Nitrogen-containing heterocyclic compounds, pharmaceutical compositions thereof and uses thereof

Abstract

Provided are nitrogen-containing heterocyclic compounds, pharmaceutical compositions thereof, and uses thereof. The structure of the nitrogen-containing heterocyclic compounds is shown in Formula I. The nitrogen-containing heterocyclic compounds have relatively good inhibitory effects on various PI3K-mediated disease cells, and are expected to be used in the treatment and / or prevention of various PI3K-mediated diseases. [Formula 1] TIFF2025531798000308.tif45170

Description

[Technical Field]

[0001] The present invention relates to nitrogen-containing heterocyclic compounds, pharmaceutical compositions and uses thereof. (CROSS-REFERENCE TO RELATED APPLICATIONS)

[0002] This application claims priority to a Chinese application filed on September 9, 2022, with application number 202211102124.1, and a Chinese application filed on February 10, 2023, with application number 202310108466.2, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] Cancer has become a widespread and common disease that seriously threatens human health and life. The PI3K / AKt / mTOR signaling pathway is one of many mechanisms that regulate the cell cycle and apoptosis, and dysfunction of one component in the pathway can lead to tumor development. Receptor tyrosine kinases (RTKs) regulate the activation of the PI3K / AKt signaling pathway through the activation of growth factors such as insulin-like growth factors (IGFs), epidermal growth factors (EGFs), and hepatocyte growth factors (HGFs), which activate RTKs by phosphorylating tyrosine residues. Binding of PI3K to the phosphorylated tyrosine residues activates the catalytic subunit of PI3K. After activation of the catalytic subunit of type IA PI3K, p110α binds to p85α, activating PI3K, which further phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3, an important second messenger and mediator, recruits AKt from the cytoplasm to the plasma membrane through interaction with the PH domain of AKt. The translocation of AKt to the plasma membrane and the phosphorylation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) and 3-phosphoinositide-dependent protein kinase 2 (PDK2) at Thr308 and Ser473, respectively, are essential for AKt activation. Fully activated AKt regulates processes such as cell proliferation and apoptosis through its upstream and downstream regulation. Dysregulation of the PI3K signaling pathway is involved in most human cancers, and PIK3CA (encoding the PI3K catalytic subunit alpha) is one of the commonly mutated oncogenes in human tumors.As research has found, mutations in the oncogene PIK3CA are present in approximately 2-5% of human solid tumors, with mutation rates of 32%, 27%, 25%, 8% and 4% in colon cancer, glioblastoma, gastric cancer, breast cancer and lung cancer, respectively, and 11% in esophageal squamous cell carcinoma and 6% in esophageal adenocarcinoma for other gastrointestinal tumors. Summary of the Invention [Problem to be solved by the invention]

[0004] The technical problem to be solved by the present invention is that the prior art lacks effective PI3K inhibitors for clinical use. In view of this, the present invention provides nitrogen-containing heterocyclic compounds, pharmaceutical compositions thereof, and uses thereof. The inhibitors are expected to be useful in the treatment and / or prevention of PI3K-related diseases.

[0005] The present invention solves the above technical problems by the following technical solutions.

[0006] The present invention provides a nitrogen-containing heterocyclic compound represented by formula I, 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, [ka]

[0007] where Z is N or C;

[0008] E is N, C or CH;

[0009] X is CH, CR X or N,

[0010] Y is -C(O), CR Y or N,

[0011] Q is CH or N;

[0012] a is a single bond or a double bond,

[0013] when a is a single bond, Y is —C(O)— or N;

[0014] When a is a double bond, Y is CR Y or N,

[0015] R 1 -L 1 -R 1A and L 1 is a bond and R 1A is C 6-20 an aryl group, one or more R 1C C replaced by 6-20 an aryl group, or one or more R 1D and each R is a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S, and N, substituted with 1C and R 1D are each independently a halogen, C 1-6 C substituted with alkyl groups, -COOH, or one or more halogens 1-6 is an alkyl group,

[0016] R 2 -L 2 -R 2A and L 2 is a bond, -NH-, -NH-C(O)-, or -NH-C(O)CHOH-, and R 2A is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R 2C1 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, substituted with one or more R 2C2 C replaced by 6-20 an aryl group, one or more R 2C3 C containing 1 to 3 heteroatoms selected from O, S and N, substituted by 8-10 a benzoheterocycloalkenyl group, one or more R 2C4a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from O, S and N, substituted by one or more R 2C5 C replaced by 8-10 is a benzocycloalkenyl group, and R 2C1 , R 2C2 , R 2C3 , R 2C4 and R 2C5 are each independently a halogen, a hydroxyl group, or C 1-6 Alkyl group, C 3-8 Cycloalkyl group, or R 2C11 C replaced by 1-6 is an alkyl group, and R 2C11 is a halogen or hydroxy group,

[0017] R 3 -L 3 -R 3A and L 3 is a bond and R 3A is a halogen, C 1-6 an alkyl group, ═O, or one or more R 3C C replaced by 1-6 alkyl group or any two R 3 and the carbon atom to which it is bonded, C 3-8 Cycloalkane or C 6-20 forming aromatic hydrocarbons,

[0018] R 3C are independently deuterium, halogen, or -NR 3C1 R 3C2 and

[0019] R 3C1 and R 3C2 are each independently hydrogen or C 1-6 is an alkyl group,

[0020] R Y and R x are each independently -L Y -R YA and L Yis a bond, -NH- or -NH-C(O)-, and R YA is hydrogen, halogen, cyano group, -N3, hydroxy group, -NH2, -C 2-6 Alkynyl group, formula 2 below: -B(OH)2, C 1-6 alkyl group, one or more R YA1 C replaced by 1-6 Alkyl group, -OC 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R YA2 a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA3 a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA4 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COR YA5 , the following formula 3, the following formula 4 or the following formula 5, [ka] [ka] [ka] [ka]

[0021] R YA1 , R YA2 , R YA3 , R YA4 and R YA5 are each independently a halogen, a hydroxy group, a cyano group, -NH2, C 1-6Alkyl group, -OC 1-6 alkyl groups, 4-10 membered heterocycloalkyl groups containing 1-4 heteroatoms selected from O, S and N, -NH2, C 3-8 Cycloalkyl groups, C 6-20 Aryl group, or R YA11 C replaced by 1-6 is an alkyl group, and R YA11 is a halogen or a phenyl group,

[0022] Ring A is C 6-10 an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S; a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; or C 8-10 is a benzoheterocycloolefin,

[0023] n is 0, 1, 2, 3 or 4.

[0024] In one alternative, in the nitrogen-containing heterocyclic compound of formula I, 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, some groups are defined as below, and definitions of groups not mentioned are as described in any of the alternatives above (the content of this paragraph is hereinafter referred to as "in one alternative").

[0025] In one embodiment, the nitrogen-containing heterocyclic compound represented by formula I, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof, wherein the nitrogen-containing heterocyclic compound represented by formula I has a structure represented by formula II, [ka]

[0026] where E is N or C,

[0027] X is N or CH;

[0028] R 1 -L 1 -R 1A and L 1 is a bond and R 1A is C 6-20 an aryl group, one or more R 1C C replaced by 6-20 an aryl group, or one or more R 1D and each R is a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S, and N, substituted with 1C and R 1D are each independently a halogen, C 1-6 C substituted with alkyl groups, -COOH, or one or more halogens 1-6 is an alkyl group,

[0029] R 2 -L 2 -R 2A and L 2 is a bond, -NH-, -NH-C(O)-, or -NH-C(O)CHOH-, and R 2A is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R 2C1 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, substituted with one or more R 2C2 C replaced by 6-20 an aryl group, one or more R 2C3 C containing 1 to 3 heteroatoms selected from O, S and N, substituted by 8-10 a benzoheterocycloalkenyl group, one or more R 2C4 a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from O, S and N, substituted by one or more R 2C5 C replaced by 8-10 is a benzocycloalkenyl group, and R 2C1 , R 2C2 , R 2C3 , R 2C4 and R2C5 are each independently a halogen, a hydroxyl group, or C 1-6 Alkyl group, C 3-8 Cycloalkyl group, or R 2C11 C replaced by 1-6 is an alkyl group, and R 2C11 is a halogen or hydroxy group,

[0030] R 3 -L 3 -R 3A and L 3 is a bond and R 3A is a halogen, C 1-6 an alkyl group, ═O, or one or more R 3C C replaced by 1-6 alkyl group or any two R 3 and the carbon atom to which it is bonded, C 3-8 Cycloalkane or C 6-20 forming aromatic hydrocarbons,

[0031] R 3C are independently deuterium, halogen, or -NR 3C1 R 3C2 and

[0032] R 3C1 and R 3C2 are each independently hydrogen or C 1-6 is an alkyl group,

[0033] R Y -L Y -R YA and L Y is a bond, -NH- or -NH-C(O)-, and R YA is hydrogen, halogen, cyano group, -N3, hydroxy group, -NH2, -C 2-6 Alkynyl group, represented by the following formula -B(OH)2, C 1-6 alkyl group, one or more R YA1 C replaced by 1-6 Alkyl group, -OC 1-6 Alkyl group, C 3-8a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R YA2 a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA3 a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA4 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COR YA5 , the following formula 8, the following formula 9 or the following formula 10, [ka] [ka] [ka] [ka]

[0034] R YA1 , R YA2 , R YA3 , R YA4 and R YA5 are each independently a halogen, a hydroxy group, a cyano group, -NH2, C 1-6 Alkyl group, -OC 1-6 alkyl groups, 4-10 membered heterocycloalkyl groups containing 1-4 heteroatoms selected from O, S and N, -NH2, C 3-8 Cycloalkyl groups, C 6-20 Aryl group, or R YA11 C replaced by 1-6 is an alkyl group, and R YA11 is a halogen or a phenyl group,

[0035] Ring A is C 6-10 an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S; a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; or C 8-10 is a benzoheterocycloolefin,

[0036] n is 0, 1 or 2.

[0037] In one scheme, the nitrogen-containing heterocyclic compound represented by formula II, its pharmaceutically acceptable salt, its solvate, its solvate of a pharmaceutically acceptable salt, its crystalline form, its stereoisomer, its tautomer, or its isotopic compound, wherein the nitrogen-containing heterocyclic compound represented by formula II is defined in scheme 1, scheme 2, scheme 3, or scheme 4,

[0038] Plan 1:

[0039] E is N or C,

[0040] X is CH;

[0041] R 1 -L 1 -R 1A and L 1 is a bond and R 1A is C 6-20 an aryl group, one or more R 1C C replaced by 6-20 an aryl group, or one or more R 1D and each R is a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S, and N, substituted with 1C and R 1D are each independently a halogen, C 1-6 C substituted with alkyl groups, -COOH, or one or more halogens 1-6 is an alkyl group,

[0042] R 2 -L 2-R 2A and L 2 is a bond, -NH- or -NH-C(O)-, and R 2A is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R 2C1 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, substituted with one or more R 2C2 C replaced by 6-20 an aryl group, or one or more R 2C3 C containing 1 to 3 heteroatoms selected from O, S and N, substituted by 8-10 is a benzoheterocycloalkenyl group, R 2C1 , R 2C2 and R 2C3 are each independently a halogen, a hydroxy group, or R 2C11 C replaced by 1-6 is an alkyl group, and R 2C11 is a halogen,

[0043] R 3 -L 3 -R 3A and L 3 is a bond and R 3A is C 1-6 an alkyl group or one or more R 3C C replaced by 1-6 is an alkyl group,

[0044] R 3C are independently deuterium, halogen, or -NR 3C1 R 3C2 and

[0045] R 3C1 and R 3C2 are each independently C 1-6 is an alkyl group,

[0046] R Y -L Y -R YA and L Yis a bond, -NH- or -NH-C(O)-, and R YA is hydrogen, halogen, cyano group, -N3, hydroxy group, -NH2, -C 2-6 Alkynyl group, the following formula: -B(OH)2, C 1-6 alkyl group, one or more R YA1 C replaced by 1-6 Alkyl group, -OC 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R YA2 a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA3 a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA4 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COR YA5 Or the following formula 12: [ka] [ka]

[0047] R YA1 , R YA2 , R YA3 , R YA4 and R YA5 are each independently a halogen, a hydroxy group, a cyano group, or C 1-6 Alkyl group, -OC 1-6 alkyl groups, 4-10 membered heterocycloalkyl groups containing 1-4 heteroatoms selected from O, S and N, -NH2, C 3-8 Cycloalkyl groups, C 6-20 Aryl group, or RYA11 C replaced by 1-6 is an alkyl group, and R YA11 is a halogen or a phenyl group,

[0048] Ring A is C 6-10 an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S, or a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S;

[0049] n is 0, 1 or 2;

[0050] Plan 2:

[0051] E is N, CH or C;

[0052] X is N or CH;

[0053] R 1 -L 1 -R 1A and L 1 is a bond and R 1A is C 6-20 an aryl group, one or more R 1C C replaced by 6-20 is an aryl group, and R 1C is a halogen, C 1-6 C substituted with alkyl or halogen 1-6 is an alkyl group,

[0054] R 2 -L 2 -R 2A and L 2 is a bond, -NH-, -NH-C(O)-, or -NH-C(O)CHOH-, and R 2A is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R 2C1 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, substituted with one or more R2C2 C replaced by 6-20 an aryl group, one or more R 2C3 C containing 1 to 3 heteroatoms selected from O, S and N, substituted by 8-10 a benzoheterocycloalkenyl group, or one or more R 2C4 and R is a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from O, S and N, substituted by 2C1 , R 2C2 , R 2C3 and R 2C4 are each independently a halogen, a hydroxyl group, or C 1-6 Alkyl group, C 3-8 Cycloalkyl group, or R 2C11 C replaced by 1-6 is an alkyl group, and R 2C11 is a halogen or hydroxy group,

[0055] R 3 -L 3 -R 3A and L 3 is a bond and R 3A is halogen or =O, or any two R 3 and the carbon atom to which it is bonded, C 3-8 Cycloalkane or C 6-20 forming aromatic hydrocarbons,

[0056] R Y -L Y -R YA and L Y is a bond, -NH- or -NH-C(O)-, and R YA is hydrogen, halogen, cyano group, -N3, hydroxy group, -NH2, the following formula 13, the following formula 14, -B(OH)2, -COOH, C 1-6 alkyl group, one or more R YA1 C replaced by 1-6 Alkyl group, -OC 1-6 Alkyl group, C 3-8a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R YA2 a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA3 a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA4 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COOR YA5 , the following formula 15, the following formula 16 or the following formula 17, [ka] [ka] [ka] [ka] [ka]

[0057] R YA1 , R YA2 , R YA3 , R YA4 and R YA5 are each independently a halogen, a hydroxy group, a cyano group, or C 1-6 alkyl groups, 4-10 membered heterocycloalkyl groups containing 1-4 heteroatoms selected from O, S and N, -NH2, C 3-8 Cycloalkyl groups, C 6-20 Aryl group, or R YA11 C replaced by 1-6 is an alkyl group, and R YA11is a halogen or a phenyl group,

[0058] Ring A is C 6-10 an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S; a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; or C 8-10 is a benzoheterocycloolefin,

[0059] n is 0, 1 or 2;

[0060] Plan 3:

[0061] E is N or C,

[0062] X is CH;

[0063] R 1 -L 1 -R 1A and L 1 is a bond and R 1A is C 6-20 an aryl group, one or more R 1C C replaced by 6-20 is an aryl group, and R 1C is a halogen or C 1-6 is an alkyl group,

[0064] R 2 -L 2 -R 2A and L 2 is a bond, -NH- or -NH-C(O)-, and R 2A is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R 2C1 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, substituted with one or more R 2C2 C replaced by 6-20 an aryl group, one or more R 2C3C containing 1 to 3 heteroatoms selected from O, S and N, substituted by 8-10 is a benzoheterocycloalkenyl group, R 2C1 , R 2C2 and R 2C3 are each independently a halogen, a hydroxy group, or R 2C11 C replaced by 1-6 is an alkyl group, and R 2C11 is a halogen,

[0065] n is 0,

[0066] R Y -L Y -R YA and L Y is a bond, -NH- or -NH-C(O)-, and R YA is hydrogen, halogen, cyano group, -N3, hydroxy group, the following formula 18, the following formula 19, -B(OH)2, -COOH, C 1-6 alkyl group, one or more R YA1 C replaced by 1-6 Alkyl group, -OC 1-6 Alkyl group, C 3-8 a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R YA2 a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA3 a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R YA4 an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COOR YA5 Or the following formula 20: [ka] [ka] [ka]

[0067] R YA1 , R YA2 , R YA3 , R YA4 and R YA5 are each independently a halogen, a hydroxy group, a cyano group, or C 1-6 alkyl groups, 4-10 membered heterocycloalkyl groups containing 1-4 heteroatoms selected from O, S and N, -NH2, C 3-8 Cycloalkyl groups, C 6-20 Aryl group, or R YA11 C replaced by 1-6 is an alkyl group, and R YA11 is a halogen or a phenyl group,

[0068] Ring A is C 6-10 an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S, or a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S;

[0069] Plan 4:

[0070] E is N, CH or C;

[0071] X is N or CH;

[0072] L 1 , L 3 and L X are both bonds,

[0073] R 1A is r 1 R 1C R replaced by 1D and R 1C is a halogen, C 1-6C substituted with alkyl or halogen 1-6 is an alkyl group, and R 1D is C 6-20 is an aryl group,

[0074] L 2 is a bond, —NH—C(O)— or —NH—,

[0075] R 2A is r 2 R 2C R replaced by 2D and R 2C is a halogen, a hydroxy group, or a C substituted with one or more halogens 1-6 is an alkyl group, and R 2D is C 6-20 an aryl group, a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, N, and S, or C 8-10 is a benzocycloalkenyl group,

[0076] R 3A is R 3B , or r 3 R 3C R replaced by 3D and R 3B is a halogen and R 3C is a halogen or hydroxy group, and R 3D is C 1-6 is an alkyl group,

[0077] L Y is a bond, and C 1-6 alkylene, -NH- or -O-;

[0078] R YA is R YB , or r 5 R YC R replaced by YD and

[0079] R YBis hydrogen, halogen, cyano group, -N3, -OR, -B(OR)2, -C(O)OR, -C(O)NR2 or -C(O)R,

[0080] R YC is a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S, and N; C 3-8 Cycloalkyl group, halogen, -NR2, C 1-6 C substituted with alkyl groups or one or more halogens 1-6 is an alkyl group,

[0081] R YD represents a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N; an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; -OC 1-6 Alkyl group, C 1-6 an alkyl group, a 3- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S, and N, or C 3-8 is a cycloalkyl group,

[0082] Each R is independently hydrogen, C 1-6 Alkyl groups, optionally substituted C 1-6 alkyl groups, where the substitution in "optionally substituted" means substituted with one or more of halogen;

[0083] Ring A is a benzene ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms selected from O, N, and S, or a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S;

[0084] r 1 , r 2 , r 3 , r 4 , r 5 and R 6 are each independently 0, 1, 2, or 3;

[0085] n is 0, 1 or 2.

[0086] In one version, X is N or CH.

[0087] In one proposal, R 1 , R 1C , R 1D , R 2C1 , R 2C2 , R 2C3 , R 2C4 , R 2C5 , R 2C11 , R 3A , R 3C , R YA , R YA1 , R YA2 , R YA3 , R YA4 , R YA5 and R YA11 When a halogen is mentioned in the definition of , said halogen is fluorine, chlorine, bromine or iodine.

[0088] In one proposal, R 2C1 , R 2C2 , R 2C3 , R 2C4 , R 2C5 , R YA , R YA1 , R YA2 , R YA3 , R YA4 and R YA5 In the definition of C 3-8 When a cycloalkyl group is mentioned, the C 3-8 A cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, for example cyclopropyl.

[0089] In one proposal, R 1C , R 1D , R 2C1 , R 2C2 , R 2C3 , R 2C4 , R 2C5 , R 3A , R 3C1 , R 3C2 , R YA , RYA1 , R YA2 , R YA3 , R YA4 and R YA5 In the definition of C 1-6 Alkyl group or -OC 1-6 When an alkyl group is mentioned, the C 1-6 The alkyl group is C 1-4 It is an alkyl group, and furthermore is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, or a t-butyl group.

[0090] In one proposal, R 1A , R 2A , R YA1 , R YA2 , R YA3 , R YA4 and R YA5 In the definition of C 6-20 When an aryl group is mentioned, the C 6-20 The aryl group is a phenyl group or a naphthyl group.

[0091] In one proposal, R 2A and R YA are each independently a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, the "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N" is a "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O and N", and examples thereof include a 1H-tetrazolyl group (the following formula 21), a pyrazole group (the following formula 22, the following formula 23, the following formula 24), a pyridyl group (the following formula 25), and an oxazole group (the following formula 26). [ka] [ka] [ka] [ka] [ka] [ka]

[0092] In one proposal, R 2A and R YA are each independently an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, the "8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N" is a [1,2,4]-triazolo[1,5-a]pyridyl group (formula 27 below), an indazolyl group (formula 28 below), an indolyl group, an isoquinoline group, a benzothienyl group, or a benzimidazole group (formula 29 below). [ka] [ka] [ka]

[0093] In one version, a is a double bond and Y is CR Y , E is N, C or CH.

[0094] In one version, X is N or CH.

[0095] In one version, Z is C.

[0096] In one version, E is N or C.

[0097] In one proposal, R 1A is one or more R 1D When R is a "5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S, and N" substituted with 1Ais one or more R 1D and "a 5- to 6-membered heteroaryl group containing 1 to 2 independently selected heteroatoms N" substituted with, for example, one or more R 1D Examples of the pyridyl group include a pyridyl group substituted by:

[0098] In one proposal, R 2A is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R 2C1 and containing 1 to 3 heteroatoms selected from O, S and N" is a 9- to 10-membered bicyclic heteroaryl group containing 1 to 2 N heteroatoms, and examples thereof include a benzothienyl group, an indolyl group, a quinolyl group, an isoquinoline group, a benzimidazole group, and a benzothiazolyl group.

[0099] In one proposal, R 2A is one or more R 2C3 "C containing 1 to 3 heteroatoms selected from O, S and N" substituted by 8-10 When the "benzoheterocycloalkenyl group" is a "benzoheterocycloalkenyl group", the "C 8-10 The "benzoheterocycloalkenyl group" is an 8- to 10-membered benzoheterocycloalkenyl group containing 1 or 2 N, and is preferably an indolinyl group, and examples thereof include those represented by the following formula: [ka]

[0100] In one proposal, R 2A is one or more "R 2C4 and a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with 2C4The "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N, substituted by" means a "5- to 6-membered heteroaryl group containing 1 or 2 N", and examples thereof include a pyridyl group.

[0101] In one proposal, R 2A is one or more R 2C5 C replaced by 8-10 When it is a benzocycloalkenyl group, 8-10 The benzocycloalkenyl group is C 9-10 Benzocycloalkenyl groups include, for example, indanyl groups.

[0102] In one proposal, L Y is -NH-C(O)-, the C-terminus is R YA and combine.

[0103] In one proposal, R YA means "a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N"; one or more R YA2 In the case where the "4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S and N" is substituted by, the "4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S and N" is a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from O and N, and examples thereof include an oxetanyl group, an azetidinyl group, a pyranyl group, and a morpholinyl group.

[0104] In one proposal, R YA means "a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N"; one or more R YA3In the case where the "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" is substituted by, the "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" is a "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O and N", and examples thereof include a pyridyl group, a pyrimidinyl group, a pyrazole group, a tetrazolyl group, a triazolyl group, a pyrrolyl group, an imidazolyl group, and an oxazolyl group.

[0105] In one proposal, R YA represents "an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N," and one or more R YA4 and containing 1 to 3 heteroatoms selected from O, S, and N" is a "9 to 10-membered bicyclic heteroaryl group containing 1 to 3 N heteroatoms," and examples thereof include an indazolyl group, an imidazo[1,2-a]pyridyl group, a 3H-imidazo[4,5-b]pyridyl group, an imidazo[1,2-a]pyridyl group, a 5H-pyrrolo[3,2-D]pyrimidinyl group, a 7-azaindolyl group, and a [1,2,4]triazolo[1,5-a]pyridyl group.

[0106] R YA1 , R YA2 , R YA3 , R YA4 and R YA5 are each independently R YA11 C replaced by 1-6 is an alkyl group, and R YA11 is halogen, YA11 C replaced by 1-6 The alkyl group is a C substituted with halogen. 1-2 It is an alkyl group, and examples thereof include a trifluoromethyl group and a difluoromethyl group.

[0107] In some embodiments, R 1is one of the following formulas: [ka]

[0108] In some embodiments, R 2 is one selected from the following formulas: [ka]

[0109] For example, it is any one selected from the following formulas: [ka]

[0110] For example, the following formula: [ka]

[0111] In one proposal, R Y is any one selected from hydrogen, -CN, -N3, -F, Br, -OH, -NH2, -B(OH)2, -COOH, -CONH2, -COOMe, -CH3, -OCH3, and the following formulas 35 to 36. [ka] [ka]

[0112] In one proposal, R 3 is F, -Me, -Et, -CD3, the following formula 37, the following formula 38, the following formula 39 or =O, or two R 3 and the carbon atom to which it is attached form a cyclopropane or benzene ring. [ka] [ka] [ka]

[0113] In one version, n is 0, 1, or 2.

[0114] In one version, Q is CH.

[0115] In one version, X is CH and Y is CR Y is.

[0116] In one example, the following formula is any one selected from formulas: [ka] [ka]

[0117] For example, it is any one selected from the following formulas: [ka]

[0118] Each group in the formula is defined as above.

[0119] In one example, the following formula 43 is any one selected from formula 44: [ka] [ka]

[0120] For example, it is any one selected from the following formulas: [ka]

[0121] In one example, the following formula 46 is any one selected from formula 47: [ka] [ka]

[0122] Each group in the formula is defined as above.

[0123] In one example, the following formula is any one selected from formulas: [ka] [ka]

[0124] Each group in the formula is defined as above.

[0125] In one example, in the nitrogen-containing heterocyclic compound represented by formula I, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof, the nitrogen-containing heterocyclic compound represented by formula I has any one structure selected from the following formulas 50 to 59. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0126] In one embodiment, in the nitrogen-containing heterocyclic compound represented by formula I, 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, the nitrogen-containing heterocyclic compound represented by formula I is any one of the following compounds:

[0127] The compound of the following formula (60), which had a retention time of 5.153 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0128] The compound of the following formula (61), which had a retention time of 5.581 minutes, was obtained under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0129] The compound of the following formula (62), which had a retention time of 4.512 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0130] The compound of the following formula (63), which had a retention time of 5.408 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0131] The compound of the following formula (64), which had a retention time of 4.561 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 60 / 40, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0132] The compound of the following formula (65), which had a retention time of 5.012 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 60 / 40, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0133] The compound of the following formula (66), which had a retention time of 4.561 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0134] The compound of the following formula (67), which had a retention time of 5.561 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0135] The compound of the following formula (68) had a retention time of 0.707 minutes under the following conditions: Instrument: SFC-150 (Waters), Chromatography column: OJ-H 4.6 × 100 mm 5 μm, Column temperature: 40°C, Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)], Flow rate: 3.0 mL / min, Back pressure: 2000 psi, Measurement wavelength: 214 nm. [ka]

[0136] The compound of the following formula (69) had a retention time of 1.449 minutes under the following conditions: Instrument: SFC-150 (Waters), Chromatography column: OJ-H 4.6 × 100 mm 5 μm, Column temperature: 40°C, Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)], Flow rate: 3.0 mL / min, Back pressure: 2000 psi, Measurement wavelength: 214 nm. [ka]

[0137] The compound of the following formula (70) had a retention time of 3.245 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: OD 20 × 250 mm, 10 μm (Daicel), column temperature: 35°C, mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 65 / 35, flow rate: 100.0 mL / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0138] The compound of the following formula (71), which had a retention time of 3.456 minutes, was obtained under the following conditions: instrument: SFC-150 (Waters), chromatography column: OD 20 × 250 mm, 10 μm (Daicel), column temperature: 35°C, mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 65 / 35, flow rate: 100.0 mL / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0139] The compound of the following formula (72), which had a retention time of 0.56 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0140] The compound of the following formula (73) had a retention time of 1.21 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0141] The compound of the following formula (74) had a retention time of 0.38 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0142] The compound of the following formula (75), which had a retention time of 0.8 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0143] The compound of the following formula (76) had a retention time of 1.74 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0144] The compound of the following formula 77, which had a retention time of 3.45 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0145] The compound of the following formula (78) had a retention time of 1.08 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35°C, mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0146] The compound of the following formula 79, which had a retention time of 2.32 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0147] The compound of the following formula (80) had a retention time of 0.38 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0148] The compound of the following formula 81, which had a retention time of 0.84 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0149] The compound of the following formula 82, which had a retention time of 2.32 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO / MeOH [0.2% NH (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm [ka]

[0150] The compound of the following formula 83 had a retention time of 3.38 minutes under the following conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), column temperature: 35°C, mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm. [ka]

[0151] In one example, in the nitrogen-containing heterocyclic compound represented by formula I, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof, the nitrogen-containing heterocyclic compound represented by formula I is any one compound selected from the following formulas 84 to 85. [ka] [ka]

[0152] The present invention further provides a pharmaceutical composition, comprising a substance A and a pharmaceutical adjuvant, wherein the substance A is a therapeutically effective amount of a nitrogen-containing heterocyclic compound represented by the above formula I, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

[0153] The present invention further provides the use of Substance A in the preparation of a PI3K inhibitor, wherein Substance A is a nitrogen-containing heterocyclic compound represented by the above formula I, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

[0154] The present invention further provides the use of substance A in the preparation of a medicament for treating or preventing a PI3K-mediated disease, wherein substance A is a nitrogen-containing heterocyclic compound represented by formula I above, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

[0155] The term "plurality" means two, three, four or five.

[0156] The term "pharmacologically acceptable salt" refers to a salt prepared with a compound of the present invention and a relatively non-toxic, pharmacologically acceptable acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmacologically acceptable base in a solution or in a suitable inert solvent. Pharmacologically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts, and the like. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmacologically acceptable acid in a solution or in a suitable inert solvent. The pharmacologically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmacologically acceptable acid includes organic acids, including, but not limited to, acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, (E)-2-butenedioic acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylenebis(3-hydroxy-2-naphthoic acid)), amino acids (such as glutamic acid and arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base or acid addition salts.In particular, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0157] The term "tautomer" refers to functional isomers resulting from the rapid migration of atoms in a molecule between two positions. For example, acetone and 1-propen-2-ol can be interconverted by the rapid migration of a hydrogen atom on the oxygen and α-carbon.

[0158] The term "isotopic compound" refers to a compound in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Illustrative examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., H, C, C, N, O, O, F, S, and Cl). Isotopic compounds of the present invention can generally be prepared by substituting isotopic-labeled reagents for non-isotopic-labeled reagents according to the methods described herein.

[0159] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0160] The term "C" 3-8 "Cycloalkyl group" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0161] The term "C" 1-6 The "alkyl group" is preferably a C 1-4It is an alkyl group, and furthermore is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, or a t-butyl group.

[0162] The term "C substituted by one or more halogens" 1-6 The alkyl group is defined as "C substituted with one or more halogens." 1-2 The term "alkyl group" refers to an "alkyl group," and includes, for example, a trifluoromethyl group or a difluoromethyl group.

[0163] The term "alkyl group" refers to a straight or branched chain alkyl group containing the specified number of carbon atoms. Illustrative alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0164] The terms "cycloalkyl group" and "carbocycle" refer to a saturated cyclic group consisting solely of carbon atoms having a specified number of carbon atoms (e.g., C3-C6), and may be monocyclic, bridged, or spirocyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0165] The term "aryl group" refers to an aromatic group of carbon atoms in which each ring has its own aromatic character, such as a phenyl group or a naphthyl group.

[0166] The term "heteroaryl group" refers to a cyclic group having a specified number of ring atoms (e.g., 5-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which may be monocyclic or polycyclic, and in which at least one ring is aromatic (satisfies Hückel's rule). Heteroaryl groups are connected to other fragments within the molecule by either an aromatic or non-aromatic ring. Heteroaryl groups include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazole, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0167] The terms "heterocyclo group," "heterocyclo," or "heterocycloalkyl group" refer to a cyclic group having a specified number of ring atoms (e.g., 3-8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which may be monocyclic, bridged, or spirocyclic, and each ring may be saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidinyl, and the like.

[0168] The term "hydroxy" refers to one -OH group.

[0169] The term "cyano" refers to a -CN group.

[0170] The term "oxo" refers to one =O group.

[0171] Unless contrary to common knowledge in the art, the above-mentioned preferable conditions can be arbitrarily combined to obtain a preferable embodiment of the present invention.

[0172] All reagents and raw materials used in the present invention are commercially available.

[0173] The present invention has the following beneficial effects: The present invention provides nitrogen-containing heterocyclic compounds, pharmaceutical compositions thereof, and uses thereof. The nitrogen-containing heterocyclic compounds have relatively good inhibitory effects on various PI3K-mediated disease cells, and are expected to be used in the treatment and / or prevention of various PI3K-mediated diseases. DETAILED DESCRIPTION OF THE INVENTION

[0174] The present invention will be further described below using examples, but the present invention is not limited to the scope of the examples described. In the following examples, experimental methods for which specific conditions are not specified can be selected according to conventional methods and conditions or product instructions.

[0175] In the present invention, room temperature refers to ambient temperature, which is 10° C. to 35° C., and overnight refers to 8 to 15 hours. Reflux refers to the solvent reflux temperature at normal pressure.

[0176] DMF: N,N-dimethylformamide

[0177] Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium

[0178] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium

[0179] Pd(dppf)Cl2:1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0180] EDTA: Ethylenediaminetetraacetic acid

[0181] HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0182] DIEA: N,N-diisopropylethylamine

[0183] S-Phos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0184] LDA: lithium diisopropylamide

[0185] PPA: Polyphosphoric acid

[0186] Eaton's Reagent: Phosphorus Pentoxide, Methanesulfonic Acid

[0187] Example 1: Synthetic route to compound YL001 [ka]

[0188] Synthesis of compound 2

[0189] 6-Bromoindoline (CAS: 63839-24-7) (compound 1, 500 mg, 2.52 mmol) was added to a reaction vial and dissolved in 3 mL of acetic acid. The vial was then placed in an ice bath. Potassium cyanate (410 mg, 5.05 mmol) was added and the reaction was continued for 1 hour with stirring in the ice bath. After the reaction was completed, the reaction product was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 55%-65%) to obtain compound 2 (460 mg, 1.908 mmol, 99.01%, yield: 75.6%) as a white solid. LC-MS (ESI): m / z 241.0 / 243.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 7.99(d,J=1.9Hz,1H),7.10-7.05(m,1H),6.98(dd,J=7.9,1.9Hz,1H),6.42(s,2H),3.88(dd,J=9.3,8.3Hz,2H),3.05(td,J=8.7,8.3,1.2Hz,2H).

[0190] Synthesis of compound 3

[0191] To a reaction vial was added compound 2 (420 mg, 1.7 mmol), 2-chloro-5-fluorobenzaldehyde (compound 1A, 668 mg, 4.2 mmol), and polyphosphoric acid (5 mL). o C~105 o The mixture was stirred at RT for 34 min. The reaction mixture was poured into cold saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The crude product was purified using an automated column (Biotage) (mobile phase: petroleum ether / ethyl acetate = 50 / 50 to 28 / 72) to obtain target compound 3 (0.4 g) as a pale yellow solid. LC-MS (ESI): m / z 381.1 (M+H) + .

[0192] Synthesis of compound 4

[0193] Compound 3 (172 mg, 0.45 mmol), sodium azide (62 mg, 0.95 mmol), copper(I) iodide (9 mg, 0.05 mmol), sodium ascorbate (5 mg, 0.03 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (11 mg, 0.08 mmol), ethanol (3 mL), and water (1.3 mL) were added to a reaction vial. The mixture was stirred at 90°C overnight. The mixture was cooled to room temperature and 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 aqueous sodium chloride solution and concentrated under reduced pressure to 10 mL. The crude product was used directly in the next reaction step. LC-MS (ESI): m / z 344.1 (M+H). + .

[0194] Synthesis of compound 5

[0195] Compound 4 (crude, 9 mL ethyl acetate solution) and platinum(IV) oxide (102 mg, 0.45 mmol) were added to a reaction vial, degassed, and purged with hydrogen gas three times. The mixture was stirred overnight at room temperature. The filtrate was suction filtered, concentrated under reduced pressure, and the crude product was purified using an automated column (Biotage) (mobile phase: petroleum ether / ethyl acetate = 35 / 65 to 20 / 80) to obtain the target compound 5 (25 mg) as a pale yellow solid. LC-MS (ESI): m / z 318.1 (M+H). + .

[0196] Synthesis of compound YL001

[0197] Compound 5 (15 mg, 0.05 mmol), pyridine (8 mg, 0.1 mmol), 3-fluoro-5-(trifluoromethyl)benzoyl chloride (12 mg, 0.05 mmol), and acetonitrile (1 mL) were added to a reaction vial. The mixture was stirred at room temperature under nitrogen gas protection for 1 hour. After the reaction was completed, saturated brine solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure to obtain the crude product. The crude product was purified using an automated column (Biotage) (mobile phase: petroleum ether / ethyl acetate = 30 / 70 to 20 / 80) to obtain the target compound YL001 (3.5 mg, 11%) as a pale yellow solid.

[0198] Spectral data of compound YL001: LC-MS (ESI): m / z 508.1 (M+H) + ; 1H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),7.93(d,J=8.5Hz,1H),7.90-7.81(m,2H),7.43(d,J=2.6Hz ,1H),7.32(dd,J=8.9,5.2Hz,1H),7.20(d,J=7.8Hz,1H),7.09(ddd,J=8. 8,8.0,3.1Hz,1H),6.83(dd,J=9.3,3.1Hz,1H),6.72(d,J=7.8Hz,1H),6. 13-6.06(m,1H),3.99(dtd,J=23.4,10.3,7.3Hz,2H),3.23-3.17(m,2H).

[0199] Example 2: Synthetic route to compound YL002 [ka]

[0200] Synthesis of compound 7

[0201] 1-Benzothiophene-3-carboxylic acid (compound 6, 2 g, 11.2 mmol), ammonium chloride (774 mg, 14.6 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.4 g, 16.8 mmol), N,N-diisopropylethylamine (6 mL, 33.3 mmol), and anhydrous N,N-dimethylformamide (8 mL) were added to a reaction vial. The mixture was stirred at room temperature under nitrogen gas protection for 1 h. 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 aqueous sodium chloride and concentrated under reduced pressure. The crude product was purified by automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate = 40 / 60 to 20 / 80) to obtain the target compound 7 (1.26 g) as a pale yellow solid. LC-MS(ESI):m / z 178.1(M+H) + .

[0202] Synthesis of compound 8

[0203] To a reaction vial was added compound 2 (410 mg, 1.7 mmol), 2-methylbenzaldehyde (492 mg, 4.1 mmol), and polyphosphoric acid (6 mL). o C~105 o The mixture was stirred at RT for 0.5 h. The mixture was cooled to room temperature and 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 aqueous sodium chloride solution and concentrated under reduced pressure. The crude product was purified by automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate = 50 / 50 to 30 / 70) to obtain target compound 8 (180 mg) as a pale yellow solid. LC-MS (ESI): m / z 343.1 (M+H) + .

[0204] Synthesis of compound YL002

[0205] Compound 8 (100 mg, 0.29 mmol), compound 7 (106 mg, 0.60 mmol), copper(I) iodide (30 mg, 0.16 mmol), N,N'-dimethylethylenediamine (26 mg, 0.30 mmol), potassium phosphate tribasic (190 mg, 0.9 mmol), potassium iodide (26 mg, 0.16 mmol), and N,N-dimethylformamide (1 mL) were added to a reaction vial. The mixture was subjected to a microwave reaction at 150 °C for 9 hours under nitrogen gas protection. After the reaction was completed, the reaction was quenched by adding saturated brine solution. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using an automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate = 10 / 90 to 0 / 100) to obtain compound YL002 (36.6 mg, 17%) as a pale yellow solid. 5.6 mg of compound YL002 was used for activity testing, and the remainder was used for other reactions.

[0206] Spectral data of compound YL002: LC-MS (ESI): m / z 440.1 (M+H) + . 1H NMR (400MHz, DMSO-d6)δ 9.77(s,1H),8.24-8.16(m,1H),8.14-7.95(m,2H),7.45-7.36(m,2H),7.32(d,J=2.8Hz,1H),7.17(d,J=7.8Hz,1H),7.08-6.96(m,3H), 6.91(dd,J=7.4,1.7Hz,1H),6.77(d,J=7.8Hz,1H),6.07(d,J=2.7Hz,1H),4.06-3.89(m,2H),3.22(dd,J=10.0,7.3Hz,2H),2.17(s,3H).

[0207] Example 3: Synthesis of Compound YL003 [ka]

[0208] Synthesis of compound 10

[0209] 7-Bromo-1,2,3,4-tetrahydroquinoline (compound 9, 2 g, 53.277 mmol) was dissolved in acetic acid (15 mL), degassed, and purged with N2. Potassium cyanate (1.53 g, 18.86 mmol) was added at 0 °C and the mixture was allowed to react at 5 °C for 1 h. The reaction mixture was rotary evaporated and the pH was adjusted to greater than 7 with saturated aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 10 (2.4 g, 99.76%). ESI: (m / z) = 257.0 [M+H] + ; 1 H NMR(400MHz,Chloroform-d)δ 7.59(d,J=2.0Hz,1H),7.16(dd,J=8.2,2.0Hz,1H),7.00(d,J=8.1Hz,1H),5.1 9(s,2H),3.70(t,J=6.3Hz,2H),2.69(t,J=6.6Hz,2H),1.92(p,J=6.5Hz,2H).

[0210] Synthesis of compound 11

[0211] Compound 10 (0.5 g, 1.96 mmol) was dissolved in polyphosphoric acid (50 g), and 2-chloro-5-fluorobenzaldehyde (compound 1A, 0.31 g, 1.96 mmol) was added. The mixture was allowed to react at 105°C for 20 minutes. The reaction mixture was poured into a cold 2 mol / L sodium hydroxide solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 10 / 1) to give compound 11 (180 mg, 23.21%). ESI: (m / z) = 396.9 [M+H]. + ; 1 H NMR (400 MHz, Chloroform-d) δ 7.39(dd,J=8.8,5.0Hz,1H),7.15(d,J=8.2Hz,1H),7.02(d,J=8.2Hz,1H),6 .94(ddd,J=8.8,7.7,3.0Hz,1H),6.31(dd,J=9.0,3.0Hz,1H),6.06(dd,J=3. 3,1.2Hz,1H),5.70(d,J=3.2Hz,1H),3.93(ddd,J=12.9,9.2,3.8Hz,1H),3.7 2(dddd,J=12.9,6.5,3.7,1.2Hz,1H),2.91-2.72(m,2H),2.12-1.91(m,2H).

[0212] Synthesis of compound 12

[0213] Compound 11 (140 mg, 0.354 mmol) was dissolved in 1,4-dioxane (5 mL), and cesium carbonate (346 mg, 1.062 mmol), tert-butyl carbamate (62 mg, 0.531 mmol), XPHOS (34 mg, 0.071 mmol), and palladium(II) acetate (8 mg, 0.035 mmol) were added. The mixture was incubated at 100 °C for 1 h. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 to 10 / 1) to give compound 12 (100 mg, 65.44%). ESI: (m / z) = 432.1 [M+H]. + .

[0214] Synthesis of compound 13

[0215] Compound 12 (100 mg, 0.776 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution to adjust the pH to above 7, and then diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 13 (100 mg). ESI: (m / z) = 332.0 [M+H] + .

[0216] Synthesis of compound YL003

[0217] Compound 13 (30 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL), pyridine (0.015 mL, 0.181 mmol) was added, degassed, and purged with N2. The mixture was cooled to 0 °C, and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (25 mg, 0.109 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. Compound YL003 (13 mg, 27.5%) was obtained by HPLC (High Performance Liquid Chromatography). ESI: (m / z) = 522.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),7.97(s,1H),7.91(dd,J=19.3,9.0Hz,2H),7.76(d,J=3.4Hz,1H),7.34 (dd,J=8.8,5.2Hz,1H),7.18(d,J=8.0Hz,1H),7.11(ddd,J=8.9,8.0,3.1Hz,1H),6.81 (d,J=8.0Hz,1H),6.70(dd,J=9.3,3.1Hz,1H),6.05(dd,J=3.3,1.4Hz,1H),3.82(ddd, J=12.5,8.2,4.2Hz,1H),3.76-3.67(m,1H),2.92-2.76(m,2H),1.94(q,J=5.4Hz,2H).

[0218] Example 4: Synthetic route to compound YL004 [ka]

[0219] Synthesis of compound 15

[0220] 7-Bromo-1-naphthoic acid (compound 14, 1 g, 3.983 mmol) was dissolved in DMF (15 mL), TEA (1.661 mL, 11.948 mmol), and HATU (2.27 g, 5.974 mmol) were added, and the mixture was allowed to react at room temperature for 0.5 hours. Ammonium acetate (610 mg, 7.966 mmol) was added, and the mixture was allowed to react at room temperature for 0.5 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give compound 15 (980 mg, 98.39%).

[0221] Synthesis of compound 16

[0222] Compound 15 (0.8 g, 3.199 mmol) was dissolved in polyphosphoric acid (80 g), 2-methylbenzaldehyde (0.31 g, 2.559 mmol) was added, and the mixture was reacted at 105 °C for 2 hours. The reaction mixture was poured into a cold 2N sodium hydroxide solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 10 / 1) to give compound 16 (120 mg, 10.65%). ESI: (m / z) = 352.0 [M+H] + .

[0223] Synthesis of compound 17

[0224] Compound 16 (115 mg, 0.326 mmol) was dissolved in 1,4-dioxane (5 mL), and cesium carbonate (320 mg, 0.979 mmol), tert-butyl carbamate (57 mg, 0.49 mmol), XPHOS (31 mg, 0.065 mmol), and palladium(II) acetate (7.3 mg, 0.033 mmol) were added. The mixture was incubated at 100 °C for 1 h. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 to 10 / 1) to give compound 17 (120 mg, 94.61%). ESI: (m / z) = 389.2 [M+H]. + ; 1 H NMR (400MHz, Chloroform-d)δ 8.39(dd,J=7.2,1.2Hz,1H),8.02(dd,J=8.3,1.3Hz,1H),7.87(s,2H),7.58(dd,J=8.2,7.2Hz,1H),7.22(dd,J=6. 4,1.5Hz,2H),7.12-7.03(m,1H),6.88(d,J=7.8Hz,1H),6.37-6.21(m,2H),5.93(s,1H),2.45(s,3H),1.43(s,9H).

[0225] Synthesis of compound 18

[0226] Compound 17 (120 mg, 0.776 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution to adjust the pH to above 7, and then diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 18 (100 mg). ESI: (m / z) = 289.1 [M+H] + .

[0227] Synthesis of compound 1C

[0228] 1-Benzothiophene-3-carboxylic acid (200 mg, 0.776 mmol) was dissolved in dichloromethane (5 mL), degassed, purged with N2, cooled to 0 °C, and oxalyl chloride (0.285 mL, 3.367 mmol) was added. Two drops of DMF were added and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was rotary evaporated to give crude compound 1C (200 mg).

[0229] Synthesis of compound YL004

[0230] Compound 18 (40 mg, 0.139 mmol) was dissolved in dichloromethane (5 mL), pyridine (0.056 mL, 0.694 mmol) was added, degassed, and purged with N2. The mixture was cooled to 0 °C, and compound 1C (41 mg, 0.208 mmol) was added. The mixture was allowed to react at room temperature for 0.5 hours. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. Compound YL004 (13 mg, 27.5%) was obtained via HPLC.

[0231] Spectral data of compound YL004: ESI: (m / z) = 449.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.04(s,1H),8.75(d,J=3.0Hz,1H),8.25(ddd,J=18.1,7.8,1.3Hz,3H), 8.18-8.14(m,1H),8.10-8.03(m,2H),7.73(dd,J=8.3,7.2Hz,1H),7.54(d ,J=8.7Hz,1H),7.48-7.37(m,2H),7.00(td,J=7.3,1.4Hz,1H),6.92-6.8 1(m,2H),6.58(d,J=3.0Hz,1H),6.51(dd,J=7.9,1.4Hz,1H),2.16(s,3H).

[0232] Example 5: Synthetic route to compound YL005 [ka]

[0233] Synthesis of compound 20

[0234] 6-Bromo-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (compound 19, 2 g, 9.43 mmol) was dissolved in acetic acid (15 mL), degassed, and purged with N2. Potassium cyanate (1.52 g, 18.686 mmol) was added at 0 °C and the mixture was allowed to react at 5 °C for 1 h. The reaction mixture was rotary evaporated and the pH was adjusted to greater than 7 with saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 20 (2.4 g, 99.76%). ESI: (m / z) = 257.0 [M+H] + ; 1 H NMR(400MHz,Chloroform-d)δ 7.54(d,J=2.4Hz,1H),7.15(dd,J=8.8,2.3Hz,1H),6.81(d,J=8.7Hz,1H),5.25(s,2H),4.31-4.17(m,2H),3.90-3.79(m,2H).

[0235] Synthesis of compound 21

[0236] Compound 20 (1 g, 3.89 mmol) was dissolved in polyphosphoric acid (100 g), and 2-chloro-5-fluorobenzaldehyde (0.62 g, 3.89 mmol) was added. The mixture was allowed to react at 105 °C for 20 minutes. The reaction mixture was poured into a cold 2N sodium hydroxide solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 10 / 1) to give compound 21 (600 mg, 38.71%). ESI: (m / z) = 398.9 [M+H].+ ; 1 H NMR(400MHz,Chloroform-d)δ 7.40(dd,J=8.8,5.0Hz,1H),7.14(d,J=8.7Hz,1H),6.96(ddd,J=8.8,7.6,3.0Hz,1H),6.87(d,J=8.7Hz,1H),6.36(dd,J=8.9,3.0Hz,1H),6. 07(dd,J=3.2,1.1Hz,1H),5.75(d,J=3.3Hz,1H),4.34(ddd,J=11.9,6.2,2.8Hz,1H),4.26-4.16(m,2H),3.71(ddd,J=13.1,6.8,2.9Hz,1H).

[0237] Synthesis of compound 22

[0238] Compound 21 (300 mg, 0.754 mmol) was dissolved in 1,4-dioxane (5 mL), and cesium carbonate (737.46 mg, 2.263 mmol), tert-butyl carbamate (132.6 mg, 1.132 mmol), XPHOS (72 mg, 0.151 mmol), and palladium(II) acetate (17 mg, 0.075 mmol) were added. The mixture was incubated at 100 °C for 1 h. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 to 10 / 1) to give compound 22 (100 mg, 65.44%). ESI: (m / z) = 434.1 [M+H] + ; 1H NMR(400MHz,Chloroform-d)δ 7.40(dd,J=8.8,5.0Hz,1H),7.02-6.90(m,3H),6.50(dd,J=8.9,3.0Hz,1H),6.07(dd,J=3.2,1.2Hz,1H),5.58(d,J=5.1Hz,2H),4. 32(ddd,J=11.1,5.9,2.9Hz,1H),4.23(dt,J=7.5,3.8Hz,1H),4.20-4.12(m,1H),3.75(ddd,J=13.4,6.6,2.9Hz,1H),1.39(s,9H).

[0239] Synthesis of compound 23

[0240] Compound 22 (100 mg, 0.776 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution to adjust the pH to above 7, and then diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 23 (100 mg). ESI: (m / z) = 334.1 [M+H] + .

[0241] Synthesis of compound YL005

[0242] Compound 23 (70 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL), pyridine (0.034 mL, 0.419 mmol) was added, degassed, and purged with N2. The temperature was lowered to 0 °C, and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (57 mg, 0.252 mmol) was added and reacted at room temperature for 1 hour. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. Compound YL005 (44 mg, 40.05%) was obtained via HPLC. ESI: (m / z) = 522.0 [M+H] + ;1 H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),7.93(d,J=5.7Hz,2H),7.87(dt,J=11.4,2.5Hz,2H),7.33(dd,J=8.9,5.1Hz,1H ),7.12(ddd,J=8.8,7.9,3.1Hz,1H),6.94(d,J=8.6Hz,1H),6.83(dd,J=9.2,3.1Hz,1H),6.77( d,J=8.6Hz,1H),6.07(dd,J=3.1,1.3Hz,1H),4.37(ddd,J=11.1,6.3,2.9Hz,1H),4.25(ddd,J= 11.2,6.1,3.0Hz,1H),3.95(ddd,J=13.3,6.4,3.1Hz,1H),3.79(ddd,J=13.3,6.2,2.9Hz,1H).

[0243] Example 6: Synthetic route to compound YL006 [ka]

[0244] To a reaction vial were added YL001 (15 mg, 0.05 mmol), DDQ (8 mg, 0.1 mmol), and 1,4-dioxane (anhydrous) (1 mL). The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS, and after completion of the reaction, saturated saline solution was added to quench the reaction. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride solution, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was separated by SFC to obtain compound YL006 (5 mg, 33%). LC-MS (ESI): m / z 506.1 (M+H) + .

[0245] Example 7: Synthetic route to compound YL007 [ka]

[0246] Synthesis of compound 25

[0247] A 100 mL three-neck flask was charged with 4-bromo-1H-indole-6-amino (compound 24, 1000 mg, 4.738 mmol), triethylamine (1.317 mL, 9.476 mmol), and dichloromethane (40 mL), in that order. The mixture was cooled to 0°C, and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1180.73 mg, 5.212 mmol) was added. The mixture was reacted at 0°C for 0.5 hours, then warmed to room temperature and reacted for an additional hour. The reaction mixture was concentrated and subjected to column chromatography (eluent: petroleum ether:ethyl acetate 5:1 to 3:1) to give compound 25 (1809 mg, 4.509 mmol, 95.18%).

[0248] Synthesis of compound 26

[0249] Compound 25 (802 mg, 1.999 mmol), acetic acid (30 mL), and sodium cyanoborohydride (376.89 mg, 5.998 mmol) were added to a 100 mL three-neck flask in this order. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was concentrated, and ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the mixture. The organic phase was concentrated and subjected to column chromatography (eluent: petroleum ether:ethyl acetate 10:1 to 3:1) to give compound 26 (350 mg, 0.868 mmol, 43.42%).

[0250] Synthesis of compound 27

[0251] Compound 26 (320 mg, 0.794 mmol) and acetic acid (10 mL) were added sequentially to a 100 mL three-neck flask. The mixture was cooled to 0°C, and potassium cyanate (128.77 mg, 1.587 mmol) was added. The mixture was allowed to react at 0°C for 0.5 hours. The reaction mixture was concentrated, and saturated aqueous sodium bicarbonate solution was added thereto. The mixture was filtered, and the filter cake was washed with water and dried to give compound 27 (280 mg, 0.628 mmol, 79.06%).

[0252] Synthesis of compound YL007

[0253] Polyphosphoric acid (20 mL) was added to a 100 mL three-neck flask and heated to 105 °C. Compound 27 (150 mg, 0.336 mmol) and 2-chloro-5-fluorobenzaldehyde (53.28 mg, 0.336 mmol) were then added in that order. The reaction was continued at this temperature for an additional 0.5 h. Dichloromethane and saturated aqueous sodium bicarbonate were added, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 20:1 to 10:1) to obtain compound YL007 (47 mg, 0.080 mmol, 23.83%).

[0254] Spectral data for compound YL007:

[0255] LC-MS(ESI):m / z 587.9(M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),7.95(dt,J=8.6,1.9Hz,1H),7.89-7.77(m,2H),7.54(d,J=2.6Hz,1H),7.32(dd,J=8.8,5.2Hz,1H),7.09(ddd,J=8.8, 8.0,3.1Hz,1H),6.95(s,1H),6.90(dd,J=9.2,3.1Hz,1H),6.14-5.97(m,1H),4.16-3.87(m,2H),3.17(ddd,J=9.6,6.9,4.6Hz,2H).

[0256] Example 8: Synthetic route to compound YL008 [ka]

[0257] A 10 mL microwave tube was charged with YL007 (50 mg, 0.085 mmol), zinc cyanide (15.01 mg, 0.128 mmol), zinc powder (0.56 mg, 0.009 mmol), Pd(PPh3)4 (9.85 mg, 0.009 mmol), and DMF (1 mL), in that order. The reaction was carried out in a microwave oven at 120 °C for 1.5 h under nitrogen gas protection. After the reaction was completed, the reaction mixture was filtered and directly subjected to reverse-phase column chromatography (eluent: 10 nM NH4HCO3:MeCN = 40:60) to obtain compound YL008 (4 mg, 0.008 mmol, 8.81%).

[0258] Spectral data for compound YL008:

[0259] LC-MS(ESI):m / z 533.1(M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),7.96(d,J=8.4Hz,1H),7.84(d,J=15.3Hz,2H),7.63(d,J=2.5Hz,1H),7.33(dd,J=8.9,5.1Hz,1H), 7.18-7.04(m,2H),6.93(dd,J=9.1,3.1Hz,1H),6.15(d,J=2.7Hz,1H),4.07(td,J=8.9,6.8Hz,2H),3.35(s,2H).

[0260] Example 9: Synthetic route to compound YL009 [ka]

[0261] Synthesis of compound 29

[0262] 6-Bromo-4-aminoindole (compound 28, 4.5 g, 21.321 mmol) was dissolved in dichloromethane (50 mL), triethylamine (8.891 mL, 63.963 mmol) was added, and the mixture was degassed and purged with N2. Trifluoroacetic anhydride (8.96 g, 42.642 mmol) was added at 0 °C. The reaction mixture was warmed to room temperature and reacted for 3 h. 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 phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 29 (5.8 g, 88.55%). ESI: (m / z) = 306.9 [M+H] + .

[0263] Synthesis of compound 30

[0264] Compound 29 (3.85 g, 12.538 mmol) was dissolved in acetic acid (40 mL), sodium cyanoborohydride (2.36 g, 37.614 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. Further sodium cyanoborohydride (2.36 g, 37.614 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was rotary evaporated, added dropwise to cold saturated aqueous sodium bicarbonate, and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 30 (1.47 g, 37.89%). ESI: (m / z) = 309.8 [M+H]. + .

[0265] Synthesis of compound 31

[0266] Compound 30 (1.47 g, 4.756 mmol) was dissolved in acetic acid (15 mL), the temperature was lowered to 5 °C, potassium cyanate (770 mg, 9.512 mmol) was added, and the mixture was allowed to react at 5 °C for 1 hour. The reaction mixture was then rotary evaporated, and saturated aqueous sodium bicarbonate was added to make it alkaline. Water was added, and the mixture was filtered to give crude compound 31 (1.58 g, 94.6%). ESI: (m / z) = 351.9 [M+H] + .

[0267] Synthesis of compound 32

[0268] Compound 31 (1.5 g, 4.26 mmol) was dissolved in polyphosphoric acid (150 g), and 2-chloro-5-fluorobenzaldehyde (1.22 g, 7.668 mmol) was added. The mixture was allowed to react at 105 °C for 0.5 h. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol 1 / 0 to 20 / 1) to give compound 32 (800 mg, 30%). ESI: (m / z) = 491.9 [M+H]. + .

[0269] Synthesis of compound 33

[0270] Compound 32 (770 mg, 1.563 mmol) was dissolved in 1,4-dioxane (10 mL), and cesium carbonate (1527.8 mg, 2.263 mmol), tert-butyl carbamate (366.21 mg, 3.126 mmol), XPHOS (149 mg, 0.313 mmol), and palladium(II) acetate (35 mg, 0.156 mmol) were added. The mixture was reacted at 100 °C overnight. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol 10 / 1 to 20 / 1) to give compound 33 (170 mg, 51.95%). ESI: (m / z) = 434.1 [M+H] + .

[0271] Synthesis of compound 34

[0272] Compound 33 (170 mg, 0.321 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution to adjust the pH to above 7, and then diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. Drying, filtration, and evaporation of the filtrate gave crude compound 34 (140 mg). ESI: (m / z) = 429.0 [M+H] + .

[0273] Synthesis of compound YL009

[0274] Compound 34 (140 mg, 0.350 mmol) was dissolved in dichloromethane (10 mL), pyridine (0.056 mL, 0.694 mmol) was added, degassed, and purged with N2. The mixture was cooled to 0 °C, and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (118.9 mg, 0.525 mmol) was added. The mixture was allowed to react at room temperature for 5 h. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol 1 / 0 to 20 / 1) to obtain compound YL009 (15 mg).

[0275] Spectral data of compound YL009: ESI: (m / z) = 619.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.24(s,1H),10.19(s,1H),7.95(d,J=8.6Hz,1H),7.85(d,J=12.7Hz,2H),7.52(d,J=2.6Hz,1H),7.33(dd,J=8.8,5.2Hz,1H),7.10(dd d,J=8.8,7.9,3.1Hz,1H),6.86(dd,J=9.2,3.1Hz,1H),6.79(s,1H),6.09(dd,J=2.6,1.0Hz,1H),4.17-3.83(m,2H),3.21-2.99(m,2H).

[0276] Example 10: Synthetic route to compounds YL010-P1 and YL010-P2 [ka]

[0277] Synthesis of compound YL010

[0278] YL009 (70 mg, 0.113 mmol) was dissolved in methanol (3 mL), water (1 mL), and LiOH (28.5 mg, 0.679 mmol) were added, and the mixture was reacted at 60 °C for 3 hours. The reaction mixture was subjected to rotary evaporation and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to obtain compound YL010 (11 mg).

[0279] Spectral data of compound YL010: ESI: (m / z) = 523.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.92(s,1H),7.93-7.88(m,1H),7.87-7.78(m,2H),7.28(dd,J=8.8,5.2Hz,1H),7.24(d,J=2.7Hz,1H),7.05(ddd,J=8.8,7.9,3.1Hz,1 H),6.77(dd,J=9.3,3.1Hz,1H),6.03(s,1H),5.92(dd,J=2.7,1.3Hz,1H),5.29(s,2H),4.02-3.87(m,2H),2.96(dd,J=9.5,7.4Hz,2H).

[0280] Compound YL010 was subjected to chiral separation by SFC to obtain compounds YL010-P1 and YL010-P2.

[0281] Chiral separation conditions: Instrument: SFC-150 (Waters), Chromatography column: AS 20 x 250 mm, 10 μm (Daicel).

[0282] Column temperature: 35℃, mobile phase: CO2 / MeOH[0.2%NH3(7M in MeOH)]=70 / 30.

[0283] Flow rate: 100g / min, back pressure: 100bar, measurement wavelength: 214nm.

[0284] Sample solution: 198 mg dissolved in 40 mL of methanol. Sample injection volume: 2.0 mL.

[0285] Separation by SFC gave compounds YL010-P1 (retention time 5.153 min) and YL010-P2 (retention time 5.581 min).

[0286] YL010-P1:LC-MS(ESI):m / z 522.86(M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),7.85(s,3H),7.36-7.24(m,2H),7.17-7.03(m,1H),6.78(d,J=9.3Hz,1 H),6.04(s,1H),5.97-5.80(m,1H),5.30(s,2H),3.98(m,2H),2.96(d,J=2.1Hz,2H).

[0287] YL010-P2:LC-MS(ESI):m / z 522.86(M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),7.85(s,3H),7.26(m,2H),7.11(t,1H),6.78(d,1H),6.04(s, 1H),5.93(s,1H),5.30(s,2H),3.95(dt,J=13.1,8.4Hz,2H),2.96(t,2H).

[0288] Example 11: Synthesis of Compound YL011 [ka]

[0289] Synthesis of compound YL011

[0290] Compound YL010 (30 mg, 0.057 mmol) was dissolved in acetonitrile (3 mL), degassed, and purged with N2. The temperature was lowered to 0 °C, and tert-butyl nitrite (8.88 mg, 0.086 mmol) and trimethylsilyl azide (7.93 mg, 0.069 mmol) were added and reacted at room temperature for 1 h. The reaction mixture was rotary evaporated and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL011 (6.4 mg). ESI: (m / z) = 549.1 [M+H]. + ; 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),7.95(dt,J=8.6,2.0Hz,1H),7.85(d,J=12.5Hz,2H),7.51(d,J=2.6Hz,1H),7.32(dd,J=8.8,5.2Hz,1H),7.09(ddd,J=8.9 ,8.0,3.1Hz,1H),6.86(dd,J=9.2,3.1Hz,1H),6.62(s,1H),6.08(dd,J=2.6,1.0Hz,1H),4.07-3.92(m,2H),3.16(td,J=8.3,2.3Hz,2H).

[0291] Example 12: Synthetic route to compound YL012 [ka]

[0292] Synthesis of compound YL012

[0293] Compound YL007 (100 mg, 0.170 mmol) was dissolved in 1,4-dioxane (5 mL), and cesium carbonate (110.78 mg, 0.34 mmol), 3,3-difluoroazetidine hydrochloride (15.86 mg, 0.187 mmol), Xantphos (9.84 mg, 0.017 mmol), and Pd(dba) (7.78 mg, 0.009 mmol) were added. The mixture was degassed and purged with N, and the reaction was allowed to proceed overnight at 100 °C. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL012 (58 mg). ESI: (m / z) = 599.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.06(s,1H),7.92(dd,J=8.4,2.4Hz,1H),7.89-7.81(m,2H),7.40(d,J=2.7Hz,1H),7.30(dd,J=8.8,5.2Hz,1H),7.07(ddd,J=8.9,7.9,3.1 Hz,1H),6.80(dd,J=9.3,3.1Hz,1H),5.99(dd,J=2.6,1.2Hz,1H),5.93(s,1H),4.47-4.27(m,4H),4.02-3.87(m,2H),3.19(t,J=8.5Hz,2H).

[0294] Example 13: Synthesis of Compound YL013 [ka]

[0295] Synthesis of compound YL013

[0296] Compound YL007 (100 mg, 0.170 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Potassium carbonate (47.11 mg, 0.341 mmol), 3-amino-1H-indazole-5-boronic acid pinacol ester (50 mg, 0.187 mmol), and Pd(dppf)Cl2 (12.5 mg, 0.017 mmol) were added. The mixture was degassed and purged with N2, and the reaction mixture was heated at 100 °C for 1 h. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified using a column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to obtain compound YL013 (45 mg). ESI: (m / z) = 639.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.48(s,1H),10.21(s,1H),7.92(q,J=10.9,9.2Hz,4H),7.53(d,J=2.7H z,1H),7.44(dd,J=8.7,1.7Hz,1H),7.38-7.27(m,2H),7.11(ddd,J=8.9, 7.9,3.1Hz,1H),6.95-6.85(m,2H),6.15(dd,J=2.8,1.1Hz,1H),5.44(s, 2H),4.12-3.93(m,2H),3.48(dt,J=17.2,8.7Hz,1H),2.28-3.30(m,1H).

[0297] Example 14: Synthesis of Compound YL014 [ka]

[0298] Synthesis of compound YL014

[0299] Compound YL007 (100 mg, 0.170 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), potassium carbonate (47.11 mg, 0.341 mmol), 1-methyl-3-trifluoromethylpyrazole-5-boronic acid (82.42 mg, 0.425 mmol), and Pd(dppf)Cl2 (12.5 mg, 0.017 mmol) were added, degassed, and purged with N2. The mixture was reacted at 100 °C for 1 h. 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 phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL014 (65 mg). ESI: (m / z) = 656.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.22(s,1H),7.95(d,J=8.5Hz,1H),7.92-7.84(m,2H),7.58(d,J=2.6Hz,1H),7.35(dd,J=8.8,5.2Hz,1H),7.11(ddd,J=8.8,7.9,3.1H z,1H),6.99(s,1H),6.94(dd,J=9.2,3.0Hz,1H),6.91(s,1H),6.18-6.13(m,1H),4.08-3.95(m,2H),3.88(s,3H),3.22(t,J=8.5Hz,2H).

[0300] Example 15: Synthesis of Compound YL015 [ka]

[0301] Synthesis of compound YL015

[0302] Compound YL007 (100 mg, 0.170 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), potassium carbonate (47.11 mg, 0.341 mmol), 1-methyl-1H-pyrazole-4-boronic acid (50 mg, 0.187 mmol), and Pd(dppf)Cl2 (12.5 mg, 0.017 mmol) were added, degassed, and purged with N2. The mixture was reacted at 100 °C for 1 h. 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 phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to obtain compound YL015 (60 mg). ESI: (m / z) = 588.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),8.11(s,1H),7.99-7.78(m,4H),7.47(d,J=2.6Hz,1H),7.32(dd,J=8.8,5.1Hz,1H),7.09(td,J=8.4,3.0Hz,1H),6 .97(s,1H),6.88(dd,J=9.2,3.1Hz,1H),6.12-6.01(m,1H),4.04(ddd,J=20.3,10.4,4.5Hz,2H),3.89(s,3H),3.37-3.44(m,2H).

[0303] Example 16: Synthesis of Compound YL016 [ka]

[0304] Synthesis of compound 39

[0305] Compound YL007 (0.5 g, 0.852 mmol), potassium acetate (250.85 mg, 2.556 mmol), biboronic acid pinacol ester (CAS no.

[0111] :73183-34-3) (540.89 mg, 2.130 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) (62.34 mg, 0.085 mmol) were placed in a reaction vial and dissolved in 1,4-dioxane (7 mL). The mixture was heated to 100 °C under nitrogen gas protection and reacted for 2 h. Potassium acetate (83.6 mg, 0.852 mmol), biboronic acid pinacol ester (216.0 mg, 0.852 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (62.34 mg, 0.085 mmol) were added and reacted for an additional 2 h. After concentration, the crude product was purified by normal phase pre-TLC (eluent: DCM:MeOH = 10:1). The target compound 39 (400 mg, 74.06%) was obtained as a tan solid. LC-MS (ESI): m / z 634.1 (M+H) + .

[0306] Synthesis of compound YL016

[0307] Compound 39 (100 mg, 0.158 mmol), potassium carbonate (39.7 mg, 0.287 mmol), 5-bromo[1,2,4]triazolo[4,3-a]pyridine (28.4 mg, 0.143 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.51 mg, 0.014 mmol) were placed in a reaction vial and dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was heated to 100 °C under nitrogen gas protection and reacted for 2 h. The solvent was then rotary evaporated and purified using normal phase chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1). The target compound YL016 (25 mg, 27.89%) was obtained. LC-MS (ESI): m / z 625.1 (M+H). + , 1H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),9.15(s,1H),8.07-7.77(m,4H),7.62(d,J=2.6Hz,1H),7.51(dd,J=9.3,6.7Hz,1H),7.36 (dd,J=8.8,5.1Hz,1H),7.19-6.95(m,4H),6.24(d,J=2.6Hz,1H),4.13-3.92(m,2H),3.19-3.05(m,2H).

[0308] Example 17: Synthesis of Compound YL017 [ka]

[0309] Compound 39 (100 mg, 0.158 mmol), potassium carbonate (39.7 mg, 0.287 mmol), 4-bromo-1-(3,4,5,6-tetrahydropyran-4-yl)pyrazole (33.15 mg, 0.143 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.51 mg, 0.014 mmol) were placed in a reaction vial and dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was heated to 100 °C under nitrogen gas protection and reacted for 2 h. The solvent was then rotary evaporated and purified using normal phase chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to obtain the target compound YL019 (15 mg, 15.89%). LC-MS (ESI): m / z 658.16 (M+H). + , 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),8.21(s,1H),8.00-7.82(m,4H),7.48(d,J=2.7Hz,1H),7.33(dd,J=8.8,5.1Hz,1H),7.15-7.06(m,1H),7.00(s,1H),6.87(dd, J=9.2,3.1Hz,1H),6.08(dd,J=2.7,1.1Hz,1H),4.51-4.38(m,1H),4.15-3.94(m,4H),3.57-3.33(m,4H),2.00(td,J=10.2,9.0,4.0Hz,4H).

[0310] Example 18: Synthesis of Compound YL018 [ka]

[0311] Example 18 Synthesis of Compound YL018

[0312] Compound 39 (100 mg, 0.158 mmol), potassium carbonate (39.7 mg, 0.287 mmol), 4-bromo-1,3-oxazole (21.22 mg, 0.143 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.51 mg, 0.014 mmol) were placed in a reaction vial and dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was heated to 100 °C under nitrogen gas protection and reacted for 2 h. The solvent was then rotary evaporated and purified using normal phase chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1). The target compound YL018 (33 mg, 40.02%) was obtained. LC-MS (ESI): m / z 575.08 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),8.28(d,J=0.8Hz,1H),7.90(s,1H),7.89(m,2H),7.56(d,J=2.6Hz,1H),7.46(d,J=0.8Hz,1H),7.39(s ,1H),7.35(m,1H),7.11(m,1H),6.96-6.89(m,1H),6.21-6.13(m,1H),4.07(d,J=10.7Hz,2H),3.56(d,J=8.5Hz,2H).

[0313] Example 19: Synthetic route to compound YL019 [ka]

[0314] YL007 (100 mg, 0.170 mmol), potassium acetate (50.17 mg, 0.511 mmol), biboronic acid pinacol ester (108.18 mg, 0.426 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12.47 mg, 0.017 mmol) were placed in a reaction vial and dissolved in 1,4-dioxane (1 mL) under the protection of nitrogen gas. The mixture was heated to 100 °C and reacted for 2 hours. Potassium acetate (16.72 mg, 0.170 mmol), biboronic acid pinacol ester (43.2 mg, 0.170 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12.47 mg, 0.017 mmol) were added and reacted for another 2 hours. The mixture was then purified using reverse phase chromatography (mobile phase: water / acetonitrile = 1 / 0 to 2 / 1). Compound YL019 (13 mg, 13.83%) was obtained. LC-MS (ESI): m / z 552.08 (M+H). + .

[0315] Example 20: Synthesis of Compound YL020 [ka]

[0316] Synthesis of compound YL020

[0317] 20-1 (50 mg, 0.085 mmol) was dissolved in 1,4-dioxane (2 mL), and tripotassium phosphate (54.26 mg, 0.256 mmol), 20-2 (20 mg, 0.341 mmol), and Pd(dppf)Cl2 (6.24 mg, 0.009 mmol) were added. The mixture was degassed and purged with N2, and the reaction mixture was heated at 100 °C for 1 h. 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 phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL020 (17 mg). ESI: (m / z) = 522.1 [M+H]. + ; 1H NMR(400MHz,DMSO-d6)δ 10.07(s,1H),7.93(d,J=8.5Hz,1H),7.89-7.82(m,2H),7.40(d,J=2.5Hz,1H),7.31(ddd,J=8.9,5.1,1.6Hz,1H),7.08(tt,J=8.8,2.4H z,1H),6.82(dt,J=9.3,2.3Hz,1H),6.57(s,1H),6.06(s,1H),4.00(ddd,J=19.8,10.0,5.2Hz,2H),3.13(t,J=8.8Hz,2H),2.21(s,3H).

[0318] Example 21: Synthesis of Compound YL021 [ka]

[0319] Synthesis of compound 21-3

[0320] 21-1 (300 mg, 1.998 mmol) was dissolved in dichloromethane (8 mL), triethylamine (0.56 mL, 3.996 mmol) was added, and the mixture was degassed and purged with N2. 3-Fluoro-5-(trifluoromethyl)benzoyl chloride (500 mg, 2.198 mmol) was added at 0 °C. The reaction mixture was warmed to room temperature and reacted for 1 h. 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 phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 21-3 (600 mg, 93.19%). ESI: (m / z) = 341.0 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 11.48-11.39(m,1H),10.51(s,1H),8.18(td,J=1.6,0.8Hz,1H),8.13(dt,J=9.3,2.0Hz,1H),7.96(dt,J=8.6,2.0Hz,1 H),7.89(t,J=1.2Hz,1H),7.37(dd,J=3.1,2.4Hz,1H),7.21(dd,J=12.5,1.5Hz,1H),6.46(ddd,J=3.0,2.0,0.9Hz,1H).

[0321] Synthesis of compound 21-4

[0322] 21-3 (300 mg, 0.882 mmol) was dissolved in acetic acid (5 mL), sodium cyanoborohydride (166 mg, 2.645 mmol) was added, and the mixture was allowed to react at room temperature overnight. The reaction mixture was rotary evaporated, poured into cold saturated aqueous sodium bicarbonate, and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 21-4 (160 mg, 37.89%). ESI: (m / z) = 343.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.31(s,1H),8.13-8.10(m,1H),8.08(dt,J=9.3,2.0Hz,1H),7.95(dt,J=8.7,2.0Hz,1H) ,6.88-6.79(m,2H),6.00-5.95(m,1H),3.50(td,J=8.6,1.8Hz,2H),2.93(t,J=8.5Hz,2H).

[0323] Synthesis of compound 21-5

[0324] 21-4 (160 mg, 0.467 mmol) was dissolved in acetic acid (5 mL), the temperature was lowered to 5 °C, potassium cyanate (76 mg, 0.935 mmol) was added, and the mixture was allowed to react at 5 °C for 0.5 h. The reaction mixture was then rotary evaporated, and saturated aqueous sodium bicarbonate solution was added to make it alkaline. Water was added, and the mixture was filtered to give the crude product of compound 21-5 (200 mg). ESI: (m / z) = 386.1 [M+H] + .

[0325] Synthesis of compound YL021

[0326] 21-5 (180 mg, 0.845 mmol) was dissolved in polyphosphoric acid (20 g), and 2-chloro-5-fluorobenzaldehyde (148 mg, 7.668 mmol) was added. The mixture was allowed to react at 105°C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified using a column (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL021 (64 mg). ESI: (m / z) = 526.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.17(s,1H),7.95(dt,J=8.6,1.9Hz,1H),7.84(d,J=14.9Hz,2H),7.53(d,J=2.6Hz,1H),7.32(dd,J=8.8,5.2Hz,1H),7.13-7.04(m ,1H),6.87(dd,J=9.2,3.1Hz,1H),6.63(d,J=9.9Hz,1H),6.08(d,J=2.5Hz,1H),4.04(pd,J=10.4,7.8Hz,2H),3.25(t,J=8.6Hz,2H).

[0327] Example 22: Synthetic route to compound YL022 [ka]

[0328] Synthesis of compound YL022

[0329] 22-1 (50 mg, 0.096 mmol) was dissolved in 1,4-dioxane (2 mL), and sodium carbonate (20.27 mg, 0.191 mmol), 22-2 (16 mg, 0.191 mmol), 2,2'-bipyridine (15 mg, 0.096 mmol), and anhydrous copper(II) acetate (17 mg, 0.096 mmol) were added. The mixture was allowed to react at 70 °C for 2 hours. The reaction mixture was then rotary evaporated and purified using a reverse-phase column to give compound YL022 (18 mg). ESI: (m / z) = 563.2 [M+H]. + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.04(s,1H),7.91(d,J=8.5Hz,1H),7.89-7.82(m,2H),7.33-7.22(m,2H),7 .07(ddd,J=8.8,7.9,3.1Hz,1H),6.77(dd,J=9.3,3.1Hz,1H),6.27(s,1H),5 .99(s,1H),5.93(dd,J=2.7,1.2Hz,1H),4.05-3.84(m,2H),2.97(t,J=8.5Hz ,2H),2.38-2.27(m,1H),0.66(dd,J=6.6,2.3Hz,2H),0.43(t,J=3.1Hz,2H).

[0330] Example 23: Synthesis of compound YL023 [ka]

[0331] Synthesis of compound YL023

[0332] 22-1 (50 mg, 0.096 mmol) was dissolved in 1,4-dioxane (2 mL), and cesium carbonate (63 mg, 0.192 mmol), 23-1 (33 mg, 0.144 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-bisphenyl (5 mg, 0.01 mmol), and 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (8 mg, 0.01 mmol) were added. The mixture was allowed to react overnight at 100 °C. Rotary evaporation of the reaction mixture afforded compound YL023 (34 mg). ESI: (m / z) = 673.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.95(s,1H),7.90(d,J=8.4Hz,1H),7.79(d,J=5.9Hz,2H),7.69(s,1H),7.37(s,1H) ),7.33-7.25(m,3H),7.06(td,J=8.4,3.1Hz,1H),6.78(dd,J=9.3,3.1Hz,1H),6.14 (s,1H),5.97-5.91(m,1H),4.32(dd,J=10.1,5.1Hz,1H),3.96(ddt,J=21.9,11.7,3 .4Hz,4H),3.43(td,J=11.5,4.4Hz,3H),3.02(t,J=10.4Hz,2H),1.97-1.86(m,4H).

[0333] Example 24: Synthesis of Compound YL024 [ka]

[0334] Synthesis of compound YL024

[0335] 22-1 (50 mg, 0.096 mmol) was dissolved in acetic acid (3 mL) and dichloroethane (1 mL), sodium borohydride triacetate (102 mg, 0.48 mmol) and 24-1 (2 mL) were added, and the mixture was allowed to react at 70 °C overnight. The reaction mixture was subjected to rotary evaporation and purified on a column (DCM:MeOH = 20:1) to obtain compound YL024 (26 mg). ESI: (m / z) = 565.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.96(s,1H),7.91(d,J=8.5Hz,1H),7.85(d,J=13.4Hz,2H),7.34-7.21(m,2H),7.06(td,J=8.4,3.1Hz,1H),6.78(dd,J=9.3,3.1Hz,1H),5 .99(s,1H),5.95-5.90(m,1H),5.11(d,J=8.2Hz,1H),4.04-3.86(m,2H),3.62-3.47(m,1H),2.98(t,J=8.6Hz,2H),1.15(t,J=6.0Hz,6H).

[0336] Example 25: Synthesis of Compound YL025 [ka]

[0337] Synthesis of compound YL025

[0338] 22-1 (50 mg, 0.096 mmol) was dissolved in 1,4-dioxane (2 mL), and cesium carbonate (37.5 mg, 0.115 mmol) and 25-1 (33 mg, 0.143 mmol) were added. 2-(di-tert-butylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-bisphenyl (5 mg, 0.01 mmol), and 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (8 mg, 0.01 mmol) were added, and the mixture was allowed to react overnight at 100 °C. The reaction mixture was rotary evaporated and purified using a reverse-phase column to obtain compound YL025 (9 mg). ESI: (m / z) = 671.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.99(s,1H),8.03(s,1H),7.91(d,J=8.4Hz,1H),7.79(s,2H),7.38(d,J=2.6Hz,1H),7.30(dd,J=8.9,5.1Hz,1H),7.07(td,J=8.4,3.1Hz ,1H),6.82(dd,J=9.2,3.1Hz,1H),6.43(s,1H),6.06(s,1H),6.02-5.97(m,1H),4.08-3.93(m,2H),3.73(s,3H),3.03(t,J=10.3Hz,2H).

[0339] Example 26: Synthesis of Compound YL026 [ka]

[0340] Synthesis of compound YL026

[0341] 22-1 (30 mg, 0.057 mmol) was dissolved in 1,4-dioxane (2 mL), and cesium carbonate (37.5 mg, 0.115 mmol), 26-1 (14 mg, 0.086 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-bisphenyl (3 mg, 0.006 mmol), and 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (5 mg, 0.006 mmol) were added. The mixture was allowed to react overnight at 100 °C. Rotary evaporation of the reaction mixture afforded compound YL026 (11 mg). ESI: (m / z) = 603.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.94(s,1H),7.90(d,J=8.4Hz,1H),7.80(d,J=7.2Hz,2H),7.59(s,1H),7.35-7.21(m,4H),7.11-7.01(m,1H),6.78(dd,J=9 .3,3.1Hz,1H),6.12(s,1H),5.95(dd,J=2.6,1.2Hz,1H),3.98(td,J=9.9,7.1Hz,2H),3.77(s,3H),3.03(d,J=11.2Hz,2H).

[0342] Example 27: Synthesis of Compound YL027 [ka]

[0343] Synthesis of compound YL027

[0344] 22-1 (30 mg, 0.057 mmol) was dissolved in methanol (2 mL), acetic acid (2 drops) and 27-1 (11 mg, 0.143 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (8 mg, 0.115 mmol) was added, and the mixture was allowed to react at room temperature overnight. The reaction mixture was subjected to rotary evaporation to give compound YL027 (11 mg). ESI: (m / z) = 579.1 [M+H]+ ; 1 H NMR(400MHz,DMSO-d6)δ 9.97(s,1H),7.90(d,J=8.5Hz,1H),7.83(d,J=12.2Hz,2H),7.32-7.23(m,2H),7.06(ddd,J=8.8,7.9,3.1Hz,1H),6.77(dd,J=9.3,3.1Hz,1H),6. 17(d,J=5.4Hz,1H),5.92(dd,J=2.7,1.2Hz,1H),5.75(s,1H),4.80(d,J= 8.4Hz,2H),4.57-4.43(m,3H),4.05-3.88(m,2H),3.04(t,J=8.6Hz,2H).

[0345] Example 28: Synthesis of Compound YL028 [ka]

[0346] Synthesis of compound YL028

[0347] 22-1 (50 mg, 0.096 mmol) was dissolved in methanol (2 mL), acetic acid (2 drops) and 28-1 (24 mg, 0.239 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (12 mg, 0.191 mmol) was added, and the mixture was allowed to react at room temperature overnight. The reaction mixture was subjected to rotary evaporation to obtain compound YL028 (13 mg). ESI: (m / z) = 607.15 [M+H] + .

[0348] Example 29: Synthetic route to compound YL029 [ka]

[0349] Synthesis of compound YL029

[0350] Compound 39 (60 mg, 0.095 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). Potassium carbonate (26.17 mg, 0.189 mmol), 29-2 (14 mg, 0.095 mmol), and Pd(dppf)Cl (7 mg, 0.009 mmol) were added. The mixture was stirred at 100 °C for 1.5 hours. The reaction mixture was then rotary evaporated to give compound YL029 (10 mg). ESI: (m / z) = 574.8 [M+H]. + ; 1 H NMR(400MHz,DMSO-d6)δ 13.10(s,1H),10.17(s,1H),8.07(s,1H),7.99-7.83(m,4H),7.47(d,J=2.6Hz,1H),7.32(dd,J=8.8,5.2Hz,1H),7.09(ddd,J=8. 7,7.8,3.1Hz,1H),7.01(s,1H),6.87(dd,J=9.2,3.1Hz,1H),6.07(dd,J=2.8,1.1Hz,1H),4.17-3.94(m,2H),3.51-3.39(m,2H).

[0351] Example 30: Synthesis of Compound YL030 [ka]

[0352] Synthesis of compound YL030

[0353] 22-1 (40 mg, 0.077 mmol) was dissolved in DMF (2 mL), 30-1 (6.7 mg, 0.077 mmol), EDCI (30 mg, 0.153 mmol), and HOBt (21 mg, 0.153 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction 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, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. Compound YL030 (10 mg) was obtained after pre-HPLC purification. ESI: (m / z) = 595.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.18(s,1H),9.32(s,1H),7.95(d,J=8.6Hz,1H),7.89-7.80(m,2H),7.47(d, J=2.7Hz,1H),7.32(dd,J=8.8,5.2Hz,1H),7.15-7.05(m,2H),6.82(dd,J=9.2, 3.1Hz,1H),6.04(dd,J=2.5,1.1Hz,1H),5.82(d,J=5.2Hz,1H),4.24-4.11(m,1 H),4.06-3.89(m,2H),3.15(td,J=7.9,7.2,3.0Hz,2H),1.30(d,J=6.7Hz,3H).

[0354] Example 31: Synthesis of Compound YL031 [ka]

[0355] Synthesis of compound YL031

[0356] 22-1 (40 mg, 0.077 mmol) was dissolved in DMF (2 mL), 31-1 (6.7 mg, 0.077 mmol), EDCI (30 mg, 0.153 mmol), and HOBt (21 mg, 0.153 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction 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, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by prep-HPLC to give compound YL031 (8 mg). ESI: (m / z) = 595.0 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),9.30(s,1H),8.00-7.92(m,1H),7.89-7.79(m,2H),7.47(d,J=2.6H z,1H),7.32(dd,J=8.8,5.1Hz,1H),7.15(s,1H),7.09(td,J=8.4,3.1Hz,1H),6.83 (dd,J=9.1,3.1Hz,1H),6.04(dd,J=2.6,1.1Hz,1H),5.84(d,J=5.1Hz,1H),4.17(q d,J=6.7,5.0Hz,1H),4.09-3.92(m,2H),3.25-3.07(m,2H),1.31(d,J=6.8Hz,3H).

[0357] Example 32: Synthesis of Compound YL032 [ka]

[0358] Synthesis of compound 32-8

[0359] 32-7 (0.6 g, 2.642 mmol) was dissolved in 1,4-dioxane (5 mL), and aqueous ammonia (6.61 g, 52.842 mmol, 28%) was added. The mixture was allowed to react at room temperature for 2 h. TLC monitoring showed that the starting materials had reacted sufficiently and a new spot had formed. The reaction mixture was then rotary evaporated to give crude compound 32-8 (0.59 g, 99.64%).

[0360] Synthesis of compound 32-9

[0361] 32-8 (0.59 g, 2.633 mmol) was dissolved in ethanol (10 mL), 5% wet palladium on carbon (102 mg, 0.527 mmol) was added, and the mixture was degassed and purged with H2 at room temperature overnight. The reaction mixture was filtered and rotary evaporated to give crude compound 32-9 (0.5 g, 97.83%). ESI: (m / z) = 195.1 [M+H] + ; 1H NMR (400MHz, Chloroform-d) δ 6.84 (dd, J=10.2, 1.8Hz, 1H), 6.75 (s, 1H), 3.79-3.33 (m, 4H).

[0362] Synthesis of compound 32-2

[0363] 32-1 (3.5 g, 17.67 mmol) was dissolved in dichloromethane (50 mL), triethylamine (7.4 mL, 53.01 mmol), di-tert-butyl dicarbonate (7.71 g, 35.34 mmol), and DMAP (0.22 g, 1.767 mmol) were added, and the mixture was allowed to react at room temperature overnight. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 32-2 (3.8 g, 72.12%). 1 H NMR(400MHz,DMSO-d6)δ 7.82(s,1H),7.13(d,J=7.9Hz,1H),7.07(dd,J=7.9,1.9Hz,1H),3.91(t,J=8.7Hz,2H),3.01(t,J=8.7Hz,2H),1.50(s,9H).

[0364] Synthesis of compound 32-3

[0365] 32-2 (1.9 g, 0.882 mmol) was dissolved in methanol (10 mL) and DMF (10 mL), triethylamine (2.2 mL, 15.93 mmol), and Pd(dppf)Cl2 (0.47 g, 0.637 mmol) were added, and the mixture was degassed and purged with CO. The reaction mixture was then heated at 100 °C overnight. The reaction mixture was then rotary evaporated and 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give compound 32-3 (950 mg, 53.67%). ESI: (m / z) = 222.1 [M-tBu]. + .

[0366] Synthesis of compound 32-4

[0367] 32-3 (840 mg, 3.03 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (3 mL), water (3 mL), and lithium hydroxide (763 mg, 18.17 mmol) were added, and the mixture was allowed to react at 60 °C for 3 hours. The reaction mixture was subjected to rotary evaporation, and 0.5 M diluted hydrochloric acid was added dropwise in an ice bath to neutralize the mixture. The mixture was extracted with ethyl acetate and rotary evaporated to give crude compound 32-4 (750 mg, 94.04%). ESI: (m / z) = 208.1 [M-tBu] + .

[0368] Synthesis of compound 32-5

[0369] 32-4 (400 mg, 1.52 mmol) was dissolved in polyphosphoric acid (8 g), and 32-9 (295 mg, 1.52 mmol) was added. The mixture was reacted at 140 °C for 1 h. The reaction mixture was added dropwise to a cold 2N sodium hydroxide solution to adjust the pH to above 7, and then diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give compound 32-5 (170 mg, 34.83%). ESI: (m / z) = 322.6 [M+H] + .

[0370] Synthesis of compound 32-6

[0371] 32-5 (160 mg, 0.498 mmol) was dissolved in acetic acid (3 mL), cooled to 5 °C, and potassium cyanate (80 mg, 0.996 mmol) was added. The mixture was allowed to react at 5 °C for 0.5 h. The reaction mixture was rotary evaporated, added dropwise to cold saturated sodium bicarbonate solution to adjust the pH to greater than 7, and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 32-6 (200 mg). ESI: (m / z) = 365.2 [M+H] + .

[0372] Synthesis of compound YL032

[0373] 32-6 (100 mg, 0.274 mmol) was dissolved in polyphosphoric acid (7 g), and 21-6 (110 mg, 0.686 mmol) was added. The mixture was reacted at 105 °C for 2 h. The mixture was added dropwise to a cold sodium hydroxide solution to adjust the pH to above 7, and then diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL032 (30 mg, 21.65%). ESI: (m / z) = 505.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 13.52(s,1H),7.65-7.53(m,3H),7.47(d,J=7.7Hz,1H),7.44-7.33(m,2H),7.08(d,J=3.6Hz,1H),7. 03(td,J=8.4,3.0Hz,1H),6.52(dd,J=9.5,3.0Hz,1H),4.00(td,J=9.0,8.4,4.7Hz,2H),3.32(s,2H).

[0374] Example 33: Synthesis of compound YL033 [ka]

[0375] Synthesis of compound YL033

[0376] Compound 39 (70 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). Potassium carbonate (45.8 mg, 0.331 mmol), 33-1 (23.53 mg, 0.11 mmol), and Pd(dppf)Cl (8.1 mg, 0.011 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction mixture was then rotary evaporated to give compound YL033 (13 mg, 18.4%). ESI: (m / z) = 640.0 [M+H]. + ; 1H NMR(400MHz,DMSO-d6)δ 11.35(s,1H),10.29(s,1H),8.16(s,1H),8.03-7.84(m,5H),7.46(d,J=2.6Hz,1H),7.33(dd,J=8.8, 5.2Hz, 1H), 7.11 (td, J = 8.3, 3.1Hz, 1H), 6.93-6.81 (m, 3H), 6.06 (d, J = 2.6Hz, 1H), 4.20-3.94 (m, 4H).

[0377] Example 34: Synthesis of Compound YL034 [ka]

[0378] Synthesis of compound YL034

[0379] Compound 39 (70 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). Potassium carbonate (45.8 mg, 0.331 mmol), 34-1 (19 mg, 0.11 mmol), and Pd(dppf)Cl (8.1 mg, 0.011 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction mixture was then rotary evaporated to give compound YL034 (8 mg). ESI: (m / z) = 598.0 [M+H]. + ; 1 H NMR(400MHz,DMSO-d6)δ 12.60(s,1H),10.19(s,1H),8.00-7.83(m,3H),7.56(d,J=1.7Hz,1H),7.50(d,J=2.7Hz,1H),7.37-7.27(m,2H),7.10(td,J=8.3,3.0 Hz,1H),6.98(s,1H),6.87(dd,J=9.2,3.1Hz,1H),6.07(d,J=2.6Hz,1H),4.03(dtd,J=30.3,10.5,6.5Hz,2H),3.45(d,J=9.6Hz,2H).

[0380] Example 35: Synthesis of Compound YL035 [ka]

[0381] Synthesis of compound YL035

[0382] 22-1 (40 mg, 0.077 mmol) was dissolved in DMF (2 mL), 35-1 (26.17 mg, 0.189 mmol), EDCI (30 mg, 0.153 mmol), and HOBt (21 mg, 0.153 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction 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, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give compound YL035 (3.5 mg). ESI: (m / z) = 580.5 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),9.32(s,1H),7.94(d,J=8.3Hz,1H),7.84(d,J=8.6Hz,2H),7.46(d,J=2.7Hz,1H),7.32(dd,J=8.9,5.2Hz,1H) ,7.15(s,1H),7.13-7.06(m,1H),6.82(dd,J=9.2,3.1Hz,1H),6.03(d,J=2.5Hz,1H),4.07-3.90(m,4H),3.22-3.09(m,2H).

[0383] Synthetic route for compound YL-036 [ka]

[0384] Synthesis of compound YL036

[0385] Compound 39 (70 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). Potassium carbonate (45.8 mg, 0.331 mmol), 36-1 (29.3 mg, 0.11 mmol), and Pd(dppf)Cl (8.1 mg, 0.011 mmol) were added. The mixture was stirred at 100 °C for 2 hours. The reaction mixture was then rotary evaporated to give compound YL036 (4.5 mg). ESI: (m / z) = 692.0 [M+H]. + ; 1 H NMR(400MHz,DMSO-d6)δ 12.62(s,1H),10.20(s,1H),8.65(d,J=2.0Hz,1H),8.43(d,J=2.1Hz,1H) ,8.04(s,1H),7.96(d,J=8.5Hz,1H),7.88(d,J=13.6Hz,2H),7.52(d,J=2. 6Hz,1H),7.35(dd,J=8.8,5.2Hz,1H),7.16-7.04(m,2H),6.94(dd,J=9.2 ,3.1Hz,1H),6.21-6.12(m,1H),4.04(dt,J=9.8,6.8Hz,2H),3.17(s,2H).

[0386] Example 37: Synthesis of Compound YL037 [ka]

[0387] Synthesis of compound 37-3

[0388] 37-1 (0.68 g, 1.586 mmol) was dissolved in 1,4-dioxane (15 mL), and cesium carbonate (1.03 g, 3.172 mmol), 37-2 (0.98 g, 3.331 mmol), Xantphos (0.18 g, 0.317 mmol), and Pd(dba) (0.15 g, 0.159 mmol) were added. The mixture was degassed and purged with N, and the reaction mixture was heated at 110 °C for 2 h. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol 1 / 0 to 20 / 1) to give compound 37-3 (0.65 g, 63.73%). ESI: (m / z) = 642.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.23(s,1H),9.00(s,1H),8.25-8.19(m,1H),8.14(dd,J=8.8,2.4Hz,1H),7.87(d,J=6.1Hz,1H),7.41(d,J=2.5Hz,1H),7.12-7.06(m,2H),6 .94(td,J=8.4,3.1Hz,1H),6.75(s,1H),6.63(dd,J=9.3,3.1Hz,1H),5.92(d,J=1.9Hz,1H),4.01(dq,J=22.9,10.3Hz,2H),3.21-3.09(m,2H).

[0389] Synthesis of compound 37-4

[0390] 37-3 (0.65 g, 1.013 mmol) was dissolved in methanol (6 mL) and water (2 mL), and lithium hydroxide (0.25 g, 6.076 mmol) was added. The mixture was reacted at 70 °C for 3 h. The reaction mixture was then rotary evaporated and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 37-4 (480 mg, 86.83%). ESI: (m / z) = 546.0 [M+H] + .

[0391] Synthesis of compound 37-6

[0392] 37-4 (70 mg, 0.128 mmol) was dissolved in 1,4-dioxane (2 mL), and cesium carbonate (83.56 mg, 9.512 mmol), 37-5 (56.8 mg, 0.192 mmol), t-BuBrettphos (12.44 mg, 0.026 mmol), and t-BuBrettphos Pd G3 (1.57 mg, 0.002 mmol) were added. The mixture was incubated overnight at 100 °C. The reaction mixture was rotary evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 37-6 (40 mg, 41.16%). ESI: (m / z) = 760.0 [M+H]. + .

[0393] Synthesis of compound YL037

[0394] 37-6 (40 mg, 0.053 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was rotary evaporated, added dropwise to a cold saturated sodium bicarbonate solution, and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL037 (3 mg, 10%). ESI: (m / z) = 630.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 12.32(s,1H),8.77(s,1H),8.10(td,J=8.8,2.6Hz,2H),7.85(d,J=6.2Hz,1H),7.66(d,J=2.0Hz,1H),7.17(d,J=2.5Hz,1H),7.08-7.00(m,3H) ),6.92(td,J=8.4,3.1Hz,1H),6.57(dd,J=9.4,3.1Hz,1H),5.84(s,1H),5.76-5.70(m,1H),4.07-3.90(m,2H),3.04(dt,J=13.3,5.1Hz,2H).

[0395] Example 38: Synthesis of Compound YL038 [ka]

[0396] Synthesis of compound 38-2

[0397] 38-1 (150 mg, 0.698 mmol) was dissolved in tetrahydrofuran (5 mL), degassed, and purged with N2. The temperature was lowered to 0 °C. NaH (42 mg, 1.047 mmol, 60%) was added, and the reaction mixture was warmed to room temperature and stirred for 0.5 h. SEM-Cl (174.5 mg, 1.047 mmol) was added, and the mixture was allowed to react at room temperature for 2 h. The mixture was quenched with saturated aqueous ammonium chloride solution and 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 38-2 (220 mg, 91.32%). 1 H NMR(400MHz,DMSO-d6)δ 7.22(d,J=56.7Hz,1H),5.54(d,J=3.6Hz,2H),3.57(q,J=7.6Hz,2H),0.90-0.75(m,2H),-0.07(d,J=3.0Hz,9H).

[0398] Synthesis of compound 38-3

[0399] 37-4 (100 mg, 0.183 mmol) was dissolved in 1,4-dioxane (2 mL), and cesium carbonate (120 mg, 0.366 mmol), 38-2 (95 mg, 0.275 mmol), t-BuBrettphos (17.8 mg, 0.037 mmol), and t-BuBrettphos Pd G3 (31.32 mg, 0.037 mmol) were added. The mixture was incubated overnight at 100 °C. The reaction mixture was rotary evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 38-3 (50 mg, 33.3%). ESI: (m / z) = 810.2 [M+H]. + .

[0400] Synthesis of compound YL038

[0401] 38-3 (50 mg, 0.062 mmol) was dissolved in tetrahydrofuran (5 mL), TBAF (1 mL) was added, and the mixture was reacted at 80°C for 4 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 sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 10 / 1) to give compound YL038 (12 mg, 28.5%). ESI: (m / z) = 680.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 13.19(s,1H),8.83(s,1H),8.23(s,1H),8.11(d,J=9.1Hz,2H),7.88(d,J=6.2Hz,1H),7.25(s,1H),7.06(dd,J=9.0,5.3Hz,2H),6.93(td,J =8.3,3.1Hz,1H),6.60(dd,J=9.3,3.1Hz,1H),6.29(d,J=16.2Hz,2H),5.83(d,J=1.8Hz,1H),4.00(q,J=9.4,8.7Hz,2H),3.08-3.00(m,2H).

[0402] Example 39: Synthesis of Compound YL039 [ka]

[0403] Synthesis of compound 22-1

[0404] 20-1 (1 g, 1.704 mmol) was dissolved in DMSO (7 mL) and potassium carbonate (710 mg, 5.113 mmol), L-proline (80 mg, 0.682 mmol), and CuI (60 mg, 0.341 mmol) were added. The mixture was degassed and purged with N2. Aqueous ammonia (2.13 g, 17.04 mmol) was added and the mixture was incubated at 100 °C overnight. The reaction 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 phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 22-1 (340 mg, 38.2%). ESI: (m / z) = 523.1 [M+H]. + .

[0405] Synthesis of compound 39-2

[0406] 22-1 (50 mg, 0.096 mmol) was dissolved in DMF (2 mL), 39-1 (25.13 mg, 0.143 mmol), EDCI (37 mg, 0.191 mmol), and HOBt (26 mg, 0.191 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 39-2 (50 mg, 76.89%). ESI: (m / z) = 680.2 [M+H] + .

[0407] Synthesis of compound YL039

[0408] 39-2 (50 mg, 0.074 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture to neutralize it, and the mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol 1 / 0 to 20 / 1) to give compound YL039 (15 mg, 35.2%). ESI: (m / z) = 580.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),7.94(d,J=8.5Hz,1H),7.84(d,J=7.7Hz,2H),7.45(d,J=2.7Hz,1H),7.35-7.27(m,2H),7.09(td,J=8.4,3.1H z,1H),6.82(dd,J=9.2,3.1Hz,1H),6.03(d,J=2.5Hz,1H),4.09-3.93(m,2H),3.40(s,2H),3.17(td,J=7.9,7.4,4.4Hz,2H).

[0409] Example 40: Synthesis of Compound YL040 [ka]

[0410] Synthesis of compound 40-2

[0411] 22-1 (50 mg, 0.096 mmol) was dissolved in dichloromethane (1 mL), and 40-1 (90.5 mg, 0.478 mmol), TEA (0.04 mL, 0.287 mmol), and the condensing agent HATU (91.3 mg, 0.287 mmol, 50% in EA) were added. The mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 40-2 (50 mg, 75.34%). ESI: (m / z) = 694.1 [M+H]. + .

[0412] Synthesis of compound YL040

[0413] 40-2 (50 mg, 0.074 mmol) was dissolved in dichloromethane (2.1 mL), trifluoroacetic acid (0.7 mL) was added, and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture to neutralize it, and the mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 10 / 1) to give compound YL040 (15 mg, 35.1%). ESI: (m / z) = 594.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.18(d,J=2.3Hz,1H),7.98-7.90(m,1H),7.88-7.80(m,2H),7.45(d,J=2.6Hz,1H),7.35-7.23(m,2H),7.09(td,J=8.3,3.1Hz,1H),6.82(dd ,J=9.2,3.1Hz,1H),6.04(d,J=2.6Hz,1H),4.01(dtd,J=23.6,10.4,7.2Hz,2H),3.51(dd,J=6.9,4.1Hz,1H),3.22-3.10(m,2H),1.25(s,3H).

[0414] Example 41: Synthesis of Compound YL041 [ka]

[0415] Synthesis of compound 41-2

[0416] 22-1 (50 mg, 0.096 mmol) was dissolved in dichloromethane (1 mL), 41-1 (103 mg, 0.478 mmol), TEA (0.04 mL, 0.287 mmol), and HATU (91.3 mg, 0.287 mmol, 50% in EA) were added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol 1 / 0 to 20 / 1) to give compound 41-2 (50 mg, 72.6%). ESI: (m / z) = 720.0 [M+H] + .

[0417] Synthesis of compound YL041

[0418] 41-2 (50 mg, 0.074 mmol) was dissolved in dichloromethane (2.1 mL), trifluoroacetic acid (0.7 mL) was added, and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture to neutralize it, and the mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 10 / 1) to give compound YL041 (21 mg, 48.8%). ESI: (m / z) = 620.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),9.93(d,J=6.2Hz,1H),7.94(d,J=8.3Hz,1H),7.88-7.80(m,2H),7. 45(d,J=2.6Hz,1H),7.37-7.28(m,2H),7.13-7.05(m,1H),6.82(dd,J=9.2,3.1Hz ,1H),6.04(d,J=3.5Hz,1H),4.11-3.92(m,2H),3.80-3.69(m,1H),3.20-3.11(m, 2H), 2.91(ddd,J=24.7,9.4,6.5Hz,2H),2.12-1.94(m,2H),1.67(q,J=6.8Hz,2H).

[0419] Example 42: Synthetic route to compound YL042 [ka]

[0420] Synthesis of compound 42-2

[0421] 42-1 (3 g, 14.21 mmol) was dissolved in dichloromethane (40 mL), triethylamine (5.9 mL, 42.64 mmol) was added, and the mixture was degassed and purged with N2. Trifluoroacetic anhydride (5.97 g, 28.43 mmol) was added at 0 °C, and the reaction mixture was warmed to room temperature and reacted for 3 h. 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 phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 42-2 (3.8 g, 87.16%). ESI: (m / z) = 307.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),11.25(s,1H),7.99-7.85(m,1H),7.54(d,J=1.7Hz,1H),7.51-7.48(m,1H),6.38(t,J=2.6Hz,1H).

[0422] Synthesis of compound 42-3

[0423] 42-2 (3.85 g, 12.538 mmol) was dissolved in acetic acid (30 mL), sodium cyanoborohydride (1.17 g, 18.56 mmol) was added, and the mixture was allowed to react at room temperature overnight. The reaction mixture was rotary evaporated, poured into cold saturated aqueous sodium bicarbonate, and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 42-3 (0.7 g, 36.6%). ESI: (m / z) = 308.8 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.02(s,1H),7.01(d,J=1.7Hz,1H),6.82(d,J=1.7Hz,1H),6.15(d,J=1.9Hz,1H),3.49(td,J=8.7,1.7Hz,2H),2.89(t,J=8.6Hz,2H).

[0424] Synthesis of compound 42-4

[0425] 42-3 (1.4 g, 4.529 mmol) was dissolved in acetic acid (25 mL), the temperature was lowered to 5 °C, potassium cyanate (730 mg, 9.06 mmol) was added, and the mixture was allowed to react at 5 °C for 0.5 hours. The reaction mixture was rotary evaporated, and saturated aqueous sodium bicarbonate solution was added to make it alkaline. Water was added and the mixture was filtered to obtain the crude product of compound 42-4 (1.9 g, crude). ESI: (m / z) = 352.8 [M+H] + .

[0426] Synthesis of compound 42-5

[0427] 42-4 (1.7 g, 4.83 mmol) was dissolved in polyphosphoric acid (10 g), and 21-6 (1.53 g, 9.66 mmol) was added. The mixture was reacted at 105 °C for 0.5 h. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 42-5 (1.2 g, 50%). ESI: (m / z) = 492.0 [M+H] + .

[0428] Synthesis of compound 42-6

[0429] 42-5 (1.2 g, 2.441 mmol) was dissolved in methanol (21 mL) and water (7 mL), and lithium hydroxide (610 mg, 14.64 mmol) was added. The mixture was allowed to react at 70 °C for 4 hours. The reaction mixture was subjected to rotary evaporation and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give the crude product of compound 42-6 (1 g, crude). ESI: (m / z) = 396.0 [M+H] + .

[0430] Synthesis of compound 37-2

[0431] 42-7 (2.8 g, 1.563 mmol) was dissolved in tribromoxyphosphine (17.36 g, 60.57 mmol) at 60 °C, and the mixture was heated to 110 °C and reacted for 10 hours. The reaction mixture was poured into ice water, and 10 N sodium hydroxide solution was added to adjust the pH to 9. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 37-2 (3.3 g, 92.7%).

[0432] Synthesis of compound YL042

[0433] 42-6 (300 mg, 0.758 mmol) was dissolved in 1,4-dioxane (7 mL), 37-2 (446 mg, 1.516 mmol), cesium carbonate (494 mg, 1.516 mmol), Xantphos (87.8 mg, 0.152 mmol), and Pd2(dba)3 (69.4 mg, 0.076 mmol) were added, and the mixture was reacted at 100 °C overnight. 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 phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL042 (300 mg, 65%). ESI: (m / z) = 611.0 [M+H] + .

[0434] Example 43: Synthesis of compound YL043 [ka]

[0435] Synthesis of compound YL043

[0436] YL042 (20 mg, 0.033 mmol) was dissolved in DMF (1 mL), zinc cyanide (7.7 mg, 0.066 mmol), and Pd(PPh3)4 (5.7 mg, 0.005 mmol) were added, and the mixture was stirred at 100 °C overnight. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified on a column (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1). Compound YL043 (7 mg) was obtained by reverse-phase column purification. ESI: (m / z) = 556.0 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 9.08(s,1H),8.18(t,J=9.8Hz,2H),7.88(d,J=6.1Hz,1H),7.52(d,J=2.3Hz,1H),7.16-7.05(m,3H),6.93( dt,J=8.8,4.4Hz,1H),6.72-6.65(m,1H),6.01(d,J=2.3Hz,1H),4.12-4.05(m,2H),3.39(d,J=9.3Hz,2H).

[0437] Example 44: Synthesis of Compound YL044 [ka]

[0438] Synthesis of compound 44-2

[0439] YL042 (200 mg, 0.329 mmol) was dissolved in 1,4-dioxane (5 mL), potassium acetate (130 mg, 1.15 mmol), 44-1 (292 mg, 1.15 mmol), and Pd(dppf)Cl2 (48 mg, 0.066 mmol) were added, stirred at 100 °C for 2 h, and 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 44-2 (200 mg, 92.8%). ESI: (m / z) = 657.0 [M+H] + .

[0440] Synthesis of compound YL044

[0441] 44-2 (100 mg, 0.152 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL), potassium carbonate (42 mg, 0.305 mmol), 44-3 (49.4 mg, 0.305 mmol), and Pd(dppf)Cl2 (11.2 mg, 0.015 mmol) were added, and the mixture was stirred at 100 °C for 2 h and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL044 (22 mg, 32.2%). ESI: (m / z) = 612.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),8.98(s,1H),8.25(d,J=10.0Hz,1H),8.13(dd,J=8.8,2.4 Hz,1H),7.86(d,J=6.2Hz,1H),7.34(s,1H),7.11-7.03(m,3H),6.94(td, J=8.4,3.1Hz,1H),6.66(dd,J=9.2,3.1Hz,1H),5.93(s,1H),5.65(s,1H) ,4.94(s,2H),4.01(dq,J=18.3,10.4,8.5Hz,2H),3.42(d,J=7.3Hz,2H).

[0442] Example 45: Synthesis of Compound YL045 [ka]

[0443] Synthesis of compound 45-2

[0444] 45-1 (1 g, 6.66 mmol) was dissolved in dichloromethane (15 mL), triethylamine (2.8 mL, 19.98 mmol) was added, and the mixture was degassed and purged with N2. Trifluoroacetic anhydride (2.8 g, 13.32 mmol) was added at 0 °C. The reaction mixture was warmed to room temperature and reacted for 3 h. 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 phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 45-2 (1.5 g, 91.46%). ESI: (m / z) = 247.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 11.52(s,1H),11.25(s,1H),7.78(t,J=1.2Hz,1H),7.48-7.35(m,1H),7.12(dd,J=12.1,1.6Hz,1H),6.48(t,J=2.6Hz,1H).

[0445] Synthesis of compound 45-3

[0446] 45-2 (1.4 g, 5.687 mmol) was dissolved in acetic acid (10 mL), sodium cyanoborohydride (1.07 g, 17.062 mmol) was added, and the mixture was allowed to react overnight at room temperature. The reaction mixture was rotary evaporated, added dropwise to a cold saturated aqueous solution of sodium bicarbonate, and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 45-3 (420 mg, 29.76%). ESI: (m / z) = 249.1 [M+H] + .

[0447] Synthesis of compound 45-4

[0448] 45-3 (0.42 g, 1.69 mmol) was dissolved in acetic acid (5 mL), the temperature was lowered to 5 °C, potassium cyanate (275 mg, 3.385 mmol) was added, and the mixture was allowed to react at 5 °C for 0.5 h. The reaction mixture was rotary evaporated, and saturated aqueous sodium bicarbonate solution was added to make it alkaline. Water was added and the mixture was filtered to obtain the crude product of compound 45-4 (0.45 g, crude). ESI: (m / z) = 292.0 [M+H] + .

[0449] Synthesis of compound 45-5

[0450] 45-4 (0.48 g, 1.65 mmol) was dissolved in polyphosphoric acid (5 g), and 21-6 (0.52 g, 3.30 mmol) was added. The mixture was reacted at 105 °C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 45-5 (0.28 g, 39.4%). ESI: (m / z) = 432.0 [M+H] + .

[0451] Synthesis of compound 45-6

[0452] 45-5 (0.28 g, 0.65 mmol) was dissolved in methanol (6 mL) and water (2 mL), and lithium hydroxide (163 mg, 3.89 mmol) was added. The mixture was allowed to react at 70 °C for 4 hours. The reaction mixture was subjected to rotary evaporation and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give the crude product of compound 45-6 (200 mg, crude). ESI: (m / z) = 335.9 [M+H] + .

[0453] Synthesis of compound YL045

[0454] 45-6 (100 mg, 0.298 mmol) was dissolved in 1,4-dioxane (2 mL), 37-2 (175 mg, 0.596 mmol), cesium carbonate (194 mg, 0.596 mmol), Xantphos (34.8 mg, 0.06 mmol), and Pd2(dba)3 (27.3 mg, 0.03 mmol) were added, and the mixture was reacted at 100 °C overnight. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) and pulped with ethyl acetate to give compound YL045 (80 mg, 48.9%). ESI: (m / z) = 549.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.97(s,1H),8.23-8.10(m,2H),7.89(d,J=6.2Hz,1H),7.42(d,J=2.5Hz,1H),7.14-7.03(m,2H),6.92(td,J=8.4,3.1Hz, 1H),6.63(dd,J=9.3,3.1Hz,1H),6.58(d,J=10.1Hz,1H),5.92(d,J=1.9Hz,1H),4.12-3.95(m,2H),3.25(t,J=8.6Hz,2H).

[0455] Example 46: Synthesis of Compound YL046 [ka]

[0456] Synthesis of compound 46-2

[0457] 46-1 (190 mg, 1.152 mmol) was dissolved in tetrahydrofuran (5 mL), degassed, and purged with N2. NaH (69 mg, 1.73 mmol, 60%) was added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 0.5 h. 2-(trimethylsilyl)ethoxymethyl chloride (288 mg, 1.73 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 46-2 (300 mg, 88.2%).

[0458] Synthesis of compound 46-3

[0459] 46-2 (100 mg, 0.152 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). Potassium carbonate (63 mg, 0.457 mmol), 44-2 (54 mg, 0.183 mmol), and Pd(dppf)Cl2 (11.2 mg, 0.015 mmol) were added, and the mixture was stirred at 100 °C for 1 h and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 46-3 (90 mg, 79.6%). ESI: (m / z) = 745.4 [M+H]. + .

[0460] Synthesis of compound YL046

[0461] 46-3 (90 mg, 0.152 mmol) was dissolved in tetrahydrofuran (5 mL), TBAF (1.2 mL) was added, and the mixture was stirred at 70 °C for 4 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL046 (27 mg, 36.36%). ESI: (m / z) = 615.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.01(s,1H),8.25-8.19(m,1H),8.13(dd,J=8.8,2.4Hz,1H),8.04(d,J=2.1H z,1H),7.86(d,J=6.1Hz,1H),7.37(d,J=2.5Hz,1H),7.09(dd,J=8.8,5.2Hz, 2H),6.95(td,J=8.4,3.1Hz,1H),6.88(s,1H),6.66(dd,J=9.2,3.1Hz,1H),5 .92(t,J=1.7Hz,1H),4.03(ddt,J=18.4,10.4,4.7Hz,2H),3.28-3.3(m,2H).

[0462] Example 47: Synthetic Routes for Compounds YL047-P1 and YL047-P2 [ka]

[0463] Synthesis of compounds YL047-P1 and YL047-P2

[0464] YL042 (180 mg, 0.131 mmol) was dissolved in DMF (2 mL), zinc cyanide (31 mg, 0.263 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) were added, and the mixture was stirred at 100 °C overnight. 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 phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) and separated by SFC (see Example YL010 for separation conditions) to give compounds YL047-P1 (24 mg) and YL047-P2 (28 mg).

[0465] YL047-P1 (retention time: 4.512 minutes), ESI: (m / z)=556.0[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.07(s,1H),8.18(t,J=9.3Hz,2H),7.88(d,J=6.1Hz,1H),7.52(d,J=2.3Hz,1H),7.13(s,2H),7.08(dd,J=8.9,5.1Hz,1 H),6.92(td,J=8.4,3.0Hz,1H),6.68(dd,J=9.2,3.1Hz,1H),6.01(d,J=2.2Hz,1H),4.07(q,J=8.6Hz,2H),3.39(s,2H).

[0466] YL047-P2 (retention time: 5.408 minutes):ESI:(m / z)=556.0[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.07(s,1H),8.18(t,J=9.8Hz,2H),7.88(d,J=6.1Hz,1H),7.52(d,J=2.3Hz,1H),7.12(d,J=6.0Hz,2H),7.08(dd,J=8.8,5.2Hz ,1H),6.92(td,J=8.4,3.0Hz,1H),6.68(dd,J=9.2,3.1Hz,1H),6.01(d,J=2.3Hz,1H),4.07(q,J=8.4Hz,2H),3.42-3.37(m,2H).

[0467] Example 48: Synthetic route to compound YL048 [ka]

[0468] Synthesis of compound YL048

[0469] Compound 39 (150 mg, 0.237 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). Potassium carbonate (98.3 mg, 0.711 mmol), 48-1 (72.5 mg, 0.284 mmol), and Pd(dppf)Cl2 (17.4 mg, 0.024 mmol) were added, stirred at 100 °C for 1 h, and 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL048 (12 mg, 7.4%). ESI: (m / z) = 682.1 [M+H]. + ; 1 H NMR(400MHz,DMSO-d6)δ 13.31(s,1H),10.19(d,J=20.4Hz,1H),7.94(d,J=8.4Hz,1H),7.86(d,J= 7.6Hz,2H),7.51(d,J=2.6Hz,1H),7.43-7.29(m,1H),7.19-7.05(m,1H), 6.85(dd,J=18.3,9.1Hz,1H),6.58(d,J=3.8Hz,1H),6.11(d,J=28.5Hz,1 H),4.08-3.90(m,2H),3.17-2.85(m,2H),1.73(s,1H),1.05-0.73(m,4H).

[0470] Example 49: Synthetic route to compound YL049 [ka]

[0471] Synthesis of compound YL049

[0472] Compound 39 (150 mg, 0.237 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). Potassium carbonate (98.3 mg, 0.711 mmol), 4-bromo-5-phenyl-3-trifluoromethylpyrazole (83 mg, 0.284 mmol), and Pd(dppf)Cl2 (17.4 mg, 0.024 mmol) were added, stirred at 100 °C for 1 h, and 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol 1 / 0 to 20 / 1) to give compound YL049 (13 mg, 7.5%). ESI: (m / z) = 718.1 [M+H]. + ; 1 H NMR(400MHz,DMSO-d6)δ 14.17(s,1H),10.21(d,J=11.8Hz,1H),7.93(d,J=8.4Hz,1H),7.87-7.77 (m,2H),7.48(s,1H),7.44-7.34(m,6H),7.12(td,J=8.4,3.0Hz,1H),6.7 8(d,J=9.3Hz,1H),6.64(d,J=4.8Hz,1H),6.10(s,1H),3.87(ddd,J=31.4 ,15.1,6.7Hz,2H),2.81(dt,J=16.3,7.6Hz,1H),2.62(d,J=37.8Hz,1H).

[0473] Example 50: Synthetic Route to Compound YL050 [ka]

[0474] Synthesis of compound 50-2

[0475] To a pyridine solution of 4-fluoro-2-(trifluoromethyl)benzaldehyde (compound 50-1, 5.00 g, 26.03 mmol), propanedioic acid (2.98 g, 28.63 mmol) and piperidine (222 mg, 2.60 mmol) were added. The reaction mixture was refluxed for 4.5 hours, then cooled. Ice water (100 mL) was added, and the mixture was stirred at 0°C for 5 minutes. 6N hydrochloric acid (50 mL) was added, followed by stirring for an additional 15 minutes. The mixture was filtered, washed with water, and dried to give compound 50-2 (3.23 g, 53%) as a yellow solid. LC-MS (ESI): no ionization. 1 H NMR (400MHz, DMSO-d6): δ 12.76 (s, 1H), 8.13 (dd, J = 8.8, 5.4Hz, 1H), 7.81-7.69 (m, 2H), 7.62 (td, J = 8.5, 2.8Hz, 1H), 6.63 (d, J = 15.7Hz, 1H).

[0476] Synthesis of compound 50-3

[0477] To a solution of compound 50-2 (733 mg, 3.13 mmol) in toluene (anhydrous) (12 mL), diphenyl azidophosphate (CAS number: 26386-88-9) (0.68 mL, 3.13 mmol) and triethylamine (0.61 mL, 4.38 mmol) were added, and the reaction mixture was stirred at room temperature under nitrogen gas protection for 5 hours. The solvent was evaporated by rotary evaporation, and column purification (mobile phase: ethyl acetate / petroleum ether = 3-20%) gave compound 50-3 (580 mg, 71%). LC-MS (ESI): m / z 258.2 (M-N + CHCN). + . 1 H NMR(400MHz,DMSO-d6)δ 8.23(dd, J=8.9,5.4Hz,1H),7.86(dd,J=15.6,2.2Hz,1H),7.78(dd,J=9.1,2.7Hz,1H),7.67(d,J=2.7Hz,1H),6.84(d,J=15.6Hz,1H).

[0478] Synthesis of compound 50-4

[0479] A mixture of compound 50-3 (7.00 g, 27.01 mmol) and diphenylmethane (21 mL) was reacted at 270°C for 3 hours. The reaction mixture was purified by column chromatography (mobile phase: ethyl acetate / (petroleum ether / dichloromethane = 1:1) = 0% to 30%) to obtain compound 50-4 (1.81 g, 29%). LC-MS (ESI): m / z 232.0 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.78(s,1H),8.19(dd,J=8.8,2.8Hz,1H),8.11(dd,J=8.8,2.8Hz,1H),7.43-7.34(m,1H),6.63-6.55(m,1H).

[0480] Synthesis of compound 50-5

[0481] Under nitrogen gas protection, compound 50-4 (116 mg, 0.50 mmol) was added to phosphorus tribromide (2 g, 6.97 mmol) at 60°C, and the reaction mixture was stirred at 110°C for 4 hours. After cooling, ice water (15 mL) was slowly added, and the mixture was extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and evaporated. Column purification (mobile phase: ethyl acetate / petroleum ether = 5% to 20%) gave compound 50-5 (100 mg, 68%) as a white solid. LC-MS (ESI): m / z 295.9 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 8.49(d,J=6.0Hz,1H),8.44(dd,J=8.8,2.6Hz,1H),8.31(dd,J=9.2,2.6Hz,1H),8.01-7.95(m,1H).

[0482] Synthesis of compound YL050

[0483] Compound 50-5 (37 mg, 0.13 mmol), compound 5 (40 mg, 0.13 mmol), cesium carbonate (82 mg, 0.25 mmol), Xantphos (15 mg, 0.025 mmol), and Pd(dba) (12 mg, 0.013 mmol) were added to a reaction vial. After degassing and purging with nitrogen, 1,4-dioxane (1 mL) was added. The mixture was degassed and purged with nitrogen three times, heated to 110 °C, and stirred for 16 h. The solvent was evaporated, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane = 0% to 5%) to obtain the crude product. The crude product was purified by reverse-phase column chromatography (mobile phase: A: 10 mM NHHCO aqueous solution, B: acetonitrile, B / A = 10% to 60%) to obtain compound YL050 (27 mg, 40%). LC-MS(ESI):m / z 531.2(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 8.92(s,1H),8.23(dd,J=10.4,2.5Hz,1H),8.12(dd,J=8.8,2.4Hz,1H),7.8 4(d,J=6.1Hz,1H),7.31(d,J=2.5Hz,1H),7.19(d,J=7.8Hz,1H),7.11-7.02 (m,1H),6.93(ddd,J=8.9,8.0,3.1Hz,1H),6.71(d,J=7.7Hz,1H),6.63(dd, J=9.3,3.1Hz,1H),5.99-5.91(m,1H),4.09-3.90(m,1H),3.26-3.17(m,2H).

[0484] Example 51. Synthetic route to compound YL051 [ka]

[0485] Synthesis of compound 51-2

[0486] 4-Chloro-5,7-difluoroquinazoline (compound 51-1, 200 mg, 1.00 mmol) and a 7N solution of ammonia in methanol (10.0 mL) were added to a sealed tube and stirred at 30°C for 16 hours. The reaction mixture was rotary evaporated to give compound 51-2 (180 mg, 100%). LC-MS (ESI): m / z 181.9 (M+H). + . 1 H NMR (400MHz, DMSO-d6): δ 8.39(s,1H),7.98(s,1H),7.41(ddd,J=12.0,9.4,2.6Hz,2H),7.29(ddd,J=10.1,2.6,1.4Hz,1H).

[0487] Synthesis of compound YL051

[0488] Compound 51-2 (30 mg, 0.079 mmol), compound 3 (16 mg, 0.086 mmol), cesium carbonate (77 mg, 0.24 mmol), Xantphos (9.1 mg, 0.016 mmol), and Pd(dba) (7.2 mg, 0.008 mmol) were added to a reaction vial. After degassing and purging with nitrogen, 1,4-dioxane (1 mL) was added. The mixture was degassed and purged with nitrogen three times, heated to 110 °C, and stirred for 16 h. The solvent was evaporated, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane = 0% to 4%) to obtain the crude product. The crude product was purified by reverse-phase column chromatography (mobile phase: A: 10 mM NHHCO aqueous solution, B: acetonitrile, B / A = 10% to 60%) to obtain compound YL051 (32 mg, 84%). LC-MS(ESI):m / z 482.1(M+H) + . 1H NMR(400MHz,DMSO-d6):δ 8.98(s,1H),8.10(s,1H),7.56-7.38(m,2H),7.32(dd,J=9.3,2.5Hz,1H),7.20(d,J=7.8Hz,1H),6.98(dd,J=8.8,5.2Hz,1H),6. 91(td,J=8.4,3.0Hz,1H),6.84(dd,J=9.3,3.0Hz,1H),6.73(d,J=7.8Hz,1H),6.06(s,1H),4.09-3.90(m,2H),3.27-3.16(m,2H).

[0489] Example 52. Synthetic route to compound YL052 [ka]

[0490] Synthesis of compound 52-2

[0491] 2-Amino-3-chloro-5-fluorobenzoic acid (2.50 g, 13.19 mmol), formamidine acetate (5.49 g, 52.75 mmol), and absolute ethanol (20 mL) were added to a casserole and stirred at 110 °C for 16 h. After cooling and filtration, the solid was washed with ethanol and dried to give 52-2 (2.30 g, 89%) as a light gray solid. LC-MS (ESI): m / z 198.8 (M+H). + . 1 H NMR (400MHz, DMSO-d6): δ 12.63(s,1H),8.21(s,1H),8.06(dd,J=8.6,3.0Hz,1H),7.80(dd,J=8.3,2.9Hz,1H).

[0492] Synthesis of compound 52-3

[0493] Under nitrogen gas protection, compound 52-2 (1.0 g, 1.24 mmol) and thionyl chloride (7.3 mL) were added to a reaction vial and stirred at 85°C under reflux for 10 hours. The reaction mixture was subjected to rotary evaporation, diluted with dichloromethane, and then rotary evaporated again. The residue was purified by column chromatography (mobile phase: dichloromethane / petroleum ether = 10% to 80%) to give compound 52-3 (1.06 g, 97%). LC-MS (ESI): m / z 216.8 (M+H). + . 1 H NMR (400MHz, CDCl3): δ 9.15 (s, 1H), 7.89 (ddd, J=10.5, 8.1, 2.7Hz, 2H).

[0494] Synthesis of compound 52-4

[0495] 52-3 (268 mg, 1.24 mmol) and 7N methanolic ammonia solution (15.0 mL) were added to a sealed tube and stirred at 30°C for 40 hours. The reaction mixture was rotary evaporated to give compound 52-4 (328 mg, 100%). LC-MS (ESI): m / z 197.9 (M+H). + . 1 H NMR (400MHz, DMSO-d6): δ 8.46 (s, 1H), 8.11 (dd, J=9.5, 2.8Hz, 1H), 8.07-7.99 (m, 3H).

[0496] Synthesis of compound YL052

[0497] Compound 52-4 (30 mg, 0.079 mmol), compound 3 (21 mg, 0.10 mmol), cesium carbonate (77 mg, 0.24 mmol), Xantphos (9.10 mg, 0.016 mmol), and Pd(dba) (7.2 mg, 0.008 mmol) were added to a reaction vial. The mixture was degassed and purged with nitrogen gas. 1,4-Dioxane (1 mL) was added, degassed and purged with nitrogen gas three times, and then heated to 110 °C and stirred for 16 h. The solvent was evaporated, and the residue was purified by column chromatography (mobile phase: methanol / dichloromethane = 0% to 4%) to obtain the crude product. The crude product was purified by reverse-phase column chromatography (mobile phase: A: 10 mM NHHCO aqueous solution, B: acetonitrile, B / A = 10% to 50%) to obtain compound YL052 (10 mg, 26%). LC-MS(ESI):m / z 498.0(M+H) + . 1 H NMR(400MHz,DMSO-d6):δ 9.60(s,1H),8.32(s,1H),8.08(dd,J=8.6,2.7Hz,1H),7.99(dd,J=9.5,2.8Hz,1H),7.43(d,J=2.5Hz,1H),7.23(d,J=7.8Hz,1H),7.09(dd,J=8.8 ,5.2Hz,1H),6.95(td,J=8.3,3.0Hz,1H),6.78(dd,J=9.3,3.0Hz,1H),6 .74(d,J=7.7Hz,1H),5.99(s,1H),4.09-3.93(m,2H),3.28-3.18(m,2H).

[0498] Example 53. Synthetic Routes for Compounds YL053-P1 and YL053-P2 [ka]

[0499] Synthesis of compound YL053

[0500] Compound 39 (270 mg, 0.43 mmol), 3-bromo-1H-pyrazole-5-amino (140 mg, 0.86 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (32 mg, 0.044 mmol), potassium carbonate (119 mg, 0.86 mmol), 1,4-dioxane (11 mL), and water (2 mL) were added to a reaction vial. The mixture was stirred at 110 °C for 4 h under nitrogen gas protection. After the reaction was completed, half of the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an automated column (Biotage) (mobile phase: dichloromethane / methanol = 92 / 8 to 90 / 10) to obtain the target compound YL053 (19 mg, 15%) as a white solid. LC-MS (ESI): m / z 589.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.70(s,1H),10.17(s,1H),7.97-7.84(m,3H),7.45(d,J=2.7Hz,1H),7.33(dd,J=8.8,5.2Hz,1H),7.13-7.03(m,2H),6.87(dd,J =9.2,3.1Hz,1H),6.08(dd,J=2.6,1.1Hz,1H),5.66(s,1H),4.95(s,2H),4.02(ddd,J=22.1,10.3,5.8Hz,2H),3.45-3.39(m,2H).

[0501] SFC separation of 62 mg of YL053 was performed using an SFC-150 (Waters) column (AS 20 × 250 mm, 10 μm (Daicel) column, column temperature: 35 °C, mobile phase: CO₂ / MeOH [0.2% NH₃ (7 M in MeOH)] = 60 / 40, flow rate: 100 mL / min, back pressure: 100 bar, wavelength: 214 nm, circulation time: 6 min, sample solution: 69 mg dissolved in 20 mL of methanol, sample injection volume: 4 mL), to obtain the target compounds YL053-P1 (30.3 mg, 12%) and YL053-P2 (25.7 mg, 10%) as white solids.

[0502] YL053-P1: retention time: 4.561 minutes, LC-MS (ESI): m / z 589.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 11.75(s,1H),10.19(s,1H),7.99-7.83(m,3H),7.48(d,J=2.6Hz,1H),7.33(dd,J=8.8,5.1Hz,1H),7.15-7.03(m,2H),6.87(d d,J=9.2,3.1Hz,1H),6.09(dd,J=2.5,1.1Hz,1H),5.65(s,1H),4.97(s,2H),4.01(dq,J=18.1,10.4,8.5Hz,2H),3.42(s,2H).

[0503] YL053-P2: retention time: 5.012 minutes, LC-MS (ESI): m / z 589.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 11.73(s,1H),10.19(s,1H),8.01-7.81(m,3H),7.48(s,1H),7.33(dd,J=8.9,5.2Hz,1H),7.15-7.01(m,2H), 6.87(d,J=9.2Hz,1H),6.08(dd,J=2.6,1.1Hz,1H),5.64(s,1H),5.08(s,2H),4.09-3.95(m,2H),3.41(s,2H).

[0504] Example 54: Synthesis route of compound YL054

change

[0505] Synthesis of compound YL054

[0506] Compound 39 (55 mg, 0.087 mmol), 5-iodopyrazole (33 mg, 0.17 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (7 mg, 0.009 mmol), potassium carbonate (23 mg, 0.17 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) were added to a reaction vial. The mixture was stirred at 110 °C under nitrogen gas protection for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using an automated column (Biotage) (mobile phase: petroleum ether / ethyl acetate = 7 / 93 to 3 / 97) to obtain the crude product. The resulting solid was purified (Welch Xtimate C18, 21.2 × 250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature: 25 °C, measurement wavelength: 254 nm) to obtain the target compound YL054 (8.2 mg, 16%) as a white solid. LC-MS (ESI): m / z 574.1 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 13.08(s,1H),10.21(s,1H),7.90(td,J=23.5,22.9,11.3Hz,4H),7.49(s,1H),7.34(dd,J=8.8,5.1Hz,1H),7.20(s,1H),7.10 (td,J=8.4,3.1Hz,1H),6.88(dd,J=9.2,3.1Hz,1H),6.67(s,1H),6.13-6.08(m,1H),4.09-3.98(m,2H),3.47(d,J=8.8Hz,2H).

[0507] Example 55: Synthetic route to compound YL055 [ka]

[0508] Regarding the synthesis method, refer to the synthesis of compound 39, and synthesize compound 53-1 by using 5-trifluoromethylbenzoyl chloride instead of 3-chloro-5-fluorobenzoyl chloride.

[0509] Synthesis of compound YL055

[0510] Compound 53-1 (60 mg, 0.109 mmol), 5-bromo-3-trifluoromethylpyrazole (23.38 mg, 0.109 mmol), potassium carbonate (30.06 mg, 0.218 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.96 mg, 0.011 mmol) were placed in a reaction vial, and dioxane (1 mL) and water (0.20 mL) were added. The mixture was heated to 100 °C and stirred for 2 h. The solvent was dried, and the sample was mixed with silica gel and purified by column chromatography (methanol:dichloromethane = 1:20) to give compound YL055 (17 mg, 0.025 mmol, 23.13%). LC-MS (ESI): m / z 607.06 (M+H). + .

[0511] Example 56: Synthetic route to compound YL056 [ka]

[0512] Synthesis of compound YL056

[0513] Compound YL007 (150 mg, 0.256 mmol), morpholine (0.022 mL, 0.256 mmol), LHMDS (65.41 mg, 0.391 mmol), cyjohnphos (2.98 mg, 0.009 mmol), and Pd2(dba)3 (6.88 mg, 0.009 mmol) were placed in a reaction vial, DMA (1 mL) was added, and the reaction was performed in a microwave oven at 120 °C for 0.5 hours. The mixture was extracted with ethyl acetate and purified by column chromatography (methanol:dichloromethane = 1:20) to give YL056 (3 mg, 0.005 mmol, 5.64%). LC-MS (ESI): m / z 593.95 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ 10.12(s,1H),8.03-7.79(m,3H),7.43(d,J=2.7Hz,1H),7.32(dd,J=8.8,5.1Hz,1H),7.15-7.07(m,1H),6.82(dd,J=9.2,3.1Hz,1H),6.55( s,1H),6.12-5.94(m,1H),3.98(ddd,J=13.8,9.6,7.8Hz,2H),3.65(d,J=6.2Hz,2H),3.12(td,J=8.2,2.3Hz,2H),3.03(s,3H),2.84(s,3H).

[0514] Example 57: Synthetic route to compound YL057 [ka]

[0515] Synthesis of compound 57-1

[0516] A 100 mL three-neck flask was charged with 4-bromo-1H-indole-6-amino (1000 mg, 4.738 mmol), triethylamine (1.317 mL, 9.476 mmol), and dichloromethane (40 mL) in that order. The mixture was cooled to 0 °C, and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1180.73 mg, 5.212 mmol) was added. The mixture was reacted at 0 °C for 0.5 h, then warmed to room temperature and reacted for an additional 1 h. The reaction mixture was concentrated and subjected to column chromatography (eluent: petroleum ether:ethyl acetate 5:1-3:1) to give compound 57-1 (1809 mg, 4.509 mmol, 95.18%).

[0517] Synthesis of compound 57-2

[0518] Compound 57-1 (802 mg, 1.999 mmol), acetic acid (30 mL), and sodium cyanoborohydride (376.89 mg, 5.998 mmol) were added to a 100 mL three-neck flask in this order. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was concentrated, and ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the mixture. The organic phase was concentrated and subjected to column chromatography (eluent: petroleum ether:ethyl acetate = 10:1-3:1) to give compound 57-2 (350 mg, 0.868 mmol, 43.42%).

[0519] Synthesis of compound 57-3

[0520] Compound 57-2 (320 mg, 0.794 mmol) and acetic acid (10 mL) were placed in a 100 mL three-neck flask. The mixture was cooled to 0 °C, and potassium cyanate (128.77 mg, 1.587 mmol) was added. The mixture was allowed to react at 0 °C for 0.5 h. The reaction mixture was concentrated, and saturated aqueous sodium bicarbonate solution was added thereto. The mixture was filtered, and the filter cake was washed with water and dried to give 57-3 (280 mg, 0.628 mmol, 79.06%).

[0521] Synthesis of compound YL057

[0522] Polyphosphoric acid (20 mL) was placed in a two-neck flask and heated to 105 °C. After stable stirring, compound 57-3 (4-bromo-2,3-dihydroindol-6-yl-5-fluoro-3-trifluoromethylbenzamide (200 mg, 0.448 mmol) and naphthalene-1-carboxaldehyde (140.01 mg, 0.896 mmol) were added, and the reaction was continued for 0.5 hours. The mixture was quenched with sodium bicarbonate, extracted with dichloromethane, and purified by column chromatography (methanol / dichloromethane = 1:20) to give YL057. LC-MS (ESI): m / z 585.37 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ 9.94(s,1H),8.09(d,J=8.6Hz,1H),7.79(dd,J=19.9,8.1Hz,3H),7.60(d,J=2.7Hz,1H),7.41(d,J=13.0Hz,2H),7 .31(t,J=7.8Hz,2H),7.26-7.13(m,2H),6.92(s,1H),6.58(d,J=2.6Hz,1H),4.16-4.00(m,2H),3.28-3.14(m,2H).

[0523] Example 58: Synthetic route to compound YL058 [ka]

[0524] Synthesis of compound 58-1

[0525] Compound YL007 (150 mg, 0.256 mmol), triethylamine (0.071 mL, 0.511 mmol), Pd(dppf)Cl2 (18.71 mg, 0.026 mmol), N,N-dimethylformamide (3 mL), and methanol (3 mL) were added to a 50 mL three-neck flask in this order. The reaction was carried out at 60 °C for 18 h under carbon monoxide protection. LCMS showed only a small amount of product was present, so dichloromethane and water were added, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 40:1 to 20:1) to give compound 58-1 (9.2 mg, 0.016 mmol, 6.36%). LC-MS (ESI): m / z 566.1 (M+H). + ; 1H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),7.96(dd,J=8.3,2.5Hz,1H),7.91-7.82(m,2H),7.57(d,J=2.5Hz,1H),7.39-7.25(m,2H),7.10(td,J=8.4,3.1Hz, 1H),6.89(dd,J=9.2,3.1Hz,1H),6.17(d,J=2.4Hz,1H),4.02(dtd,J=18.7,10.4,8.2Hz,2H),3.85(s,3H),3.48(t,J=8.6Hz,2H).

[0526] Synthesis of compound YL058

[0527] Compound 58-1 was placed in a reaction vial, and water (0.2 mL), methanol (0.40 mL), and tetrahydrofuran (0.80 mL) were added as solvents. Lithium hydroxide (19.28 mg, 0.459 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. Extraction with dichloromethane and column purification (methanol / dichloromethane = 1:20) gave the product YL058 (17 mg, 0.025 mmol, 23.13%). LC-MS (ESI): m / z 552.85 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 13.05(s,1H),10.21(s,1H),7.95(d,J=8.5Hz,1H),7.88(d,J=4.6Hz,2H),7.53(d,J=2.6Hz,1H),7.33(dd,J=8.9,5.2Hz,1H),7. 28(s,1H),7.10(dd,J=3.1,0.9Hz,1H),6.88(dd,J=9.2,3.1Hz,1H),6.19-6.11(m,1H),4.09-3.93(m,2H),3.47(t,J=8.6Hz,2H).

[0528] Example 59: Synthetic route to compound YL059 [ka]

[0529] Synthesis of compound YL059

[0530] Compound 59-1 (50 mg, 0.091 mmol), ammonium acetate (13.97 mg, 0.181 mmol), and HATU (51.68 mg, 0.136 mmol) were placed in a reaction vial, DMF (1 mL) was added as a solvent, and triethylamine (0.038 mL, 0.272 mmol) was added. The mixture was reacted at room temperature for 1 hour, extracted with ethyl acetate, and purified by column chromatography (methanol:dichloromethane = 1:20) to give the product YL059 (26 mg, 0.045 mmol, 49.49%). LC-MS (ESI): m / z 551.87 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.02-7.84(m,3H),7.76(s,1H),7.53(d,J=2.6Hz,1H),7.40(s,1H),7.34(dd,J=8.9,5.2Hz,1H),7 .15-7.07(m,2H),6.87(dd,J=9.2,3.1Hz,1H),6.11(dd,J=2.5,1.1Hz,1H),4.11-3.88(m,2H),3.57-3.35(m,2H).

[0531] Example 60: Synthetic route to compound YL060 [ka]

[0532] Synthesis of compound YL060

[0533] The raw material YL057 (58 mg, 0.099 mmol), L-proline (4.57 mg, 0.040 mmol), copper(I) iodide (3.78 mg, 0.020 mmol), and potassium carbonate (41.15 mg, 0.298 mmol) were placed in a reaction vial, and 1.5 mL of DMSO was added as a solvent. After degassing and purging with nitrogen gas, aqueous ammonia (8.70 mg, 0.248 mmol) was added. The reaction was allowed to proceed at 100°C for 6 hours, followed by extraction with ethyl acetate and column purification (methanol:dichloromethane = 1:20) to give the product YL060 (14 mg, 0.026 mmol, 25.75%). LC-MS (ESI): m / z 521.49 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 9.67(s,1H),8.06(d,J=8.6Hz,1H),7.87-7.67(m,3H),7.42(s,2H),7.37-7.08(m,5H),6 .38(d,J=2.6Hz,1H),6.01(s,1H),5.22(s,2H),4.11-3.91(m,2H),3.00(t,J=8.5Hz,2H).

[0534] Example 61: Synthetic route to compound YL061 [ka]

[0535] Synthesis of compound 61-2

[0536] 3-Bromo-4-fluoropyrazole (100 mg, 0.606 mmol) and tetrahydrofuran (5 mL) were placed in a reaction vial, cooled in an ice-water bath, sodium hydride (21.82 mg, 0.909 mmol) was added, and the mixture was allowed to warm to room temperature and react for 0.5 h. (Bromomethyl)benzene (0.108 mL, 0.909 mmol) was added, and the mixture was allowed to react at room temperature for 2 h. The mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and purified by column chromatography (ethyl acetate:petroleum ether = 1:3) to give product 61-2 (110 mg, 0.431 mmol, 71.14%). No product signal was detected by HPLC-MS.

[0537] Synthesis of compound YL061

[0538] Compound 61-2 (28 mg, 0.110 mmol), compound 39 (76.53 mg, 0.121 mmol), K2CO3 (30.34 mg, 0.220 mmol), and Pd(dppf)Cl2 (8.03 mg, 0.011 mmol) were placed in a reaction vial, and 1,4-dioxane (3 mL) and 0.6 mL of water were added. The mixture was degassed and purged with nitrogen gas, heated to 100 °C, and reacted for 2 hours. The solvent was dried, and the sample was mixed with silica gel and purified by column chromatography (ethyl acetate / petroleum ether:dichloromethane = 1:1:1) to obtain YL061 (50 mg, 0.073 mmol, 66.79%) as a yellow solid. LC-MS (ESI): m / z 682.14 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 10.18(s,1H),8.27(d,J=2.3Hz,1H),7.94(d,J=9.1Hz,1H),7.86(d,J=10.8Hz,2H),7.49(d,J=2.9Hz,1H),7.39-7.29(m, 6H),7.11(dd,J=8.4,3.1Hz,1H),6.91-6.82(m,2H),6.09(d,J=2.4Hz,1H),5.27(s,2H),4.12-3.96(m,2H),3.28(s,2H).

[0539] Example 62: Synthetic route to compound YL062 [ka]

[0540] Synthesis of compound YL062

[0541] Polyphosphoric acid (15 mL) was placed in a two-neck flask and heated to 105 °C. After stable stirring, compound 57-3 (100 mg, 0.224 mmol) and 3-fluorobenzaldehyde (55.63 mg, 0.448 mmol) were added and allowed to react for 0.5 hours. After the reaction, the reaction mixture was poured into a cold saturated aqueous solution of sodium bicarbonate, dichloromethane was added, and the mixture was stirred until the organic phase was free of viscous material. The mixture was extracted with dichloromethane and purified using normal phase (methanol:dichloromethane) to give YL062 (28.4 mg, 0.049 mmol, 21.80%). LC-MS (ESI): m / z 552.03 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),8.05-7.93(m,1H),7.85(s,2H),7.65(d,J=3.1Hz,1H),7.34-7.21(m,1H),7.14-6.99(m,2H),6.97 -6.90(m,1H),6.85(dt,J=9.7,2.2Hz,1H),5.82(d,J=2.9Hz,1H),4.00(td,J=8.9,5.4Hz,2H),3.22-3.10(m,2H).

[0542] Example 63: Synthetic route to compound YL063 [ka]

[0543] Synthesis of compound YL063

[0544] Polyphosphoric acid (20 mL) was placed in a two-neck flask and heated to 105 °C. After stable stirring, compound 57-3 (100 mg, 0.224 mmol) and 2-bromo-5-fluorobenzaldehyde (91.00 mg, 0.448 mmol) were added and allowed to react for 0.5 hours. After the reaction, the reaction solution was poured into a cold saturated aqueous solution of sodium bicarbonate, dichloromethane was added, and the mixture was stirred until the organic phase was free of viscous material. The mixture was extracted with dichloromethane and purified using normal phase (methanol:dichloromethane) to give YL063 (48.2 mg, 0.073 mmol, 32.37%). LC-MS (ESI): m / z 631.94 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 10.15(s,1H),7.95(d,J=8.4Hz,1H),7.83(d,J=11.2Hz,2H),7.58-7.41(m,2H),7.08-6.97(m,1H),6.94- 6.84(m,2H),6.03(dd,J=2.4,1.0Hz,1H),4.03(td,J=9.5,8.0Hz,2H),3.17(ddd,J=9.5,6.8,4.2Hz,2H).

[0545] Example 64: Synthetic route to compound YL064 [ka]

[0546] Synthesis of compound YL064

[0547] Polyphosphoric acid (15 mL) was placed in a two-neck flask and heated to 105 °C. After stable stirring, compound 57-3 (100 mg, 0.224 mmol) and benzaldehyde (0.045 mL, 0.448 mmol) were added and allowed to react for 0.5 hours. After the reaction, the reaction mixture was poured into a cold saturated aqueous solution of sodium bicarbonate, dichloromethane was added, and the mixture was stirred until the organic phase was free of viscous material. The mixture was extracted with dichloromethane and purified using normal phase purification (methanol:dichloromethane = 1:20) to give YL064 (38.5 mg, 0.068 mmol, 30.54%). LC-MS (ESI): m / z 534.04 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 10.22(s,1H),7.97(d,J=8.4Hz,1H),7.85(s,2H),7.62(d,J=3.0Hz,1H),7.32-7.17(m ,3H),7.09(q,J=3.2Hz,3H),5.80(d,J=3.0Hz,1H),4.00(d,J=3.4Hz,2H),3.16(s,2H).

[0548] Example 65: Synthetic Routes for Compounds YL065-P1 and YL065-P2 [ka]

[0549] Synthesis of compounds YL065-P1 and YL065-P2

[0550] Compound 39 (1 g, 1.578 mmol), 5-bromo-3-trifluoromethylpyrazole (0.31 g, 1.434 mmol), potassium carbonate (0.40 g, 2.869 mmol), and Pd(dppf)Cl (0.10 g, 0.143 mmol) were placed in a reaction vial, dioxane (10 mL) and water (2.00 mL) were added, and the mixture was degassed and purged with nitrogen gas. The reaction was then heated at 105 °C for 5 h. The mixture was extracted with ethyl acetate and water, rotary evaporated, and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give YL065 (560 mg, 0.872 mmol, 60.82%). Separation by SFC (the same method as in Example YL010) gave compounds YL065-P1 and YL065-P2.

[0551] YL065-P1 Retention time: 4.561 minutes; LC-MS(ESI): m / z 642.09(M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 14.03(d,J=2.1Hz,1H),10.30(s,1H),8.10-7.84(m,3H),7.61(d,J=2.7Hz ,1H),7.35(dd,J=8.8,5.1Hz,1H),7.18(s,1H),7.13(dd,J=8.2,3.1Hz,1H) ,7.03(d,J=1.9Hz,1H),6.93(dd,J=9.1,3.1Hz,1H),6.13(d,J=2.6Hz,1H), 4.07(dd,J=32.9,6.5Hz,2H),3.53(d,J=6.9Hz,1H),3.38(d,J=4.7Hz,1H).

[0552] YL065-P2 Retention time: 5.561 minutes; LC-MS(ESI): m / z 642.09(M+H) + ; 1H NMR(400MHz,DMSO-d6)δ 14.03(s,1H),10.30(s,1H),8.08-7.80(m,3H),7.61(d,J=2.7Hz,1H),7.35(dd,J=8.9,5.2Hz,1H),7.18(s,1H),7.12(d,J=3.1Hz,1H),7.0 3(s,1H),6.93(dd,J=9.2,3.1Hz,1H),6.13(d,J=2.5Hz,1H),4.06(ddd,J=23.1,10.6,6.5Hz,2H),3.61-3.45(m,1H),3.36(d,J=6.1Hz,1H).

[0553] Example 66: Synthetic route to compound YL066 [ka]

[0554] Synthesis of compound YL066

[0555] Polyphosphoric acid (15 mL) was placed in a two-neck flask and heated to 105 °C. After stable stirring, compound 57-3 (100 mg, 0.224 mmol) and 2-chlorobenzaldehyde (63.01 mg, 0.448 mmol) were added and the reaction was continued for 0.5 hours. The reaction was monitored, quenched with sodium bicarbonate, extracted with dichloromethane, and purified using a normal phase column (MeOH:DCM = 1:20) to give compound YL066 (69.2 mg, 0.116 mmol, 51.57%). LC-MS (ESI): m / z 568.00 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),7.95(dd,J=8.4,2.3Hz,1H),7.90-7.81(m,2H),7.58(d,J=2.7Hz,1H),7.30-7.12(m, 4H),6.95(s,1H),6.13(d,J=2.6Hz,1H),4.03(td,J=9.0,6.2Hz,2H),3.18(dd,J=10.2,7.2Hz,2H).

[0556] Example 67: Synthetic route to compound YL067 [ka]

[0557] Synthesis of compound YL067

[0558] Compound 39 (50 mg, 0.079 mmol), 5-bromo-2-methylimidazole (12.70 mg, 0.079 mmol), potassium carbonate (21.80 mg, 0.158 mmol), and Pd(dppf)Cl (5.77 mg, 0.008 mmol) were placed in a reaction vial, and 3 mL of a mixed solvent (1,4-dioxane:water = 5:1) was added. The mixture was degassed and purged with nitrogen gas three times, and the reaction was carried out at 100 °C overnight. The reaction was monitored by HPLC-MS, and the solvent was evaporated by rotary evaporation. The mixture was purified by normal phase column chromatography (MeOH:DCM = 1:10) to obtain compound YL067 (8 mg, 0.013 mmol, 16.39%). LC-MS (ESI): m / z 588.11 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.98(s,1H),10.17(s,1H),8.01-7.85(m,3H),7.45(s,1H),7.32(td,J=8.6,8.1,4.6Hz,3H),7.09(td,J=8.3,3.0Hz, 1H),6.86(dd,J=9.4,2.9Hz,1H),6.08(d,J=2.6Hz,1H),4.04(ddd,J=14.9,10.2,7.2Hz,2H),3.39(s,2H),2.31(s,3H).

[0559] Example 68: Synthetic route to compound YL068 [ka]

[0560] Synthesis of compound YL068

[0561] Compound 39 (50 mg, 0.079 mmol), 5-bromo-4-methylimidazole (12.70 mg, 0.079 mmol), potassium carbonate (21.80 mg, 0.158 mmol), and Pd(dppf)Cl (5.77 mg, 0.008 mmol) were placed in a reaction vial, and 3 mL of a mixed solvent (1,4-dioxane:water = 3:1) was added. The mixture was degassed and purged with nitrogen gas three times, and the reaction was carried out at 100 °C overnight. The reaction was monitored by HPLC-MS, and the solvent was rotary evaporated and purified by normal phase column (MeOH:DCM = 1:10) to give the product YL068 (8 mg, 0.013 mmol, 16.39%). LC-MS (ESI): m / z 588.11 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 12.06(s,1H),10.15(s,1H),8.00-7.85(m,3H),7.62(s,1H),7.46(d,J=2.7Hz,1H),7.33(dd,J=8.9,5.1Hz,1H),7.10(td,J=8.3,3 .1Hz,1H),6.88(dd,J=9.1,3.1Hz,1H),6.80(s,1H),6.11(d,J=2.6Hz,1H),4.14-3.83(m,2H),3.41(d,J=10.0Hz,2H),2.33(s,3H).

[0562] Example 69 Synthesis of Compound YL069 [ka]

[0563] Synthesis of compound 69-1

[0564] Compound YL007 (250 mg, 0.426 mmol, purity: 83.9%), tert-butyldimethylsilylacetylene (478.24 mg, 3.41 mmol), copper(I) iodide (162.30 mg, 0.852 mmol), potassium iodide (70.73 mg, 0.426 mmol), diisopropylamine (646.75 mg, 6.39 mmol), tetrakis(triphenylphosphine)palladium (246.19 mg, 0.213 mmol), and DMF (70 mL) were added to a reaction vial. The mixture was heated to 100 °C under nitrogen gas protection and stirred overnight. The next day, the reaction mixture was cooled to room temperature, saturated ethylenediaminetetraacetic acid solution was added, and the mixture was stirred at room temperature for 1 hour. 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 phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate = 100 / 45 to 100 / 50) to give compound 69-1 (200 mg, purity: 95%, yield: 72.6%) as a white solid. LC-MS (ESI): m / z 646.3 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 10.11(s,1H),7.94(d,J=8.4Hz,1H),7.89-7.81(m,2H),7.51(d,J=2.6Hz,1H),7.32(dd,J=8.9,5.1Hz,1H),7.08(ddd,J=8.8,7.9,3.1Hz,1 H),6.88(dd,J=9.2,3.1Hz,1H),6.82(s,1H),6.11(dd,J=2.5,1.0Hz,1H),4.06-3.97(m,2H),3.24-3.17(m,2H),0.98(s,9H),0.17(s,6H).

[0565] Synthesis of compound YL069

[0566] 69-1 (130 mg, 0.426 mmol), THF (20 mL), and tetrabutylammonium fluoride-tetrahydrofuran solution (1 M, 0.65 mL) were added to a reaction vial and stirred at room temperature for 0.5 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 saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified using an automated column (Biotage) (mobile phase: petroleum ether / ethyl acetate = 100 / 45 to 100 / 50) to obtain compound YL069 (70 mg, purity: 97%, yield: 65.4%) as a white solid. LC-MS (ESI): m / z 532.1 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),7.94(dt,J=8.5,1.9Hz,1H),7.89-7.80(m,2H),7.50(d,J=2.5Hz,1H),7.32(dd,J=8.8,5.2Hz,1H),7.09(ddd,J=8.8,8.0,3.1Hz, 1H),6.88(dd,J=9.2,3.1Hz,1H),6.82(s,1H),6.10(dd,J=2.6,1.0Hz,1H),4.43(s,1H),4.07-3.97(m,2H),3.23(ddd,J=11.1,7.4,3.1Hz,2H).

[0567] Example 70: Synthetic route to compound YL070 [ka]

[0568] Compound 39 (50.00 mg, 78.89 μmol), 3-bromo-5-methyl-1H-pyrazole (25.40 mg, 157.78 μmol), potassium carbonate (32.71 mg, 236.67 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.54 mg, 15.78 μmol), 1,4-dioxane (10 mL), and water (2 mL) were added to a reaction vial. The mixture was heated to 100 °C under nitrogen gas protection and stirred for 1 h. 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 aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol = 100 / 3 to 100 / 4) to obtain compound YL070 (12 mg, purity: 94%, yield: 25.8%) as a white solid. LC-MS (ESI): m / z 588.2 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 12.72(s,1H),10.18(s,1H),7.96-7.86(m,3H),7.46(s,1H),7.33(dd,J=8.8,5.1Hz,1H),7.18-7.07(m,2H),6.88(dd ,J=9.2,3.2Hz,1H),6.39(s,1H),6.10(d,J=2.6Hz,1H),4.09-3.97(m,2H),3.45(dd,J=17.8,9.4Hz,2H),2.27(s,3H).

[0569] Example 71: Synthetic route to compound YL071 [ka]

[0570] Compound 39 (250.00 mg, 394.44 μmol), 4-bromo-5-(trifluoromethyl)-1H-pyrazole (169.59 mg, 788.88 μmol), potassium carbonate (163.54 mg, 1.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57.72 mg, 78.89 μmol), 1,4-dioxane (20 mL), and water (4 mL) were added to a reaction vial. The mixture was heated to 110 °C under nitrogen gas protection and stirred for 3 h. 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 aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified using an automated column (Biotage) (mobile phase: dichloromethane / methanol = 100 / 5 to 100 / 6). The crude product was purified (Boston pHlex ODS, 21.2 x 250 mm, 10 μm column, water (0.05% ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) to give compound YL071 (45 mg, purity: 96%, yield: 17.7%) as a white solid. LC-MS (ESI): m / z 642.2 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ 13.85(s,1H),10.20(s,1H),8.25(s,1H),7.95(d,J=8.5Hz,1H),7.88(s,2H),7.54(d,J=2.7Hz,1H),7.34(dd,J=8.9,5.1Hz,1H),7.11(td, J=8.3,3.1Hz,1H),6.88(dd,J=9.1,3.0Hz,1H),6.68(s,1H),6.11(d,J=2.6Hz,1H),3.99(dtd,J=28.2,10.4,6.6Hz,2H),3.30-3.07(m,2H).

[0571] Example 72: Synthetic route to compound YL072 [ka]

[0572] Synthesis of compound YL072

[0573] Compound 39 (250.00 mg, 394.44 μmol), 4-bromo-3-methyl-5-(trifluoromethyl)-1H-pyrazole (180.65 mg, 788.88 μmol), potassium carbonate (163.54 mg, 1.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57.72 mg, 78.89 μmol), 1,4-dioxane (20 mL), and water (4 mL) were added to a reaction vial. The mixture was heated to 110 °C under nitrogen gas protection and stirred for 3 h. 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 aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified using an automated column (Biotage) (mobile phase: dichloromethane / methanol = 100 / 5 to 100 / 6). The crude product was purified (Boston pHlex ODS, 21.2 x 250 mm, 10 μm column, water (0.05% ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) to obtain compound YL072 (16 mg, purity: 94%, yield: 6.2%) as a white solid. LC-MS (ESI): m / z 656.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 13.56(s,1H),10.19(s,1H),7.91(d,J=33.2Hz,3H),7.51(s,1H),7.36(s,1H),7.12(s,1 H),6.87(s,1H),6.55(s,1H),6.11(s,1H),4.07-3.90(m,2H),2.93(s,2H),2.16(s,3H).

[0574] Example 73: Synthesis of compound YL073 [ka]

[0575] Synthesis of compound 73-2

[0576] 4-Bromo-1H-pyrazol-3-amine (400 mg, 2.47 mmol), di-tert-butyl dicarbonate (2.16 g, 9.88 mmol), 4-dimethylaminopyridine (60.34 mg, 493.86 μmol), triethylamine (0.8 mL), and dichloromethane (6 mL) were added to a reaction vial and stirred at room temperature for 2 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane and water. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on an automated column (Biotage) using a mobile phase of petroleum ether / ethyl acetate (100 / 10 to 100 / 11) to give compound 73-2 (4.6 g, purity: 88.5%, yield: 46.5%) as a white solid. LC-MS(ESI):m / z 364.0(M+H) + .

[0577] Synthesis of compound 73-3

[0578] A reaction vial was charged with 73-2 (200.00 mg, 315.55 μmol), compound 39 (228.60 mg, 631.11 μmol), potassium carbonate (130.83 mg, 946.66 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.18 mg, 63.11 μmol), 1,4-dioxane (20 mL), and water (2 mL). The mixture was heated to 110 °C under nitrogen gas protection and stirred for 3 h. 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 aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol = 100 / 8 to 100 / 10) to give compound 73-3 (75 mg, purity: 47%, yield: 14%) as a white solid. LC-MS (ESI): m / z 789.3 (M+H). + .

[0579] Synthesis of compound YL073

[0580] Compound 73-3 (200.00 mg, 315.55 μmol), dichloromethane (35 mL), and water (3.5 mL) were added to a reaction vial and stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified using an automated column (Biotage) (mobile phase: dichloromethane / methanol = 100 / 8 to 100 / 10) to obtain compound YL073 (8 mg, purity: 92%, yield: 29.7%) as a light brown solid. LC-MS (ESI): m / z 589.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ 11.81(s,1H),10.12(s,1H),7.95(d,J=8.5Hz,1H),7.93-7.85(m,2H),7.60(s,1H),7.47(d,J=2.8Hz,1H),7.33(dd,J=8.7,5.1H z,1H),7.09(td,J=8.4,3.1Hz,1H),6.91-6.85(m,2H),6.11(d,J=3.2Hz,1H),4.70(s,2H),4.05-3.91(m,2H),3.31-3.15(m,2H).

[0581] Example 74: Synthetic route to compound YL074 [ka]

[0582] Synthesis of compound 74-2

[0583] 4-Bromo-1H-imidazole (500.00 mg, 3.40 mmol), di-tert-butyl dicarbonate (3.71 g, 17.01 mmol), 4-dimethylaminopyridine (83.12 mg, 680.39 μmol), triethylamine (1 mL), and dichloromethane (10 mL) were added to a reaction vial and stirred at room temperature for 2 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane and water. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on an automated column (Biotage) using a mobile phase of petroleum ether / ethyl acetate (100 / 5 to 100 / 6) to give compound 74-2 (700 mg, purity: 97.6%, yield: 81.2%) as a white solid. LC-MS(ESI):m / z 249.1(M+H) + .

[0584] Synthesis of compound YL074

[0585] Compound 74-2 (200.00 mg, 315.55 μmol), compound 39 (155.94 mg, 631.11 μmol), potassium carbonate (130.83 mg, 946.66 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.18 mg, 63.11 μmol), 1,4-dioxane (15 mL), and water (1.5 mL) were added to a reaction vial. The mixture was heated to 110 °C under nitrogen gas protection and stirred for 2 h. 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 aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by automated column chromatography (Biotage) (mobile phase: dichloromethane / methanol = 100 / 8 to 100 / 9) to obtain compound YL074 (50 mg, purity: 97.5%, yield: 22.9%) as a white solid. LC-MS (ESI): m / z 574.2 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ 12.33(s,1H),10.20(s,1H),7.99-7.85(m,3H),7.77(s,1H),7.47(d,J=14.6Hz,2H),7.37-7.29(m,2H),7.09(t d,J=8.4,3.2Hz,1H),6.86(dd,J=9.1,3.1Hz,1H),6.08(d,J=2.6Hz,1H),4.13-3.96(m,2H),3.49-3.37(m,2H).

[0586] Example 75: Synthesis of compound YL075 [ka]

[0587] Synthesis of compound YL075

[0588] Compound 39 (93.00 mg, 146.73 μmol, purity: 57.9%), 4-bromo-5-(difluoromethyl)-1H-pyrazole (57.81 mg, 293.46 μmol), potassium carbonate (60.84 mg, 440.20 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.47 mg, 29.35 μmol), 1,4-dioxane (10 mL), and water (1 mL) were added to a reaction vial. The mixture was heated to 110 °C under nitrogen gas protection and stirred for 3 h. 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 aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified using an automated column (Biotage) (mobile phase: dichloromethane / methanol = 100 / 7 to 100 / 8). The crude product was purified (Boston pHlex ODS, 21.2 x 250 mm, 10 μm column, water (0.05% ammonium bicarbonate) / acetonitrile, flow rate 30 mL / min, column temperature: 25 °C, measurement wavelength: 254 nm) to obtain compound YL075 (6 mg, purity: 94%, yield: 10.6%) as a white solid. LC-MS (ESI): m / z 624.1 (M+H) + ; 1H NMR(400MHz,DMSO-d6)δ 13.58(s,1H),10.20(s,1H),8.15(s,1H),8.00-7.80(m,3H),7.53(d,J=2.7Hz,1H),7.33(dd,J=8.9,5.1Hz,1H),7.27 -7.03(m,2H),6.89(dd,J=9.3,3.3Hz,1H),6.80(s,1H),6.11(s,1H),4.07-3.96(m,2H),3.19(dd,J=10.3,5.9Hz,2H).

[0589] Example 76: Synthesis of Compound YL076 [ka]

[0590] Synthesis of compound YL076

[0591] Compound 39 (123 mg, 0.194 mmol), acetone (4 mL), water (4 mL), and potassium peroxymonosulfate (131.23 mg, 0.213 mmol) were added to a reaction vial. The reaction was allowed to proceed at room temperature for 2 hours. LCMS analysis showed the reaction was complete. The reaction mixture was concentrated, dichloromethane was added, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 40:1 to 20:1) to give YL076 (41 mg, 0.078 mmol, 40.33%). LC-MS (ESI): m / z 524.0 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 10.00(s,1H),9.76(s,1H),7.92(dd,J=8.6,2.1Hz,1H),7.83(d,J=11.1Hz,2H),7.49-7.22(m,2H),7.07(ddd,J=8.8,7.9,3.1 Hz,1H),6.79(dd,J=9.3,3.1Hz,1H),6.23(s,1H),5.99(dd,J=2.6,1.2Hz,1H),4.04-3.79(m,2H),3.07(dd,J=9.8,7.4Hz,2H).

[0592] Example 77: Synthesis of Compound YL077 [ka]

[0593] Synthesis of compound YL077

[0594] A 25 mL three-neck flask was charged with 39 (123 mg, 0.194 mmol), acetone (4 mL), water (4 mL), and potassium peroxymonosulfate (131.23 mg, 0.213 mmol). The reaction was allowed to proceed at room temperature for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated, dichloromethane was added, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 40:1 to 20:1) to give YL077 (41 mg, 0.078 mmol, 40.33%). LC-MS (ESI): m / z 524.0 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 10.00(s,1H),9.76(s,1H),7.92(dd,J=8.6,2.1Hz,1H),7.83(d,J=11.1Hz,2H),7.49-7.22(m,2H),7.07(ddd,J=8.8,7.9,3.1 Hz,1H),6.79(dd,J=9.3,3.1Hz,1H),6.23(s,1H),5.99(dd,J=2.6,1.2Hz,1H),4.04-3.79(m,2H),3.07(dd,J=9.8,7.4Hz,2H).

[0595] Example 78: Synthetic route to compound YL078 [ka]

[0596] Synthesis of compound YL078

[0597] Compound YL077 (28 mg, 0.053 mmol), potassium carbonate (8.86 mg, 0.064 mmol), N,N-dimethylformamide (2 mL), and iodomethane (0.005 mL, 0.059 mmol) were added to a 25 mL three-neck flask in this order. The reaction was allowed to proceed at room temperature for 1 hour. LCMS analysis indicated partial reaction. Water and ethyl acetate were added to the reaction mixture, and the organic phase was concentrated and subjected to reverse-phase column chromatography (eluent: 10 nM NH4HCO3:methanol = 40:60 to 20:80) to obtain YL078 (12 mg, 0.022 mmol, yield: 41.74%). LC-MS (ESI): m / z 538.2 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 10.14(s,1H),8.02-7.79(m,3H),7.40(d,J=2.6Hz,1H),7.31(dd,J=8.8,5.1Hz,1H),7.08(td,J=8.4,3.1Hz ,1H),6.91-6.76(m,1H),6.42(s,1H),6.06-5.95(m,1H),4.06-3.90(m,2H),3.77(s,3H),3.15-3.05(m,2H).

[0598] Example 79: Synthetic Routes for Compounds YL079-P1 and YL079-P2 [ka]

[0599] YL007 (89.5 mg) was separated using a Waters SFC-150 column (OJ-H 4.6 x 100 mm, 5 μm column), a CO₂ / MeOH [0.2% NH₃ (7 M in MeOH)] mobile phase, a flow rate of 3.0 mL / min, a back pressure of 2000 psi, a wavelength of 214 nm, and a column temperature of 40°C. This gave YL079-P1 (retention time: 0.707 min, 33.0 mg) and YL079-P2 (retention time: 1.449 min, 29.6 mg). LC-MS (ESI): m / z 588.0 (M+H). + .

[0600] YL079-P2 data: LC-MS (ESI): m / z 588.0 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.95(dt,J=8.6,1.9Hz,1H),7.89-7.77(m,2H),7.54(d,J=2.6Hz,1H),7.32(dd,J=8.8,5.2Hz,1H),7.09( ddd,J=8.8,8.0,3.1Hz,1H),6.95(s,1H),6.90(dd,J=9.2,3.1Hz,1H),6.14-5.97(m,1H),4.16-3.87(m,2H),3.17(ddd,J=9.6,6.9,4.6Hz,2H).

[0601] Example 80: Synthetic route to compound YL080 [ka]

[0602] Synthesis of compound YL080

[0603] A 25 mL three-neck flask was charged with 2-di-tert-butylphosphonium-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (8.19 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (7.80 mg, 0.009 mmol), 1,4-dioxane (2.5 mL), and toluene (0.5 mL), in that order. The mixture was reacted at 110 °C for 0.5 h under nitrogen gas protection. The mixture was then cooled to room temperature, and compound YL007 (50 mg, 0.085 mmol), 3-(trifluoromethyl)pyrazole (34.79 mg, 0.256 mmol), and tripotassium phosphate (54.26 mg, 0.256 mmol) were added. The mixture was reacted at 110 °C for an additional 3 h under nitrogen gas protection. LCMS showed the reaction was successful, and the reaction mixture was concentrated and subjected to reverse phase purification (alkaline method) to give YL080 (28.8 mg, 0.045 mmol, 52.65%). LC-MS (ESI): m / z 642.2 (M+H). + ; 1H NMR (400 MHz, DMSO-d6) δ 8.74(s,1H),8.20(dd,J=10.4,2.5Hz,1H),8.09(dd,J=8.7,2.4Hz,1H),7.83 (d,J=6.2Hz,1H),7.13(d,J=2.6Hz,1H),7.03(dd,J=8.8,5.2Hz,2H),6.90(t d,J=8.4,3.2Hz,1H),6.60(dd,J=9.4,3.1Hz,1H),6.01(s,1H),5.78-5.65(m ,1H),5.23(s,2H),3.95(pd,J=11.0,10.4,6.0Hz,2H),2.97(t,J=8.5Hz,2H).

[0604] Example 81: Synthetic route to compound YL081 [ka]

[0605] Synthesis of compound YL081

[0606] A 25 mL three-neck flask was charged with 2-di-tert-butylphosphonium-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (8.19 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (7.80 mg, 0.009 mmol), 1,4-dioxane (2.5 mL), and toluene (0.5 mL), in that order. The mixture was reacted under nitrogen gas protection at 110 °C for 0.5 h, cooled to room temperature, and then compound YL007 (50 mg, 0.085 mmol), 4-(trifluoromethyl)-1H-pyrazole (34.79 mg, 0.256 mmol), and tripotassium phosphate (54.26 mg, 0.256 mmol) were added. The mixture was reacted under nitrogen gas protection at 110 °C for an additional 3 h. LCMS showed the reaction was successful, and the reaction mixture was concentrated and subjected to reverse phase purification (alkaline method) to give YL081 (28.7 mg, 0.045 mmol, 52.47%). LC-MS (ESI): m / z 642.2 (M+H). + ; 1H NMR(400MHz,DMSO-d6)δ 10.28(s,1H),9.01(t,J=1.0Hz,1H),8.26(s,1H),8.06-7.78(m,3H),7.63(d,J=2.6Hz,1H),7.35(dd,J=8.9,5.1Hz,1H),7.23(s,1H),7.11(d dd,J=8.9,7.9,3.1Hz,1H),6.94(dd,J=9.2,3.1Hz,1H),6.15(dd,J=2.7,1.0Hz,1H),4.04(dtd,J=30.4,10.4,6.7Hz,2H),3.66-3.35(m,2H).

[0607] Example 82: Synthetic route to compound YL082 [ka]

[0608] Synthesis of compound YL082

[0609] 2-Di-tert-butylphosphonium-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (8.19 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (7.80 mg, 0.009 mmol), 1,4-dioxane (2.5 mL), and toluene (0.5 mL) were added to a 25 mL three-neck flask in this order. The mixture was reacted under nitrogen gas protection at 110 °C for 0.5 hours, cooled to room temperature, and then compound YL007 (50 mg, 0.085 mmol), 4-fluoro-1H-pyrazole (22.00 mg, 0.256 mmol), and tripotassium phosphate (54.26 mg, 0.256 mmol) were added. The mixture was reacted under nitrogen gas protection at 110 °C for an additional 3 hours. LCMS showed the reaction was successful, and the reaction mixture was concentrated and subjected to reverse phase purification (alkaline method) to give YL082 (22.8 mg, 0.039 mmol, 45.20%). LC-MS (ESI): m / z 592.2 (M+H). + ; 1H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),8.54(d,J=4.4Hz,1H),8.06-7.73(m,4H),7.59(d,J=2.6Hz,1H),7.34(dd,J=8.9,5.2Hz,1H),7.21-6.99( m,2H),6.92(dd,J=9.2,3.1Hz,1H),6.12(dd,J=2.6,1.0Hz,1H),4.03(dtd,J=28.1,10.4,6.7Hz,2H),3.61-3.38(m,2H).

[0610] Example 83: Synthesis of Compound YL083 [ka]

[0611] Synthesis of compound YL083

[0612] A 25 mL three-neck flask was charged with 2-di-tert-butylphosphonium-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (8.19 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (7.80 mg, 0.009 mmol), 1,4-dioxane (2.5 mL), and toluene (0.5 mL), in that order. The mixture was incubated at 110 °C under nitrogen gas protection for 0.5 h. The mixture was then cooled to room temperature and treated with compound YL007 (50 mg, 0.085 mmol), 5-(trifluoromethyl)-1H-1,2,3-triazole (35.04 mg, 0.256 mmol), and potassium phosphate tripotassium (54.26 mg, 0.256 mmol). The mixture was then incubated at 110 °C for an additional 3 h under nitrogen gas protection. LCMS showed the reaction was successful, and the reaction mixture was concentrated and purified by reverse phase chromatography (alkaline method) to give YL083 (5.8 mg, 0.009 mmol, 10.59%). LC-MS (ESI): m / z 643.2 (M+H). + .

[0613] Example 84: Synthetic route to compound YL084 [ka]

[0614] Synthesis of compound YL084

[0615] Compound YL007 (50 mg, 0.085 mmol), dimethylphosphine oxide (13.30 mg, 0.170 mmol), tripotassium phosphate (54.26 mg, 0.256 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.86 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (7.80 mg, 0.009 mmol), and dioxane (3 mL) were added to a 25 mL three-neck flask in this order. The reaction was carried out at 100 °C for 12 h under nitrogen gas protection. LCMS showed the reaction was successful. Ethyl acetate and water were added, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 40:1 to 20:1) to give YL084 (20 mg, 0.034 mmol, 40.20%). LC-MS(ESI):m / z 584.2(M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),7.95(d,J=8.4Hz,1H),7.92-7.83(m,2H),7.56(d,J=2.6Hz,1H),7.34(dd,J=8.9,5.2Hz,1H),7.11(ddd,J=8.8,7.9,3.1Hz,1H),7. 03(d,J=11.7Hz,1H),6.89(dd,J=9.1,3.1Hz,1H),6.11(d,J=2.5Hz,1H),4.14-3.84(m,2H),3.43(t,J=8.6Hz,2H),1.68(dd,J=13.4,2.8Hz,6H).

[0616] Example 85: Synthetic route to compound YL085 [ka]

[0617] Synthesis of compound YL085

[0618] A 25 mL three-neck flask was charged with 85-1 (50 mg, 0.094 mmol), sodium azide (61.00 mg, 0.938 mmol), ammonium chloride (50.19 mg, 0.938 mmol), and N,N-dimethylformamide (4 mL) in that order. The reaction was carried out at 70 °C for 18 h under nitrogen gas protection. LCMS showed the reaction was successful. Ethyl acetate and water were added, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 10:1-5:1) to give YL085 (9.3 mg, 0.016 mmol, 17.21%). LC-MS (ESI): m / z 574.0 (M+H). - ; 1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.07-7.68(m,3H),7.41(d,J=2.5Hz,2H),7.33(dd,J=8.9,5.1Hz,1H),7.09(ddd,J=8.9,7.9,3.1Hz,1 H),6.87(dd,J=9.3,3.1Hz,1H),6.11(dd,J=2.6,1.0Hz,1H),4.03(dtd,J=22.9,10.3,7.7Hz,2H),3.60-3.48(m,2H).

[0619] Example 86: Synthetic route to compound YL086 [ka]

[0620] Synthesis of compound 86-1

[0621] 1-Bromo-7-fluoro-5-trifluoromethylisoquinoline (20.57 mg, 0.070 mmol), compound 34 (30 mg, 0.070 mmol), cesium carbonate (45.59 mg, 0.140 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.10 mg, 0.014 mmol), tris(dibenzylideneacetone)dipalladium (6.41 mg, 0.007 mmol), and 1,4-dioxane (4 mL) were added to a 25 mL three-neck flask in this order. The mixture was reacted at 110 °C for 3 hours under nitrogen gas protection. LCMS showed the reaction was successful, water and ethyl acetate were added, and the organic phase was concentrated and subjected to column chromatography (eluent dichloromethane:methanol = 20:1 to 10:1) to give 86-1 (17.1 mg, 0.027 mmol, 38.07%). LC-MS (ESI): m / z 642.1 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 11.23(s,1H),9.00(s,1H),8.18(ddd,J=28.6,9.5,2.5Hz,2H),7.87(d,J=6.2Hz,1H),7.41(d,J=2.5Hz,1H),7.19-7.01(m,2H),6.94(td, J=8.5,3.1Hz,1H),6.75(s,1H),6.63(dd,J=9.2,3.1Hz,1H),5.92(dd,J=2.5,1.2Hz,1H),4.18-3.87(m,2H),3.16(tt,J=9.6,4.6Hz,2H).

[0622] Synthesis of compound YL086

[0623] A 25 mL single-neck flask was charged with 86-1 (40 mg, 0.062 mmol), lithium hydroxide (7.84 mg, 0.187 mmol), methanol (6 mL), and water (2 mL) in that order. The reaction was allowed to proceed at 70 °C for 3 hours. LCMS analysis showed the reaction was complete. Dichloromethane and water were added, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 20:1 to 15:1) to give YL086 (19.6 mg, 0.036 mmol, 57.62%). LC-MS (ESI): m / z 546.0 (M+H). + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.74(s,1H),8.20(dd,J=10.4,2.5Hz,1H),8.09(dd,J=8.7,2.4Hz,1H),7.83 (d,J=6.2Hz,1H),7.13(d,J=2.6Hz,1H),7.03(dd,J=8.8,5.2Hz,2H),6.90(t d,J=8.4,3.2Hz,1H),6.60(dd,J=9.4,3.1Hz,1H),6.01(s,1H),5.78-5.65(m ,1H),5.23(s,2H),3.95(pd,J=11.0,10.4,6.0Hz,2H),2.97(t,J=8.5Hz,2H).

[0624] Example 87: Synthetic route to compound YL087 [ka]

[0625] Synthesis of compound YL087

[0626] 1-Bromo-7-fluoro-5-trifluoromethylisoquinoline (20.57 mg, 0.070 mmol), compound 34 (30 mg, 0.070 mmol), cesium carbonate (45.59 mg, 0.140 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.10 mg, 0.014 mmol), tris(dibenzylideneacetone)dipalladium (6.41 mg, 0.007 mmol), and 1,4-dioxane (4 mL) were added to a 25 mL three-neck flask in this order. The mixture was reacted at 110 °C for 3 hours under nitrogen gas protection. LCMS showed the reaction was successful, water and ethyl acetate were added, and the organic phase was concentrated and subjected to column chromatography (eluent dichloromethane:methanol = 20:1 to 10:1) to give YL087 (17.1 mg, 0.027 mmol, 38.07%). LC-MS (ESI): m / z 642.1 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 11.23(s,1H),9.00(s,1H),8.18(ddd,J=28.6,9.5,2.5Hz,2H),7.87(d,J=6.2 Hz,1H),7.41(d,J=2.5Hz,1H),7.19-7.01(m,2H),6.94(td,J=8.5,3.1Hz,1H),6.75(s,1H),6.63( dd,J=9.2,3.1Hz,1H),5.92(dd,J=2.5,1.2Hz,1H),4.18-3.87(m,2H),3.16(tt,J=9.6,4.6Hz,2H).

[0627] Example 88: Synthetic route to compound YL088 [ka]

[0628] Synthesis of compound YL088

[0629] A 25 mL single-neck flask was charged with 88-1 (50 mg, 0.096 mmol), cyanamide (8.04 mg, 0.191 mmol), 1,4-dioxane (2 mL), and hydrochloric acid (1,4-dioxane) (0.5 mL) in that order. The reaction was allowed to proceed at 80 °C for 3 h. LCMS analysis showed the reaction was successful. Saturated sodium carbonate solution and ethyl acetate were added to the reaction vial, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 20:1 to 10:1) to give YL088 (22.9 mg, 0.041 mmol, 42.39%). LC-MS (ESI): m / z 565.2 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 9.99(s,1H),7.91(d,J=8.1Hz,1H),7.83(d,J=11.7Hz,2H),7.39-7.19(m,2H),7.07(td,J=8.4,3.1Hz,1H),6.86(dd,J=9.3, 3.1Hz,1H),6.19(s,1H),6.03(t,J=1.9Hz,1H),5.36(s,4H),3.92(pd,J=10.5,7.6Hz,2H),2.96(td,J=7.9,6.7,2.4Hz,2H).

[0630] Example 89: Synthetic route to compound YL089 [ka]

[0631] Synthesis of compound YL089

[0632] A 25 mL three-neck flask was charged with 89-1 (80 mg, 0.141 mmol) and tetrahydrofuran (5 mL). Under nitrogen gas protection, methylmagnesium bromide (0.423 mL, 1 mol / L) was added at -78 °C. The mixture was allowed to react at -78 °C for 0.5 hours. The mixture was then warmed to room temperature and reacted overnight. LCMS showed the reaction was successful. Saturated ammonium chloride and ethyl acetate were added to the reaction mixture, and the organic phase was concentrated and subjected to column chromatography (eluent: dichloromethane:methanol = 20:1 to 10:1) to give YL089 (9.8 mg, 0.017 mmol, 12.25%). LC-MS (ESI): m / z 566.2 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),8.11-7.72(m,3H),7.44(d,J=2.7Hz,1H),7.32(dd,J=8.9,5.2Hz,1H),7.23-7.02(m,1H),6.90-6.66 (m,2H),6.05(dd,J=2.6,1.2Hz,1H),5.06(s,1H),4.11-3.80(m,2H),3.39(t,J=8.7Hz,2H),1.44(d,J=9.4Hz,6H).

[0633] Example 90: Synthesis of Compound YL90 [ka]

[0634] Synthesis of compound 90-2

[0635] Compound 90-1 (280 mg, 0.53 mmol), dichloromethane (8 mL), and trifluoroacetic acid (2 mL) were added to a reaction vial. The mixture was stirred at room temperature under nitrogen gas protection for 1 hour. The reaction mixture was concentrated under reduced pressure, and dichloromethane and saturated aqueous sodium bicarbonate solution were added to dilute the reaction mixture. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The crude product was purified by automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate = 55 / 45 to 45 / 55) to obtain target compound 90-2 (180 mg) as a pale yellow solid. LC-MS (ESI): m / z 429.1 (M+H) + .

[0636] Synthesis of compound 90-4

[0637] To a reaction vial was added compound 90-2 (45 mg, 0.11 mmol), dichloromethane (3 mL), dioxane (0.4 mL), and N,N-diisopropylethylamine (492 mg, 4.1 mmol). o At C, triphosgene (12 mg dissolved in 1 mL of dichloromethane) was added dropwise. o The mixture was stirred at RT for 0.5 hours. Compound 90-3 (31 mg) was added dropwise. The mixture was then further treated in an ice bath. The mixture was stirred for 40 minutes. Dichloromethane and saturated aqueous sodium bicarbonate solution were added and diluted. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The crude product was purified by automated column chromatography (Biotage) (mobile phase: methanol / dichloromethane = 32 / 68 to 40 / 60) to obtain target compound 90-4 (72 mg) as a pale yellow solid. LC-MS (ESI): m / z 674.1 (MH) - .

[0638] Synthesis of compound YL90

[0639] A reaction vial was charged with 90-4 (52 mg, 0.08 mmol), lithium hydroxide (13 mg, 0.54 mmol), methanol (3 mL), and water (1 mL). The mixture was stirred at 60°C under nitrogen gas protection for 4 hours. Dichloromethane and saturated saline solution were added for dilution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The crude product was purified by automated column chromatography (Biotage) (mobile phase: methanol / dichloromethane = 6 / 94 to 9 / 91) to obtain the crude product. Further purification by automated column chromatography (Biotage) (mobile phase: acetonitrile / 10 mM aqueous ammonium bicarbonate = 30 / 70 to 37 / 63) gave the target compound YL090 (18 mg) as a pale yellow solid. LC-MS (ESI): m / z 440.1 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 8.18(d,J=12.4Hz,1H),7.89(dd,J=9.0,4.7Hz,0.47H),7.83-7.75(m,0.50H),7 .41(d,J=6.9Hz,1H),7.32-7.18(m,4H),7.08(dtd,J=11.7,8.4,3.1Hz,1H),6.80 (dt,J=9.3,3.5Hz,1H),6.03-5.93(m,2H),5.23(d,J=3.3Hz,2H),4.31(d,J=12.2 Hz,0.64H),3.99-3.89(m,2H),3.83(t,J=11.9Hz,1.31H),2.95(t,J=8.5Hz,2H).

[0640] Example 91 Synthesis route of compound YL091 [ka]

[0641] Compound 91-2 synthesis

[0642] Compound 91-1 (100 mg, 0.606 mmol) was placed in an 8 mL reaction vial, THF (1.5 mL) was added, the mixture was degassed and purged with nitrogen, and the mixture was placed in an ice-water bath. NaH (21.82 mg, 0.909 mmol) was added, and the mixture was allowed to warm to room temperature for 0.5 h. 2-(trimethylsilyl)ethoxymethyl chloride (151.59 mg, 0.909 mmol) was added, and the mixture was allowed to react at room temperature for 1 h. The mixture was quenched with two drops of saturated ammonium chloride, extracted with ethyl acetate, and purified by column chromatography (petroleum ether:ethyl acetate 3:1) to give compound 91-2 (105 mg, 0.356 mmol, 58.67%) as a colorless liquid. LC-MS (ESI): m / z 295.02 (M+H). + .

[0643] Compound 91-3 synthesis

[0644] Compound 91-2 (42.4 mg, 0.144 mmol), compound 39 (100.13 mg, 0.158 mmol), potassium carbonate (39.70 mg, 0.287 mmol), and Pd(dppf)Cl (10.51 mg, 0.014 mmol) were placed in an 8 mL reaction vial, 1,4-dioxane (1 mL) and water (0.20 mL) were added, degassed, and purged with nitrogen gas. The mixture was heated to 100 °C and reacted for 1.5 hours. The sample was mixed with silica gel and purified by column chromatography (ethyl acetate / petroleum ether = 1:3) to give compound 91-3 (60 mg, 0.079 mmol, 54.96%) as a yellow solid. LC-MS (ESI): m / z 722.17 (M+H). + .

[0645] Synthesis of compound YL091

[0646] Compound 91-3 (50 mg, 0.069 mmol) was placed in a reaction vial, and DCM (6.00 mL) and TFA (2 mL) were added. The reaction was monitored at room temperature for 1 hour. After purification, YL091 (4.5 mg, 0.008 mmol, 10.98%) was obtained. LC-MS (ESI): m / z 592.09 (M+H) + ; 1H NMR(400MHz,DMSO-d6)δ 12.73(s,1H),10.21(s,1H),8.05(d,J=2.1Hz,1H),7.95(d,J=8.4Hz,1H),7.87(d,J=10.3Hz,2H),7.51(d,J=2.6Hz,1H),7. 33(dd,J=8.7,5.1Hz,1H),7.10(td,J=8.6,3.1Hz,1H),6.88(d,J=9.1Hz,2H),6.09(s,1H),4.12-3.96(m,2H),3.28(s,2H).

[0647] Example 92: Synthetic Routes for Compounds YL092-P1 and YL092-P2 [ka]

[0648] Synthesis of compound 92-2

[0649] Compound 92-1 (100 mg, 0.201 mmol), bis(pinacolato)diboron (178.92 mg, 0.705 mmol), potassium acetate (78.91 mg, 0.805 mmol), and Pd(dppf)Cl (29.46 mg, 0.040 mmol) were placed in a reaction vial, and dioxane (2 mL) was added. The mixture was degassed and purged with nitrogen gas, and the reaction was carried out at 100 °C for 2 hours. The reaction was monitored, and the solvent was evaporated by rotary evaporation. The mixture was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain YL92-2 (100 mg, 0.184 mmol, 91.34%) as a yellow oily solid. LC-MS (ESI): m / z 544.21 (M+H). + .

[0650] Synthesis of compound 92-4

[0651] Compound 92-2 (50 mg, 0.092 mmol), compound 92-3 (26.02 mg, 0.092 mmol), potassium carbonate (31.77 mg, 0.230 mmol), and Pd(dppf)Cl (6.73 mg, 0.009 mmol) were placed in a reaction vial, 1,4-dioxane (3 mL) was added, and the mixture was degassed and purged with nitrogen gas at 100 °C overnight. The reaction was monitored, the solvent was removed, and normal phase purification (methanol:dichloromethane = 1:20) gave product 92-4 (17 mg, 0.027 mmol, 29.82%). LC-MS (ESI): m / z 620.14 (M+H). + .

[0652] Synthesis of compound YL092

[0653] Compound 92-4 (15 mg, 0.024 mmol) was dissolved in DCM (1 mL) and trifluoroacetic acid (0.2 mL, 2.612 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored, neutralized with sodium bicarbonate, extracted with ethyl acetate, and purified using normal phase chromatography without separation. Purification afforded compound YL092 (3.7 mg, 0.007 mmol, 27.94%). LC-MS (ESI): m / z 520.09 (M+H). + .

[0654] Synthesis of compounds YL092-P1 and YL092-P2

[0655] YL092-4 (200 mg, 0.323 mmol) was dissolved in DCM (6 mL), and TFA (2 mL, 26.118 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored, alkalized with sodium bicarbonate, extracted with ethyl acetate, and purified using normal phase chromatography without separation. Purification using a reverse phase column gave YL092 (77 mg, 0.141 mmol, 43.62%). LC-MS (ESI): m / z 520.09 (M+H). +Separation by SFC (separation conditions: instrument: SFC-150 (Waters), chromatography column: OD 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / MeOH (0.2% NH3 (7 M in MeOH) = 65 / 35), flow rate: 100 mL / min, back pressure: 100 bar, measurement wavelength: 214 nm) gave compounds YL092-P1 (retention time: 3.245 min) and YL092-P2 (retention time: 3.456 min).

[0656] YL092-P2: 1 H NMR(400MHz,DMSO-d6)δ 13.35(s,1H),7.58(s,1H),7.50-7.17(m,3H),6.98(td,J=8.4,3.1Hz,1H),6.79(d,J=36. 1Hz, 2H), 6.53 (dd, J=9.5, 3.1Hz, 1H), 5.53 (s, 2H), 4.09-3.87 (m, 2H), 3.16-2.97 (m, 2H).

[0657] Example 93: Synthetic route to compound YL093 [ka]

[0658] Synthesis of compound YL093

[0659] Polyphosphoric acid (20 mL) was placed in a two-neck flask and heated to 105 °C. After stable stirring, compound 57-3 (100 mg, 0.224 mmol) and compound 93-2 (78.40 mg, 0.448 mmol) were added and the mixture was allowed to react for 0.5 hours. The mixture was adjusted to alkaline with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and purified by column chromatography (dichloromethane:methanol = 20:1) to give YL093 (70 mg, 0.116 mmol, 51.78%). LC-MS (ESI): m / z 601.96 (M+H). + .

[0660] 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),7.96(dd,J=8.5,2.2Hz,1H),7.88-7.80(m,2H),7.49(d,J=2.4Hz,1H),7.33(d,J=8.6Hz) ,1H),7.28(d,J=2.6Hz,1H),7.06(d,J=2.5Hz,1H),6.92(s,1H),6.03(d,J=2.3Hz,1H),4.16-3.88(m,2H),3.26-3.04(m,2H).

[0661] Example 94: Synthetic route to compound YL094 [ka]

[0662] Synthesis of compound YL094

[0663] Compound YL093 (77 mg, 0.128 mmol), L-proline (5.87 mg, 0.051 mmol), CuI (4.86 mg, 0.026 mmol), and potassium carbonate (52.93 mg, 0.383 mmol) were placed in a reaction vessel, 1 mL of DSMO solvent was added, and the mixture was degassed and purged with nitrogen gas. Aqueous ammonia (25%) (11.19 mg, 0.319 mmol) was added, the mixture was heated to 100 °C, and the reaction was allowed to proceed for 18 hours. The mixture was then diluted with dichloromethane and water. The organic phase was rotary evaporated to give compound YL094 (25 mg, 0.046 mmol, 36.31%). LC-MS (ESI): m / z 539.06 (M+H). + .

[0664] 1 H NMR(500MHz,DMSO-d6)δ 9.93(s,1H),7.92(d,J=8.4Hz,1H),7.88-7.78(m,2H),7.28(d,J=8.5Hz,1H),7.23(dd,J=16.7,2.7Hz,2H),6.96( d,J=2.5Hz,1H),6.00(s,1H),5.89(d,J=2.5Hz,1H),5.31(s,2H),4.03-3.85(m,2H),2.95(td,J=8.2,2.6Hz,2H).

[0665] Example 95: Synthetic route to compound YL095 [ka]

[0666] Synthesis of compound 95-1

[0667] Compound 57-3 (0.4 g, 0.896 mmol) was dissolved in polyphosphoric acid (50 g), and 5-chloro-2-trifluoromethylbenzaldehyde (0.37 g, 1.793 mmol) was added. The mixture was allowed to react at 105 °C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium hydroxide solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 57-4 (260 mg, 45.5%). ESI: (m / z) = 636.1 [M+H]. + .

[0668] Synthesis of compound YL095

[0669] Compound 95-1 (260 mg, 0.408 mmol), potassium carbonate (170 mg, 1.225 mmol), L-proline (19 mg, 0.163 mmol), and copper(I) iodide (15.5 mg, 0.082 mmol) were placed in a reaction vial, dimethyl sulfoxide (3 mL) was added, and under nitrogen gas protection, aqueous ammonia (0.52 g, 4.083 mmol, 25%) was added via syringe. The mixture was heated to 100 °C and reacted overnight. The mixture was then diluted with dichloromethane and water. The organic phase was rotary evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL095 (96 mg, 41%). LCMS (ESI): m / z 573.0 (M+H). + ; 1H NMR(400MHz,DMSO-d6)δ 9.90(s,1H),7.90(d,J=8.0Hz,1H),7.84-7.74(m,2H),7.56(d,J=8.6Hz,1H),7.52-7.45(m,1H),7.09(d,J=2.1Hz,1H),6. 99(d,J=2.7Hz,1H),6.05(s,1H),5.85(d,J=2.7Hz,1H),5.40(s,2H),4.05-3.88(m,2H),3.00(td,J=7.8,6.8,2.9Hz,2H).

[0670] Example 96: Synthetic route to compound YL096 [ka]

[0671] Synthesis of compound 96-1

[0672] Compound 57-3 (0.4 g, 0.896 mmol) was dissolved in polyphosphoric acid (50 g), and 5-fluoro-2-(trifluoromethyl)benzaldehyde (0.34 g, 1.792 mmol) was added. The mixture was allowed to react at 105°C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium hydroxide solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified using a column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 96-1 (450 mg, 80.9%). ESI: (m / z) = 620.1 [M+H] + .

[0673] Synthesis of compound YL096

[0674] Compound 96-1 (260 mg, 0.725 mmol), potassium carbonate (300 mg, 2.176 mmol), L-proline (33 mg, 0.29 mmol), and copper(I) iodide (27.6 mg, 0.145 mmol) were placed in a reaction vial, dimethyl sulfoxide (5 mL) was added, and under nitrogen gas protection, aqueous ammonia (0.9 g, 7.255 mmol, 25%) was added via syringe. The mixture was heated to 100 °C and reacted overnight. The mixture was then diluted with dichloromethane and water. The organic phase was rotary evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL096 (176 mg, 43.6%). LCMS (ESI): m / z 557.1 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 9.90(s,1H),7.90(d,J=8.3Hz,1H),7.84-7.75(m,2H),7.62(dd,J=8.9,5.4Hz,1H),7.27(td,J=8.3,2.6Hz,1H),6.96(d,J=2.8Hz,1H),6 .87(dd,J=9.9,2.6Hz,1H),6.06(s,1H),5.86(s,1H),5.39(s,2H),3.96(dtd,J=28.6,10.3,7.2Hz,2H),3.00(td,J=7.7,6.7,3.3Hz,2H).

[0675] Example 97: Synthetic route to compound YL097 [ka]

[0676] Synthesis of compound 97-1

[0677] Compound 57-3 (0.4 g, 0.896 mmol) was dissolved in polyphosphoric acid (50 g), and 2-chloro-5-trifluoromethylbenzaldehyde (0.37 g, 1.792 mmol) was added. The mixture was allowed to react at 105°C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium hydroxide solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified using a column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 97-1 (420 mg, 73.6%). ESI: (m / z) = 636.1 [M+H]. + .

[0678] Synthesis of compound YL097

[0679] Compound 97-1 (420 mg, 0.66 mmol), potassium carbonate (273 mg, 1.98 mmol), L-proline (30 mg, 0.264 mmol), and copper(I) iodide (25 mg, 0.132 mmol) were placed in a reaction vial, dimethyl sulfoxide (5 mL) was added, and under nitrogen gas protection, aqueous ammonia (0.8 g, 6.596 mmol, 25%) was added via syringe. The mixture was heated to 100 °C and reacted overnight. The mixture was then diluted with dichloromethane and water. The organic phase was rotary evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL097 (130 mg, 34.4%). LCMS (ESI): m / z 573.1 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 9.89(s,1H),7.91(d,J=8.5Hz,1H),7.83-7.76(m,2H),7.51(d,J=1.3Hz,2H),7.24(s,1H),7.14(d,J =2.4Hz,1H),5.98(d,J=1.9Hz,2H),5.29(s,2H),3.95(t,J=8.4Hz,2H),2.94(dd,J=9.7,7.3Hz,2H).

[0680] Example 98: Synthetic route to compound YL098 [ka]

[0681] Synthesis of compound 98-1

[0682] Compound 57-3 (0.4 g, 0.896 mmol) was dissolved in polyphosphoric acid (50 g), and 2-chloro-5-trifluoromethylbenzaldehyde (0.35 g, 1.792 mmol) was added. The mixture was allowed to react at 105°C for 1 hour. The reaction mixture was added dropwise to a cold saturated sodium hydroxide solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified using a column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 98-1 (420 mg, 75.5%). ESI: (m / z) = 620.1 [M+H] + .

[0683] Synthesis of compound YL098

[0684] Compound 98-1 (420 mg, 0.67 mmol), potassium carbonate (280 mg, 2.03 mmol), L-proline (31 mg, 0.27 mmol), and copper(I) iodide (25 mg, 0.135 mmol) were placed in a reaction vial, dimethyl sulfoxide (5 mL) was added, and under nitrogen gas protection, aqueous ammonia (0.85 g, 6.76 mmol, 25%) was added via syringe. The mixture was heated to 100 °C and reacted overnight. The mixture was then diluted with dichloromethane and water. The organic phase was rotary evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound YL098 (85 mg, 22.6%). LCMS (ESI): m / z 557.1 (M+H). + ; 1H NMR(400MHz,DMSO-d6)δ 9.89(s,1H),7.92(d,J=8.3Hz,1H),7.86-7.79(m,2H),7.49(d,J=9.1Hz,1H),7.16(d,J=2.4Hz,1H),7.07( d,J=7.9Hz,1H),5.99(s,1H),5.87(d,J=2.4Hz,1H),5.30(s,2H),4.00-3.88(m,2H),2.96(d,J=9.5Hz,2H).

[0685] Example 99: Synthesis of compound YL099 [ka]

[0686] Synthesis of compound 99-1

[0687] 92-1 (220 mg, 0.443 mmol) was dissolved in 1,4-dioxane (5 mL), potassium acetate (175 mg, 1.771 mmol), biboronic acid pinacol ester (395 mg, 1.55 mmol), and Pd(dppf)Cl2 (65 mg, 0.089 mmol) were added, and the mixture was stirred at 100 °C for 2 h. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 99-1 (90 mg, 37.5%). ESI: (m / z) = 544.3 [M+H] + .

[0688] Synthesis of compound 99-2

[0689] 99-1 (90 mg, 0.166 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). Potassium carbonate (92 mg, 0.663 mmol), 2-bromo-6-chloro-1H-benzimidazole (42 mg, 0.182 mmol), and Pd(dppf)Cl2 (24 mg, 0.033 mmol) were added, and the mixture was stirred at 100 °C overnight and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 99-2 (40 mg, 42.5%). ESI: (m / z) = 568.1 [M+H]. + .

[0690] Synthesis of compound YL099

[0691] 99-2 (40 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then adjusted to alkaline with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give compound YL099 (9 mg, 27%). ESI: (m / z) = 468.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 12.69(s,1H),7.53-7.27(m,4H),7.15(dd,J=8.6,2.0Hz,1H),6.98(td,J=8.4,3.1Hz,1H),6.86(dd,J=3.6 ,1.4Hz,1H),6.71(s,1H),6.51(dd,J=9.5,3.1Hz,1H),5.46(s,2H),4.00-3.89(m,2H),3.10-2.99(m,2H).

[0692] Example 100: Synthetic Route to Compound YL100 [ka]

[0693] Synthesis of Compound 100-1

[0694] 99-1 (50 mg, 0.092 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). Potassium carbonate (51 mg, 0.368 mmol), 2-bromo-5,6-chloro-1H-benzimidazole (27 mg, 0.101 mmol), and Pd(dppf)Cl2 (13.5 mg, 0.018 mmol) were added, and the mixture was stirred at 100 °C for 3 h. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 100-1 (30 mg, 54%). ESI: (m / z) = 602.1 [M+H]. + .

[0695] Synthesis of compound YL100

[0696] 100-1 (30 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then adjusted to alkaline with saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give compound YL100 (12 mg, 48%). ESI: (m / z) = 502.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 12.89(s,1H),7.71(s,1H),7.60(s,1H),7.40-7.34(m,2H),6.99(ddd,J=8.9, 8.0,3.1Hz,1H),6.81(dd,J=3.6,1.4Hz,1H),6.69(s,1H),6.53(dd,J=9.5,3.2 Hz,1H),5.49(s,2H),3.96(td,J=9.1,4.1Hz,2H),3.05(t,J=8.6Hz,2H).

[0697] Example 101: Synthetic Route to Compounds YL101-P1 and YL101-P2 [ka]

[0698] Synthesis of Compound 101-1

[0699] 57-3 (4 g, 8.965 mmol) was dissolved in polyphosphoric acid (50 g), and 2,5-dichlorobenzaldehyde (6.06 g, 22.413 mmol) was added. The mixture was reacted at 105°C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium hydroxide solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 101-1 (2.5 g, 46.21%). ESI: (m / z) = 603.9 [M+H] + .

[0700] Synthesis of compounds YL101-P1 and YL101-P2

[0701] 101-1 (2.5 g, 4.268 mmol) was dissolved in DMF (15 mL), and zinc cyanide (1 g, 8.536 mmol) and Pd(PPh3)4 (0.74 g, 0.64 mmol) were added. The mixture was stirred at 100 °C overnight. 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 sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The column was purified (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) and separated by SFC (SFC separation conditions: SFC-150 (Waters), chromatographic column: AS 20 × 250 mm, 10 μm (Daicel), mobile phase: CO₂ / MeOH [0.2% NH₃ (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm) to obtain compounds YL101-P1 (0.7 g) and YL101-P2 (0.9 g). ESI: (m / z) = 549.1 [M+H]. + .

[0702] YL101-P1 (holding time: 0.56min): 1 H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),7.96(dt,J=8.5,2.0Hz,1H),7.89-7.76(m,2H),7.56(d,J=2.3Hz,1H),7.34(d,J=8.6Hz,1H),7.28(dd,J=8 .6,2.5Hz,1H),7.14(s,1H),7.09(d,J=2.5Hz,1H),6.12(d,J=2.3Hz,1H),4.07(td,J=8.4,5.8Hz,2H),3.42-3.35(m,2H).

[0703] YL101-P2 (holding time: 1.21min): 1H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),7.96(dt,J=8.5,1.9Hz,1H),7.88-7.79(m,2H),7.56(d,J=2.3Hz,1H),7.34(d,J=8.6Hz,1H),7.28(dd ,J=8.6,2.5Hz,1H),7.14(s,1H),7.09(d,J=2.5Hz,1H),6.12(d,J=2.2Hz,1H),4.13-4.00(m,2H),3.45-3.35(m,2H).

[0704] Example 102 Synthesis route of compound YL102 (102-P1 & 102-P2) [ka]

[0705] Synthesis of Compound 102-2

[0706] 7-Bromo-5-nitro-1H-indazole (compound 102-1, 22 g, 90.898 mmol) was dissolved in DMF (250 mL), potassium hydroxide (20.4 g, 363.591 mmol) was added, and the mixture was degassed and purged with N2. Iodine (46.14 g, 181.8 mmol) was added, and the reaction was carried out at 70 °C for 4 hours. The reaction solution was washed twice with 5% aqueous sodium thiosulfate solution, and the aqueous phase was adjusted to weak acidity using aqueous citric acid, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated, and pulped three times with dichloromethane / methanol (10 / 1). The solid was collected and the filtrate was further purified by column chromatography (mobile phase: dichloromethane / methanol = 1 / 0 to 20 / 1) to give compound 102-2 (27 g, 80.74%).

[0707] Synthesis of compound 102-3

[0708] 102-2 (15 g, 40.769 mmol) was dissolved in ethyl acetate (650 mL), trimethyloxonium tetrafluoroborate (9.05 g, 61.153 mmol) was added, and the mixture was degassed and purged with N2, followed by overnight reaction at room temperature. A solid precipitated from the reaction mixture, which was filtered. The filtrate was rotary evaporated and pulped with dichloromethane / methanol to give crude compound 102-3 (11.7 g, 75.13%). ESI: (m / z) = 382.0 [M+H] + .

[0709] Synthesis of compound 102-4

[0710] 102-3 (11.7 g, 30.631 mmol) was dissolved in DMF (100 mL) and methanol (100 mL), triethylamine (13 mL, 91.894 mmol), and Pd(dppf)Cl (2.24 g, 3.063 mmol) were added, and the mixture was degassed and purged with CO gas. The reaction mixture was then heated at 70 °C for 8 h. The methanol was removed by rotary evaporation, and the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / dichloromethane 40% / 60%) to give compound 102-4 (1.6 g, 16.63%). ESI: (m / z) = 314.0 [M+H]. + .

[0711] Synthesis of compound 102-5

[0712] 102-4 (1.6 g, 5.094 mmol) was dissolved in ethanol (20 mL) and water (4 mL), and solid ammonium chloride (0.82 g, 15.282 mmol) and iron powder (1.42 g, 25.47 mmol) were added. The mixture was reacted at 70 °C for 4 hours. The reaction mixture was filtered through diatomaceous earth, washed with dichloromethane, and rotary evaporated to give compound 102-5 (1.4 g, 96.5%). ESI: (m / z) = 284.0 [M+H] + .

[0713] Synthesis of compound 102-6

[0714] 102-5 (1.4 g, 4.928 mmol) was dissolved in dichloromethane (30 mL), triethylamine (2.055 mL, 14.783 mmol) was added, degassed, and purged with N2. The mixture was cooled to 0 °C, and 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1.67 g, 7.392 mmol) was added and reacted at room temperature for 1 h. A solid precipitated from the reaction mixture, which was filtered. The filtrate was rotary evaporated and then pulped with dichloromethane. The filtrate was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 102-6 (2.12 g, 90.6%). ESI: (m / z) = 475.9 [M+H]. + .

[0715] Synthesis of compound 102-7

[0716] 102-6 (2.1 g, 4.428 mmol) was dissolved in tetrahydrofuran (120 mL) and water (50 mL), and lithium hydroxide (0.56 g, 13.285 mmol) was added. The mixture was allowed to react at 50 °C for 2 hours. The tetrahydrofuran was evaporated by rotary evaporation, and 1 mol / L dilute hydrochloric acid was added to adjust the pH to 3-4. The solid precipitated, which was extracted with ethyl acetate and rotary evaporated to give the crude product of compound 102-7 (2.18 g, crude). ESI: (m / z) = 458.0 [MH] + .

[0717] Synthesis of compound 102-8

[0718] 102-7 (2.18 g, 4.737 mmol) was dissolved in DMF (20 mL), and solid ammonium chloride (0.51 g, 9.475 mmol), HATU (2.7 g, 7.106 mmol), and DIEA (1.84 g, 14.212 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction 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, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 102-8 (2.1 g, 96.3%). ESI: (m / z) = 458.9 [M+H]+ .

[0719] Synthesis of compound 102-9

[0720] 102-8 (1.9 g, 4.138 mmol) was dissolved in Eaton's reagent (20 mL), and 2-chloro-5-fluorobenzaldehyde (0.79 g, 4.965 mmol) was added. The mixture was reacted at 80°C for 2 hours. The reaction 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 phase was washed with water, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate ~ 3 / 1) to give compound 102-9 (600 mg, 24.2%). ESI: (m / z) = 598.9 [M+H] + .

[0721] Synthesis of compounds YL102-P1 and YL102-P2

[0722] 102-9 (200 mg, 0.333 mmol) was dissolved in DMF (2 mL), and zinc hydroxide (78 mg, 0.667 mmol) and Pd(PPh3)4 (57.8 mg, 0.05 mmol) were added. The mixture was reacted in a microwave oven at 120 °C for 1 hour. The reaction 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 aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The column was purified (mobile phase: petroleum ether / ethyl acetate 3 / 1) and separated by SFC (SFC separation conditions: SFC-150 (Waters), AS 20 × 250 mm, 10 μm (Daicel), mobile phase: CO₂ / MeOH [0.2% NH₃ (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm) to give compound YL102-P1 (17 mg, 9.4%) and compound YL102-P2 (15 mg, 8.25%).

[0723] Compound YL102-P1 (retention time: 0.38 min): H NMR: 1 H NMR(400MHz,DMSO-d6)δ 10.47(s,1H),8.78(d,J=2.2Hz,1H),7.98(d,J=8.4Hz,1H),7.87(s,1H),7.81(d,J=9.0Hz,1H),7.77(s,1 H),7.32(dd,J=8.8,5.1Hz,1H),7.12-7.03(m,1H),7.01(dd,J=9.1,3.1Hz,1H),6.45(s,1H),4.50(s,3H).

[0724] Compound YL102-P2 (holding time: 0.8 min): H NMR: 1 H NMR(400MHz,DMSO-d6)δ 10.48(s,1H),8.78(d,J=2.2Hz,1H),7.98(d,J=8.4Hz,1H),7.87(s,1H),7.81(d,J=9.4Hz,1H),7.77(s,1 H),7.32(dd,J=8.8,5.1Hz,1H),7.07(td,J=8.4,3.1Hz,1H),7.04-6.98(m,1H),6.46(s,1H),4.50(s,3H).

[0725] Synthetic route of compound YL103

change

[0726] Synthesis of compound 103-2

[0727] Compound 103-1 (9640 mg, 39.993 mmol), potassium carbonate (16581.10 mg, 119.979 mmol), and N,N-dimethylformamide (80 mL) were added sequentially to a 250 mL three-neck flask. The mixture was cooled to 0 °C, and iodomethane (12.983 mL, 159.973 mmol) was added. The mixture was then heated to 50 °C and reacted overnight. LCMS showed the reaction was complete. Water and ethyl acetate were added, and the organic phase was concentrated and subjected to column chromatography (eluent: petroleum ether:ethyl acetate 20:1 to 10:1) to give 103-2 (3500 mg, 13.006 mmol, 32.52%). LC-MS (ESI): m / z 269.0 (M+H). + .

[0728] Compound 103-3 synthesis

[0729] A 100 mL three-neck flask was charged with 103-2 (725 mg, 2.694 mmol), 3-fluoro-5-(trifluoromethyl)benzamide (837.06 mg, 4.041 mmol), cesium carbonate (1755.63 mg, 5.388 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (311.79 mg, 0.539 mmol), tris(dibenzylideneacetone)dipalladium (246.71 mg, 0.269 mmol), and 1,4-dioxane (20 mL), in that order. The mixture was reacted at 80 °C for 5 h under nitrogen gas protection. LCMS showed the reaction was successful. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with a large amount of ethyl acetate, and the organic phase was concentrated and subjected to column chromatography (eluent: petroleum ether:ethyl acetate 5:1 to 1:1) to give 103-3 (825 mg, 2.087 mmol, 77.46%). LC-MS (ESI): m / z 396.1 (M+H). + .

[0730] Synthesis of compound 103-4

[0731] 5-(3-Fluoro-5-trifluoromethyl)benzamido-2-methyl-2H-indazole-3-carboxylate (compound 103-3, 790 mg, 2 mmol), lithium hydroxide (144 mg, 6 mmol), tetrahydrofuran (10 mL), and water (5 mL) were added sequentially to a 50 mL three-neck flask. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, excess tetrahydrofuran was removed by rotary evaporation, and 1N hydrochloric acid was added to adjust the pH to 2. The resulting mixture was then filtered and lyophilized to give 103-4 (530 mg, 1.390 mmol, 69.56%). LC-MS (ESI): m / z 382.1 (M+H). + .

[0732] Synthesis of compound 103-5

[0733] A 50 mL three-neck flask was charged with 103-4 (530 mg, 1.390 mmol), ammonium chloride (111.53 mg, 2.085 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (399.70 mg, 2.085 mmol), 1-hydroxybenzotriazole (281.75 mg, 2.085 mmol), N,N-diisopropylethylamine (538.98 mg, 4.170 mmol), and N,N-dimethylformamide (10 mL), in that order. The reaction was carried out at room temperature under nitrogen gas protection for 6 hours. After the reaction was completed, a large amount of water was added, the mixture was filtered, and the filter cake was lyophilized to give 103-5 (400 mg, 1.052 mmol, 75.67%). LC-MS (ESI): m / z 381.2 (M+H). + .

[0734] Synthesis of compound YL103

[0735] A 50 mL three-neck flask was charged with 103-5 (100 mg, 0.263 mmol), 2-chloro-5-fluorobenzaldehyde (62.54 mg, 0.394 mmol), and Eaton's reagent (5 mL) in that order. The reaction was carried out at 80 °C for 2 hours under nitrogen gas protection. LCMS showed the reaction was complete, and the reaction solution was poured into a cold sodium bicarbonate solution, ethyl acetate was added, and the organic phase was concentrated and reverse-phase purified to give compound YL103 (20 mg, 0.038 mmol, 14.60%). LC-MS (ESI): m / z 521.1 (M+H). + ; 1 H NMR(400MHz,DMSO-d6)δ 10.41(s,1H),8.45(d,J=2.2Hz,1H),8.00-7.91(m,1H),7.83(dd,J=9.2,2.3Hz,1H),7.76(s,1H),7.66(dd,J=8.8,1.0Hz,1H),7.31(dd ,J=8.9,5.2Hz,1H),7.18(d,J=8.8Hz,1H),7.06(td,J=8.4,3.1Hz,1H),6.90(dd,J=9.3,3.1Hz,1H),6.41(d,J=2.0Hz,1H),4.44(s,3H).

[0736] Synthetic route for compound YL104 (104-P1 and 104-P2) [ka]

[0737] Synthesis of compound YL104 (104-P1 and 104-P2)

[0738] A 50 mL three-neck flask was charged with 130 mg (0.342 mmol), 2,5-dichlorobenzaldehyde (89.74 mg, 0.513 mmol), and Eaton's reagent (5 mL) in that order. The reaction was carried out at 80 °C for 2 h under nitrogen gas protection. LCMS showed the reaction was complete. Ethyl acetate and aqueous sodium hydroxide were added to the reaction mixture, and the organic phase was concentrated and purified by reverse phase chromatography to give YL104 (37 mg, 0.069 mmol, 20.14%). Separation by SFC yielded 104-P1 (10 mg) and 104-P2 (17 mg).

[0739] 104-P1 (10 mg) (retention time: 0.81 min): LC-MS (ESI): m / z 537.0 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 10.41(s,1H),8.42(d,J=2.2Hz,1H),7.96(dt,J=8.5,1.9Hz,1H),7.82(dt,J=9.4,1.9Hz,1H),7.74(s,1H),7.66(dd,J=8.8,1.1H z,1H),7.32(d,J=8.5Hz,1H),7.25(dd,J=8.5,2.6Hz,1H),7.16(d,J=8.9Hz,1H),7.08(d,J=2.5Hz,1H),6.34(s,1H),4.44(s,3H).

[0740] 104-P2 (17mg) (retention time: 1.31min): LC-MS (ESI): m / z 537.0 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ 10.45(s,1H),8.42(d,J=2.2Hz,1H),7.95(d,J=8.4Hz,1H),7.84(d,J=9.1Hz,1H),7.75(s,1H),7.65(dd,J=8.8,1.1Hz,1H) ,7.32(d,J=8.5Hz,1H),7.24(dd,J=8.6,2.6Hz,1H),7.17(d,J=8.9Hz,1H),7.10(d,J=2.6Hz,1H),6.35(s,1H),4.44(s,3H).

[0741] The conditions for SFC separation were as follows: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, circulation time: 13.8 min.

[0742] Synthetic route to compound YL105 [ka]

[0743] Synthesis of compound 105-2

[0744] 102-8 (300 mg, 0.5 mmol) was dissolved in 1,4-dioxane (8 mL), biboronic acid pinacol ester (445 mg, 1.751 mmol), potassium acetate (196 mg, 2.001 mmol), and Pd(dppf)Cl (73.2 mg, 0.1 mmol) were added, and the mixture was degassed and purged with N. The reaction mixture was then heated at 100 °C for 1 h. The reaction mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product of compound 105-2 (300 mg, crude).

[0745] Synthesis of compound YL105

[0746] 105-2 (300 mg, 0.531 mmol), 5-bromo-3(trifluoromethyl)pyrazole (114 mg, 0.531 mmol), potassium carbonate (220 mg, 1.594 mmol), and Pd(dppf)Cl2 (38.8 mg, 0.053 mmol) were placed in a reaction vial, dioxane (2 mL) and water (0.4 mL) were added, and the mixture was degassed and purged with nitrogen gas. The reaction was carried out at 105 °C for 1 hour. Extraction with ethyl acetate and water and rotary evaporation afforded compound YL105 (12 mg, 3.4%). LCMS (ESI): m / z 655.0 (M+H) + ;1 H NMR(400MHz,DMSO-d6)δ 10.50(s,1H),8.63(d,J=2.1Hz,1H),7.98(d,J=8.4Hz,1H),7.89-7.81(m,2H),7.79(s,1H),7.58(s,1H),7.3 3(dd,J=8.8,5.1Hz,1H),7.08(td,J=8.4,3.1Hz,1H),6.97(dd,J=9.1,3.1Hz,1H),6.42(s,1H),4.53(s,3H).

[0747] Synthetic route to compound YL106 [ka]

[0748] Synthesis of compound 106-2

[0749] 2-Amino-6-cyanopyridine (compound 106-1, 15 g, 125.91 mmol) was dissolved in dichloromethane (60 mL) and methanol (60 mL), and tetrabutylammonium tribromide (69.82 g, 144.8 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction 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 phase was washed with water, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate 3 / 1) to give compound 106-2 (10.2 g, 40.11%).

[0750] Synthesis of compound 106-4

[0751] 106-2 (10.2 g, 51.51 mmol) was dissolved in isopropanol (150 mL), N,N-dimethylformamide dimethyl acetal (7.98 g, 66.96 mmol) was added, and the mixture was reacted at 80 °C for 3 hours to obtain crude product 106-3. The temperature of the reaction mixture was lowered to 50 °C, and hydroxylamine hydrochloride (4.65 g, 66.96 mmol) was added, followed by overnight reaction at 50 °C. The reaction mixture was directly filtered, and the filter cake was washed with ethanol to obtain compound 106-4 (10 g, 80.52%). ESI: (m / z) = 241.0 [M+H] + .

[0752] Synthesis of compound 106-5

[0753] 106-4 (5 g, 20.743 mmol) was dissolved in tetrahydrofuran (50 mL), the temperature of the reaction mixture was lowered to 0 °C, trifluoroacetic anhydride (8.71 g, 41.485 mmol) was added dropwise, and the mixture was reacted at 60 °C overnight. The reaction 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 aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate ~ 2 / 1) to give compound 106-5 (1.1 g, 23.76%). ESI: (m / z) = 223.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.73 (s, 1H), 8.20 (d, J = 9.5Hz, 1H), 8.06 (d, J = 9.5Hz, 1H).

[0754] Synthesis of compound YL106 (106-P1 & 106-P2)

[0755] 105-2 (200 mg, 0.309 mmol), 106-5 (70 mg, 0.308 mmol), potassium carbonate (128 mg, 0.923 mmol), and Pd(dppf)Cl2 (22.6 mg, 0.031 mmol) were placed in a reaction vial, dioxane (2 mL) and water (0.4 mL) were added, and the mixture was degassed and purged with nitrogen gas. The mixture was reacted at 100 °C for 1.5 h, extracted with ethyl acetate and water, and rotary evaporated. The mixture was then separated by SFC (SFC separation conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)]=45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm), compound YL106-P1 (9 mg) and compound YL106-P2 (YL-16572) (28 mg) were obtained. LCMS(ESI):m / z 663.0(M+H) + .

[0756] Compound YL106-P1: 1 H NMR(400MHz,DMSO-d6)δ 10.56(s,1H),8.81(s,1H),8.67(s,1H),8.39(d,J=9.3Hz,1H),8.19(d,J=9.3Hz,1H),7.97(d,J=8.7Hz,1H),7.90-7.78( m,2H),7.61(s,1H),7.36(dd,J=8.9,5.2Hz,1H),7.12(d,J=8.2Hz,1H),7.01(d,J=9.1Hz,1H),6.48(s,1H),4.48(s,3H).

[0757] Compound YL106-P2: 1H NMR(400MHz,DMSO-d6)δ 10.56(s,1H),8.81(s,1H),8.66(s,1H),8.39(d,J=9.3Hz,1H),8.19(d,J=9.3Hz,1H),7.97(d,J=8.3Hz,1H),7.85(d,J=9.1Hz ,1H),7.80(s,1H),7.61(s,1H),7.36(dd,J=8.9,5.1Hz,1H),7.14-7.07(m,1H),7.03-6.97(m,1H),6.48(s,1H),4.48(s,3H).

[0758] Synthetic route of compound YL107 [ka]

[0759] Synthesis of compound 107-1

[0760] 102-7 (1.5 g, 3.267 mmol) was dissolved in Eaton's reagent (20 mL), and 2,5-dichlorobenzene-1-carboxaldehyde (0.74 g, 4.247 mmol) was added. The mixture was allowed to react at 80°C for 2 hours. The reaction 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 phase was washed with water, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate 3 / 1) to give compound 107-1 (450 mg, 22.4%). ESI: (m / z) = 617.0 [M+H] + .

[0761] Synthesis of compound 107-2

[0762] 107-1 (100 mg, 0.162 mmol) was dissolved in 1,4-dioxane (2 mL), biboronic acid pinacol ester (62 mg, 0.243 mmol), potassium acetate (48 mg, 0.487 mmol), and Pd(dppf)Cl (24 mg, 0.032 mmol) were added, and the reaction mixture was heated at 80 °C for 2 h. The reaction mixture was used directly in the next step.

[0763] Synthesis of compound YL107

[0764] Compound YL107-2 (142 mg, 0.387 mmol), potassium carbonate (64 mg, 0.465 mmol), and Pd(dppf)Cl2 (11 mg, 0.015 mmol) were placed in a reaction vial, dioxane (1 mL) and water (0.2 mL) were added, and the mixture was degassed and purged with nitrogen gas. The reaction was carried out at 100 °C for 1 hour. After extraction with ethyl acetate and water and rotary evaporation, compound YL107 (38 mg) was obtained. LCMS (ESI): m / z 679.0 (M+H) + .

[0765] Compound YL107: 1 H NMR(400MHz,DMSO-d6)δ 10.60(s,1H),8.81(s,1H),8.62(s,1H),8.38(d,J=9.3Hz,1H),8.19(d,J=9.3Hz,1H),7.97(d,J=8.5Hz,1H),7.84(d,J=9.5Hz,1H) ),7.78(s,1H),7.59(s,1H),7.37(d,J=8.5Hz,1H),7.29(dd,J=8.5,2.5Hz,1H),7.18(d,J=2.6Hz,1H),6.42(s,1H),4.48(s,3H).

[0766] Synthetic route for compound YL108 (108-P1 & 108-P2) [ka]

[0767] Synthesis of compound YL108 (108-P1 & 108-P2)

[0768] 39 (200 mg, 0.341 mmol), 106-5 (76 mg, 0.341 mmol), potassium carbonate (141 mg, 1.023 mmol), and Pd(dppf)Cl2 (25 mg, 0.034 mmol) were placed in a reaction vial, dioxane (2 mL) and water (0.4 mL) were added, and the mixture was degassed and purged with nitrogen gas. The reaction was then carried out at 100 °C for 1.5 h. The product was extracted with ethyl acetate and water, and the mixture was rotary evaporated. The product was then separated by SFC (conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)]=45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, circulation time: 13.8 min), compound YL108-P1 (13 mg) and compound YL108-P2 (63 mg) were obtained. LCMS(ESI):m / z 650.0(M+H) + .

[0769] Compound YL108-P1 (retention time: 1.74min): 1 H NMR(400MHz,DMSO-d6)δ 10.34(s,1H),8.78(s,1H),8.32(d,J=9.3Hz,1H),7.99-7.85(m,4H),7.64(d,J=2.6Hz,1H),7.37(dd,J=8.9,5.2Hz,1H),7.14( td,J=8.3,3.0Hz,1H),7.00(s,1H),6.95(dd,J=9.2,3.0Hz,1H),6.19(s,1H),4.13-3.95(m,2H),3.23(dd,J=10.7,7.0Hz,2H).

[0770] Compound YL108-P2 (retention time: 3.45min): 1H NMR(400MHz,DMSO-d6)δ 10.34(s,1H),8.78(s,1H),8.32(d,J=9.2Hz,1H),8.00-7.85(m,4H),7.64(s,1H),7.37(dd,J=8.8,5.2Hz,1H),7.14(td, J=8.3,3.1Hz,1H),7.00(s,1H),6.95(dd,J=9.2,3.1Hz,1H),6.18(d,J=2.5Hz,1H),4.14-3.95(m,2H),3.29-3.19(m,2H).

[0771] Synthetic route for compound YL109 (109-P1 & 109-P2) [ka]

[0772] Synthesis of compound YL109-1 (109-P1 & 109-P2)

[0773] 093 (100 mg, 0.162 mmol) was dissolved in 1,4-dioxane (2 mL), biboronic acid pinacol ester (62 mg, 0.243 mmol), potassium acetate (48 mg, 0.487 mmol), and Pd(dppf)Cl (24 mg, 0.032 mmol) were added, and the mixture was reacted at 80 °C for 2 h to give crude 109-1, which was used directly in the next step.

[0774] 109-1 (200 mg, 0.308 mmol), 106-5 (70 mg, 0.308 mmol), potassium carbonate (127 mg, 0.923 mmol), and Pd(dppf)Cl2 (22.5 mg, 0.031 mmol) were placed in a reaction vial, dioxane (2 mL) and water (0.4 mL) were added, and the mixture was degassed and purged with nitrogen gas. The mixture was reacted at 100 °C for 1.5 h, extracted with ethyl acetate and water, and rotary evaporated. The mixture was then separated by SFC (SFC chiral separation conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)]=45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm), compound YL109-P1 (15 mg) and compound YL109-P2 (54 mg) were obtained. LCMS(ESI):m / z 666.0(M+H) + .

[0775] Compound YL109-P1 (retention time: 1.08min): 1 H NMR(400MHz,DMSO-d6)δ 10.33(s,1H),8.78(s,1H),8.31(d,J=9.3Hz,1H),7.99-7.84(m,4H),7.56(s,1H),7.38(d,J=8.6Hz,1H),7.31(dd, J=8.5,2.5Hz,1H),7.11(d,J=2.6Hz,1H),6.97(s,1H),6.15(d,J=2.4Hz,1H),4.10-3.94(m,2H),3.28-3.19(m,2H).

[0776] Compound YL109-P2 (retention time: 2.32min): 1 H NMR(400MHz,DMSO-d6)δ 10.33(s,1H),8.78(s,1H),8.31(d,J=9.2Hz,1H),8.00-7.83(m,4H),7.56(d,J=2.4Hz,1H),7.11(d ,J=2.5Hz,1H),6.97(s,1H),6.15(d,J=2.4Hz,1H),4.05(td,J=10.3,7.1Hz,2H),3.28-3.17(m,2H).

[0777] Synthetic route to compound YL110 [ka]

[0778] 39 (250 mg, 0.426 mmol), 106-5 (90 mg, 0.426 mmol), potassium carbonate (177 mg, 1.278 mmol), and Pd(dppf)Cl2 (31.2 mg, 0.043 mmol) were placed in a reaction vial, dioxane (2 mL) and water (0.4 mL) were added, and the mixture was degassed and purged with nitrogen gas. The reaction was allowed to proceed at 100 °C for 1 hour. After extraction with ethyl acetate and water and rotary evaporation, compound YL110 (52 mg) was obtained. LCMS (ESI): m / z 639.3 (M+H). + .

[0779] Compound YL110: 1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.57(s,1H),7.94(d,J=8.5Hz,1H),7.90-7.77(m,3H),7.65(d,J=9.2Hz,1H),7.55(d,J=2.6Hz,1H),7.36(dd,J=8.8,5.1Hz,1H ),7.12(td,J=8.4,3.1Hz,1H),6.96(dd,J=9.2,3.1Hz,1H),6.75(s,1H),6.18-6.12(m,1H),4.01(h,J=10.1Hz,2H),3.07(s,2H),2.67(s,3H).

[0780] Synthetic route for compound YL111 (111-P1 & 111-P2) [ka]

[0781] Synthesis of compound YL111 (111-P1 & 111-P2)

[0782] 107-1 (200 mg, 0.333 mmol) was dissolved in DMF (2 mL), and zinc cyanide (76 mg, 0.667 mmol) and Pd(PPh3)4 (56.3 mg, 0.05 mmol) were added. The mixture was then heated at 120 °C for 1 hour using a microwave. The reaction 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 aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate 3 / 1). Acid preparation was then performed, followed by separation by SFC (SFC separation conditions: instrument: SFC-150 (Waters); chromatography column: AS 20 × 250 mm, 10 μm (Daicel); mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55; flow rate: 120 g / min; back pressure: 100 bar; measurement wavelength: 214 nm), to give compound YL111-P1 (19 mg) and compound YL111-P2 (15.5 mg).

[0783] Compound YL111-P1 (retention time: 0.38min): 1 H NMR(400MHz,DMSO-d6)δ 10.48(s,1H),8.72(d,J=2.2Hz,1H),8.02-7.95(m,1H),7.85(s,1H),7.82-7.77(m,1H),7.75(s,1H) ),7.33(d,J=8.5Hz,1H),7.26(dd,J=8.5,2.5Hz,1H),7.22-7.17(m,1H),6.40(s,1H),4.51(s,3H).

[0784] Compound YL111-P2 (retention time: 0.84min): 1 H NMR(400MHz,DMSO-d6)δ 10.48(s,1H),8.72(d,J=2.2Hz,1H),8.02-7.95(m,1H),7.85(s,1H),7.82-7.77(m,1H),7.75(s,1H) ),7.33(d,J=8.5Hz,1H),7.26(dd,J=8.5,2.5Hz,1H),7.22-7.17(m,1H),6.40(s,1H),4.51(s,3H).

[0785] Synthetic route to compound YL112 [ka]

[0786] Under nitrogen gas protection, Pd(dppf)Cl2 (45.24 mg, 0.062 mmol) was added to a mixture of 105-2 (280.0 mg, 0.309 mmol), 4-bromo-5-(difluoromethyl)-1H-pyrazole (60.90 mg, 0.309 mmol), potassium carbonate (128.18 mg, 0.928 mmol), 1,4-dioxane (10 mL), and water (2 mL) and heated to 90 °C for 1.5 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was filtered through diatomaceous earth, and the filtrate was concentrated and purified by preparative HPLC (Base) to give the off-white product (30 mg, ~89%). Further purification by TLC (methanol / dichloromethane (v / v) = 1:20) gave compound YL112 (10 mg, yield: 5.1%) as a white product. ESI: m / z 637.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ13.65(s,1H),10.45(s,1H),8.67(s,1H),8.52(d,J=2.2Hz,1H),7.96(d,J=8.4Hz,1H),7.82(d,J=9.3Hz,1H),7.73(s ,1H),7.39(d,J=5.1Hz,1H),7.33(dd,J=8.9,5.1Hz,1H),7.08(tt,J=8.4,4.1Hz,1H),6.90(dd,J=9.2,3.1Hz,1H),6.38(s,1H),4.49(s,3H).

[0787] Synthetic route of compound YL113 [ka]

[0788] Synthesis of compounds 113-1 & 113-2

[0789] NaH (18.19 mg, 0.455 mmol) was added to a solution of 4-bromo-3-fluoro-1H-pyrazole (50.0 mg, 0.303 mmol) in THF (3 mL) under ice-water bath conditions, and the mixture was stirred for 0.5 h. SEMCl (60.64 mg, 0.364 mmol) was added, and the mixture was allowed to warm to room temperature and react for 1 h. The reaction mixture was quenched with water, extracted three times with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0% to 10%) to give a mixture of compounds 113-1 and 113-2 (30 mg, yield: 33.6%).

[0790] Synthesis of compounds 113-3 & 113-4

[0791] Under nitrogen gas protection, Pd(dppf)Cl2 (18.10 mg, 0.025 mmol) was added to a mixture of 105-2 (80 mg, 0.124 mmol), compounds 113-3 and 113-4 (32.86 mg, 0.111 mmol), potassium carbonate (51.28 mg, 0.371 mmol), 1,4-dioxane (5 mL), and water (1 mL) and heated to 90 °C for 1.5 h. The reaction mixture was diluted with water and ethyl acetate, separated, and the organic phase was obtained. The organic phase was concentrated and purified using a column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compounds 113-3 and 113-4 (70 mg, 0.095 mmol, 76.98%). (ESI): (m / z) = 735.0 [M+H] + .

[0792] Synthesis of compound YL113

[0793] TFA (1.2 mL, 15.671 mmol) was added to a solution of compounds 113-3 and 113-4 (30 mg, 0.041 mmol) in THF (4 mL), heated to 80 °C, and reacted for 8 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution to neutralize it, extracted with dichloromethane, and separated. The organic phase was concentrated and purified to give compound YL113 (6.5 mg). (ESI): (m / z) = 605.1 [M+H]+ ; 1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),10.43(s,1H),8.57(d,J=1.8Hz,1H),8.51(d,J=2.2Hz,1H),7.96(d,J=8.5Hz,1H),7.82(d,J=9. 0Hz,1H),7.74(s,1H),7.39(s,1H),7.32(dd,J=8.8,5.1Hz,1H),7.07(td,J=8.4,3.1Hz,1H),6.89(dd,J=9.2,3.1Hz,1H),6.38(s,1H).

[0794] Synthetic route for compound YL114 (114-P1 & 114-P2) [ka]

[0795] 107-2 (230 mg, 0.354 mmol), 114-1 (70 mg, 0.354 mmol), potassium carbonate (147 mg, 1.061 mmol), and Pd(dppf)Cl2 (26 mg, 0.035 mmol) were placed in a reaction vial, dioxane (2 mL) and water (0.4 mL) were added, and the mixture was degassed and purged with nitrogen gas. The mixture was reacted at 100 °C for 1 h. The mixture was extracted with ethyl acetate and water, and purified by rotary evaporation. The product was then separated by SFC (conditions: instrument: SFC-150 (Waters), chromatography column: AS 20 × 250 mm, 10 μm (Daicel), mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)]=45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, circulation time: 13.8 min), compound YL114-P1 (49 mg) and compound YL114-P2 (50 mg) were obtained. LCMS(ESI):m / z 641.2(M+H) + .

[0796] Compound YL114-P1 (retention time: 2.32min): LCMS (ESI): m / z 641.2 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),8.01-7.81(m,3H),7.62(d,J=8.7Hz,1H),7.49(d,J=2.4Hz,1H),7.35(d,J=8.6Hz,1H),7.29(dd,J=8.6,2.5Hz,1H),7.0 7(d,J=2.5Hz,1H),6.80(d,J=8.8Hz,1H),6.75(s,2H),6.12(d,J=2.4Hz,1H),4.00(dtd,J=21.4,10.4,6.8Hz,2H),3.26-3.05(m,2H).

[0797] Compound YL114-P2 (retention time: 3.38 min): LCMS (ESI): m / z 641.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 10.26(s,1H),7.95-7.83(m,3H),7.62(d,J=8.7Hz,1H),7.47(s,1H),7.35(d,J=8.6Hz,1H),7.29(dd,J=8.6,2.6Hz,1H) ,7.06(d,J=2.5Hz,1H),6.80(d,J=8.7Hz,1H),6.75(s,2H),6.12(d,J=2.5Hz,1H),4.06-3.92(m,2H),3.24-3.05(m,2H).

[0798] Synthetic route of compound YL115

change

[0799] Synthesis of compound 115-2

[0800] A reaction vial was charged with 5-bromoindazole-3-carboxylic acid (115-1, 9 g, 37.338 mmol), potassium carbonate (15.48 g, 112.015 mmol), DMF (550 mL), and iodoethane (11.65 g, 74.676 mmol). The mixture was stirred at 80 °C overnight and then cooled to room temperature. The mixture was concentrated under reduced pressure to remove most of the DMF, followed by dilution with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The crude product was purified by automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate = 100 / 6 to 100 / 15) to give the target compound 115-2 (4.9 g, purity: 87.3%, yield: 38.56%). 1 H NMR(400MHz,DMSO-d6)δ 8.10(dd,J=1.9,0.7Hz,1H),7.77(dd,J=9.0,0.7Hz,1H),7.48(dd,J=9.1,1.9Hz,1H),4.84(q,J=7.2 Hz,2H),4.44(q,J=7.1Hz,2H),1.47(t,J=7.2Hz,3H),1.41(t,J=7.1Hz,3H),ESI:(m / z)=298.9[M+H] + .

[0801] Synthesis of compound 115-3

[0802] 115-2 (2.65 g, 10.863 mmol) was dissolved in 1,4-dioxane (110 mL), cesium carbonate (2.83 g, 8.691 mmol), Xantphos (0.50 g, 0.869 mmol), and Pd2(dba)3 (0.40 g, 0.437 mmol) were added, and the mixture was reacted at 110 °C for 3 h. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: ethyl acetate / petroleum ether = 100 / 15 to 100 / 20) to give compound 115-3 (760 mg, purity: 98.4%, yield: 40.65%). ESI: (m / z) = 424.5 [M+H] + .

[0803] Synthesis of compound 115-4

[0804] 115-3 (750 mg, 1.772 mmol) was dissolved in tetrahydrofuran (120 mL) and water (40 mL), and lithium hydroxide (743.32 mg, 17.715 mmol) was added. The mixture was allowed to react at room temperature overnight. The reaction mixture was rotary evaporated and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give crude compound 115-4 (470 mg, purity: 87%, yield: 96%). ESI: (m / z) = 394.0 [MH] - .

[0805] Synthesis of compound 115-5

[0806] A reaction vial was charged with 115-4 (450 mg, 1.138 mmol), ammonium chloride (182.67 mg, 3.415 mmol), HOBt (230.74 mg, 1.708 mmol), EDCI (327.33 mg, 1.708 mmol), DMF (45 mL), and DIEA (441.39 mg, 3.415 mmol). The mixture was then allowed to react at room temperature overnight. After the reaction was complete, the reaction mixture was quenched with water and 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 aqueous sodium chloride, concentrated under reduced pressure, and purified using a column chromatography (mobile phase: petroleum ether / ethyl acetate = 100 / 40 to 100 / 50) to obtain the crude target compound 115-5 (310 mg, purity: 96.8%, yield: 66.85%) as a white solid. ESI: (m / z) = 395.1 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ 10.59(s,1H),8.37(d,J=1.8Hz,1H),8.21(s,1H),8.16(d,J=9.1Hz,1H),8.02-7.89(m,3H),7. 72(d,J=9.2Hz,1H),7.63(dd,J=9.2,1.9Hz,1H),4.69(q,J=7.2Hz,2H),1.46(t,J=7.2Hz,3H).

[0807] Synthesis of compound YL115

[0808] 115-5 (305 mg, 0.773 mmol) was dissolved in Eaton's reagent (40 mL), and 2-chloro-5-fluorobenzaldehyde (245.28 mg, 1.547 mmol) was added. The mixture was reacted at 80° C. for 2.5 hours. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The crude product was purified (Boston pHlex ODS, 21.2 × 250 mm, 10 μm column, water (0.05% ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) to give the target compound YL115 (20 mg, purity: 99.2%, yield: 4.80%) as a white solid. ESI: (m / z) = 535.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 10.36(s,1H),8.44(d,J=2.2Hz,1H),7.95(dt,J=8.6,1.9Hz,1H),7.81(dt,J= 9.3,1.9Hz,1H),7.75(s,1H),7.68(dd,J=8.8,1.1Hz,1H),7.31(dd,J=8.9,5. 1Hz,1H),7.17(d,J=8.9Hz,1H),7.06(td,J=8.4,3.1Hz,1H),6.87(dd,J=9.2, 3.1Hz, 1H), 6.38 (s, 1H), 4.83 (qd, J=13.2, 7.2Hz, 2H), 1.55 (t, J=7.2Hz, 3H).

[0809] Synthetic route to compound YL116 [ka]

[0810] Synthesis of compound 116-2

[0811] A reaction vial was charged with 5-bromoindazole-3-carboxylic acid (115-1, 4 g, 16.595 mmol), potassium carbonate (6.88 g, 49.784 mmol), DMF (240 mL), and iodoethane (9.62 g, 66.379 mmol). The mixture was stirred at 80 °C overnight and then cooled to room temperature. The mixture was concentrated under reduced pressure to remove most of the DMF, 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 saturated aqueous sodium chloride and concentrated under reduced pressure. The crude product was purified using an automated column (Biotage) (mobile phase: petroleum ether / ethyl acetate = 100 / 12 to 100 / 20) to obtain the product and by-products. The product with the less polar structure was the target compound 116-2 (2.1 g, purity: 96%, yield: 44.16%). 1 H NMR (400MHz, DMSO-d6) δ 8.07 (dd, J = 2.0, 0.7 Hz, 1H), 7.73 (dd, J = 9.0, 0.7 Hz, 1H), 7.45 (dd, J = 9.1, 1.9 Hz, 1H). By-product (2.3g, purity: 97.3%, yield: 49.01%), 1 H NMR (400MHz, DMSO-d6) δ 8.13 (dd, J = 1.9, 0.7 Hz, 1H), 7.76 (dd, J = 8.9, 0.7 Hz, 1H), 7.60 (dd, J = 9.0, 1.9 Hz, 1H). ESI:(m / z)=275.0 / 277.0[M+H] + .

[0812] Synthesis of compound 116-3

[0813] 116-2 (1.6 g, 5.815 mmol) was dissolved in 1,4-dioxane (230 mL), 115-2A (1.45 g, 6.979 mmol), cesium carbonate (3.79 g, 11.631 mmol), Xantphos (0.67 g, 1.163 mmol), and Pd2(dba)3 (0.53 g, 0.582 mmol) were added, and the mixture was reacted at 110 °C for 4 h. 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, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: ethyl acetate / petroleum ether = 100 / 14 to 100 / 17) to give compound 116-3 (1.5 g, purity: 90.6%, yield: 34.94%). 1 H NMR(400MHz,DMSO-d6)δ 10.65(s,1H),8.52(d,J=1.9Hz,1H),8.21(s,1H),8.16(dt,J=9.5,1.9Hz,1H),7.98(dt,J=8.4 ,1.9Hz,1H),7.80(dd,J=9.2,0.8Hz,1H),7.71(dd,J=9.2,2.0Hz,1H).ESI:(m / z)=402.1[M+H] + .

[0814] Synthesis of compound 116-4

[0815] 116-3 (0.7 g, 1.744 mmol) was dissolved in tetrahydrofuran (110 mL) and water (37 mL), and lithium hydroxide (0.73 g, 17.441 mmol) was added. The mixture was allowed to react at room temperature overnight. The reaction mixture was rotary evaporated and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give the crude product of compound 116-4 (650 mg, purity: 91.2%, yield: 88.44%). 1H NMR(400MHz,DMSO-d6)δ 10.64(s,1H),8.56(d,J=1.9Hz,1H),8.21(d,J=17.0Hz,2H),8.11-8.01(m,1H),7.95(d,J=8.5Hz,1H),7.67-7.57(m,2H).,ESI:(m / z)=383.1[MH] - .

[0816] Synthesis of compound 116-5

[0817] A reaction vial was charged with 116-4 (640 mg, 1.665 mmol), ammonium chloride (267.24 mg, 4.996 mmol), HOBt (337.56 mg, 2.498 mmol), EDCI (478.88 mg, 2.498 mmol), DMF (80 mL), and DIEA (645.75 mg, 4.996 mmol). The reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with water and 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 aqueous sodium chloride, and concentrated under reduced pressure to directly obtain the crude target compound 116-5 (575 mg, purity: 94.4%, yield: 85.03%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.74(s,1H),8.40(s,1H),8.22(d,J=9.2Hz,2H),8.06(d,J=27.6Hz,1H),7.90(d,J=12.9Hz,2H),7.69(s,2H).ESI:(m / z)=384.1[M+H] + .

[0818] Synthesis of compound YL116

[0819] 116-5 (570 mg, 1.487 mmol) was dissolved in Eaton's reagent (42 mL), and 2-chloro-5-fluorobenzaldehyde (471.56 mg, 2.974 mmol) was added. The mixture was allowed to react at 80 °C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 1 to 100 / 2) to give compound 116 (66 mg, purity: 92.7%, yield: 7.85%). 1 H NMR(400MHz,DMSO-d6)δ 10.36(s,1H),8.45(d,J=2.2Hz,1H),7.95(dt,J=8.5,2.0Hz,1H),7.81(dt,J=9.3,1.9Hz,1H),7.75(s,1H),7.66(dd,J=8.9,1.1Hz,1H), 7.31(dd,J=8.8,5.2Hz,1H),7.17(d,J=8.9Hz,1H),7.10-7.04(m,1H),6.87(dd,J=9.2,3.1Hz,1H),6.38(s,1H),ESI:(m / z)=524.0[M+H] + .

[0820] Synthetic route for compound YL117 [ka]

[0821] Synthesis of compound 117-1

[0822] 27 (500 mg, 1.116 mmol) was dissolved in Eaton's reagent (25 mL), and methyl 2-formylbenzoate (CAS number: 4122-56-9) (366.25 mg, 2.231 mmol) was added. The mixture was reacted at 80 °C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 3 to 100 / 4) to give compound 117-1 (100 mg, purity: 89.65%, yield: 13.52%). ESI: (m / z) = 594.1 [M+H] + .

[0823] Synthesis of compound YL117

[0824] 117-1 (90 mg, 0.152 mmol) was dissolved in tetrahydrofuran (50 mL) and water (17 mL), and lithium hydroxide (63.75 mg, 1.519 mmol) was added. The mixture was allowed to react at room temperature for 2 days. The reaction mixture was subjected to rotary evaporation and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give compound YL117 (45 mg, purity: 92.17%, yield: 47.20%). 1 H NMR(400MHz,DMSO-d6)δ 11.85(s,1H),8.89(s,1H),7.86(d,J=8.3Hz,1H),7.81(dd,J=7.6,1.5H z,1H),7.60-7.54(m,2H),7.15(td,J=7.5,1.3Hz,1H),7.02(td,J=7.5, 1.6Hz,1H),6.55(s,1H),6.47-6.40(m,3H),3.98(ddd,J=10.1,7.8,5.7 Hz,2H),3.10(td,J=8.1,7.5,3.5Hz,2H).ESI:(m / z)=577.9 / 579.9[M+H] + .

[0825] Synthetic route for compound YL118 [ka]

[0826] Synthesis of compound 118-2

[0827] A reaction vial was charged with 5-bromoindazole-3-carboxylic acid (115-1, 4 g, 16.595 mmol), potassium carbonate (6.88 g, 49.784 mmol), DMF (240 mL), and 2-iodopropane (11.28 g, 66.379 mmol). The mixture was stirred at 60 °C for 24 h and then cooled to room temperature. The mixture was concentrated under reduced pressure to remove most of the DMF, 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 saturated aqueous sodium chloride and concentrated under reduced pressure. The crude product was purified by automated column chromatography (Biotage) (mobile phase: petroleum ether / ethyl acetate = 100 / 12 to 100 / 20). The less polar spot was identified as the target compound 118-2 (2.4 g, purity: 93.6%, yield: 41.62%). 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=1.8Hz,1H),7.80(d,J=9.0Hz,1H),7.47(dd,J=9.1,1.9Hz,1H),5.83(p, J=6.5Hz,1H), 5.25(p,J=6.3Hz,1H),1.54(d,J=6.5Hz,6H),1.42(d,J=6.2Hz,6H).

[0828] Synthesis of compound 118-3

[0829] 118-2 (1.4 g, 4.305 mmol) was dissolved in 1,4-dioxane (175 mL), 115-2A (1.16 g, 5.596 mmol), cesium carbonate (2.81 g, 8.610 mmol), Xantphos (0.50 g, 0.869 mmol), and Pd(dba) (0.39 g, 0.430 mmol) were added, and the mixture was reacted at 110 °C overnight. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: ethyl acetate / petroleum ether = 100 / 15 to 100 / 17) to give compound 118-3 (1.15 g, purity: 98.8%, yield: 58.47%). 1 H NMR(400MHz,DMSO-d6)δ 10.62(s,1H),8.68(d,J=1.9Hz,1H),8.20-8.12(m,2H),7.96(dt,J=8.5,1.9Hz,1H),7.82(d,J=9.1Hz,1H),7.62(dd,J=9.2,2.0H z,1H),5.83(hept,J=6.5Hz,1H),5.26(hept,J=6.2Hz,1H),1.55(d,J=6.6Hz,6H),1.44(d,J=6.2Hz,6H).ESI:(m / z)=452.6[M+H] + .

[0830] Synthesis of compound 118-4

[0831] 118-3 (1.1 g, 2.437 mmol) was dissolved in tetrahydrofuran (135 mL) and water (45 mL), and lithium hydroxide (1.02 g, 24.368 mmol) was added and reacted at 50 °C overnight. The reaction mixture was rotary evaporated and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to directly obtain compound 118-4 (1 g, purity: 91.6%, yield: 91.83%). 1H NMR(400MHz,DMSO-d6)δ 10.71(s,1H),8.63-8.56(m,1H),8.30-8.19(m,2H),7.93(dt,J=8.5,2.0Hz,1H),7.60(qd ,J=9.1,1.4Hz,2H),6.40(p,J=6.6Hz,1H),1.48(d,J=6.6Hz,6H).ESI:(m / z)=408.0[MH] - .

[0832] Synthesis of compound 118-5

[0833] A reaction vial was charged with 118-4 (1 g, 2.443 mmol), ammonium chloride (0.39 g, 7.329 mmol), HOBt (0.50 g, 3.664 mmol), EDCI (0.70 g, 3.664 mmol), DMF (75 mL), and DIEA (0.95 g, 7.329 mmol). The mixture was then allowed to react at room temperature overnight. After the reaction was complete, the mixture was quenched with water and 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 aqueous sodium chloride, and concentrated under reduced pressure to directly obtain the target compound 118-5 (0.8 g, purity: 93.4%, yield: 74.90%) as a crude solid product. 1 H NMR(400MHz,DMSO-d6)δ 10.59(s,1H),8.35(d,J=1.8Hz,1H),8.22(s,1H),8.17(dt,J=9.3,2.0Hz,1H),7.97(dq,J=7.3,3.1,2.6Hz,3H),7. 73(d,J=9.2Hz,1H),7.63(dd,J=9.3,1.9Hz,1H),5.48(hept,J=6.5Hz,1H),1.53(d,J=6.6Hz,6H).LC-MS(ESI):m / z 409.5(M+H) + .

[0834] Synthesis of compound YL118

[0835] 118-5 (555 mg, 1.359 mmol) was dissolved in Eaton's reagent (30 mL), and 2-chloro-5-fluorobenzaldehyde (431.00 mg, 2.718 mmol) was added. The mixture was allowed to react at 80 °C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified using a column (mobile phase: petroleum ether / ethyl acetate = 100 / 35 to 100 / 40) to obtain the crude product (200 mg, purity: 67.9%). The resulting crude product was purified (Welch Xtimate C18, 21.2 × 250 mm, 10 μm, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25°C, measurement wavelength: 254 nm) and lyophilized to obtain solid compound YL118 (85 mg, purity: 97.4%, yield: 11.10%). 1 H NMR(400MHz,DMSO-d6)δ 11.25(s,1H),9.31(d,J=2.2Hz,1H),8.84(d,J=8.2Hz,1H),8.74-8.68(m, 1H),8.64(s,1H),8.58(d,J=8.9Hz,1H),8.20(dd,J=8.9,5.1Hz,1H),8.05 (d,J=8.9Hz,1H),7.96(td,J=8.4,3.1Hz,1H),7.76(dd,J=9.2,3.1Hz,1H) ,7.25(s,1H),6.59(p,J=6.6Hz,1H),4.22(s,6H).ESI:(m / z)=549.2[M+H] + .

[0836] Synthesis of compound YL119 [ka]

[0837] 27 (1.1 g, 2.465 mmol) was dissolved in Eaton's reagent (30 mL), and 2,5-dichloropyridine-4-carboxaldehyde (431.00 mg, 2.718 mmol) was added. The mixture was allowed to react at 80 °C for 3 h. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 4 to 100 / 6) to give compound YL119 (670 mg, purity: 69.7%, yield: 31.35%). The resulting crude product (400 mg) was purified (Welch Xtimate C18, 21.2 × 250 mm, 10 μm column, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) and lyophilized to give solid compound YL119 (145 mg, purity: 92.8%). ESI: (m / z) = 605.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.16(s,1H),8.36(s,1H),7.98(d,J=8.4Hz,1H),7.90(s,1H),7.85(d,J=9.4Hz,1H),7.52(d,J=2.3Hz,1 H),7.19(s,1H),6.94(s,1H),6.01(d,J=2.2Hz,1H),4.10-3.98(m,2H),3.16(ddd,J=9.9,7.0,2.8Hz,2H).

[0838] Synthetic route for compound YL120 [ka]

[0839] A reaction vial was charged with 5-bromoindazole-3-carboxylic acid (115-1, 6.05 g, 25.100 mmol), cesium carbonate (32.71 g, 100.400 mmol), DMF (310 mL), and (2-bromoethyl)dimethylamine hydrobromide (CAS number: 2862-39-7) (17.54 g, 75.299 mmol). The mixture was stirred overnight at room temperature. After concentration under reduced pressure to remove most of the DMF, 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 aqueous sodium chloride, and concentrated under reduced pressure. The crude product was purified multiple times using an automated column (Biotage) (mobile phase: dichloromethane / methanol = 100 / 4 to 100 / 6) to obtain target compound 120-2 (0.55 g, purity: 90.09%, yield: 5.15%). 1 H NMR(400MHz,DMSO-d6)δ 8.29(dd,J=1.9,0.7Hz,1H),7.78(dd,J=9.0,0.7Hz,1H),7.48(dd,J=9.1,1.9Hz,1H),4.93(t,J=6.6H z,2H),4.46(t,J=5.6Hz,2H),2.78(t,J=6.6Hz,2H),2.68(t,J=5.5Hz,2H),2.26(s,6H),2.17(s,6H). ESI:(m / z)=383.2 / 385.2[M+H] + In addition, NOESY results confirmed that the 2-position of the indazole was substituted.

[0840] Synthesis of compound 120-3

[0841] 120-2 (1015 mg, 2.648 mmol) was dissolved in 1,4-dioxane (130 mL), 115-2A (658.18 g, 3.178 mmol), cesium carbonate (1725.62 mg, 5.296 mmol), Xantphos (306.46 mg, 0.530 mmol), and Pd2(dba)3 (242.50 mg, 0.265 mmol) were added, and the mixture was reacted at 110 °C for 3 hours. After the reaction was complete, the reaction product 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 sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: ethyl acetate / petroleum ether = 100 / 10 to 100 / 20) to obtain compound 120-2 (285 mg, purity: 93.9%, yield: 22.34%). 1 H NMR(400MHz,DMSO-d6)δ 10.66(s,1H),8.52(d,J=1.9Hz,1H),8.24-8.13(m,2H),7.98(dt,J=8.5,2.0Hz,1H),7.85-7.78(m,1H),7.71(dd, J=9.2,2.0Hz,1H),4.94(t,J=6.7Hz,2H),3.99(s,3H),2.82(t,J=6.7Hz,2H),2.22(s,6H),ESI:(m / z)=453.2[M+H] + .

[0842] Synthesis of compound 120-4

[0843] 120-3 (700 mg, 1.547 mmol) was dissolved in tetrahydrofuran (105 mL) and water (35 mL), and lithium hydroxide (649.23 mg, 15.473 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. After the reaction was completed, dilute hydrochloric acid was slowly added to neutralize the reaction mixture. The mixture was then rotary evaporated and 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 aqueous sodium chloride and concentrated under reduced pressure to directly obtain the target compound 120-4 (340 mg, purity: 72.7%, yield: 36.44%). 1H NMR(400MHz,DMSO-d6)δ 10.69(s,1H),8.58(d,J=1.9Hz,1H),8.24(d,J=8.7Hz,2H),7.99-7.92(m,1H),7.66(dd,J=9.2,2.0Hz,1H), 7.59(d,J=9.2Hz,1H),5.09(t,J=6.6Hz,2H),4.18(s,1H),3.00(s,2H),2.34(s,6H).ESI:(m / z)=437.2[MH] - .

[0844] Synthesis of compound 120-5

[0845] A reaction vial was charged with 120-4 (330 mg, 0.753 mmol), ammonium chloride (120.80 mg, 2.258 mmol), HATU (429.35 mg, 1.129 mmol), DMF (70 mL), and DIEA (291.89 mg, 2.258 mmol). The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with water and 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 aqueous sodium chloride solution and concentrated under reduced pressure to directly obtain the target compound 120-5 (380 mg, purity: 88.7%, yield: 86.72%) as a crude solid. LC-MS (ESI): m / z 438.7 (M+H). + .

[0846] Synthesis of compound YL120

[0847] 120-5 (350 mg, 0.800 mmol) was dissolved in Eaton's reagent (35 mL), and 2-chloro-5-fluorobenzaldehyde (253.75 mg, 1.600 mmol) was added. The mixture was allowed to react at 80 °C for 3 hours. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified using a column (mobile phase: dichloromethane / methanol = 100 / 14 to 100 / 16) to obtain compound YL120 (120 mg, purity: 42.4%). The crude product was purified (Welch Xtimate C18, 21.2 x 250 mm, 10 μm column, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) and lyophilized to give the solid target compound YL120 (14 mg, purity: 92.9%, yield: 2.81%). ESI: (m / z) = 578.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.40(s,1H),8.43(d,J=2.2Hz,1H),7.95(d,J=8.5Hz,1H),7.84(d,J=8.9Hz,1H),7.76( s,1H),7.67(dd,J=8.9,1.1Hz,1H),7.32(dd,J=8.8,5.2Hz,1H),7.18(d,J=8.9Hz,1H),7 .06(td,J=8.4,3.1Hz,1H),6.87(dd,J=9.2,3.1Hz,1H),6.42-6.35(m,1H),4.97(dt,J=1 3.1,6.5Hz,1H),4.85(dt,J=13.0,6.1Hz,1H),2.89(dq,J=24.8,6.3Hz,2H),2.19(s,6H).

[0848] Synthetic route for compound YL121 [ka]

[0849] Synthesis of compound 121-2

[0850] A reaction vial was charged with 5-bromo-1H-indazole-3-carboxylate (121-1, 3.10 g, 12.15 mmol), potassium carbonate (5.04 g, 36.46 mmol), DMF (110 mL), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.64 g, 24.31 mmol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove most of the DMF, 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 saturated aqueous sodium chloride and concentrated under reduced pressure. The crude product was purified using an automated column (Biotage) (mobile phase: petroleum ether / ethyl acetate 100 / 8 to 100 / 15) to obtain the target compound 121-2 (1.1 g, purity: 97.1%, yield: 26.07%). 1H NMR(400MHz,DMSO-d6)δ 8.24-8.18(m,1H),7.87(dd,J=9.2,0.7Hz,1H),7.58(dd,J=9.2,1.9Hz,1H),5.86(q,J=8.7Hz,2H),4.02(s,3H).

[0851] Synthesis of compound 121-3

[0852] 121-2 (1.1 g, 3.26 mmol) was dissolved in 1,4-dioxane (140 mL), 115-2A (811.07 mg, 3.92 mmol), cesium carbonate (2.13 g, 6.53 mmol), Xantphos (377.63 mg, 0.653 mmol), and Pd(dba) (298.82 mg, 0.326 mmol) were added, and the mixture was reacted at 110 °C for 2 h. 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: methanol / dichloromethane = 100 / 4 to 100 / 6) to give compound 121-3 (1.2 g, purity: 69.3%, yield: 55.01%). ESI: (m / z) = 464.3 [M+H] + .

[0853] Synthesis of compound 121-4

[0854] 121-3 (1.2 g, 2.59 mmol) was dissolved in tetrahydrofuran (165 mL) and water (55 mL), and lithium hydroxide (620.24 mg, 25.90 mmol) was added. The mixture was allowed to react at room temperature for 3 hours. After the reaction was completed, dilute hydrochloric acid was slowly added to neutralize the reaction mixture. The mixture was then rotary evaporated and 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 aqueous sodium chloride and concentrated under reduced pressure to directly obtain the target compound 121-4 (800 mg, purity: 77.6%, yield: 53.35%). 1 H NMR(400MHz,DMSO-d6)δ 10.64(s,1H),8.64(t,J=1.5Hz,1H),8.23(s,1H),8.17(dd,J=9.2,2.2Hz,1H),8.01-7.93(m,1H) ,7.67(d,J=1.4Hz,2H),6.07(q,J=9.0Hz,2H),4.03(q,J=7.1Hz,1H).LC-MS(ESI):m / z=448.0[MH] - .

[0855] Synthesis of compound 121-5

[0856] A reaction vial was charged with 121-4 (800 mg, 1.78 mmol), ammonium chloride (285.73 mg, 5.34 mmol), HATU (1015.58 mg, 2.67 mmol), DMF (70 mL), and DIEA (690.41 mg, 5.34 mmol). The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with water and 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 aqueous sodium chloride and concentrated under reduced pressure to directly obtain the target compound 121-5 (800 mg, purity: 88%, yield: 88.19%) as a crude solid. LC-MS (ESI): m / z 449.2 (M+H). + .

[0857] Synthesis of compound YL121

[0858] 121-5 (435 mg, 0.97 mmol) was dissolved in Eaton's reagent (25 mL), and 2-chloro-5-chlorobenzaldehyde (339.63 mg, 1.94 mmol) was added. The mixture was allowed to react at 80 °C for 2 h. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and 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, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The crude product was purified by column purification (mobile phase: dichloromethane / methanol 100 / 6 to 100 / 8) (Welch Xtimate C18, 21.2 × 250 mm, 10 μm column, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm). Because the purity of the prepared sample did not meet the requirements, it was further purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 3 to 100 / 5) and lyophilized to obtain the solid target compound YL121 (28 mg, purity: 97.5%, yield: 4.65%). 1 H NMR(400MHz,DMSO-d6)δ 10.51(s,1H),8.63(d,J=2.2Hz,1H),7.96(d,J=8.3Hz,1H),7.84(dd,J=9.3,2.3Hz,1H),7.78-7.71(m,2H),7.34(d,J=8.5Hz ,1H),7.26(dd,J=8.7,2.9Hz,2H),7.11(d,J=2.5Hz,1H),6.36(s,1H),5.75(q,J=8.7Hz,2H),ESI:(m / z)=605.1 / 607.1[M+H] + .

[0859] Synthetic route to compound YL122 [ka]

[0860] Synthesis of compound YL122-1

[0861] 4-Bromo-6-aminoindole (10 g, 47.380 mmol) was dissolved in dichloromethane (150 mL), triethylamine (19.757 mL, 142.140 mmol) was added, and the mixture was degassed and purged with N2. Trifluoroacetic anhydride (19.90 g, 94.760 mmol) was added at 0 °C, and the reaction mixture was warmed to room temperature and reacted for 3 h. 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, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to directly obtain compound YL122-1 (14.2 g, purity: 87.16%, yield: 82.15). ESI: (m / z) = 308.7 [M+H] + .

[0862] Synthesis of compound YL122-2

[0863] YL122-1 (14.2 g, 46.244 mmol) was dissolved in acetic acid (250 mL), sodium cyanoborohydride (5.81 g, 92.487 mmol) was added, and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was rotary evaporated, added dropwise to a cold saturated aqueous solution of sodium bicarbonate, and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and column purified (mobile phase: petroleum ether / ethyl acetate = 100 / 13 to 100 / 14) to give compound YL122-2 (4.6 g, purity: 96%, yield: 30.90%). ESI: (m / z) = 310.6 [M+H] + .

[0864] Synthesis of compound YL122-3

[0865] YL122-2 (4.5 g, 14.559 mmol) was dissolved in acetic acid (100 mL), the temperature was lowered to 10 °C, potassium cyanate (2.36 g, 29.118 mmol) was added, and the mixture was allowed to react at 10 °C for 0.5 hours. The reaction mixture was subjected to rotary evaporation, and saturated aqueous sodium bicarbonate solution was added to make it alkaline. Water was added and the mixture was filtered to obtain the crude product of compound YL122-3 (5.15 g, purity: 74.4%, yield: 74.74%). ESI: (m / z) = 353.8 [M+H] + .

[0866] Synthesis of compound YL122-4

[0867] YL122-3 (5.1 g, 14.484 mmol) was dissolved in Eaton's reagent (45 mL), and 2-chloro-5-fluorobenzaldehyde (4.59 g, 28.968 mmol) was added. The mixture was reacted 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 combined organic phases were washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 3 to 100 / 5) to give compound YL122-4 (6.8 g, purity 70%, yield 66.71%). ESI: (m / z) = 493.8 [M+H] + .

[0868] Synthesis of compound YL122-5

[0869] YL122-4 (6.8 g, 9.662 mmol) was dissolved in methanol (150 mL) and water (50 mL), and lithium hydroxide (10.14 g, 241.551 mmol) was added. The mixture was reacted at 80°C for 7 hours. The reaction mixture was subjected to rotary evaporation and diluted with dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give the crude product of compound YL122-5 (3.7 g, purity 63.8%, yield: 61.60%). ESI: (m / z) = 397.8 [M+H] + .

[0870] Synthesis of compound YL122

[0871] To a reaction vial was added YL122-5 (250 mg, 0.630 mmol), dichloromethane (20 mL), dioxane (15 mL), and N,N-diisopropylethylamine (1629.31 mg, 12.606 mmol). o At C, triphosgene (224.43 mg, dichloromethane solution) was added dropwise. o The mixture was stirred at RT for 0.5 hours. 3-Trifluoromethane-5-fluoroaniline (338.69 mg, dichloromethane: 5 mL) was added dropwise. The mixture was then further treated in an ice bath. The mixture was stirred for 2 hours. The mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The crude product was purified using an automated column (Biotage) (mobile phase: methanol / dichloromethane = 100 / 4 to 100 / 5) to obtain the crude target compound as a pale yellow solid. The crude product was purified (Boston pHlex ODS, 21.2 × 250 mm, 10 μm column, water (0.05% ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) to obtain the target compound YL122 (25 mg, purity: 99.2%, yield: 6.54%) as a white solid. LC-MS (ESI): m / z 602.9 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ 9.25(s,1H),8.24(s,1H),7.61-7.57(m,2H),7.53(dt,J=11.3,2.2Hz,1H),7.42(dd,J=8.8,5.2Hz,1H),7.21(d,J=8.5Hz,1H),7. 12(td,J=8.4,3.1Hz,1H),6.97(s,1H),6.90(dd,J=9.3,3.1Hz,1H),6.08(d,J=3.0Hz,1H),4.04-3.96(m,2H),3.18-3.10(m,2H).

[0872] Synthetic route for compound YL-123 [ka]

[0873] Synthesis of compound YL123

[0874] 103-5 (330 mg, 0.868 mmol) was dissolved in Eaton's reagent (20 mL), and 2,5-dichloro-4-fluorobenzaldehyde (334.95 mg, 1.735 mmol) was added. The mixture was allowed to react at 80 °C for 2 hours. The reaction mixture was added dropwise to a cold saturated sodium bicarbonate solution and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated and purified by column chromatography (mobile phase: dichloromethane / methanol = 100 / 3 to 100 / 5) to give the crude product (250 mg, purity: 37.7%). The crude product was purified (Welch Xtimate C18, 21.2 x 250 mm, 10 μm column, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) and lyophilized to give the solid target compound YL123 (30 mg, purity: 99.4%, yield: 6.19%). ESI: (m / z) = 555.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),8.42-8.32(m,1H),7.96(d,J=8.3Hz,1H),7.84(d,J=9.1Hz,1H),7.71(s,1H),7.66(dd,J=8.8 ,1.1Hz,1H),7.56(d,J=9.0Hz,1H),7.25(d,J=7.9Hz,1H),7.16(d,J=8.9Hz,1H),6.33(s,1H),4.44(s,3H).

[0875] Synthetic route to compound YL124 [ka]

[0876] Synthesis of compound YL124

[0877] A reaction vial containing 39 (350 mg, 0.552 mmol), 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (123.92 mg, 0.663 mmol), potassium carbonate (228.95 mg, 1.657 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80.81 mg, 0.110 mmol), 1,4-dioxane (40 mL), and water (8 mL) was added. The mixture was heated to 100 °C under nitrogen gas protection and stirred for 9 h. 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 aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Biotage automated column (mobile phase: dichloromethane / methanol = 100 / 8 to 100 / 9). The crude product was purified (Welch Xtimate C18, 21.2 x 250 mm, 10 μm column, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) and lyophilized to give the solid target compound YL124 (45 mg, purity: 99.3%, yield: 13.18%). ESI: (m / z) = 614.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),10.27(s,1H),7.96(d,J=8.8Hz,1H),7.86(d,J=12.5Hz,2H),7.51(d,J=2.5Hz,1H),7.36-7.32(m,1H),7.11(d t,J=11.5,3.3Hz,2H),6.89(dd,J=9.3,3.1Hz,1H),6.49(s,2H),6.09(d,J=2.4Hz,1H),4.05-3.95(m,2H),3.49-3.36(m,2H).

[0878] Synthetic route to compound YL125 [ka]

[0879] Synthesis of compound YL125

[0880] A reaction vial was charged with 39 (350 mg, 0.552 mmol), 3-bromo-1H-pyrazole-4-carbonitrile (113.97 mg, 0.663 mmol), potassium carbonate (228.95 mg, 1.657 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80.81 mg, 0.110 mmol), 1,4-dioxane (35 mL), and water (7 mL). The mixture was heated to 100 °C under nitrogen gas protection and stirred for 9 h. 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 aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified on a Biotage automated column (mobile phase: dichloromethane / methanol = 100 / 5 to 100 / 6). The crude product was purified (Welch Xtimate C18, 21.2 x 250 mm, 10 μm column, water (10 mM ammonium bicarbonate) / acetonitrile, flow rate: 30 mL / min, column temperature: 25 °C, wavelength: 254 nm) and lyophilized to give the solid target compound YL125 (32 mg, purity: 98.3%, yield: 9.51%). ESI: (m / z) = 599.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.98(s,1H),10.30(s,1H),8.68(s,1H),7.96(d,J=8.4Hz,1H),7.87(d ,J=10.4Hz,2H),7.55(d,J=2.6Hz,1H),7.34(dd,J=8.9,5.1Hz,1H...

Claims

1. A nitrogen-containing heterocyclic compound represented by formula I, 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, 【Chemical 1】 where Z is N or C; E is N, C or CH; X is CH, CR Ｘ or N, Y is —C(O), and CR Ｙ or N, Q is CH or N; a is a single bond or a double bond, when a is a single bond, Y is —C(O)— or N; When a is a double bond, Y is CR Ｙ or N, R １ Is, -L １ -R １Ａ and L １ is a bond, and R １Ａ is C ６－２０ an aryl group, one or more R １Ｃ C substituted by ６－２０ an aryl group, or one or more R １Ｄ and each R is a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S, and N, substituted with １Ｃ and R １Ｄ are each independently a halogen, C １－６ C substituted with an alkyl group, —COOH, or one or more halogens １－６ is an alkyl group, R ２ Is, -L ２ -R ２Ａ and L ２ is a bond, —NH—, —NH—C(O)—, or —NH—C(O)CHOH—, and R ２Ａ is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R ２Ｃ１ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by one or more R ２Ｃ２ C substituted by ６－２０ an aryl group, one or more R ２Ｃ３ C containing 1 to 3 heteroatoms selected from O, S and N, substituted by ８－１０ a benzoheterocycloalkenyl group, one or more R ２Ｃ４ a 5-6 membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N, substituted by one or more R ２Ｃ５ C substituted by ８－１０ is a benzocycloalkenyl group, and R ２Ｃ１ , R ２Ｃ２ , R ２Ｃ３ , R ２Ｃ４ and R ２Ｃ５ are each independently a halogen, a hydroxy group, or C １－６ Alkyl group, C ３－８ a cycloalkyl group, or R ２Ｃ１１ C substituted by １－６ is an alkyl group, and R ２Ｃ１１ is a halogen or hydroxy group, R ３ Is, -L ３ -R ３Ａ and L ３ is a bond, and R ３Ａ is a halogen, C １－６ an alkyl group, ═O, or one or more R ３Ｃ C substituted by １－６ an alkyl group or any two R ３ and the carbon atom to which it is bonded ３－８ Cycloalkane or C ６－２０ forming aromatic hydrocarbons, R ３Ｃ are independently deuterium, halogen, or —NR ３Ｃ１ R ３Ｃ２ and R ３Ｃ１ and R ３Ｃ２ are each independently hydrogen or C １－６ is an alkyl group, R Ｙ and R ｘ are each independently -L Ｙ -R ＹＡ and L Ｙ is a bond, —NH— or —NH—C(O)—, and R ＹＡ is hydrogen, halogen, cyano group, -N ３ , hydroxy group, —NH ２ , -C ２－６ Alkynyl group, represented by the following formula: —B(OH) ２ , C １－６ an alkyl group, one or more R ＹＡ１ C substituted by １－６ Alkyl group, —OC １－６ Alkyl group, C ３－８ a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R ＹＡ２ a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ３ a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ４ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COR ＹＡ５ , the following formula 3, the following formula 4 or the following formula 5, 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ are each independently a halogen, a hydroxy group, a cyano group, or —NH ２ , C １－６ Alkyl group, —OC １－６ an alkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N; —NH ２ , C ３－８ Cycloalkyl group, C ６－２０ an aryl group, or R ＹＡ１１ C substituted by １－６ is an alkyl group, and R ＹＡ１１ is a halogen or a phenyl group, Ring A is C ６－１０ an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S; a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; or C ８－１０ is a benzoheterocycloolefin, n is 0, 1, 2, 3 or 4 Nitrogen-containing heterocyclic compounds, pharmacologically acceptable salts thereof, solvates thereof, solvates of pharmacologically acceptable salts thereof, crystalline forms thereof, stereoisomers thereof, tautomers thereof, or isotope compounds thereof.

2. The nitrogen-containing heterocyclic compound of formula I has a structure represented by formula II, 【Chemistry 6】 where E is N or C; X is N or CH; R １ Is, -L １ -R １Ａ and L １ is a bond, and R １Ａ is C ６－２０ an aryl group, one or more R １Ｃ C substituted by ６－２０ an aryl group, or one or more R １Ｄ and each R is a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S, and N, substituted with １Ｃ and R １Ｄ are each independently a halogen, C １－６ C substituted with an alkyl group, —COOH, or one or more halogens １－６ is an alkyl group, R ２ Is, -L ２ -R ２Ａ and L ２ is a bond, —NH—, —NH—C(O)—, or —NH—C(O)CHOH—, and R ２Ａ is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R ２Ｃ１ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by one or more R ２Ｃ２ C substituted by ６－２０ an aryl group, one or more R ２Ｃ３ C containing 1 to 3 heteroatoms selected from O, S and N, substituted by ８－１０ a benzoheterocycloalkenyl group, one or more R ２Ｃ４ a 5-6 membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N, substituted by one or more R ２Ｃ５ C substituted by ８－１０ is a benzocycloalkenyl group, and R ２Ｃ１ , R ２Ｃ２ , R ２Ｃ３ , R ２Ｃ４ and R ２Ｃ５ are each independently a halogen, a hydroxy group, or C １－６ Alkyl group, C ３－８ a cycloalkyl group, or R ２Ｃ１１ C substituted by １－６ is an alkyl group, and R ２Ｃ１１ is a halogen or hydroxy group, R ３ Is, -L ３ -R ３Ａ and L ３ is a bond, and R ３Ａ is a halogen, C １－６ an alkyl group, ═O, or one or more R ３Ｃ C substituted by １－６ an alkyl group or any two R ３ and the carbon atom to which it is bonded ３－８ Cycloalkane or C ６－２０ forming aromatic hydrocarbons, R ３Ｃ are each independently deuterium, halogen, or —NR ３Ｃ１ R ３Ｃ２ and R ３Ｃ１ and R ３Ｃ２ are each independently hydrogen or C １－６ is an alkyl group, R Ｙ Is, -L Ｙ -R ＹＡ and L Ｙ is a bond, —NH— or —NH—C(O)—, and R ＹＡ is hydrogen, halogen, cyano group, -N ３ , hydroxy group, —NH ２ , -C ２－６ Alkynyl group, represented by the following formula (7): -B(OH) ２ , C １－６ an alkyl group, one or more R ＹＡ１ C substituted by １－６ Alkyl group, —OC １－６ Alkyl group, C ３－８ a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R ＹＡ２ a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ３ a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ４ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COR ＹＡ５ , the following formula 8, the following formula 9 or the following formula 10, 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ are each independently a halogen, a hydroxy group, a cyano group, or —NH ２ , C １－６ Alkyl group, —OC １－６ an alkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N; —NH ２ , C ３－８ Cycloalkyl group, C ６－２０ an aryl group, or R ＹＡ１１ C substituted by １－６ is an alkyl group, and R ＹＡ１１ is a halogen or a phenyl group, Ring A is C ６－１０ an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S; a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; or C ８－１０ is a benzoheterocycloolefin, n is 0, 1 or 2 The nitrogen-containing heterocyclic compound according to claim 1, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

3. R １ , R １Ｃ , R １Ｄ , R ２Ｃ１ , R ２Ｃ２ , R ２Ｃ３ , R ２Ｃ４ , R ２Ｃ５ , R ２Ｃ１１ , R ３Ａ , R ３Ｃ , R ＹＡ , R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ , R ＹＡ５ and R ＹＡ１１ When a halogen is mentioned in the definition of the formula (I), said halogen is fluorine, chlorine, bromine or iodine; and / or R ２Ｃ１ , R ２Ｃ２ , R ２Ｃ３ , R ２Ｃ４ , R ２Ｃ５ , R ＹＡ , R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ In the definition of C ３－８ When a cycloalkyl group is mentioned, the C ３－８ the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and / or R １Ｃ , R １Ｄ , R ２Ｃ１ , R ２Ｃ２ , R ２Ｃ３ , R ２Ｃ４ , R ２Ｃ５ , R ３Ａ , R ３Ｃ１ , R ３Ｃ２ , R ＹＡ , R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ In the definition of C １－６ Alkyl group or —OC １－６ When an alkyl group is mentioned, the C １－６ The alkyl group is C １－４ alkyl group, further including methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, or t-butyl; and / or R １Ａ , R ２Ａ , R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ In the definition of C ６－２０ When an aryl group is mentioned, the C ６－２０ the aryl group is a phenyl group or a naphthyl group; and / or R ２Ａ and R ＹＡ are each independently a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, the "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N" is a "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O and N", and is a 1H-tetrazolyl group, a pyrazole group, a pyridyl group, or an oxazole group; and / or R ２Ａ and R ＹＡ are each independently an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N, the "8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N" is a [1,2,4]-triazolo[1,5-a]pyridyl group, an indazolyl group, an indolyl group, an isoquinoline group, a benzothienyl group, or a benzimidazole group, and / or X is N or CH; and / or Z is C; and / or E is N or C; and / or R １Ａ is one or more R １Ｄ In the case where R is a "5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S, and N" substituted with １Ａ is one or more R １Ｄ and "a 5- to 6-membered heteroaryl group containing 1 to 2 independently selected heteroatoms N" substituted by and / or R ２Ａ is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R ２Ｃ１ In the case where the "8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N" is substituted with, the "8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N" is a 9- to 10-membered bicyclic heteroaryl group containing 1 to 2 N heteroatoms, and / or R ２Ａ is one or more R ２Ｃ３ "C containing 1 to 3 heteroatoms selected from O, S and N" substituted by ８－１０ When the "benzoheterocycloalkenyl group" is a "C group containing 1 to 3 heteroatoms selected from O, S, and N," ８－１０ The "benzoheterocycloalkenyl group" is an 8- to 10-membered benzoheterocycloalkenyl group containing 1 or 2 N, and / or R ２Ａ is one or more "R ２Ｃ４ In the case where the "R ２Ｃ４ "a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N, substituted with" is "a 5- to 6-membered heteroaryl group containing 1 to 2 N", and / or R ２Ａ is one or more R ２Ｃ５ C substituted by ８－１０ When it is a benzocycloalkenyl group, ８－１０ The benzocycloalkenyl group is C ９－１０ is a benzocycloalkenyl group, and / or L Ｙ is —NH—C(O)—, the C-terminus is R ＹＡ Combined with and / or R ＹＡ represents "a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N," one or more R ＹＡ２ and the "4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N" is a "4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from O and N," and / or R ＹＡ is a "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N", one or more R ＹＡ３ In the case where the "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" is substituted with, the "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" is a "5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O and N", and / or R ＹＡ represents "an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N", one or more R ＹＡ４ In the case where the "8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N" is substituted with, the "8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N" is a "9- to 10-membered bicyclic heteroaryl group containing 1 to 3 N heteroatoms", and / or R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ are each independently R ＹＡ１１ C substituted by １－６ is an alkyl group, and R ＹＡ１１ is halogen, ＹＡ１１ C substituted by １－６ The alkyl group is a C substituted with halogen. １－２ is an alkyl group The nitrogen-containing heterocyclic compound according to claim 1, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

4. a is a double bond and Y is CR Ｙ , E is N, C or CH; and / or R １ is one of the following formulas: 【Chemistry 11】 and / or R ２ is any one selected from the following formulas: 【Chemistry 12】 and / or R Ｙ is hydrogen, -CN, -N ３ , -F, Br, -OH, -NH ２ , -B(OH) ２ , -COOH, -CONH ２ , -COOMe, -CH ３ , -OCH ３ , any one selected from the following formulas 13 to 14, 【Chemistry 13】 【Chemistry 14】 and / or R ３ -F, -Me, -Et, -CD ３ , the following formula 15, the following formula 16, the following formula 17, ═O, or two R3 and the carbon atoms to which they are bonded form a cyclopropane or benzene ring, 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 and / or n is 0, 1 or 2; and / or Q is CH; And / or, the following formula 18 is any one selected from formula 19: 【Chemistry 18】 【Chemistry 19】 The nitrogen-containing heterocyclic compound according to claim 1, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

5. The following formula 20 is any one selected from formula 21: 【Chemistry 20】 【Chemical 21】 The nitrogen-containing heterocyclic compound according to claim 4, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

6. The nitrogen-containing heterocyclic compound represented by formula II is defined as Scheme 1, Scheme 2, Scheme 3 or Scheme 4, Plan 1: E is N or C; X is CH; R １ Is, -L １ -R １Ａ and L １ is a bond, and R １Ａ is C ６－２０ an aryl group, one or more R １Ｃ C substituted by ６－２０ an aryl group, or one or more R １Ｄ and each R is a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, S, and N, substituted with １Ｃ and R １Ｄ are each independently a halogen, C １－６ C substituted with an alkyl group, —COOH, or one or more halogens １－６ is an alkyl group, R ２ Is, -L ２ -R ２Ａ and L ２ is a bond, —NH— or —NH—C(O)—, and R ２Ａ is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R ２Ｃ１ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by one or more R ２Ｃ２ C substituted by ６－２０ an aryl group, or one or more R ２Ｃ３ C containing 1 to 3 heteroatoms selected from O, S and N, substituted by ８－１０ is a benzoheterocycloalkenyl group, and R ２Ｃ１ , R ２Ｃ２ and R ２Ｃ３ are each independently a halogen, a hydroxy group, or R ２Ｃ１１ C substituted by １－６ is an alkyl group, and R ２Ｃ１１ is a halogen, R ３ Is, -L ３ -R ３Ａ and L ３ is a bond, and R ３Ａ is C １－６ an alkyl group, or one or more R ３Ｃ C substituted by １－６ is an alkyl group, R ３Ｃ are independently deuterium, halogen, or —NR ３Ｃ１ R ３Ｃ２ and R ３Ｃ１ and R ３Ｃ２ are each independently C １－６ is an alkyl group, R Ｙ Is, -L Ｙ -R ＹＡ and L Ｙ is a bond, —NH— or —NH—C(O)—, and R ＹＡ is hydrogen, halogen, cyano group, -N ３ , hydroxy group, —NH ２ , -C ２－６ Alkynyl group, the following formula: —B(OH) ２ , C １－６ an alkyl group, one or more R ＹＡ１ C substituted by １－６ Alkyl group, —OC １－６ Alkyl group, C ３－８ a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R ＹＡ２ a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ３ a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ４ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COR ＹＡ５ Or the following formula: 【Chemical 22】 【Chemical 23】 R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ are each independently a halogen, a hydroxy group, a cyano group, or C １－６ Alkyl group, —OC １－６ an alkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N; —NH ２ , C ３－８ Cycloalkyl group, C ６－２０ an aryl group, or R ＹＡ１１ C substituted by １－６ is an alkyl group, and R ＹＡ１１ is a halogen or a phenyl group, Ring A is C ６－１０ an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S, or a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; n is 0, 1 or 2; Plan 2: E is N, CH or C; X is N or CH; R １ Is, -L １ -R １Ａ and L １ is a bond, and R １Ａ is C ６－２０ an aryl group, one or more R １Ｃ C substituted by ６－２０ is an aryl group, and R １Ｃ is a halogen, C １－６ C substituted with alkyl group or halogen １－６ is an alkyl group, R ２ Is, -L ２ -R ２Ａ and L ２ is a bond, —NH—, —NH—C(O)—, or —NH—C(O)CHOH—, and R ２Ａ is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R ２Ｃ１ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by one or more R ２Ｃ２ C substituted by ６－２０ an aryl group, one or more R ２Ｃ３ C containing 1 to 3 heteroatoms selected from O, S and N, substituted by ８－１０ a benzoheterocycloalkenyl group, or one or more R ２Ｃ４ and R is a 5-6 membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N, substituted by ２Ｃ１ , R ２Ｃ２ , R ２Ｃ３ and R ２Ｃ４ are each independently a halogen, a hydroxy group, or C １－６ Alkyl group, C ３－８ a cycloalkyl group, or R ２Ｃ１１ C substituted by １－６ is an alkyl group, and R ２Ｃ１１ is a halogen or hydroxy group, R ３ Is, -L ３ -R ３Ａ and L ３ is a bond, and R ３Ａ is halogen or ═O, or any two R ３ and the carbon atom to which it is bonded ３－８ Cycloalkane or C ６－２０ forming aromatic hydrocarbons, R Ｙ Is, -L Ｙ -R ＹＡ and L Ｙ is a bond, —NH— or —NH—C(O)—, and R ＹＡ is hydrogen, halogen, cyano group, -N ３ , hydroxy group, —NH ２ , the following formula 24, the following formula 25, -B(OH) ２ , -COOH, C １－６ an alkyl group, one or more R ＹＡ１ C substituted by １－６ Alkyl group, —OC １－６ Alkyl group, C ３－８ a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R ＹＡ２ a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ３ a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ４ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COOR ＹＡ５ , the following formula 26, the following formula 27 or the following formula 28, 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical formula 28】 R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ are each independently a halogen, a hydroxy group, a cyano group, or C １－６ an alkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N; —NH ２ , C ３－８ Cycloalkyl group, C ６－２０ an aryl group, or R ＹＡ１１ C substituted by １－６ is an alkyl group, and R ＹＡ１１ is a halogen or a phenyl group, Ring A is C ６－１０ an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S; a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; or C ８－１０ is a benzoheterocycloolefin, n is 0, 1 or 2; Plan 3: E is N or C; X is CH; R １ Is, -L １ -R １Ａ and L １ is a bond, and R １Ａ is C ６－２０ an aryl group, one or more R １Ｃ C substituted by ６－２０ is an aryl group, and R １Ｃ is a halogen or C １－６ is an alkyl group, R ２ Is, -L ２ -R ２Ａ and L ２ is a bond, —NH— or —NH—C(O)—, and R ２Ａ is an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; one or more R ２Ｃ１ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by one or more R ２Ｃ２ C substituted by ６－２０ an aryl group, one or more R ２Ｃ３ C containing 1 to 3 heteroatoms selected from O, S and N, substituted by ８－１０ is a benzoheterocycloalkenyl group, and R ２Ｃ１ , R ２Ｃ２ and R ２Ｃ３ are each independently a halogen, a hydroxy group, or R ２Ｃ１１ C substituted by １－６ is an alkyl group, and R ２Ｃ１１ is a halogen, n is 0, R Ｙ Is, -L Ｙ -R ＹＡ and L Ｙ is a bond, —NH— or —NH—C(O)—, and R ＹＡ is hydrogen, halogen, cyano group, -N ３ , hydroxy group, the following formula 29, the following formula 30, -B(OH) ２ , -COOH, C １－６ an alkyl group, one or more R ＹＡ１ C substituted by １－６ Alkyl group, —OC １－６ Alkyl group, C ３－８ a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, one or more R ＹＡ２ a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ３ a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N, substituted with one or more R ＹＡ４ an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S and N, substituted by -COOR ＹＡ５ Or the following formula 31: 【Chemical 29】 【Chemistry 30】 【Chemical 31】 R ＹＡ１ , R ＹＡ２ , R ＹＡ３ , R ＹＡ４ and R ＹＡ５ are each independently a halogen, a hydroxy group, a cyano group, or C １－６ an alkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from O, S, and N; —NH ２ , C ３－８ Cycloalkyl group, C ６－２０ an aryl group, or R ＹＡ１１ C substituted by １－６ is an alkyl group, and R ＹＡ１１ is a halogen or a phenyl group, Ring A is C ６－１０ an aromatic ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms independently selected from O, N, and S, or a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; Plan 4: E is N, CH or C; X is N or CH; L １ , L ３ and L Ｘ are both bonds, R １Ａ is r １ R １Ｃ R substituted by １Ｄ and R １Ｃ is a halogen, C １－６ C substituted with alkyl group or halogen １－６ is an alkyl group, and R １Ｄ is C ６－２０ is an aryl group, L ２ is a bond, —NH—C(O)— or —NH—, R ２Ａ is r ２ R ２Ｃ R substituted by ２Ｄ and R ２Ｃ is a halogen, a hydroxy group, or a C substituted with one or more halogens １－６ is an alkyl group, and R ２Ｄ is C ６－２０ an aryl group, a 5- to 10-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from O, N, and S, or C ８－１０ is a benzocycloalkenyl group, R ３Ａ is R ３Ｂ , or r ３ R ３Ｃ R substituted by ３Ｄ and R ３Ｂ is a halogen, and R ３Ｃ is a halogen or hydroxy group, and R ３Ｄ is C １－６ is an alkyl group, L Ｙ is a bond, and C １－６ alkylene, —NH—, or —O—; R ＹＡ is R ＹＢ , or r ５ R ＹＣ R substituted by ＹＤ and R ＹＢ is hydrogen, halogen, cyano group, -N ３ , -OR, -B(OR) ２ , -C(O)OR, -C(O)NR ２ or —C(O)R, R ＹＣ is a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S and N; C ３－８ Cycloalkyl group, halogen, —NR ２ , C １－６ C substituted with an alkyl group or one or more halogens １－６ is an alkyl group, R ＹＤ represents a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S, and N; an 8- to 10-membered bicyclic heteroaryl group containing 1 to 3 heteroatoms selected from O, S, and N; —OC １－６ Alkyl group, C １－６ an alkyl group, a 3- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S, and N, or C ３－８ is a cycloalkyl group, Each R is independently hydrogen, C １－６ alkyl groups, optionally substituted C １－６ alkyl groups, where substitution in "optionally substituted" means substituted with one or more of halogen; Ring A is a benzene ring, a 4- to 10-membered cycloalkene containing 1 to 3 heteroatoms selected from O, N, and S, or a 5- to 12-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N, and S; r １ , r ２ , r ３ , r ４ , r ５ and R ６ are each independently 0, 1, 2, or 3; n is 0, 1 or 2 The nitrogen-containing heterocyclic compound according to claim 2, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof.

7. The nitrogen-containing heterocyclic compound according to claim 1, characterized in that the nitrogen-containing heterocyclic compound represented by formula I has any one structure selected from the following formulas 32 to 41: 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】

8. The nitrogen-containing heterocyclic compound according to claim 1, characterized in that the nitrogen-containing heterocyclic compound represented by formula I is any one of the following compounds: a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof. Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 5.153 minutes under the conditions: 【Chemistry 42】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 5.581 minutes under the conditions: 【Chemistry 43】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 4.512 minutes under the conditions: 【Chemical 44】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 5.408 minutes under the conditions: 【Chemistry 45】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 60 / 40, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 4.561 minutes under the conditions: 【Chemistry 46】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 60 / 40, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 5.012 minutes under the conditions: 【Chemistry 47】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 4.561 minutes under the conditions: 【Chemistry 48】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 70 / 30, flow rate: 100 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 5.561 minutes under the conditions: 【Chemistry 49】 Instrument: SFC-150 (Waters), Chromatography column: OJ-H 4.6 × 100 mm 5 μm, Column temperature: 40°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)], flow rate: 3.0 mL / min, back pressure: 2000 psi, measurement wavelength: 214 nm, the retention time was 0.707 minutes under the conditions of 【Chemistry 50】 Instrument: SFC-150 (Waters), Chromatography column: OJ-H 4.6 × 100 mm 5 μm, Column temperature: 40°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)], flow rate: 3.0 mL / min, back pressure: 2000 psi, measurement wavelength: 214 nm, the retention time was 1.449 minutes under the conditions of 【Chemistry 51】 Instrument: SFC-150 (Waters), Chromatography column: OD 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 65 / 35, flow rate: 100.0 mL / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 3.245 minutes under the conditions: 【Chemistry 52】 Instrument: SFC-150 (Waters), Chromatography column: OD 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 65 / 35, flow rate: 100.0 mL / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 3.456 minutes under the conditions: 【Chemistry 53】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 0.56 minutes under the conditions: [Chemical 54] Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 1.21 minutes under the conditions: 【Chemistry 55】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 0.38 minutes under the conditions of 【Chemical 56】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 0.8 minutes under the conditions of 【Chemical 57】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 1.74 minutes under the conditions: 【Chemistry 58】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 3.45 minutes under the conditions: 【Chemical Formula 59】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 1.08 minutes under the conditions: 【Chemistry 60】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 2.32 minutes under the conditions: 【Hua 61】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 0.38 minutes under the conditions of 【Hua 62】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 0.84 minutes under the conditions of 【Chemistry 63】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 2.32 minutes under the conditions: 【Hua 64】 Instrument: SFC-150 (Waters), Chromatography column: AS 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO ２ / MeOH [0.2% NH ３ (7M in MeOH)] = 45 / 55, flow rate: 120 g / min, back pressure: 100 bar, measurement wavelength: 214 nm, the retention time was 3.38 minutes under the conditions. 【Chemistry 65】

9. The nitrogen-containing heterocyclic compound according to claim 1, characterized in that the nitrogen-containing heterocyclic compound represented by formula I is any one compound selected from the following formulas: 【Hua 66】

10. The present invention relates to a pharmaceutical composition comprising a substance A and a pharmaceutical adjuvant, wherein the substance A is a therapeutically effective amount of a nitrogen-containing heterocyclic compound represented by formula I according to any one of claims 1 to 9, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof. A pharmaceutical composition comprising:

11. 1. Use of substance A in the preparation of a PI3K inhibitor, comprising: The substance A is a nitrogen-containing heterocyclic compound represented by formula I according to any one of claims 1 to 9, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof. Use of substance A in the preparation of a PI3K inhibitor.

12. 1. Use of substance A in the preparation of a medicament, comprising: The medicament is used for treating or preventing a PI3K-mediated disease, and the substance A is a nitrogen-containing heterocyclic compound represented by formula I according to any one of claims 1 to 9, a pharmacologically acceptable salt thereof, a solvate thereof, a solvate of a pharmacologically acceptable salt thereof, a crystalline form thereof, a stereoisomer thereof, a tautomer thereof, or an isotope thereof. Use of substance A in the preparation of a medicament.

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