EGFR c797s inhibitor and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry, and specifically to an EGFR C797S inhibitor represented by formula (I) and a use thereof.

Description

EGFR C797S Inhibitors and Their Uses

[0001] This application is based on and claims priority to CN application number 202510494432.0 filed on April 18, 2025, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention belongs to the field of medicinal chemistry, specifically relating to the EGFR C797S inhibitor shown in formula (I) and its uses. Background Technology

[0003] EGFR (epidermal growth factor receptor) is a member of the epidermal growth factor receptor family, which includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3), and HER4 (erbB4). By binding to its ligand, EGFR can form homodimers on the cell membrane or heterodimers with other receptors in the family. The formation of these dimers can induce phosphorylation of key tyrosine residues in EGFR cells, thereby activating many downstream signaling pathways in the cell. Disruptions in the EGFR signaling pathway (including increased ligand and receptor expression), EGFR gene amplification, and alterations (e.g., mutations, deletions) can promote malignant transformation of cells and play a crucial role in tumor cell proliferation, invasion, metastasis, and angiogenesis.

[0004] The successful development of EGFR inhibitors has improved the quality of life for cancer patients. After years of research and clinical practice, EGFR inhibitors have evolved from first-generation to second-generation to third-generation inhibitors, with three generations now widely used in cancer treatment. However, drug resistance issues still exist. Currently, fourth-generation EGFR inhibitors targeting the EGFR C797S mutation have entered clinical trials, but studies have shown problems such as dose-limiting toxicities. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a novel EGFR C797S inhibitor.

[0006] The first aspect of the present invention provides a compound of formula (I), or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0007] in,

[0008] Ring A is a 5-6 membered heteroaryl group;

[0009] T is selected from C and N;

[0010] L1 is selected from the key, -NR a -、-NR a C(=O)-、-NR a S(=O)2-, -O-, -S-, -S(=O)-, -S(=O)2- and -C 1-6 alkylene-, the R a Selected from hydrogen and C 1-4 alkyl;

[0011] R1 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, -S(=O)2NR2, C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, where R is independently selected from H and C. 1-6 Alkyl, C 3-12 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. 11 replace,

[0012] R 11 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, the -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Substitution of alkylene-NH2 and 4-7 membered heterocyclic groups;

[0013] L2 is selected from the key, -C 1-6 Alkylene-, -NR b -, -O-, -S-, -S(=O)-, -S(=O)2-, -NR b C(=O)-、-NR b S(=O)2-、-NR b -C 1-6 Alkylene-, -OC 1-6 Alkylene-, -SC 1-6 Alkylene-, -NR b C(=O)-C 1-6 Alkylene-, -NR b C(=O)-C 1-6 Alkylene-NR b -、-NR b C(=O)-C 1-6 Alkylene-O-, -NR b C(=O)-C 1-6 Alkylene-S-,-C(=O)NR b -C 1-6 Alkylene-,-C(=O)NR b -C 1-6 Alkylene-NR b -、-C(=O)NR b -C 1-6 Alkylene-O- and -C(=O)NR b -C 1-6 alkylene-S-, the R b Selected from hydrogen and C 1-4 alkyl;

[0014] R2 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, -S(=O)2NR2, C 1-6 Alkyl, C 3-12 cycloalkyl, C4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, where R is independently selected from H and C. 1-6 Alkyl, C 3-12 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. 21 replace,

[0015] R 21 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OR c -NHR c -N(R) c )2、-SR c -S(=O)R c -S(=O)2R c -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6- 12 Aryl, 5-12 heteroaryl, -C 1-4 Alkylene-R c -C 2-4 imide-R c -OC 1-4 Alkylene-R c -SC 1-4 Alkylene-R c -NHC 1-4 Alkylene-R c -C 1-4 Alkylene-OR c -C 1-4 Alkylene-SR c and -C 1-4 Alkylene-NHR c The C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12The aryl group and the 5-12 heteroaryl group are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -NHCH3, -N(CH3)2, C 1-6 Alkyl and C 1-6 The substituted group of the haloalkyl group, wherein R c Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 The aryl group, or 5-10 heteroaryl group, is optionally surrounded by one or more elements selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl group substitution;

[0016] R3 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0017] R4 is selected from hydrogen, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-12 Cycloalkyl, -S(=O)2-4-12-membered heterocyclic groups, -NHS(=O)2-C 1-6 Alkyl group, -NHS(=O)2-C 3-12 Cycloalkyl, -NHS(=O)2-4-12-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl group, -NHC(=O)-C 1- 6-alkyl, -C(=O)NH-C 1-6 Alkyl group, -NHC(=O)-C3-12 Cycloalkyl, -C(=O)NH-C 3-12 Cycloalkyl, -NHC(=O)-4-12-membered heterocyclic group, -C(=O)NH-4-12-membered heterocyclic group, -C 1-6 Alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-4-12-membered heterocyclic group, C 1-6 Alkyl, C 3-12 Cycloalkyl groups and 4-12 membered heterocyclic groups, wherein the aforementioned groups are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl groups and -C(=O)NH-C 1-6 Alkyl group substitution;

[0018] The condition is that when R3 is F and L2 is a bond, R2 is not hydrogen.

[0019] In some implementations,

[0020] Ring A is a 5-6 membered heteroaryl group;

[0021] T is selected from C and N;

[0022] L1 is selected from the key, -NR a -、-NR a C(=O)-、-NR a S(=O)2-, -O-, -S-, -S(=O)-, -S(=O)2- and -C 1-6 alkylene-, the R a Selected from hydrogen and C 1-4 alkyl;

[0023] R1 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, -S(=O)2NR2, C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, where R is independently selected from H and C. 1-6 Alkyl, C3-12 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. 11 replace,

[0024] R 11 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, the -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Substitution of alkyl halogroups and 4-7 membered heterocyclic groups;

[0025] L2 is selected from the key, -C 1-6 Alkylene-, -NR b -, -O-, -S-, -S(=O)-, -S(=O)2-, -NR b C(=O)-、-NR b S(=O)2-、-NR b -C1-6 Alkylene-, -OC 1-6 Alkylene-, -SC 1-6 Alkylene-, -NR b C(=O)-C 1-6 Alkylene-, -NR b C(=O)-C 1-6 Alkylene-NR b -、-NR b C(=O)-C 1-6 Alkylene-O-, -NR b C(=O)-C 1-6 Alkylene-S-,-C(=O)NR b -C 1-6 Alkylene-,-C(=O)NR b -C 1-6 Alkylene-NR b -、-C(=O)NR b -C 1-6 Alkylene-O- and -C(=O)NR b -C 1-6 alkylene-S-, the R b Selected from hydrogen and C 1-4 alkyl;

[0026] R2 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, -S(=O)2NR2, C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, where R is independently selected from H and C. 1-6 Alkyl, C 3-12 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. 21 replace,

[0027] R 21 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OR c -NHR c -N(R) c )2、-SR c -S(=O)R c -S(=O)2Rc -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6- 12 Aryl, 5-12 heteroaryl, -C 1-4 Alkylene-R c -C 2-4 imide-R c -OC 1-4 Alkylene-R c -SC 1-4 Alkylene-R c -NHC 1-4 Alkylene-R c -C 1-4 Alkylene-OR c -C 1-4 Alkylene-SR c and -C 1-4 Alkylene-NHR c The C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -NHCH3, -N(CH3)2, C 1-6 Alkyl and C 1-6 The substituted group of the haloalkyl group, wherein R c Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 The aryl group, or 5-10 heteroaryl group, is optionally surrounded by one or more elements selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl group substitution;

[0028] R3 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OC 1-6Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0029] R4 is selected from hydrogen, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-12 Cycloalkyl, -S(=O)2-4-12-membered heterocyclic groups, -NHS(=O)2-C 1-6 Alkyl group, -NHS(=O)2-C 3-12 Cycloalkyl, -NHS(=O)2-4-12-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl group, -NHC(=O)-C 1- 6-alkyl, -C(=O)NH-C 1-6 Alkyl group, -NHC(=O)-C 3-12 Cycloalkyl, -C(=O)NH-C 3-12 Cycloalkyl, -NHC(=O)-4-12-membered heterocyclic group, -C(=O)NH-4-12-membered heterocyclic group, -C 1-6 Alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-4-12-membered heterocyclic group, C 1-6 Alkyl, C 3-12 Cycloalkyl groups and 4-12 membered heterocyclic groups, wherein the aforementioned groups are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl groups and -C(=O)NH-C 1-6 Alkyl group substitution;

[0030] The condition is that when R3 is F and L2 is a bond, R2 is not hydrogen.

[0031] In some implementations, -L2-R2 is not hydrogen.

[0032] In some implementations, ring A is a 5-membered heteroaryl group.

[0033] In some embodiments, ring A is selected from thiazolyl, isothiazolyl, thiophenyl, pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, and furanyl.

[0034] In some implementations, ring A is selected from... Among them, connection site 1 and The two linkage sites are connected: site 2 is connected to the phenyl group, and site 3 is connected to R4.

[0035] In some implementations, L1 is selected from key, -NR a -、-NR a C(=O)-, -O-, -S- and -C 1-4 alkylene-, the R a Selected from hydrogen and C 1-4 Alkyl groups, such as hydrogen, methyl, ethyl, and isopropyl.

[0036] In some implementations, L1 is selected from bond, -NH-, -NH-C(=O)-, -O-, -S-, and -C. 1-4 Alkylene-.

[0037] In some implementations, L1 is selected from bond, -NH- and -NH-C(=O)-*, wherein the * end is connected to R1.

[0038] In some embodiments, R1 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, C 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, where R is independently selected from H and C. 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. 11 Replace, R 11 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-4Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-NH2, C 3-8 The cycloalkyl group and the 4-10 membered heterocyclic group are optionally surrounded by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Substitution with haloalkyl groups and 4-6 membered heterocyclic groups.

[0039] In some embodiments, R1 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, C 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, where R is independently selected from H and C. 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. 11 Replace, R 11 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, C3-8 The cycloalkyl group and the 4-10 membered heterocyclic group are optionally surrounded by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NH-C. 1- 4-alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Substitution with haloalkyl groups and 4-6 membered heterocyclic groups.

[0040] In some implementations, R 11 Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl groups and 4-7 membered heterocyclic groups, wherein the -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 The alkyl group and the 4-7 membered heterocyclic group are optionally surrounded by 1, 2, 3, 4 or 5 groups selected from hydrogen, OH, -NH-C. 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Substitution of alkylene-NH2 and 4-6 membered heterocyclic groups.

[0041] In some implementations, R 11 Each is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)CH2CH3, -CH3, -CH2CH3, pyrrolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, wherein -OCH3, -OCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)CH2CH3, -CH3, -CH2CH3, pyrrolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl are optionally substituted with 1, 2, or 3 groups selected from hydrogen, -OH, NHCH3, N(CH3)2, NHCH2CH3, NHCH2CH2CH3, N(CH2CH3)2, CH2OH, CH2CH2OH, CH2CH2CH2OH, CH2NH2, CH2CH2CH2NH2, CH3, CH2CH3, azirrobutyl, pyrrolyl, piperidinyl, piperazinyl, and morpholinyl.

[0042] In some implementations, R 11 Each is independently selected from F, OCH3,

[0043] In some implementations, R 11 Each is independently selected from hydrogen, -CN, -OH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl groups and 4-7 membered heterocyclic groups, wherein the -OC 1-4 Alkyl, -NH-C 1- 4-alkyl, -N-(C 1-4 Alkyl)2, C 1-4 The alkyl and 4-7 membered heterocyclic groups may be optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, OH, NHCH3, N(CH3)2, CH3, CH2CH3, aziridine, pyrrolidinyl, piperidinyl, piperazine, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl.

[0044] In some implementations, R 11 Each group is independently selected from hydrogen, -CN, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)CH2CH3, -CH3, -CH2CH3, pyrrolyl, piperidinyl, piperazine, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, wherein the -OCH3, -OCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)CH2CH3, -CH3, -CH2CH3, pyrrolyl, piperidinyl, piperazine, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl groups are optionally substituted with 1, 2, or 3 groups selected from hydrogen, -OH, NHCH3, N(CH3)2, CH3, CH2CH3, aziridine, pyrrolyl, piperidinyl, piperazine, and morpholinyl groups.

[0045] In some implementations, R 11 Each is independently selected from OCH3,

[0046] In some embodiments, R1 is selected from hydrogen, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 4-6 cycloalkyl, C 6-10 Aryl and 5-9 membered heteroaryl, the C 1-4 Alkyl, C 4-6 cycloalkyl, C6-10 Aryl and 5-9 quinone heteroaryl groups are optionally coupled with one or more R groups. 11 Instead, the R 11 As defined in any embodiment of the present invention.

[0047] In some embodiments, R1 is selected from hydrogen, -CN, -OH, -COOH, -NH2, methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, benzopyrazolyl, benzimidazolyl, and pyridopyrrolyl, wherein the methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, benzopyrazolyl, benzimidazolyl, and pyridopyrrolyl groups are optionally represented by 1, 2, or 3 R1 groups. 11 Instead, the R 11 As defined in any embodiment of the present invention.

[0048] In some implementations, R1 is selected from H, NH2, CH3, The Choose 1, 2, or 3 Rs 11 Instead, the R 11 As defined in any embodiment of the present invention.

[0049] In some implementations, R1 is selected from H, NH2, CH3,

[0050] In some embodiments, R1 is selected from hydrogen, -CN, -OH, -COOH, -NH2, methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoleyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, benzopyrazolyl, and pyridopyrrolyl, wherein the methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazoleyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and indoleyl groups are optionally replaced by 1, 2, or 3 R1 groups. 11 Instead, the R 11 As defined in any embodiment of the present invention.

[0051] In some implementations, R1 is selected from H, NH2, CH3, The Choose 1, 2, or 3 Rs 11 Instead, the R 11 As defined in any embodiment of the present invention.

[0052] In some implementations, R1 is selected from H, NH2, CH3,

[0053] In some implementations, L2 is selected from key, -C 1-4 Alkylene-, -NR b -、-O-、-S-、-NR b C(=O)-、-NR b -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, -NR b C(=O)-C 1-4 Alkylene-, -NR b C(=O)-C 1-4 Alkylene-NR b -、-NR b C(=O)-C 1-4 alkylene-O- and -NR b C(=O)-C 1-4 alkylene-S-, the R b Selected from hydrogen and C 1-4 Alkyl groups, such as hydrogen, methyl, ethyl, and isopropyl.

[0054] In some embodiments, L2 is selected from the following: -CH2-, -CH2CH2-, -CH(CH3)-, -NH-, -N(CH3)-, -O-, -NHC(=O)-, -NHCH2-, -NHCH2CH2-, -NHCH(CH3)CH2-, -OCH2-, -OCH2CH2-, -OCH(CH3)CH2-, -SCH2-, -SCH2CH2-, -SCH(CH3)CH2-, -NHC(=O)CH2-, -NHC(=O)CH2NH-, -NHC(=O)CH2O-, and -NHC(=O)CH2S-.

[0055] In some implementations, L2 is selected from the following: -CH2-, -NH-, -O-, -NHCH2-*, -NHC(=O)-*, -NHC(=O)CH2-*, -NHC(=O)CH2O-*, -OCH2-*, and -CH2O-*, wherein the * end is connected to R2.

[0056] In some implementations, R2 is selected from hydrogen, halogen, -CN, -OR, -COOR, -NR2, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10Aryl and 5-12 heteroaryl groups, where R is independently selected from H and C. 1- 4-alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3- 10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. 21 Replace, R 21 Each is independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OR c -NHR c -SR c -S(=O)R c -S(=O)2R c -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkylene-R c -C 2-4 imide-R c -OC 1-4 Alkylene-R c -SC 1-4 Alkylene-R c -NHC 1-4 Alkylene-R c -C 1-4 Alkylene-OR c -C 1-4 Alkylene-SR c and -C 1-4 Alkylene-NHR c The C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally surrounded by one or more elements selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -NHCH3, -N(CH3)2, C 1-4 Alkyl and C 1-4 The substituted group of the haloalkyl group, wherein R c Each is independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C1-4 Alkyl, C 3-7 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, C 3-7 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally surrounded by one or more elements selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, and C. 1-4 Alkyl groups are substituted.

[0057] In some implementations, R 21 Each is independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OR c -NHR c -SR c -S(=O)R c -S(=O)2R c -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c C 1-4 Alkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl, -CH2R c -CH=CHR c -OCH2-R c -SCH2-R c -NHCH2-R c -CH2OR c -CH2SR c and -CH2NHR c The C 1-4 Alkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl groups are optionally surrounded by one or more elements selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl and C 1-4 The substituted group of the haloalkyl group, wherein R c Each is independently selected from hydrogen and C. 1-4 Alkyl, 4-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl, wherein C 1-4 Alkyl, 4-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups may be selected by one or more elements chosen from hydrogen, halogen, -CN, -OH, -COOH, -NH2, and C. 1-4 Alkyl groups are substituted.

[0058] In some implementations, R 21Each is independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OR c -NHR c -SR c -S(=O)R c -S(=O)2R c -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophene, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -CH2R c -CH=CHR c -OCH2-R c -SCH2-R c -CH2OR c and -CH2SR c The methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl groups are optionally substituted by 1, 2, 3, 4, or 5 groups selected from hydrogen, halogens, -CN, -OH, -COOH, -NH2, CH3, CHF2, CH2F, and CF3, wherein R c Each group is independently selected from hydrogen, methyl, ethyl, isopropyl, aziridine, pyrrolyl, piperidinyl, piperazine, oxadiazine, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophene, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyrazinyl, wherein the methyl, ethyl, isopropyl, aziridine, pyrrolyl, piperidinyl, piperazine, oxadiazine, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophene, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyrazinyl groups are optionally substituted by 1, 2, 3, 4, or 5 groups selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, and methyl.

[0059] In some implementations, R 21 Each is independently selected from H, F, Cl, Br, NH2, OH, CH3, CH(CH3)2, CH2F, CF3, CH2OH, OCH3, OCH2CH3, -NHC(=O)CH3, -NHS(=O)2CH3, -C(=O)NHCH3, cyclopropyl, phenyl,

[0060] In some embodiments, R2 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. 21 Instead, the R 21 As defined in any embodiment of the present invention.

[0061] In some embodiments, R2 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 5-8 Polycyclic cycloalkyl groups, 4-8 membered monocyclic heterocyclic groups, C 6-10 The compounds include aryl, 5-10 membered heteroaryl, pyrimidinone, thienocyclopentenyl, 3,4-dihydro-1H-benzopyranyl, and tetrahydroquinolinyl, wherein the 4-8 membered monocyclic heterocyclic group contains one or two heteroatoms selected from N and O, and the 5-10 membered heteroaryl group contains one, two, or three heteroatoms selected from N, O, and S. 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 5-8 Polycyclic cycloalkyl groups, 4-8 membered monocyclic heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, pyrimidinone, thienocyclopentenyl, 3,4-dihydro-1H-benzopyranyl, and tetrahydroquinolinyl are optionally separated by one or more R 21 Instead, the R 21 As defined in any embodiment of the present invention.

[0062] In some embodiments, R2 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, methyl, ethyl, propyl, isopropyl, CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.4]heptyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, aziryl, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyridine Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, furanyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzopyrrolyl, benzopyrazolyl, benzoimidazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, quinolinyl, isoquinolinyl, pyrimidinone, thiophenecyclopentenyl, 3,4-dihydro-1H -Benzopyranyl and tetrahydroquinolinyl, wherein the methyl, ethyl, propyl, isopropyl, CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.4]heptyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, aziridine, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, furanyl alkyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzopyrroleyl, benzopyrazolyl, benzoimidazolyl, benzothiopheneyl, benzothiazolyl, benzofuranyl, pyridopyrroleyl, pyridopyrazolyl, pyridimidazolyl, quinolinyl, isoquinolinyl, pyrimidinoneyl, thienocyclopentenyl, 3,4-dihydro-1H-benzopyranyl, and tetrahydroquinolinyl are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 21 Instead, the R 21 As defined in any embodiment of the present invention.

[0063] In some embodiments, R2 is selected from H, Cl, Br, CN, OH, NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, The CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, Choose any 1, 2, 3, 4 or 5 Rs 21 Instead, the R 21 As defined in any embodiment of the present invention.

[0064] In some embodiments, R2 is selected from H, Cl, Br, CN, OH, NH2, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CF3, CH2OH,

[0065] In some implementations, R2 is not H.

[0066] In some embodiments, R3 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0067] In some implementations, R3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, and -NH2.

[0068] In some implementations, R3 is selected from H and F.

[0069] In some implementations, R4 is selected from hydrogen, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-10 Cycloalkyl, -S(=O)2-4-10-membered heterocyclic groups, -NHS(=O)2-C 1-6 Alkyl group, -NHS(=O)2-C 3-10 Cycloalkyl, -NHS(=O)2-4-10-membered heterocyclic groups, -NHC(=O)-C 1-6 Alkyl group, -NHC(=O)-C 3-10 Cycloalkyl, -NHC(=O)-4-10 membered heterocyclic groups, -C 1-4 Alkylene-C 3-10 cycloalkyl, -C 1-4 alkylene-4-10-membered heterocyclic group, C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 4-10 membered heterocyclic groups, wherein the aforementioned groups are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl groups and -C(=O)-C 1-6 Alkyl groups are substituted.

[0070] In some implementations, R4 is selected from hydrogen, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, -SC 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl group, -S(=O)2-C 3-7 cycloalkyl, -NHS(=O)2-C 1-4 Alkyl group, -NHS(=O)2-C 3-7 Cycloalkyl, -NHC(=O)-C 1-4 Alkyl group, -NHC(=O)-C 3-7 Cycloalkyl, -NHC(=O)-4-8 membered heterocyclic groups, -C 1-4 Alkylene-C 3-7 cycloalkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl groups and 4-10 membered heterocyclic groups, wherein the aforementioned groups are optionally surrounded by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -COOH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkylene-OH, C 1-4 Alkylene -NH2, -S(=O)2-C 1-4 Alkyl groups and -C(=O)-C 1-4 Alkyl group substitutions, such as hydrogen, fluorine, chlorine, bromine, -OH, -COOH, -NH2, -CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CH2CF3, CF2CF3, CH2OH, CH2CH2OH, CH2NH2, CH2CH2NH2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2;

[0071] Preferably, R4 is selected from H, CH3, The aforementioned groups may be optionally replaced by 1, 2, 3, 4, or 5 elements selected from F, -OH, -CN, CH3, CH2OH, CF3, ... The group is substituted.

[0072] In some implementations, R4 is selected from H,

[0073] In some implementations, R4 is selected from hydrogen, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, -SC 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl group, -S(=O)2-C 3-7 cycloalkyl, -NHS(=O)2-C 1-4 Alkyl group, -NHS(=O)2-C 3-7 Cycloalkyl, -NHC(=O)-C 1-4 Alkyl group, -NHC(=O)-C 3-7 Cycloalkyl, -NHC(=O)-4-8 membered heterocyclic groups, -C 1-4 Alkylene-C 3-7 cycloalkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl groups and 4-8 membered heterocyclic groups, wherein the aforementioned groups are optionally surrounded by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -COOH, -NH2, C 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl groups and -C(=O)-C 1-4 Alkyl group substitution, such as hydrogen, fluorine, chlorine, bromine, -OH, -COOH, -NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2.

[0074] In some implementations, R4 is selected from H, The aforementioned groups may be optionally replaced by 1, 2, 3, 4, or 5 elements selected from F, CH3, The group is substituted.

[0075] In some implementations, R4 is selected from H,

[0076] In some embodiments, the compound is selected from the compounds shown in formula (I-1).

[0077] in,

[0078] X is selected from N, O, and S;

[0079] The definitions of T, L1, R1, L2, R2, R3, and R4 are as described in any embodiment of the present invention.

[0080] In some embodiments, the compound is selected from the compounds shown in formula (I-1A).

[0081] The definitions of T, L1, R1, L2, R2, R3, and R4 are as described in any embodiment of the present invention.

[0082] In some embodiments, R2 is selected from H, Cl, Br, CN, OH, NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, The CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, Optional by one or more R 21 Instead, the R 21 The definition is as described in any embodiment of the present invention. In some embodiments, R 21 Selected from F, OH, CH3, CH2F and

[0083] In some embodiments, R2 is selected from H, Cl, Br, CN, OH, NH2, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CF3, CH2OH,

[0084] In some embodiments, the compound is selected from the compounds shown in formula (I-1A-1), (I-1A-2), (I-1A-3), and (I-1A-4).

[0085] R2 is defined as described in any embodiment of the present invention.

[0086] In some embodiments, the compound is selected from the compounds shown in formula (I-1B).

[0087] The definitions of T, L1, R1, L2, R2, R3, and R4 are as described in any embodiment of the present invention.

[0088] In some implementations, R2 is selected from H, NH2, CH3, CH2CH3, The CH3, CH2CH3, Choose any 1, 2, 3, 4 or 5 Rs 21 Instead, the R 21 As defined in any embodiment of the present invention, in some embodiments, R 21 Selected from H, F, Cl, Br, NH2, OH, CH3, CH(CH3)2, CF3, CH2OH, OCH3, OCH2CH3, -NHC(=O)CH3, -NHS(=O)2CH3, -C(=O)NHCH3, phenyl,

[0089] In some implementations, R2 is selected from H, NH2, CH3, CH2CH3,

[0090] In some embodiments, the compound is selected from:

[0091] A second aspect of the present invention provides a pharmaceutical composition comprising at least one compound described in the first aspect of the present invention, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers and / or excipients.

[0092] The third aspect of the invention provides the use of the compounds, stereoisomers thereof, tautomers thereof, solvates thereof, isotopically labeled compounds thereof, or pharmaceutically acceptable salts thereof, of the pharmaceutical compositions of the second aspect of the invention in the preparation of medicaments for treating and / or preventing diseases or conditions or reducing the severity of said diseases or conditions, wherein said diseases or conditions are related to EGFR C797S.

[0093] The third aspect of the invention also provides the compounds described in the first aspect of the invention, or stereoisomers thereof, or tautomers thereof, or solvates thereof, or isotopically labeled compounds thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in the second aspect of the invention, for the treatment and / or prevention of diseases or conditions or for the reduction of the severity of said diseases or conditions, wherein said diseases or conditions are associated with EGFR C797S.

[0094] A third aspect of the invention also provides a method for treating and / or preventing a disease or condition or for reducing the severity of said disease or condition, comprising administering to an individual in need an effective amount of a compound of the first aspect of the invention, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the second aspect of the invention, wherein said disease or condition is associated with EGFR C797S.

[0095] In some implementations, the disease or condition is selected from cancer.

[0096] In some implementations, the disease or condition is selected from lung cancer, stomach cancer, prostate cancer, ovarian cancer, testicular cancer, colon cancer, hematologic malignancy, breast cancer, multiple myeloma, liver cancer, pancreatic cancer, melanoma, glioma, and brain glioma.

[0097] In some implementations, the disease or condition is non-small cell lung cancer.

[0098] Terminology Definition

[0099] In this application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, to better understand this application, definitions and explanations of relevant terms are provided below.

[0100] In the event that the compound name used in this application is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0101] As used in this application, the term "stereoisomer" refers to an isomer formed by at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0102] Similarly, the compounds of this application may exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0103] Unless otherwise stated, the compounds of this application may exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of this application may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0104] The compounds of this invention may exist as solvates (such as hydrates), wherein the compounds of this application contain a solvent, such as water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the solvent may be stoichiometric or non-stoichiometric.

[0105] As used herein, the term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms of the same number but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in compounds of this application include, but are not limited to, hydrogen isotopes such as... 2 H, 3 H; carbon isotopes, for example 11 C, 13 C and 14 C; Chlorine isotopes, for example 36 Cl; fluorine isotopes, for example 18 F; Iodine isotopes, for example 123 I and 125 I; nitrogen isotopes, for example 13 N and 15 N; oxygen isotopes, for example 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0106] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: salts formed by addition to inorganic acids or acids formed with organic acids, or salts containing acidic protons on the parent compound but surrounded by metal ions, or coordination compounds formed with organic bases.

[0107] Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and similar salts.

[0108] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and similar salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using the relative ions of halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0109] Pharmaceutically acceptable salts are also intended to include hemisalts, wherein the ratio of compound to acid is 2:1. Exemplary hemisalts are those derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary hemisalts are those derived from diprotic mineral acids (e.g., sulfuric acid). Preferred exemplary hemisalts include (but are not limited to) hemi-maleic acid salts, hemi-fumaric acid salts, and hemi-succinic acid salts.

[0110] As used in this application, the term "optionally substituted" means that the group may be unsubstituted or substituted, for example, "C..." 1-6 "Alkyl optional halogen substitution" indicates C 1-6 Alkyl groups can be unsubstituted or substituted with halogens to give haloalkyl groups. It should be understood that -N-(C 1-6 Alkyl)2 indicates that two carbon atoms are attached to the nitrogen atom. 1- 6 alkyl groups, where the two alkyl groups can be the same or different.

[0111] Unless otherwise defined, divalent groups are not directionally restricted. For example, ALB is AC(=O)-NH-B or A-NH-C(=O)-B when L is -C(=O)-NH-.

[0112] As used herein, unless otherwise expressly indicated, the descriptive phrase “...each independently selected” used throughout may mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0113] As used in this invention, “selected from bond” indicates that the groups on both sides of the variable are directly connected, for example, ALB, when L is a bond, ALB is AB.

[0114] As used in this application, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0115] As used in this application, the term "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group, such as C10. 1-8 Alkyl groups refer to those having 1 to 8 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C 1-6 Alkyl groups refer to those having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms. The C... 1-8 Alkyl groups include C 1-6 Alkyl, C 1-4 Alkyl groups, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, etc., wherein the propyl group includes n-propyl and isopropyl, and the butyl group includes n-butyl, isobutyl, and neobutyl.

[0116] As used in this application, the term "alkylene" refers to a straight-chain or branched divalent saturated hydrocarbon group, such as C 1-4 Alkylenes refer to compounds having 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. Examples of alkylenes include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0117] As used in this application, the term "alkenyl" refers to a straight-chain or branched unsaturated divalent saturated hydrocarbon group containing at least one double bond, such as C 1-4 An alkenyl group refers to a group having 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, -CH=CH-, -CH=CH-CH=CH-, etc.

[0118] As used in this application, the term "halogenated" refers to a modified group being substituted with one or more halogens, for example, substituted with 1, 2, 3, 4, 5, or 6 halogens. For example, "C 1-6 "Halogenated alkyl" refers to C as defined above. 1-6 The alkyl group is substituted with one or more halogens, including but not limited to CF3, CHF2, or CF2CF3.

[0119] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms. For example, C 3- 12 The cycloalkyl group has 3 to 12 carbon atoms, such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein the C 3-12 Cycloalkyl groups include C 3-8 cycloalkyl, C 3-6 cycloalkyl, C 6-12 cycloalkyl, C 6-10 cycloalkyl, C 6-8 Cycloalkyl groups, etc. The cycloalkyl groups include monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, cyclohexyl, cycloheptyl, adamantyl, etc.

[0120] As used herein, the term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of carbon atoms. For example, C 4-12 The cycloalkenyl group has 4 to 12 carbon atoms, such as 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein the C 4-12 Cycloalkenyl groups include C 4-8 Cycloalkenyl, C 6-12 Cycloalkenyl, C 6-10 Cycloalkenyl, C 6-8 Cycloalkenyl groups, etc. The cycloalkenyl groups include monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, cyclohexenyl and hexahydronaphthyl.

[0121] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated monovalent cyclic group composed of ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized. For example, a 5-12 membered heterocyclic group refers to a group composed of 5-12 ring atoms, including 5-10 membered heterocyclic groups, 5-7 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-6 membered heterocyclic groups, etc. The heterocyclic group includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Examples include, but are not limited to, oxo-heterobutyl, azirrobutyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0122] As used in this application, the term "partially unsaturated" refers to a ring system that is neither saturated (i.e., does not contain double bonds) nor completely unsaturated (i.e., contains the maximum possible number of double bonds). In other words, a partially unsaturated ring system contains at least one double bond, but not the maximum possible number of double bonds.

[0123] As used in this application, the term "aryl" refers to an unsaturated carbocyclic group having a conjugated π-electron system, such as C6- 10 The aryl group consists of 6 to 10 carbon atoms (e.g., 6, 7, 8, 9, or 10). Non-limiting examples include, but are not limited to, phenyl.

[0124] As used herein, the term "heteroaryl" refers to an unsaturated group consisting of ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms, and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized. For example, 5-10-membered heteroaryls consist of 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms, including 5-9-membered, 9-10-membered, and 5-6-membered heteroaryls, etc. The heteroaryls include monocyclic and polycyclic compounds, examples of which include, but are not limited to, imidazolyl, pyridinyl, quinolinyl, or isoquinolinyl compounds.

[0125] As used herein, the term "pharmaceutical carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, as is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutical carriers and / or excipients include, but are not limited to: pH adjusters, surfactants, ionic strength enhancers, diluents, agents for maintaining osmotic pressure, agents for delaying absorption, preservatives, and stabilizers. For example, pH adjusters include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. Agents for maintaining osmotic pressure include, but are not limited to, sugars, NaCl, and their analogues. Agents for delaying absorption include, but are not limited to, monostearates and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols, and polyols (such as glycerol). Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc. Stabilizers have the meaning commonly understood by those skilled in the art for stabilizing the desired activity of the active ingredient in a pharmaceutical product, including, but not limited to, monosodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin, or casein) or their degradation products (such as lactalbumin hydrolysate), etc.

[0126] As used in this application, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to a certain extent.

[0127] As used herein, the term "treatment" aims to alleviate, reduce, improve, or eliminate a targeted disease state or symptom. A subject is successfully "treated" if, in accordance with the methods described herein, a therapeutic amount of a compound, its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, its pharmaceutically acceptable salt, or a combination thereof, and the subject exhibits an observable and / or detectable reduction or improvement in one or more indications and symptoms. It should also be understood that treatment of a disease state or symptom includes not only complete treatment but also the achievement of some biological or medically relevant outcome without achieving complete treatment.

[0128] As used in this application, the term "prevention" aims to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms before the onset of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, reducing the risk of a subject developing a specific disease or disease-related symptoms after the administration of the relevant drug, or lessening the severity of subsequently occurring related symptoms, can be considered as "prevention" of the onset or development of the disease. Detailed Implementation

[0129] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0130] I. Intermediates

[0131] Intermediate A-1: ​​5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluoroaniline

[0132] Step 1, Synthesis of Intermediate A-1-1: Ethyl 3-(((benzyloxy)carbonyl)amino)-4-fluorobenzoate: Ethyl 3-amino-4-fluorobenzoate (1 eq, 5 mmol) was dissolved in a mixture of THF (10 mL) and water (5 mL). After cooling to 0 °C, NaHCO3 (1.5 eq, 7.5 mmol) was added, followed by the slow dropwise addition of Cb2-Cl (1.1 eq, 5.5 mmol). The mixture was gradually brought to room temperature and reacted overnight. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. A-1-1 (1.3 g, 4.2 mmol), a white solid, was obtained by rapid preparative liquid chromatography with a yield of 84%. Ms(ESI,m\z):[M+H] + 318.24.

[0133] Step 2, Synthesis of Intermediate A-1-2: (5-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)carbamate: A-1-1 (1 eq, 4.2 mmol) and 2-chloro-4-methylpyrimidine (1.1 eq, 4.6 mmol) were dissolved in anhydrous THF (10 mL), and the mixture was cooled to 0 °C under argon protection. Then, LIHMDS (2.2 eq, 9.2 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued at this temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. The mixture was purified by rapid preparative liquid chromatography to obtain intermediate ketone A-1-2 and an enol mixture (1.1 g, 2.8 mmol), a white solid, in 68% yield. Ms(ESI,m\z):[M+H] + 400.05.

[0134] Step 3, Synthesis of Intermediate A-1-3: (5-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)carbamate: A mixture of intermediate ketone A-1-2 and enol (1 eq, 2 mmol) was dissolved in anhydrous DMF (10 mL), cooled to 0 °C, and then NBS (1.1 eq, 2.2 mmol) was added in portions. After the addition was complete, the reaction continued for 1 hour, and water was added to precipitate a yellow solid. The solid was filtered, dried, and then rapidly prepared by HPLC to obtain intermediate A-1-3 (904 mg, 1.9 mmol), a pale yellow solid, with a yield of 95%.

[0135] Step 4, Synthesis of Intermediate A-1-4: (5-(5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)thiazolyl)2-fluorophenyl)carbamate benzyl ester: A-1-3 (1 eq, 1.9 mmol) and 4-aminomethylthioylpiperidin-1-carboxylic acid tert-butyl ester (1 eq, 1.9 mmol) were dissolved in 10 mL DMF. The reactants were heated to 90 °C and reacted overnight. After the reaction was complete, the mixture was concentrated and evaporated under reduced pressure. Intermediate A-1-4 (576 mg, 1.1 mmol), a brown solid, was obtained by rapid preparative liquid chromatography with a yield of 58%. Ms(ESI,m\z):[M+H] + 524.76.

[0136] Step 5, Synthesis of Intermediate A-1-5: (5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluorophenyl)benzyl carbamate: A-1-4 (1 eq, 1.1 mmol) was dissolved in 10 mL of DCM and cooled to 0 °C. Then, TEA (3 eq, 3.3 mmol) and ethylsulfonyl chloride (1.2 eq, 1.3 mmol) were added. After the addition was complete, the mixture was transferred to room temperature and reacted for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by rapid preparative liquid chromatography to obtain intermediate A-1-5 (615 mg, 1.0 mmol), a white solid, in 91% yield. Ms(ESI, m\z): [M+H] + 616.89.

[0137] Step 6, Synthesis of Intermediate A-1-6: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)2-fluoroaniline: A-1-5 (1 eq, 1.0 mmol) was dissolved in 1 mL of anhydrous DCM, cooled to 0 °C, and then hydrobromic acid-acetic acid solution (30% in HOAc) (3 eq, 3 mmol) was added. The mixture was then transferred to room temperature and reacted for 1 hour. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate on the organic layer, and the reaction mixture was concentrated under reduced pressure. Intermediate A-1-6 (385 mg, 0.8 mmol) was obtained by rapid preparative liquid chromatography purification, as a white solid with a yield of 80%. Ms(ESI,m\z):[M+H] + 482.54. 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=5.1Hz,1H),7.33-7.26(m,2H),7.16-7.11(m,2H),5.66(d,J=10.7Hz,2H),3.72(d,J=12 .4Hz,2H),3.29(tt,J=11.3,3.2Hz,1H),3.11-3.03(m,4H),2.25(d,J=13.1Hz,2H),1.85-1.70(m,2H),1.28-1.19(m,3H).

[0138] Step 7, Synthesis of Intermediate A-1: ​​5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-N-ethyl-2-fluoroaniline: A-1-6 (1 eq, 0.3 mmol) was dissolved in 1 mL of ethanol, acetaldehyde (3 eq, 0.9 mmol) was added, and the mixture was stirred for 0.5 h. Then, sodium cyanoborohydride (1.5 eq, 0.45 mmol) was added, and the reaction was continued for 5 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by rapid preparative liquid chromatography to obtain intermediate A-1 (102 mg, 0.2 mmol), a yellow solid, in 67% yield. Ms(ESI,m\z):[M+H] + 510.45. 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=5.1Hz,1H),7.33-7.26(m,2H),7.16-7.11(m,2H),5.85(d,J=10.7Hz,1H),3.72(d,J=12.4Hz,2H),3 .68(d,J=11.6Hz,2H),3.29(tt,J=11.3,3.2Hz,1H),3.11-3.03(m,4H),2.25(d,J=13.1Hz,2H),1.85-1.70(m,2H),1.26-1.17(m,6H).

[0139] Intermediate A-2: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluoro-N-methylaniline

[0140] Following the synthesis method of A-1, a yellow solid was produced in 40% yield. Ms(ESI,m\z):[M+H] + 497.33. 1 H NMR (600MHz, DMSO-d6) δ8.55(d,J=5.1Hz,1H),7.37-7.21(m,2H),7.18-7.10(m,2H),5.80(d,J=10.6Hz,1H),3.77(d,J=12 .4Hz,2H),3.25(tt,J=11.3,3.2Hz,1H),3.14-3.03(m,4H),2.29(d,J=13.1Hz,2H),1.85-1.72(m,2H),1.25(t,J=7.4,3H).

[0141] Intermediate A-3: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluoro-N-isopropylaniline

[0142] A-1-6 (1 eq, 0.1 mmol) was dissolved in 1 mL of ethanol, and acetone (10 eq, 1 mmol) was added. The mixture was heated to 60 °C and reacted for 2 hours. After cooling to room temperature, sodium cyanoborohydride (1.5 eq, 0.45 mmol) was added, and the reaction was continued for another 5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by rapid preparative liquid chromatography to obtain intermediate A-3 (32 mg, 0.06 mmol), a yellow solid, in 60% yield, Ms(ESI, m\z): [M+H]. + 524.14. 1 H NMR (600MHz, DMSO-d6) δ8.44(d,J=5.3Hz,1H),7.32-7.20(m,2H),7.25-7.18(m,2H),5.80(d,J=10.9Hz,1H),3.96(s,1H),3.77( d,J=12.4Hz,2H),3.25(tt,J=11.3,3.2Hz,1H),3.14-3.03(m,4H),2.29(d,J=13.1Hz,2H),1.85-1.72(m,2H),1.25-1.16(m,9H).

[0143] Intermediate A-4: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-N-cyclopropyl-2-fluoroaniline

[0144] Step 1: Synthesis of intermediate A-4-1: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)-N-(1-ethoxycyclopropyl)-2-fluoroaniline: A-1-6 (1 eq, 0.3 mmol) was dissolved in a MeOH / AcOH mixture (2:3, 3 mL). Under argon protection, (1.5 eq, 0.45 mmol) trimethylsilane was slowly added dropwise, and the reaction was gradually heated to 70 °C for 6 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, washed with water, extracted multiple times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by preparative liquid chromatography to obtain intermediate A-4-1 (100 mg, 0.18 mmol), a yellow solid, in 60% yield, Ms(ESI, m\z): [M+H]. + 566.78.

[0145] Step 2, Synthesis of Intermediate A-4: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-N-cyclopropyl-2-fluoroaniline: A-4-1 (1 eq, 0.18 mmol) was dissolved in 2 mL of anhydrous THF. NaBH4 (1.5 eq, 0.27 mmol) was added in portions at 0 °C. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 hours. Then, under argon protection, the mixture was cooled to -5 °C, and boron trifluoride diethyl ether solution (1.5 eq, 0.27 mmol) was slowly added. The temperature was gradually increased to 50 °C and the reaction was carried out for 6 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the reaction mixture was concentrated under reduced pressure. Intermediate A-4 (52 mg, 0.1 mmol), a yellow solid, was obtained by rapid preparative liquid chromatography with a yield of 56%. Ms(ESI, m\z): [M+H] + 522.34. 1 H NMR (600MHz, DMSO-d6) δ8.57(d,J=5.4Hz,1H),7.33-7.24(m,2H),7.18-7.11(m,2H),5.85(d,J=10.8Hz,1H),3.77(d,J=12.4Hz,2H),3.2 5(tt,J=11.3,3.2Hz,1H),3.14-3.03(m,4H),2.54(tt,J=12.6,3.7Hz,1H),2.29(d,J=13.1Hz,2H),1.85-1.72(m,2H),1.25-0.65(m,7H),

[0146] Intermediate A-5: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluoro-N-(3-fluorocyclopentyl)aniline

[0147] Following the synthesis method of A-3, a yellow solid was produced in 30% yield. Ms(ESI,m\z):[M+H] + 568.45. 1H NMR (600MHz, DMSO-d6) δ8.58(d,J=7.5Hz,1H),7.61-7.56(m,2H),7.54-7.19(m,2H),5.87(d,J=10.8Hz,1H),3.71(d,J=12.3Hz,2H),3.46(tt,J=11 .2,3.4Hz,1H),3.27(tt,J=11.2,3.2Hz,1H),3.09-3.01(m,4H),2.20(d, J=13.1Hz,2H),1.82-1.73(m,2H),1.99-1.67(m,6H),1.23(t,J=7.4,3H).

[0148] Intermediate A-6: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluorophenyl)spiro[2,4]heptane-5-amine

[0149] Following the synthesis method of A-3, a yellow solid was produced in 30% yield. Ms(ESI,m\z):[M+H] + 576.43. 1 H NMR (600MHz, DMSO-d6) δ8.59(d,J=7.5Hz,1H),7.62-7.55(m,2H),7.33-7.26(m,2H),5.84(d,J=11.0Hz,1H),4.04(tt,J=12.2,3.3Hz,1H ),3.71(d,J=12.3Hz,2H),3.27(tt,J=11.2,3.2Hz,1H),3.09-3.01(m,4H),2.20(d,J=13.1Hz,2H),1.82-1.73(m,8H),1.23-0.74(m,7H).

[0150] Intermediate A-7: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-N-cyclopropylmethyl-2-fluoroaniline

[0151] Following the synthesis method of A-1, a yellow solid was produced in 60% yield. Ms(ESI,m\z):[M+H] + 536.18. 1H NMR(600MHz,DMSO-d6)δ8.58(d,J=7.5Hz,1H),7.61-7.54(m,2H),7.33-7.26(m,1H),6.85(dd,J=4.9,1.5Hz,1H),6.70(t,J=5.9H z,1H),3.39-3.21(m,8H),3.16(p,J=7.0Hz,1H),2.42-2.24(m,4H),1.79-1.63(m,1H),1.45-1.35(m,4H),1.30(t,J=8.0Hz,3H).

[0152] Intermediate A-8: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluorophenyl)tetrahydro-2H-pyran-4-amine

[0153] Following the synthesis method of A-3, a white solid was produced in 37% yield. Ms(ESI,m\z):[M+H] + 566.19. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),7.61-7.54(m,3H),7.28-7.21(m,1 H),5.86(d,J=11.4Hz,1H),3.99(dp,J=11.4,7.0Hz,1H),3.72(dt,J=12.5,7.1Hz,2H), 3.55(dt,J=12.4,7.1Hz,2H),3.36(d,J=8.0Hz,1H),3.33(d,J=8.0Hz,1H),3.33-3.21( m,4H),3.16(p,J=7.0Hz,1H),2.41-2.24(m,4H),1.94-1.79(m,4H),1.34-1.27(m,3H).

[0154] Intermediate A-9: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluorophenyl)acetamide

[0155] A-1-6 (1 eq, 0.1 mmol) was dissolved in 1 mL of anhydrous DCM and cooled to 0 °C. Then, DIPEA (3 eq, 0.3 mmol) and acetic anhydride (1.5 eq, 0.15 mmol) were added, and the mixture was reacted at this temperature for 3 hours. After the reaction was complete, the mixture was washed with saturated sodium bicarbonate, followed by extraction with dichloromethane. The organic phase was concentrated under reduced pressure and purified by preparative liquid chromatography to give intermediate A-9 (45 mg, 0.085 mmol), a yellow solid, in 85% yield. Ms(ESI, m / z): [M+H] + 524.16. 1 H NMR(600MHz,Chloroform-d)δ9.66(s,1H),8.58(d,J=7.5Hz,1H),7.98(dd,J=5.0, 1.4Hz,1H),7.58(d,J=7.5Hz,1H),7.42-7.35(m,1H),7.28(ddd,J=7.5,4.9,1.5Hz, 1H),3.36(d,J=8.0Hz,1H),3.33(d,J=8.0Hz,1H),3.33-3.25(m,2H),3.28-3.21(m ,2H),3.16(p,J=7.0Hz,1H),2.42-2.24(m,4H),2.12(s,2H),1.30(t,J=8.0Hz,3H).

[0156] Intermediate A-10: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluorophenyl)propionamide

[0157] Following the synthesis method described in A-9, a yellow solid was produced in 87% yield. Ms(ESI,m\z):[M+H] + 538.16. 1H NMR(600MHz,Chloroform-d)δ9.43(s,1H),8.58(d,J=7.5Hz,1H),7.98(dd,J=5.0,1.4Hz, 1H),7.58(d,J=7.5Hz,1H),7.41-7.34(m,1H),7.29(ddd,J=7.5,5.0,1.6Hz,1H),3.36(d,J =8.0Hz,1H),3.33(d,J=8.0Hz,1H),3.33-3.25(m,2H),3.28-3.21(m,2H),3.16(p,J=7.0H z,1H),2.51(q,J=8.0Hz,2H),2.42-2.24(m,4H),1.30(t,J=8.0Hz,3H),1.18-1.11(m,3H).

[0158] Intermediate A-11: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0159] Following the synthesis method of A-9, a yellow solid was produced in 60% yield. Ms(ESI,m\z):[M+H] + 582.11. 1 H NMR(600MHz,Chloroform-d)δ9.47(s,2H),8.58(d,J=7.5Hz,2H),7.99(dd,J=5.0 ,1.5Hz,2H),7.58(d,J=7.5Hz,2H),7.34(t,J=7.7Hz,2H),7.29(ddd,J=7.5,5.1, 1.5Hz,2H),4.89(p,J=7.0Hz,1H),4.80(p,J=7.0Hz,1H),3.39-3.21(m,12H),3.1 6(p,J=7.0Hz,2H),2.85(p,J=7.0Hz,2H),2.41-2.20(m,17H),1.34-1.27(m,5H).

[0160] Intermediate A-12: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluorophenyl)oxetane-2-carboxamide

[0161] Following the synthesis method described in A-9, a yellow solid was produced in 58% yield. Ms(ESI,m\z):[M+H] + 566.11. 1H NMR(600MHz,Chloroform-d)δ9.39(s,1H),8.58(d,J=7.5Hz,1H),7.99(dd,J=5.0, 1.4Hz,1H),7.58(d,J=7.5Hz,1H),7.34-7.24(m,2H),4.53(t,J=7.1Hz,1H),3.91( td,J=7.1,2.8Hz,2H),3.40(dq,J=12.5,8.0Hz,1H),3.35-3.17(m,6H),3.16(q,J= 7.0Hz, 1H), 2.46 (dq, J=12.3, 7.0Hz, 1H), 2.41-2.23 (m, 5H), 1.30 (t, J=8.0Hz, 3H).

[0162] Intermediate A-13: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-2-fluorophenyl)-3,3,3-trifluoropropionamide

[0163] Following the synthesis method of A-9, a yellow solid was produced in 24% yield. Ms(ESI,m\z):[M+H] + 592.13. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),7.98(dd,J=5.0,1.4Hz,1H),7.58(d,J=7.5Hz,1H),7.32(t,J=7.6Hz,1H),7.28(ddd,J=7.5,5. 1,1.5Hz,1H),3.72(d,J=12.4Hz,2H),3.29(tt,J=11.3,3.2Hz,1H),3.09 -3.08(m,4H),2.75-2.64(m,2H)2.24(d,J=13.1Hz,5H)1.34-1.27(m,3H).

[0164] Intermediate A-14: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)2-fluorophenol

[0165] Step 1, Intermediate A-14-1: Synthesis of methyl 4-fluoro-3-methoxybenzoate: Methyl 3,4-fluoro-3-hydroxybenzoate (1 eq, 5 mmol) was dissolved in DMF (10 mL), cooled to 0 °C, and Cs₂CO₃ (1.5 eq, 7.5 mmol) was added, followed by slow dropwise addition of MeI (1.2 eq, 6 mmol). The mixture was gradually brought to room temperature and reacted overnight. After the reaction was complete, the mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. A-14-1 (874 mg, 4.75 mmol), a colorless oil, was obtained by rapid preparative liquid chromatography (HPLC) purification, with a yield of 95%. Ms(ESI,m\z):[M+H] + 185.67.

[0166] Step 2, Synthesis of Intermediate A-14-2: 2-(2-chloropyrimidin-4-yl)-1-(4-fluoro-3-methoxyphenyl)ethyl-1-one: Following the synthetic method of A-1-2, white solid, yield 73%. Ms(ESI,m\z):[M+H] + 281.56.

[0167] Step 3, intermediate A-14-3: Synthesis of (2-bromo-2-(2-chloropyrimidin-4-yl)-1-(4-fluoro-3-methoxyphenyl)ethyl-1-one: Refer to the synthesis method of A-1-3, pale yellow solid, yield 90%.

[0168] Step 4, Intermediate A-14-4: Synthesis of 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(piperidin-4-yl)thiazole: Following the synthetic method of A-1-4, the product is a brown solid with a yield of 60%. Ms(ESI,m\z):[M+H] + 405.08.

[0169] Step 5, Synthesis of Intermediate A-14-5: (5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole: Following the synthesis method of A-1-5, white solid, yield 88%. Ms(ESI,m\z):[M+H] + 497.13. 1H NMR(600MHz,DMSO-d6)δ8.60(d,J=5.4Hz,1H),7.38-7.29(m,2H),7.20-7.13(m,2H),3.81(s,3H),3.71(d,J=12.3Hz, 2H),3.27(tt,J=11.2,3.2Hz,1H),3.09-3.01(m,4H),2.20(d,J=13.1Hz,2H),1.82-1.73(m,2H),1.23(t,J=7.4,3H).

[0170] Step 6, Synthesis of Intermediate A-14: 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)2-fluorophenol: A-14-5 (1 eq, 3 mmol) was dissolved in anhydrous THF (5 mL), cooled to 0 °C under argon protection, and then boron tribromide solution (5 eq, 15 mmol) was added dropwise. After the addition was complete, the reaction was carried out at this temperature for 6 hours. After the reaction was completed, the reaction was quenched dropwise with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the reactants were concentrated under reduced pressure. A-14 (1.0 g, 2.2 mmol), a yellow solid, was obtained by rapid preparative liquid chromatography with a yield of 73%. Ms(ESI,m\z):[M+H] + 487.32. 1 H NMR (600MHz, DMSO-d6) δ10.34(s,1H),8.61(d,J=5.4Hz,1H),7.35-7.26(m,2H),7.23-7.11(m,2H),3.71(d,J=12.3Hz ,2H),3.27(tt,J=11.2,3.2Hz,1H),3.09-3.01(m,4H),2.20(d,J=13.1Hz,2H),1.82-1.73(m,2H),1.23(t,J=7.4,3H).

[0171] Intermediate A-15: 5-(2-chloropyrimidin-4-yl)-4-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole

[0172] A-14 (1 eq, 0.5 mmol) and (bromomethyl)cyclopropane (1.2 eq, 0.6 mmol) were dissolved in acetone (2 mL), and potassium carbonate (2 eq, 1 mmol) was added. The mixture was heated to 70 °C and reacted for 16 hours. After the reaction was complete, the mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A-15 (214 mg, 0.4 mmol), a yellow solid, was purified by rapid preparative liquid chromatography in 80% yield. Ms(ESI,m\z):[M+H] + 537.28. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),7.63-7.55(m,2H),7.20-7.14(m,2H),3.97(d,J=7.0Hz,2H),3.36(d,J=8.0Hz,1H),3.33(d,J=8.0Hz ,1H),3.33-3.25(m,2H),3.28-3.21(m,2H),3.16(p,J=7.0Hz,1H),2.42-2.2 4(m,4H),1.38(hept,J=7.0Hz,1H),1.30(t,J=8.0Hz,3H),0.72-0.36(m,4H).

[0173] Intermediate A-16: 4-(3-(benzyloxy)-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole

[0174] Following the synthesis method described in A-15, a yellow solid was produced in 83% yield. Ms(ESI,m\z):[M+H] + 573.28. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),7.64-7.55(m,2H),7.42(ddq,J=7.1 ,1.9,1.0Hz,2H),7.39-7.32(m,2H),7.35-7.28(m,1H),7.14(t,J=7.8Hz,1H),7.08(dd, J=5.0,1.5Hz,1H),5.14(d,J=1.1Hz,2H),3.71(d,J=12.3Hz,2H),3.27(tt,J=11.2,3.2H z,1H),3.09-3.01(m,4H),2.20(d,J=13.1Hz,2H),1.82-1.73(m,2H),1.23(t,J=7.4,3H).

[0175] Intermediate A-17: 4-(3-bromo-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole

[0176] Step 1, Intermediate A-17-1: Synthesis of 1-(3-bromo-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one: Following the synthetic method of A-1-2, white solid, yield 75%. Ms(ESI,m\z):[M+H] + 330.58.

[0177] Step 2, intermediate A-17-2: synthesis of 2-bromo-1-(3-bromo-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one: refer to the synthesis method of A-1-3, pale yellow solid, yield 85%.

[0178] Step 3, Intermediate A-17-3: Synthesis of 4-(3-bromo-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)thiazole: Following the synthetic method of A-1-4, the product is a brown solid with a yield of 52%. Ms(ESI,m\z):[M+H] + 454.66.

[0179] Step 4, Synthesis of Intermediate A-17: 4-(3-bromo-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole: Following the synthetic method of A-1-5, a yellow solid was obtained in 80% yield. Ms(ESI,m\z):[M+H] + 545.06. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),7.69(dd,J=5.0,1.5Hz,1H),7.58(d,J=7.3Hz,1H),7.45(ddd,J=7.5,4.9,1.5Hz,1H),7.29(t,J =7.7Hz,1H),3.71(d,J=12.3Hz,2H),3.27(tt,J=11.2,3.2Hz,1H),3.09-3 .01(m,4H),2.20(d,J=13.1Hz,2H),1.82-1.73(m,2H),1.25(t,J=7.4,3H).

[0180] Intermediate A-18: 4-(3-chloro-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole

[0181] Step 1, Intermediate A-18-1: Synthesis of 1-(3-chloro-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one: Following the synthetic method of A-1-2, white solid, yield 74%. Ms(ESI,m\z):[M+H] + 285.18.

[0182] Step 2, intermediate A-18-2: synthesis of 2-bromo-1-(3-chloro-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one: refer to the synthesis method of A-1-3, pale yellow solid, yield 88%.

[0183] Step 3, Synthesis of intermediate A-18-3: 4-(3-chloro-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)thiazole: Following the synthetic method of A-1-4, the product is a brown solid with a yield of 47%. Ms(ESI,m\z):[M+H] + 409.55.

[0184] Step 4, Synthesis of Intermediate A-18: 4-(3-chloro-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole: Following the synthetic method of A-1-5, a yellow solid was obtained in 80% yield. Ms(ESI,m\z):[M+H] + 501.23. 1 H NMR(600MHz,Chloroform-d)δ8.52(d,J=7.5Hz,1H),7.60(dd,J=5.0,1.5Hz,1H),7.58(d,J=7.3Hz,1H),7.45(ddd,J=7.5,4.9,1.5Hz,1H),7.29(t,J =7.7Hz,1H),3.71(d,J=12.3Hz,2H),3.27(tt,J=11.2,3.2Hz,1H),3.19-3 .11(m,4H),2.20(d,J=13.1Hz,2H),1.82-1.73(m,2H),1.20(t,J=7.4,3H).

[0185] Intermediate A-19: 4-(3-cyano-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole

[0186] Step 1, Intermediate A-19-1: Synthesis of 1-(3-cyano-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one: Following the synthetic method of A-1-2, white solid, yield 55%. Ms(ESI,m\z):[M+H]+ 276.18.

[0187] Step 2, intermediate A-19-2: synthesis of 2-bromo-1-(3-cyano-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one: refer to the synthesis method of A-1-3, pale yellow solid, yield 80%.

[0188] Step 3, Intermediate A-19-3: Synthesis of 4-(3-cyano-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)thiazole: Following the synthetic method of A-1-4, the product is a brown solid with a yield of 30%. Ms(ESI,m\z):[M+H] + 400.11.

[0189] Step 4, Intermediate A-19: Synthesis of 4-(3-cyano-4-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole: Refer to the synthesis method of A-1-5. Yellow solid, yield 85%. Ms(ESI,m\z):[M+H] + 492.23. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),8.00(dd,J=5.0,1.5Hz,1H),7.70(ddd,J=7.5,5.0,1.6Hz,1H),7.58(d,J=7.5Hz,1H),7.44-7. 37(m,1H),3.71(d,J=12.3Hz,2H),3.27(tt,J=11.2,3.2Hz,1H),3.09-3. 01(m,4H),2.20(d,J=13.1Hz,2H),1.82-1.73(m,2H),1.23(t,J=7.4,3H).

[0190] Intermediate A-20: 5-(2-chloropyrimidin-4-yl)-4-(3-(cyclopropoxymethyl)-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole

[0191] Step 1, Intermediate A-20-1: Synthesis of ethyl 4-fluoro-3-hydroxymethylbenzoate: Ethyl 4-fluoro-3-formylbenzoate (1 eq, 1 mmol) was dissolved in ethanol (5 mL). Sodium borohydride (1.5 eq, 1.5 mmol) was added in portions at 0 °C. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 hours. After the reaction was completed, the mixture was cooled to 0 °C, and the reaction was quenched by slow dropwise addition of dilute hydrochloric acid. The ethanol was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the reactants were concentrated under reduced pressure. A-20-1 (188 mg, 0.95 mmol), a colorless oil, was obtained by rapid preparative liquid chromatography with a yield of 95%. Ms(ESI,m\z):[M+H] + 199.08.

[0192] Step 2, Synthesis of Intermediate A-20-2: Ethyl 3-(cyclopropoxymethyl)-4-fluorobenzoate: Cyclopropyl bromide (1 eq, 0.6 mmol), A-20-1 (1.5 eq, 0.9 mmol), and sodium tert-butoxide (0.9 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was heated to 100 °C and stirred at this temperature for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by rapid preparative liquid chromatography to obtain A-20-2 (95 mg, 0.4 mmol), a colorless oil, with a yield of 67%. Ms(ESI,m\z):[M+H] + 239.43.

[0193] Step 3, Intermediate A-20-3: Synthesis of 2-(2-chloropyrimidin-4-yl)-1-(3-(cyclopropoxymethyl)-4-fluorophenyl)ethyl-1-one: Following the synthetic method of A-1-2, white solid, yield 68%. Ms(ESI,m\z):[M+H] + 321.74.

[0194] Step 4, Intermediate A-20-4: Synthesis of 2-bromo-2-(2-chloropyrimidin-4-yl)-1-(3-(cyclopropoxymethyl)-4-fluorophenyl)ethyl-1-one: Refer to the synthesis method of A-1-3, yellow solid, yield 80%.

[0195] Step 5, Intermediate A-20-5: Synthesis of 5-(2-chloropyrimidin-4-yl)-4-(3-(cyclopropoxymethyl)-4-fluorophenyl)-2-(piperidin-4-yl)thiazole: Refer to the synthesis method of A-1-4. Brown solid, yield 40%. Ms(ESI,m\z):[M+H] + 445.11.

[0196] Step 6, Synthesis of Intermediate A-20: 5-(2-chloropyrimidin-4-yl)-4-(3-(cyclopropoxymethyl)-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole: Refer to the synthesis method of A-1-5. Yellow solid, 90% yield. Ms(ESI,m\z):[M+H] + 537.28. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),7.63-7.55(m,2H),7.45(ddd,J=7.5,4.9,1.5Hz,1H),7.30(t,J=7.8Hz,1H),4.56(d,J=1.1Hz,2H),3. 71(d,J=12.3Hz,2H),3.27(tt,J=11.2,3.2Hz,1H),3.09-3.01(m,4H),2.20(d ,J=13.1Hz,2H),1.82-1.73(m,2H),1.89-1.67(m,4H),1.30(t,J=8.0Hz,3H).

[0197] Intermediate A-21: N-(5-(5-(2-chloropyrimidin-4-yl)-2-ethylthiazolyl-4-yl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0198] Step 1, Intermediate A-21-1: Synthesis of ethyl 4-fluoro-3-(3-fluorocyclobutane-1-carbamate)benzoate: Ethyl 3-amino-4-fluorobenzoate (1 eq, 1 mmol) was dissolved in anhydrous DCM (5 mL), and DIPEA (3 eq, 3 mmol) was added at 0 °C, followed by 3-fluorocyclobutane-1-carbonyl chloride (1.2 eq, 1.2 mmol). After the addition was complete, the mixture was transferred to room temperature and reacted for 3 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The reactants were concentrated under reduced pressure and purified by rapid preparative liquid chromatography to obtain A-21-1 (137 mg, 0.75 mmol), a pale yellow solid, with a yield of 75%. Ms(ESI,m\z):[M+H] + 284.77.

[0199] Step 2, Intermediate A-21-2: Synthesis of N-(5-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Following the synthesis method of A-1-2, a pale yellow solid was obtained in 37% yield. Ms(ESI,m\z):[M+H] + 366.48.

[0200] Step 3, intermediate A-21-3: Synthesis of N-(5-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Refer to the synthesis method of A-1-3, pale yellow solid, yield 80%.

[0201] Step 5, Synthesis of Intermediate A-21: N-(5-(5-(2-chloropyrimidin-4-yl)-2-ethylthiazolyl-4-yl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: A-21-3 (1 eq, 0.9 mmol) and propylthionimide (1 eq, 0.9 mmol) were dissolved in 5 mL of DMF and reacted at room temperature for 3 hours. After the reaction was complete, water was added to precipitate a yellow solid. The solid was filtered, and the residue was purified by preparative HPLC to obtain intermediate A-21 (576 mg, 1.1 mmol), a pale yellow solid, in 60% yield. Ms(ESI,m\z):[M+H] + 435.34. 1 H NMR(600MHz,Chloroform-d)δ9.30(s,1H),8.54(d,J=7.3Hz,1H),7.98(dd,J=5.0,1.5Hz,1H),7.57(d,J=7.5Hz,1H),7.37(t,J=7.7Hz,1H),7.3 0(ddd,J=7.5,5.0,1.6Hz,1H),4.85(dp,J=46.3,7.0Hz,1H),2.97(q,J= 8.0Hz,2H),2.83-2.44(m,1H),2.29-2.01(m,4H),1.34(t,J=8.0Hz,3H).

[0202] Intermediate A-22: N-(5-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0203] Following the synthesis method described in A-21, a pale yellow solid was produced in 60% yield. Ms(ESI,m\z):[M+H] + 449.50. 1H NMR(600MHz,Chloroform-d)δ9.30(s,1H),8.55(d,J=7.5Hz,1H),7.99(dd,J=5.0,1.5Hz,1H),7.58(d,J=7.5Hz,1H),7.38(t,J=7.7Hz,1H) ,7.29(ddd,J=7.5,5.1,1.5Hz,1H),4.86-4.77(m,1H),3.37(t,J=6.8Hz,1H),2.83-2.40(m,1H),2.29-2.03(m,4H),1.38(d,J=6.8Hz,6H).

[0204] Intermediate A-23: N-(5-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0205] Following the synthesis method described in A-21, a pale yellow solid was produced in 53% yield. Ms(ESI,m\z):[M+H] + 475.84. 1 H NMR(600MHz,Chloroform-d)δ9.44(s,1H),8.58(d,J=7.5Hz,1H),7.99(dd,J=5.0,1.5Hz, 1H),7.57(d,J=7.5Hz,1H),7.38(t,J=7.7Hz,1H),7.31(ddd,J=7.5,5.1,1.5Hz,1H),4.89 -4.81(m,1H),2.88(d,J=7.0Hz,2H),2.83-2.40(m,2H),2.29-2.03(m,4H),1.77-1.64(m,6H).

[0206] Intermediate A-24: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(2,2-difluorocyclopropyl)thiazolyl-4-yl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0207] Following the synthesis method described in A-21, a pale yellow solid was obtained in 46% yield. Ms(ESI,m\z):[M+H] + 483.65. 1H NMR(600MHz,Chloroform-d)δ9.46(s,1H),8.58(d,J=7.5Hz,1H),7.99(dd,J=5.0,1.5Hz, 1H),7.59(d,J=7.5Hz,1H),7.38(t,J=7.7Hz,1H),7.30(ddd,J=7.5,5.1,1.5Hz,1H),4.89 -4.80(m,1H),3.70(tt,J=20.9,7.0Hz,1H),2.83(p,J=7.0Hz,1H),2.78-2.61(m,2H),2.37-2.19(m,4H).

[0208] Intermediate A-25: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0209] Following the synthesis method described in A-21, a pale yellow solid was obtained in 57% yield. Ms(ESI,m\z):[M+H] + 491.86. 1 H NMR(600MHz,Chloroform-d)δ9.44(s,1H),8.58(d,J=7.5Hz,1H),7.99(dd,J=5.1,1.5Hz,1H),7.58(d,J=7.5Hz,1H),7.41-7.34(m,1H),7.29 (ddd,J=7.5,4.9,1.5Hz,1H),4.89-4.82(m,1H),3.79(td,J=7.1,2.4Hz,4H),3.20(p,J=7.0Hz,1H),2.83(p,J=7.0Hz,1H),2.44-2.19(m,8H).

[0210] Intermediate A-26: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-methylpiperidin-4-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0211] Step 1, Synthesis of intermediate N-(5-(5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Refer to the synthesis method in A-1-4. Brown solid, yield 30%. Ms(ESI,m\z):[M+H] + 490.58.

[0212] Step 2, Synthesis of intermediate N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-methylpiperidin-4-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Following the synthetic method in A-1, a yellow solid was obtained in 93% yield. Ms(ESI,m\z):[M+H] + 504.16. 1 H NMR(600MHz,Chloroform-d)δ9.44(s,1H),8.58(d,J=7.5Hz,1H),7.99(dd,J=5.0,1.5Hz,1H),7.58(d,J=7.5Hz,1H),7.38(t,J=7.7Hz,1H),7.28(dd d,J=7.5,4.9,1.5Hz,1H),4.92-4.83(m,1H),3.14(p,J=7.0Hz,1H),2.87- 2.75(m,4H),2.68(dt,J=12.4,7.1Hz,2H),2.33(s,3H),2.37-2.07(m,7H).

[0213] Intermediate A-27: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-methylpiperazin-4-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0214] Step 1, Synthesis of intermediate N-(5-(5-(2-chloropyrimidin-4-yl)-2-(piperazin-4-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Refer to the synthesis method in A-1-4. Brown solid, yield 35%. Ms(ESI,m\z):[M+H] + 491.67.

[0215] Step 2, Synthesis of intermediate N-(5-(5-(2-chloropyrimidin-4-yl)-2-(1-methylpiperazin-4-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Following the synthetic method in A-1, a yellow solid was obtained in 92% yield. Ms(ESI,m\z):[M+H] + 505.18.Ms(ESI,m\z):[M+H] + 504.16. 1H NMR(600MHz,Chloroform-d)δ9.44(s,1H),8.58(d,J=7.5Hz,1H),7.99(dd,J=5.0,1.5Hz,1H),7.58(d,J=7.5Hz,1H),7.38(t,J=7.7Hz,1H ),7.28(ddd,J=7.5,4.9,1.5Hz,1H),4.92-4.83(m,1H),2.87-2.75(m,4H),2.68(dt,J=12.4,7.1Hz,2H),2.33(s,3H),2.37-2.07(m,7H).

[0216] Intermediate A-28: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(methylthio)thiazolyl-4-yl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0217] Following the synthesis method described in A-21, a yellow solid was produced in 65% yield. Ms(ESI,m\z):[M+H] + 453.66.

[0218] 1 H NMR 600MHz, Chloroform-d) δ9.30 (s, 1H), 8.52 (d, J = 7.5Hz, 1H), 8.00 (dt, J = 5.0, 0.8Hz, 1H), 7.61 (d, J = 7. 5Hz,1H),7.36-7.30(m,2H),4.86-4.77(m,1H),2.83(q,J=7.0Hz,1H),2.80(s,3H),2.29-2.01(m,4H).

[0219] Intermediate A-29: N-(5-(5-(2-chloropyrimidin-4-yl)-2-(6-methyl-3,6-diazabicyclo[3.1.1]hept-3-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0220] Step 1, Synthesis of intermediate N-(5-(5-(2-chloropyrimidin-4-yl)-2-(3,6-diazabicyclo[3.1.1]hept-3-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Following the synthetic method in A-1-4, the product is a brown solid with a yield of 30%. Ms(ESI,m\z):[M+H] + 503.27.

[0221] Step 2, Synthesis of intermediate N-(5-(5-(2-chloropyrimidin-4-yl)-2-(6-methyl-3,6-diazabicyclo[3.1.1]hept-3-yl)thiazolyl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Following the synthetic method in A-1, a yellow solid was obtained in 87% yield. Ms(ESI,m\z):[M+H] + 517.56. 1 H NMR(600MHz,Chloroform-d)δ9.41(s,1H),8.56(d,J=7.5Hz,1H),7.97(dd,J=5.0 ,1.5Hz,1H),7.54(d,J=7.5Hz,1H),7.37(t,J=7.7Hz,1H),7.26(ddd,J=7.5,4.9, 1.5Hz,1H),4.89-4.80(m,1H),3.67(dd,J=12.0,6.6Hz,2H),3.39-3.25(m,4H),2 .83(p,J=7.0Hz,1H),2.43(t,J=1.5Hz,3H),2.37-2.19(m,4H),2.10-1.95(m,2H).

[0222] Intermediate A-30: N-(5-(5-(2-chloropyrimidin-4-yl)-2-methoxythiazolyl-4-yl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0223] Following the synthesis method described in A-21, a yellow solid was produced in 60% yield. Ms(ESI,m\z):[M+H] + 437.68. 1 H NMR(600MHz,Chloroform-d)δ9.30(s,1H),8.47(d,J=7.5Hz,1H),7.97(dd,J=5.0,1.4Hz,1H),7.55(d,J=7.5Hz,1H),7.33(ddd,J= 7.5,4.9,1.5Hz,1H),7.29-7.22(m,1H),4.86-4.77(m,1H),3.98(s,2H),2.83(p,J=7.1Hz,1H),2.29(dtd,J=25.2,7.0,1.7Hz,4H).

[0224] Intermediate A-31: N-(5-(5-(2-chloropyrimidin-4-yl)-2-cyclohexylthiazolyl-4-yl)2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0225] Following the synthesis method described in A-21, a yellow solid was obtained in 52% yield. Ms(ESI,m\z):[M+H] + 489.27. 1 H NMR(600MHz,Chloroform-d)δ9.45(s,1H),8.58(d,J=7.5Hz,1H),7.99(dd,J=5.1,1.5Hz,1H),7.58(d,J=7.5Hz,1H),7.41-7.34(m,1H),7.30(ddd,J =7.5,4.9,1.5Hz,1H),4.89-4.80(m,1H),3.12(p,J=6.9Hz,1H),2.83(p,J =7.0Hz,1H),2.37-2.19(m,4H),1.79-1.73(m,2H),1.73-1.67(m,2H),1.60 -1.37(m,6H).

[0226] Intermediate A-32: N-(5-(2-acetamido-5-(2-chloropyrimidin-4-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide

[0227] Step 1, Synthesis of intermediate N-(5-(2-amino-5-(2-chloropyrimidin-4-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: Following the synthetic method in A-21, a yellow solid was obtained in 85% yield. Ms(ESI,m\z):[M+H] + 422.56.

[0228] Step 2: Synthesis of intermediate N-(5-(2-acetamido-5-(2-chloropyrimidin-4-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide: A-32-1 was dissolved in 5 mL of tetrahydrofuran under argon protection at 0 °C. Sodium hydride (2 eq, 0.2 mmol) was added, and the reaction was carried out for 0.5 h. Then, acetyl chloride (1.5 eq, 0.15 mmol) was added, and the reaction was transferred to room temperature for 3 h. After the reaction was completed, saturated ammonium chloride aqueous solution was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, evaporated, and purified by rapid preparative liquid chromatography to obtain A-32 (49 mg, 0.11 mmol) as a yellow solid, with a yield of 70%. Ms(ESI,m\z):[M+H] + 464.67. 1H NMR (600MHz, Chloroform-d) δ9.35 (s, 1H), 8.54 (d, J = 7.5Hz, 1H), 8.01 (dd, J = 4.9, 1.3Hz, 1H), 7.62 (d, J = 7. 5Hz,1H),7.40-7.31(m,2H),4.86-4.77(m,1H),2.83(p,J=7.0Hz,1H),2.37-2.20-2.13(m,4H),2.05(s,3H)

[0229] Intermediate A-34: N-(5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-(3-fluorocyclobutane-1-carbamate)phenyl)thiazolyl)tetrahydro-2H-pyran-4-carboxamide

[0230] Following the synthesis method described in A-32, a yellow solid was obtained in 64% yield. Ms(ESI,m\z):[M+H] + 534.66. 1 H NMR(600MHz,Chloroform-d)δ9.45(s,1H),8.58(d,J=7.5Hz,1H),7.99(dd,J=5.1,1.5Hz,1H),7.58(d,J=7.5Hz,1H),7.41-7.34(m,1H),7.30(ddd,J=7.5,4 .9,1.5Hz,1H),4.89-4.80(m,1H),3.44-3.25(m,4H),3.12(p,J=6.9Hz,1H),2 .83(p,J=7.0Hz,1H),2.37-2.19(m,4H),1.79-1.73(m,2H),1.73-1.67(m,2H),

[0231] Intermediate A-35: 5-(2-chloropyrimidin-4-yl)-2-ethyl-4-(4-fluoro-3-methoxyphenyl)thiazole

[0232] Following the synthesis method described in A-21, a yellow solid was produced in 80% yield. Ms(ESI,m\z):[M+H] + 337.65. 1H NMR(600MHz,Chloroform-d)δ8.61(d,J=7.5Hz,1H),7.57(d,J=7.5Hz,1H),7.25(dd,J=5.0,1.5Hz,1H),7.20( ddd,J=7.5,5.1,1.5Hz,1H),7.14(t,J=7.7Hz,1H),3.91(s,3H),2.96(q,J=8.0Hz,2H),1.31(t,J=8.0Hz,3H).

[0233] Intermediate A-36: N-(5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)acetamide

[0234] Step 1, Synthesis of the intermediate 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole-2-amine: Following the synthetic method in A-21, the product is a yellow solid with a yield of 80%. Ms(ESI,m\z):[M+H] + 337.48.

[0235] Step 2, Synthesis of intermediate N-(5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)acetamide: Following the synthesis method in A-32, a yellow solid was obtained in 70% yield. Ms(ESI,m\z):[M+H] + 379.89. 1 H NMR (600MHz, Chloroform-d) δ8.55(d,J=7.5Hz,1H),7.64(d,J=7.5Hz,1H),7.26-7.18(m,2H),7.12(t,J=7.7Hz,1H),3.93(s,3H),2.20(s,3H).

[0236] Intermediate A-38: 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(1-ethylpiperidin-4-yl)thiazole

[0237] Following the synthesis method described in A-1, a yellow solid was obtained in 62% yield. Ms(ESI,m\z):[M+H] + 433.28. 1H NMR(600MHz,Chloroform-d)δ8.56(d,J=7.5Hz,1H),7.63-7.55(m,2H),7.23(dd,J=5.0,1.5Hz,1H),7.14(t ,J=7.7Hz,1H),3.88(s,3H),3.16(p,J=7.0Hz,1H),2.58-2.39(m,6H),2.29-2.13(m,4H),1.09-1.02(m,3H).

[0238] Intermediate A-39: 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(1-acetylpiperidin-4-yl)thiazole

[0239] Following the synthesis method described in A-32, a yellow solid was produced in 70% yield. Ms(ESI,m\z):[M+H] + 447.29. 1 H NMR(600MHz,Chloroform-d)δ8.55(d,J=7.5Hz,1H),7.62-7.55(m,2H),7.24(dd,J=5.0,1.5Hz,1H),7.14(t,J=7.8Hz,1H),3.87(s ,3H),3.60(td,J=7.1,1.7Hz,4H),3.19(p,J=7.0Hz,1H),2.28(dq,J=12.4,7.1Hz,2H),2.18(dq,J=12.4,7.1Hz,2H),2.11(s,3H).

[0240] Intermediate A-40: 5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-(trifluoromethoxy)phenyl)thiazole

[0241] Following the synthesis method described in A-32, a yellow solid was obtained in 78% yield. Ms(ESI,m\z):[M+H] + 551.38. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),7.62-7.55(m,2H),7.27-7.20(m,2H),3.39-3.34(m,2H),3.32(d ,J=4.5Hz,1H),3.31-3.25(m,2H),3.25-3.20(m,1H),3.16(p,J=7.0Hz,1H),2.42-2.24(m,4H),1.30(t,J=8.0Hz,3H).

[0242] Intermediate A-41: N-(4-(4-(3-aminophenyl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine

[0243] Step 1, Synthesis of 2-(2-chloropyrimidin-4-yl)-1-(3-nitrophenyl)ethyl-1-one (A-41-1): 2-chloro-4-methylpyrimidine (1 eq, 100 mmol) and ethyl 4-nitrobenzoate (1.1 eq, 110 mmol) were dissolved in 150 mL of anhydrous tetrahydrofuran. The solution was cooled to 0 °C, and lithium bis(trimethylsilylamino)hydroxide (2 eq, 200 mmol) was added dropwise. After reacting at 5–10 °C for 3 hours, the reaction was quenched with a saturated aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid pre-liquid chromatography was performed to obtain a mixture of A-41-1 one and enol (16.8 g, 67 mmol), a pale yellow solid, in 67% yield. ESI-MS: 277.0 [M+H]+.

[0244] Step 2, Synthesis of 5-(2-chloropyrimidin-4-yl)-4-(3-nitrophenyl)thiazole (A-41-2): 2-(2-chloropyrimidin-4-yl)-1-(3-nitrophenyl)ethyl-1-one (1 eq, 10 mmol) was dissolved in 15 mL of anhydrous N,N-dimethylformamide. The solution was cooled to 0 °C, and NBS (1.2 eq, 12 mmol) was added. After reacting at 5-10 °C for 1 hour, thioformamide (2 eq, 20 mmol) was added. After continuing the reaction for another hour, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded A-41-2 (956 mg, 3 mmol), a pale yellow solid, in 30% yield. ESI-MS: 319.0 [M+H]+.

[0245] Step 3, Synthesis of 3-(5-(2-chloropyrimidin-4-yl)thiazolyl)aniline (A-41-3): Following the synthesis method in 4-3, a pale yellow solid was obtained. Yield: 88%. ESI-MS: 289.0 [M+H]+.

[0246] Step 4, Synthesis of N-(4-(4-(3-aminophenyl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (A-41): Following the synthetic method for compound 71, a pale yellow solid was obtained. Yield: 54%. ESI-MS: 456.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.28(s,1H),8.86(s,1H),8.59(d,J=4.2Hz,1H),8 .25(t,J=2.2Hz,1H),7.47-7.42(m,1H),7.41-7.36(m,2H),7.35-7.28(m,2H),7. 27(d,J=5.1Hz,1H),7.01(t,J=2.3Hz,1H),6.69-6.63(m,1H),6.54(dd,J=5.1,2. 2Hz, 1H), 4.31 (s, 1H), 4.03 (t, J = 3.8Hz, 2H), 2.75 (t, J = 3.8Hz, 2H), 2.60 (s, 6H).

[0247] Intermediate A-42: N-(4-(4-(3-aminophenyl)-2-ethyl-1H-imidazol-5-yl)pyridin-2-yl)acetamide

[0248] Step 1, Synthesis of Intermediate A-42-1: 2-Ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium: 2-Ethylimidazolium (1 eq, 10.4 mmol) was dissolved in anhydrous THF (20 mL), cooled to 0 °C, and then NaH (1.1 eq, 11.4 mmol) was added in portions. After the addition was complete, the reaction was carried out at this temperature for 30 min, then SEMCl (1.1 eq, 11.4 mmol) was added, and the reaction was continued for 3 hours. After the reaction was completed, a saturated ammonium chloride solution was added dropwise to quench the reaction, water was added, and then ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, and the reactants were concentrated under reduced pressure. A-42-1 (2.2 g, 9.7 mmol), a colorless oil, was obtained by rapid preparative liquid chromatography with a yield of 94%. Ms(ESI,m\z):[M+H] + 227.15.

[0249] Step 2, Synthesis of Intermediate A-42-2: 4,5-Dibromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium: A-42-1 (1 eq, 9.7 mmol) was dissolved in DCM (30 mL), cooled to 0 °C, and NBS (2.2 eq, 21.4 mmol) was added in portions. The mixture was then transferred to room temperature and reacted overnight. After the reaction was complete, the reaction was quenched with 5% sodium bisulfite solution, extracted with ethyl acetate, and washed with saturated sodium bicarbonate and sodium chloride solutions, respectively. The organic phase was dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. Intermediate A-42-2 (2.7 g, 7.1 mmol), a yellow oil, was obtained by rapid preparative liquid chromatography with a yield of 73%. Ms(ESI,m\z):[M+2H]+ 384.03.

[0250] Step 3, Synthesis of Intermediate A-42-3: 4-Bromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium: A-42-2 (1 eq, 7.1 mmol) was dissolved in anhydrous THF (60 mL) under an argon atmosphere, cooled to -78 °C, and then 2.5 M n-BuLi n-hexane solution (1.1 eq, 7.8 mmol) was added dropwise over 20 minutes. After continuing the reaction for 0.5 hours, a saturated ammonium chloride solution was added dropwise to quench the reaction. Water was added, followed by extraction with ethyl acetate, drying with anhydrous sodium sulfate, and concentrating and evaporating under vacuum. Intermediate A-42-3 (1.9 g, 6.4 mmol), a pale yellow oil, was obtained by rapid preparative liquid chromatography with a yield of 90%. Ms(ESI,m\z):[M+H] + 305.15. 1 H NMR(600MHz,DMSO-d6)δ7.38(s,1H).5.24(s,2H),3.52-3.44(m.2H),2.84 (q,J=7.5Hz,2H),1.28(t,J=7.5Hz.3H),0.90-0.85(m,2H),-0.02(s.9H).

[0251] Step 4, Synthesis of Intermediate A-42-4: 2-Ethyl-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium: A-42-3 (1 eq, 6.4 mmol), (3-nitrophenyl)boronic acid (1.5 eq, 9.6 mmol), and potassium phosphate (3 eq, 19.2 mmol) were dissolved in 40 mL of 1,4-dioxane and 10 mL of water. The mixture was evacuated under vacuum for three cycles and backfilled with argon gas. 73 mg (2 mol%) of P(t-Bu)3Pd G3 was added, and the mixture was evacuated under vacuum three more times and backfilled with argon gas. The reactants were heated to 60 °C and reacted overnight. After the reaction was complete, saturated brine was added, and the mixture was extracted several times with ethyl acetate. The combined layers were dried over anhydrous sodium sulfate, concentrated and evaporated under vacuum, and purified by rapid preparative liquid chromatography to obtain intermediate A-42-4 (1.9 g, 5.5 mmol), a yellow solid, in 86% yield. Ms(ESI,m\z):[M+H) + 348.17.

[0252] Step 5, Synthesis of Intermediate A-42-5: 2-Ethyl-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium: A-42-4 (1 eq, 0.58 mmol) was dissolved in 10 mL of acetonitrile and cooled to -30 °C. NBS (1.1 eq, 0.64 mmol) was then added in portions. After the addition was complete, the reaction was continued at this temperature for 1 hour. After the reaction was complete, the reaction was quenched with 5% sodium bisulfite solution, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. Intermediate A-42-5 (224 mg, 0.53 mmol), a yellow solid, was obtained by rapid preparative liquid chromatography (EPC) purification, with a yield of 91%. Ms(ESI, m\z): [M+H] + 427.58.

[0253] Step 6, Synthesis of intermediate A-42-6: 2-ethyl-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium: Following the synthesis method of A-42-4, a yellow solid was obtained in 82% yield. Ms(ESI,m\z): [M+H]+482.37. 1 H NMR(600MHz,DMSO-d6)δ9.64(s,1H),8.21(t,J=1.5Hz,1H),8.19(d,J=7.5Hz, 1H),8.11(dt,J=7.5,1.5Hz,1H),7.36(dt,J=7.5,1.5Hz,1H),7.74-7.67(m,2 H),7.63(dd,J=7.5,1.5Hz,1H),5.31(s,2H),3.52-3.41(m,2H),2.81(q,J=8. 0Hz,2H),2.15(s,3H),1.34(t,J=8.0Hz,3H),0.89-0.85(m,2H),-0.02(s,9H).

[0254] Step 7, Synthesis of Intermediate A-42-7: N-(4-(4-(3-aminophenyl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide: A-42-6 (1 eq, 2.7 mmol) was dissolved in 20 mL of ethanol, and activated iron powder (5 eq, 13.5 mmol) and ammonium chloride (5 eq, 13.5 mmol) were added. The mixture was heated to 80 °C and refluxed for 5 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the reaction mixture was concentrated under reduced pressure. Intermediate A-42-7 (1.1 g, 2.4 mmol), a white solid, was obtained by rapid preparative liquid chromatography (EPC) purification, with a yield of 87%. Ms(ESI, m\z): [M+H]+ 452.47.

[0255] Step 8, Synthesis of Intermediate A-42: N-(4-(4-(3-aminophenyl)-2-ethyl-1H-imidazol-5-yl)pyridin-2-yl)acetamide: A-42-7 (1 eq, 1.3 mmol) was dissolved in a mixture of 3 mL DCM and 3 mL TFA and reacted overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by preparative liquid chromatography to obtain intermediate A-42 ((234 mg, 0.73 mmol), white solid, yield 56%). Ms(ESI, m\z): [M+H] + 322.33. 1 H NMR(600MHz,DMSO-d6)δ12.65-12.53(m,1H),10.35-10.26(m,1H),8.47-8.06(m,2H),7.89-7.82(m, 2H),7.41-7.14(m,1H),7.13-6.96(m,2H),6.27(s,2H)2.99(s,2H),2.07(s,3H),1.70-1.49(m,3H).

[0256] Intermediate A-43: 2-chloro-4-(1-(1-(1-(ethylsulfonyl)piperidin-4-yl)-3-(4-fluoro-3-methoxyphenyl)-1H-pyrazol-4-yl)pyrimidine

[0257] Step 1, Synthesis of Intermediate A-43-1: 4-(3,4-dibromo-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester: 3,4-dibromo-1H-pyrazole (1 eq, 2.0 mmol) and 4-(toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (1.2 eq, 2.2 mmol) were dissolved in DMF (10 mL), and Cs₂CO₃ (1.5 eq, 3.0 mmol) was added. The mixture was then heated to 90 °C and reacted overnight. After the reaction was complete, the mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. A-43-1 (488 mg, 1.2 mmol), a white solid, was obtained by rapid preparative liquid chromatography in a 60% yield. Ms(ESI,m\z):[M+H] + 408.34.

[0258] Step 2, Synthesis of Intermediate A-43-2: 4-(3-bromo-4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester: A-43-1 (1 eq, 1.2 mmol) was dissolved in anhydrous THF (20 mL), and the mixture was cooled to -78 °C under argon protection. Then, n-BuLi (1.1 eq, 1.3 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued at this temperature for 0.5 hours, and the reaction was monitored by LC-MS. Then, 2-chloropyrimidin (1.1 eq, 1.3 mmol) was dissolved in 5 mL of anhydrous THF and slowly added dropwise to the reaction mixture. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. Intermediate A-43-2 (386 mg, 0.88 mmol) was purified by rapid preparative liquid chromatography as a yellow solid with a yield of 73%. Ms(ESI,m\z):[M+H) + 442.09.

[0259] Step 3, Synthesis of Intermediate A-43-3: 4-(4-(2-chloropyrimidin-4-yl)-3-(4-fluoro-3-methoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester: A-43-2 (1 eq, 0.88 mmol), (4-fluoro-3-methoxyphenyl)boric acid (1.5 eq, 1.3 mmol), and potassium phosphate (3 eq, 2.6 mmol) were dissolved in 10 mL of 1,4-dioxane and 2.5 mL of water. The mixture was evacuated three times and backfilled with argon gas. 10 mg (2 mol%) of P(t-Bu)3Pd G3 was added, and the mixture was evacuated three more times and backfilled with argon gas. The reactants were heated to 90 °C and the reaction mixture was sealed and allowed to react overnight. After the reaction was complete, saturated brine was added and the mixture was extracted several times with ethyl acetate. The combined layers were dried over anhydrous sodium sulfate, concentrated and evaporated under vacuum, and purified by preparative liquid chromatography to obtain intermediate A-43-3 (364 mg, 0.75 mmol), a yellow solid, in 85% yield. Ms(ESI, m\z): [M+H] + 488.67.

[0260] Step 4, Synthesis of Intermediate A-43-4: 2-Chloro-4-(3-(4-fluoro-3-methoxyphenyl)-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine: A-43-3 (1 eq, 0.75 mmol) was dissolved in 2 mL of DCM, then added to 1 mL of HCl in a solution of 1,4-dioxane. The reaction was carried out at room temperature for 3 hours. After the reaction was complete, the solution was evaporated to dryness to give a brown solid, 100% yield. Ms(ESI,m\z):[M+H] + 387.67.

[0261] Step 5, Synthesis of Intermediate A-43: 2-Chloro-4-(1-(1-(ethylsulfonyl)piperidin-4-yl)-3-(4-fluoro-3-methoxyphenyl)-1H-pyrazol-4-yl)pyrimidine: A-43-4 (1 eq, 0.75 mmol) was dissolved in 3 mL of DCM and cooled to 0 °C. Then, TEA (5 eq, 3.75 mmol) and ethylsulfonyl chloride (1.2 eq, 0.9 mmol) were added. After the addition was complete, the mixture was transferred to room temperature and reacted for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified by rapid preparative liquid chromatography to obtain intermediate A-43 (480.16 mg, 0.62 mmol), a white solid, in 83% yield. Ms(ESI,m\z):[M+H] + 480.28. 1 H NMR(600MHz,Chloroform-d)δ8.95(d,J=7.5Hz,1H),7.71-7.66(m,2H),7.31-7.26(m,1H),7.25-7.18(m,2H),3.86(s,3H),3.71( d,J=12.3Hz,2H),3.27(tt,J=11.2,3.2Hz,1H),3.09-3.01(m,4H),2.20(d,J=13.1Hz,2H),1.82-1.73(m,2H),1.23(t,J=7.4,3H).

[0262] Intermediate A-44: 2-chloro-4-(5-(1-(ethylsulfonyl)piperidin-4-yl)-2-(4-fluoro-3-methoxyphenyl)-1H-pyrrolo-3-yl)pyrimidine

[0263] Step 1, Synthesis of Intermediate A-44-1: 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester: 4-oxopiperidin-1-carboxylic acid tert-butyl ester (1 eq, 5.0 mmol) was dissolved in DCM (10 mL), and the reaction was carried out at 0 °C. TEA (3 eq, 15 mmol) and trifluoromethanesulfonic anhydride (1.2 eq, 6 mmol) were added, and the reaction was carried out at room temperature for 10 hours. After the reaction was complete, the mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. A-44-1 (1.3 g, 4.0 mmol), a white solid, was obtained by rapid preparative liquid chromatography in 80% yield. Ms(ESI,m\z):[M+H] + 332.07.

[0264] Step 2, Synthesis of Intermediate A-44-2: 4-(1H-pyrrolo-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester: Under argon protection, A-44-1 (1 eq, 4 mmol), 2-bromo-1H-pyrrole (1.1 eq, 4.4 mmol), sodium carbonate (3 eq, 12 mmol), and tetrakis(triphenylphosphine)palladium (0.5% mmol) were dissolved in a mixture of 1,4-dioxane (20 mL) and water (5 mL), and the mixture was heated to 90 °C and reacted for 10 hours. After the reaction was complete, the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. Intermediate A-44-2 (397 mg, 1.6 mmol) was purified by rapid preparative liquid chromatography as a white solid with a yield of 40%. Ms(ESI,m\z):[M+H] + 249.68.

[0265] Step 3, Synthesis of Intermediate A-44-3: tert-butyl 4-(1H-pyrrolo-2-yl)piperidin-1-carboxylate: A-44-2 (1 eq, 4.0 mmol) was dissolved in 10 mL of methanol, and Pd(OH)₂ (0.1 eq, 100 mg) was added. The mixture was subjected to three cycles of vacuum and backfilling with hydrogen gas, and reacted overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filtrate was purified by rapid preparative liquid chromatography to obtain intermediate A-44-3 (794 mg, 3.2 mmol), a white solid, in 85% yield. Ms(ESI,m\z):[M+H] + 250.11.

[0266] Step 4, Synthesis of Intermediate A-44-4: 4-(5-bromo-1H-pyrrolo-2-yl)piperidine-1-carboxylic acid tert-butyl ester: A-44-3 (1 eq, 1.0 mmol) was dissolved in 2 mL of DCM, and NBS (1 eq, 1.0 mmol) was added in portions at 0 °C, followed by reaction at this temperature for 3 hours. After the reaction was complete, the mixture was washed with 5% sodium sulfite solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After rotary evaporation, intermediate A-44-4 (164 mg, 50%) was obtained as a yellow solid by rapid preparative liquid chromatography, with a yield of 50%. Ms(ESI,m\z):[M+H] + 329.97.

[0267] Step 5, Intermediate A-44-5: Synthesis of tert-butyl 4-(5-(4-fluoro-3-methoxyphenyl)-1H-pyrrolo-2-yl)piperidine-1-carboxylate: Refer to the synthesis method of A-43-3, yellow solid, yield 30%, Ms(ESI,m\z):[M+H] + 375.68.

[0268] Step 6, Intermediate A-44-6: Synthesis of tert-butyl 4-(4-bromo-5-(4-fluoro-3-methoxyphenyl)-1H-pyrrolo-2-yl)piperidine-1-carboxylate: Refer to the synthesis method of A-1-3, yellow solid, yield 45%, Ms(ESI,m\z):[M+H] + 453.76.

[0269] Step 7, Intermediate A-44-7: Synthesis of tert-butyl 4-(4-(2-chloropyrimidin-4-yl)-5-(4-fluoro-3-methoxyphenyl)-1H-pyrrolo-2-yl)piperidine-1-carboxylate: Refer to the synthesis method of A-43-2, yellow solid, yield 28%, Ms(ESI,m\z):[M+H] + 487.28.

[0270] Step 8, Intermediate A-44-8: Synthesis of 2-chloro-4-(2-(4-fluoro-3-methoxyphenyl)-5-(piperidin-4-yl)-1H-pyrrolo-3-yl)pyrimidine: Refer to the synthesis method of A-43-4, yellow solid, yield 73%, Ms(ESI,m\z):[M+H] + 386.13.

[0271] Step 9, Synthesis of Intermediate A-44: 2-Chloro-4-(5-(1-(ethylsulfonyl)piperidin-4-yl)-2-(4-fluoro-3-methoxyphenyl)-1H-pyrrolo-3-yl)pyrimidine: Refer to the synthesis method of A-43. Yellow solid, yield 82%, Ms(ESI,m\z):[M+H] + 479.65. 1 H NMR(600MHz,Chloroform-d)δ9.01(d,J=7.5Hz,1H),7.60(d,J=7.5Hz,1H),7.20(ddd,J=7.5,5.1,1.5Hz,1H),7.16-7.11(m,2H),6.3 1(s,1H),3.86(s,3H),3.39-3.28(m,4H),3.22(dt,J=12.3,7.1Hz,2H),3.14-3.05(m,1H),2.31-2.15(m,4H),1.30(t,J=8.0Hz,3H).

[0272] Intermediate A-45: 5-[5-(2-chloro-4-pyrimidinyl)-2-ethyl-4-thiazolyl]-2-fluoroaniline

[0273] Step 1, Synthesis of Intermediate A-45-1: (5-(5-(2-chloropyrimidin-4-yl)-2-ethylthiazolyl)2-fluorophenyl)benzyl carbamate: A-1-3 (1 eq, 1.9 mmol) and thiopropionamide (1 eq, 1.9 mmol) were dissolved in 10 mL of DMF. The reactants were heated to 90 °C and reacted overnight. After the reaction was completed, the mixture was concentrated and evaporated under reduced pressure. Intermediate A-45-1 (444 mg, 0.95 mmol), a brown solid, was obtained by rapid preparative liquid chromatography with a yield of 50%. Ms(ESI, m\z): [M+H]+469.08.

[0274] Step 2, Synthesis of Intermediate A-45: 5-[5-(2-chloro-4-pyrimidinyl)-2-ethyl-4-thiazolyl]-2-fluoroaniline: Following the synthesis method of intermediate A-1-6, a yellow oily substance was obtained, with a yield of 72%. Ms(ESI,m\z):[M+H] + 335.05. 1 H NMR(500MHz,Chloroform-d)δ8.51(d,J=4.0Hz,1H),7.57(d,J=3.8Hz,1H),7.53(dd,J=5.0,2.2Hz,1H),7.3 3(ddd,J=8.6,4.9,2.2Hz,1H),7.28–7.21(m,1H),4.28(s,2H),2.96(q,J=6.7Hz,2H),1.33(t,J=6.7Hz,3H).

[0275] Intermediate A-46: 5-(2-chloropyrimidin-4-yl)-4-(3-ethoxy-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole

[0276] 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)2-fluorophenol (1 eq, 0.2 mmol) was dissolved in DMF (1 mL), cooled to 0 °C, and then Cs₂CO₃ (1.5 eq, 0.3 mmol) was added. Iodoethane (1.2 eq, 0.24 mmol) was then slowly added, and the mixture was gradually brought to room temperature and reacted overnight. After the reaction was complete, the mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. A-46 (92 mg, 0.18 mmol), a yellow solid, was obtained by rapid preparative liquid chromatography in 90% yield. Ms(ESI,m\z):[M+H] + 511.46. 1H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,1H),7.63-7.55(m,2H),7.21-7.13(m,2H),4.13(q,J=8.0Hz,2H),3.39- 3.25(m,5H),3.25-3.20(m,1H),3.16(p,J=7.0Hz,1H),2.41-2.24(m,4H),1.43(t,J=8.0Hz,3H),1.30(t,J=8.0Hz,3H).

[0277] Intermediate A-47: 5-(2-chloropyrimidin-4-yl)-4-(3-cyclopropoxy-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole

[0278] 5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)2-fluorophenol (1 eq, 0.2 mmol) was dissolved in DMF (1 mL), Cs₂CO₃ (1.5 eq, 0.3 mmol) was added, followed by bromocyclopropane (1.2 eq, 0.24 mmol). The mixture was gradually heated to 60 °C and reacted overnight. After the reaction was complete, the mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the reaction mixture was concentrated under reduced pressure. A-47 (20 mg, 0.04 mmol), a yellow solid, was obtained by rapid preparative liquid chromatography in a 20% yield. Ms(ESI, m\z): [M+H] + 523.56. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,2H),7.63-7.55(m,4H),7.23-7.14(m,4H),4.41(p,J=7.0Hz,2H),3.36(t,J=8.0Hz,3H),3.32(d, J=4.5Hz,1H),3.31-3.25(m,6H),3.25-3.20(m,2H),3.16(p,J=7.0Hz,2H ),2.42-2.24(m,8H),1.86(dq,J=7.0,1.2Hz,8H),1.30(t,J=8.0Hz,6H).

[0279] Intermediate A-48: 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-isopropylthiazole

[0280] A-14-3 (1 eq, 0.3 mmol) was dissolved in THF, and 2-methylpropanethionimide (1.2 eq, 0.36 mmol) was added. The mixture was reacted at room temperature for 3 hours. After the reaction was complete, the solution was evaporated to dryness, and compound A-48 (76 mg, 0.21 mmol) was obtained by rapid column chromatography as a yellow solid, with a yield of 70%. Ms(ESI, m\z): [M+H] + 364.77. 1 H NMR(600MHz,Chloroform-d)δ8.59(d,J=7.5Hz,1H),7.59(d,J=7.5Hz,1H),7.25-7.18(m,2H ),7.14(dd,J=8.1,7.1Hz,1H),3.92(s,3H),3.35(hept,J=6.8Hz,1H),1.38(d,J=6.8Hz,6H).

[0281] Intermediate A-49: 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(piperidin-4-yl)thiazole

[0282] Step 1, Synthesis of 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(piperidin-4-yl)thiazole: A-14-4 (1 eq, 1 mmol) was dissolved in 2 mL of methanol, and 40% formaldehyde aqueous solution (2 eq, 2 mmol), acetic acid (1.5 eq, 1.5 mmol), and sodium cyanoborohydride (2 eq, 2 mmol) were added. After stirring at room temperature for 12 hours, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise preliminary liquid-phase purification yielded 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(1-methylpiperidin-4-yl)thiazole (293 mg, 0.7 mmol), a pale yellow oil, in 70% yield. ESI-MS: 419.1 [M+H] + .

[0283] Intermediate A-50: N-(4-(4-(-4-fluoro-3-methoxyphenyl)-2-(piperidin-4-yl)thiazolyl-5-yl)pyridin-2-yl)acetamide

[0284] Step 1, Intermediate A-50-1: Synthesis of N-(4-(2-(4-fluoro-3-methoxyphenyl)-2-oxoethyl)pyridin-2-yl)acetamide: Refer to the synthesis method of A-1-2. Yellow solid, yield 43%. Ms(ESI,m\z):[M+H] + 303.17.

[0285] Step 2, intermediate A-50-2: synthesis of N-(4-(1-bromo-2-(4-fluoro-3-methoxyphenyl)-2-oxoethyl)pyridin-2-yl)acetamide: refer to the synthesis method of A-1-3, yellow solid, yield 90%.

[0286] Step 3, Synthesis of Intermediate A-50: N-(4-(4-(-4-fluoro-3-methoxyphenyl)-2-(piperidin-4-yl)thiazolyl-5-yl)pyridin-2-yl)acetamide: Refer to the synthesis method of A-1-4, brown solid, yield 20%. Ms(ESI,m\z):[M+H] + 427.18.

[0287] Intermediate A-51: 5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methylphenyl)thiazole

[0288] Step 1, Intermediate A-51-1: Synthesis of 2-(2-chloropyrimidin-4-yl)-1-(4-fluoro-3-methylphenyl)ethyl-1-one: Following the synthetic method of A-1-2, a yellow solid was obtained in 57% yield. Ms(ESI,m\z):[M+H] + 265.33.

[0289] Step 2, intermediate A-51-2: synthesis of 2-bromo-2-(2-chloropyrimidin-4-yl)-1-(4-fluoro-3-methylphenyl)ethyl-1-one: refer to the synthesis method of A-1-3, yellow solid, yield 91%.

[0290] Step 3, Intermediate A-51-3: Synthesis of 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methylphenyl)-2-(piperidin-4-yl)thiazole: Following the synthetic method of A-1-4, a brown solid was obtained in 30% yield. Ms(ESI,m\z):[M+H] + 389.17.

[0291] Step 4, Synthesis of intermediate A-51: 5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methylphenyl)thiazole: Refer to the synthesis method of A-1-5, yellow solid, yield 60%. Ms(ESI,m\z): [M+H]+481.27.

[0292] Intermediate B-1: 1-(2-(dimethylamino)ethyl)-1H-indole-5-amine

[0293] Step 1: Synthesis of intermediate N,N-dimethyl-2-(5-nitro-1H-indole-1-yl)ethyl-1-amine: 5-nitro-1H-indole (1 eq, 10 mmol) was dissolved in 30 mL of anhydrous THF and cooled to 0 °C. NaH (4 eq, 40 mmol) was then added in portions, and the reaction was carried out at this temperature for 1 hour. 2-Bromo-N,N-dimethylethylamine hydrobromide (1.2 eq, 12 mmol) was added in portions to the reaction solution, and the mixture was transferred to room temperature and reacted for 48 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. After concentration, B-1-1 (1.8 g, 7.5 mmol), a pale yellow oil, was obtained by rapid preparative liquid chromatography with a yield of 75%. Ms(ESI,m\z):[M+H] + 234.11.

[0294] Step 2, Synthesis of intermediate 1-(2-(dimethylamino)ethyl)-1H-indole-5-amine: B-1-1 (1 eq, 7.5 mmol) was dissolved in 20 mL of methanol, and 0.36 g of palladium on carbon was added. The reaction was carried out overnight under hydrogen at one atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated. Preparative liquid chromatography was used to obtain B-1 (1.2 g, 6.0 mmol), a pale yellow oil, in 80% yield. Ms(ESI,m\z):[M+H] + 204.11. 1 H NMR(600MHz,Chloroform-d)δ7.32(d,J=7.5Hz,1H),7.26(d,J=7.5Hz,1H),6.91(dd,J=7.4,1.5Hz,1H),6.71(dd,J=7.5,1.5Hz,1 H), 6.65 (t, J = 1.5Hz, 1H), 4.82 (d, J = 5.5Hz, 1H), 4.76 (d, J = 5.5Hz, 1H), 4.10 (t, J = 7.1Hz, 2H), 2.72 (t, J = 7.1Hz, 2H), 2.22 (s, 6H).

[0295] Intermediate B-2: 1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-5-amine

[0296] Step 1, Synthesis of intermediate N,N-dimethyl-2-(5-nitro-1H-benzo[d]imidazol-1-yl)ethyl-1-amine: Following the synthesis method of B-1-1, a pale yellow oil was obtained, with a yield of 70%. Ms(ESI,m\z):[M+H] + 235.18.

[0297] Step 2, Synthesis of intermediate 1-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazol-5-amine: Following the synthesis method in B-1, a pale yellow oil was obtained, with a yield of 84%. Ms(ESI,m\z):[M+H] + 205.18. 1 H NMR(600MHz,Chloroform-d)δ7.32(d,J=7.5Hz,1H),7.26(d,J=7.5Hz,1H),6.71(dd,J=7.5,1.5Hz,1H),6.65(t,J= 1.5Hz,1H),4.82(d,J=5.5Hz,1H),4.76(d,J=5.5Hz,1H),4.10(t,J=7.1Hz,2H),2.72(t,J=7.1Hz,2H),2.25(s,6H).

[0298] Intermediate B-3: 1-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-5-amine

[0299] Step 1, Synthesis of intermediate N,N-dimethyl-2-(5-nitro-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl-1-amine: Following the synthesis method of B-1-1, a pale yellow oil was obtained in 73% yield. Ms(ESI,m\z):[M+H] + 235.18.

[0300] Step 2, Synthesis of intermediate 1-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-b]pyridine-5-amine: Following the synthesis method in B-1, a pale yellow oil was obtained in 80% yield. Ms(ESI,m\z):[M+H] + 205.18. 1 H NMR(600MHz,Chloroform-d)δ8.37(d,J=1.4Hz,1H),7.47-7.42(m,1H),7.19(d,J=7.5Hz,1H),5. 89(dd,J=7.5,1.6Hz,1H),4.92(s,2H),4.14(t,J=7.1Hz,2H),2.71(t,J=7.1Hz,2H),2.22(s,6H).

[0301] Intermediate B-4: N1-(2-(dimethylamino)ethyl)-N1-methylphenyl-1,4-diamine

[0302] Step 1, Synthesis of intermediate N1,N1,N2-trimethyl-N2-(4-nitrophenyl)ethane-1,2-diamine: Following the synthesis method of B-1-1, a pale yellow oil was obtained in 80% yield. Ms(ESI,m\z):[M+H] + 224.56.

[0303] Step 2, Synthesis of N1-(2-(dimethylamino)ethyl)-N1-methylphenyl-1,4-diamine: Following the synthesis method of B-1, a pale yellow oil was obtained, with a yield of 80%. Ms(ESI,m\z):[M+H] + 194.55. 1 H NMR (500MHz, Chloroform-d) δ6.80-6.74(m,2H),6.67-6.61(m,2H),4.73(s,2H),3.64(t,J=7.1Hz,2H),2.97(s,3H),2.74(t,J=7.1Hz,2H),2.33(s,6H).

[0304] Intermediate B-5: 1-(2-(pyrrolidone-1-yl)ethyl)-1H-indole-5-amine

[0305] Step 1, Synthesis of intermediate 5-nitro-1-(2-(pyrrolidone-1-yl)ethyl)-1H-indole: Following the synthetic method of B-1-1, a pale yellow oil was obtained in 60% yield. Ms(ESI,m\z):[M+H] + 260.38.

[0306] Step 2, Synthesis of intermediate 1-(2-(pyrrolidone-1-yl)ethyl)-1H-indole-5-amine: Following the synthesis method in B-1, a pale yellow oil was obtained, with a yield of 84%. Ms(ESI,m\z):[M+H] + 230.18. 1 H NMR(600MHz,Chloroform-d)δ7.30(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),6.91(dd,J=7.5,1.4Hz,1H),6.70(dd,J=7.5,1.6Hz,1H),6.65(t,J =1.5Hz,1H),4.86(d,J=5.5Hz,1H),4.66(d,J=5.5Hz,1H),4.09(t,J=7.1Hz,2H),2.72(t,J=7.1Hz,2H),2.62-2.53(m,4H),1.85-1.75(m,4H).

[0307] Intermediate B-6: 1-(2-(azatidine-1-yl)ethyl)-1H-indole-5-amine

[0308] Step 1, Synthesis of intermediate 1-(2-(azatidine-1-yl)ethyl)-5-nitro-1H-indole: Following the synthesis method of B-1-1, a pale yellow oil was obtained, with a yield of 7%. Ms(ESI,m\z):[M+H]+246.12.

[0309] Step 2, Synthesis of intermediate 1-(2-(azatidine-1-yl)ethyl)-1H-indole-5-amine: Refer to the synthesis method of B-1, a pale yellow oil, yield 71%. Ms(ESI,m\z):[M+H]+216.14.1H NMR(500MHz,Chloroform-d)δ7.30(d,J=8.0Hz,1H),7.24(d,J=5.0Hz,1H),6.98(t,J=2.1Hz,1H),6.68(dd,J=8.1,2.4Hz,1H),6.60( dd,J=5.1,2.0Hz,1H),4.01(t,J=3.5Hz,2H),2.85(t,J=3.5Hz,2H),2.74(t,J=5.9Hz,2H),2.65(t,J=5.9Hz,2H),1.91-1.81(m,2H).

[0310] Intermediate B-7: 1-(2-(azatidine-1-yl)ethyl)-1H-indolezol-5-amine

[0311] Step 1, Synthesis of intermediate 1-(2-(azatidine-1-yl)ethyl)-5-nitro-1H-indazole: Following the synthesis method of B-1-1, a pale yellow oil was obtained, with a yield of 7%. Ms(ESI,m\z):[M+H]+247.11.

[0312] Step 2, Synthesis of intermediate 1-(2-(azatidine-1-yl)ethyl)-1H-indazole-5-amine: Refer to the synthesis method of B-1, a pale yellow oil, yield 71%. Ms(ESI,m\z):[M+H]+217.14.1H NMR(500MHz,Chloroform-d)δ7.30(d,J=8.0Hz,1H),7.24(d,J=5.0Hz,1H),6.98(t,J=2.1Hz,1H),6.68(dd,J=8.1,2.4Hz,1H),6.60( dd,J=5.1,2.0Hz,1H),4.01(t,J=3.5Hz,2H),2.85(t,J=3.5Hz,2H),2.74(t,J=5.9Hz,2H),2.65(t,J=5.9Hz,2H),1.91-1.81(m,2H).

[0313] Intermediate B-8: 1-(2-(aza-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-5-amine

[0314] Step 1, Synthesis of intermediate 1-(2-(aza-1-yl)ethyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine: Following the synthetic method of B-1-1, a pale yellow oil was obtained in 7% yield. Ms(ESI,m\z):[M+H] + 247.11.

[0315] Step 2, Synthesis of intermediate 1-(2-(aza-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-5-amine: Following the synthesis method in B-1, a pale yellow oil was obtained in 71% yield. Ms(ESI,m\z):[M+H] + 217.14. 1 H NMR(500MHz,Chloroform-d)δ8.27(d,J=2.0Hz,1H),7.48(t,J=2.0Hz,1H),7.35(d,J=6.4Hz,1H),5.89(dd,J=6.4,2.0Hz,1H),4. 27(d,J=6.8Hz,1H),4.22(t,J=3.9Hz,2H),2.82(t,J=3.9Hz,2H),2.72(t,J=5.9Hz,2H),2.63(t,J=5.9Hz,2H),1.91-1.81(m,2H).

[0316] Intermediate B-9: 1-(2-(pyrrolidone-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-5-amine

[0317] Step 1, Synthesis of intermediate 5-nitro-1-(2-(pyrrolidine-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine: Following the synthetic method of B-1-1, a pale yellow oil was obtained in 35% yield. Ms(ESI,m\z):[M+H] + 261.13.

[0318] Step 2, Synthesis of intermediate 1-(2-(pyrrolidine-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-5-amine: Following the synthesis method in B-1, a pale yellow oil was obtained in 90% yield. Ms(ESI,m\z):[M+H] + 231.15. 1 H NMR(500MHz,Chloroform-d)δ8.27(d,J=2.0Hz,1H),7.48(t,J=2.0Hz,1H),7.35(d,J=6.4Hz,1H),5.89(dd,J=6.4,2.0Hz,1H),4. 37(d,J=6.8Hz,1H),4.27(d,J=6.8Hz,1H),4.20(t,J=4.3Hz,2H),2.80(t,J=4.3Hz,2H),2.65-2.55(m,4H),1.78(p,J=2.0Hz,4H).

[0319] Intermediate B-10: N1-(2-(dimethylamino)ethyl)-3-methoxy-N1-methylphenyl-1,4-diamine

[0320] Step 1: Synthesis of intermediate N1-(3-methoxy-4-nitrophenyl)-N1,N2,N2-trimethylethane-1,2-diamine: 4-fluoro-2-methoxy-1-nitrobenzene (1 eq, 1 mmol) and N1,N1,N2-trimethylethane-1,2-diamine (1.5 eq, 1.5 mmol) were dissolved in 5 mL of N,N-dimethylformamide. Anhydrous potassium carbonate (2 eq, 2 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to give 132 mg of the intermediate as a pale yellow oil, with a yield of 52%. Ms(ESI,m\z):[M+H] + 254.14.

[0321] Step 2, Synthesis of intermediate N1-(2-(dimethylamino)ethyl)-3-methoxy-N1-methylphenyl-1,4-diamine: Following the synthesis method in B-1, a pale yellow oil was obtained in 90% yield. Ms(ESI,m\z):[M+H] +224.17. 1 H NMR(500MHz,Chloroform-d)δ6.82(d,J=8.3Hz,1H),6.61(dd,J=8.2,2.2Hz,1H),6.19(d,J=2.2Hz,1H),4.00 (d,J=7.1Hz,1H),3.93–3.86(m,3H),3.52(t,J=6.5Hz,2H),3.00(s,2H),2.74(t,J=6.5Hz,2H), 2.60(s,6H).

[0322] Synthesis of intermediate B-11: 3-((2-(5-amino-1H-indol-1-yl)ethyl)amino)prop-1-ol

[0323] Step 1, Synthesis of 3-(2-oxooxazolidin-3-yl)propylacetate (B-11-2): Oxazolidinone (2.2 mmol, 1.0 eq) was dissolved in 4 mL of DMF and cooled to 0 °C. Sodium hydride (2.75 mmol, 1.25 eq) was carefully added, and the solution was heated to room temperature, then heated to 50 °C and held for 1 hour. Subsequently, 3-bromopropylacetate (3.3 mmol, 1.5 eq) was added, and the reaction was carried out at 150 °C for 2 hours. The organic phase was cooled to room temperature, and 1.5 mL of saturated ammonium chloride aqueous solution was slowly poured in. The crude mixture was concentrated under reduced pressure and separated by rapid column chromatography to obtain compound 3-(2-oxooxazolidin-3-yl)propylacetate (B-11-2), a yellow oil, in 82% yield. 1H-NMR(CDCl3): δ1.95(m,2H),2.12(s,3H),3.46(t,J=7,2H),3.71(m,2H),4.18(t,J=6,2H),4.40(m,2H); ESI-MS:188.1[M+H]+.

[0324] Step 2, Synthesis of 3-(3-hydroxypropyl)oxazolidin-2-one (B-11-3): Hydrazine hydrate (2.78 mmol, 1.5 eq.) was added to 5 mL of a methanol solution of 1.85 mmol (1.0 eq.) of 3-(2-oxazolidin-3-yl)propyl acetate at room temperature. The solution was heated at 50 °C for 4 hours, then allowed to return to room temperature and stirred for 2 hours. The solution was concentrated under reduced pressure and separated by rapid chromatography. 3-(3-hydroxypropyl)oxazolidin-2-one (B-11-3) was obtained as a yellow oil, with a yield of 95%. ESI-MS: 146.1 [M+H]+.

[0325] Step 3, Synthesis of 3-((2-chloroethyl)amino)propane-1-ol hydrochloride (B-11-4): 6.89 mmol, 1.0 eq of 3-(3-hydroxypropyl)oxazolidin-2-one was added to 30 mL of HCl / dioxane. The solution was refluxed for 4 hours and then stirred overnight at room temperature. The solution was concentrated under reduced pressure and separated by rapid chromatography. 3-((2-chloroethyl)amino)propane-1-ol hydrochloride (B-11-4) was obtained as a white solid with a yield of 73%. ¹H-NMR: δ 2.02 (m, 2H), 3.25 (t, J = 7, 2H), 3.51 (t, J = 7, 2H), 3.73 (t, J = 7, 2H), 4.02 (t, J = 7, 2H);

[0326] Step 4, Synthesis of 3-((2-(5-nitro-1H-indol-1-yl)ethyl)amino)prop-1-ol (B-11-5): 5-nitro-1H-indole (5.0 mmol, 1.0 eq) was added to 30 mL of THF, followed by the addition of NaH (20 mmol, 4.0 eq). The mixture was stirred at room temperature for 30 minutes. Then, 3-((2-chloroethyl)amino)prop-1-ol hydrochloride (B-11-4) (10 mmol, 2.0 eq) was added, and the solution was refluxed and stirred overnight. The solution was concentrated under reduced pressure and subjected to rapid chromatographic separation. 3-((2-(5-nitro-1H-indol-1-yl)ethyl)amino)prop-1-ol (B-11-5) was obtained as a yellow oil, with a yield of 73%. ESI-MS: 263.1 [M+H]+.

[0327] Step 5, Synthesis of 3-((2-(5-amino-1H-indol-1-yl)ethyl)amino)prop-1-ol (B-11): 2.0 mmol, 1.0 eq of 3-((2-(5-nitro-1H-indol-1-yl)ethyl)amino)prop-1-ol (B-11-5) was added to 10 mL of MeOH. Pd / C (10% wt) was added, and after H2 replacement, the mixture was stirred overnight at room temperature under H2 atmosphere. After filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure and subjected to rapid chromatographic separation. 3-((2-(5-amino-1H-indol-1-yl)ethyl)amino)prop-1-ol (B-11) was obtained as a yellow oil, with a yield of 55%. ESI-MS: 234.1 [M+H]+.

[0328] II. Implementation Examples

[0329] Example 1: 5-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2-fluoroaniline (Compound 1)

[0330] Step 1, Synthesis of 2-ethyl-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-imidazolium (1-2): 2-Ethyl-1H-imidazolium (1 eq, 52.04 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran. The solution was cooled to 0 °C, and NaH (1.2 eq, 62.45 mmol) was added. After reacting at 0 °C for 0.5 hours, 2-(trimethylsilyl)ethoxymethyl chloride (1.1 eq, 57.24 mmol) was added. The temperature was raised to room temperature, and the reaction was continued for 1 hour. The reaction was then quenched with a saturated ammonium chloride aqueous solution, and the mixture was extracted with dichloromethane. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography purification yielded 1-2 (10.6 g, 46.84 mmol), a pale yellow oil, in 90% yield. ESI-MS: 227.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ7.13(d,J=4.2Hz,1H),6.98(d,J=4.4Hz,1H),5.35(s,2H),3.52(t ,J=7.4Hz,2H),2.74(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H),0.89(t,J=7.3Hz,2H),0.04(s,9H).

[0331] Step 2, Synthesis of 4,5-dibromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (1-3): 2-ethyl-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-imidazolium (1 eq, 46.84 mmol) was dissolved in 80 mL of dichloromethane. The solution was cooled to 0 °C, NBS (2 eq, 113.68 mmol) was added, and the reaction was continued for 0.5 hours. The reaction was then quenched with water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. Precision liquid chromatography (PLC) purification yielded 1-3 (12.6 g, 32.79 mmol), a pale yellow oil, in 70% yield. ESI-MS: 383.9 [M+H]+. 1 H NMR (500MHz, Chloroform-d) δ5.38 (s, 2H), 3.50 (t, J = 7.3Hz, 2H), 2.77 (q, J = 7.1Hz, 2H), 1.31 (t, J = 7.1Hz, 3H), 0.89 (t, J = 7.3Hz, 2H), 0.04 (s, 9H).

[0332] Step 3, Synthesis of 4-bromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (1-4): 4,5-Dibromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (1 eq, 32.79 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran. The solution was cooled to -78 °C, and n-butyllithium (1 eq, 32.79 mmol) was added. The reaction was continued for 5 minutes, quenched with methanol, and the mixture was extracted with dichloromethane after warming to room temperature. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. Precise pre-HPLC purification yielded 1-4 (7.1 g, 22.95 mmol), a pale yellow oil, in 70% yield. ESI-MS: 305.1 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ7.62(s,1H),5.40(s,2H),3.52(t,J=7.4Hz,2H),2 .72(q,J=7.2Hz,2H),1.28(t,J=7.1Hz,3H),0.89(t,J=7.3Hz,2H),0.04(s,9H).

[0333] Step 4, Synthesis of 5-(2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (1-5): 4-bromo-2-ethyl-1-((2-trimethylsilyl)ethoxy)methyl)-1H-imidazolium (1 eq, 22.95 mmol) and (3-amino-4-fluorophenyl)boronic acid (1.2 eq, 27.54 mmol) were dissolved in 90 mL of 1,4-dioxane and 30 mL of water. Potassium phosphate (3 eq, 68.85 mmol) and P(t-Bu)3Pd G4 (0.025 eq, 0.57 mmol) were added. The mixture was heated to 110 °C under N2 protection. After reacting for 1 hour, the mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 1-5 (5.4 g, 16.07 mmol), a pale yellow oil, in 70% yield. ESI-MS: 336.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ7.54(s,1H),7.27-7.22(m,1H),7.15(dd,J=5.0,2.2Hz,1H),7.05(m,1H),5.41(s,2H), 4.13(s,2H),3.52(t,J=7.4Hz,2H),2.73(q,J=7.2Hz,2H),1.28(t,J=7.1Hz,3H),0.89(t,J=7.3Hz,2H),0.04(s,9H).

[0334] Step 5, Synthesis of 5-(5-bromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (A-1-6): 5-(2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (1 eq, 16.07 mmol) was dissolved in 80 mL of acetonitrile. The solution was cooled to -30 °C, and NBS (1 eq, 16.07 mmol) was added. After reacting for 1 hour, the mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 1-6 (6.3 g, 15.11 mmol), a pale yellow oil, in 94% yield. ESI-MS: 414.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ7.38-7.31(m,1H),7.22(dd,J=8.6,8.0Hz,1H),6.85(dd,J=5.0,2.3Hz,1H),5.37(s,2H) ,4.18(s,2H),3.50(t,J=7.3Hz,2H),2.74(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H),0.89(t,J=7.3Hz,2H),0.04(s,9H).

[0335] Step 6, Synthesis of 5-(2-ethyl-5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (A-1-7): 5-(5-bromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (1 eq, 15.11 mmol) and pyridine-4-boronic acid (1.5 eq, 22.67 mmol) were dissolved in 45 mL of 1,4-dioxane and 15 mL of water. Potassium phosphate (3 eq, 45.33 mmol) and P(t-Bu)3Pd G4 (0.025 eq, 0.38 mmol) were added. The mixture was heated to 110 °C under N2 protection. After reacting for 1 hour, the mixture was cooled to room temperature, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 1-7 (5.6 g, 13.6 mmol), a pale yellow oil, in 90% yield. ESI-MS: 413.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.71-8.67(m,2H),7.53-7.49(m,2H),7.28(m,1H),7.21(dd,J=8.6,7.9Hz,1H),6.82(dd,J=5.1,2.2Hz, 1H), 5.47 (s, 2H), 4.17 (s, 2H), 3.50 (t, J = 7.3Hz, 2H), 2.72 (q, J = 7.1Hz, 2H), 1.29 (t, J = 7.1Hz, 3H), 0.89 (t, J = 7.4Hz, 2H), 0.04 (s, 9H).

[0336] Step 7, Synthesis of 5-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2-fluoroaniline (Compound 1): 5-(2-ethyl-5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (1 eq, 0.24 mmol) was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (2 mL) was added. The reaction was allowed to proceed overnight at room temperature, quenched with water, and the pH was adjusted to 7 with NaHCO3. The mixture was then extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precision liquid chromatography (HPLC) purification was performed to give Compound 1 (42 mg, 0.15 mmol), a pale yellow solid, in 63% yield. ESI-MS: 283.1 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.71-8.67(m,2H),7.51-7.46(m,2H),7.24-7.19(m,1H),7.07-7.0 0(m,1H),6.81(dd,J=4.9,2.2Hz,1H),4.12(s,2H),2.89(q,J=6.2Hz,2H),1.36(t,J=6.1Hz,3H).

[0337] Example 2: N-ethyl-3-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2-fluoroaniline (Compound 2)

[0338] Step 1: Synthesis of N-ethyl-3-(2-ethyl-5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (2-1): 5-(2-ethyl-5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (1 eq, 0.24 mmol) was dissolved in 5 mL of methanol, and acetaldehyde (3 eq, 0.72 mmol) was added, followed by sodium cyanoborohydride (3 eq, 0.72 mmol). After reacting for 1 hour, the mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid pre-liquid purification yielded A-2-1 (48 mg, 0.11 mmol), a pale yellow oil, in 46% yield. ESI-MS: 441.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.72-8.67(m,2H),7.59-7.49(m,3H),7.24(dd,J=9.6,8.9Hz,1H),6.87-6.83(m,1H),5.49-5. 41(m,2H),3.50(t,J=7.3Hz,2H),3.38(m,2H),2.72(q,J=7.1Hz,2H),1.33-1.26(m,5H),0.89(t,J=7.4Hz,2H),0.04(s,9H).

[0339] Step 2, Synthesis of N-ethyl-3-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2-fluoroaniline (compound 2): Following the synthesis method of compound 1, a pale yellow solid was obtained in 43% yield. ESI-MS: 311.1 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.71-8.67(m,2H),7.51-7.46(m,2H),7.34-7.28(m,1H),7.17-7.11(m,1H),6.91-6.84 (m,1H),5.33(t,J=3.7Hz,1H),3.42-3.34(m,2H),2.89(q,J=6.2Hz,2H),1.36(t,J=6.1Hz,3H),1.29(t,J=6.1Hz,3H).

[0340] Example 3: N-cyclopropyl-3-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2-fluoroaniline (Compound 3)

[0341] Step 1, Synthesis of N-cyclopropyl-3-(2-ethyl-5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (3-1): Following the synthesis method of 2-1, a pale yellow oil was obtained in 30% yield. ESI-MS: 453.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.72-8.67(m,2H),7.55(ddd,J=9.5,5.0,1.2Hz,1H ),7.53-7.49(m,2H),7.27(d,J=9.4Hz,1H),6.94-6.87(m,1H),5.76(d,J=8.1Hz,1 H),5.47(s,1H),3.50(t,J=7.3Hz,2H),3.00(dp,J=8.0,4.5Hz,1H),2.72(q,J=7.1 Hz,2H),1.29(t,J=7.1Hz,3H),0.92-0.79(m,4H),0.74-0.64(m,2H),0.04(s,9H).

[0342] Step 2, Synthesis of N-cyclopropyl-3-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)-2-fluoroaniline (compound 3): Following the synthesis method of compound 1, a pale yellow solid was obtained in 40% yield. ESI-MS: 323.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.71-8.67(m,2H),7.51-7.46(m,2H),7.33(d,J=9.4Hz,1H),7.17-7.11(m,1H),6.97-6.90(m,1H),5.70(d,J=8.1Hz ,1H),3.05-2.96(m,1H),2.89(q,J=6.2Hz,2H),1.36(t,J=6.1Hz,3H),0. 91-0.83(m,1H),0.87-0.79(m,1H),0.75-0.67(m,1H),0.71-0.63(m,1H).

[0343] Example 4: N-(3-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 4)

[0344] Step 1, Synthesis of 2-ethyl-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (4-1): Following the synthetic methods in 1-5, a pale yellow oil was obtained in 92% yield. ESI-MS: 348.2 [M+H]+.

[0345] Step 2, Synthesis of 5-bromo-2-ethyl-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (4-2): Following the synthetic methods in 1-6, a pale yellow oil was obtained in 91% yield. ESI-MS: 426.1 [M+H]+.

[0346] Step 3, Synthesis of 3-(5-bromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)aniline (4-3): 5-bromo-2-ethyl-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (1 eq, 1 mmol) was dissolved in 8 mL of methanol and 2 mL of water. Iron powder (5 eq, 5 mmol) and ammonium chloride (10 eq, 10 mmol) were added. After reacting at 80 °C for 1 hour, the mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid pre-liquid chromatography purification yielded A-4-3 (305 mg, 0.77 mmol), a pale yellow oil, in 77% yield. ESI-MS: 396.1 [M+H]+.

[0347] Step 4, Synthesis of N-(3-(5-bromo-2-ethyl-1-)((trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (4-4): 3-(5-bromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)aniline (1 eq, 0.77 mmol) and 3-methyl-1H-indole-4-carboxylic acid (1 eq, 0.77 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and HATU (1.5 eq, 1.15 mmol) and DIPEA (2.5 eq, 1.92 mmol) were added. The mixture was heated to 50 °C and reacted overnight. The reaction was quenched with water and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 4-4 (48 mg, 0.11 mmol), a pale yellow solid, in 36% yield. ESI-MS: 553.1 [M+H]+.

[0348] Step 5, Synthesis of N-(3-(2-ethyl-5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (4-5): Following the synthetic methods described in 1-7, a pale yellow oil was obtained in 91% yield. ESI-MS: 552.3 [M+H]+.

[0349] Step 6, Synthesis of N-(3-(2-ethyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (compound 4): Following the synthesis method of compound 1, a pale yellow solid was obtained in 33% yield. ESI-MS: 422.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.50(s,1H),9.07(d,J=7.3Hz,1H),8.71-8.67(m,2H),7.98(t,J=2.1Hz,1H),7.88-7.81(m ,2H),7.53-7.42(m,5H),7.39(dd,J=8.1,1.4Hz,1H),7.07(d,J=7.3Hz,1H),2.89(q,J=6.2Hz,2H),1.36(t,J=6.1Hz,3H).

[0350] Example 5: N-(3-(5-(2-aminopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 5)

[0351] Step 1, Synthesis of N-(3-(5-(2-aminopyridin-4-yl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (5-1): Following the method described in 4-5, a pale yellow oil was obtained in 77% yield. ESI-MS: 567.3 [M+H]+.

[0352] Step 2, Synthesis of N-(3-(5-(2-aminopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (compound 5): Following the synthetic method for compound 1, a pale yellow solid was obtained in 36% yield. ESI-MS: 437.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.50(s,1H),9.07(d,J=7.3Hz,1H),8.27(d,J=4.4Hz ,1H),7.99(t,J=2.2Hz,1H),7.88-7.81(m,2H),7.53-7.47(m,2H),7.49-7.42(m,2H ),7.39(dd,J=8.1,1.3Hz,1H),7.34(d,J=1.9Hz,1H),7.07(d,J=7.3Hz,1H),5.57(d ,J=6.6Hz,1H),5.35(d,J=6.6Hz,1H),2.89(q,J=6.2Hz,2H),1.36(t,J=6.1Hz,3H).

[0353] Example 6: N-(3-(5-(2-acetamidopyridin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 6)

[0354] Step 1, Synthesis of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (6-2): Following the synthesis method in 1-2, a pale yellow oil was obtained, with a yield of 77%. ESI-MS: 277.0 [M+H]+.

[0355] Step 2, Synthesis of 4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (6-3): Following the synthetic methods in 1-5, a pale yellow oil was obtained in 77% yield. ESI-MS: 320.1 [M+H]+.

[0356] Step 3, Synthesis of 5-bromo-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (6-4): 4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (1 eq, 1 mmol) was dissolved in 5 mL of acetonitrile, and NBS (1.1 eq, 1.1 mmol) was added. The mixture was stirred overnight at room temperature, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 6-4 (170 mg, 0.43 mmol), a pale yellow oil, in 43% yield. ESI-MS: 398.1 [M+H]+.

[0357] Step 4, Synthesis of N-(4-(4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide (6-5): Following the synthetic method in steps 1-5, a pale yellow oil was obtained in 82% yield. ESI-MS: 454.3 [M+H]+.

[0358] Step 5, Synthesis of N-(4-(4-(3-aminophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide (6-7): Following the method described in 4-3, a pale yellow oil was obtained in 82% yield. ESI-MS: 424.3 [M+H]+.

[0359] Step 6, Synthesis of N-(3-(5-(2-acetamidopyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (6-8): Following the method described in 4-4, a pale yellow oil was obtained in 21% yield. ESI-MS: 581.3 [M+H]+.

[0360] Step 7, Synthesis of N-(3-(5-(2-acetamidopyridin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (compound 6): N-(3-(5-(2-acetamidopyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (1 eq, 0.03 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of TABF (1 M in THF, 5 eq, 0.15 mmol) was added dropwise. The temperature was raised to 70 °C. After reacting for 1 hour, the mixture was cooled to room temperature, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded compound 6 (2 mg, 0.005 mmol), a pale yellow oil, in 18% yield. ESI-MS: 451.1 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.07(d,J=7.3Hz,1H),8.71(s,1H), 8.38(d,J=4.7Hz,1H),7.99(t,J=2.2Hz,1H),7.88-7.81(m,2H),7.73(dd,J=4. 8,2.0Hz,1H),7.65(dd,J=4.0,2.1Hz,2H),7.53-7.47(m,1H),7.47-7.42(m,2H ),7.39(dd,J=8.1,1.4Hz,1H),7.07(d,J=7.3Hz,1H),2.48(s,3H),2.17(s,3H).

[0361] Example 7: N-(3-(5-(2-acetamidopyridin-4-yl)thiazolyl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 7)

[0362] Step 1, Synthesis of 4-(3-nitrophenyl)thiazole (7-2): Following the synthetic methods in 1-5, a pale yellow oil was obtained in 84% yield. ESI-MS: 207.0 [M+H]+.

[0363] Step 2, Synthesis of 5-bromo-4-(3-nitrophenyl)thiazole (7-3): 4-(3-nitrophenyl)thiazole (1 eq, 9.69 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and NBS (2 eq, 19.39 mmol) was added. The mixture was heated to 80 °C and reacted for 16 hours. After cooling to room temperature, the reaction was quenched with water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. A mixture of 7-3 and 7-2 was obtained, with a liquid chromatography yield of 61%. ESI-MS: 285.1 [M+H]+.

[0364] Step 3, Synthesis of N-(4-(4-(3-nitrophenyl)thiazolyl-5-yl)pyridin-2-yl)acetamide (7-4): Following the synthetic methods in 1-5, a pale yellow oil was obtained, with a yield of 62%. ESI-MS: 341.0 [M+H]+.

[0365] Step 4, Synthesis of N-(4-(4-(3-aminophenyl)thiazolyl-5-yl)pyridin-2-yl)acetamide (7-5): Following the synthesis method in 4-3, a pale yellow oil was obtained, yielding 51%. ESI-MS: 311.0 [M+H]+.

[0366] Step 5, Synthesis of N-(3-(5-(2-acetamidopyridin-4-yl)thiazolyl)phenyl)-3-methyl-1H-indole-4-carboxamide (compound 7): Following the synthetic method in 4-4, a pale yellow oil was obtained in 12% yield. ESI-MS: 468.1 [M+H]+.

[0367] 1 H NMR(500MHz,Chloroform-d)δ9.07(d,J=7.3Hz,1H),8.79(s,1H),8.61(s,1H),8.34(d,J=4.2Hz,1H),7.98(t,J=2.2Hz,1H),7.88-7.81(m,2H ),7.78(d,J=1.9Hz,1H),7.55-7.49(m,2H),7.47-7.42(m,2H),7.39(dd,J=8.1,1.4Hz,1H),7.07(d,J=7.3Hz,1H),2.48(s,3H),2.17(s,3H).

[0368] Example 8: 3-Methyl-N-(3-(5-(pyridin-4-yl)thiazolyl-4-yl)phenyl)-1H-indole-4-carboxamide (Compound 8)

[0369] Step 1, Synthesis of 4-(3-nitrophenyl)-5-(pyridin-4-yl)thiazole (8-1): Following the synthetic method in steps 1-5, a pale yellow oil was obtained in 84% yield. ESI-MS: 284.1 [M+H]+.

[0370] Step 2, Synthesis of 3-(5-(pyridin-4-yl)thiazolyl)aniline (8-2): Following the synthesis method in 4-3, a pale yellow oil was obtained, with a yield of 51%. ESI-MS: 254.1 [M+H]+.

[0371] Step 3, Synthesis of 3-methyl-N-(3-(5-(pyridin-4-yl)thiazolyl-4-yl)phenyl)-1H-indole-4-carboxamide (compound 8): Following the synthetic method in 4-4, a pale yellow oil was obtained in 25% yield. ESI-MS: 411.1 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.07(d,J=7.3Hz,1H),8.80(s,1H),8.70-8.66(m,2H),7.98(t,J=2.3Hz,1H),7.88-7 .81(m,2H),7.57-7.49(m,3H),7.48-7.42(m,2H),7.39(dd,J=8.1,1.4Hz,1H),7.07(d,J=7.3Hz,1H),2.48(s,3H).

[0372] Example 9: 5-(2-ethyl-5-(pyridin-4-yl)thiazolyl-4-yl)-2-fluoroaniline (compound 9)

[0373] Step 1, Synthesis of 4-bromo-2-vinylthiazole (9-2): 2,4-Dibromothiazole (1 eq, 1.80 mmol) was added to 10 mL of toluene, followed by tri-n-butyl(vinyl)tin (1.05 eq, 1.89 mmol), and then tetrakis(triphenylphosphine)palladium (0.1 eq, 0.180 mmol). The mixture was heated at 100 °C. After 21 h, the mixture was concentrated under vacuum by evaporation and rapidly purified by liquid chromatography to obtain 9-2 (285 mg, 0.005 mmol), a pale yellow oil in 83% yield. ESI-MS: 190.1 [M+H]+. 1 H NMR (500MHz, Chloroform-d) δ7.13 (s, 1H), 6.86 (dd, J = 17.5, 11.0Hz, 1H), 6.09 (d, J = 17.5Hz, 1H), 5.59 (d, J = 10.5Hz, 1H).

[0374] Step 2, Synthesis of 4-bromo-2-ethylthiazole (9-3): 4-bromo-2-vinylthiazole (1 eq, 1.47 mmol) was dissolved in 15 mL of ethanol, and PtO2 (0.15 eq, 0.220 mmol) was added. The resulting mixture was stirred at 25 °C under a hydrogen atmosphere for 4 hours. The mixture was then filtered through a short silica gel stopper, eluted with EtOAc, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 9-3 (236 mg, 1.23 mmol), a pale yellow oil, in 84% yield. ESI-MS: 192.1 [M+H]+. 1 H NMR (500MHz, Chloroform-d) δ7.08 (s, 1H), 3.03 (q, J = 7.5Hz, 2H), 1.37 (t, J = 7.5Hz, 2H).

[0375] Step 3, Synthesis of 2-ethyl-4-(4-fluoro-3-nitrophenyl)thiazole (9-4): Following the synthesis methods in 1-5, a pale yellow oil was obtained in 84% yield. ESI-MS: 253.0 [M+H]+.

[0376] Step 4, Synthesis of 5-bromo-2-ethyl-4-(4-fluoro-3-nitrophenyl)thiazole (9-5): 2-ethyl-4-(4-fluoro-3-nitrophenyl)thiazole (1 eq, 0.8 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and NBS (1.2 eq, 0.96 mmol) was added. The reaction was carried out at room temperature for 16 hours, quenched with water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 9-5 (154 mg, 0.46 mmol), a yellow oil, in 58% yield. ESI-MS: 332.2 [M+H]+.

[0377] Step 5, Synthesis of 2-ethyl-4-(4-fluoro-3-nitrophenyl)-5-(pyridin-4-yl)thiazole (9-6): Following the synthetic methods in steps 1-5, a pale yellow oil was obtained in 20% yield. ESI-MS: 330.1 [M+H]+.

[0378] Step 6, Synthesis of 5-(2-ethyl-5-(pyridin-4-yl)thiazolyl-4-yl)-2-fluoroaniline (compound 9): Following the synthetic method in 4-3, a pale yellow oil was obtained in 15% yield. ESI-MS: 300.1 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.71-8.66(m,2H),7.55-7.50(m,2H),7.33-7.27(m,1H),7.24(t,J= 8.3Hz, 1H), 6.82 (dd, J = 5.1, 2.2Hz, 1H), 4.28 (s, 2H), 2.96 (q, J = 6.8Hz, 2H), 1.33 (t, J = 6.7Hz, 3H).

[0379] Example 10: N-ethyl-5-(2-ethyl-5-(pyridin-4-yl)thiazolyl-4-yl)-2-fluoroaniline (Compound 10)

[0380] Following the synthesis method in 2-1, the product was a light solid with a yield of 30%. ESI-MS: 328.1 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.71-8.66(m,2H),7.55-7.50(m,2H),7.34-7.28(m,1H),7.18(dd,J=5.0,2.2Hz,1H ),7.12(dd,J=8.9,8.0Hz,1H),5.69(t,J=3.7Hz,1H),3.42-3.34(m,2H),2.96(q,J=6.8Hz,2H),1.36-1.26(m,6H).

[0381] Example 11: N-(cyclopropylmethyl)-5-(2-ethyl-5-(pyridin-4-yl)thiazolyl-4-yl)-2-fluoroaniline (Compound 11)

[0382] Following the synthesis method in 2-1, the product was a light solid with a yield of 10%. ESI-MS: 354.1 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.71-8.66(m,2H),7.55-7.50(m,2H),7.35-7.28(m,1H),7.12(dd,J=8.9,8.0Hz,1H),7.01(dd,J=5.0,2.2Hz, 1H), 6.01 (t, J = 4.8Hz, 1H), 3.30 (dd, J = 4.9, 3.8Hz, 2H), 2.96 (q, J = 6.8Hz, 2H), 1.33 (t, J = 6.7Hz, 3H), 1.27-1.18 (m, 1H), 0.43-0.26 (m, 4H).

[0383] Example 12: N-(3-(5-(2-acetamidopyrimidin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 12)

[0384] Step 1, Synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (12-2): Following the synthetic method in 1-2, a pale yellow oil was obtained, yielding 91%. ESI-MS: 199.2 [M+H]+.

[0385] Step 2, Synthesis of 4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (12-3): Following the synthetic method in steps 1-3, a pale yellow oil was obtained in 91% yield. ESI-MS: 355.1 [M+H]+.

[0386] Step 3, Synthesis of 6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-chloro-1,2-dihydropyrimidine (12-4): 4,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (1 eq, 0.765 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran. Under N2 protection, the mixture was cooled to -78 °C, and n-butyllithium (1 eq, 0.765 mmol) was added. The reaction was continued for 5 minutes, followed by the addition of 2-chloropyrimidine (1.1 eq, 0.845 mmol). The reaction was allowed to proceed for 30 minutes, quenched with saturated ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum to give crude 12-4 as a brown oil. ESI-MS: 391.0 [M+H]+.

[0387] Step 4, Synthesis of 4-(5-bromo-1-((2-trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-chloropyrimidine (12-5): 6-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-chloro-1,2-dihydropyrimidine was dissolved in 5 mL of ethyl acetate, and activated manganese dioxide (1 eq, 0.765 mmol) was added. The reaction was allowed to proceed overnight at room temperature, quenched with saturated ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 12-5 (179 mg, 0.46 mmol), a yellow oil, in 64% yield. ESI-MS: 389.0 [M+H]+.

[0388] Step 5, Synthesis of 3-(4-(2-chloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)aniline (12-6): Following the synthetic method in steps 1-5, a pale yellow oil was obtained in 66% yield. ESI-MS: 402.1 [M+H]+.

[0389] Step 6, Synthesis of N-(3-(4-(2-chloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (12-7): Following the method described in 4-4, a pale yellow oil was obtained in 22% yield. ESI-MS: 559.2 [M+H]+.

[0390] Step 7, Synthesis of N-(3-(5-(2-acetamidopyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (12-8): N-(3-(4-(2-chloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (1 eq, 0.04 mmol) was dissolved in anhydrous 1,4-dioxane, and acetamide (1 eq, 0.04 mmol), XantPhos (0.15 eq, 0.006 mmol), Pd2(dba)3 (0.05 eq, 0.002 mmol) and Cs2CO3 (2 eq, 0.08 mmol) were added. Under N2 protection, the reaction was carried out at 110 °C for 12 hours, cooled to room temperature, quenched with aqueous solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography purification yielded 12-8 (12 mg, 0.02 mmol), a yellow solid, in 51% yield. ESI-MS: 582.3 [M+H]+.

[0391] Step 8, Synthesis of N-(3-(5-(2-acetamidopyrimidin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (compound 12): Following the synthetic method of compound 1, a pale yellow solid was obtained in 42% yield. ESI-MS: 452.2.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.07(d,J=7.3Hz,1H),8.74(d,J=4.8Hz,1H),8.03(t,J=2.1Hz,1H),7.97(d,J=6.8Hz,1H),7.88-7.81( m,2H),7.56(d,J=4.8Hz,1H),7.52-7.46(m,1H),7.50-7.42(m,2H),7.39 (dd,J=8.1,1.4Hz,1H),7.07(d,J=7.3Hz,1H),2.48(s,3H),2.28(s,3H).

[0392] Example 13: N-(3-(2-ethyl-5-(2-(phenylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 13)

[0393] Step 1, Synthesis of 6-(5-bromo-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-chloro-1,2-dihydropyrimidine (13-1): Following the synthesis method in 12-4, a pale yellow oil was obtained. ESI-MS: 419.0 [M+H]+.

[0394] Step 2, Synthesis of 4-(5-bromo-2-ethyl-1-((2-trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-chloropyrimidine (13-2): Following the synthetic method in 12-5, a pale yellow oil was obtained. Yield 60%. ESI-MS: 417.0 [M+H]+.

[0395] Step 3, Synthesis of 3-(4-(2-chloropyrimidin-4-yl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)aniline (13-3): Following the synthetic method in steps 1-5, a pale yellow oil was obtained. Yield: 68%. ESI-MS: 430.2 [M+H]+.

[0396] Step 4, Synthesis of N-(3-(4-(2-chloropyrimidin-4-yl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (13-4): Following the method described in 4-4, a pale yellow oil was obtained. Yield: 33%. ESI-MS: 587.3 [M+H]+.

[0397] Step 5, Synthesis of N-(3-(2-ethyl-5-(2-(phenylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (compound 13): N-(3-(4-(2-chloropyrimidin-4-yl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (1 eq, 0.03 mmol) was dissolved in 1 mL of n-butanol, and aniline (1 eq, 0.03 mmol) and trifluoroacetic acid (2 eq, 0.06 mmol) were added. The reaction flask was sealed and reacted overnight at 120 °C. After cooling to room temperature, the solution was dried under vacuum and concentrated by evaporation under vacuum. The solution was rapidly purified by liquid chromatography to give compound 13 (7 mg, 0.01 mmol) as a yellow solid, in 48% yield. ESI-MS: 514.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.50(s,1H),9.07(d,J=7.3Hz,1H),8.83(s,1H),8.64(d,J=4.8 Hz,1H),8.03(t,J=2.1Hz,1H),7.88-7.81(m,2H),7.68-7.62(m,2H),7.54-7.45(m,2H),7.45( t,J=8.1Hz,1H),7.39(dd,J=8.1,1.3Hz,1H),7.32(d,J=4.8Hz,1H),7.29-7.22(m,2H),7.07( d,J=7.3Hz,1H),6.99-6.92(m,1H),2.88(q,J=6.2Hz,2H),2.48(s,2H),1.36(t,J=6.1Hz,3H).

[0398] Example 14: N-(5-(2-ethyl-5-(2-(2-methoxyphenyl)amino)pyridin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)cyclopropaneformamide (Compound 14)

[0399] Following the synthesis method in 4-4, a pale yellow solid was obtained. The yield was 33%. ESI-MS: 472.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.95(s,1H),8.34-8.28(m,2H),8.12(s,1H),7.72-7.65(m,1H),7.55(dd,J=4.7,1.9Hz,1H),7.53-7.46(m,1H),7.32-7 .24(m,2H),7.07-6.98(m,2H),7.01-6.95(m,1H),3.88(s,3H),2.89(q,J=6 .2Hz,2H),2.05(q,J=5.5Hz,1H),1.36(t,J=6.1Hz,3H),1.00-0.81(m,4H).

[0400] Example 15: N-(5-(2-ethyl-5-(2-(2-methoxyphenyl)amino)pyridin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)-2-fluorobenzamide (Compound 15)

[0401] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 33%. ESI-MS: 526.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.64(s,1H),8.35-8.30(m,2H),8.12(s,1H),7.8 2-7.76(m,1H),7.72-7.65(m,1H),7.55(dd,J=4.7,1.9Hz,1H),7.55-7.46(m,2 H),7.33-7.24(m,3H),7.23-7.16(m,1H),7.07-7.01(m,1H),7.04-6.98(m,1H) ,7.00-6.95(m,1H),3.88(s,3H),2.89(q,J=6.2Hz,2H),1.36(t,J=6.1Hz,3H).

[0402] Example 16: N-(3-(2-ethyl-5-(2-(2-methoxyphenyl)amino)pyridin-4-yl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 16)

[0403] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 21%. ESI-MS: 543.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.50(s,1H),9.07(d,J=7.3Hz,1H),8.32(d,J=4.7Hz,1H),8 .12(s,1H),7.99(t,J=2.2Hz,1H),7.88-7.81(m,2H),7.72-7.65(m,1H),7.55(dd,J=4.7,1 .9Hz,1H),7.53-7.47(m,1H),7.49-7.42(m,2H),7.39(dd,J=8.1,1.4Hz,1H),7.30(s,1H), 7.10-6.94(m,5H),3.88(s,3H),2.89(q,J=6.2Hz,2H),2.48(s,3H),1.36(t,J=6.1Hz,3H).

[0404] Example 17: N-(5-(2-ethyl-5-(2-(2-methoxyphenyl)amino)pyridin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)-3-methyl-1H-indole-4-carboxamide (Compound 17)

[0405] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 21%. ESI-MS: 561.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.07(d,J=7.3Hz,1H),8.37-8.30(m,2H),8.12(s,1 H),7.85(dd,J=7.9,1.3Hz,1H),7.72-7.65(m,1H),7.55(dd,J=4.8,2.2Hz,1H),7. 53-7.42(m,2H),7.39(dd,J=8.1,1.4Hz,1H),7.32-7.24(m,2H),7.10-6.94(m,4H) ,3.88(s,3H),2.89(q,J=6.2Hz,2H),2.48(d,J=0.7Hz,3H),1.36(t,J=6.1Hz,3H).

[0406] Example 18: 4-(4-(3-amino-4-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (Compound 18)

[0407] Step 1, Synthesis of 2-ethyl-4-(4-fluoro-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (18-1): Following the synthetic methods in 1-5, a pale yellow oil was obtained. Yield 72%. ESI-MS: 346.2 [M+H]+.

[0408] Step 2, Synthesis of 5-bromo-2-ethyl-4-(4-fluoro-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (18-2): Following the synthetic methods described in 1-6, a pale yellow oil was obtained. Yield 82%. ESI-MS: 444.0 [M+H]+.

[0409] Step 3, Synthesis of 4-(2-ethyl-4-(4-fluoro-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-amine (18-3): Following the synthetic method described in 1-7, a pale yellow oil was obtained. Yield 71%. ESI-MS: 458.2 [M+H]+.

[0410] Step 4, Synthesis of 4-(2-ethyl-4-(4-fluoro-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (18-4): 4-(2-ethyl-4-(4-fluoro-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine-2-amine (1 eq, 0.437 mmol) was dissolved in 4 mL of 1,4-dioxane and 1 mL of n-butanol. 1-Bromo-2-methoxybenzene (1.2 eq, 0.524 mmol) was added, followed by cesium carbonate (5 eq, 2.185 mmol) and Brettphos Pd G1 (0.025 eq, 0.01 mmol). The reaction was carried out under N2 protection at 120 °C for 1 hour. The mixture was cooled to room temperature, quenched with aqueous solution, and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise preliminary liquid chromatography (PLC) purification yielded 18-4 (172 mg, 0.306 mmol), a yellow solid, in 70% yield. ESI-MS: 564.3 [M+H]+.

[0411] Step 5, Synthesis of 4-(4-(3-amino-4-fluorophenyl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (18-5): Following the method described in 4-3, a pale yellow oil was obtained. Yield 52%. ESI-MS: 534.3 [M+H]+.

[0412] Step 6, Synthesis of 4-(4-(3-amino-4-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (Compound 18): Following the synthetic method for Compound 1, a pale yellow solid was obtained. Yield: 50%. ESI-MS: 404.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.32(d,J=4.7Hz,1H),8.12(s,1H),7.72-7.66(m,1H),7.55(dd,J=4.8,2.2Hz,1H),7.30(d,J=2.3Hz,1H),7.26-7.19 (m,1H),7.07-6.98(m,3H),7.01-6.95(m,1H),6.82(dd,J=5.1,2.2Hz,1H ),4.12(s,2H),3.88(s,2H),2.89(q,J=6.2Hz,2H),1.36(t,J=6.1Hz,3H).

[0413] Example 19: 4-(4-(3-aminophenyl)-2-ethyl-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (Compound 19)

[0414] Step 1, Synthesis of 4-(2-ethyl-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridine-2-amine (19-1): Following the synthetic method in 1-7, a pale yellow oil was obtained. Yield 69%. ESI-MS: 440.2 [M+H]+.

[0415] Step 2, Synthesis of 4-(2-ethyl-4-(3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (19-2): Following the method described in 18-4, a yellow solid was obtained in 70% yield. ESI-MS: 546.2 [M+H]+.

[0416] Step 3, Synthesis of 4-(4-(3-aminophenyl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (19-3): Following the method described in 4-3, a pale yellow oil was obtained. Yield: 52%. ESI-MS: 516.3 [M+H]+.

[0417] Step 4, 4-(4-(3-aminophenyl)-2-ethyl-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (compound 19): synthesized as compound 1, pale yellow solid. Yield 50%. ESI-MS: 386.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.32(d,J=4.7Hz,1H),8.12(s,1H),7.72-7.65(m,1H),7.55(dd,J=4.8,2.2Hz,1H),7.41-7.28(m,3H),7.07-7 .01(m,1H),7.04-6.98(m,2H),7.01-6.94(m,1H),6.70-6.64(m,1H),4 .31(s,2H),3.88(s,3H),2.89(q,J=6.2Hz,2H),1.36(t,J=6.1Hz,3H).

[0418] Example 20: 4-(2-ethyl-4-(3-(ethylamino)-4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (Compound 20)

[0419] Step 1, Synthesis of 4-(2-ethyl-4-(3-(ethylamino)-4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (20-1): Following the method described in 2-1, a pale yellow solid was obtained. Yield: 42%. ESI-MS: 562.3 [M+H]+.

[0420] Step 2, 4-(2-ethyl-4-(3-(ethylamino)-4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (compound 20): synthesized as compound 1, pale yellow solid. Yield 42%. ESI-MS: 562.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.32(d,J=4.7Hz,1H),8.12(s,1H),7.72-7.65(m,1H),7.55(dd,J=4.7,1.9Hz,1H),7.33-7.26(m,2H),7.16-7.09(m,2H), 7.07-6.94(m,3H),5.41(t,J=3.7Hz,1H),3.88(s,3H),3.38(qd,J=6.2,3.7 Hz, 2H), 2.89 (q, J = 6.2Hz, 2H), 1.36 (t, J = 6.1Hz, 3H), 1.29 (t, J = 6.1Hz, 3H).

[0421] Example 21: N-(3-(5-(2-(cyclohexylamino)pyrimidin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 21)

[0422] Following the synthetic method for compound 13, the product is a pale yellow solid. Yield: 33%. ESI-MS: 520.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.50(s,1H),9.07(d,J=7.3Hz,1H),8.57(d,J=4.6Hz,1H),8.03( t,J=2.1Hz,1H),7.88-7.81(m,2H),7.53-7.42(m,3H),7.39(dd,J=8.1,1.3Hz,1H),7.32(d,J=4 .6Hz,1H),7.07(d,J=7.3Hz,1H),6.37(d,J=7.1Hz,1H),3.94-3.84(m,1H),2.88(q,J=6.2Hz,2H ),2.48(s,2H),1.96-1.87(m,2H),1.67-1.48(m,5H),1.45-1.38(m,2H),1.36(t,J=6.1Hz,3H).

[0423] Example 22: N-(3-(5-(2-(cyclohexylamino)pyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 22)

[0424] Step 1, Synthesis of N-(3-(5-(2-(cyclohexylamino)pyridin-4-yl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (22-1): Following the method described in 18-4, a pale yellow oil was obtained. Yield 19%. ESI-MS: 649.4 [M+H]+.

[0425] Step 2, Synthesis of N-(3-(5-(2-(cyclohexylamino)pyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (compound 22): Following the synthetic method for compound 1, a pale yellow solid was obtained. Yield: 32%. ESI-MS: 519.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.50(s,1H),9.07(d,J=7.3Hz,1H),8.30(d,J=4.8H z,1H),7.99(t,J=2.2Hz,1H),7.88-7.81(m,2H),7.56-7.36(m,5H),7.10-7.05(m ,2H),6.88(d,J=7.3Hz,1H),3.94-3.85(m,1H),2.89(q,J=6.2Hz,2H),2.48(s,3H ),1.86-1.75(m,2H),1.67-1.52(m,3H),1.50-1.38(m,5H),1.36(t,J=6.1Hz,3H).

[0426] Example 23: 4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (Compound 23)

[0427] Step 1, Synthesis of 5-(4-fluorophenyl)-2-(methylthio)-1H-imidazolium (23-2): S-methylisothiourea hemisulfate (1 eq, 1 mmol) was suspended in a mixture of tetrahydrofuran / water (4:1). NaHCO3 (2.0 eq, 2 mmol) was added at room temperature. The reaction mixture was heated under reflux for 15 min. 2-bromo-1-(4-fluorophenyl)ethyl-1-one (1.0 eq, 1 mmol) dissolved in THF was added dropwise to the reflux suspension. The mixture was heated again for 30 min, and the color changed from pale yellow to deep red. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The dark residue was suspended in water, and the pH was adjusted to 8. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-liquid purification yielded 23-2 (159 mg, 0.5 mmol), a pale yellow oil. Yield: 50%. ESI-MS:209.1[M+H]+.1H NMR(500MHz,DMSO-d6)δ12.29(s,1H),7.86-7.70(m,2H),7.62(s,1H),7.23-7.07(m,2H),2.55(s,3H).

[0428] Step 2, Synthesis of 4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (23-4): 5-(4-fluorophenyl)-2-(methylthio)-1H-imidazolium (1 eq, 0.5 mmol) was dissolved in dry tetrahydrofuran and cooled to -15 °C, and 60% sodium hydride (1.1 eq, 0.55 mmol) was added. The resulting suspension was heated to room temperature. After stirring at room temperature for 30 minutes, the suspension was cooled again to -15 °C, and SEM-Cl (1 eq, 0.5 mmol) was added dropwise. After reacting for 30 minutes, saturated brine and ethyl acetate were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum to produce a regioisomeric mixture of products. This crude mixture was dissolved in dry acetonitrile (0.3 M). A catalytic amount (5 mol%) of SEMCl was added to the solution, and the mixture was stirred overnight at 70 °C. After cooling to room temperature, volatiles were removed by rotation, and the solution was rapidly purified by liquid chromatography to obtain 23-4 (150 mg, 0.46 mmol), a pale yellow oil. Yield: 91%. ESI-MS: 339.1 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ 7.88–7.67 (m, 3H), 7.31–7.02 (m, 2H), 5.26 (s, 2H), 3.52 (t, J = 7.9 Hz, 2H), 2.58 (s, 3H), 0.81–0.90 (t, J = 7.9 Hz, 2H), 0.01 (s, 9H).

[0429] Step 3, Synthesis of 5-bromo-4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium (23-5): Following the synthetic methods in 1-6, a pale yellow oil was obtained in 55% yield. ESI-MS: 417.0 [M+H]+.

[0430] Step 4, Synthesis of N-(4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide (23-6): Following the synthetic methods in steps 1-5, a pale yellow oil was obtained in 80% yield. ESI-MS: 473.2 [M+H]+.

[0431] Step 5, Synthesis of 4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-amine (23-7): N-(4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide (1.0 eq, 0.1 mmol) was dissolved in methanol (20 mL / mmol), and 5 M NaOH aqueous solution (25 eq, 2.5 mmol) was added to the reaction solution. The mixture was stirred overnight at room temperature. The mixture was neutralized with saturated NH4Cl aqueous solution. Methanol was removed by rotary evaporation, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 23-7 (30 mg, 0.072 mmol), a pale yellow oil, in 72% yield. ESI-MS: 431.2 [M+H]+.

[0432] Step 6, Synthesis of 4-(4-(4-fluorophenyl)-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (23-8): Following the method described in 18-4, a pale yellow oil was obtained in 81% yield. ESI-MS: 537.2 [M+H]+.

[0433] Step 7, Synthesis of 4-(4-(4-fluorophenyl)-2-(methylthio)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)pyridine-2-amine (compound 23): Following the synthetic method for compound 1, a pale yellow solid was obtained in 58% yield. ESI-MS: 407.1 [M+H]+.

[0434] 1H NMR(500MHz,Chloroform-d)δ8.31(d,J=4.7Hz,1H),8.12(s,1H),7.77-7.70(m,2H),7.72-7.65(m,1H),7.56(dd,J=4.8 ,2.0Hz,1H),7.31(d,J=1.9Hz,1H),7.23-7.16(m,1H),7.06-7.00(m,2H),6.99-6.96(m,1H),3.88(s,3H),2.60(s,3H).

[0435] Example 24: 4-(4-(3-amino-4-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 24)

[0436] Following the synthetic method for compound 13, a pale yellow solid was obtained. Yield: 31%. ESI-MS: 573.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.79(s,1H),8.64(d,J=4.8Hz,1H),7.58-7.52(m,2H),7.34-7.17(m,4H),6.89-6.83(m,2H),4. 12(s,2H),3.27-3.16(m,5H),2.88(q,J=6.2Hz,2H),2.84-2.76(m,2H),2.61-2.53(m,2H),2.29(s,3H),1.36(t,J=6.1Hz,3H).

[0437] Example 25: 4-(4-(3-amino-4-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 25)

[0438] Step 1, Synthesis of 5-(5-(2-chloropyrimidin-4-yl)-2-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-N-ethyl-2-fluoroaniline (25-1): Following the synthetic methods in steps 1-5, a pale yellow oil was obtained. Yield: 70%. ESI-MS: 476.2 [M+H]+.

[0439] Step 2, Synthesis of 4-(4-(3-amino-4-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 25): Following the synthesis method of Compound 13, a pale yellow solid was obtained. Yield: 38%. ESI-MS: 499.28 [M+H]+. 1H NMR (500MHz, Chloroform-d) δ 9.15 (s, 1H), 8.26 (d, J = 7.5 Hz, 1H), 7.54 (dd, J = 7.5, 1.2 Hz, 3H), 7.49 (ddd, J = 7.5, 5.0, 1.6 Hz, 1H), 7.36–7.30 (m, 2H), 6.92–6.87 (m, 2H), 6.78 (dd, J = 5.0, 1.5H). z,1H),6.22(t,J=5.7Hz,1H),3.40(qd,J=8.0,5.8Hz,2H),3.16(t,J=7.0Hz,4H),2.96-2.87(m ,4H),2.66(dt,J=12.5,7.1Hz,2H),2.27(s,3H),1.41(t,J=8.0Hz,3H),1.26(t,J=8.0Hz,3H).

[0440] Example 26: Synthesis of (E)-N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-6-bromo-2-(2-(thiophen-2-yl)vinyl)quinoline-4-carboxamide (Compound 26)

[0441] A-42 (1 eq, 0.062 mmol) and (E)-6-bromo-2-(2-(thiophen-2-yl)vinyl)quinoline-4-carboxylic acid (1.2 eq, 0.068 mmol) were dissolved in 0.5 mL of anhydrous DMF. HATU (1.2 eq, 0.068 mmol) and DIPEA (4 eq, 0.27 mmol) were added, and the mixture was heated to 50 °C and reacted for 6 hours. After the reaction was complete, 3 mL of water was added and the mixture was stirred vigorously. The precipitated solid was filtered and purified by reverse-phase chromatography to give compound 25 (20 mg, 0.031 mmol), a brown solid, in 50% yield, as a mixture of tautomers. Ms(ESI,m\z):[M+H] + 664.90.

[0442] 1H NMR(600MHz,DMSO-d6)δ12.74-12.43(m,1H),10.65-10.48(m,1H),10.13-9.83(m,1H),8.93-8.86(m,1H),8.49-8.16(m,2H),8.24-8.16(m,3H )7.89-7.80(m,2H),7.60-7.55(m,1H),7.41-7.14(m,2H),7.13-6.96( m,4H),6.67-6.56(m,1H),2.97(s,2H),2.05(s,3H),1.68-1.54(m,3H).

[0443] Example 27: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-(piperidin-1-ylsulfonyl)thiophene-2-carboxamide (Compound 27)

[0444] Following the synthetic method for compound 26, the product is a white solid with a yield of 52%, Ms(ESI, m\z): [M+H] + 579.45. 1 H NMR(600MHz,DMSO-d6)12.88-12.55(m,1H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,3H),7 .89-7.80(m,2H),7.41-7.14(m,2H),7.13-6.96(m,2H),3.56-2.97(s,6H),2.05(s,3H),1.84-1.46(m,9H).

[0445] Example 28: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-(thiophen-2-ylmethoxy)benzamide (Compound 28)

[0446] Following the synthetic method for compound 26, the product is a white solid with a yield of 52%, Ms(ESI, m\z): [M+H] + 538.18. 1H NMR(600MHz,DMSO-d6)12.80-12.53(m,1H),10.56-10.34(m,1H),10.14-9.79(m,1H),8.41-8.13(m,2H),7.89-7.70(m,4H) ,7.64-7.53(m,1H),7.41-7.14(m,2H),7.13-6.96(m,4H),5.67-5.44(m,2H),2.97(s,2H),2.03(s,3H),1.70-1.48(m,3H).

[0447] Example 29: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-(1H-pyrrolo-1-yl)-5,6-dihydro-4H-cyclopentathiophene-3-carboxamide (Compound 29)

[0448] Following the synthetic method for compound 26, the product is a white solid with a yield of 59%, Ms(ESI, m\z): [M+H] + 537.28. 1 H NMR(600MHz,DMSO-d6)12.90-12.54(m,1H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,2H),7.89-7.80 (m,2H),7.41-7.14(m,4H),7.13-6.96(m,1H),6.56-6.33(m,2H),3.15-2.90(m,8H),2.05(s,3H),1.70-1.48(m,3H).

[0449] Example 30: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-6-fluoro-1H-indole-4-carboxamide (Compound 30)

[0450] Following the synthetic method for compound 26, the product is a yellow solid with a yield of 65%, Ms(ESI,m\z):[M+H] + 483.56. 1H NMR (600MHz, DMSO-d6)12.85-12.57(m,1H),10.45-10.28(m,1H),10.04-9.83(m,2H),8.41-8.16(m,2H),7.89-7. 76(m,2H),7.58-7.45(m,2H),7.41-7.14(m,1H),7.13-6.96(m,4H),2.97(s,2H),2.07(s,3H),1.72-1.49(m,3H).

[0451] Example 31: N1-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-N2-methylphthalamide (Compound 31)

[0452] Following the synthetic method of compound 26, the product is a yellow solid with a yield of 58%, Ms(ESI,m\z):[M+H]+483.26. 1 H NMR(500MHz,Chloroform-d)δ9.50(s,1H),9.33(s,1H),8.39(d,J=7.5Hz,1H),8.03( q,J=3.7Hz,1H),7.87-7.80(m,3H),7.80-7.77(m,1H),7.76(t,J=1.5Hz,1H),7.68(d ,J=1.6Hz,1H),7.65(dd,J=7.5,1.5Hz,1H),7.58-7.49(m,2H),7.42(t,J=7.4Hz,1H) ,7.38(dt,J=7.5,1.6Hz,1H),2.95-2.87(m,5H),2.14(s,3H),1.41(t,J=8.0Hz,3H).

[0453] Example 32: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-(pyrrolidine-1-carbonyl)benzamide (Compound 32)

[0454] Following the synthetic method for compound 26, the product is a brown solid with a yield of 43%, Ms(ESI,m\z):[M+H] + 523.95. 1H NMR(600MHz,DMSO-d6)12.88-12.55(m,1H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,4H),7.89-7.80 (m,4H),7.41-7.14(m,1H),7.13-6.96(m,2H),3.54-3.30(m,4H),2.97(s,2H),2.08-1.90(m,7H),1.70-1.46(m,3H).

[0455] Example 33: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-methyl-1H-indole-4-carboxamide (Compound 33)

[0456] Following the synthetic method for compound 26, the product is a white solid with a yield of 61%, Ms(ESI, m\z): [M+H] + 479.65. 1 H NMR(600MHz,DMSO-d6)12.80-12.56(m,1H),10.56-10.15(m,2H),10.04-9.83(m,1H),8.41-8.01(m,3H),7 .79-7.57(m,3H),7.41-7.14(m,2H),7.13-6.96(m,3H),2.97(s,2H),2.23-2.05(m,6H),1.72-1.48(m,3H).

[0457] Example 34: (3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-7-fluoroisoquinoline-1-carboxamide (Compound 34)

[0458] Following the synthetic method of compound 35, the product is a white solid with a yield of 50%, Ms(ESI, m\z): [M+H] + 495.23. 1 H NMR(600MHz,DMSO-d6)δ12.44-12.38(m,1H),10.70-10.31(m,1H),10.23-10.16(m,1H),8.64-8.52(m,2H),8.42-7.90(m, 4H),7.95-7.67(m,3H),7.45-7.23(m,1H),7.19-7.04(m,2H),2.75-2.65(m,2H),2.06-2.01(m,3H),1.28(t,J=7.6Hz,3H).

[0459] Example 35: (3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-5-amino-2-(trifluoromethyl)benzamide (Compound 35)

[0460] A-42 (2 eq, 0.16 mmol), B-25 (1 eq, 0.08 mmol), DCC (1 eq, 0.08 mol), and a catalytic amount of DMAP (0.1 eq, 0.08 mmol) were dissolved in DMF (0.5 mL), and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, 3 mL of water was added and the mixture was stirred vigorously. The precipitated solid was filtered and purified by reverse-phase chromatography to give compound 35 as a white solid in 35% yield, Ms(ESI, m\z): [M+H]. + 509.23. 1 H NMR(600MHz,DMSO-d6)12.90-12.76(m,1H),10.79-10.36(m,1H),10.04-9.79(m,1H),8.41-8.06(m,2H),7.79 -7.57(m,3H),7.41-7.22(m,2H),7.13-6.96(m,3H),6.45(s,2H)2.97(s,2H),2.05(s,3H),1.70-1.53(m,3H).

[0461] Example 36: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-5-amino-2-chloronicotinamide (Compound 36)

[0462] Following the synthetic method of compound 35, the product is a white solid with a yield of 29%, Ms(ESI, m\z): [M+H] + 476.80 1 H NMR(600MHz,DMSO-d6)δ12.34-12.20(m,1H),10.50-10.30(m,1H),10.15-10.05(m,1H),8.42-8.04(m,3H),7.95 -7.78(m,3H),7.45-7.23(m,1H),7.19-7.04(m,2H),6.84-6.73(m,2H),2.75-2.65(m,2H),2.06-2.01(m,3H),1.28(t,J=7.6Hz,3H).

[0463] Example 37: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-methoxybenzamide (Compound 37)

[0464] Following the synthetic method of compound 35, the product is a white solid with a yield of 68%, Ms(ESI, m\z): [M+H] + 456.55. 1 H NMR (600MHz, DMSO-d6)12.49-12.34(m,1H),10.57-10.38(m,1H),10.25-10.13(m,1H),8.47-8.24(m,3H),7.93-7.58(m,4 H),7.43-7.22(m,2H),7.11-7.04(m,2H),3.94-3.77(m,3H),2.73-2.68(m,2H),2.13-2.07(m,3H),1.35(t,J=7.6Hz,3H).

[0465] Example 38: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-bromo-5-(hydroxymethyl)benzamide (Compound 38)

[0466] Following the synthetic method for compound 35, the product is a brown solid with a yield of 45%, and Ms(ESI, m\z): [M+H]. + 534.68 1 H NMR(600MHz,DMSO-d6)δ12.40-12.16(m,1H),10.75-10.55(m,1H),10.25-10.20(m,1H),8.42-7.92(m,3H),7.95 -7.70(m,4H),7.45-7.23(m,1H),7.19-7.04(m,2H),5.46-5.34(m,1H),4.5 2-4.32(m,2H)2.78-2.65(m,2H),2.06-2.03(m,3H),1.29(t,J=7.6Hz,3H).

[0467] Example 39: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-1H-benzo[d]imidazol-4-carboxamide (Compound 39)

[0468] Following the synthetic method of compound 35, the product is a white solid with a yield of 63%, Ms(ESI, m\z): [M+H]+ 466.79. 1 H NMR(600MHz,DMSO-d6)12.47-12.23(m,2H),10.34-10.15(m,1H),10.02-9.88(m,1H),8.19-8.04(m,3H),7.90- 7.54(m,4H),7.48-7.25(m,2H),7.11-7.01(m,2H),2.85-2.60(m,2H),2.13-2.01(m,3H),1.33(t,J=7.6Hz,3H).

[0469] Example 40: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)imidazo[1,5-a]pyridine-5-carboxamide (Compound 40)

[0470] Following the synthetic method for compound 35, the product is a white solid with a yield of 62%, Ms(ESI, m\z): [M+H] + 466.18 1 H NMR(600MHz,DMSO-d6)δ12.38-12.22(m,1H),10.78-10.63(m,1H),10.49-10.29(m,1H),8.92-8.86(m,1H),8.43-7.98(m,3H), 7.93-7.73(m,2H),7.57(s,1H),7.49-7.20(m,3H),7.13-6.89(m,2H),2.75-2.60(m,2H),2.09-2.00(m,2H),1.31-1.23(m,3H).

[0471] Example 41: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-4-amino-5-chloro-2-ethoxybenzamide (Compound 41)

[0472] Following the synthetic method of compound 35, the product is a white solid with a yield of 30%, Ms(ESI, m\z): [M+H] + 519.20 1H NMR(600MHz,DMSO-d6)δ12.34-12.25(m,1H),10.54-10.37(m,1H),10.19-10.01(m,1H),8.46-8.04(m,2H),7.95 -7.78(m,3H),7.45-7.26(m,1H),7.27-7.14(m,2H),6.84-6.73(m,2H),6.52-6.36( m,1H),4.52-4.37(m,2H),2.75-2.65(m,2H),2.06-2.01(m,3H),1.36-1.28(m,6H).

[0473] Example 42: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxamide (Compound 42)

[0474] Following the synthetic method of compound 35, the product is a white solid with a yield of 63%, Ms(ESI, m\z): [M+H] + 466.18. 1 H NMR (600MHz, DMSO-d6) δ12.34-12.20(m,1H),11.74-11.66(m,1H),10.50-10.30(m,1H),10.15-10.05(m,1H),8.88-8.70(m,1H),8.4 2-8.04(m,2H),7.95-7.67(m,4H),7.45-7.23(m,1H),7.19-7.04(m,2H),2.75-2.65(m,2H),2.06-2.01(m,3H),1.28(t,J=7.6Hz,3H).

[0475] Example 43: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-methyl-2-(methylsulfonamido)benzamide (Compound 43)

[0476] Following the synthetic method for compound 35, the product is a yellow solid with a yield of 63%, Ms(ESI,m\z):[M+H] + 533.19. 1H NMR(600MHz,DMSO-d6)δ12.34-12.29(m,1H),10.50-10.37(m,2H),10.15-10.05(m,1H),8.42-8.04(m,2H),7.95 -7.78(m,3H),7.45-7.23(m,2H),7.19-6.92(m,3H),3.40-3.31(m,2H),2.75-2.65(m,2H),2.12-2.01(m,6H),1.28(t,J=7.6Hz,3H).

[0477] Example 44: NN-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-1-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-carboxamide (Compound 44)

[0478] Following the synthetic method of compound 35, the product is a white solid with a yield of 50%, Ms(ESI, m\z): [M+H] + 560.11. 1 H NMR(600MHz,DMSO-d6)12.67-12.40(m,1H),10.63-10.33(m,1H),10.34-10.20(m,1H),8.65(s,1H),8.36-7.95(m,3H ),7.79-7.57(m,3H),7.41-7.14(m,4H),7.05-6.96(m,2H),2.80-2.64(m,2H),2.09-2.00(m,2H),1.70-1.46(m,3H).

[0479] Example 45: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (Compound 45)

[0480] Following the synthetic method of compound 35, the product is a white solid with a yield of 36%, Ms(ESI, m\z): [M+H] + 481.22. 1H NMR(600MHz,DMSO-d6)12.47-12.25(m,1H),10.45-10.31(m,1H),10.06-10.90(m,1H),8.47-8.14(m,3H),7.83-7.53(m,3 H),7.36-7.18(m,1H),7.04-6.87(m,3H),6.50-6.43(m,1H),2.93-2.69(m,6H),2.08-1.97(m,5H),1.36(t,J=7.6Hz,3H).

[0481] Example 46: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-(pyrrolidine-1-ylmethyl)benzamide (Compound 46)

[0482] Following the synthetic method of compound 35, the product is a white solid with a yield of 43%, Ms(ESI, m\z): [M+H] + 509.24 1 H NMR(600MHz,DMSO-d6)δ12.34-12.20(m,1H),10.50-10.30(m,1H),10.15-10.05(m,1H),8.42-8.04(m,4H),7.95 -7.78(m,4H),7.45-7.23(m,1H),7.19-7.04(m,2H),3.66-3.31(m,2H),2.75-2.65(m,6H),2.06-1.88(m,7H),1.28(t,J=7.6Hz,3H).

[0483] Example 47: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-5-(hydroxymethyl)furan-2-carboxamide (Compound 47)

[0484] Following the synthetic method of compound 35, the product is a white solid with a yield of 25%, Ms(ESI, m\z): [M+H] + 446.27. 1H NMR(600MHz,DMSO-d6)δ12.34-12.20(m,1H),10.50-10.30(m,1H),10.15-10.05 (m,1H),8.42-8.20(m,1H),8.19-8.04(m,1H),7.95-7.84(m,1H),7.83-7.78(m, 1H),7.45-7.23(m,2H),7.19-7.04(m,2H),6.52-6.48(m,1H),5.46-5.30(m,1H) ,4.52-4.37(m,2H),2.75-2.65(m,2H),2.06-2.01(m,3H),1.28(t,J=7.6Hz,3H).

[0485] Example 48: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-6-oxo-3,6-dihydropyrimidine-4-carboxamide (Compound 48)

[0486] Following the synthetic method of compound 35, the product is a brown solid with a yield of 40%, Ms(ESI,m\z):[M+H] + 444.16 1 H NMR(600MHz,DMSO-d6)δ12.56-12.37(m,1H),10.45-10.24(m,1H),10.05-9.95(m,1H),8.42-8.04(m,4H),7.95 -7.78(m,2H),7.45-7.23(m,1H),7.19-7.04(m,2H),6.54-6.45(m,1H),2.75-2.65(m,2H),2.06-2.01(m,3H),1.28(t,J=7.6Hz,3H).

[0487] Example 49: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-(1H-imidazol-1-yl)benzamide (Compound 49)

[0488] Following the synthetic method for compound 26, the product is a white solid with a yield of 45%, Ms(ESI, m\z): [M+H] + 492.67. 1H NMR(600MHz, DMSO-d6)12.90-12.56(m,1H),10.58-10.26(m,1H),10.04-9.83(m,1H),9.13-9.02(m,1H),8.41-8. 06(m,4H),7.79-7.57(m,3H),7.41-7.22(m,4H),7.13-6.96(m,2H),2.94(s,2H),2.05(s,3H),1.70-1.46(m,3H).

[0489] Example 50: Synthesis of N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-((2-fluorophenyl)thio)-2-phenylacetamide (Compound 50)

[0490] Following the synthetic method for compound 26, the product is a white solid with a yield of 47%, Ms(ESI,m\z):[M+H] + 566.78. 1 H NMR(600MHz,DMSO-d6)δ12.88-12.55(m,1H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,2H),7.89-7.80(m,2H) ),7.54-7.45(m,2H),7.41-7.14(m,6H),7.13-6.96(m,3H),5.19-5.11(m,1H)2.97(s,2H),2.05(s,3H),1.70-1.46(m,3H).

[0491] Example 51: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)benzopyran-5-carboxamide (Compound 51)

[0492] Following the synthetic method for compound 26, the product is a white solid with a yield of 50%, Ms(ESI, m\z): [M+H] + 482.12. 1H NMR(600MHz,DMSO-d6)12.83-12.51(m,1H),10.65-10.36(m,1H),10.23-9.79(m,1H),8.21-8.05(m,2H),7.79-7.54(m ,4H),7.41-7.25(m,2H),7.13-6.98(m,2H),4.05-3.90(m,2H),2.97-2.83(m,4H),2.15-2.03m,5H),1.70-1.46(m,3H).

[0493] Example 52: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-4-fluoro-4'-methyl-[1,1'-biphenyl]-3-carboxamide (Compound 52)

[0494] Following the synthetic method for compound 26, the product is a white solid with a yield of 55%, Ms(ESI,m\z):[M+H] + 534.66. 1 H NMR(600MHz,DMSO-d6)12.91-12.57(m,1H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.83-8.75(m,1H),8.41-8.06(m,2H) ,7.79-7.57(m,4H),7.41-7.22(m,3H),7.13-6.96(m,4H),2.97(s,2H),2.43-2.31(m,3H),2.05(s,3H),1.70-1.46(m,3H).

[0495] Example 53: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-methylbenzo[d]thiazol-7-carboxamide (Compound 53)

[0496] Following the synthetic method for compound 26, the product is a white solid with a yield of 55%, Ms(ESI,m\z):[M+H] + 497.23. 1H NMR(600MHz,DMSO-d6)12.85-12.56(m,1H),10.50-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,3H),8.14-8.03 (m,1H),7.79-7.57(m,3H),7.41-7.22(m,1H),7.13-6.96(m,2H),2.95-2.83(m,5H),2.05(s,3H),1.70-1.46(m,3H).

[0497] Example 54: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-isopropylthiazolyl-5-carboxamide (Compound 54)

[0498] Following the synthetic method for compound 26, the product is a white solid with a yield of 50%, Ms(ESI, m\z): [M+H] + 475.29. 1 H NMR (600MHz, DMSO-d6)12.88-12.55(m,1H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,3H),7.79-7. 57(m,2H),7.41-7.22(m,1H),7.13-6.96(m,2H),3.39-3.28(m,1H),2.97(s,2H),2.05(s,3H),1.70-1.34(m,9H).

[0499] Example 55: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-(4-chlorobenzoyl)benzamide (Compound 55)

[0500] Following the synthetic method for compound 26, the product is a white solid with a yield of 59%, Ms(ESI, m\z): [M+H] + 564.10. 1 H NMR (600MHz, DMSO-d6)12.88-12.64(m,1H),10.57-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,4H),7.92-7. 83(m,4H),7.79-7.57(m,4H),7.41-7.22(m,1H),7.13-6.96(m,2H),2.97(s,2H),2.05(s,3H),1.70-1.46(m,3H).

[0501] Example 56: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-4-fluorobenzamide (Compound 56)

[0502] Following the synthetic method for compound 26, the product is a white solid with a yield of 30%, Ms(ESI, m\z): [M+H] + 444.17. 1 H NMR(600MHz,DMSO-d6)12.85-12.62(m,1H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,4H) ,7.79-7.57(m,4H),7.41-7.22(m,1H),7.13-6.96(m,2H),2.97(s,2H),2.05(s,3H),1.70-1.46(m,3H).

[0503] Example 57: 3-acetamido-N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)benzamide (compound 57)

[0504] Following the synthetic method for compound 26, the product is a white solid with a yield of 53%, Ms(ESI, m\z): [M+H] + 483.17. 1 H NMR(600MHz,DMSO-d6)12.83-12.62(m,1H),10.55-10.26(m,1H),10.04-9.79(m,2H),8.41-8.06(m,3H),7 .79-7.57(m,5H),7.41-7.22(m,1H),7.13-6.96(m,2H),2.97(s,2H),2.05-1.98(m,6H),1.72-1.48(m,3H).

[0505] Example 58: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 58)

[0506] Following the synthetic method for compound 26, the product is a white solid with a yield of 56%, Ms(ESI, m\z): [M+H] + 466.25. 1H NMR(600MHz,DMSO-d6)12.80-12.64(m,2H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,3H),7.88-7 .82(m,1H)7.79-7.57(m,2H),7.41-7.22(m,2H),7.13-6.96(m,3H),2.97(s,2H),2.05(s,3H),1.70-1.40(m,3H).

[0507] Example 59: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-8-fluoro-1-naphthoamide (Compound 59)

[0508] Following the synthetic method for compound 26, the product is a white solid with a yield of 60%, Ms(ESI, m\z): [M+H] + 494.18. 1 H NMR(600MHz,DMSO-d6)12.89-12.35(m,1H),10.72-10.36(m,1H),10.45-9.89(m,1H),8.71-8.06(m,6H) ,7.79-7.57(m,5H),7.41-7.22(m,1H),7.13-6.96(m,2H),2.93(s,2H),2.19(s,3H),1.70-1.54(m,3H).

[0509] Example 60: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-((2-fluorophenyl)thio)-2-phenylacetamide (Compound 60)

[0510] Following the synthetic method for compound 26, the product is a white solid with a yield of 60%, Ms(ESI, m\z): [M+H] + 555.47. 1 H NMR(600MHz,DMSO-d6)δ12.90-12.52(m,1H),10.66-10.36(m,1H),10.14-9.79(m,1H),8.41-8.06(m,2H),7.89-7.80(m,2H) ),7.41-7.14(m,6H),7.13-6.96(m,2H),5.56-5.48(m,2H),2.56-2.34(m,2H),2.97(s,2H),2.05(s,3H),1.70-1.46(m,3H).

[0511] Example 61: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-((2-chlorobenzyl)oxy)benzamide (Compound 61)

[0512] Following the synthetic method for compound 26, the product is a white solid with a yield of 59%, Ms(ESI, m\z): [M+H] + 567.08. 1 H NMR (600MHz, DMSO-d6) δ12.88-12.55(m,1H),10.55-10.26(m,1H),10.04-9.79(m,1H),8.41-8.06(m,2H),7.89-7.80(m,3H) ),7.68-7.60(m,1H),7.41-7.14(m,6H),7.13-6.96(m,3H),5.56-5.40(m,2H),2.97(s,2H),2.05(s,3H),1.70-1.46(m,3H).

[0513] Example 62: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-2-((thiophen-3-ylmethyl)thio)benzamide (Compound 62)

[0514] Following the synthetic method for compound 26, the product is a white solid with a yield of 45%, Ms(ESI, m\z): [M+H] + 554.65. 1 H NMR(600MHz,DMSO-d6)δ12.76-12.68(m,1H),10.58-10.46(m,1H),10.24-9.79(m,1H),8.31-8.09(m,2H),7.93-7.85(m,2H),7.73-7 .65(m,3H),7.41-7.14(m,3H),7.13-6.96(m,2H),6.87-6.81(m,2H),5.05-4.60(m,2H),2.87(s,2H),2.06(s,3H),1.67-1.56(m,3H).

[0515] Example 63: 5-Amino-2-chloro-N-(5-(2-ethyl-5-(2-(2-(2-methoxyphenyl)amino)pyridin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)nicotinamide (Compound 63)

[0516] Following the synthetic method for compound 26, the product is a white solid with a yield of 50%, Ms(ESI, m\z): [M+H] + 557.17. 1 H NMR(500MHz,Chloroform-d)δ9.36(s,1H),8.27(d,J=7.5Hz,1H),7.97(d,J=1.4Hz,1H),7.88(d d,J=4.9,1.5Hz,1H),7.72(d,J=1.4Hz,1H),7.44(dd,J=7.5,1.5Hz,1H),7.37-7.30(m,2H),7.2 6(ddd,J=7.5,5.1,1.5Hz,1H),7.23-7.18(m,1H),7.08-7.00(m,2H),7.00-6.93(m,1H),5.22(d ,J=6.8Hz,1H),5.12(d,J=6.8Hz,1H),3.82(s,3H),2.91(q,J=8.0Hz,2H),1.40(t,J=8.0Hz,3H).

[0517] Example 64: 5-amino-N-(5-(2-ethyl-5-(2-(2-methoxyphenyl)amino)pyridin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)-2-(trifluoromethyl)benzamide (Compound 64)

[0518] Following the synthetic method for compound 26, the product is a white solid with a yield of 50%, Ms(ESI, m\z): [M+H] + 591.28. 1 H NMR(500MHz,Chloroform-d)δ9.99(s,1H),9.36(s,1H),8.27(d,J=7.5Hz,1H),7.89(dd,J=4.9,1.5 Hz,1H),7.53(d,J=7.5Hz,1H),7.41(dd,J=7.5,1.5Hz,1H),7.36-7.29(m,2H),7.29-7.26(m,1H),7. 21(dd,J=7.2,1.7Hz,1H),7.18(d,J=1.4Hz,1H),7.07-6.96(m,3H),6.96(dd,J=3.8,1.8Hz,1H),4.7 7(d,J=5.3Hz,1H),4.56(d,J=5.5Hz,1H),3.82(s,3H),2.91(q,J=8.0Hz,2H),1.40(t,J=8.0Hz,3H).

[0519] Example 65: N-(5-(2-ethyl-5-(2-(2-methoxyphenyl)amino)pyridin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)-6-fluoro-1H-indole-4-carboxamide (Compound 65)

[0520] Following the synthetic method for compound 26, the product is a white solid with a yield of 50%, Ms(ESI, m\z): [M+H] + 565.28. 1 H NMR(500MHz,Chloroform-d)δ9.98(d,J=8.4Hz,1H),9.80(s,1H),9.36(s,1H),8.27(d,J=7.5Hz,1H),7.89(dd,J=5.0,1.5Hz,1H),7.50(dd,J=8.0,1.5H z,1H),7.41(dd,J=7.5,1.5Hz,1H),7.36-7.18(m,6H),7.09-6.98(m,3H),6 .98-6.94(m,1H),3.82(s,3H),2.91(q,J=8.0Hz,2H),1.40(t,J=8.0Hz,3H).

[0521] Example 66: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-1-((2-cyanophenyl)sulfonyl)piperidine-4-carboxamide (Compound 66)

[0522] Following the synthetic method for compound 26, the product is a brown solid with a yield of 48%, and Ms(ESI,m\z):[M+H]. + 598.46. 1 H NMR(600MHz,DMSO-d6)δ12.89-12.64(m,1H),10.43-10.28(m,1H),10.06-9.80(m,1H),8.43-8.08(m,4H),7.89-7.80(m,4H),7 .41-7.14(m,1H),7.13-6.96(m,2H),3.56-3.11(m,4H),2.97(s,2H),2.33-2.27(m,1H),2.05-1.94(m,5H),1.70-1.48(m,7H).

[0523] Example 67: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-4-bromo-2-(1H-1,2,4-triazol-1-yl)benzamide (Compound 67)

[0524] Following the synthetic method for compound 26, the product is a brown solid with a yield of 56%, Ms(ESI,m\z):[M+H] + 572.68. 1 H NMR(600MHz,DMSO-d6)δ12.78-12.6(m,1H),10.55-10.29(m,1H),10.11-9.86(m,1H),9.34-9.18(m,1H)8.49-8. 06(m,3H),7.89-7.80(m,5H),7.41-7.14(m,1H),7.13-6.96(m,2H),2.90(s,2H),2.07(s,3H),1.74-1.46(m,3H).

[0525] Example 68: N-(3-(5-(2-acetamidopyridin-4-yl)-2-ethyl-1H-imidazol-4-yl)phenyl)-3-(((1-methyl-1H-imidazol-2-yl)thio)methyl)benzamide (Compound 68)

[0526] Following the synthetic method for compound 26, the product is a white solid with a yield of 50%, Ms(ESI, m\z): [M+H] + 552.38. 1 H NMR(600MHz,DMSO-d6)12.88-12.57(m,1H),10.45-10.28(m,1H),10.09-9.80(m,1H),8.45-8.06(m,4H),7.95-7.81(m,4H) ,7.41-7.16(m,2H),7.13-6.98(m,3H),4.95-4.45(m,2H),3.68-3.55(m,3H),2.97(s,2H),2.05(s,3H),1.70-1.49(m,3H).

[0527] Example 69: N-(3-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)isobutyramide (compound 69)

[0528] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 21%. ESI-MS: 526.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.53(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8. 25(t,J=2.2Hz,1H),7.98(t,J=2.2Hz,1H),7.68-7.62(m,1H),7.58-7.52(m,1H),7.45(dd,J=8. 5,7.9Hz,1H),7.42-7.36(m,2H),7.33(dd,J=8.1,2.2Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.03 (t,J=3.8Hz,2H),2.75(t,J=3.8Hz,2H),2.68-2.61(m,1H),2.60(s,6H),1.15(d,J=6.5Hz,6H).

[0529] Example 70: N-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)isobutyramide (Compound 70)

[0530] Step 1, Synthesis of ethyl 4-fluoro-3-isobutylaminobenzoate (70-1): Ethyl 3-amino-4-fluorobenzoate (1 eq, 10 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran. The solution was cooled to 0 °C, and triethylamine (2 eq, 20 mmol) was added, followed by dropwise addition of isobutyryl chloride (1.2 eq, 12 mmol). After reacting at 5–10 °C for 3 hours, the reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 70-1 (2.2 g, 8.8 mmol), a pale yellow oil, in 88% yield. ESI-MS: 254.1 [M+H]+.

[0531] Step 2, Synthesis of N-(5-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)isobutyramide (70-2): Following the synthetic method of A-41-1, a pale yellow solid was obtained. Yield: 32%. ESI-MS: 336.1 [M+H]+.

[0532] Step 3, Synthesis of N-(5-(5-(2-chloropyrimidin-4-yl)thiazolyl)-2-fluorophenyl)isobutyramide (70-3): Following the synthetic method in A-41-2, a pale yellow solid was obtained. Yield: 18%. ESI-MS: 376.1 [M+H]+.

[0533] Step 4, Synthesis of N-(4-(4-(3-aminophenyl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (compound 70): Following the synthetic method for compound 71, a pale yellow solid was obtained. Yield: 42%. ESI-MS: 544.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.28(s,1H),8.98(s,1H),8.93(s,1H),8.59(d,J=4.2Hz,1H),8.29-8.23(m,2H),7.60-7.53(m,1H),7.42-7.31(m,3H),7 .30-7.23(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),2.75( t,J=3.8Hz,2H),2.64(p,J=6.5Hz,1H),2.60(s,6H),1.16(d,J=6.5Hz,6H).

[0534] Example 71: (1-(2-(dimethylamino)ethyl)-N-(4-(4-(3-(ethylamino)-4-fluorophenyl)-2-(1-(ethanesulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)1H-indole-5-amine (Compound 71)

[0535] A-1 (1 eq, 0.5 mmol) and B-1 (2 eq, 1.0 mmol) were dissolved in 10 mL of n-butanol, and trifluoroacetic acid (1.5 eq, 0.75 mmol) was added. The mixture was reacted at 120 °C for 10 hours. After the reaction was complete, the reaction mixture was concentrated and purified by rapid preparative liquid chromatography to give compound 71 (202 mg, 0.3 mmol) as a yellow solid, in 60% yield. Ms(ESI, m\z): [M+H] + 677.68.

[0536] 1H NMR(600MHz,DMSO-d6)δ9.50(s,1H),8.28(d,J=5.2Hz,1H),7.95(s,1H),7.53(d,J=7.4Hz,1H) ,7.42-7.33(m,4H),7.22(t,J=9.0Hz,1H),6.78(s,1H),6.44-6.34(m,2H),4.25(t,J=6.8Hz,2H ),3.71(d,J=12.0Hz,2H),3.57-3.21(m,3H),3.09(q,J=7.3Hz,2H),3.01(t,J=11.8Hz,2H),2. 69(s,2H),2.32-2.23(m,9H),2.20(d,J=13.1Hz,2H),1.83-1.71(m,2H),1.24(t,J=7.5Hz,3H).

[0537] Example 72: N-(4-(4-(3-amino-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 72)

[0538] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 63% and Ms(ESI,m\z):[M+H]+649.26. 1 H NMR (600MHz, DMSO-d6) δ9.55 (s, 1H), 8.50 (d, J = 7.5Hz, 1H), 7.56-7.48 (m, 3H), 7.39-7.33 ( m,2H),7.31(d,J=7.3Hz,1H),7.21(t,J=7.7Hz,1H),6.49-6.34(m,2H),4.77(s,2H),4.10(t ,J=7.1Hz,2H),3.71(d,J=12.0Hz,2H),3.27-3.21(m,1H),3.09(q,J=7.3Hz,2H),3.01(t,J =11.8Hz,2H),2.70(t,J=7.0Hz,2H),2.41-2.25(m,5H),2.25(s,5H),1.29(t,J=7.5Hz,3H).

[0539] Example 73: N-(4-(4-(3-bromo-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 73)

[0540] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 56%, Ms(ESI,m\z):[M+H] + 712.58.

[0541] 1 H NMR (600MHz, DMSO-d6) δ9.58(s,1H),8.50(d,J=7.5Hz,1H),7.69(dd,J=4.9,1.5Hz,1H),7.54(d,J=7.5Hz,1H ),7.52-7.46(m,2H),7.36(d,J=7.5Hz,1H),7.31(d,J=7.4Hz,1H),7.29-7.24(m,1H),7.10(dd,J=7.5,1.5Hz, 1H),6.47(dd,J=7.6,1.5Hz,1H),4.10(t,J=7.1Hz,2H),3.71(d,J=12.0Hz,2H),3.27-3.21(m,1H),3.09(q,J= 7.3Hz,2H),3.01(t,J=11.8Hz,2H),2.70(t,J=7.0Hz,2H),2.41-2.24(m,4H),2.22(s,6H),1.34-1.27(m,3H).

[0542] Example 74: N-(4-(4-(3-chloro-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 74)

[0543] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 60%, Ms(ESI,m\z):[M+H] + 668.33.

[0544] 1H NMR (600MHz, DMSO-d6) δ9.50(s,1H),8.28(d,J=5.2Hz,1H),7.95(s,1H),7.53(d,J=7.4Hz,1H),7. 42-7.33(m,4H),7.22(t,J=9.0Hz,1H),6.44(d,J=5.2Hz,1H),6.34(d,J=3.0Hz,1H),4.25(t,J=6. 8Hz,2H),3.71(d,J=12.0Hz,2H),3.27-3.21(m,1H),3.09(q,J=7.3Hz,2H),3.01(t,J=11.8Hz,2H) ,2.69(s,2H),2.32-2.23(m,6H),2.20(d,J=13.1Hz,2H),1.83-1.71(m,2H),1.24(t,J=7.5Hz,3H).

[0545] Example 75: N-(4-(4-(3-amino-4-fluorophenyl)-2-ethyl-1H-imidazol-5-yl)pyridin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 75)

[0546] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 66%, Ms(ESI,m\z):[M+H] + 484.27.

[0547] 1 H NMR(500MHz,Chloroform-d)δ8.98(s,1H),8.26(d,J=7.5Hz,1H),7.58(t,J=1.7Hz,1H),7.56-7.47(m,2 H),7.34(d,J=1.4Hz,1H),7.32-7.25(m,2H),7.24(dd,J=7.5,1.5Hz,1H),6.99(ddd,J=7.5,5.1,1.5Hz,1 H),6.82(dd,J=5.1,1.5Hz,1H),6.47(dd,J=7.6,1.5Hz,1H),4.49(d,J=6.6Hz,1H),4.42(d,J=6.6Hz,1H) ,4.10(t,J=7.1Hz,2H),2.91(q,J=8.0Hz,2H),2.72(t,J=7.1Hz,2H),2.26(s,6H),1.41(t,J=8.0Hz,3H).

[0548] Example 76: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-(methylamino)phenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 76)

[0549] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 61%, Ms(ESI,m\z):[M+H] + 663.58.

[0550] 1 H NMR (600MHz, DMSO-d6) δ9.50 (s, 1H), 8.28 (d, J = 5.2Hz, 1H), 7.95 (s, 1H), 7.53 (d, J = 7.4Hz, 1H), 7.42-7. 33(m,4H),7.22(t,J=9.0Hz,1H),7.02(t,J=9.0Hz,1H), 6.44(d,J=5.2Hz,1H),6.34(d,J=3.0Hz,1H),4. 25(t,J=6.8Hz,2H),3.71(d,J=12.0Hz,2H),3.27-3.21(m,1H),3.09(q,J=7.3Hz,2H),3.01(t,J=11.8Hz ,2H),2.69(s,2H),2.32-2.23(m,9H),2.20(d,J=13.1Hz,2H),1.83-1.71(m,2H),1.24(t,J=7.5Hz,3H).

[0551] Example 77: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-(isopropylamino)phenyl)thiazo-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 77)

[0552] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 61%, Ms(ESI,m\z):[M+H] + 691.34. 1H NMR(600MHz,Chloroform-d)δ8.70(s,1H),8.50(d,J=7.5Hz,1H),7.62(ddd,J=7.5,5.0,1.6Hz,1H),7.58-7.50(m ,2H),7.43(t,J=1.5Hz,1H),7.36(d,J=7.5Hz,1H),7.34-7.28(m,2H),7.11(dd,J=7.5,1.5Hz,1H),6.47(dd,J=7.6 ,1.5Hz,1H),5.65(d,J=9.0Hz,1H),4.10(t,J=7.1Hz,2H),3.67(dhept,J=9.0,6.8Hz,1H),3.36(q,J=8.0Hz,2H),3 .33-3.12(m,5H),2.70(t,J=7.0Hz,2H),2.41-2.24(m,4H),2.22(s,6H),1.34-1.27(m,3H),1.20(d,J=6.8Hz,6H).

[0553] Example 78: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-(cyclopropylamino)phenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 78)

[0554] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 62%, Ms(ESI,m\z):[M+H] + 689.27. 1 H NMR (600MHz, Chloroform-d) δ8.70 (s, 1H), 8.50 (d, J = 7.5Hz, 1H), 7.62 (ddd, J = 7.5, 5.0, 1. 5Hz,1H),7.58-7.50(m,2H),7.43(t,J=1.5Hz,1H),7.36(d,J=7.5Hz,1H),7.34-7.29(m,2H) ,7.11(dd,J=7.5,1.5Hz,1H),6.49-6.43(m,2H),4.10(t,J=7.1Hz,2H),3.40-3.12(m,8H),2 .70(t,J=7.0Hz,2H),2.41-2.24(m,4H),2.22(s,6H),1.36-1.26(m,5H),0.92-0.82(m,2H).

[0555] Example 79: 5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)2-fluorophenol (Compound 79)

[0556] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 50%, Ms(ESI,m\z):[M+H] + 650.33. 1 H NMR (600MHz, Chloroform-d) δ9.03 (s, 1H), 8.70 (s, 1H), 8.50 (d, J = 7.5Hz, 1H), 7.66 (ddd, J=7.5,4.9,1.5Hz,1H),7.55-7.48(m,2H),7.36(d,J=7.5Hz,1H),7.31(d,J=7.3Hz,1H),7. 20-7.14(m,2H),7.14-7.08(m,1H),6.47(dd,J=7.6,1.5Hz,1H),4.10(t,J=7.1Hz,2H),3. 40-3.12(m,7H),2.70(t,J=7.0Hz,2H),2.41-2.25(m,5H),2.25(s,5H),1.34-1.27(m,3H).

[0557] Example 80: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 80)

[0558] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 50%, Ms(ESI,m\z):[M+H] + 664.26. 1H NMR (600MHz, DMSO-d6) δ9.51 (s, 1H), 8.31 (t, J = 4.2Hz, 1H), 7.96 (s, 1H), 7.41-7.28 (m, 5H), 7.14 (t,J=5.7Hz,1H),6.49(t,J=4.2Hz,1H),6.36(s,1H),4.30(s,2H),3.81(d,J=3.0Hz,3H),3.76-3. 70(m,2H),3.26(td,J=10.5,9.6,5.4Hz,1H),3.10(dt,J=9.6,6.9Hz,2H),3.02(t,J=12.0Hz,2H) ,2.83(s,2H),2.35(s,6H),2.21(d,J=13.0Hz,2H),1.77(q,J=12.4Hz,2H),1.24(t,J=2.9Hz,3H).

[0559] Example 81: 5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)2-fluorobenzonitrile (Compound 81)

[0560] Following the synthetic method of compound 71, the product is a yellow solid with a yield of 58%, Ms(ESI,m\z):[M+H] + 659.48.

[0561] 1 H NMR (600MHz, DMSO-d6) δ9.50(s,1H),8.34(d,J=5.2Hz,1H),7.95(s,1H),7.67(d,J=7.4Hz,1H),7. 42-7.33(m,4H),7.27(t,J=9.0Hz,1H),6.44(d,J=5.2Hz,1H),6.34(d,J=3.0Hz,1H),4.25(t,J=6. 8Hz,2H),3.71(d,J=12.0Hz,2H),3.27-3.21(m,1H),3.09(q,J=7.3Hz,2H),3.01(t,J=11.8Hz,2H) ,2.69(s,2H),2.32-2.23(m,6H),2.20(d,J=13.1Hz,2H),1.83-1.71(m,2H),1.28(t,J=7.5Hz,3H).

[0562] Example 82: N-(3-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)-3-methylbutyramide (Compound 82)

[0563] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 20%. ESI-MS: 540.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.33(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25 (t,J=2.0Hz,1H),7.89(t,J=1.9Hz,1H),7.71-7.65(m,1H),7.58-7.52(m,1H),7.49-7.42(m,1H), 7.42-7.36(m,2H),7.33(dd,J=8.1,1.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H) ,2.75(t,J=3.8Hz,2H),2.60(s,6H),2.31-2.26(m,1H),2.20-2.08(m,1H),0.96(d,J=6.9Hz,6H).

[0564] Example 83: N-(3-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)-2-fluoro-5-hydroxybenzamide (Compound 83)

[0565] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 12%. ESI-MS: 594.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.36(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H), 8.25(t,J=2.0Hz,1H),8.03(t,J=1.9Hz,1H),7.86-7.81(m,1H),7.58-7.52(m,1H),7.45(dd ,J=8.6,7.8Hz,1H),7.42-7.36(m,2H),7.36-7.29(m,2H),7.29-7.19(m,1H),6.95-6.88(m, 1H), 6.54 (dd, J=5.0, 2.2Hz, 1H), 4.03 (t, J=3.8Hz, 2H), 2.75 (t, J=3.8Hz, 2H), 2.60 (s, 6H).

[0566] Example 84: N-(3-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)-2,2-difluorocyclopropane-1-carboxamide (Compound 84)

[0567] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 28%. ESI-MS: 560.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.52(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H ),8.25(t,J=2.0Hz,1H),7.98(t,J=1.9Hz,1H),7.67-7.61(m,1H),7.58-7.52(m,1H),7.49 -7.42(m,1H),7.42-7.36(m,2H),7.33(dd,J=8.2,1.9Hz,1H),6.54(dd,J=5.0,2.2Hz,1H) ,4.09-3.98(m,2H),3.13-3.00(m,1H),2.81-2.69(m,2H),2.61-2.39(m,2H),2.60(s,6H).

[0568] Example 85: (S)-N-(3-(5-(2-((2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)oxetane-2-carboxamide (Compound 85)

[0569] Following the synthesis method in 4-4, a pale yellow solid was obtained. The yield was 35%. ESI-MS: 540.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H ),7.96(t,J=1.9Hz,1H),7.69-7.64(m,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36(m,2H) ,7.33(dd,J=8.2,1.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.47(t,J=5.2Hz,1H),4.09-3.94(m,3H), 3.84(dt,J=12.3,5.7Hz,1H),2.81-2.69(m,2H),2.60(s,6H),2.40-2.30(m,1H),2.14-2.04(m,1H).

[0570] Example 86: N-(3-(5-(2-((2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl-4-yl)phenyl)-3-hydroxycyclohexane-1-carboxamide (Compound 86)

[0571] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 11%. ESI-MS: 582.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.35(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J=2.0Hz ,1H),7.98(t,J=1.9Hz,1H),7.67-7.61(m,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36(m,2H),7.33 (dd,J=8.2,1.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.09-3.98(m,2H),3.86-3.77(m,1H),2.81-2.69(m,2H) ,2.60(s,6H),2.59-2.50(m,1H),2.04-1.95(m,1H),1.95-1.84(m,1H),1.81-1.58(m,5H),1.52-1.39(m,1H).

[0572] Example 87: N-(3-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)-1-methylpyrrolidine-2-carboxamide (Compound 87)

[0573] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 17%. ESI-MS: 567.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.28(s,1H),9.22(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.97( t,J=1.9Hz,1H),7.64(ddd,J=7.9,2.0,1.3Hz,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36(m,2H),7.33(dd,J= 8.1,1.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.09-3.98(m,2H),3.92(tq,J=4.7,1.5Hz,1H),2.90(ddd,J=12.5,5.0,3.5 Hz,1H),2.85-2.69(m,3H),2.60(s,6H),2.35(d,J=1.4Hz,3H),2.09-2.00(m,1H),2.00-1.91(m,1H),1.85-1.71(m,2H).

[0574] Example 88: (S)-N-(3-(5-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)tetrahydrofuran-3-carboxamide (Compound 88)

[0575] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 20%. ESI-MS: 554.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.36(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.98 (t,J=1.9Hz,1H),7.67-7.61(m,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36(m,2H),7.33(dd,J=8.2,1.9Hz,1 H),6.54(dd,J=5.1,2.2Hz,1H),4.09-3.98(m,2H),3.94-3.84(m,2H),3.78(ddd,J=12.5,4.6,2.7Hz,1H),3.73-3.66(m ,1H),3.04(dtd,J=6.4,4.3,2.3Hz,1H),2.81-2.69(m,2H),2.60(s,6H),2.25(td,J=4.8,3.1Hz,1H),2.08-2.00(m,1H).

[0576] Example 89: N-(3-(5-(2-((2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl-4-yl)phenyl)-1-methylazazolbut-2-carboxamide (Compound 89)

[0577] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 24%. ESI-MS: 553.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.35(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J=2.0H z,1H),7.97(t,J=1.9Hz,1H),7.67-7.61(m,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36(m,2H),7. 33(dd,J=8.1,1.9Hz,1H),6.54(dd,J=5.0,2.2Hz,1H),4.09-3.98(m,3H),3.01(dt,J=12.3,8.5Hz,1H),2.9 2-2.82(m,1H),2.81-2.69(m,2H),2.60(s,6H),2.36(d,J=1.4Hz,3H),2.32-2.21(m,1H),2.08-1.98(m,1H).

[0578] Example 90: 2-Cyclopropyl-N-(3-(5-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)propionamide (Compound 90)

[0579] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 24%. ESI-MS: 552.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.28(s,1H),9.10(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J= 2.0Hz,1H),7.98(t,J=1.9Hz,1H),7.67-7.61(m,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36 (m,2H),7.33(dd,J=8.1,1.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.09-3.98(m,2H),2.81-2.69(m,2H) ,2.60(s,6H),2.59-2.54(m,1H),1.93-1.83(m,1H),1.07(dd,J=5.3,1.5Hz,3H),0.47(d,J=6.1Hz,4H).

[0580] Example 91: N-(3-(5-(2-((2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)-3-fluorocyclobutane-1-carboxamide (Compound 91)

[0581] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 21%. ESI-MS: 556.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.42-9.39(m,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t, J=2.0Hz,1H),7.98(t,J=2.0Hz,1H),7.67-7.61(m,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36(m ,2H),7.33(dd,J=8.2,1.9Hz,1H),7.27(s,0H),6.54(dd,J=5.1,2.2Hz,1H),4.69-4.54(m,1H),4.03(t,J=3 .8Hz,2H),2.85(p,J=6.1Hz,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.16-2.02(m,2H).

[0582] Example 92: 2-(1-Cyclopropylethoxy)-N-(3-(5-(2-)((2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)acetamide (Compound 92)

[0583] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 21%. ESI-MS: 582.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.66(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H ),7.91(t,J=1.9Hz,1H),7.69(dt,J=7.9,1.6Hz,1H),7.58-7.52(m,1H),7.45(dd,J=8.5,7.9Hz,1H),7.42-7.36 (m,2H),7.33(dd,J=8.1,1.9Hz,1H),6.54(dd,J=5.0,2.2Hz,1H),4.19(s,2H),4.09-3.98(m,2H),3.53(dq,J=5. 9,4.2Hz,1H),2.81-2.69(m,2H),2.60(s,6H),1.46-1.35(m,1H),1.19(dd,J=4.3,1.5Hz,3H),0.54-0.33(m,4H).

[0584] Example 93: N-(3-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl-4-yl)phenyl)-2-(1-(fluoromethyl)cyclopropyl)acetamide (Compound 93)

[0585] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 21%. ESI-MS: 570.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.28(d,J=1.1Hz,2H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J=2 .0Hz,1H),7.90(t,J=1.9Hz,1H),7.71-7.65(m,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36 (m,2H),7.33(dd,J=8.2,1.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.25(s,1H),4.16(s,1H),4.03(t, J=3.8Hz,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.52(s,2H),1.33-1.21(m,2H),0.68-0.56(m,2H).

[0586] Example 94: N-(3-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)phenyl)tetrahydro-2H-pyran-4-carboxamide (Compound 94)

[0587] Following the synthesis method in 4-4, a pale yellow solid was obtained. Yield: 32%. ESI-MS: 568.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.38(s,1H),9.28(s,1H),8.92(s,1H),8.59(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.98 (t,J=1.9Hz,1H),7.64(ddd,J=7.9,1.9,1.2Hz,1H),7.58-7.52(m,1H),7.49-7.42(m,1H),7.42-7.36(m,2H),7.33(dd,J =8.2,1.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.74-3.68(m,1H),3.71-3.66(m,1H),3.61(ddd,J =12.4,6.0,3.4Hz,2H),2.75(t,J=3.8Hz,2H),2.67(p,J=5.9Hz,1H),2.60(s,6H),1.99-1.90(m,2H),1.87-1.78(m,2H).

[0588] Example 95: N-(4-(4-(3-((cyclopropylmethyl)amino)-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 95)

[0589] Following the synthetic method for compound 71, a pale yellow solid was obtained. Yield: 47%. ESI-MS: 70 3.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.67(ddd,J=8.8,4.9,2.2Hz,1H),7.42 -7.31(m,3H),7.27(d,J=5.1Hz,1H),7.12(dd,J=9.0,8.0Hz,1H),7.04(dd,J=5.0,2.2Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),6.01 (t,J=4.8Hz,1H),4.03(t,J=3.8Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.30(dd,J=4.8,3.8Hz,2H),3.22-3.10(m,5H),2. 75(t,J=3.8Hz,2H),2.60(s,6H),2.34-2.14(m,4H),1.29(t,J=9.5Hz,3H),1.23(ttd,J=5.5,3.8,1.9Hz,1H),0.43-0.26(m,4H).

[0590] Example 96: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-)(3-fluoropentyl)amino)phenyl)thiazo-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 96)

[0591] Following the synthetic method for compound 71, a pale yellow solid was obtained. Yield: 41%. ESI-MS: 735.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.67(ddd,J=8.8,4.9,2. 2Hz,1H),7.42-7.31(m,4H),7.27(d,J=5.1Hz,1H),7.15(dd,J=8.9,7.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),5.64 (d,J=7.7Hz,1H),4.54-4.40(m,1H),4.06-3.98(m,3H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,5H),2 .75(t,J=3.8Hz,2H),2.60(s,6H),2.34-2.14(m,4H),2.13-2.00(m,1H),1.98-1.80(m,5H),1.29(t,J=9.5Hz,3H).

[0592] Example 97: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-(spiro[2,4]heptane-5-ylamino)phenyl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 97)

[0593] Following the synthetic method of compound 71, the product is a pale yellow solid. Yield: 41%. ESI-MS: 743.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.67(ddd,J=8.8,4.9,2.2Hz,1H),7.42-7.31(m, 4H),7.27(d,J=5.1Hz,1H),7.15(dd,J=8.9,7.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),5.56(d,J=8.2Hz,1H),4.03(t,J=3.8Hz,2H),3.77(d tt,J=8.2,5.0,3.2Hz,1H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,5H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.33-2.16(m,4H) ,1.95-1.87(m,1H),1.87-1.80(m,1H),1.65-1.53(m,3H),1.49-1.40(m,1H),1.29(t,J=9.5Hz,3H),1.24-1.16(m,2H),0.70-0.60(m,2H).

[0594] Example 98: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-)((tetrahydro-2H-pyran-4-yl)amino)phenyl)thiazo-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 98)

[0595] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 733.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.67(ddd,J=8.8,4.9,2.2Hz,1H),7.4 2-7.31(m,4H),7.27(d,J=5.1Hz,1H),7.15(dd,J=8.9,7.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),5.71(d,J=8.4Hz,1H),4.03(t, J=3.8Hz,2H),3.94(dp,J=8.6,4.9Hz,1H),3.59(t,J=4.3Hz,4H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,5H),2.75 (t,J=3.8Hz,2H),2.60(s,6H),2.34-2.14(m,4H),1.93(dtd,J=12.4,4.9,4.1Hz,2H),1.70-1.61(m,2H),1.29(t,J=9.5Hz,3H).

[0596] Example 99: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-(trifluoromethoxy)phenyl)thiazo-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 99)

[0597] Following the synthetic method for compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 718.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.51(dd,J =5.0,2.3Hz,1H),7.45(ddd,J=8.8,5.0,2.3Hz,1H),7.39(d,J=8.1Hz,1H),7.37-7.31(m,2H),7.31 -7.26(m,1H),6.54(dd,J=5.0,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2 H),3.22-3.10(m,5H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.34-2.14(m,4H),1.29(t,J=9.5Hz,3H).

[0598] Example 100: 1-(2-(dimethylamino)ethyl)-N-(4-(4-(3-ethyl-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 100)

[0599] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 662.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.58(ddd,J=8.6,4.9,2.2H z,1H),7.50(ddt,J=5.0,2.1,1.0Hz,1H),7.42-7.31(m,2H),7.27(d,J=5.1Hz,1H),7.14(dd,J=8.7,8.0Hz,1H),6.5 4(dd,J=5.0,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,5H),2.75(t,J=3 .7Hz,2H),2.69(qd,J=7.1,1.1Hz,2H),2.60(s,6H),2.34-2.14(m,4H),1.29(t,J=9.5Hz,3H),1.22(t,J=7.1Hz,3H).

[0600] Example 101: N-(4-(4-(3-cyclopropoxy-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 101)

[0601] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 690.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.4 7(ddd,J=8.6,4.9,2.2Hz,1H),7.42-7.22(m,6H),6.54(dd,J=5.1,2.2Hz,1H),4.48(p,J=4. 6Hz,1H),4.03(t,J=3.8Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,5H),2.7 5(t,J=3.8Hz,2H),2.60(s,6H),2.34-2.14(m,4H),1.69-1.56(m,4H),1.29(t,J=9.5Hz,3H).

[0602] Example 102: N-(4-(4-(3-(cyclopropoxy)-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 102)

[0603] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 704.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.65-7.56(m,2H),7.40 -7.31(m,3H),7.27(d,J=5.1Hz,1H),7.19-7.12(m,1H),6.54(dd,J=5.1,2.2Hz,1H),4.65(d,J=0.9Hz,2H),4.03( t,J=3.8Hz,2H),3.62(p,J=4.4Hz,1H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,5H),2.75(t,J=3.8Hz, 2H),2.60(s,6H),2.34-2.14(m,4H),1.61-1.54(m,1H),1.57-1.49(m,1H),1.46-1.34(m,2H),1.33-1.26(m,3H).

[0604] Example 103: N-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)acetamide (compound 103)

[0605] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 791.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),9.23(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.96( dd,J=5.0,2.2Hz,1H),7.54(ddd,J=8.8,5.0,2.2Hz,1H),7.39(d,J=8.1Hz,1H),7.37-7.32(m,2H),7.30-7. 23(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3. 10(m,5H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.34-2.24(m,2H),2.23-2.15(m,5H),1.29(t,J=9.5Hz,3H).

[0606] Example 104: N-(5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)acetamide (compound 104)

[0607] Following the synthetic method for compound 71, the product is a pale yellow solid. Yield: 43%. ESI-MS: 691.38 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ9.64(s,1H),8.70(s,1H),8.45(d,J=7.5Hz,1H),7.98(dd,J=5.0,1.5 Hz,1H),7.55(d,J=7.5Hz,1H),7.45-7.38(m,2H),7.38-7.34(m,1H),7.34-7.28(m,2H),7.11(dd,J =7.5,1.5Hz,1H),6.47(dd,J=7.6,1.5Hz,1H),4.10(t,J=7.1Hz,2H),3.36(q,J=8.0Hz,2H),3.33-3 .12(m,5H),2.70(t,J=7.0Hz,2H),2.41-2.24(m,4H),2.22(s,6H),2.12(s,3H),1.34-1.27(m,3H).

[0608] Example 105: N-(5-(5-(2-(1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)propionamide (Compound 105)

[0609] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 70 5.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),9.10(s,1H),8.66(d,J=4.2Hz,1H),8.27-8.22(m,2H),7.54(d dd,J=8.8,5.0,2.2Hz,1H),7.39(d,J=8.1Hz,1H),7.37-7.32(m,2H),7.30-7.23(m,2H),6.54(dd,J=5.0,2 .2Hz,1H),4.03(t,J=3.8Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,5H),2.75(t,J=3.8Hz ,2H),2.60(s,6H),2.54(q,J=7.1Hz,2H),2.34-2.14(m,4H),1.29(t,J=9.5Hz,3H),1.18(t,J=7.1Hz,3H).

[0610] Example 106: N-(5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 106)

[0611] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 749.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.66(d,J=4.2Hz,1H),8.30-8.23(m,2H),7.5 4(ddd,J=8.8,5.0,2.2Hz,1H),7.42-7.31(m,3H),7.30-7.23(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.62 (dp,J=46.3,5.9Hz,1H),4.03(t,J=3.8Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,6H ),2.81(p,J=6.2Hz,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.39-1.98(m,4H),1.29(t,J=9.5Hz,3H).

[0612] Example 107: 1-(2-(dimethylamino)ethyl)-N-(4-(4-(4-(4-fluoro-3-methoxyphenyl)-2-(4-methylcyclohexyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 107)

[0613] Step 1, Synthesis of 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(4-methylcyclohexyl)thiazole (107-1): Following the synthetic method in A-21, a yellow solid was obtained in 51% yield. Ms(ESI,m\z):[M+H] + 418.27.

[0614] Step 2, synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(4-(4-(4-fluoro-3-methoxyphenyl)-2-(4-methylcyclohexyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (compound 107): Following the method used for compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 585.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.47(ddd,J=8.8,4.9,2 .2Hz,1H),7.42-7.24(m,6H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.07(p,J=5.4Hz, 1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),1.96(ddt,J=12.3,8.1,5.3Hz,2H),1.81(ddt,J=12.3,8.0,5.4Hz,2H), 1.62(ddt,J=12.3,8.1,5.5Hz,2H),1.54-1.45(m,1H),1.40(ddt,J=12.1,8.1,5.5Hz,2H),0.91(d,J=6.1Hz,3H).

[0615] Example 108: N-(5-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)oxetane-2-carboxamide (Compound 108)

[0616] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 733.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.96(s,1H),8.66(d,J=4.2Hz,1H),8.30(dd,J=5.0,2.2Hz,1H),8.25( t,J=2.0Hz,1H),7.56-7.49(m,1H),7.39(d,J=8.1Hz,1H),7.37-7.32(m,2H),7.31-7.24(m,2H),6.54(dd,J=5.0, 2.2Hz,1H),4.50(t,J=3.8Hz,1H),4.06-3.96(m,3H),3.92-3.84(m,1H),3.48-3.38(m,2H),3.22-3.10(m,5H),2. 75(t,J=3.8Hz,2H),2.60(s,6H),2.43-2.34(m,1H),2.34-2.15(m,4H),2.15-2.06(m,1H),1.29(t,J=9.5Hz,3H).

[0617] Example 109: N-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)-3,3,3-trifluoropropionamide (Compound 109)

[0618] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 759.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.67(s,1H),9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H ),8.02(dd,J=5.0,2.2Hz,1H),7.57-7.50(m,1H),7.39(d,J=8.1Hz,1H),7.37-7.32(m,2H),7.30-7. 23(m,2H),6.54(dd,J=5.0,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.48-3.38(m,2H),3.21-3.12(m,5H), 3.09(q,J=9.0Hz,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.34-2.14(m,4H),1.29(t,J=9.5Hz,3H).

[0619] Example 110: N-(5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-ethylthiazolyl-4-yl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 110)

[0620] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 60 2.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.66(d,J=4.2Hz,1H),8.29-8.23(m,2H) ,7.57-7.50(m,1H),7.39(d,J=8.1Hz,1H),7.37-7.32(m,2H),7.30-7.23(m,2H),6.54(dd,J=5.1, 2.2Hz,1H),4.73-4.50(m,1H),4.03(t,J=3.8Hz,2H),2.96(q,J=6.7Hz,2H),2.81(p,J=6.2Hz,1H) ,2.75(t,J=3.8Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.16-2.02(m,2H),1.33(t,J=6.7Hz,3H).

[0621] Example 111: NN-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(isopropylamino)thiazolyl-4-yl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 111)

[0622] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 631.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.31-8.23(m,2H ),7.58-7.51(m,1H),7.42-7.37(m,2H),7.36-7.31(m,1H),7.30-7.23(m,2H),6.54(dd,J=5.1, 2.2Hz,1H),6.05(d,J=6.2Hz,1H),4.73-4.52(m,1H),4.10-3.98(m,3H),2.81(p,J=6.2Hz,1H), 2.75(t,J=3.8Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.16-2.02(m,2H),1.25(d,J=5.3Hz,6H).

[0623] Example 112: N-(5-(2-(cyclobutylmethyl)-5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 112)

[0624] Following the synthetic method of compound 71, it is a pale yellow solid. Yield 40%. ESI-MS: 642.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.66(d,J=4.2Hz,1H),8.29-8.23(m,2H),7.54(ddd,J=8.8,5 .0,2.2Hz,1H),7.39(d,J=8.1Hz,1H),7.37-7.32(m,2H),7.30-7.23(m,2H),6.54(dd,J=5.0,2.2Hz,1H),4.62(dp,J= 46.3,5.9Hz,1H),4.03(t,J=3.8Hz,2H),2.97(dd,J=14.5,5.1Hz,1H),2.90(dd,J=14.5,5.1Hz,1H),2.81(p,J=6.2Hz ,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.20-2.02(m,3H),1.85-1.68(m,4H),1.68-1.57(m,2H).

[0625] Example 113: N-(5-(2-(2,2-difluorocyclopropyl)-5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 113)

[0626] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 650.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.66(d,J=4.2Hz,1H),8.30-8.23 (m,2H),7.57-7.50(m,1H),7.39(d,J=8.1Hz,1H),7.37-7.32(m,2H),7.30-7.23(m,2H),6. 54(dd,J=5.1,2.2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4.09-3.98(m,2H),3.66(tt,J=20. 9,4.4Hz,1H),2.86-2.64(m,4H),2.66-2.53(m,7H),2.35-2.21(m,2H),2.16-2.02(m,2H).

[0627] Example 114: N-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-morpholinthiazolyl-4-yl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 114)

[0628] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 659.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.27-8.21(m,2H),7.5 2(ddd,J=8.8,5.0,2.2Hz,1H),7.39(d,J=8.1Hz,1H),7.36-7.30(m,1H),7.30-7.23(m,2H),6.54(dd,J =5.1,2.2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4.03(t,J=3.8Hz,2H),3.86-3.77(m,4H),3.67-3.51(m ,4H),2.81(p,J=6.2Hz,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.16-2.02(m,2H).

[0629] Example 115: N-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(4-methylpiperazin-1-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 115)

[0630] Following the synthetic method of compound 71, it is a pale yellow solid. Yield 40%. ESI-MS: 672.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.27-8.21(m,2H),7.52(d dd,J=8.8,5.0,2.2Hz,1H),7.39(d,J=8.1Hz,1H),7.36-7.30(m,1H),7.30-7.23(m,2H),6.54(dd,J=5.0,2 .2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4.03(t,J=3.8Hz,2H),3.65(qdd,J=12.5,5.9,3.5Hz,4H),2.84- 2.77(m,3H),2.75(t,J=3.8Hz,2H),2.68-2.61(m,2H),2.60(s,6H),2.35-2.21(m,5H),2.16-2.04(m,2H).

[0631] Example 116: N-(5-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(4-methylpiperazin-1-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 116)

[0632] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 671.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.27-8.21(m,2H),7.52(d dd,J=8.8,5.0,2.2Hz,1H),7.39(d,J=8.1Hz,1H),7.36-7.30(m,1H),7.30-7.23(m,2H),6.54(dd,J=5.0,2 .2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4.03(t,J=3.8Hz,2H),3.65(qdd,J=12.5,5.9,3.5Hz,4H),2.84- 2.77(m,3H),2.75(t,J=3.8Hz,2H),2.68-2.61(m,2H),2.60(s,6H),2.35-2.21(m,5H),2.16-2.04(m,2H).

[0633] Example 117: N-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(methylthio)thiazo-4-yl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 117)

[0634] Following the synthetic method for compound 71, the product is a pale yellow solid. Yield: 40%. ESI-MS: 620.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.0Hz,1H),8.30-8.23(m, 2H),7.58-7.51(m,1H),7.42-7.37(m,2H),7.33(dd,J=8.1,1.9Hz,1H),7.30-7.23(m,2H),6.5 4(dd,J=5.1,2.2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4.03(t,J=3.8Hz,2H),2.81(p,J=6.2H z,1H),2.78(s,3H),2.75(t,J=3.7Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.16-2.02(m,2H).

[0635] Example 118: N-(5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 118)

[0636] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 684.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.27-8.21(m,2H),7.56- 7.49(m,1H),7.39(d,J=8.1Hz,1H),7.35-7.31(m,2H),7.30-7.22(m,2H),6.54(dd,J=5.0,2.2Hz,1H),4 .62(dp,J=46.3,5.9Hz,1H),4.09-3.98(m,4H),3.68(dd,J=12.4,4.3Hz,2H),3.42-3.33(m,2H),2.86-2 .69(m,3H),2.60(s,6H),2.39(t,J=1.5Hz,3H),2.35-2.21(m,2H),2.17-2.03(m,3H),1.99-1.91(m,1H).

[0637] Example 119: N-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-methoxythiazolyl-4-yl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 119)

[0638] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 604.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.27-8.22(m,2H),7. 53(ddd,J=8.8,4.9,2.2Hz,1H),7.39(d,J=8.1Hz,1H),7.36-7.31(m,2H),7.29-7.22(m,2H),6.54(d d,J=5.1,2.2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4.03(t,J=3.8Hz,2H),3.98(s,2H),2.81(p,J=6. 2Hz,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.09(ddt,J=25.2,12.2,6.0Hz,2H).

[0639] Example 120: N-(5-(2-cyclohexyl-5-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 120)

[0640] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 656.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.66(d,J=4.2Hz,1H),8.30-8.23(m,2H),7.54(ddd,J=8.8,5.0,2.2Hz ,1H),7.39(d,J=8.1Hz,1H),7.37-7.32(m,2H),7.30-7.23(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4 .03(t,J=3.8Hz,2H),3.13-3.05(m,1H),2.81(p,J=6.2Hz,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.09(dd t,J=25.2,12.2,6.0Hz,2H),2.00-1.88(m,2H),1.83-1.68(m,4H),1.61-1.48(m,3H),1.42(dddd,J=11.0,8.4,4.9,2.0Hz,1H).

[0641] Example 121: N-(5-(2-acetamido-5-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)-3-fluorocyclobutane-1-carboxamide (Compound 121)

[0642] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 631.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.31-8.23(m,2H),7 .55(ddd,J=9.0,5.0,2.3Hz,1H),7.42-7.37(m,2H),7.36-7.31(m,1H),7.30-7.23(m,2H),6.54(dd, J=5.1,2.2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4.03(t,J=3.8Hz,2H),2.81(p,J=6.2Hz,1H),2.75 (t,J=3.8Hz,2H),2.60(s,6H),2.35-2.21(m,2H),2.20(s,3H),2.09(ddt,J=25.2,12.2,6.0Hz,2H).

[0643] Example 122: N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-(3-fluorocyclobutane-1-carboxamide)phenyl)thiazolyl-2-yl)cyclohexanecarboxamide (Compound 122)

[0644] Step 1, Synthesis of intermediate N-(5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-(3-fluorocyclobutane-1-carbamate)phenyl)thiazo-2-yl)cyclohexaneformamide (122-1): Following the synthetic method for compound 26, a yellow solid was obtained in 75% yield. Ms(ESI,m\z):[M+H] + 532.26.

[0645] Step two, following the synthetic method for compound 71, yielded a pale yellow solid. Yield 40%. ESI-MS: 699.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.31-8.23(m,2H),7.55(ddd,J=9.0,5.0,2.3H z,1H),7.42-7.37(m,2H),7.36-7.31(m,1H),7.30-7.23(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4. 03(t,J=3.8Hz,2H),2.81(p,J=6.2Hz,1H),2.75(t,J=3.8Hz,2H),,2.60(s,6H),2.58(p,J=5.7Hz,1H),2.35-2.21(m,2H),2.0 9(ddt,J=25.2,12.2,6.0Hz,2H),1.91(ddt,J=12.2,8.6,5.7Hz,2H),1.74-1.62(m,2H),1.62-1.50(m,3H),1.47-1.36(m,3H).

[0646] Example 123: N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-(3-fluorocyclobutane-1-carbamate)phenyl)thiazolyl-2-yl)tetrahydro-2H-pyran-4-carboxamide (Compound 123)

[0647] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 701.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.94(s,1H),8.65(d,J=4.2Hz,1H),8.31-8.23(m,2H),7.55(ddd,J=9.0,5.0,2.3Hz ,1H),7.42-7.37(m,2H),7.36-7.31(m,1H),7.30-7.23(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.62(dp,J=46.3,5.9Hz,1H),4.03 (t,J=3.8Hz,2H),3.65(dddd,J=44.1,12.4,6.0,3.5Hz,4H),2.81(p,J=6.2Hz,1H),2.75(t,J=3.8Hz,2H),2.70(p,J=5.9Hz,1H ),2.60(s,6H),2.35-2.21(m,2H),2.09(ddt,J=25.2,12.2,6.0Hz,2H),1.97-1.87(m,2H),1.80(dtd,J=12.3,5.9,3.4Hz,2H).

[0648] Example 124: 1-(2-(dimethylamino)ethyl)-N-(4-(2-ethyl-4-(4-fluoro-3-methoxyphenyl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 124)

[0649] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 517.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.47(ddd,J=8.8,5.0,2.3Hz,1H),7.41-7.24(m,6H),6 .54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),2.96(q,J=6.7Hz,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),1.33(t,J=6.7Hz,3H).

[0650] Example 125: 1-(2-(dimethylamino)ethyl)-N-(4-(4-(4-(4-fluoro-3-methoxyphenyl)-2-(methylthio)thiazo-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 125)

[0651] Step 1, Synthesis of intermediate 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(methylthio)thiazole (125-1): Following the synthetic method in A-21, a yellow solid was obtained in 73% yield. Ms(ESI,m\z):[M+H] + 368.03.

[0652] Step two, following the synthetic method for compound 71, yielded a pale yellow solid. Yield 40%. ESI-MS: 535.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.0Hz,1H),8.25(t,J=2.0Hz,1H),7.48(ddd,J=8.8,5.0,2.3Hz,1 H),7.42-7.24(m,6H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),2.80-2.72(m,4H),2.60(s,6H).

[0653] Example 126: N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)acetamide (Compound 126)

[0654] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 517.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.49(ddd,J=8.8,5.0,2.2Hz,1H),7.42-7.36(m, 3H),7.36-7.24(m,3H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.20(s,3H).

[0655] Example 127: 1-(2-(dimethylamino)ethyl)-N-(4-(4-(4-(4-fluoro-3-methoxyphenyl)-2-(1-methylpiperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 127)

[0656] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 586.2 [M+H]+. 1 H NMR (500MHz, Chloroform-d) δ9.27 (s, 1H), 8.66 (d, J = 4.2Hz, 1H), 8.25 (t, J = 2. 0Hz,1H),7.47(ddd,J=8.8,4.9,2.2Hz,1H),7.40-7.25(m,6H),6.54(dd,J=5.1 ,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.15(p,J=4.9Hz,1H),2.75(t ,J=3.8Hz,2H),2.72-2.60(m,4H),2.60(s,6H),2.30(s,3H),2.15-2.03(m,4H).

[0657] Example 128: 1-(4-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)piperidin-1-yl)ethane-1-one (Compound 128)

[0658] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 614.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0H z,1H),7.47(ddd,J=8.8,4.9,2.2Hz,1H),7.42-7.24(m,6H),6.54(dd,J=5.1,2.2 Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.68-3.42(m,4H),3.18(p,J=5.0Hz, 1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.16(td,J=7.5,4.9Hz,4H),2.07(s,3H).

[0659] Example 129: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-ethylpiperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 129)

[0660] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 600.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz, 1H),7.47(ddd,J=8.8,4.9,2.2Hz,1H),7.42-7.22(m,6H),6.54(dd,J=5.1,2.2Hz,1 H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.15(p,J=4.9Hz,1H),2.88-2.71(m,4H),2. 66-2.47(m,10H),2.09(td,J=7.2,4.9Hz,4H),1.04(d,J=14.0Hz,1H),1.04(s,1H).

[0661] Example 130: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 130)

[0662] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 664.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1 H),7.47(ddd,J=8.8,4.9,2.2Hz,1H),7.42-7.25(m,6H),6.54(dd,J=5.1,2.2Hz,1H) ,4.03(t,J=3.8Hz,2H),3.90(s,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10 (m,5H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.34-2.14(m,4H),1.29(t,J=9.5Hz,3H).

[0663] Example 131: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-amine (Compound 131)

[0664] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 665.3 [M+H]+.1H NMR (500MHz, Chloroform-d) δ 9.24-9.20 (m, 1H), 8.63 (s, 1H), 8.50 (d, J = 7.5Hz, 1H), 8.40 (d, J = 1.4Hz, 1H), 7.62 (ddd, J = 7.5, 4.9, 1.5Hz, 1H), 7.36 (d, J = 7.5Hz, 1H), 7.27 (d, J = 7.5Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.12 (dd, J = 5.0, 1.5Hz, 1H), 5.93 (dd, J = 7.5,1.5Hz,1H),4.20(t,J=7.1Hz,2H),3.86(s,3H),3.36(q,J=8.0Hz,2H),3.32-3.27(m,2H),3.25(d,J=7.3Hz,1H),3.22(d, J=7.0Hz,1H),3.21-3.18(m,1H),3.18-3.12(m,1H),2.68(t,J=7.1Hz,2H),2.41-2.24(m,4H),2.22(s,6H),1.34-1.27(m,3H).

[0665] Example 132: 1-(2-(dimethylamino)ethyl)-N-(4-(2-ethyl-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 132)

[0666] Following the synthetic method of compound 13, the product is a yellow solid with a yield of 50% and Ms(ESI,m\z):[M+H]+500.25. 1 H NMR (600MHz, Chloroform-d) δ8.85 (s, 1H), 8.45 (d, J = 7.5Hz, 1H), 7.57 (ddd, J = 7. 5,4.9,1.5Hz,1H),7.53-7.45(m,2H),7.31(d,J=7.5Hz,1H),7.27-7.20(m,2H),7 .15-7.07(m,2H),6.47(dd,J=7.6,1.5Hz,1H),4.10(t,J=7.1Hz,2H),3.87(s,3H) ,2.92(q,J=8.0Hz,2H),2.72(t,J=7.1Hz,2H),2.25(s,6H),1.41(t,J=8.0Hz,3H).

[0667] Example 133: 4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (Compound 133)

[0668] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 652.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.71-8.64(m,2H),7.58-7.52(m,2H),7.47(ddd,J=8.8,4. 9,2.2Hz,1H),7.40-7.34(m,2H),7.30(dd,J=8.7,8.0Hz,1H),6.89-6.83(m,2H),3.90(s ,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.27-3.10(m,9H),2.80(ddd,J=12.3,5.7,3. 8Hz,2H),2.57(ddd,J=12.4,5.7,3.8Hz,2H),2.34-2.14(m,10H),1.29(t,J=9.5Hz,3H).

[0669] Example 134: 5-(5-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-2-fluorobenzonitrile (Compound 134)

[0670] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 649.2 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.72(s,1H),8.66(d,J=4.2Hz,1H),8.18(dd,J=5.0,2.3Hz,1H),7. 80(ddd,J=8.6,4.9,2.2Hz,1H),7.52-7.46(m,2H),7.39(dd,J=8.6,7.9Hz,1H),7.36(d,J=4.2Hz ,1H),6.88-6.83(m,2H),3.52(t,J=6.5Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10( m,5H),2.98(s,2H),2.74(t,J=6.5Hz,2H),2.60(s,6H),2.33-2.15(m,5H),1.29(t,J=9.5Hz,3H).

[0671] Example 135: 5-(2-(1-(ethylsulfonyl)piperidin-4-yl)-5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorobenzonitrile (Compound 135)

[0672] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 647.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.71-8.64(m,2H),8.18(dd,J=5.0,2.3Hz,1H),7.80(d dd,J=8.6,4.9,2.2Hz,1H),7.58-7.52(m,2H),7.42-7.34(m,1H),6.89-6.83(m,2H), 3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.27-3.10(m,9H),2.80(ddd,J=12.3,5.7,3.8H z,2H),2.57(ddd,J=12.4,5.7,3.7Hz,2H),2.34-2.14(m,10H),1.29(t,J=9.5Hz,3H).

[0673] Example 136: N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1-(2-(pyrrolidine-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-5-amine (Compound 136)

[0674] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 690.4 [M+H]+.1H NMR (500MHz, Chloroform-d) δ 9.24–9.20 (m, 1H), 8.63 (s, 1H), 8.50 (d, J = 7.5 Hz, 1H), 8.40 (d, J = 1.4 Hz, 1H), 7.63 (ddd, J = 7.5, 5.0, 1.6 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 7.23–7.16 (m, 1H), 7.12 (dd, J = 5.0, 1.5 Hz, 1H), 5.93 (dd, J = 7.5, 1.5 Hz). ,1H),4.15(t,J=7.1Hz,2H),3.88(s,3H),3.36(q,J=8.0Hz,2H),3.32-3.27(m,2H),3.25(d,J=7.3Hz,1H),3.22(d,J=7.0Hz,1H), 3.17(td,J=14.3,7.1Hz,2H),2.73(t,J=7.1Hz,2H),2.65-2.56(m,4H),2.41-2.24(m,4H),1.84-1.74(m,4H),1.34-1.27(m,3H).

[0675] Example 137: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)oxazol-5-yl)pyrimidin-2-yl)-1H-indole-4-amine (Compound 137)

[0676] Step 1, Synthesis of tert-butyl-4-(oxazol-2-yl)piperidine-1-carboxylate (137-1): 2-Bromooxazole (1 eq, 3 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)piperidine-1-carboxylate (1.2 eq, 3.6 mmol) were dissolved in 15 mL of 1,4-dioxane, and sodium carbonate (3 eq, 6 mmol) and tetrakis(triphenylphosphine)palladium (0.1 eq, 0.3 mmol) were added. Under N2 protection, the reaction was heated to 90 °C for 4 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Preparative liquid chromatography (HPLC) purification yielded 137-1 (530 mg, 2.1 mmol), a pale yellow oil, in 70% yield. ESI-MS: 253.15 [M+H]+.

[0677] Step 2, Synthesis of 2-(piperidin-4-yl)oxazole (137-2): Tert-butyl-4-(oxazol-2-yl)piperidin-1-carboxylate (1 eq, 2.1 mmol) was dissolved in 3 mL of hydrochloric acid / ethyl acetate and reacted overnight at room temperature. The pH was neutralized to 8 with sodium carbonate, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 137-2 (288 mg, 1.9 mmol), a pale yellow oil, in 90% yield. ESI-MS: 153.1 [M+H]+.

[0678] Step 3, Synthesis of 2-(1-(ethylsulfonyl)piperidin-4-yl)oxazole (137-3): 2-(piperidin-4-yl)oxazole (1 eq, 1.9 mmol) was dissolved in 10 mL of tetrahydrofuran, and triethylamine (5 eq, 9.5 mmol) was added. The mixture was cooled to 0 °C, and ethylsulfonyl chloride (1.5 eq, 2.85 mmol) was added. The reaction was carried out at room temperature for 4 hours, quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-liquid chromatography was performed to obtain 137-3 (417 mg, 1.71 mmol), a pale yellow oil, in 90% yield. ESI-MS: 245.1 [M+H]+.

[0679] Step 4, Synthesis of 4,5-dibromo-2-(1-(ethylsulfonyl)piperidin-4-yl)oxazole (137-4): Following the synthetic method in 1-3, a pale yellow solid was obtained in 70% yield. ESI-MS: 401.1 [M+H]+.

[0680] Step 5, Synthesis of 4-bromo-2-(1-(ethylsulfonyl)piperidin-4-yl)oxazole (137-5): Following the synthetic methods in steps 1-4, a pale yellow oil was obtained in 70% yield. ESI-MS: 323.0 [M+H]+.

[0681] Step 6, Synthesis of 2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)oxazole (137-6): Following the synthetic methods in 1-5, a pale yellow oil was obtained in 70% yield. ESI-MS: 369.1 [M+H]+.

[0682] Step 7, Synthesis of 5-bromo-2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)oxazole (137-7): Following the synthetic method in 6-4, a pale yellow oil was obtained in 40% yield. ESI-MS: 447.0 [M+H]+.

[0683] Step 8, Synthesis of 2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)oxazole (137-8): 5-bromo-2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)oxazole (1 eq, 1 mmol) was dissolved in 5 mL of 1,4-dioxane. Dipinacol borate (1.1 eq, 1.1 mmol), potassium phosphate (3 eq, 3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.025 eq, 0.025 mmol) were added. Under N2 protection, the reaction was carried out at 90 °C for 4 hours. Cool to room temperature, add water, extract the light organic phase with dichloromethane, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 137-8 (159 mg, 0.32 mmol), a yellow oil, in 32% yield. ESI-MS: 495.2 [M+H]+.

[0684] Step nine, synthesis of 5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)oxazole (137-9): Following the synthesis method of 137-1, a yellow oil was obtained in 21% yield. ESI-MS: 481.1 [M+H]+.

[0685] Step 10, Synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)piperidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)oxazol-5-yl)pyrimidin-2-yl)-1H-indole-4-amine (compound 137): Following the method used for compound 71, a pale yellow solid was obtained. Yield: 21%. ESI-MS: 648.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.04(s,1H),8.64(d,J=4.6Hz,1H),7.55(d,J=4.6Hz,1H),7.36 (ddt,J=6.9,3.2,1.6Hz,4H),7.34-7.26(m,2H),7.17(s,1H),6.87(d,J=4.9Hz,1H),4.06(t,J =3.7Hz,2H),3.90(s,2H),3.39(td,J=12.1,9.2Hz,2H),3.20-3.05(m,5H),2.75(t,J=3.8Hz,2 H),2.60(s,6H),2.22-2.10(m,2H),2.05(tdd,J=12.1,9.2,5.5Hz,2H),1.29(t,J=9.5Hz,3H).

[0686] Example 138: 1-(2-(dimethylamino)ethyl)-N-(4-(5-(1-(ethylsulfonyl)piperidin-4-yl)-2-(4-fluoro-3-methoxyphenyl)-1H-pyrrolo-3-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 138)

[0687] Following the synthetic method of compound 139, the product is a yellow solid with a yield of 53% and Ms(ESI,m\z):[M+H]+646.39. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=7.5Hz,2H),7.55-7.48(m,2H),7.32(dd,J=7.4,5.0Hz, 2H),7.19-7.13(m,1H),7.11(dd,J=7.5,1.4Hz,2H),7.07(dd,J=5.0,1.5Hz,1H),6.47(dd,J=7.5 ,1.4Hz,1H),6.35(s,1H),4.10(t,J=7.1Hz,2H),3.86(s,3H),3.40-3.28(m,4H),3.22(dt,J=12 .5,7.1Hz,2H),3.13-3.04(m,1H),2.70(t,J=7.0Hz,2H),2.31-2.15(m,10H),1.34-1.27(m,3H).

[0688] Example 139: (1-(2-(dimethylamino)ethyl)-N-(4-(4-(3-(ethylamino)-4-fluorophenyl)-2-(1-(ethanesulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 139)

[0689] A-43 (1 eq, 0.5 mmol) and B-1 (2 eq, 1.0 mmol) were dissolved in 10 mL of n-butanol, and trifluoroacetic acid (1.5 eq, 0.75 mmol) was added. The mixture was reacted at 120 °C for 10 hours. After the reaction was complete, the reaction mixture was concentrated and purified by rapid preparative liquid chromatography to obtain C-1 (161 mg, 0.25 mmol), a yellow solid, in 50% yield. Ms(ESI, m\z): [M+H] + 647.68. 1H NMR(600MHz,Chloroform-d)δ8.85(s,1H),8.55(d,J=7.5Hz,1H),7.62-7.56(m,2H),7.55-7.48(m,2H ),7.40(d,J=7.5Hz,1H),7.31(d,J=7.3Hz,1H),7.22(t,J=7.7Hz,1H),7.15(dd,J=5.0,1.5Hz,1H),7. 11(dd,J=7.5,1.5Hz,1H),6.47(dd,J=7.6,1.5Hz,1H),4.53-4.44(m,1H),4.10(t,J=7.1Hz,2H),3.86 (s,3H),3.40-3.25(m,6H),2.70(t,J=7.0Hz,2H),2.22(s,6H),2.07-1.90(m,4H),1.34-1.27(m,3H).

[0690] Example 140: (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(piperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (compound 140)

[0691] Step 1, Synthesis of methyl 4-fluoro-3-carboxybenzoate (140-2): 4-fluoro-3-carboxybenzoic acid (1 eq, 4.8 mmol) was dissolved in 10 mL of anhydrous N,N-dimethylformamide, and potassium carbonate (1.2 eq, 5.7 mmol) and iodomethane (1.2 eq, 5.7 mmol) were added. After stirring at room temperature for 12 hours, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 140-2 (710 mg, 3.9 mmol), a pale yellow oil, in 82% yield. ESI-MS: 183.0 [M+H]+.

[0692] Step 2, Synthesis of methyl 4-fluoro-3-(hydroxymethyl)benzoate (140-3): Methyl 4-fluoro-3-carboxylbenzoate (1 eq, 3.9 mmol) was dissolved in 5 mL of anhydrous methanol. The solution was cooled to 0 °C, sodium borohydride (1.1 eq, 4.29 mmol) was added, and the reaction was brought to room temperature for 1 hour. The reaction was quenched with water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 140-3 (700 mg, 3.8 mmol), a pale yellow oil, in 98% yield. ESI-MS: 185.1 [M+H]+.

[0693] Step 3, Synthesis of methyl 3-((tert-butyldimethylsilyl)oxy)methyl)-4-fluorobenzoate (140-4): Methyl 4-fluoro-3-(hydroxymethyl)benzoate (1 eq, 3.8 mmol) was dissolved in 5 mL of anhydrous dichloromethane, and imidazole (1.2 eq, 4.56 mmol) and tert-butyldimethylchlorosilane (1.2 eq, 4.56 mmol) were added. The mixture was stirred at room temperature for 12 hours. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid pre-liquid chromatography purification yielded 140-4 (679 mg, 2.28 mmol), a red solid, in 60% yield. ESI-MS: 299.4 [M+H]+.

[0694] Step 4, Synthesis of 1-(3-((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one (140-5): Following the synthetic method in A-41-1, a pale yellow solid was obtained. Yield: 80%. ESI-MS: 395.13 [M+H]+

[0695] Step 5, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (140-6): Following the synthetic method in A-41-2, a pale yellow solid was obtained. Yield: 18%. ESI-MS: 405.1 [M+H]+.

[0696] Step 6, Synthesis of (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)methanol (140): Following the synthesis method of compound 71, a pale yellow solid was obtained. Yield 42%. ESI-MS: 572.2 [M+H]+.1H NMR (500MHz, Chloroform-d) δ 9.27 (s, 1H), 8.66 (d, J = 4.2Hz, 1H), 8.25 (t, J = 2.2Hz, 1H), 7.63-7.55 (m, 2H), 7.39 (d, J = 8.1Hz, 1H), 7.37-7.31 (m, 2H), 7.05 (dd, J = 8.6, 7.9Hz, 1H),6.54(dd,J=5.1,2.2Hz,1H),4.63(dd,J=5.5,1.1Hz,2H),4.08-4.01(m,3H),3.17- 3.08(m,2H),3.04-2.88(m,4H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.07-1.95(m,4H).

[0697] Example 141: (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-methylpiperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (compound 141)

[0698] Step 1, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(1-methylpiperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (141-1): 140-6 (1 eq, 1 mmol) was dissolved in 2 mL of methanol, and 40% formaldehyde aqueous solution (2 eq, 2 mmol), acetic acid (1.5 eq, 1.5 mmol), and sodium cyanoborohydride (2 eq, 2 mmol) were added. After stirring at room temperature for 12 hours, the mixture was quenched with saturated ammonium chloride aqueous solution and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-liquid chromatography was performed to obtain 141-1 (293 mg, 0.7 mmol), a pale yellow oil, in 70% yield. ESI-MS: 419.1 [M+H]+.

[0699] Step 2, Synthesis of (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-methylpiperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (compound 141): Following the synthesis method of compound 71, a pale yellow solid was obtained. Yield: 42%. ESI-MS: 586.3 [M+H]+.1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.2Hz,1H),7. 63-7.55(m,2H),7.39(d,J=8.1Hz,1H),7.37-7.31(m,2H),7.05(dd,J=8.6,7.9Hz,1H),6.5 4(dd,J=5.0,2.2Hz,1H),4.63(dd,J=5.5,1.1Hz,2H),4.08-4.01(m,3H),3.15(p,J=4.9Hz, 1H),2.75(t,J=3.8Hz,2H),2.71-2.61(m,4H),2.60(s,6H),2.30(s,3H),2.16-2.03(m,4H).

[0700] Example 142: (5-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(6-methyl-6-azabicyclo[3.1.1]heptane-3-yl)thiazolyl)-2-fluorophenyl)methanol (Compound 142)

[0701] Step 1, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(6-methyl-6-azabicyclo[3.1.1]heptane-3-yl)thiazolyl)-2-fluorophenyl)methanol (142-1): Following the synthesis method of A-41-2, a pale yellow solid was obtained. Yield: 18%. ESI-MS: 431.1 [M+H]+.

[0702] Step 2, synthesis of (5-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(6-methyl-6-azabicyclo[3.1.1]heptane-3-yl)thiazolyl)-2-fluorophenyl)methanol (compound 142): Following the synthesis method of compound 71, a pale yellow solid was obtained. Yield 42%. ESI-MS: 598.3 [M+H]+.1H NMR (500MHz, Chloroform-d) δ9.27 (s, 1H), 8.66 (d, J = 4.2Hz, 1H), 8.25 (t, J = 2.2Hz, 1H), 7.63-7.55 (m, 2H), 7.39 (d, J = 8. 1Hz,1H),7.37-7.31(m,2H),7.05(dd,J=8.6,7.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.63(dd,J=5.5,1.1Hz,2H),4.08-4 .01(m,3H),3.29(p,J=5.1Hz,1H),3.16-3.07(m,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.45(t,J=1.6Hz,3H),2.20(ddd ,J=12.4,6.7,5.1Hz,2H),1.93(dt,J=12.3,5.5Hz,1H),1.83(ddd,J=12.4,6.7,5.1Hz,2H),1.64(dt,J=12.5,5.5Hz,1H).

[0703] Example 143: (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-morpholinthiazolyl-4-yl)-2-fluorophenyl)methanol (compound 143)

[0704] Step 1, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-morpholinthiazolyl-4-yl)-2-fluorophenyl)methanol (143-1): Following the synthesis method of A-41-2, a pale yellow solid was obtained. Yield: 18%. ESI-MS: 407.1 [M+H]+.

[0705] Step 2, synthesis of (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-morpholinthiazolyl-4-yl)-2-fluorophenyl)methanol (compound 143): Following the synthesis method of compound 71, a pale yellow solid was obtained. Yield 42%. ESI-MS: 574.2 [M+H]+.1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.2Hz,1H),7.58(ddd,J=8.5,5 .0,1.9Hz,1H),7.58-7.53(m,1H),7.36-7.30(m,2H),7.27(d,J=5.1Hz,1H),7.05(dd,J=8.7,8.0Hz,1H),6. 54(dd,J=5.1,2.2Hz,1H),4.63(dd,J=5.5,1.1Hz,2H),4.08-4.01(m,3H),3.82(dd,J=5.0,4.2Hz,4H),3.67 -3.61(m,1H),3.63-3.59(m,1H),3.59-3.55(m,1H),3.58-3.52(m,1H),2.75(t,J=3.8Hz,2H).2.60(s,6H).

[0706] Example 144: (5-(5-(2-((1-(2-(aza-1-yl)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(piperidin-1-yl)thiazo-4-yl)-2-fluorophenyl)methanol (compound 144)

[0707] Step 1, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(piperidin-1-yl)thiazolyl-4-yl)-2-fluorophenyl)methanol (144-1): Following the synthetic method in A-41-2, a pale yellow solid was obtained. Yield: 18%. ESI-MS: 405.1 [M+H]+.

[0708] Step 2, synthesis of (5-(5-(2-((1-(2-(aza-1-yl)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(piperidin-1-yl)thiazo-4-yl)-2-fluorophenyl)methanol (compound 144): Following the synthesis method of compound 71, a pale yellow solid was obtained. Yield 42%. ESI-MS: 584.2 [M+H]+.1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.2Hz,1H),7.61-7.53(m,2H),7.36- 7.30(m,2H),7.27(d,J=5.1Hz,1H),7.05(dd,J=8.7,8.0Hz,1H),6.54(dd,J=5.1,2.3Hz,1H),4.63(dd,J=5.5,1.1 Hz,2H),4.05(t,J=5.5Hz,1H),4.01(t,J=3.5Hz,2H),3.59(td,J=6.7,3.9Hz,4H),2.85(t,J=3.5Hz,2H),2.74(t, J=5.9Hz,2H),2.65(t,J=5.8Hz,2H),1.87(dp,J=15.4,5.8Hz,2H),1.73(tq,J=6.6,4.0Hz,4H),1.69-1.60(m,2H).

[0709] Example 145: (5-(5-(2-((1-(2-((azatidine-1-yl)ethyl)-1H-indolezol-5-yl)amino)pyrimidin-4-yl)-2-(piperidin-1-yl)thiazo-4-yl)-2-fluorophenyl)methanol (compound 145)

[0710] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 42%. ESI-MS: 584.3 [M+H]+.1H NMR (500MHz, Chloroform-d) δ 9.24 (s, 1H), 8.65 (d, J = 4.2Hz, 1H), 7.97 (d, J = 2.0Hz, 1H), 7.79 (td, J = 2.0, 0.8Hz, 1H), 7.61–7.53 (m, 2H), 7.45–7.37 (m, 2H), 7.32 (d, J = 4.2Hz, 1H), 7.05 (dd, J = 8.7, 8.0Hz, 1H), 4.63 (dd, J = 5.5, 1.1Hz, 2H) ,4.31(t,J=3.5Hz,2H),4.05(t,J=5.5Hz,1H),3.59(td,J=6.7,3.9Hz,4H),2.91(t,J=3.5Hz,2H),2.71(d,J=11.7Hz, 1H),2.71(s,1H),2.62(t,J=5.8Hz,2H),1.87(dp,J=15.5,5.9Hz,2H),1.73(tq,J=6.6,4.0Hz,4H),1.69-1.60(m,2H).

[0711] Example 146: (5-(5-(2-(1-(2-(aza-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)pyrimidin-4-yl)-2-(piperidin-1-yl)thiazolyl-4-yl)-2-fluorophenyl)methanol (compound 146)

[0712] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 42%. ESI-MS: 584.3 [M+H]+.1H NMR (500MHz, Chloroform-d) δ 8.97 (s, 1H), 8.65 (d, J = 4.2Hz, 1H), 8.28 (d, J = 2.0Hz, 1H), 7.78 (t, J = 2.1Hz, 1H), 7.61–7.53 (m, 2H), 7.32 (d, J = 4.2Hz, 1H), 7.05 (dd, J = 8.7, 8.0Hz, 1H), 5.93 (dd, J = 6.4, 2.2Hz, 1H), 4.63 (dd, J = 5.5, 1. 1Hz,2H),4.22(t,J=3.9Hz,2H),4.05(t,J=5.5Hz,1H),3.59(td,J=6.7,3.9Hz,4H),2.82(t,J=3.9Hz,2H),2.72(t, J=5.9Hz,2H),2.63(t,J=5.9Hz,2H),1.87(dp,J=15.4,5.8Hz,2H),1.73(tq,J=6.7,4.0Hz,4H),1.69-1.60(m,2H).

[0713] Example 147: N-(4-(2-(tert-butyl)-4-(4-fluoro-3-(trifluoromethoxy)phenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 147)

[0714] Step 1, Synthesis of 2-(2-chloropyrimidin-4-yl)-1-(4-fluoro-3-(trifluoromethoxy)phenyl)ethyl-1-one (147-2): Following the synthetic method of A-41-1, a pale yellow solid was obtained. Yield: 80%. ESI-MS: 335.1 [M+H]+

[0715] Step 2, Synthesis of 2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-(trifluoromethoxy)phenyl)thiazole (147-3): Following the synthetic method of A-41-2, a pale yellow solid was obtained. Yield: 18%. ESI-MS: 432.1 [M+H]+.

[0716] Step 3, Synthesis of N-(4-(2-(tert-butyl)-4-(4-fluoro-3-(trifluoromethoxy)phenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (compound 147): Following the synthetic method for compound 71, a pale yellow solid was obtained. Yield: 42%. ESI-MS:599.2[M+H]+.1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.69(d,J=4.2Hz,1H),8.25(s,1H),7.51(dd,J=5.1,1.7Hz,1H),7.48- 7.24(m,6H),6.54(dd,J=5.1,2.3Hz,1H),4.03(t,J=3.8Hz,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),1.49(s,9H).

[0717] Example 148: 1-(2-(aza-1-yl)ethyl)-N-(4-(2-(tert-butyl)-4-(4-fluoro-3-methoxyphenyl)thiazo-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 148)

[0718] Step 1, Synthesis of 2-(2-chloropyrimidin-4-yl)-1-(4-fluoro-3-methoxyphenyl)ethyl-1-one (148-2): Following the synthetic method of A-41-1, a pale yellow solid was obtained. Yield: 80%. ESI-MS: 281.1 [M+H]+

[0719] Step 2, Synthesis of 2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole (148-3): Following the synthetic method of A-41-2, a pale yellow solid was obtained. Yield: 18%. ESI-MS: 378.1 [M+H]+.

[0720] Step 3, Synthesis of 1-(2-(aza-1-yl)ethyl)-N-(4-(2-(tert-butyl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (compound 148): Following the synthetic method for compound 71, a pale yellow solid was obtained. Yield: 42%. ESI-MS: 557.2 [M+H]+.1H NMR (500MHz, Chloroform-d) δ9.27 (s, 1H), 8.69 (d, J = 4.2Hz, 1H), 8.25 (t, J = 2. 2Hz,1H),7.47(ddd,J=8.8,5.1,1.8Hz,1H),7.42-7.26(m,5H),6.54(dd,J=5.1, 2.2Hz,1H),4.01(t,J=3.5Hz,2H),3.90(s,2H),2.85(t,J=3.5Hz,2H),2.74(t, J=5.9Hz,2H),2.65(t,J=5.9Hz,2H),1.87(dp,J=15.4,5.8Hz,2H),1.49(s,9H).

[0721] Example 149: N-(5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)acetamide (compound 149)

[0722] Following the synthetic method of compound 71, a pale yellow solid was obtained. Yield: 40%. ESI-MS: 691.2 [M+H]+.1H NMR (500MHz, Chloroform-d) δ 9.27 (s, 1H), 9.23 (s, 1H), 8.66 (d, J = 4.2Hz, 1H), 8.25 (t, J = 2.2Hz, 1H), 7.96 (dd, J = 5.0, 1.9Hz, 1H), 7.54 (ddd, J = 9.0, 5.1, 2.0Hz, 1H), 7.39 (d, J = 8.1Hz, 1H), 7.37–7.32 (m, 2H), 7.30–7. 23(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3. 10(m,5H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.33-2.24(m,2H),2.23-2.15(m,5H),1.29(t,J=9.5Hz,3H).

[0723] Example 150: (5-(2-(tert-butyl)-5-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (Compound 150)

[0724] Step 5, Synthesis of (5-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (150-1): 1-(3-((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one (1 eq, 2.3 mmol) was dissolved in 5 mL of anhydrous N,N-dimethylformamide. The mixture was cooled to 0 °C, and N-bromosuccinimide (1 eq, 2.3 mmol) was added. After reacting at 0 °C for 1 hour, 2,2-dimethylpropanethioamide (1.5 eq, 3.45 mmol) was added. The mixture was then heated to room temperature for 3 hours. The reaction was quenched with water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 150-1 (600 mg, 1.6 mmol), a pale yellow oil, in 72% yield. ESI-MS: 378.1 [M+H]+.

[0725] Step 6, Synthesis of (5-(2-(tert-butyl)-5-(2-(4-(((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (compound 150): 1 eq, 1 mmol of (5-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (1 eq, 1 mmol) was dissolved in 5 mL of anhydrous n-butanol. N1-(2-(dimethylamino)ethyl)-N1-methylphenyl-1,4-diamine (1 eq, 1 mmol) and trifluoroacetic acid (1.5 eq, 1.5 mmol) were added. The reaction was carried out at 120 °C for 16 hours. After cooling to room temperature, the mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded compound 150 (321 mg, 0.6 mmol) as a yellow solid, in 60% yield. ESI-MS: 535.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.74-8.67(m,1H),7.63-7.54(m,1H),7.52-7.46(m,1H),7.05(dd,J=8.6,7.9Hz,0H),6.88-6.83(m,1H), 4.63(dd,J=5.5,1.0Hz,1H),4.05(t,J=5.5Hz,0H),3.52(t,J=6.6Hz,1H),2.98(s,1H),2.74(t,J=6.5Hz,1H),2.60(s,6H),2.34(s,2H).

[0726] Example 151: (5-(2-(tert-butyl)-5-(2-(1-(2-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (compound 151)

[0727] Following the synthetic method of compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 545.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.69(d,J=4.2Hz,1H),8.25(t,J=2.0H z,1H),7.62-7.54(m,2H),7.39(d,J=8.1Hz,1H),7.37-7.31(m,2H),7.27(d,J=5. 1Hz, 1H), 7.05 (dd, J=8.6, 7.8Hz, 1H), 6.54 (dd, J=5.1, 2.0Hz, 1H), 4.63 (dd, J=5. 5,1.1Hz,2H),4.08-4.01(m,3H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.28(s,5H).

[0728] Example 152: (5-(2-(tert-butyl)-5-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (compound 152)

[0729] Following the synthetic method of compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 565.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ8.69(d,J=4.2Hz,1H),8.01(s,1H),7.63-7.54(m,2H ),7.37-7.31(m,2H),7.05(dd,J=8.6,7.9Hz,1H),6.73(dd,J=8.2,2.0Hz,1H),6.30 (d,J=1.9Hz,1H),4.63(dd,J=5.5,1.0Hz,2H),4.05(t,J=5.5Hz,1H),3.88(s,2H),3 .52(t,J=6.5Hz,2H),3.00(s,2H),2.74(t,J=6.5Hz,2H),2.60(s,6H),2.34(s,5H).

[0730] Example 153: (5-(5-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (compound 153)

[0731] Step 1, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)thiazolyl-4-yl)-2-fluorophenyl)methanol (153-2): 1-(3-((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-2-(2-chloropyrimidin-4-yl)ethyl-1-one (1 eq, 2.3 mmol) was dissolved in 5 mL of anhydrous N,N-dimethylformamide. The temperature was lowered to 0 °C, and N-bromosuccinimide (1 eq, 2.3 mmol) was added. After reacting at 0 °C for 1 hour, tert-butyl 4-aminomethylthioylpiperidin-1-carboxylic acid (1.5 eq, 3.45 mmol) was added. The temperature was then raised to 90 °C and reacted for 16 hours. The mixture was quenched with water and extracted with dichloromethane. The aqueous phase was concentrated by evaporation under vacuum and rapidly purified by preparative liquid chromatography to give 153-2 (557 mg, 1.3 mmol), a pale yellow oil, in 60% yield. ESI-MS: 405.1 [M+H]+.

[0732] Step 2, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (153-3): (5-(5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (1 eq, 1.3 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran. The mixture was cooled to 0 °C, and triethylamine (5 eq, 6.5 mmol) and ethylsulfonyl chloride (1.5 eq, 1.95 mmol) were added. The reaction was allowed to proceed at room temperature for 4 hours. The reaction was quenched with water, and the mixture was extracted with dichloromethane. The aqueous phase was concentrated by evaporation under vacuum, and rapid pre-liquid chromatography was performed to obtain 153-3 (580 mg, 1.17 mmol), a pale yellow solid, in 90% yield. ESI-MS: 498.0 [M+H]+.

[0733] Step 3, Synthesis of (5-(5-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (153): Following the synthesis method of compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 654.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ8.72(s,1H),8.66(d,J=4.2Hz,1H),7.63-7.55(m,2H),7.52-7.46 (m,2H),7.35(s,0H),7.05(dd,J=8.6,7.9Hz,1H),6.88-6.83(m,2H),4.63(dd,J=5.5,1.1Hz,2H) ,4.05(t,J=5.5Hz,1H),3.52(t,J=6.5Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m ,5H),2.98(s,2H),2.74(t,J=6.5Hz,2H),2.60(s,6H),2.34-2.14(m,5H),1.29(t,J=9.5Hz,3H).

[0734] Example 154: (5-(5-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)-2-fluorophenyl)methanol (compound 154)

[0735] Following the synthetic method of compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 684.3 [M+H]+.1 H NMR(500MHz,Chloroform-d)δ8.66(d,J=4.2Hz,1H),8.01(s,1H),7.63-7.54(m,2H),7.38-7.31(m,2H), 7.05(dd,J=8.6,7.9Hz,1H),6.73(dd,J=8.2,2.0Hz,1H),6.30(d,J=1.9Hz,1H),4.63(dd,J=5.5,1.1Hz,2 H),4.05(t,J=5.5Hz,1H),3.88(s,2H),3.52(t,J=6.5Hz,2H),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22 -3.10(m,5H),3.00(s,2H),2.74(t,J=6.5Hz,2H),2.60(s,6H),2.34-2.14(m,5H),1.29(t,J=9.5Hz,3H).

[0736] Example 155: (5-(5-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)-2-(piperidin-1-yl)thiazolyl)-2-fluorophenyl)methanol (compound 155)

[0737] Step 1, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(piperidin-1-yl)thiazolyl-4-yl)-2-fluorophenyl)methanol (155-2): Following the synthesis method of 150-1, a yellow solid was obtained in 60% yield. ESI-MS: 405.1 [M+H]+.

[0738] Step 2, Synthesis of (5-(5-(2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)-2-(piperidin-1-yl)thiazolyl)-2-fluorophenyl)methanol (compound 155): Following the synthesis method of compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 562.1 [M+H]+.

[0739] 1H NMR(500MHz,Chloroform-d)δ8.65(d,J=4.2Hz,0H),7.61-7.53(m,1H),7.52-7.46(m,1H),7.3 2(d,J=4.2Hz,0H),7.05(dd,J=8.7,7.9Hz,0H),6.88-6.83(m,1H),4.63(dd,J=5.5,1.1Hz,1H) ,4.05(t,J=5.5Hz,0H),3.59(td,J=6.7,3.9Hz,2H),3.52(t,J=6.6Hz,1H),2.98(s,1H),2.74( t,J=6.5Hz,1H),2.60(s,6H),1.73(tq,J=6.6,4.1Hz,2H),1.64(dtt,J=10.0,6.8,4.1Hz,1H).

[0740] Example 156: (5-(5-(2-((1-(2-(2-(dimethylamino)ethyl)-1H-indolezol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazo-4-yl)-2-fluorophenyl)methanol (compound 156)

[0741] Following the synthetic method of compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 665.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.24(s,1H),8.66(d,J=4.2Hz,1H),7.97(d,J=2.0Hz,1H),7.81-7.76( m,1H),7.63-7.55(m,2H),7.45-7.37(m,2H),7.36(d,J=4.2Hz,1H),7.05(dd,J=8.6,7.9Hz,1H),4.63 (dd,J=5.5,1.1Hz,2H),4.32(t,J=3.8Hz,2H),4.05(t,J=5.5Hz,1H),3.43(ddd,J=12.3,10.1,7.3Hz, 2H),3.22-3.10(m,5H),2.86(t,J=3.8Hz,2H),2.60(s,6H),2.34-2.14(m,4H),1.29(t,J=9.5Hz,3H).

[0742] Example 157: (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(piperidin-1-yl)thiazolyl-4-yl)-2-fluorophenyl)methanol (compound 157)

[0743] Following the synthetic method for compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 572.3 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.61-7 .53(m,2H),7.36-7.30(m,2H),7.27(d,J=5.1Hz,1H),7.05(dd,J=8.7,7.9Hz,1H),6.54(dd,J=5 .1,2.2Hz,1H),4.63(dd,J=5.5,1.1Hz,2H),4.08-4.01(m,3H),3.59(td,J=6.7,3.9Hz,4H),2.7 5(t,J=3.8Hz,2H),2.60(s,6H),1.73(tq,J=6.6,4.1Hz,4H),1.64(dtt,J=10.0,6.8,4.1Hz,2H).

[0744] Example 158: (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)pyrrolidine-3-yl)thiazolyl)-2-fluorophenyl)methanol (compound 158)

[0745] Step 1, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(pyrrolidine-3-yl)thiazolyl)-2-fluorophenyl)methanol (158-2): Following the synthesis method of 153-2, a yellow solid was obtained in 60% yield. ESI-MS: 391.1 [M+H]+.

[0746] Step 2, Synthesis of (5-(5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)pyrrolidine-3-yl)thiazolyl)-2-fluorophenyl)methanol (158-3): Following the synthesis method of 153-3, a yellow solid was obtained in 60% yield. ESI-MS: 391.1 [M+H]+.

[0747] Step 3, Synthesis of (5-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-2-(1-(ethylsulfonyl)pyrrolidine-3-yl)thiazolyl-4-yl)-2-fluorophenyl)methanol (compound 158): Following the method for compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 650.2 [M+H]+. 1H NMR (500MHz, Chloroform-d) δ9.27 (s, 1H), 8.66 (d, J = 4.2Hz, 1H), 8.25 (t, J = 2.0Hz, 1H), 7.63-7.55 (m, 2H), 7.39 (d, J = 8. 1Hz,1H),7.37-7.31(m,2H),7.05(dd,J=8.6,7.9Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.63(dt,J=5.5,1.1Hz,2H),4.09-3 .98(m,3H),3.78-3.71(m,1H),3.55-3.41(m,2H),3.25(ddd,J=12.5,8.6,6.8Hz,1H),3.20-3.06(m,2H),3.03(p,J=3.7Hz ,1H),2.81-2.69(m,2H),2.60(s,6H),2.35-2.27(m,1H),2.18(dddd,J=12.3,8.6,6.8,3.7Hz,1H),1.29(t,J=9.5Hz,3H).

[0748] Example 159: 1-(2-(azatidine-1-yl)ethyl)-N-(4-(4-(3-(cyclopropylamino)-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 159)

[0749] Following the synthetic method of compound 150, a yellow solid was obtained in 60% yield. ESI-MS: 70 1.3 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(s,1H),7.67(ddd,J=8.8,4.9,2.2Hz,1H),7.42-7.31(m, 4H),7.27(d,J=5.1Hz,1H),7.15(dd,J=8.9,8.0Hz,1H),6.54(dd,J=5.0,2.3Hz,1H),5.85(d,J=8.1Hz,1H),4.01(t,J=3.5Hz,2H ),3.43(ddd,J=12.3,10.1,7.3Hz,2H),3.22-3.10(m,5H),3.05-2.96(m,1H),2.85(t,J=3.5Hz,2H),2.74(t,J=5.9Hz,2H),2.65 (t,J=5.9Hz,2H),2.34-2.14(m,4H),1.87(dp,J=15.4,5.8Hz,2H),1.29(t,J=9.5Hz,3H),0.90-0.80(m,2H),0.75-0.64(m,2H).

[0750] Example 160: N-(4-(1-(cyclopropylsulfonyl)-3-(4-fluoro-3-methoxyphenyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 160)

[0751] Step 1, Synthesis of 3-chloro-4-iodo-1H-pyrazole (160-2): 3-chloro-1H-pyrazole (1 eq, 9 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. The solution was cooled to 0 °C, and NIS (1.3 eq, 11.7 mmol) was added. The mixture was heated to room temperature and reacted for 1 hour. The reaction was then quenched with saturated ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 160-2 (1.8 g, 7.92 mmol), a pale yellow oil, in 88% yield. ESI-MS: 229.0 [M+H]+.

[0752] Step 2, Synthesis of 3-chloro-1-(cyclopropylsulfonyl)-4-iodo-1H-pyrazole (160-3): 3-chloro-4-iodo-1H-pyrazole (1 eq, 7.92 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. The solution was cooled to 0 °C, and NaH (1.5 eq, 11.88 mmol) was added. After reacting for another 0.5 hours, cyclopropylsulfonyl chloride (1.2 eq, 9.5 mmol) was added. The reaction was allowed to proceed overnight at room temperature, quenched with water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 160-3 (2.1 g, 6.33 mmol), a pale yellow oil, in 80% yield. ESI-MS: 333.5 [M+H]+.

[0753] Step 3, Synthesis of 3-chloro-1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1H-pyrazole (160-4): 3-chloro-1-(cyclopropylsulfonyl)-4-iodo-1H-pyrazole (1 eq, 6.33 mmol) was dissolved in 10 mL of 1,4-dioxane. Dipinacol boronic acid ester (1.2 eq, 7.6 mmol), Pd(dppf)Cl2 (0.1 eq, 0.63 mmol), and potassium phosphate (3 eq, 18.99 mmol) were added. Under N2 protection, the mixture was heated to 90 °C and stirred overnight, then cooled to room temperature. The mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 160-4 (1.2 g, 3.90 mmol), a pale yellow oil, in 60% yield. ESI-MS: 333.1 [M+H]+.

[0754] Step 4, Synthesis of 4-(3-chloro-1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-2-amine (160-5): 3-chloro-1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1H-pyrazole (1 eq, 3.9 mmol) and 4-chloropyrimidin-2-amine (1 eq, 3.9 mmol) were dissolved in 10 mL of 1,4-dioxane and 3 mL of water. Cesium carbonate (3 eq, 111.7 mmol) and tetrakis(triphenylphosphine)palladium (0.1 eq, 0.4 mmol) were added. The mixture was heated to 100 °C under N2 protection. After reacting for 6 hours, the mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 160-5 (1.2 g, 3.51 mmol), a pale yellow oil, in 90% yield. ESI-MS: 300.0 [M+H]+

[0755] Step 5, Synthesis of 4-(1-(cyclopropylsulfonyl)-3-(4-fluoro-3-methoxyphenyl)-1H-pyrazol-4-yl)pyrimidine-2-amine (160-6): Following the synthesis method of 160-5, a pale yellow oil was obtained in 70% yield. ESI-MS: 390.1 [M+H]+.

[0756] Step 6, Synthesis of N-(4-(1-(cyclopropylsulfonyl)-3-(4-fluoro-3-methoxyphenyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (compound 160): Following the method used for compound 71, a pale yellow solid was obtained in 63% yield. ESI-MS: 576.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.25(s,1H),8.63(d,J=4.8Hz,1H),8.25(t,J=2.2Hz,1 H),7.87(s,1H),7.51(ddd,J=8.8,5.1,1.8Hz,1H),7.46(d,J=4.8Hz,1H),7.42-7.24 (m,5H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.65(p,J=7 .7Hz,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),1.88-1.75(m,2H),1.75-1.63(m,2H).

[0757] Example 161: N-(4-(2-(cyclopropylsulfonyl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 161)

[0758] Step 1, Synthesis of 4-chloro-2-(cyclopropylthiothio)thiazole (161-2): Cyclopropylthiol (1 eq, 4.8 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. The solution was cooled to 0 °C, and NaH (1 eq, 4.8 mmol) was added. The mixture was heated to room temperature and reacted for another 0.5 hours, followed by the addition of 2-bromo-4-chlorothiazole (1 eq, 4.8 mmol). The reaction was allowed to proceed overnight at room temperature, quenched with saturated ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 161-2 (552 mg, 2.88 mmol), a pale yellow oil, in 60% yield. ESI-MS: 192.0 [M+H]+.

[0759] Step 2, Synthesis of 1-(4-chloro-2-(cyclopropylthio)thiazol-5-yl)ethyl-1-one (161-3): 4-chloro-2-(cyclopropylthio)thiazolium (1 eq, 2.88 mmol) was dissolved in 10 mL of anhydrous dichloromethane. The solution was cooled to 0 °C, and acetyl chloride (1.5 eq, 4.32 mmol) was added, followed by slow addition of aluminum trichloride (3 eq, 8.64 mmol). The reaction was carried out at 0 °C for 3 hours, quenched with water, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. Precise pre-HPLC purification yielded 161-3 (359 mg, 1.5 mmol), a pale yellow oil, in 52% yield. ESI-MS: 240.8 [M+H]+.

[0760] Step 3, Synthesis of (E)-1-(4-chloro-2-(cyclopropylthio)thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (161-4): 1-(4-chloro-2-(cyclopropylthio)thiazol-5-yl)ethyl-1-one (1 eq, 1.5 mmol) was added to DMF·DMA (5 eq, 7.5 mmol), and the mixture was microwaved at 150 °C for half an hour, then cooled to room temperature. The mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 161-4 (130 mg, 0.45 mmol), a pale yellow oil, in 30% yield. ESI-MS: 289.0 [M+H]+.

[0761] Step 4, Synthesis of 4-(4-chloro-2-(cyclopropylthio)thiazo-5-yl)pyrimidine-2-amine (161-5): (E)-1-(4-chloro-2-(cyclopropylthio)thiazo-5-yl)-3-(dimethylamino)prop-2-en-1-one (1 eq, 0.45 mmol) and guanidine (2 eq, 0.9 mmol) were dissolved in 5 mL of ethanol, and potassium carbonate (3 eq, 1.35 mmol) was added. The mixture was heated to 90 °C. After reacting for 1 hour, the mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 161-5 (115 mg, 0.41 mmol), a pale yellow oil, in 90% yield. ESI-MS: 285.0 [M+H]+

[0762] Step 5, Synthesis of 4-(4-chloro-2-(cyclopropylsulfonyl)thiazo-5-yl)pyrimidine-2-amine (161-6): 4-(4-chloro-2-(cyclopropylthio)thiazo-5-yl)pyrimidine-2-amine (1 eq, 0.41 mmol) was dissolved in 5 mL of dichloromethane. m-chloroperoxybenzoic acid (3 eq, 1.23 mmol) was added, and the reaction was carried out for 3 hours. Water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. Precise pre-HPLC purification yielded 161-6 (85 mg, 0.27 mmol), a pale yellow oil, in 65% yield. ESI-MS: 317.0 [M+H]+

[0763] Step 6, Synthesis of 4-(2-(cyclopropylsulfonyl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidine-2-amine (161-7): Following the synthesis method of 160-5, a pale yellow oil was obtained in 60% yield. ESI-MS: 407.1 [M+H]+

[0764] Step 7, N-(4-(2-(cyclopropylsulfonyl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (compound 161): synthesized as compound 71, pale yellow solid, 63% yield. ESI-MS: 593.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.69(d,J=4.2Hz,1H),8.25(t,J=2.0H z,1H),7.50(ddd,J=8.8,4.9,2.2Hz,1H),7.44-7.36(m,3H),7.36-7.29(m,2H),7 .27(d,J=5.1Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s, 2H),3.59(p,J=7.4Hz,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),1.84-1.65(m,4H).

[0765] Example 162: 2-(6-azabicyclo[3.1.1]heptane-3-yl)-5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole (Compound 162)

[0766] Step 1, Synthesis of 2-(6-azabicyclo[3.1.1]heptane-3-yl)-5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole (162-2): 2-(2-chloropyrimidin-4-yl)-1-(4-fluoro-3-methoxyphenyl)ethyl-1-one (1 eq, 0.7 mmol) was dissolved in 10 mL of anhydrous DMF. The solution was cooled to 0 °C, and NBS (1 eq, 0.7 mmol) was added. After reacting for 1 hour, tert-butyl-3-carbamoyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (1.5 eq, 1.1 mmol) was added. The mixture was incubated overnight at 90 °C, quenched with a saturated ammonium chloride aqueous solution, and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Rapid preparative liquid chromatography (HPLC) purification yielded 162-2 (233 mg, 0.56 mmol), a pale yellow oil, in 80% yield. ESI-MS: 417.2 [M+H]+.

[0767] Step 2, Synthesis of 2-(6-azabicyclo[3.1.1]heptane-3-yl)-5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole (compound 162): Following the synthetic method of compound 71, a pale yellow solid was obtained in 66% yield. ESI-MS: 574.3 [M+H]+. 1 H NMR (500MHz, Chloroform-d) δ8.72 (s, 1H), 8.66 (d, J = 4.2Hz, 1H), 7.52-7.44 (m, 3H), 7. 40-7.34(m,2H),7.30(dd,J=8.7,8.0Hz,1H),6.88-6.83(m,2H),3.90(s,2H),3.52(t,J =6.6Hz,2H),3.31-3.25(m,1H),3.28-3.21(m,2H),2.98(s,2H),2.80-2.71(m,3H),2.6 0(s,6H),2.16(dt,J=12.4,5.3Hz,2H),1.97-1.85(m,3H),1.66(dt,J=12.4,3.9Hz,1H).

[0768] Example 163: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(6-(ethylsulfonyl)-6-azabicyclo[3.1.1]heptane-3-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 163)

[0769] Step 1, Synthesis of 5-(2-chloropyrimidin-4-yl)-2-(6-(ethylsulfonyl)-6-azabicyclo[3.1.1]heptane-3-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole (163-2): 2-(6-azabicyclo[3.1.1]heptane-3-yl)-5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole (1 eq, 0.5 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and then... Triethylamine (5 eq, 2.5 mmol) and ethylsulfonyl chloride (1.5 eq, 0.75 mmol) were reacted at room temperature for 1 h, quenched with saturated ammonium chloride aqueous solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by evaporation under vacuum. Precise pre-HPLC purification yielded 163-2 (230 mg, 0.56 mmol), a pale yellow oil, in 90% yield. ESI-MS: 509.2 [M+H]+.

[0770] Step 2, synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(2-(6-(ethylsulfonyl)-6-azabicyclo[3.1.1]heptane-3-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (compound 163): Following the synthesis method of compound 71, a pale yellow solid was obtained in 56% yield. ESI-MS: 676.2 [M+H]+. 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.47(ddd,J=8.8,4.9,2.2Hz,1H), 7.42-7.35(m,2H),7.38-7.31(m,2H),7.34-7.24(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3. 70(tt,J=7.7,6.6Hz,2H),3.31(p,J=5.0Hz,1H),3.25-3.06(m,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.20(ddd,J=12.6, 7.6,5.1Hz,2H),2.06-1.97(m,1H),1.87(ddd,J=12.5,7.6,5.1Hz,2H),1.72(dt,J=12.3,6.5Hz,1H),1.29(t,J=9.1Hz,3H).

[0771] Example 164: N-(4-(2-(azatidine-1-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (Compound 164)

[0772] Step 1, Synthesis of 2-(azatidine-1-yl)-5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole (164-2): Following the synthesis method of 162-2, a pale yellow oil was obtained in 30% yield. ESI-MS: 377.2 [M+H]+.

[0773] Step 2, Synthesis of N-(4-(2-(azatidine-1-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1-(2-(dimethylamino)ethyl)-1H-indole-5-amine (compound 164): Following the synthetic method for compound 71, a pale yellow solid was obtained in 46% yield. ESI-MS: 676.2 [M+H]+ 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.0Hz ,1H),7.47(ddd,J=8.8,4.9,2.2Hz,1H),7.42-7.26(m,6H),6.54(dd,J=5.1,2.0Hz ,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.75(td,J=6.5,1.1Hz,2H),3.68(td,J= 6.5,0.9Hz,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),2.03(dq,J=12.8,6.5Hz,2H).

[0774] Example 165: 1-(2-(dimethylamino)ethyl)-N-(4-(4-(4-(4-fluoro-3-methoxyphenyl)-2-(piperidin-1-yl)thiazo-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 165)

[0775] Step 1, synthesis of 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(piperidin-1-yl)thiazole (165-2), following the synthesis method of 162-2, yielded a pale yellow oil in 55% yield. ESI-MS: 405.1 [M+H]+.

[0776] Step 2, Synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(4-(4-(4-fluoro-3-methoxyphenyl)-2-(piperidin-1-yl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (compound 165): Following the synthetic method for compound 71, a pale yellow solid was obtained in 46% yield. ESI-MS: 572.3 [M+H]+ 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.0Hz, 1H),7.47(ddd,J=8.8,4.9,2.2Hz,1H),7.42-7.26(m,5H),6.54(dd,J=5.1,2.0Hz,1 H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.59(td,J=6.7,3.9Hz,4H),2.75(t,J=3.8H z,2H),2.60(s,6H),1.73(tq,J=6.6,4.1Hz,4H),1.64(dtt,J=10.0,6.8,4.1Hz,2H).

[0777] Example 166: 1-(2-(dimethylamino)ethyl)-N-(4-(4-(4-(4-fluoro-3-methoxyphenyl)-2-(1-methylpiperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 166)

[0778] Step 1, synthesis of 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(1-methylpiperidin-4-yl)thiazole (166-2), following the synthesis method of 162-2, yielded a pale yellow oil in 55% yield. ESI-MS: 419.1 [M+H]+.

[0779] Step 2, Synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(4-(4-(4-fluoro-3-methoxyphenyl)-2-(1-methylpiperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (compound 166): Following the synthetic method for compound 71, a pale yellow solid was obtained in 46% yield. ESI-MS: 586.3 [M+H]+ 1H NMR (500MHz, Chloroform-d) δ9.27 (s, 1H), 8.66 (d, J = 4.2Hz, 1H), 8.25 (t, J = 2. 0Hz,1H),7.47(ddd,J=8.8,4.9,2.2Hz,1H),7.42-7.26(m,6H),6.54(dd,J=5.1 ,2.0Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.15(p,J=4.9Hz,1H),2.75(t ,J=3.8Hz,2H),2.78-2.73(m,4H),2.60(s,6H),2.30(s,3H),2.15-2.03(m,4H).

[0780] Example 167: 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)pyrrolidine-3-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 167)

[0781] Step 1, synthesis of 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)-2-(pyrrolidine-3-yl)thiazole (167-2), following the synthesis method of 162-2, yielded a pale yellow oil in 65% yield. ESI-MS: 391.1 [M+H]+.

[0782] Step 2, synthesis of 5-(2-chloropyrimidin-4-yl)-2-(1-(ethylsulfonyl)pyrrolidine-3-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole (167-3), following the synthetic method of 163-2, yielded a pale yellow oil in 85% yield. ESI-MS: 483.1 [M+H]+.

[0783] Step 3, synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(2-(1-(ethylsulfonyl)pyrrolidine-3-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (compound 167), following the same method as compound 71, yielded a pale yellow solid in 41% yield. ESI-MS: 650.2 [M+H]+ 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.47(ddd,J=8.8,4.9,2.2Hz,1H),7.42 -7.34(m,3H),7.33(dd,J=8.2,1.9Hz,1H),7.30(dd,J=8.7,8.0Hz,1H),7.27(d,J=5.1Hz,1H),6.54(dd,J=5.1,2.2Hz,1H),4.09- 3.98(m,2H),3.90(s,2H),3.78-3.71(m,1H),3.55-3.41(m,2H),3.25(ddd,J=12.5,8.6,6.8Hz,1H),3.20-3.06(m,2H),3.03(p,J =3.7Hz,1H),2.81-2.69(m,2H),2.60(s,6H),2.35-2.27(m,1H),2.18(dddd,J=12.3,8.6,6.8,3.7Hz,1H),1.29(t,J=9.5Hz,3H).

[0784] Example 168: N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)cyclopropaneformamide (Compound 168)

[0785] Step 1, synthesis of 5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazole-2-amine (168-2), following the synthesis method of 162-2, yielded a pale yellow oil in 65% yield. ESI-MS: 337.1 [M+H]+.

[0786] Step 2, synthesis of N-(5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)cyclopropaneformamide (168-3), following the synthesis method of 160-3, yielded a pale yellow oil in 85% yield. ESI-MS: 405.1 [M+H]+.

[0787] Step 3, synthesis of N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)cyclopropaneformamide (compound 168), following the same method as compound 71, yielded a pale yellow solid in 44% yield. ESI-MS: 572.2 [M+H] 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.49(ddd,J=8.8,5.0,2.2Hz,1H),7.42-7.36(m,3H),7.36-7.2 4(m,3H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),2 .75(t,J=3.8Hz,2H),2.60(s,6H),2.14(p,J=5.5Hz,1H),1.04-0.89(m,4H).

[0788] Example 169: N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)ethanesulfonamide (Compound 169)

[0789] Step 1, synthesis of N-(5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)ethanesulfonamide (169-2), following the synthesis method of 160-3, yielded a pale yellow oil in 85% yield. ESI-MS: 429.0 [M+H]+.

[0790] Step two, the synthesis of N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)ethanesulfonamide (compound 169), was performed following the same method as compound 71. The product was a pale yellow solid in 44% yield. ESI-MS: 596.2 [M+H] 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.0 Hz,1H),7.49(ddd,J=8.8,5.0,2.2Hz,1H),7.42-7.36(m,3H),7.36-7.24(m,3H) ,6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3.18(q,J=8.7 Hz,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),1.32(s,1H),1.32(d,J=17.4Hz,1H).

[0791] Example 170: N-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)cyclopropanesulfonamide (Compound 170)

[0792] Step 1, synthesis of N-(5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)cyclopropanesulfonamide (170-2), following the synthesis method of 160-3, yielded a pale yellow oil in 80% yield. ESI-MS: 441.0 [M+H]+.

[0793] Step 2, synthesis of N-(5-(2-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)cyclopropanesulfonamide (compound 170), following the same method as compound 71, yielded a pale yellow solid in 44% yield. ESI-MS: 608.2 [M+H] 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.49(ddd,J=8.8,5.0,2.2Hz,1H),7.42-7.36(m,3H),7.36-7.2 4(m,3H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),3 .43(p,J=7.1Hz,1H),2.75(t,J=3.8Hz,2H),2.60(s,6H),1.80-1.58(m,4H).

[0794] Example 171: N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)propionamide (Compound 171)

[0795] Step 1, synthesis of N-(5-(2-chloropyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)propionamide (171-2), following the synthesis method in step 160-3, yielded a pale yellow oil in 80% yield. ESI-MS: 393.1 [M+H]+.

[0796] Step 2, synthesis of N-(5-(2-((1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)amino)pyrimidin-4-yl)-4-(4-fluoro-3-methoxyphenyl)thiazolyl-2-yl)propionamide (compound 171), following the same method as compound 71, yielded a pale yellow solid in 44% yield. ESI-MS: 560.2 [M+H] 1 H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.65(d,J=4.2Hz,1H),8.25(t,J=2.0Hz,1H),7.49(ddd,J=8.8,5.0,2.2Hz,1H),7.42-7.36(m,3H),7.36-7.24 (m,3H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H),2.7 5(t,J=3.8Hz,2H),2.60(s,6H),2.46(q,J=7.1Hz,2H),1.18(t,J=7.1Hz,3H).

[0797] Example 172: 1-(2-(dimethylamino)ethyl)-N-(4-(2-ethyl-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 172)

[0798] Step 1, synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(2-ethyl-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (172-2), following the method described in 162-2, yielded a pale yellow oil in 65% yield. ESI-MS: 350.0 [M+H]+.

[0799] Step 2, synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(2-ethyl-4-(4-fluoro-3-methoxyphenyl)thiazolyl-5-yl)pyrimidin-2-yl)-1H-indole-5-amine (compound 172), following the same method as compound 71, yielded a pale yellow solid in 54% yield. ESI-MS: 517.2 [M+H] 1H NMR(500MHz,Chloroform-d)δ9.27(s,1H),8.66(d,J=4.2Hz,1H),8.25(t,J=2.0H z,1H),7.47(ddd,J=8.8,5.0,2.3Hz,1H),7.42-7.35(m,2H),7.38-7.31(m,2H),7 .34-7.24(m,2H),6.54(dd,J=5.1,2.2Hz,1H),4.03(t,J=3.8Hz,2H),3.90(s,2H) ,2.96(q,J=6.7Hz,2H),2.75(t,J=3.8Hz,2H),2.60(s,6H),1.33(t,J=6.7Hz,3H).

[0800] Example 173: 1-(2-(dimethylamino)ethyl)-N-(4-(4-(3-ethyl-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (Compound 173)

[0801] Step 1, Synthesis of ethyl 3-ethyl-4-fluorobenzoate (173-2): Ethyl 3-bromo-4-fluorobenzoate (1 eq, 9 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and Pd(dppf)Cl2 (0.1 eq, 0.9 mmol), cesium acetate (3 eq, 27 mmol), and triethylboron (10 eq, 90 mmol) were added. The mixture was heated to 80 °C and reacted for 16 hours. The reaction was then quenched with saturated ammonium chloride solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under vacuum. Precise pre-liquid chromatography was performed to obtain 173-2 (89 mg, 0.45 mmol), a pale yellow oil, in 50% yield. ESI-HRMS: 197.1 [M+H]+.

[0802] Step 2, Synthesis of 2-(2-chloropyrimidin-4-yl)-1-(3-ethyl-4-fluorophenyl)ethyl-1-one (173-3): Following the method used for the synthesis of 2-(2-chloropyrimidin-4-yl)-1-(3-nitrophenyl)ethyl-1-one (A-41-1), a pale yellow solid was obtained in 70% yield. ESI-MS: 279.1 [M+H]+.

[0803] Step 3, Synthesis of 5-(2-chloropyrimidin-4-yl)-4-(3-ethyl-4-fluorophenyl)-2-(piperidin-4-yl)-2,5-dihydrothiazole (173-4): Following the synthetic method of 162-2, a pale yellow oil was obtained in 65% yield. ESI-MS: 405.1 [M+H]+.

[0804] Step 4, Synthesis of 5-(2-chloropyrimidin-4-yl)-4-(3-ethyl-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazole (173-5): Following the synthesis method of 163-2, a pale yellow oil was obtained in 70% yield. ESI-MS: 495.1 [M+H]+.

[0805] Step 5, Synthesis of 1-(2-(dimethylamino)ethyl)-N-(4-(4-(3-ethyl-4-fluorophenyl)-2-(1-(ethylsulfonyl)piperidin-4-yl)thiazolyl)pyrimidin-2-yl)-1H-indole-5-amine (compound 173): Following the synthetic method for compound 71...

Claims

1. The compound of formula (I), or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, in, Ring A is a 5-6 membered heteroaryl group; T is selected from C and N; L1 is selected from the key, -NR a -、-NR a C(=O)-、-NR a S(=O)2-, -O-, -S-, -S(=O)-, -S(=O)2- and -C 1-6 alkylene-, the R a Selected from hydrogen and C 1-4 alkyl; R1 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, -S(=O)2NR2, C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, where R is independently selected from H and C. 1-6 Alkyl, C 3-12 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. 11 replace, R 11 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, the -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC. 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Substitution of alkylene-NH2 and 4-7 membered heterocyclic groups; L2 is selected from the key, -C 1-6 Alkylene-, -NR b -, -O-, -S-, -S(=O)-, -S(=O)2-, -NR b C(=O)-、-NR b S(=O)2-、-NR b -C 1-6 Alkylene-, -OC 1-6 Alkylene-, -SC 1-6 Alkylene-, -NR b C(=O)-C 1-6 Alkylene-, -NR b C(=O)-C 1-6 Alkylene-NR b -、-NR b C(=O)-C 1-6 Alkylene-O-, -NR b C(=O)-C 1-6 Alkylene-S-,-C(=O)NR b -C 1-6 Alkylene-,-C(=O)NR b -C 1-6 Alkylene-NR b -、-C(=O)NR b -C 1-6 Alkylene-O- and -C(=O)NR b -C 1-6 alkylene-S-, the R b Selected from hydrogen and C 1-4 alkyl; R2 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, -S(=O)2NR2, C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups, where R is independently selected from H and C. 1-6 Alkyl, C 3-12 Cycloalkyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl, the C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. 21 replace, R 21 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OR c -NHR c -N(R) c )2、-SR c -S(=O)R c -S(=O)2R c -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6- 12 Aryl, 5-12 heteroaryl, -C 1-4 Alkylene-R c -C 2-4 imide-R c -OC 1-4 Alkylene-R c -SC 1-4 Alkylene-R c -NHC 1-4 Alkylene-R c -C 1-4 Alkylene-OR c -C 1-4 Alkylene-SR c and -C 1-4 Alkylene-NHR c The C 1-6 Alkyl, C 3-12 cycloalkyl, C 4-12 Cycloalkenyl, 4-12 membered heterocyclic groups, C 6-12 The aryl group and the 5-12 heteroaryl group are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -NHCH3, -N(CH3)2, C 1-6 Alkyl and C 1-6 The substituted group of the haloalkyl group, wherein R c Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 The aryl group, or 5-10 heteroaryl group, is optionally surrounded by one or more elements selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, and C. 1-6 Alkyl group substitution; R3 is selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R4 is selected from hydrogen, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-12 Cycloalkyl, -S(=O)2-4-12-membered heterocyclic groups, -NHS(=O)2-C 1-6 Alkyl group, -NHS(=O)2-C 3-12 Cycloalkyl, -NHS(=O)2-4-12-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl group, -NHC(=O)-C 1- 6-alkyl, -C(=O)NH-C 1-6 Alkyl group, -NHC(=O)-C 3-12 Cycloalkyl, -C(=O)NH-C 3-12 Cycloalkyl, -NHC(=O)-4-12-membered heterocyclic group, -C(=O)NH-4-12-membered heterocyclic group, -C 1-6 Alkylene-C 3-12 cycloalkyl, -C 1-6 alkylene-4-12-membered heterocyclic group, C 1-6 Alkyl, C 3-12 Cycloalkyl groups and 4-12 membered heterocyclic groups, wherein the aforementioned groups are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -S(=O)2NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OH, C 1-6 Alkylene -NH2, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl groups and -C(=O)NH-C 1-6 Alkyl group substitution; The condition is that when R3 is F and L2 is a bond, R2 is not hydrogen.

2. The compound of claim 1, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, Ring A is a 5-membered heteroaryl group; Preferably, ring A is selected from thiazolyl, isothiazolyl, thiophenyl, pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, and furanyl; Preferably, ring A is selected from Among them, connection site 1 and The two linkage sites are connected: site 2 is connected to the phenyl group, and site 3 is connected to R4.

3. The compound of claim 1 or 2, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L1 is selected from the key, -NR a -、-NR a C(=O)-, -O-, -S- and -C 1-4 alkylene-, the R a Selected from hydrogen and C 1- 4 alkyl groups, such as hydrogen, methyl, ethyl, and isopropyl; Preferably, L1 is selected from bonds, -NH-, -NH-C(=O)-, -O-, -S- and -C 1-4 alkylene-; Preferably, L1 is selected from bond, -NH- and -NH-C(=O)-*, wherein the * end is connected to R1.

4. The compound of any one of claims 1-3, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R1 is selected from hydrogen, halogen, nitro, -CN, -OR, -COOR, -NR2, C 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, where R is independently selected from H and C. 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. 11 replace, R 11 Each is independently selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1- 4-alkylene-OH, C 1-4 Alkylene-NH2, C 3-8 The cycloalkyl group and the 4-10 membered heterocyclic group are optionally surrounded by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2, -NH-C. 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Substitution of alkyl halogroups and 4-6 membered heterocyclic groups; Preferably, R 11 Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, -OC 1-4 Alkyl, -NH-C 1- 4-alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl groups and 4-7 membered heterocyclic groups, wherein the -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 The alkyl group and the 4-7 membered heterocyclic group are optionally surrounded by 1, 2, 3, 4 or 5 groups selected from hydrogen, OH, -NH-C. 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Substitution of alkylene-NH2 and 4-6 membered heterocyclic groups; Preferably, R 11 Each is independently selected from hydrogen, halogen, -CN, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)CH2CH3, -CH3, -CH2CH3, pyrrolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, wherein -OCH3, -OCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)CH2CH3, -CH3, -CH2CH3, pyrrolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl are optionally substituted with 1, 2, or 3 groups selected from hydrogen, -OH, NHCH3, N(CH3)2, NHCH2CH3, NHCH2CH2CH3, N(CH2CH3)2, CH2OH, CH2CH2OH, CH2CH2CH2OH, CH2NH2, CH2CH2CH2NH2, CH3, CH2CH3, aziridine, pyrrolyl, piperidinyl, piperazinyl, and morpholinyl; Preferably, R 11 Each is independently selected from F, OCH3, Preferably, R1 is selected from hydrogen, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 4-6 cycloalkyl, C 6-10 Aryl and 5-9 membered heteroaryl, the C 1-4 Alkyl, C 4-6 cycloalkyl, C 6-10 Aryl and 5-9 quinone heteroaryl groups are optionally coupled with one or more R groups. 11 Instead, the R 11 As defined in these claims; Preferably, R1 is selected from hydrogen, -CN, -OH, -COOH, -NH2, methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, benzopyrazolyl, benzimidazolyl, and pyridopyrrolyl, wherein the methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, benzopyrazolyl, benzimidazolyl, and pyridopyrrolyl groups are optionally represented by 1, 2, or 3 R1 groups. 11 Instead, the R 11 As defined in these claims; Preferably, R1 is selected from H, NH2, CH3, The Choose 1, 2, or 3 Rs 11 Instead, the R 11 As defined in these claims; Preferably, R1 is selected from H, NH2, CH3, 5. The compound of any one of claims 1-4, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, L2 is selected from the key, -C 1-4 Alkylene-, -NR b -、-O-、-S-、-NR b C(=O)-、-NR b -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -SC 1-4 Alkylene-, -NR b C(=O)-C 1-4 Alkylene-, -NR b C(=O)-C 1-4 Alkylene-NR b -、-NR b C(=O)-C 1-4 alkylene-O- and -NR b C(=O)-C 1-4 alkylene-S-, the R b Selected from hydrogen and C 1-4 Alkyl groups, such as hydrogen, methyl, ethyl, and isopropyl. Preferably, L2 is selected from the following: -CH2-, -CH2CH2-, -CH(CH3)-, -NH-, -N(CH3)-, -O-, -NHC(=O)-, -NHCH2-, -NHCH2CH2-, -NHCH(CH3)CH2-, -OCH2-, -OCH2CH2-, -OCH(CH3)CH2-, -SCH2-, -SCH2CH2-, -SCH(CH3)CH2-, -NHC(=O)CH2-, -NHC(=O)CH2NH-, -NHC(=O)CH2O-, and -NHC(=O)CH2S-. Preferably, L2 is selected from the following: -CH2-, -NH-, -O-, -NHCH2-*, -NHC(=O)-*, -NHC(=O)CH2-*, -NHC(=O)CH2O-*, -OCH2-*, and -CH2O-*, wherein the * end is connected to R2.

6. The compound of any one of claims 1-5, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from hydrogen, halogen, -CN, -OR, -COOR, -NR2, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups, where R is independently selected from H and C. 1-4 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl and 5-12 heteroaryl groups are optionally coupled with one or more R groups. 21 replace, R 21 Each is independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OR c -NHR c -SR c -S(=O)R c -S(=O)2R c -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkylene-R c -C 2-4 imide-R c -OC 1-4 Alkylene-R c -SC 1-4 Alkylene-R c -NHC 1-4 Alkylene-R c -C 1-4 Alkylene-OR c -C 1-4 Alkylene-SR c and -C 1-4 Alkylene-NHR c The C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally surrounded by one or more elements selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -NHCH3, -N(CH3)2, C 1-4 Alkyl and C 1-4 The substituted group of the haloalkyl group, wherein R c Each is independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1-4 Alkyl, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl, the C 1-4 Alkyl, C 3-7 cycloalkyl, 4-8 membered heterocyclic, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally surrounded by one or more elements selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, and C. 1-4 Alkyl group substitution; Preferably, R 21 Each is independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OR c -NHR c -SR c -S(=O)R c -S(=O)2R c -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c C 1-4 Alkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl, -CH2R c -CH=CHR c -OCH2-R c -SCH2-R c -NHCH2-R c -CH2OR c -CH2SR c and -CH2NHR c The C 1-4 Alkyl, C 3-7 Cycloalkyl, phenyl, 5-6 heteroaryl groups are optionally surrounded by one or more elements selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1- 4-alkyl and C 1-4 The substituted group of the haloalkyl group, wherein R c Each is independently selected from hydrogen and C. 1-4 Alkyl, 4-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl, wherein C 1-4 Alkyl, 4-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups may be selected by one or more elements chosen from hydrogen, halogen, -CN, -OH, -COOH, -NH2, and C. 1-4 Alkyl group substitution; Preferably, R 21 Each is independently selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, -OR c -NHR c -SR c -S(=O)R c -S(=O)2R c -NHC(=O)R c -NHS(=O)2R c -C(=O)R c -C(=O)NHR c , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophene, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -CH2R c -CH=CHR c -OCH2-R c -SCH2-R c -CH2OR c and -CH2SR c The methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl groups are optionally substituted by 1, 2, 3, 4, or 5 groups selected from hydrogen, halogens, -CN, -OH, -COOH, -NH2, CH3, CHF2, CH2F, and CF3, wherein R c Each of the following groups is independently selected from hydrogen, methyl, ethyl, isopropyl, aziridine, pyrrolyl, piperidinyl, piperazine, oxadiazine, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, wherein the methyl, ethyl, isopropyl, aziridine, pyrrolyl, piperidinyl, piperazine, oxadiazine, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl groups are optionally substituted by 1, 2, 3, 4, or 5 groups selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, and methyl; Preferably, R 21 Each is independently selected from H, F, Cl, Br, NH2, OH, CH3, CH(CH3)2, CH2F, CF3, CH2OH, OCH3, OCH2CH3, -NHC(=O)CH3, -NHS(=O)2CH3, -C(=O)NHCH3, cyclopropyl, phenyl, Preferably, R2 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coupled with one or more R groups. 21 Instead, the R 21 As defined in these claims; Preferably, R2 is selected from hydrogen, halogen, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 5-8 Polycyclic cycloalkyl groups, 4-8 membered monocyclic heterocyclic groups, C 6-10 The compounds include aryl, 5-10 membered heteroaryl, pyrimidinone, thienocyclopentenyl, 3,4-dihydro-1H-benzopyranyl, and tetrahydroquinolinyl, wherein the 4-8 membered monocyclic heterocyclic group contains one or two heteroatoms selected from N and O, and the 5-10 membered heteroaryl group contains one, two, or three heteroatoms selected from N, O, and S. 1-6 Alkyl, C 3-7 Monocyclic cycloalkyl, C 5-8 Polycyclic cycloalkyl groups, 4-8 membered monocyclic heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, pyrimidinone, thienocyclopentenyl, 3,4-dihydro-1H-benzopyranyl, and tetrahydroquinolinyl are optionally separated by one or more R 21 Instead, the R 21 As defined in these claims; Preferably, R2 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, -NH2, methyl, ethyl, propyl, isopropyl, CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.4]heptyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, aziroxybutyl, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrrolidinyl, pyridine Azolyl, imidazole, triazolyl, thiophene, thiazolyl, furanyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, benzopyrroleyl, benzopyrazolyl, benzoimidazolyl, benzothiopheneyl, benzothiazolyl, benzofuranyl, pyridopyrroleyl, pyridopyrazolyl, pyridoimidazolyl, quinolinyl, isoquinolinyl, pyrimidinoneyl, thiophenecyclopentenyl, 3,4-dihydro-1H-benzo[] Pyranyl and tetrahydroquinolinyl, wherein the methyl, ethyl, propyl, isopropyl, CH2CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.4]heptyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, aziridine, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, phenyl, naphthyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, furanyl Oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzopyrroleyl, benzopyrazolyl, benzoimidazolyl, benzothiopheneyl, benzothiazolyl, benzofuranyl, pyridopyrroleyl, pyridopyrazolyl, pyridimidazoleyl, quinolinyl, isoquinolinyl, pyrimidinoneyl, thienocyclopentenyl, 3,4-dihydro-1H-benzopyranyl, and tetrahydroquinolinyl are optionally represented by 1, 2, 3, 4, or 5 R groups. 21 Instead, the R 21 As defined in these claims; Preferably, R2 is selected from H, Cl, Br, CN, OH, NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, As mentioned, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, Choose any 1, 2, 3, 4 or 5 Rs 21 Instead, the R 21 As defined in these claims; Preferably, R2 is selected from H, Cl, Br, CN, OH, NH2, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CF3, CH2OH, 7. The compound of any one of claims 1-6, or its stereoisomer, its tautomer, its solvate, its isotopically labeled compound, or its pharmaceutically acceptable salt, wherein, R3 is selected from hydrogen, halogens, -CN, -OH, -COOH, -NH2, -OC. 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, Preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, -CN, -OH, -COOH, and -NH2; Preferably, R3 is selected from H and F.

8. The compound of any one of claims 1-7, or a stereoisomer thereof, a tautomer thereof, a solvate thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from hydrogen, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-10 Cycloalkyl, -S(=O)2-4-10-membered heterocyclic groups, -NHS(=O)2-C 1-6 Alkyl group, -NHS(=O)2-C 3-10 Cycloalkyl, -NHS(=O)2-4-10-membered heterocyclic groups, -NHC(=O)-C 1-6 Alkyl group, -NHC(=O)-C 3-10 Cycloalkyl, -NHC(=O)-4-10 membered heterocyclic groups, -C 1-4 Alkylene-C 3-10 cycloalkyl, -C 1-4 alkylene-4-10-membered heterocyclic group, C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 4-10 membered heterocyclic groups, wherein the aforementioned groups are optionally surrounded by one or more groups selected from hydrogen, halogen, nitro, -CN, -OH, -COOH, -NH2, C 1-6 Alkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N-(C 1-6 Alkyl)2, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl groups and -C(=O)-C 1-6 Alkyl group substitution; Preferably, R4 is selected from hydrogen, -OC 1-4 Alkyl, -NH-C 1-4 Alkyl, -N-(C 1-4 Alkyl)2, -SC 1-4 Alkyl group, -S(=O)2-C 1-4 Alkyl group, -S(=O)2-C 3-7 Cycloalkyl, -NHS(=O)2-C 1-4 Alkyl group, -NHS(=O)2-C 3-7 cycloalkyl, -NHC(=O)-C 1-4 Alkyl group, -NHC(=O)-C 3-7 Cycloalkyl, -NHC(=O)-4-8 membered heterocyclic group, -C 1-4 Alkylene-C 3-7 cycloalkyl, C 1-6 Alkyl, C 3-7 Cycloalkyl groups and 4-10 membered heterocyclic groups, wherein the aforementioned groups are optionally surrounded by 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -COOH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkylene-OH, C 1-4 Alkylene -NH2, -S(=O)2-C 1-4 Alkyl groups and -C(=O)-C 1-4 Alkyl group substitutions, such as hydrogen, fluorine, chlorine, bromine, -OH, -COOH, -NH2, -CN, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CH2CF3, CF2CF3, CH2OH, CH2CH2OH, CH2NH2, CH2CH2NH2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2; Preferably, R4 is selected from H, CH3, The aforementioned groups may be optionally replaced by 1, 2, 3, 4, or 5 elements selected from F, -OH, -CN, CH3, CH2OH, CF3, ... Substitution of groups; Preferably, R4 is selected from H, 9. The compound of any one of claims 1-8, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the compound shown in formula (I-1). in, X is selected from N, O, and S; The definitions of T, L1, R1, L2, R2, R3, and R4 are as described in any one of claims 1-8; 1) Preferably, the compound is selected from the compounds shown in formula (I-1A). The definitions of T, L1, R1, L2, R2, R3, and R4 are as described in any one of claims 1-8; Preferably, R2 is selected from H, Cl, Br, CN, OH, NH2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, As mentioned, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, Optional by one or more R 21 Instead, the R 21 The definition is as described in any one of claims 1-8, preferably, R 21 Selected from F, OH, CH3, CH2F and Preferably, R2 is selected from H, Cl, Br, CN, OH, NH2, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CF3, CH2CF3, CH2OH, More preferably, the compound is selected from the compounds shown in formula (I-1A-1), formula (I-1A-2), formula (I-1A-3), and formula (I-1A-4). R2 is defined as described in any one of claims 1-8 or this claim; 2) Preferably, the compound is selected from the compounds shown in formula (I-1B). The definitions of T, L1, R1, L2, R2, R3, and R4 are as described in any one of claims 1-8; Preferably, R2 is selected from H, NH2, CH3, CH2CH3, The CH3, CH2CH3, Choose any 1, 2, 3, 4 or 5 Rs 21 Instead, the R 21 The definition is as described in any one of claims 1-8, preferably, R 21 Selected from H, F, Cl, Br, NH2, OH, CH3, CH(CH3)2, CF3, CH2OH, OCH3, OCH2CH3, -NHC(=O)CH3, -NHS(=O)2CH3, -C(=O)NHCH3, phenyl, Preferably, R2 is selected from H, NH2, CH3, CH2CH3, 10. The compound of any one of claims 1-9, or a stereoisomer thereof, a tautomer thereof, a solvate thereof, an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

11. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 10, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical carriers and / or excipients.

12. The use of any compound of claims 1 to 10, or a stereoisomer thereof, or a tautomer thereof, or a solvate thereof, or an isotopically labeled compound thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 11, in the preparation of a medicament for treating and / or preventing a disease or condition or for reducing the severity of said disease or condition, wherein said disease or condition is associated with EGFR C797S. Preferably, the disease or symptom is selected from cancer; Preferably, the disease or symptom is selected from lung cancer, stomach cancer, prostate cancer, ovarian cancer, testicular cancer, colon cancer, hematologic malignancy, breast cancer, multiple myeloma, liver cancer, pancreatic cancer, melanoma, glioma, and brain glioma. Preferably, the disease or condition is non-small cell lung cancer.

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