hour. The reaction mixture was diluted with acetonitrile and filtered through celite. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford compound 59 (28 mg, 25.71% yield). (ESI): m / z 470.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.70(d,J=5.0Hz,1H),8.61(d,J=8.1 Hz,1H),8.46(d,J=1.8Hz,1H),8.27(t,J=8.4Hz,1H),8.10(s,1H),7.93(d,J =7.6Hz,1H),7.73(d,J=8.2Hz,1H),7.68(s,1H),3.74(s,2H),3.68(s,2H), 2.89(q,J=6.4,5.9Hz,1H),2.50(s,3H),2.35(s,3H),0.70(d,J=7.4Hz,4H).

[0740] Synthesis route of Example Compound 60

[0741] Synthesis of compound YL240807-103

[0742] Under nitrogen, Pd(dtbpf)Cl2 (0.23 g, 0.357 mmol) was added to a mixture of methyl 6-chloro-5-nitronicotinate (0.77 g, 3.570 mmol), methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (cas: 1400976-17-1) (1.00 g, 3.570 mmol), and triethylamine (1.489 mL, 10.710 mmol) in N,N-dimethylformamide (25 mL) and water (5 mL). The mixture was heated to 100°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5% to 30%) to obtain YL240807-103 (400 mg, yield 33.61%). (ESI): m / z 334.0, 351.1 [M+H, M+NH4] + .

[0743] Synthesis of compound YL240807-111

[0744] Under nitrogen, iron powder (335.10 mg, 6.001 mmol) and ammonium chloride (192.60 mg, 3.601 mmol) were added to a mixture of YL240807-103 (400 mg, 1.200 mmol) in ethanol (10 mL) and water (1 mL). The mixture was heated to 80°C and reacted for 16 hours. The reaction solution was filtered through celite, and the filter cake was added with tetrahydrofuran and methanol (v / v = 4:1). The fragments were stirred for 16 hours and filtered again. The filtrates were combined, concentrated, and purified by slurrying with dichloromethane and petroleum ether (v / v = 1:1) to obtain YL240807-110 (380 mg, crude product). (ESI): m / z 272.2 [M+H] + .

[0745] Synthesis of compound YL240807-117

[0746] Lithium aluminum hydride (1M) in tetrahydrofuran (2.4 mL, 2.435 mmol) was added dropwise to a mixture of YL240807-111 (380 mg, 1.217 mmol) in tetrahydrofuran (12 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched with water (2 drops) at 0°C, followed by the addition of sodium hydroxide solution (6 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.8 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield YL240807-117 (300 mg, 101.31% yield). (ESI): m / z 244.2 [M+H]+ .

[0747] Synthesis of compound YL240807-120

[0748] Thionyl chloride (1467.19 mg, 12.333 mmol) was slowly added to a mixture of YL240807-117 (300 mg, 1.233 mmol) in dichloromethane (18 mL) and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with water, the pH was adjusted to a weak base with solid sodium bicarbonate, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield YL240807-119 (250 mg, 78.13%). (ESI): m / z 262.0 [M+H] + .

[0749] Synthesis of compound 60

[0750] Potassium iodide (3.81 mg, 0.023 mmol) and DIEA (88.91 mg, 0.688 mmol) were added to a mixture of YL240807-120 (60 mg, 0.229 mmol) and YL240807-045-A (80.16 mg, 0.275 mmol) in acetonitrile (3 mL). The mixture was heated to 80°C for 2 hours. The reaction solution was concentrated, dissolved in DMSO, and filtered. The clarified filtrate was purified by preparative HPLC (NH4HCO3) to obtain calyx product 60 (40 mg, 37.77% yield). (ESI): m / z 517.6 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.93(d,J=8.1Hz,1H),8.40–8.25(m, 4H), 7.94 (dd, J=7.7, 1.6Hz, 1H), 7.46 (td, J=8.6, 2.5Hz, 1H), 7.37 (d, J=1. 6Hz,1H),7.23(dd,J=8.3,1.6Hz,1H),4.09–3.94(m,1H),3.70(s,2H),3.67 (s,2H),3.15(s,3H),2.54(s,2H),2.35(s,3H),2.08(qd,J=8.8,2.7Hz,2H).

[0751] Synthesis route of Example Compound 61

[0752] Synthesis of compound 61

[0753] YL230804-264-A (40 mg, 0.160 mmol) was dissolved in acetonitrile (1.5 mL), and YL240807-122-A (58 mg, 0.191 mmol), N,N-diisopropylethylamine (62 mg, 0.479 mmol), and potassium iodide (2.6 mg, 0.016 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried to obtain compound 61 (40 mg, 50%). ESI: (m / z) = 506.7 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),8.92(d,J=8.1Hz,1H),8.25(dd,J=9.2,7.7Hz,1H),8. 17(dd,J=2.9,1.5Hz,1H),7.89(ddd,J=18.3,8.1,1.4Hz,2H),7.22(dd,J=8.5,7.0Hz,1H),7 .07(dd,J=3.9,1.5Hz,1H),6.70(dd,J=3.9,2.8Hz,1H),4.08–3.95(m,1H),3.72(s,2H),3.6 6(s,2H),3.63–3.56(m,1H),3.14(s,3H),2.58–2.52(m,2H),2.33(s,3H),2.13–2.01(m,2H).

[0754] Synthesis route of Example Compound 62

[0755] Synthesis of compound YL240807-118

[0756] Under nitrogen, Pd(dtbpf)Cl2 (0.30 g, 0.46 mmol) was added to a mixture of methyl 6-chloro-5-nitronicotinate (1.00 g, 4.64 mmol), YL240807-112 (1.69 g, 6.03 mmol), triethylamine (1.9 mL, 13.92 mmol) in N,N-dimethylformamide (40 mL) and water (8 mL). The mixture was heated to 100°C for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 5% to 30%) to obtain YL240807-118 (150 mg, 9.68% yield). (ESI): m / z 351.2 [M+NH4] + .

[0757] Synthesis of compound YL240807-125

[0758] Under nitrogen, iron powder (126 mg, 2.25 mmol) and ammonium chloride (72 mg, 1.35 mmol) were added to a mixture of YL240807-118 (150 mg, 0.45 mmol) in ethanol (10 mL) and water (1 mL). The mixture was heated to 80°C for 16 hours. The reaction solution was diluted with tetrahydrofuran and filtered through celite. The filter cake was rinsed several times with a mixture of tetrahydrofuran and methanol. The filtrate was concentrated and purified by slurrying with dichloromethane and petroleum ether (v / v = 1:1) to obtain YL240807-125 (150 mg, crude). (ESI): m / z 272.2 [M+H] + .

[0759] Synthesis of compound YL240807-132

[0760] Lithium aluminum hydride (1M) in tetrahydrofuran (2.1 mL, 2.07 mmol) was added dropwise to a mixture of YL240807-125 (350 mg, 1.03 mmol) in tetrahydrofuran (12 mL) at 0°C in an ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched by the addition of water (2 drops) at 0°C, followed by the addition of sodium hydroxide solution (6 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.8 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield YL240807-132 (300 mg, crude). (ESI): m / z 244.2 [M+H] + .

[0761] Synthesis of compound YL240807-133

[0762] Thionyl chloride (1.22 mg, 10.28 mmol) was slowly added to a mixture of YL240807-132 (220 mg, 0.90 mmol) in dichloromethane (15 mL) and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with water, the pH was adjusted to a weak base with solid sodium bicarbonate, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (tetrahydrofuran / petroleum ether (v / v) = 5% to 100%) to obtain YL240807-133 (160 mg, yield 59.49%). (ESI): m / z 262.0 [M+H] + .

[0763] Synthesis of compound 62

[0764] Potassium iodide (4 mg, 0.023 mmol) and DIEA (89 mg, 0.69 mmol) were added to a mixture of YL240807-133 (60 mg, 0.23 mmol) and YL240807-122 (80 mg, 0.28 mmol) in acetonitrile (5 mL). The mixture was heated to 80°C for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to give compound 62 (45 mg, 37.99% yield). (ESI): m / z 517.7 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),8.94(d,J=8.1Hz,1H),8.45(dd,J=8.4,1.7Hz,1H),8.29(dd,J=9.2 ,7.6Hz,1H),8.22(dd,J=7.8,1.4Hz,1H),7.94(dd,J=7.7,1.6Hz,1H),7.74(ddd,J=13.6,8.0,1.4Hz,1H) ,7.66(td,J=8.0,5.0Hz,1H),7.42(d,J=1.7Hz,1H),7.27(dd,J=8.0,1.4Hz,1H),4.08–3.96(m,1H),3.70 (s,2H),3.67(s,2H),3.66–3.57(m,1H),3.15(s,3H),2.59–2.53(m,2H),2.35(s,3H),2.13–2.04(m,2H).

[0765] Synthesis route of Example Compound 63

[0766] Synthesis of compound YL230784-419-C1

[0767] To a 50mL three-necked flask, methyl 6-chloro-5-nitronicotinate (2000mg, 9.234mmol), ethanol (30mL), iron powder (2578mg, 46.172mmol), ammonium chloride (1481mg, 27.703mmol) and water (5mL) were added in sequence, and the temperature was raised to 70°C under nitrogen protection for 2 hours. Hot filter, rinse with hot ethanol, and concentrate under reduced pressure. The iron powder was slurried with dichloromethane, filtered, the filtrate was combined with the solid, water was added, the liquid was separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain YL230784-419-C1 (1342mg, 7.192mmol, 77.88%). LC-MS (ESI): m / z 187.2 (M+H) + .

[0768] Synthesis of compound YL230784-421-C1

[0769] To a 50 mL three-necked flask, YL230784-419-C1 (1.34 g, 7.182 mmol) and dioxane hydrochloride solution (20 mL) were added sequentially, and the mixture was reacted at room temperature for 2 hours under nitrogen protection. The mixture was concentrated under reduced pressure to obtain YL230784-421-C1 (1570 mg, 7.039 mmol, 98.01%).

[0770] Synthesis of compound YL230784-432-C1

[0771] To a 50 mL three-necked flask, add YL230784-421-C1 (250 mg, 1.121 mmol), 1,4-dioxane (10 mL), water (1 mL), methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzoate (740 mg, 2.242 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (80 mg, 0.112 mmol), and potassium phosphate (774 mg, 3.363 mmol). The mixture was heated to 100°C under nitrogen and allowed to react overnight. Ethyl acetate and water were added to dilute the mixture. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 0-70%) to obtain YL230784-432-C1 (85 mg, 0.264 mmol, 23.53%). LC-MS (ESI): m / z 323.2 (M+H) + .

[0772] Synthesis of compound YL230784-439-C1

[0773] To a 50 mL three-necked flask, YL230784-432-C1 (85 mg, 0.264 mmol) and tetrahydrofuran (5 mL) were added sequentially. The mixture was cooled to 0°C under nitrogen protection, and 1 M lithium aluminum hydride tetrahydrofuran solution (1.3 mL) was added dropwise. The mixture was then returned to room temperature and reacted for 1 hour. Ethyl acetate was added to quench the mixture, and 1.5 mL of water was added. The mixture was stirred for 30 minutes, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Purification by column chromatography (methanol / dichloromethane = 0-3%) gave YL230784-439-C1 (27 mg, 0.092 mmol, 34.79%). LC-MS (ESI): m / z 295.2 (M+H) + .

[0774] Synthesis of compound YL230784-477-C1

[0775] To a 50 mL three-necked flask, YL230784-439-C1 (27 mg, 0.092 mmol), dichloromethane (5 mL), and N,N-dimethylformamide (0.2 mL) were added in sequence. The temperature was lowered to 0°C under nitrogen protection, and thionyl chloride (163 mg, 1.376 mmol) was added dropwise. The temperature was then raised to room temperature and the reaction was allowed to proceed overnight. Saturated sodium bicarbonate was added to quench the mixture, and the mixture was extracted with dichloromethane. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain YL230784-477-C1 (31 mg, 0.089 mmol, 97.24%). LC-MS (ESI): m / z 313.1 (M+H) + .

[0776] Synthesis of compound 63

[0777] To a 50 mL three-necked flask were added YL230784-477-C1 (31 mg, 0.099 mmol), acetonitrile (5 mL), YL240807-061-A (36 mg, 0.129 mmol), potassium iodide (3 mg, 0.020 mmol), and N,N-diisopropylethylamine (64 mg, 0.496 mmol). The mixture was heated to 70°C under nitrogen and allowed to react for 2.5 hours. The mixture was concentrated under reduced pressure and sent to the preparation to obtain compound 63 (16 mg, 0.031 mmol, 30.83%). LC-MS (ESI): m / z 524.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.88 (s, 1H), 9.16 (d, J = 8.2Hz, 1H), 8.70 (d, J = 5.0Hz, 1H), 8.52 (d, J = 1.8Hz, 1H), 8.28 (s, 1H), 8.17 (d, J = 7.6Hz, 1H), 8.0 5(t, J=7.9Hz, 1H), 7.94(d, J=7.7Hz, 1H), 7.74–7.69(s, 1H), 3.78(s, 2H) , 3.70 (s, 2H), 2.90 (d, J = 5.5Hz, 1H), 2.37 (s, 3H), 0.70 (d, J = 5.3Hz, 4H).

[0778] Synthesis route of Example Compound 64

[0779] Synthesis of compound YL230804-308-A

[0780] YL230804-293-A (160 mg, 0.544 mmol) was added to a 1,4-dioxane hydrochloride solution (3 mL, 4 M) and allowed to react at room temperature for 1 hour. The reaction mixture was concentrated and adjusted to alkalinity with 7 M amine methanol. The mixture was then dried to give YL230804-308-A (100 mg, crude). LC-MS (ESI): m / z 225.1 (M+H). + ;

[0781] Synthesis of compound 64

[0782] YL230804-264-A (40 mg, 0.160 mmol) was dissolved in acetonitrile, and DIEA (62 mg, 0.479 mmol) was added. YL230804-308-A (37 mg, 0.191 mmol) and potassium iodide (2.6 mg, 0.016 mmol) were added, and the mixture was stirred at 80°C for 2 hours. Compound 64 (33 mg, 50.63%) was obtained. LC-MS (ESI): m / z 409.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),8.17(dd,J=2.9,1.5Hz,1H),7.96(dd,J=9.7,8.3Hz,1H),7.89–7.83(m,1H),7.21(dd,J=8.5,7.0Hz,1H ),7.07(dd,J=3.8,1.4Hz,1H),6.78(dd,J=8.3,1.2Hz,1H),6.70(dd,J=3.9,2.8Hz,1H),3.86(s,3H),3.69(s,2H),3.58(s,2H),2.30(s,3H).

[0783] Synthesis route of Example Compound 65

[0784] Synthesis of compound YL240807-138

[0785] Under nitrogen, Pd(dppf)Cl2 (1.19 g, 1.62 mmol) was added to a mixture of methyl 3-bromopicolinate (3.50 g, 16.20 mmol), (2-amino-4-(methoxycarbonyl)phenyl)borate hydrochloride (536 mg, 2.31 mmol), and potassium carbonate (11.19 g, 81.01 mmol) in 1,4-dioxane (70 mL) and water (7 mL). The mixture was heated to 100°C for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was separated, concentrated, and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to afford YL240807-138 (1.90 g, 46.13% yield). (ESI): m / z 255.1 [M+H] + .

[0786] Synthesis of compound YL240807-140

[0787] Lithium aluminum hydride (1M) in tetrahydrofuran (0.8 mL, 0.79 mmol) was added dropwise to a mixture of YL240807-138 (100 mg, 0.39 mmol) in tetrahydrofuran (5 mL) in an ice-water bath at 0°C. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched by the addition of water (2 drops) at 0°C, followed by the addition of sodium hydroxide solution (6 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.8 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield YL240807-140 (100 mg, crude). (ESI): m / z 227.3 [M+H] + .

[0788] Synthesis of compound YL240807-143

[0789] Thionyl chloride (468 mg, 3.93 mmol) was slowly added to a mixture of YL240807-140 (100 mg, 0.39 mmol) in dichloromethane (10 mL) and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with water, the pH was adjusted to a weak base with solid sodium bicarbonate, and the organic phase was separated. The organic phase was concentrated and purified by silica gel column chromatography (tetrahydrofuran / petroleum ether (v / v) = 5-80%) to afford YL240807-143 (60 mg, 62.33% yield). (ESI): m / z 245.2 [M+H] + .

[0790] Synthesis of compound 65

[0791] Potassium iodide (4 mg, 0.025 mmol) was added to a mixture of YL240807-143 (60 mg, 0.25 mmol), YL240807-122 (86 mg, 0.29 mmol), and N,N-diisopropylethylamine (95 mg, 0.74 mmol) in acetonitrile (5 mL). The mixture was heated to 80°C for 2 hours. The reaction solution was concentrated, dissolved in dimethyl sulfoxide, filtered, and the clear filtrate was purified by preparative HPLC (NH4HCO3) to afford compound 65 (11 mg, 8.98% yield). (ESI): m / z 500.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),9.00–8.91(m,2H),8.88(d,J=4.3Hz,1H),8.37 (d,J=8.2Hz,1H),8.29(t,J=8.5Hz,1H),7.94(d,J=7.7Hz,1H),7.83(dd,J=8.1,4.4H z,1H),7.39(s,1H),7.26(d,J=8.1Hz,1H),4.08–3.97(m,1H),3.69(d,J=15.0Hz,4H) ,3.64–3.56(m,1H),3.14(s,3H),2.61–2.54(m,2H),2.35(s,3H),2.15–2.03(m,2H).

[0792] Synthesis route of Example Compound 66

[0793] Synthesis of compound YL240807-175

[0794] Under nitrogen, Pd(dppf)Cl2 (87 mg, 0.12 mmol) was added to a mixture of methyl 6-bromo-2,3-difluorobenzoate (500 mg, 1.99 mmol), bis(pinacolato) borate (556 mg, 2.19 mmol), and potassium acetate (586 mg, 5.98 mmol) in 1,4-dioxane (6 mL), and the mixture was heated to 100°C for 16 hours. The reaction solution was cooled to room temperature, and then methyl 3-amino-4-iodobenzoate (552 mg, 1.99 mmol), triethylamine (0.8 mL, 5.98 mmol), Pd(dtbpf)Cl2 (129 mg, 0.20 mmol), N,N-dimethylformamide (3 mL), and water (1 mL) were added. The nitrogen atmosphere was replaced three times, and the mixture was heated to 100°C for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (tetrahydrofuran / petroleum ether (v / v) = 5-30%) to obtain YL240807-175 (150 mg, crude). (ESI): m / z 290.0, 301.7 [M+H] + .

[0795] Synthesis of compound YL240807-178

[0796] Lithium aluminum hydride (1M) in tetrahydrofuran (1.0 mL, 1.04 mmol) was added dropwise to a mixture of YL240807-175 (150 mg, crude) in tetrahydrofuran (10 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched by the addition of water (1 drop) at 0°C, followed by the addition of sodium hydroxide solution (3 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.05 g, Na2SO4) was added and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield YL240807-178 (150 mg, crude, 13.9% purity). (ESI): m / z 262.2 [M+H] + .

[0797] Synthesis of compound YL240807-179

[0798] YL240807-178 (150 mg, 0.080 mmol) was added to a mixed solvent of thionyl chloride and dichloromethane (v / v = 1:10) (10 mL) and allowed to react at room temperature for 16 hours. The reaction solution was quenched with water and the pH was adjusted to 9-10 with saturated sodium bicarbonate solid. The organic phase was separated and concentrated, and then purified by silica gel column chromatography (tetrahydrofuran / petroleum ether (v / v) = 5%-30%) to obtain YL240807-179 (15 mg, yield 67.20%). (ESI): m / z 280.2 [M+H] + .

[0799] Synthesis of compound 66

[0800] Potassium iodide (2 mg, 0.011 mmol) was added to a mixture of YL240807-179 (15 mg, 0.054 mmol), YL230783-368 (19 mg, 0.059 mmol), and N,N-diisopropylethylamine (21 mg, 0.16 mmol). The mixture was heated to 80°C for 4 hours. The reaction solution was concentrated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-5%) to obtain a pale yellow solid. The pale yellow solid was further purified by reverse phase preparative chromatography (C18, NH4HCO3) to obtain calyx product 66 (2.2 mg, yield 7.67%). (ESI): m / z 535.2 [M+H] + .

[0801] Synthesis of Example Compound 67

[0802] Synthesis of compound YL230783-242-A

[0803] 2-Bromopyridine-3-carboxylic acid (3.5 g, 17.326 mmol), methyl 3-amino-2-fluorobenzoate (3.52 g, 20.791 mmol), and HATU (7.91 g, 20.791 mmol) were dissolved in DMF (50 mL), and triethylamine (7.225 mL, 51.978 mmol) was added. The reaction was continued at room temperature overnight, and the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was washed with ethyl acetate. The organic phases were combined and washed with a saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was purified by automatic column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 25 to 100 / 30) to obtain compound YL230783-242-A (2.4 g, 6.592 mmol, 38.05%), ESI: (m / z) = 353.0 / 355.0 [M+H] + , 1 H NMR(400MHz,Chloroform-d)δ8.64(ddd,J=8.4,7.0,1.7Hz,1H),8.53–8.42(m,2H),8.07(dd,J=7.6,2.0Hz,1 H),7.71(ddd,J=8.3,6.8,1.7Hz,1H),7.42(dd,J=7.7,4.7Hz,1H),7.25(dd,J=8.1,1.2Hz,1H),3.93(s,3H).

[0804] Synthesis of compound YL230783-296-A

[0805] YL230783-242-A (1.6 g, 4.531 mmol) and potassium carbonate (1.88 g, 13.592 mmol) were dissolved in DMF (60 mL). p-Methoxybenzyl chloride (0.85 g, 5.437 mmol) was then added and the reaction continued at 90°C for 2 hours. The mixture was diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain compound YL230783-296-A (2.2 g, 4.648 mmol, 102.59%). ESI: (m / z) = 473.1 / 475.1 [M+H] + .

[0806] Synthesis of compound YL230783-298-A

[0807] YL230783-296-A (2.2 g, 4.648 mmol), 1,3-bis(diphenylphosphino)propane (0.59 g, 1.394 mmol), potassium carbonate (1.93 g, 13.945 mmol), palladium acetate (0.31 g, 1.394 mmol), tri-n-butylphosphine (57.26 mg, 0.283 mmol) were dissolved in DMF (110 mL) and nitrogen was replaced under microwave conditions at 140 °C. The reaction was continued for 1 hour. LCMS monitoring confirmed that the starting material was completely consumed. The reaction solvent was vortexed and the resulting crude product was purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 1 to 100 / 3 and dichloromethane / methanol 100 / 25 to 100 / 30) to obtain compound YL230783-298-A (1.2 g, 2.752 mmol, 59.21%). ESI: (m / z) = 393.6 [M+H] + and YL230783-298-B (1.05 g, 2.664 mmol, 57.32%), ESI: (m / z) = 379.6 [M+H] + .

[0808] Synthesis of compound YL230783-305-A

[0809] Compounds YL230783-302-A and YL230783-298-A (2.15 g, 5.479 mmol) were weighed into a reaction flask and placed on an ice bath. Trifluoroacetic acid (180 mL) was then added and the temperature was raised to 60°C for 5 hours. After completion, the reaction was diluted with ethyl acetate and water, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness. The crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 5) to obtain compound YL230783-305-A (565 mg, 2.075 mmol, 37.88%). ESI: (m / z) = 273.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),9.13(d,J=4.1Hz,1H),8.67(d,J=8.0Hz,1H),8.51(d,J=8.6Hz,1H),7.84–7.67(m,2H),3.92(s,3H).

[0810] Synthesis of compound YL230783-307-A

[0811] YL230783-305-A (565 mg, 2.075 mmol) and tetrahydrofuran (220 mL) were added to the reaction flask. The mixture was cooled to 0°C, and then lithium aluminum hydride tetrahydrofuran solution (1 M) (10.4 mL) was slowly added. The mixture was then stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with 50 mL of ethyl acetate and then 5 mL of water was added. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 10 to 100 / 15) to obtain compound YL230783-307-A (275 mg, 1.088 mmol, 52.41%). LC-MS (ESI): m / z 245.2 / (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),9.06(dd,J=4.6,1.8Hz,1H),8.62(dd,J=8.0,1.8Hz,1H),8.41(dd,J=8.3,1.1 Hz,1H),7.69(dd,J=8.0,4.6Hz,1H),7.39(dd,J=8.3,6.6Hz,1H),5.44(t,J=5.8Hz,1H),4.68(dd,J=5.8,1.4Hz,2H).

[0812] Synthesis of compound YL230783-311-A

[0813] YL230783-307-A (240 mg, 0.983 mmol), dichloromethane (150 mL), and DMF (0.040 mL, 0.491 mmol) were added to the reaction flask. The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Thionyl chloride (1753.49 mg, 14.740 mmol) was then slowly added dropwise. After the addition, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was evaporated to give compound YL230783-311-A (270 mg, 0.759 mmol, 77.20%). LC-MS (ESI): m / z 263.2 (M+H) + .

[0814] Synthesis of compound 67

[0815] YL230783-311-A (80 mg, 0.305 mmol) and YL230783-287-A (88.73 mg, 0.305 mmol) were dissolved in acetonitrile (50 mL) at room temperature, and then N,N-diisopropylethylamine (196.82 mg, 1.523 mmol) was added, and the reaction was continued at 80°C for 2 hours. The mixture was diluted with ethyl acetate and water, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was purified by preparative purification (Welch Xtimate C18, 21.2*250mm, 10um, water (10mM ammonium bicarbonate) / acetonitrile, flow rate 30mL / min, column temperature 25°C, detection wavelength 254nm) to give compound 67 (80mg, 0.153mmol, 50.25%), ESI: (m / z) = 518.7[M+H] + , 1H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.15–9.03(m,1H),8.92(d,J=8.1Hz,1H),8.63(d,J=8 .0Hz,1H),8.41(d,J=8.3Hz,1H),8.26(t,J=8.4Hz,1H),7.91(d,J=7.8Hz,1H),7.70(dd,J=8. 0,4.6Hz,1H),7.36(t,J=7.4Hz,1H),4.01(q,J=8.2Hz,1H),3.80(s,2H),3.70(s,2H),3.61(p ,J=7.3Hz,1H),3.14(s,3H),2.55(d,J=7.9Hz,2H),2.36(s,3H),2.08(q,J=10.1,9.7Hz,2H).

[0816] Synthesis of Example Compound 68

[0817] Synthesis of compound YL230783-243-A

[0818] o-Bromobenzoic acid (3.5 g, 17.411 mmol), methyl 2-fluoro-3-aminobenzoate (3.53 g, 20.893 mmol), and HATU (7.94 g, 20.893 mmol) were dissolved in DMF (50 mL), and triethylamine (7.260 mL, 52.234 mmol) was added. The reaction was continued overnight at room temperature. After the reaction was completed, the mixture was poured into a large amount of ice water to precipitate a large amount of solid. The solid was filtered, and the filter cake was washed with saturated sodium chloride aqueous solution and then with water to directly obtain compound YL230783-243-A (3.5 g, 9.939 mmol, 57.08%). ESI: (m / z) = 352.0 / 354.0 [M+H] + .

[0819] Synthesis of compound YL230783-306-A

[0820] YL230783-243-A (3.4 g, 9.655 mmol) and potassium carbonate (4.00 g, 28.964 mmol) were dissolved in DMF (100 mL), followed by the addition of p-methoxybenzyl chloride (1.81 g, 11.586 mmol). The reaction was then continued at 90°C for 2 hours. The mixture was diluted with ethyl acetate and water, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vortexing. The resulting crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 2 to 100 / 3) to yield compound YL230783-306-A (3.2 g, 6.165 mmol, 63.86%). ESI: (m / z) = 472.1 / 474.1 [M+H] + .

[0821] Synthesis of compound YL230783-310-A

[0822] YL230783-306-A (3.2 g, 6.775 mmol), 1,3-bis(diphenylphosphino)propane (0.86 g, 2.033 mmol), palladium acetate (0.46 g, 2.033 mmol), tributylphosphine (5.88 g, 6.775 mmol), potassium carbonate (2.81 g, 20.326 mmol) were dissolved in DMF (160 mL) and nitrogen was replaced for protection. The mixture was heated under microwave conditions at 140 °C. The reaction was continued for 2 hours. LCMS monitoring confirmed the complete consumption of the starting material. The reaction solvent was vortexed and the crude product was purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 1 to 100 / 2 and dichloromethane / methanol 100 / 25 to 100 / 30) to obtain compound YL230783-310-A ​​(2.8 g, 4.018 mmol, 89.8%), ESI: (m / z) = 392.2 [M+H] + , 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=8.2Hz,1H),8.47–8.37(m,2H),7.99–7.89(m,1H),7.78(t,J=7.6Hz,1H),7 .69(dd,J=8.5,6.2Hz,1H),7.09(d,J=8.6Hz,2H),6.90–6.78(m,2H),5.58(s,2H),3.84(s,3H),3.70(s,3H).

[0823] Synthesis of compound YL230783-318-A

[0824] Compound YL230783-310-A ​​(2.75 g, 7.026 mmol) was added to a reaction flask at room temperature, and trifluoroacetic acid (45 mL, 587.660 mmol) was added. The temperature was raised to 60°C and the reaction was allowed to proceed for 2 hours. After the reaction was completed, the mixture was poured into ice water, and a large amount of solid precipitated. The residue was then filtered and dried to directly obtain compound YL230783-318-A (1.98 g, 6.935 mmol, 98.70%). ESI: (m / z) = 272.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.55(d,J=8.2Hz,1H),8.34(dd,J=24.6 ,8.3Hz,2H),7.92(t,J=7.7Hz,1H),7.71(dt,J=37.7,7.6Hz,2H),3.90(s,3H)

[0825] Synthesis of compound YL230783-320-A

[0826] YL230783-318-A (650 mg, 2.396 mmol) and anhydrous tetrahydrofuran (150 mL) were added to the reaction flask. The mixture was cooled to 0°C, and then lithium aluminum hydride tetrahydrofuran solution (1M) (10.4 mL) was slowly added. The mixture was stirred at 0°C for 2 hours. After the reaction, it was quenched with 30 mL of ethyl acetate and then 5 mL of water was added. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 7) to obtain compound YL230783-320-A (350 mg, 1.425 mmol, 59.45%). LC-MS (ESI): m / z 244.2 (M+H). + , 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),8.49(d,J=8.1Hz,1H),8.34(dd,J=7.9,1.4Hz,1H),8.20(d,J=8.3Hz,1H),7.87(ddd,J=8.3, 7.1,1.5Hz,1H),7.67(td,J=7.6,7.2,1.1Hz,1H),7.33(dd,J=8.3,6.9Hz,1H),5.39(t,J=5.8Hz,1H),4.66(dd,J=5.9,1.4Hz,2H).

[0827] Synthesis of compound YL230783-322-A

[0828] YL230783-320-A (340 mg, 1.398 mmol), dichloromethane (110 mL), and DMF (0.023 mL, 0.280 mmol) were added to the reaction flask. The mixture was replaced with nitrogen and cooled to 0°C. Thionyl chloride (997.69 mg, 8.387 mmol) was then slowly added dropwise. After the addition, the mixture was heated to room temperature and stirred for 1 hour. After the reaction was completed, the solvent was evaporated to give compound YL230783-322-A (400 mg, 1.345 mmol, 96.23%). LC-MS (ESI): m / z 262.2 (M+H) + .

[0829] Synthesis of compound 68

[0830] YL230783-322-A (80 mg, 0.306 mmol), YL230783-287-A (89.06 mg, 0.306 mmol), and potassium iodide (50.75 mg, 0.306 mmol) were dissolved in acetonitrile (50 mL) at room temperature. N,N-diisopropylethylamine (197.57 mg, 1.529 mmol) was then added, and the reaction was continued at 80°C for 2 hours. The mixture was then diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative chromatography (Welch Xtimate C18, 21.2*250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature 25°C, detection wavelength 254 nm) to give compound 68 (96 mg, 0.185 mmol, 60.49%), ESI: (m / z) = 517.7 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),8.92(d,J=8.0Hz,1H),8.49(d,J=8.2Hz,1H),8.34(d d,J=7.9,1.5Hz,1H),8.25(dd,J=9.2,7.7Hz,1H),8.20(d,J=8.4Hz,1H),7.93–7.84(m,2H) ,7.70–7.64(m,1H),7.29(dd,J=8.3,6.7Hz,1H),4.06–3.95(m,1H),3.78(s,2H),3.69(s,2 H),3.64–3.56(m,1H),3.14(s,3H),2.52(d,J=3.0Hz,2H),2.35(s,3H),2.12–2.04(m,2H).

[0831] Synthesis of Example Compound 69

[0832] Synthesis of compound YL230783-242-A

[0833] 2-Bromopyridine-3-carboxylic acid (3.5 g, 17.326 mmol), methyl 3-amino-2-fluorobenzoate (3.52 g, 20.791 mmol), and HATU (7.91 g, 20.791 mmol) were dissolved in DMF (50 mL), and triethylamine (7.225 mL, 51.978 mmol) was added. The reaction was continued at room temperature overnight, and the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was washed with ethyl acetate. The organic phases were combined and washed with a saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was purified by automatic column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 25 to 100 / 30) to obtain compound YL230783-242-A (2.4 g, 6.592 mmol, 38.05%), ESI: (m / z) = 353.0 / 355.0 [M+H] + , 1 H NMR(400MHz,Chloroform-d)δ8.64(ddd,J=8.4,7.0,1.7Hz,1H),8.53–8.42(m,2H),8.07(dd,J=7.6,2.0Hz,1 H),7.71(ddd,J=8.3,6.8,1.7Hz,1H),7.42(dd,J=7.7,4.7Hz,1H),7.25(dd,J=8.1,1.2Hz,1H),3.93(s,3H).

[0834] Synthesis of compound YL230783-296-A

[0835] YL230783-242-A (1.6 g, 4.531 mmol) and potassium carbonate (1.88 g, 13.592 mmol) were dissolved in DMF (60 mL). p-Methoxybenzyl chloride (0.85 g, 5.437 mmol) was then added and the reaction continued at 90°C for 2 hours. The mixture was diluted with ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain compound YL230783-296-A (2.2 g, 4.648 mmol, 102.59%). ESI: (m / z) = 473.1 / 475.1 [M+H] + .

[0836] Synthesis of compound YL230783-298-A

[0837] YL230783-296-A (2.2 g, 4.648 mmol), 1,3-bis(diphenylphosphino)propane (0.59 g, 1.394 mmol), potassium carbonate (1.93 g, 13.945 mmol), palladium acetate (0.31 g, 1.394 mmol), tri-n-butylphosphine (57.26 mg, 0.283 mmol) were dissolved in DMF (110 mL) and nitrogen was replaced under microwave conditions at 140 °C. The reaction was continued for 1 hour. LCMS monitoring confirmed that the starting material was completely consumed. The reaction solvent was vortexed and the resulting crude product was purified by automatic column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 1 to 100 / 3 and dichloromethane / methanol 100 / 25 to 100 / 30) to obtain compound YL230783-298-A (1.2 g, 2.752 mmol, 59.21%). ESI: (m / z) = 393.6 [M+H] + and YL230783-298-B (1.05 g, 2.664 mmol, 57.32%), ESI: (m / z) = 379.6 [M+H] + .

[0838] Synthesis of compound YL230783-305-A

[0839] Compounds YL230783-302-A and YL230783-298-A (2.15 g, 5.479 mmol) were placed in a reaction flask and placed on an ice bath. Trifluoroacetic acid (180 mL) was then added and the temperature was raised to 60°C for 5 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and water, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness. The crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 5) to obtain compound YL230783-305-A (565 mg, 2.075 mmol, 37.88%). ESI: (m / z) = 273.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),9.13(d,J=4.1Hz,1H),8.67(d,J=8.0Hz,1H),8.51(d,J=8.6Hz,1H),7.84–7.67(m,2H),3.92(s,3H).

[0840] Synthesis of compound YL230783-307-A

[0841] YL230783-305-A (565 mg, 2.075 mmol) and tetrahydrofuran (220 mL) were added to the reaction flask. The mixture was cooled to 0°C, and then lithium aluminum hydride tetrahydrofuran solution (1 M) (10.4 mL) was slowly added. The mixture was then stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with 50 mL of ethyl acetate and then 5 mL of water was added. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 10 to 100 / 15) to obtain compound YL230783-307-A (275 mg, 1.088 mmol, 52.41%). LC-MS (ESI): m / z 245.2 / (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),9.06(dd,J=4.6,1.8Hz,1H),8.62(dd,J=8.0,1.8Hz,1H),8.41(dd,J=8.3,1.1 Hz,1H),7.69(dd,J=8.0,4.6Hz,1H),7.39(dd,J=8.3,6.6Hz,1H),5.44(t,J=5.8Hz,1H),4.68(dd,J=5.8,1.4Hz,2H).

[0842] Synthesis of compound YL230783-311-A

[0843] YL230783-307-A (240 mg, 0.983 mmol), dichloromethane (150 mL), and DMF (0.040 mL, 0.491 mmol) were added to the reaction flask. The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Thionyl chloride (1753.49 mg, 14.740 mmol) was then slowly added dropwise. After the addition, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was evaporated to give compound YL230783-311-A (270 mg, 0.759 mmol, 77.20%). LC-MS (ESI): m / z 263.2 (M+H) + .

[0844] Synthesis of compound YL230783-321-A

[0845] YL240807-041-A1 (300 mg, 0.973 mmol), 4-aminotetrahydropyran (147.64 mg, 1.460 mmol), and HATU (554.99 mg, 1.460 mmol) were dissolved in DMF (20 mL), followed by the addition of triethylamine (0.676 mL, 4.865 mmol). The reaction was continued at room temperature for 1 hour, diluted with ethyl acetate and water, the organic phases separated, and the aqueous phase extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give compound YL230783-321-A (450 mg, 0.906 mmol, 93.10%). ESI: (m / z) = 392.5 [M+H] + .

[0846] Synthesis of compound YL230783-325-A

[0847] YL230783-321-A (450 mg, 1.150 mmol) was dissolved in a 4M hydrochloric acid-1,4-dioxane solution (30 mL) at room temperature and the reaction was continued for 4 hours. After the reaction was completed, the solvent was evaporated to obtain compound YL230783-325-A (360 mg, 1.112 mmol, 96.74%). ESI: (m / z) = 292.1 [M+H] + .

[0848] Synthesis of compound 69

[0849] YL230783-311-A (80 mg, 0.305 mmol), YL230783-325-A (88.73 mg, 0.305 mmol), and potassium iodide (50.56 mg, 0.305 mmol) were dissolved in acetonitrile (60 mL) at room temperature. N,N-diisopropylethylamine (196.82 mg, 1.523 mmol) was then added, and the reaction was continued at 80°C for 2 hours. The mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by preparative chromatography (Welch Xtimate C18, 21.2*250mm, 10um, water (10mM ammonium bicarbonate) / acetonitrile, flow rate 30mL / min, column temperature 25°C, detection wavelength 254nm) to give compound 69 (64mg, 0.116mmol, 38.17%), ESI: (m / z) = 518.7[M+H]+, 1H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.07(d,J=4.5Hz,1H),8.66–8.57(m,2H),8.41(d,J=8.3Hz,1H),8.26(t,J=8.4Hz,1H),7.94(d,J=7.6Hz,1H),7 .70(dd,J=8.1,4.5Hz,1H),7.36(t,J=7.4Hz,1H),3.87(d,J=11.4Hz,2H),3 .80(s,2H),3.70(s,2H),3.37(s,2H),2.36(s,3H),1.71(d,J=12.8Hz,4H).

[0850] Synthesis route of Example Compound 70

[0851] Synthesis of compound YL230783-343-A

[0852] Methyl 2-chloro-6-iodobenzoate (3.1 g, 10.456 mmol), 2-amino-4-methoxycarbonylphenyl boronate hydrochloride (2.66 g, 11.501 mmol), and potassium carbonate (7.22 g, 52.279 mmol) were dissolved in 1,4-dioxane (320 mL) and water (32 mL). Tetrakis(triphenylphosphine)palladium (2.42 g, 2.091 mmol) was then added, nitrogen was purged for protection, and the mixture was reacted at 100 °C for 8 hours. The mixture was diluted with ethyl acetate and water, and the organic phase was separated. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 5 to 100 / 10) to give solid compound YL230783-343-A (1.15 g, 3.797 mmol, 36.32%). LC-MS (ESI): m / z = 288.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),8.53(dd,J=8.3,1.2Hz,1H),8.46(d,J=8.6Hz ,1H),7.90(d,J=1.7Hz,1H),7.79(t,J=8.0Hz,1H),7.75–7.66(m,2H),3.89(s,3H).

[0853] Synthesis of compound YL230783-362-A

[0854] YL230783-343-A (770 mg, 2.676 mmol) and tetrahydrofuran (280 mL) were added to the reaction flask. The mixture was cooled to 0°C, and then lithium aluminum hydride tetrahydrofuran solution (1M) (10.4 mL) was slowly added. The mixture was stirred at 0°C for 1 hour. After completion of the reaction, it was quenched with 10 mL of ethyl acetate and then 2 mL of water was added. The resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness. The resulting residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 7 to 100 / 8) to obtain compound YL230783-362-A (915 mg, 2.466 mmol, 92.15%). LC-MS (ESI): m / z 260.6 / (M+H). + .

[0855] Synthesis of compound YL230783-364-A

[0856] YL230783-362-A (910 mg, 3.504 mmol), dichloromethane (110 mL), and DMF (0.042 mL, 0.526 mmol) were added to the reaction flask. The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Thionyl chloride (1250.58 mg, 10.513 mmol) was then slowly added dropwise. After the addition, the mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the solvent was evaporated to give compound YL230783-364-A (1.05 g, 3.209 mmol, 91.57%). LC-MS (ESI): m / z 278.1 / 280.1 (M+H) + .

[0857] Synthesis of compound YL230783-365-A

[0858] YL230783-364-A (250 mg, 0.899 mmol), YL240807-122-A1 (261.86 mg, 0.899 mmol), and potassium iodide (149.21 mg, 0.899 mmol) were dissolved in acetonitrile (120 mL) at room temperature. N,N-diisopropylethylamine (116.18 mg, 0.899 mmol) was then added, and the reaction was continued at 80°C for 2 hours. The mixture was then diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting crude product was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol 100 / 3 to 100 / 5) to give compound 70 (115 mg, 0.211 mmol, 23.52%), ESI: (m / z) = 533.7 [M+H] + , 1 H NMR(400MHz, DMSO-d6)δ11.63(s,1H),8.94(d,J=8.0Hz,1H),8.54–8.45(m,1H),8.34–8.23( m,2H),7.93(dd,J=7.6,1.6Hz,1H),7.75(t,J=8.0Hz,1H),7.63(dd,J=7.8,1.0Hz,1H),7.32( d,J=1.7Hz,1H),7.21(dd,J=8.3,1.7Hz,1H),4.09–3.96(m,1H),3.67(d,J=8.7Hz,4H),3.63– 3.55(m,1H),3.14(s,3H),2.62–2.51(m,2H),2.34(s,3H),2.08(tdd,J=9.2,6.6,2.8Hz,2H).

[0859] Using the synthetic method of Example 63, pyridine was used to replace 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzoic acid methyl ester with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzoic acid methyl ester to obtain the following intermediate 19, which further provided compounds 71-75;

[0860] Using the synthetic method of Example 63, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzoic acid methyl ester was replaced with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-fluoro-benzoic acid methyl ester to obtain the following intermediate 20, which further provided compounds 76-78;

[0861] The synthesis method of compound 66 was used to replace 6-bromo-2,3-difluorobenzoic acid methyl ester with 6-bromo-2-fluorobenzoic acid methyl ester to obtain the following intermediate 15, and Examples 79-87 were obtained;

[0862] Compounds 88 and 89 were obtained by the method of compound 68.

[0863] Using the synthesis method of compound 68, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzoic acid methyl ester was replaced with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzoic acid methyl ester to obtain the following intermediate 16, which further gave compounds 92-108;

[0864] Using one of the intermediates 1-15, compounds 109-125 can be obtained using similar reaction types;

[0865] Biological activity test using the embodiment:

[0866] Material:

[0867] PARP1 (BPS, Cat. No. 80501)

[0868] PARP2 (BPS, Cat. No. 80502)

[0869] ·Histone (Active Motif, Cat.No.81167)

[0870] ·Activited DNA (Genscript, Cat.No.L05182-01&02&03)

[0871] ·anti-rabbit IgG, HRP-linked Antibody (CST, Cat.No.7074P2)

[0872] ·anti-Poly / Mono-ADP Ribose(E6F6A)Rabbit mAb(CST, Cat.No.83732S)

[0873] ·SuperSignal ELISA Femto Substrate (THERMO PIERCE, Cat.No.37074)

[0874] ·Biotin-NAD+ (R&D, Cat.No.6573)

[0875] NAD+ (TCI, Cat. No. D0919-5G)

[0876] ·Strep-HRP (Thermo Pierce, Cat.No.21127)

[0877] QuantaRed Enhanced Chemiluminescent HRP Substrate Kit (Thermo Pierce, Cat. No. 15159)

[0878] Experimental steps:

[0879] PARP1:

[0880] 1. Preparation of Buffer

[0881] PBST: 1X PBS, 0.05% Tween-20

[0882] Blocking solution: 1X PBS, 0.05% Tween-20, 5% BSA

[0883] Reaction buffer: 50 mM Tris-HCl (pH 7.5), 0.005% Tween-20, 0.01% BSA

[0884] 2. Coating

[0885] Prepare 50 ng / mL Histone coating solution with 1xPBS, transfer 25uL of the coating solution to a 384-well reaction plate, and coat at 4°C overnight.

[0886] 3. Washing

[0887] After coating, discard the coating solution and wash with PBST solution. The method is to transfer 50uL PBST to a 384-well reaction plate, let it stand for 5 minutes, discard the washing solution, refill it, repeat the washing three times, and finally pat the reaction plate dry and wait for the next step of blocking.

[0888] 4. Closed

[0889] Transfer 50uL of blocking solution to a 384-well reaction plate and let it stand for 1 hour.

[0890] 5. Washing

[0891] After blocking, discard the blocking solution and wash the plate three times with PBST solution according to step 2. Finally, pat the reaction plate dry.

[0892] 6. Prepare 2000-fold compound in a 384-well Echo plate, transfer 50 nL of compound to the 384-well middle plate, add 20 uL of reaction buffer and mix well, then transfer 5 uL of the mixed compound to the 384-well reaction plate.

[0893] 7. Prepare a 25 / 10x PARP1-DNA solution with reaction buffer, transfer 10uL PARP1-DNA solution to a 384-well reaction plate. For the negative control well, transfer 10uL DNA solution. The final concentration of PARP1 is 0.007nM, and the final concentration of DNA is 0.8nM.

[0894] 8. Prepare a 25 / 10x NAD+ solution with reaction buffer, transfer 10uL of NAD+ solution to a 384-well reaction plate, with a final NAD+ concentration of 3.5uM, and incubate at room temperature for 60 minutes.

[0895] 9. Washing

[0896] After the reaction is completed, discard the reaction solution and wash the plate three times with PBST solution according to step 2. Finally, pat the reaction plate dry.

[0897] 10. Dilute the primary antibody (anti-Poly / Mono-ADP Ribose Rabbit mAb) 2000-fold with blocking solution, add 20uL of primary antibody, and incubate at room temperature for 1.5 hours.

[0898] 11. Washing

[0899] Discard the primary antibody, wash three times with PBST solution according to step 2, and finally pat the reaction plate dry.

[0900] 12. Dilute the secondary antibody (anti-rabbit IgG, HRP-linked Antibody) 2000 times with blocking solution, add 20uL of secondary antibody, and incubate at room temperature for 1 hour.

[0901] 13. Washing

[0902] Discard the secondary antibody, wash three times with PBST solution according to step 2, and finally pat the reaction plate dry.

[0903] 14. Color rendering

[0904] Mix Femto-ECL Substrate A and Femto-ECL Substrate B in a 1:1 ratio and transfer 25 μL to a 384-well reaction plate.

[0905] 15. Reading

[0906] Envision was used to read the chemiluminescence value (RLU).

[0907] PARP2:

[0908] 1. Preparation of Buffer

[0909] PBST: 1X PBS, 0.05% Tween-20

[0910] Blocking solution: 1X PBS, 0.05% Tween-20, 5% BSA

[0911] Reaction buffer: 50 mM HEPES (pH 7.5), 0.002% Tween-20, 0.1% BSA, 100 mM NaCl, 2 mM DTT

[0912] 2. Coating

[0913] Prepare 100 ng / mL Histone coating solution in 1xPBS, transfer 25 μL of the coating solution to a 384-well reaction plate, and coat at 4°C overnight.

[0914] 3. Washing

[0915] After coating, discard the coating solution and wash with PBST solution. The method is to transfer 50uL PBST to a 384-well reaction plate, let it stand for 5 minutes, discard the washing solution, refill it, repeat the washing three times, and finally pat the reaction plate dry and wait for the next step of blocking.

[0916] 4. Closed

[0917] Transfer 50uL of blocking solution to a 384-well reaction plate and let it stand for 1 hour.

[0918] 5. Washing

[0919] After blocking, discard the blocking solution and wash the plate three times with PBST solution according to step 2. Finally, pat the reaction plate dry.

[0920] 6. Prepare 25 / 10x PARP2 solution and transfer 10uL PARP2 solution to a 384-well reaction plate. For the negative control wells, transfer 10uL reaction buffer. The final concentration of PARP2 is 1.5nM.

[0921] 7. Prepare 2000 times the compound, transfer 50nL of the compound using echo, add 20uL of reaction buffer to the compound, mix well, and transfer 5uL of the mixed compound to a 384-well reaction plate.

[0922] 8. Prepare 25 / 10 times Biotin-NAD+ solution, transfer 10uL Biotin-NAD+ solution to a 384-well reaction plate, the final concentration of Biotin-NAD+ is 2uM, and incubate at room temperature for 60 minutes.

[0923] 9. Washing

[0924] After the reaction is completed, discard the reaction solution and wash the plate three times with PBST solution according to step 2. Finally, pat the reaction plate dry.

[0925] 10. Prepare Stre-HRP solution by diluting with blocking solution, transfer 25 μL of Stre-HRP solution to the reaction plate, and incubate at room temperature for 1 hour. The final concentration of Stre-HRP is 0.1 μg / mL.

[0926] 11. Washing

[0927] Discard the Stre-HRP solution, wash three times with PBST solution according to step 2, and finally pat the reaction plate dry.

[0928] 12. Color rendering

[0929] Mix Femto-ECL Substrate A, Femto-ECL Substrate B, and QuantaRed ADHP in a 50:50:1 ratio, transfer 25 μL to a 384-well reaction plate, incubate at room temperature for 10 minutes, and add 2.5 μL of QuantaRed Stop Solution.

[0930] 13. Reading

[0931] Fluorescence values ​​were read using Paradigm (Ex 550 / Em 620).

[0932] Results + Representative IC 50 <=50nM++ represents 50nM <IC 50 <=500nM+++ represents IC 50 >500nM

[0933] Table 1

[0934] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or variations thereof will be suggested to those skilled in the art and are intended to be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference and for all purposes.

Claims

1. A triple-bond structure compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof: in, Ring D is is a single bond or a double bond; M is -C(R 1 )=、-C(R 1 R 2 )-or-NR a -; D1 is CL D1 -R 6 , N, NR or S; D2 does not exist, CL D2 -R 7 or N, wherein when D1 is S or NR, D2 is absent; D3 is CL D3 -R 8 or N; D4 is absent, O, S, N, NR 4 or -C(R 4 R 5 ); D5 is CL D5 -R 9 or N; or D1 and D4 and the atoms to which they are attached form a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S; when When there is a double bond, any of the following conditions (1), (2), (3) and (4) apply: (1)M is -C(R 1 )=, D4 is N; R 1 For hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl; (2)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 The carbon atom to which it is attached forms Ring A is phenyl, "3-8 membered cycloalkenyl", "3-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S", or "5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; (3)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 Alkyl; or, R 4 and L D1 -R 6 Together with the carbon atom to which it is attached, it forms an optionally substituted phenyl group or a 5-6 membered aryl group containing 1-4 heteroatoms independently selected from O, N and S; (4)M is -NR a -, R 5 and R a Does not exist, R 4 For hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl; when For a single bond, either of the following conditions (5) and (6) applies: (5) D4 is NR 4 ,M is -C(R 1 )=,R 1 Does not exist, M and R 4 Forming a "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S" or "a 6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S"; the "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S" and "a 6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S" are optionally substituted by any of the following groups: C 1-6 Alkyl, Halogen, -CN, -OR, -SR, -N(R)2, -NO2, -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2 N(R)2, -N(R)C(O)R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O )OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2 or -SON(R)2; (6)M is -C(R 1 R 2 )-or-N(R a )-, D4 is absent, O, S or -C(R 4 R 5 );R 1 and R 2 are independently hydrogen, halogen, C 1-6 -C(O)N(R)2, -CN, -OR, -SR, -N(R)2, -NO2, -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R', -S(O)R', -S(O)2R', -SON(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -NRC(O)N(R)2, -NRS(O)N(R)2, -NRS(O)R', -NRS(O)2N(R)2, or -SON(R)2, or is optionally substituted by any of the following groups: C 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms independently selected from O, N and S"; or, R 1 and R 2 The carbon atom to which it is attached forms a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, a 6-10 membered saturated or partially unsaturated bicyclic carbocyclic group, a 3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms independently selected from O, N and S, a 6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms independently selected from O, N and S; or R 2 and R 4 The carbon atom to which it is attached forms Ring A' is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from O, N and S; R a For hydrogen or L R3 is a connecting key or C 1-6 alkylene; R 3 is hydrogen or any substituted C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl, 6-10 membered saturated or partially unsaturated bicyclic carbocyclyl, phenyl, "8-10 membered bicyclic aryl", "3-7 membered saturated or partially unsaturated monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from O, N and S", "6-10 membered saturated or partially unsaturated bicyclic heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S", "5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S" or "8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected from O, N and S"; R 4 and R 5 and -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R), -NRC(O)N(R), -NRS(O)N(R), -NRS(O)R', -NRS(O)N(R), or -SON(R). 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic ring, "3-7 membered saturated or partially unsaturated monoheterocyclic ring containing 1-3 heteroatoms independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic ring containing 1-4 heteroatoms independently selected from O, N and S"; or R 4 and R 5 The carbon atom connected to it forms -C=O-, -C=S-, -C=NR L -, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, a 6-10 membered saturated or partially unsaturated bicyclic carbocyclic group, a 3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S, a 6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S; or R L is hydrogen, -CN, -OR L1 or any substituted C 1-6 alkyl; R L1 For hydrogen, C 1-6 Alkyl or halogen substituted C 1-6 alkyl; Each L is independently a connecting bond, C 1-6 Alkylene or C substituted by one or more halogen 1-6 alkylene; Each R A1 are independently halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2N(R)2, -N(R)C(O)R ', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR'、-C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R' or -P(O)(R)2, or optionally substituted by any of the following groups: C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms independently selected from O, N and S"; L D1 、L D2 、L D3 and L D5 is independently a connecting bond or an optionally substituted C 1-6 alkylene; R 6 、R 7 、R 8 and R 9 are independently hydrogen, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2 N(R)2, -N(R)C(O)R', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR'、-C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R' or -P(O)(R)2, or optionally substituted by any of the following groups: C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms independently selected from O, N and S", or "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms independently selected from O, N and S"; X is a connecting bond, -C(O)-, O or NR x ; R x For hydrogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl or C 3-8 Cycloalkyl; Ring C is C 6-10 Aryl, "3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, N and S", "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S", "9-10 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S" or dihydropyridyl; R C -L C -R C1 When R C When there are multiple R C Same or different; Each L C Independently for the connecting bond, C 1-6 Alkylene or C substituted by one or more halogen 1-6 alkylene; Each R C1 are independently hydrogen, oxo, halogen, -CN, -OR, -SR, -N(R)2, -N + (R)3, -NO2, -C(O)R', -COOR, -C(O)N(R)2, -OC(O)R', -OC(O)N(R)2, -OC(O)OR, -OSO2R', -OSO2 N(R)2, -N(R)C(O)R', -N(R)SO2R', -S(O)R', -S(O)2R', -SO2N(R)2, -SO3R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R)2, -C(=NR m )NR'、-C(=NR m )N(R)2, -NRC(O)N(R)2, -NRS(O)2N(R)2, -S(O)N(R)2, -OS(O)(=R m )R', -S(O)(=R m )R', -P(O)(R)2, "a 5-12 membered heteroaryl group containing 1-3 heteroatoms independently selected from O, N and S", or the above groups are arbitrarily substituted by any of the following groups: halogen, C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms independently selected from O, N and S", "6-8 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms independently selected from O, N and S", or "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms independently selected from O, N and S"; Each R is independently hydrogen, C 1-6 Alkyl, -OC 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S" or "4-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", wherein C 1-6 Alkyl, -OC 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S" or "4-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S" any deuterated, halogen, hydroxyl, cyano, C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl and hydroxy substituted C 1-6 is substituted by one or more substituents in the alkyl group; or Two Rs and the N atom to which they are connected form a 3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S; Each R' is independently an optionally substituted or unsubstituted C 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-10 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", "5-6 membered heteroaryl containing 1-4 heteroatoms, which are independently selected from O, N and S", or "8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms, which are independently selected from O, N and S", or Two R's and the N atom to which they are connected form a "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S"; Each R m are independently -OH, -CN or R; m is 0, 1, 2, 3 or 4; p and n are independently 0, 1, 2 or 3; q is 0, 1, 2, 3, 4 or 5.

2. The triple-bond structure compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: In the triple bond structure compound shown in Formula I, Ring D is is a single bond or a double bond; M is -C(R 1 )=、-C(R 1 R 2 )-or-NR a -; D1 is CL D1 -R 6 or N; D2 is CL D2 -R 7 or N; D3 is CL D3 -R 8 or N; D4 is absent, O, S, N, NR 4 or -C(R 4 R 5 ); or D1 and D4 and the atoms to which they are attached form a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S; when When there is a double bond, any of the following conditions (1), (2), (3) and (4) apply: (1)M is -C(R 1 )=, D4 is N; R 1 For hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl; (2)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 The carbon atom to which it is attached forms Ring A is phenyl, "3-8 membered cycloalkenyl", "3-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S", or "5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; (3)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 are independently hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 Alkyl; or, R 4 and L D1 -R 6 Together with the carbon atom to which it is attached, it forms an optionally substituted phenyl group or a 5-6 membered aryl group containing 1-4 heteroatoms independently selected from O, N and S; (4)M is -NR a -, R 5 and R a Does not exist, R 4 For hydrogen, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl; when For a single bond, either of the following conditions (5) and (6) applies: (5) D4 is NR 4 ,M is -C(R 1 )=,R 1 Does not exist, M and R 4 Forming a "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S"; the "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S" is optionally substituted by any of the following groups: C 1-6 Alkyl or halogen; (6)M is -C(R 1 R 2 )-or-N(R a )-, D4 is absent, O, S or -C(R 4 R 5 ), R 1 and R 2 are independently hydrogen, halogen or C 1- 6 alkyl; or R 2 and R 4 The carbon atom to which it is attached forms Ring A' is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from O, N and S; L is a connecting bond or C 1-6 alkylene; R A1 C 1-6 Alkyl, halogen or C substituted by one or more halogens 1-6 alkyl; R a for L R3 is a connecting key or C 1-6 alkylene; R 3 is hydrogen, arbitrarily substituted C 1-6 Alkyl or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group; R 4 and R 5 are independently hydrogen; L D1 , L D2 and L D3 independently a connecting bond; R 6 、R 7 and R 8 are independently hydrogen or halogen; X is a connecting bond, -C(O)-, O or NR x ; R x For hydrogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl or C 3-8 Cycloalkyl; Ring C is C 6-10 Aryl, "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S" or dihydropyridyl; R C -L C -R C1 ; Each L C Independently for the connecting bond, C 1-6 Alkylene or C substituted by one or more halogen 1-6 alkylene; Each R C1 are independently hydrogen, oxo, halogen, -CN, -N(R)2, -OC 1-6 Alkyl, -C(O)N(R)2, C substituted by one or more halogens 1-6 Alkyl, "5-12 membered heteroaryl containing 1-3 heteroatoms, which are independently selected from O, N and S", or the above groups are optionally substituted by any of the following groups: C 1-6 alkyl; Each R is independently hydrogen, C 1-6 Alkyl, C 6-10 Aryl, -OC 1-6 Alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", "4-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", the C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-10 Aryl, 3-7 membered saturated or partially unsaturated monocyclic carbon ring, optionally substituted by deuterium, halogen, hydroxyl, cyano, C 1- 6-alkyl, cyano-substituted C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl and hydroxy substituted C 1-6 The alkyl group is substituted by one or more substituents; m is 0, 1, or 2; p and n are independently 0, 1 or 2; q is 0, 1, 2, or 3.

3. The triple-bond structure compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: In the triple bond structure compound shown in Formula I, Ring D is is a single bond or a double bond; M is -C(R 1 )=、-C(R 1 R 2 )-or-NR a -; D1 is CL D1 -R 6 or N; D2 is CL D2 -R 7 or N; D3 is CL D3 -R 8 ; D4 is absent, O, S, N, NR 4 or -C(R 4 R 5 ); or D1 and D4 and the atoms to which they are attached form a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S; when When there is a double bond, any of the following conditions (1), (2), (3) and (4) apply: (1)M is -C(R 1 )=, D4 is N; R 1 C 1-6 Alkyl or C substituted by one or more halogen 1-6 alkyl; (2)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 The carbon atom to which it is attached forms Ring A is phenyl, "3-8 membered cycloalkenyl" or "5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; m is 0, 1 or 2, L is a connecting bond or C 1-6 Alkylene, R A1 C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl or halogen; (3)M is -C(R 1 )=,R 5 Does not exist; R 1 and R 4 are independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C substituted by one or more halogen 1-6 alkyl; (4)M is -NR a -, R 5 and R a Does not exist, R 4 C 1-6 alkyl; when For a single bond, either of the following conditions (5) and (6) applies: (5) D4 is NR 4 ,M is -C(R 1 )=,R 1 Does not exist, M and R 4 Forming a "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S"; the "3-7 membered partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S" is optionally substituted by any of the following groups: C 1-6 Alkyl or halogen; (6)M is -C(R 1 R 2 )-or-N(R a )-, D4 is O or -C(R 4 R 5 );R 1 and R 2 are independently hydrogen or C 1-6 Alkyl; R a C 3-8 Cycloalkyl; R 4 and R 5 are independently hydrogen; L D1 , L D and L D3 independently a connecting bond; R 6 、R 7 and R 8 are independently hydrogen or halogen; X is a connecting bond, -C(O)-, O or NR x ; R x For hydrogen, C 1-6 Alkyl, C substituted by one or more halogen 1-6 Alkyl or C 3-8 Cycloalkyl; Ring C is C 6-10 Aryl, "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S" or dihydropyridyl; R C -L C -R C1 ; Each L C Independently for the connecting bond, C 1-6 Alkylene or C substituted by one or more halogen 1-6 alkylene; Each R C1 independently hydrogen, oxo, halogen, -CN, -N(R)2, -C(O)N(R)2, "a 5-12 membered heteroaryl group containing 1-3 heteroatoms independently selected from O, N and S", or the above groups are arbitrarily substituted by any of the following groups: C 1-6 alkyl; Each R is independently hydrogen, C 1-6 Alkyl, C 6-20 Aryl, -OC 1-6 Alkyl or 3-7 membered saturated monocyclic carbocyclic group; the C 1-6 Alkyl, C 6-20 Aryl or 3-7 membered saturated monocyclic carbocyclic group is optionally substituted with deuterium, halogen, -OC 1-6 Alkyl and C 3-8 substituted by one or more substituents in the cycloalkane; p and n are independently 0 or 1; q is 0, 1, 2, or 3.

4. The triple-bond structure compound of formula I according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: for And / or, X is a connecting bond, O, NCH3, or NH; and / or, for and / or, for 5. The triple-bond structure compound of formula I according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its crystal form, its stereoisomer, its tautomer or its isotope compound, characterized in that: The triple bond structure compound shown in Formula I is any of the following structures:

6. A compound having the following structure:

7. A pharmaceutical composition comprising a therapeutically effective dose of a triple-bond structure compound as shown in Formula I as described in any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

8. Use of a triple-bond structure compound as shown in Formula I according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof in the preparation of a PARP inhibitor drug.

9. Use of a triple-bond structure compound as shown in Formula I according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof in the preparation of a medicament for treating cancer, ischemic disease, or neurodegenerative disease.

10. The use according to claim 9, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer, colorectal cancer, gastrointestinal cancer and lung cancer.

Images