Aromatic ring compounds, process for their preparation and use thereof

Abstract

The present application discloses an aromatic ring compound capable of treating diseases mediated by HPK1.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to an aromatic ring compound and its preparation and uses. Technical Background

[0002] Hematopoietic progenitor cell kinase 1 (HPK1, also known as mitogen-activated protein kinase kinase 1 (MAP4K1)) is a Ste20-associated serine / threonine kinase expressed at the hematopoietic site. HPK1 participates in the regulation of multiple downstream signaling pathways, including JKN (c-Jun N-terminal kinase), AP-1 (activator protein 1), and NF-κB. These related pathways regulate cell proliferation, apoptosis, and immune cell activation, and therefore have important relationships with the pathogenesis of autoimmune diseases and cancer (Sawasdikosol S, et al., Immunol Res., 2012, 54, 262). In T cells and B cells, the T cell receptor (TCR) and B cell receptor (BCR) activate HPK1 by inducing the interaction between HPK1 / SLP-76 in T cells and HPK1 / BLANK (B cell linker protein) in B cells, respectively (Wang X, et al., J Biol Chem. 2012, 287, 34091; Wang X, J Biol Chem. 2012, 287, 11037). Activated HPK1 can phosphorylate SLP-76 in T cells or BLANK in B cells to affect the binding of 14-3-3, thereby negatively regulating the T cell receptor signaling pathway and the B cell receptor signaling pathway.

[0003] In terms of functionalities, the HPK1.KO mouse model exhibited enhanced T cell function upon antigen stimulation, reduced PGE2-induced cancer growth, and enhanced dendritic cell maturation upon LPS stimulation. (Alzabin S., et al, J. Immunol. 2009, 182, 6187; Alzabin S., et al., Cancer Immunol. Immunother. 2010, 59, 419; Shui JW, Nat., et al, Immunol. 2007, 8, 84) The HPK1 kinase-dead mouse model showed inhibitory effects on tumor growth and synergistic effects with PD-L1 antibodies. (Hernandez S, et al. Cell Rep. 2018, 25, 80; Liu J, et al. PLoS One 2019, 14, e0212670) Furthermore, unlike some other negative regulators such as CTLA4, which can lead to lethal inflammation, no significant autoimmune disease was observed in the HKP1.KO or HPK1.KD models. Further analysis of immune cells in the tumor microenvironment revealed that loss of HPK1 activity enhances effector T cell function and reduces the number of immunosuppressive Foxp3+ regulated T cells. Currently, there are no marketed drugs targeting HPK1. To better meet the enormous clinical demand, more effective HPK1 inhibitors need to be developed. Summary of the Invention

[0004] This invention provides a novel and highly efficient HPK1 inhibitor with advantages such as high activity, good selectivity and low toxicity, as well as good physicochemical properties and drug-like characteristics.

[0005] On the one hand, the present invention provides a compound, said compound being a compound of formula (I), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof:

[0006]

[0007] Y and Z are independently selected from C atoms and N atoms, respectively. When Z is a C atom, R3 is selected from H, F, and Cl; when Z is an N atom, R3 does not exist. When Y is a C atom, R6 is selected from H, F, and Cl; when Y is an N atom, R6 does not exist. Preferably, Y is a C atom and Z is a C atom; or Y is an N atom and Z is a C atom; or Y is a C atom and Z is an N atom.

[0008] Cy1 ring is selected from 3-20 membered cycloalkyl, 3-20 membered heterocyclic, 5-20 membered aryl, and 5-20 membered heteroaryl; each of the 3-20 membered heterocyclic and 5-20 membered heteroaryl independently contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; preferably, Cy1 ring is selected from 5-12 membered cycloalkyl, 5-15 membered heterocyclic, 5-12 membered aryl, and 5-15 membered heteroaryl, each of the 5-15 membered heterocyclic and 5-15 membered heteroaryl independently contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; more preferably, Cy1 ring is selected from phenyl and 5-15 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the heterocyclic alkyl and heteroaryl are monocyclic, spirocyclic, bridged, or fused ring structures;

[0009] R1 is a substituent at any position on the Cy1 ring, and each time R1 appears, it is independently selected from: oxo (=O), halogen, cyano, carboxyl, hydroxyl, nitro, C. 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 heteroaryl, SR a -SO2NR b R c -C(O)R b -CO2R b -C(O)NR b R c -NR b R c -NR b COR c -NR b SONR c R d -NR b S(O)2R c -R d and -NR b SO2R c The C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-20 cycloalkyl, C 3-20 Heterocyclic alkyl, C 6-20 Aryl and C 5-20Hybrid aryl groups are optionally subjected to p independent R 1a replace;

[0010] Preferably, each occurrence of R1 is independently selected from: oxo (=O), halogen, cyano, carboxyl, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-18 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 heteroaryl, SR a -SO2NR b R c -C(O)R b -CO2R b -C(O)NR b R c -NR b R c -NR b COR c -NR b SONR c R d -NR b S(O)2R c -R d and -NR b SO2R c The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-18 cycloalkyl, C 3-18 Heterocyclic alkyl, C 6-18 Aryl and C 5-18 Hybrid aryl groups are optionally subjected to p independent R 1a replace;

[0011] More preferably, each occurrence of R1 is independently selected from: oxo (=O), halogen, cyano, carboxyl, hydroxyl, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-15 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-15 Heterocyclic alkyl, C 6-15Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-15 heteroaryl, SR a -SO2NR b R c -C(O)R b -CO2R b -C(O)NR b R c -NR b R c -NR b COR c -NR b SONR c R d -NR b S(O)2R c -R d and -NR b SO2R c The C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-15 cycloalkyl, C 3-15 Heterocyclic alkyl, C 6-15 Aryl and C 5-15 Hybrid aryl groups are optionally subjected to p independent R 1a replace

[0012] R 1a Each time it appears, it is selected independently from: C 1-8 Alkyl, C 1-8 Alkoxy, C 3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 heteroaryl, carboxyl, hydroxyl and The C 3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 The heteroaryl group is optionally surrounded by 0, 1, 2, 3, or 4 independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-8 Alkyl and C 1-8 Substitution of alkoxy groups;

[0013] Preferably, R1a Each time it appears, it is selected independently from: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-18 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 heteroaryl, carboxyl, hydroxyl and The C 3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-18 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 The heteroaryl group is optionally surrounded by 0, 1, 2, 3, or 4 independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0014] More preferably, R 1a Each time it appears, it is selected independently from: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-15 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-15 Heterocyclic alkyl, C 6-15 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-15 heteroaryl, carboxyl, hydroxyl and The C 3-15 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-15 Heterocyclic alkyl, C 6-15 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-15 The heteroaryl group is optionally surrounded by 0, 1, 2, 3, or 4 independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups;

[0015] R 1b and R 1c Each is independently selected from: H, hydroxyl, C 1-8 Alkyl, C 1-8 Alkoxy group, -CH=C(C 1-8 Alkyl groups, -CH=CH, -C≡C(C 1-8 Alkyl), -C≡CH, C3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 Heteroaryl; preferably, R 1b and R 1c Each is independently selected from: H, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy group, -CH=C(C 1-6 Alkyl groups, -CH=CH, -C≡C(C 1-6 Alkyl), -C≡CH, C 3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-18 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 heteroaryl; more preferably, R 1b and R 1c Each is independently selected from: H, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy group, -CH=C(C 1-3 Alkyl groups, -CH=CH, -C≡C(C 1-3 Alkyl), -C≡CH, C 3-15 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-15 Heterocyclic alkyl, C 6-15 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-15 Mixed aromatics;

[0016] Or R 1b and R 1c The atoms connected between them form C 3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 Heteroaryl, or C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 3-20 Heterocyclic alkyl, C 4-9 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 cyclic lactam, C 3-7 cyclic lactones and C 3-7 Cyclic ketones, wherein the C3-20 cycloalkyl, C 3-20 Heterocyclic alkyl, C 6-20 Aryl, C 5-20 heteroaryl, C 3-20 Heterocyclic alkyl, C 4-9 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 cyclic lactam, C 3-7 cyclic lactones and C 3-7 Cyclic ketones, each selected individually by a hydroxyl group, C... 1-8 Alkyl, -SO2, -SO2N(C) 1-10 Alkyl)(C 1-10 alkyl), -SO2N(C 1-10 Alkyl groups (H), -SO2NH2, -N(C) 1-10 Alkyl)SO2(C 1-10 alkyl), -N(C) 1-10 Alkyl)SO2H, -N(H)SO2(C 1-10 Alkyl), -CON(C) 1-10 Alkyl)(C 1-10 Alkyl), -CONH(C) 1-10 Alkyl), -CONH2, -N(C 1-10 Alkyl)CO(C 1-10 Alkyl), -N(H)CO(C) 1-10 alkyl), -N(C) 1-10 Alkyl)CO(H), -N(C) 1-10 Alkyl)COO(C 1-10 Alkyl), -N(H)COO(C 1-10 alkyl), -N(C) 1-10 Alkyl)COO(H), -OCON(C) 1-10 Alkyl)(C 1-10 Alkyl), -OCON(C) 1-10 Alkyl group (H), -OCONH2, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -N(C 1-10 Alkyl)(C 1-10 alkyl), -NH(C) 1-10 Alkyl group, -NH2, -OC 1-10 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heterocyclic aromatic, -O-heterocyclic aromatic and -S-heterocyclic aromatic groups;

[0017] Preferably, R 1b and R 1c The atoms connected between them form C3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-18 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 Heteroaryl, or C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 3-18 Heterocyclic alkyl, C 4-9 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 cyclic lactam, C 3-7 cyclic lactones and C 3-7 Cyclic ketones, wherein the C 3-18 cycloalkyl, C 3-18 Heterocyclic alkyl, C 6-18 Aryl, C 5-18 heteroaryl, C 3-18 Heterocyclic alkyl, C 4-9 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 cyclic lactam, C 3-7 cyclic lactones and C 3-7 Cyclic ketones, each selected individually by a hydroxyl group, C... 1-6 Alkyl, -SO2, -SO2N(C) 1-8 Alkyl)(C 1-8 alkyl), -SO2N(C 1-8 Alkyl groups (H), -SO2NH2, -N(C) 1-8 Alkyl)SO2(C 1-8 alkyl), -N(C) 1-8 Alkyl)SO2H, -N(H)SO2(C 1-8 Alkyl), -CON(C) 1-8 Alkyl)(C 1-8 Alkyl), -CONH(C) 1-8 Alkyl), -CONH2, -N(C 1-8 Alkyl)CO(C 1-8 Alkyl), -N(H)CO(C) 1-8 alkyl), -N(C) 1-8 Alkyl)CO(H), -N(C) 1-8 Alkyl)COO(C 1-8 Alkyl), -N(H)COO(C 1-8 alkyl), -N(C) 1-8 Alkyl)COO(H), -OCON(C) 1-8 Alkyl)(C 1-8 Alkyl), -OCON(C)1-8 Alkyl group (H), -OCONH2, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -N(C 1-8 Alkyl)(C 1-8 alkyl), -NH(C) 1-8 Alkyl group, -NH2, -OC 1-8 Alkyl, -OH, C 3-8 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heterocyclic aromatic, -O-heterocyclic aromatic and -S-heterocyclic aromatic groups;

[0018] L1 and L2 are each independently selected from single bonds, -CR g =N-、-CR g =CR g -、C 1-8 Alkylene, C 3-8 Cycloalkylene, -O-, -NR g -, -S-, -S(O), -S(O)2-, -C(O)-, -OC 1-8 Alkylene-, -NR g -C 1-8 Alkylene-, -SC 1-8 Alkylene-, -S(O)-C 1-8 Alkylene-,-S(O)2-C 1-8 Alkylene-, -C(O)-C 1-8 Alkylene-,-S(O)-NR g -、-S(O)2-NR g -、-C(O)-NR g -、-C 1-8 Alkylene -O-, -C 1-8 Alkylene-NR g -、-C 1-8 Alkylene-S-, -C 1-8 Alkylene-S(O)-, -C 1-8 Alkylene -S(O)2-, -C 1-8 Alkylene-C(O)-, -NR g -S(O)-、-NR g -S(O)2- and -NR g -C(O)-, where C 1-8 Alkylene and C 3-8 The cycloalkylene group is optionally surrounded by 0, 1, 2, 3 or 4 R's. h Replacement; preferably, L1 is selected from single bonds, -C=N-, -O-, -C(O)-, -OC 1-8Alkylene-, -C(O)-NH- and -NH-C(O)-; and / or L2 is selected from single bond, -C=N-, -O-, -C(O)-, -OC 1-8 Alkylene-, -C(O)-NH- and -NH-C(O)-;

[0019] The Cy2 ring is selected from 3-20-membered cycloalkyl, 3-20-membered heterocyclic, 6-20-membered aryl, and 5-20-membered heteroaryl groups, wherein each of the 3-20-membered heterocyclic and 5-20-membered heteroaryl groups independently contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; preferably, the Cy2 ring is selected from 5-12-membered cycloalkyl, 5-12-membered heterocyclic, 6-12-membered aryl, and 5-15-membered heteroaryl groups, wherein the 5-12-membered heterocyclic and 5-15-membered heteroaryl groups... Each aryl group independently contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the 5-12-membered heterocyclic alkyl group and the 5-15-membered heteroaryl group are monocyclic, bridged, spirocyclic, or fused-ring structures; more preferably, the Cy2 ring is selected from phenyl and contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and the 5-15-membered heteroaryl group is a monocyclic, bridged, spirocyclic, or fused-ring structure;

[0020] R4 is a substituent at any position on the Cy2 ring, and each time R4 appears, it is independently selected from: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C. 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 heteroaryl, -C 1-8 Alkylene-N(R) i )R j -C 1-8 Alkyl, -SR i -SO2N(R) j )R k -C(O)R j -OR j -NR i -C(O)-C 1-8 Alkylene-R j -C(O)-NR i -C 1-8 Alkylene-R j-CO2R j -NR i -C(O)R j -NR i -C 1-8 Alkylene-N(R) j )R k -C(O)-N(R) j )R k -C 1-8 Alkylene-NR j -C 1-8 Alkyl, -N(R) i )R j -NR j C(O)R k -NR j S(O)NR k R m and -NR j S(O)2R k The C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-20 cycloalkyl, C 3-20 Heterocyclic alkyl, C 6-20 Aryl and C 5-20 Heteroaryl groups are optionally divided by r independent R 4a The heterocyclic alkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure, or a fused ring structure.

[0021] Preferably, R4 is independently selected each time it appears from: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-20 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 heteroaryl, -C 1-6 Alkylene-N(R) i )R j -C 1-6 Alkyl, -SR i -SO2N(R) j )R k -C(O)R j -ORj -NR i -C(O)-C 1-6 Alkylene-R j -C(O)-NR i -C 1-6 Alkylene-R j -CO2R j -NR i -C(O)R j -NR i -C 1-6 Alkylene-N(R) j )R k -C(O)-N(R) j )R k -C 1-6 Alkylene-NR j -C 1-6 Alkyl, -N(R) i )R j -NR j C(O)R k -NR j S(O)NR k R m and -NR j S(O)2R k The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-18 cycloalkyl, C 3-18 Heterocyclic alkyl, C 6-18 Aryl and C 5-18 Heteroaryl groups are optionally divided by r independent R 4a The heterocyclic alkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure, or a fused ring structure.

[0022] More preferably, R4 is independently selected each time it appears from: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-15 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-15 Heterocyclic alkyl, C 6-15 Aryl group, containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-15 heteroaryl, -C 1-3 Alkylene-N(R)i )R j -C 1-3 Alkyl, -SR i -SO2N(R) j )R k -C(O)R j -OR j -NR i -C(O)-C 1-3 Alkylene-R j -C(O)-NR i -C 1-3 Alkylene-R j -CO2R j -NR i -C(O)R j -NR i -C 1-3 Alkylene-N(R) j )R k -C(O)-N(R) j )R k -C 1-3 Alkylene-NR j -C 1-8 Alkyl, -N(R) i )R j -NR j C(O)R k -NR j S(O)NR k R m and -NR j S(O)2R k The C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-15 cycloalkyl, C 3-15 Heterocyclic alkyl, C 6-15 Aryl and C 5-15 Heteroaryl groups are optionally divided by r independent R 4a The heterocyclic alkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure, or a fused ring structure.

[0023] R 4a Each occurrence is independently selected from: halogen, oxo (=O), -C(O)R j , cyano, amino, hydroxy, carboxyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, -C 1-8 Alkylene-CN, C3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 heteroaryl, wherein the C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 The heteroaryl group is individually selected from hydroxyl, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -SO2, C 1-8 Alkyl group, -SO2N(C) 1-10 Alkyl)(C 1-10 alkyl), -SO2N(C 1-10 Alkyl groups (H), -SO2NH2, -N(C) 1-10 Alkyl)SO2(C 1-10 alkyl), -N(C) 1-10 Alkyl)SO2H, -N(H)SO2(C 1-10 Alkyl), -CON(C) 1-10 Alkyl)(C 1-10 Alkyl), -CONH(C) 1-10 Alkyl), -CONH2, -N(C 1-10 Alkyl)CO(C 1-10 Alkyl), -N(H)CO(C) 1-10 alkyl), -N(C) 1-10 Alkyl)CO(H), -OCON(C) 1-10 Alkyl)(C 1-10 Alkyl), -OCON(C) 1-10 Alkyl)H, -OCONH2, -N(C 1-10 Alkyl)(C 1-10 alkyl), -NH(C) 1-10 Alkyl group, -NH2, -OC 1-10 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocyclic alkyl, -N-heterocyclic alkyl, -N-heterocyclic aryl, -O-heterocyclic aryl and -S-heterocyclic aryl groups;

[0024] Preferably, R 4aEach occurrence is independently selected from: halogen, oxo (=O), -C(O)R j , cyano, amino, hydroxy, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-CN, C 3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-18 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-18 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 The heteroaryl group is individually selected from hydroxyl, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -SO2, C 1-6 Alkyl group, -SO2N(C) 1-6 Alkyl)(C 1-6 alkyl), -SO2N(C 1-6 Alkyl groups (H), -SO2NH2, -N(C) 1-6 Alkyl)SO2(C 1-6 alkyl), -N(C) 1-6 Alkyl)SO2H, -N(H)SO2(C 1-6 Alkyl), -CON(C) 1-6 Alkyl)(C 1-6 Alkyl), -CONH(C) 1-6 Alkyl), -CONH2, -N(C 1-6 Alkyl)CO(C 1-6 Alkyl), -N(H)CO(C) 1-6 alkyl), -N(C) 1-6 Alkyl)CO(H), -OCON(C) 1-6 Alkyl)(C 1-6 Alkyl), -OCON(C) 1-6 Alkyl)H, -OCONH2, -N(C 1-6 Alkyl)(C 1-6 alkyl), -NH(C) 1-6 Alkyl group, -NH2, -OC1-6 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocyclic alkyl, -N-heterocyclic alkyl, -N-heterocyclic aryl, -O-heterocyclic aryl and -S-heterocyclic aryl groups;

[0025] p, q, r, and s are each independently 0, 1, 2, 3, or 4;

[0026] m and n are each independently 1, 2, 3 or 4; and when m or n is 1, R1 or R4 is not -OH, -CH3, -OCH3, -COOH, -CH2OH or a halogen;

[0027] When R2 is not connected to B to form a loop, R2 is selected from NR. e R f F, Cl, Br and I, A is a single bond, B does not exist, e is 1;

[0028] R e and R f Each group is independently selected from H, halogen, cyano, carboxyl, hydroxyl, nitro, and C. 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 Heteroaryl; preferably, R e and R f Each is independently selected from H and C. 1-8 alkyl;

[0029] When R2 is bonded to B and forms a ring structure with the bonded atom, L1 is not a single bond, A is a C atom, and B is selected from C1. a And N, preferably, B is CR a Each occurrence of R2 is independently selected from CR. a R b and NR c Preferably, R2 is NR c e can be 0, 1, 2, 3, or 4, preferably 1 or 2;

[0030] R a R b R c R d R g R h R i R jR k and R m Each time it appears, it is independently selected from H, halogen, cyano, carboxyl, hydroxyl, nitro, C. 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-20 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-20 Heterocyclic alkyl, C 6-20 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-20 heteroaryl, the C 3-20 cycloalkyl, C 3-20 Heterocyclic alkyl, C 6-20 Aryl and C 5-20 The heteroaryl group is optionally surrounded by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-8 Alkyl and C 1-8 Alkyl group substitution; preferably, R a R b R c R d R g R h R i R j R k and R m Each time it appears, it is independently selected from H, halogen, cyano, carboxyl, hydroxyl, nitro, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-18 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-18 Heterocyclic alkyl, C 6-18 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-18 Heteroaryl, the C 3-18 cycloalkyl, C 3-18 Heterocyclic alkyl, C 6-18 Aryl and C 5-18 The heteroaryl group is optionally surrounded by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl and C 1-6 Alkyl substituent substitution; more preferably, R a R b R c R d R gR h R i R j R k and R m Each time it appears, it is independently selected from H, halogen, cyano, carboxyl, hydroxyl, nitro, C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkenyl, C 2-3 alkynyl group, C 3-15 Cycloalkyl groups, containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. 3-15 Heterocyclic alkyl, C 6-15 Aryl group and C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. 5-15 Heteroaryl, the C 3-15 cycloalkyl, C 3-15 Heterocyclic alkyl, C 6-15 Aryl and C 5-15 The heteroaryl group is optionally surrounded by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups;

[0031] When Y is an N atom, Z is a C atom, R2 is -NH2, R3 is H, and L1 is -CONH-, R4 is neither -NH2 nor -C. 1-4 alkoxy-NH2; or Some are not Some are not

[0032] When Y is an N atom, Z is a C atom, R2 is -NH2, R3 is H, L2 is a single bond, and Cy1 is selected from 3- to 9-membered monocyclic heterocyclic groups, wherein the heterocyclic group contains one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur as one or more ring members, Cy2 is not...

[0033] When Y is an N atom, Z is a C atom, R2 is -NH2, R3 is H, L2 is a single bond, L1 is -O-, and Cy1 is... At that time, Cy2 is not a benzene ring;

[0034] When Y is an N atom, Z is a C atom, R2 is -NH2, R3 is H, and L1 is... When Cy1 is a pyridine ring, R4 is not...

[0035] When Y is a carbon atom, Z is a carbon atom, R3 is a hydrogen atom, and L2 is a single bond... Some are not

[0036] When Y is a C atom, Z is a C atom, R2 is -NH2, R3 is H, and R6 is H. Part of When L2 is a single bond, Cy2 is not.

[0037] When Y is a carbon atom, Z is a carbon atom, R2 is -NH2, R3 is H, R6 is H, L1 is a single bond, and Cy2 is a benzene ring. Some are not Or R4 is not -SO2R i 、 and -SO2N(R j )R k ;

[0038] When Y is a C atom, Z is a C atom, R2 is -NH2, R3 is H, and L2 is a single bond. Part of

[0039] When R4 is not a cyano group, -SO2R j R k -NR j SO2R k ,

[0040] when

[0041] When m = 1, R4 is neither a halogen nor a methoxy group; when m = 2, R4 is not entirely a halogen.

[0042] When Y is a C or N atom, Z is a C atom, R2 is -NH2, R3 is H, and R6 is H. Part of When R4 is not

[0043] When Y is a C atom, Z is a C atom, R2 is -NH2, R3 is H, R6 is H, and L1 is... When Cy1 is a benzene ring or a pyridine ring, Cy2 is not.

[0044] When Y is a C atom, Z is a C atom, R2 is -NH2, R3 is H, R6 is H, and L1 is... When Cy1 is a benzene ring or a pyridine ring, and Cy2 is a pyridine ring, R4 is not a benzene ring.

[0045] When Y is a C atom, Z is a C atom, R2 is -NH2, R3 is H, R6 is H, and L1 is a single bond, Cy1 is not...

[0046] When Y is a C atom, Z is a C atom, R2 is -NH2, R3 is F or Cl, L2 is a single bond, and the Cy1 ring is... When the Cy2 ring is a benzene ring or a pyridine ring, m≠1 and at least one of R4 is... Or when m=2, R4 represents methoxy and

[0047] When Y is a C atom, Z is a C or N atom, R2 is -NH2, L1 is a single bond, and Cy1 ring is... At that time, Cy2 ring is not When m = 1, R4 is not a cyano group or

[0048] in, Indicates the connection site. This indicates the substituent site on the ring.

[0049] In one of the technical solutions, the Cy1 ring is selected from the following group:

[0050]

[0051] In one of the technical solutions, R1 is selected from oxo (=O), F, Cl, O, S, hydroxyl, carboxyl, amino, cyano, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-6 cycloalkyl, C 1-8 Alkoxy groups, C atoms containing N, O and S atoms 3-6 Heterocyclic alkyl groups, -NH-S(O)2-C 1-8 Alkyl, -C(O)-NH-OH, -C(O)-NH-C 1-8 Alkyl, -C(O)-NH-C 1-8 Alkoxy,

[0052]

[0053] Preferably, R1 is selected from oxo (=O), F, methyl, amino, cyano, hydroxyl, carboxyl, methoxy, ethynyl, propynyl, 2-butynyl, -NH-S(O)2-CH2CH3, -C(O)-NH-CH3, -O-CH2CH3,

[0054] -C(O)-NH-O-CH3, -C(O)-NH-OH,

[0055]

[0056] In one of the technical solutions, R4 is selected from oxo (=O), amino, C 1-8 Alkyl, -C(O)-NH2, Halogen, -C(O)-N(C 1-8 Alkyl)C 1-8 Alkyl group, -S(O)2-NH-C 1-8 Alkyl, -C 1-8 alkylene-OH, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, cyano,

[0057]

[0058] -N(C 1-8 Alkyl)C 1-8 Alkyl, -NH-C(O)-C 1-8 Alkyl, -C(O)-N(C) 1-8 Alkyl)-OC 1-8 Alkyl, -N(C) 1-8 alkyl)-C 1-8 Alkylene-N(C) 1-8 Alkyl)C 1-8 Alkyl, -NH-C 1-8 Alkylene-N(C) 1-8 alkyl)-C 1-8 alkyl 、 -C 1-8 Alkylene-NH-C 1-8 Alkyl and -C 1-8 Alkylene-N(C) 1-8 Alkyl)C 1-8 Alkyl and -N(C) 1-8 alkyl)-C(O)-C 1-8 alkyl;

[0059] Preferably, R4 is selected from oxo (=O), amino, C 1-3 Alkyl, -C(O)-NH2, F, Cl, Br, I, -C(O)-N(CH3)2, -S(O)2-NH-CH3, -C 1-4 Alkyl-OH, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy, cyano, -C 1-4 Alkylene-NH-C 1-4 Alkyl, -C 1-8 Alkylene-N(C) 1-4 Alkyl)C 1-4 Alkyl, C 1-8 Alkoxy,

[0060]

[0061] -N(CH3)2, -NH-C(O)-CH3, -NH-C(O)-C2H5, -C(O)-N(CH3)-O-CH3, -N(CH3)C(O)CH3, -N(CH3)C( O)C2H5, -N(CH3)C(O)C4H9, -N(CH3)C(O)C3H7, -N(CH3)-(CH2)2-N(CH3)2, -NH-(CH2)2-N(CH3) 2、 -CH2-NH-CH3 and -CH2-NH-(CH3)2.

[0062] In one of the technical solutions, among which, Selected from:

[0063]

[0064]

[0065]

[0066] In one of the technical solutions, Cy2 is selected from:

[0067]

[0068] In one of the technical solutions, among which, Selected from:

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] In one of the technical solutions, the compound is selected from:

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] The compound numbers mentioned above are consistent with the compound numbers in the examples.

[0096] Another aspect of the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a therapeutically effective dose of the aforementioned compound and a pharmaceutically acceptable carrier or excipient.

[0097] Another aspect of the present invention provides the use of the compounds or pharmaceutical compositions described above in the preparation of medicaments for treating HPK1-mediated diseases; preferably, the HPK1-mediated diseases are cancer or tumors.

[0098] The present invention also provides a method for preparing the compound as described above or a pharmaceutically acceptable salt, solvent compound or prodrug thereof, comprising the following preparation steps:

[0099]

[0100] Among them, R1, R2, R3, R4, R e R f The definitions of Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are the same as before.

[0101] R o and R o’ Selected from halogen atoms, tin reagents, borate groups, or borate esters: The condition is: R o When R is a halogen or tin reagent o’ It is a borate group or borate ester; R o When it is a borate group or a borate ester, R o’ It is a halogen or tin reagent.

[0102] The present invention also provides a preparation method comprising the following preparation steps:

[0103]

[0104] Among them, R1, R2, R3, R4, R e R f R g The definitions of Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are the same as before.

[0105] R p and R p’ Selected from halogen atoms, tin reagents, or borate or borate groups: The condition is: R p When R is a halogen or tin reagent p’ It is a borate group or a borate ester group; R p When it is a borate group or a borate ester, R p’ It is a halogen or tin reagent.

[0106] The borate group or borate ester group is selected from...

[0107] The present invention also provides a preparation method comprising the following preparation steps:

[0108]

[0109] Among them, R1, R2, R3, R4, R e The definitions of Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are the same as before.

[0110] R q and R q’ Selected from halogen atoms, tin reagents, or borate or borate groups: The condition is: R q When R is a halogen or tin reagent q’ It is a borate group or a borate ester group; Rq When it is a borate group or a borate ester, R q’ It is a halogen or tin reagent.

[0111] The borate group or borate ester group is selected from...

[0112] The present invention also provides a preparation method comprising the following preparation steps:

[0113]

[0114] Among them, R1, R2, R3, R4, R e R f The definitions of Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are the same as before.

[0115] R r and R r’ Selected from halogen atoms, tin reagents, or borate or borate groups: The condition is: R r When R is a halogen or tin reagent r’ It is a borate group or a borate ester group; R r When it is a borate group or a borate ester, R r’ It is a halogen or tin reagent.

[0116] The borate group or borate ester group is selected from...

[0117] The present invention also provides a preparation method comprising the following preparation steps:

[0118]

[0119] Among them, R1, R2, R3, R4, R e R f The definitions of Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are the same as before.

[0120] R s and R s’ Selected from halogen atoms, tin reagents, or borate or borate groups: The condition is: R s When R is a halogen or tin reagent s’ It is a borate group or a borate ester group; R s When it is a borate group or a borate ester, R s’ It is a halogen or tin reagent.

[0121] The borate group or borate ester group is selected from...

[0122] The present invention also provides a preparation method comprising the following preparation steps:

[0123]

[0124] Among them, R1, R2, R3, R4, R e R f The definitions of Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are the same as before.

[0125] R t and R t’ Selected from halogen atoms, tin reagents, or borate or borate groups: The condition is: R t When R is a halogen or tin reagent t’ It is a borate group or a borate ester group; R t When it is a borate group or a borate ester, R t’ It is a halogen or tin reagent.

[0126] The borate group or borate ester group is selected from...

[0127] The present invention also provides a preparation method comprising the following preparation steps:

[0128]

[0129] Among them, R1, R2, R3, R4, R e R f The definitions of Cy1 ring, Cy2 ring, L2, m, n, and Y are the same as before.

[0130] R u and R u’ Selected from halogen atoms, tin reagents, or borate or borate groups: The condition is: R u When R is a halogen or tin reagent u’ It is a borate group or a borate ester group; R u When it is a borate group or a borate ester, R u’ It is a halogen or tin reagent.

[0131] The borate group or borate ester group is selected from... Definition and detailed explanation

[0132] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents chosen from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups.

[0133] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- atoms are replaced by heteroatoms selected from NH, O, and S, or where one or more -CH- atoms are replaced by N atoms; wherein the alkyl group is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable connection point, wherein the substituent is preferably independently selected independently by one or more substituents selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups.

[0134] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described herein. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents.

[0135] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in its molecule, wherein the alkyl group is defined as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from one or more substituents selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0136] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and even more preferably 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.

[0137] The cycloalkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0138] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic alkyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.

[0139] Heterocyclic alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl.

[0140] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic alkyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring. The aryl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably independently selected from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl.

[0141] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic alkyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0142] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0143] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0144] The term "amino" refers to -NH2.

[0145] The term "cyano" refers to -CN.

[0146] "Optional" or "optionally" means that the event or situation described below may but does not have to occur, and the description includes the circumstances in which the event or situation occurs or does not occur. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group may be substituted but is not required to be present, and the description includes the cases where the cyclopropyl group is substituted and the cases where the cyclopropyl group is not substituted.

[0147] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions without much effort (through experiment or theory).

[0148] "Medicinal salts" refers to salts of the compounds disclosed herein that are safe and effective when used in mammals and have the appropriate biological activity. Detailed Implementation

[0149] The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0150] The present invention will be described in detail below through embodiments, but this does not imply any adverse limitations on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0151] Example 1: Synthesis of Compound 2

[0152]

[0153] 1.1 Synthesis of 5-bromo-2-nitropyridine-3-ol

[0154] A solution of 5-bromopyridin-3-ol (300 mg, 1.72 mmol) in 2 mL of H₂SO₄ was cooled to 0 °C, and 0.5 mL of HNO₃ was added. The reaction mixture was stirred at RT for 5 hours. The solution was diluted with 5 mL of water and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated to give 5-bromo-2-nitropyridin-3-ol (56 mg, 44%) as a yellow solid. MS (ESI): [M+H] + =173.0.

[0155] 1.2 Synthesis of 4-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)pyridine-2-amine (2)

[0156] PPh3 (287 mg, 1.096 mmol) and DIAD (221 mg, 1.096 mmol) were added to a solution of 5-bromo-2-nitropyridin-3-ol (200 mg, 0.9136 mmol) and (2-aminopyridin-4-yl)methanol (147 mg, 1.187 mmol) in THF (3 mL) under N2 conditions. The reaction mixture was stirred at RT for 8 hours. The solution was diluted with water (20 mL) and extracted with EA (40 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give 4-((((5-bromo-2-nitropyridin-3-yl)oxy)methyl)pyridin-2-amine (90 mg, 44%) as a yellow solid. MS (ESI): [M+H] + =325.

[0157] 1.3 Synthesis of 4-(((5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-nitropyridin-3-yl)oxy)methyl)pyridine-2-amine

[0158] A solution of 4-(((5-bromo-2-nitropyridin-3-yl)oxymethyl)pyridin-2-amine (100 mg, 0.308 mmol) in THF:H2O = 1:1 (2 mL) containing K3PO4 (98 mg, 0.462 mmol), Pd(dppf)2Cl2-DCM (100 mg, 0.246 mmol), and 4-(((5-bromo-2-nitropyridin-3-yl)oxymethyl)pyridin-2-amine was added under N2 atmosphere. The reaction mixture was stirred at 80 °C for 4 hours and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 1:1) to give a yellow solid of 4-(((5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-nitropyridin-3-yl)oxymethyl)pyridin-2-amine (50 mg, 41%). MS (ESI): [M+H) + =406.

[0159] Fe (41 mg, 0.74 mmol) and NH₄Cl (66 mg, 1.234 mmol) were added to a solution of 4-(((5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-nitropyridin-3-yl)oxy)methyl)pyridine-2-amine (100 mg, 0.246 mmol) in EtOH:H₂O = 5:1 (2 mL). The reaction mixture was stirred at 70 °C for 3 h, concentrated under vacuum, and the residue was purified by preparative HPLC to provide 3-(((2-aminopyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-trihydroxyisoquinoline-7-yl)pyridine-2-amine (2 mg, 2%) in solid form. MS (ESI): [M+H]+ =376.48. 1 ¹H NMR (600MHz, DMSO-d⁶) δ 7.89 (d, J = 5.2Hz, 1H), 7.83 (d, J = 1.9Hz, 1H), 7.29 (d, J = 2.0Hz, 1H), 7.24–7.19 (m, 1H), 7.11–7.07 (m, 1H), 6.60 (dd, J = 5.2, 1.4Hz, 1H), 6.58–6.56 (m, 1H), 5.92 (s, 2H), 5.81 (s, 2H), 5.11 (s, 2H), 3.50 (s, 3H), 2.72–2.57 (m, 4H), 2.35 (s, 4H), 2.21 (s, 3H), 1.24 (s, 1H). Example 2: Synthesis of Compound 3

[0160]

[0161] 2.1 Synthesis of 2-(2-methylbut-3-yn-2-yl)oxy)tetrahydropyran

[0162] DHP (1.28 mg, 14.3 mmol) was added to a solution of 2-methylbut-3-yn-2-ol (1 g, 11.9 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at 0 °C for one day and detected by TLC. The solvent was concentrated under reduced pressure to obtain the crude product.

[0163] 2.2 Synthesis of (3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)phenylmethanol

[0164] Under nitrogen protection, bis(triphenylphosphine)palladium dichloride (15.1 mg, 0.14 mmol) was added to a mixture of 2-(2-methylbut-3-yn-2-yl)oxy)tetrahydropyran (700 mg, 4.17 mmol), (3-iodophenyl)methanol (325 mg, 1.39 mmol), and cuprous iodide (80 mg, 0.42 mmol) in triethylamine (0.65 mL) and dioxane (6 mL). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give the product (364 mg, 95.3%). MS (ESI): [M+H-H2O] + =257.

[0165] 2.3 Synthesis of 5-bromo-3-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine

[0166] Under nitrogen protection and in an ice bath, DIEA (309.4 mg, 1.53 mmol) was added to a mixture of (3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)phenylmethanol (420.5 mg, 1.53 mmol), 5-bromo-2-nitropyridin-3-ol (282.5 mg, 1.29 mmol), and triphenylphosphine (401.3 mg, 1.53 mmol) in tetrahydrofuran (15 mL). The reaction mixture was stirred at room temperature for 5 hours. After the reaction was completed as monitored by LCMS, it was quenched with saturated brine and extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give the product (490 mg, 80.1%). MS (ESI): [M+H] + =476.2.4 Synthesis of 2,5-dimethyl-7-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0167] Under nitrogen protection, a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (168.9 mg, 0.21 mmol) was added to a solution of 5-bromo-3-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine (490 mg, 1.03 mmol), 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline (357.4 mg, 1.24 mmol), and potassium phosphate (318 mg, 1.55 mmol) in tetrahydrofuran (10 ml) and water (10 ml). The solution was heated at 80 °C for 5 h. After the reaction was monitored by LCMS, it was quenched with saturated brine and extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the final product (342 mg, 59.8%). MS (ESI): [M+H) + =556.

[0168] 2.5 Synthesis of 4-(3-(2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yne-2-ol

[0169] 2,5-Dimethyl-7-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (300 mg, 0.54 mmol) was added to glacial acetic acid (15 mL), followed by zinc powder (353 mg, 5.40 mmol) and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. (350 mg). MS (ESI): [M+H) + =442.

[0170] Example 3 Synthesis of Compound 4

[0171]

[0172] 3.1 Synthesis of tert-butyl 2-chloro-4-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid

[0173] To a mixture of 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (50 mg, 0.164 mmol), trimethylcycloboroxane (16 μL, 0.0575 mmol, 50% in THF), and potassium carbonate (68 mg, 0.493 mmol) in tetrahydrofuran:1,4-dioxane:water (2:2:1) (1.5 mL), tetraphenylphosphine palladium (19 mg, 0.016 mmol) was added. The resulting mixture was stirred at 90 °C for 3 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Prep-TLC (petroleum ether:ethyl acetate = 2:1) to give 2-chloro-4-methyl-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (30 mg, 65% yield). MS(ESI): m / z found 228 [M+H-56] + .

[0174] 3.2 Synthesis of 2-chloro-4-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0175] The compound obtained in the previous step (30 mg, 0.106 mmol) was dissolved in hydrochloric acid (3 mL, 4 M in dioxane) and stirred at room temperature for 3 hours. The solution was concentrated to give the product (10 mg, 52% yield). MS (ESI): m / z found 184 [M+H] + Synthesis of 3,32-chloro-4,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0176] The compound obtained in the previous step (10 mg, 0.055 mmol), an aqueous solution of formaldehyde (6 μL, 0.0825 mmol, 40% aqueous solution), and sodium cyanoborohydride (5.2 mg, 0.0825 mmol) in methanol (1 mL) were slowly added. The mixture was stirred at room temperature for 5 hours under nitrogen atmosphere. The reaction mixture was quenched with water, washed with ethyl acetate and brine, and concentrated by drying over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product 2-chloro-4,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (20 mg, 58% yield). MS (ESI): m / z found 198 [M+H] + Synthesis of 3,43-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy-2-nitro-5-(trimethyltinyl)pyridine

[0177] To a solution of 5-bromo-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy-2-nitropyridine (200 mg, 0.42 mmol, 472-CW-097) and hexamethyldistin (413 mg, 1.263 mmol) in tetrahydrofuran (6 mL), palladium dichloride bis(triphenylphosphine) (30 mg, 0.042 mmol) was added. The resulting solution was stirred at 60 °C under nitrogen for 13 hours. The solution was concentrated under vacuum to give the product (300 mg), which did not require purification. MS (ESI): m / z found 459 [M+H] + .

[0178] Synthesis of 3,5-4,7-dimethyl-2-(5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy]-6-nitropyridin-3-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidine

[0179] The compound obtained in the previous step (300 mg, 0.42 mmol, crude product) and the 2-chloro-4,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine obtained in the third step (105 mg, 0.63 mmol) were added to a solution of 1,4-dioxane (4 mL) with tetraphenylphosphine palladium (46 mg, 0.042 mmol). The resulting solution was stirred at 100 °C under nitrogen for 3 hours. The reaction mixture was filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 15:1) to give the product (80 mg, 34% yield). MS (ESI): m / z found 558 [M+H] + .

[0180] 3.6 Synthesis of 5-(4,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)pyridine-2-amine

[0181] The compound obtained in the previous step (80 mg, 0.14 mmol) was mixed with iron powder (49 mg, 0.86 mmol) and ammonium chloride (23 mg, 0.43 mmol) in a mixture of ethanol (2.5 mL) and water (0.5 mL). The mixture was stirred at 50 °C for 3 hours. The reaction mixture was filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 10:1) to give the product (23 mg, 31% yield). MS (ESI): m / z found 528 [M+H] + .

[0182] 3.7 Synthesis of 4-(3-((2-amino-5-(4,7-dimethyl-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yne-2-yl)

[0183] The compound obtained in the previous step (20 mg, 0.038 mmol) was added to 1.5 mL of ethanol with pyridinium 4-methylbenzenesulfonate (15 mg, 0.057 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 5:1) to give the product (13 mg, 81% yield). MS (ESI): m / z found 444 [M+H] + .

[0184] Example 4 Synthesis of Compound 7

[0185]

[0186] 4.1 Synthesis of 6-amino-3-bromo-2-fluoro-N,N-dimethylbenzamide

[0187] HATU (148 mg, 2.6 mmol) and DIPEA (258 mg, 2.0 mmol) were added sequentially to 6-amino-3-bromo-2-fluorobenzoic acid (300 mg, 1.3 mmol) and dimethylamine in dichloromethane (5 mL), and the reaction was carried out at room temperature for 1 h. The reaction was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain a yellow oily substance (150 mg, 45%). MS (ESI): m / z found 262.1 [M+H] + .

[0188] 4.2 Synthesis of 6-amino-2-fluoro-N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide

[0189] Add BPin2 (291 mg, 1.15 mmol), KOAC (169 mg, 1.72 mmol), and Pd(dppf)2Cl2 (46 mg, 0.06 mmol) to dioxane (5 mL) of 6-amino-3-bromo-2-fluoro-N,N-dimethylbenzamide (150 mg, 0.57 mmol) (5 mL). Stir the resulting solution at 100 °C for 3 hours. Dilute the solution with water (5 mL) and extract with EA (10 mL x 2). Dry the combined organic layers with anhydrous Na2SO4 and filter. Concentrate the filtrate under vacuum. Purify the residue by silica gel column chromatography to give a yellow oily 6-amino-2-fluoro-N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide (100 mg, 56%). MS(ESI): m / z found 309.2 [M+H] + .

[0190] 4.3 Synthesis of 6-amino-2-fluoro-N,N-dimethyl-3-(5-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)benzamide To 6-amino-2-fluoro-N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzamide (100 mg, 0.32 mmol) To a mixed solution of dioxane (2 mL) and water (2 mL), 0.32 mmol of 5-bromo-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine (100 mg), 0.49 mmol of K3PO4 (100 mg), and 0.064 mmol of Pd(dppf)Cl2·CH2Cl2 (53 mg) were added. The resulting solution was stirred at 80 °C for 3 hours. The solution was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oily 6-amino-2-fluoro-N,N-dimethyl-3-(5-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)benzamide (100 mg, 53%). MS (ESI): m / z found 577.6 [M+H] + .

[0191] 4.4 Synthesis of 6-amino-3-(6-amino-5-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)pyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide

[0192] Fe (28 mg, 0.52 mmol) and NH4Cl (46 mg, 0.86 mmol) were added to a mixed solution of 6-amino-2-fluoro-N,N-dimethyl-3-(5-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)benzamide (100 mg, 0.17 mmol) in dioxane (1.2 mL) and water (0.6 mL). The resulting solution was stirred at 80 °C for 3 hours. The solution was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oily 6-amino-3-(6-amino-5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)pyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide (60 mg, 64%). MS (ESI): m / z found 547.6 [M+H] + .

[0193] 4.5 Synthesis of 6-amino-3-(6-amino-5-((3-(3-hydroxy-3-methylbut-1-yn-1-yl)benzyl)oxy)pyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide

[0194] PPTS (41 mg, 0.17 mmol) was added to a MeOH (1 mL) solution of 6-amino-3-(6-amino-5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)pyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide (60 mg, 0.11 mmol). The resulting solution was stirred at room temperature for 5 hours. The solution was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oily 6-amino-3-(6-amino-5-((3-hydroxy-3-methylbut-1-yn-1-yl)benzyl)oxy)pyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide (30 mg, 59%). MS (ESI): m / z found 462.5 [M+H] + .

[0195] Example 5 Synthesis of Compound 8

[0196]

[0197] 5.1 Synthesis of 6-amino-3-bromo-2-fluorobenzoic acid

[0198] Bromine (490 mg, 7.1 mmol) was added dropwise to a solution of 2-amino-6-fluorobenzoic acid (1 g, 6.5 mmol) in CHCl3 (100 mL) under ice-water bath conditions. After reacting at room temperature for 16 hours, the resulting solution was stirred at 0 °C for 0.5 hours. The solution was diluted with water (20 mL) and extracted with DCM (25 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give 6-amino-3-bromo-2-fluorobenzoic acid (1 g, 67%) as a yellow solid. MS (ESI): m / z found 235.0 [M+H] + .

[0199] 5.2 Synthesis of 6-amino-3-bromo-2-fluoro-N,N-dimethylbenzamide

[0200] HATU (1.7 g, 4.3 mmol) was added to a DCM (30 mL) solution of 6-amino-3-bromo-2-fluorobenzoic acid (1 g, 4.3 mmol). The resulting solution was stirred at room temperature for 0.5 h. Dimethylamine (0.8 mL) and DIEA (1.4 mL, 8.54 mmol) were added. The resulting solution was stirred at room temperature for 5 h. The solution was diluted with water (20 mL) and extracted with DCM (25 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give 6-amino-3-bromo-2-fluorobenzoic acid (400 mg, 36%) as a yellow solid. MS (ESI): m / z found 262.1 [M+H] + .

[0201] 5.3 Synthesis of 6-amino-3-(5-(((2-aminopyridin-4-yl)methoxy)-6-nitropyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide

[0202] To a mixed solution of 6-amino-3-bromo-2-fluorobenzoic acid (200 mg, 0.77 mmol) in dioxane (4.5 mL) and water (0.5 mL), (5-((2-aminopyridin-4-yl)methoxy)-6-nitropyridin-3-yl)boronic acid (223 mg, 2.77 mmol), X-phos (36 mg, 0.077 mmol), K3PO4 (489 mg, 2.32 mmol), and Pd(dppf)Cl2·CH2Cl2 (62 mg, 0.0777 mmol) were added. The resulting solution was stirred at 100 °C for 3 hours. The solution was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oily 6-amino-3-(5-(((2-aminopyridin-4-yl)methoxy)-6-nitropyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide (40 mg, 12%). MS (ESI): m / z found 427.4 [M+H] + .

[0203] 5.4 Synthesis of 6-amino-3-(6-amino-5-((2-aminopyridin-4-yl)methoxy)pyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide

[0204] Fe (16 mg, 0.3 mmol), H₂O (0.4 mL), and NH₄Cl (27 mg, 0.5 mmol) were added to an ethanol (0.8 mL) solution of 6-amino-3-(5-((2-aminopyridin-4-yl)methoxy)-6-nitropyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide (40 mg, 0.1 mmol). The resulting solution was stirred at 80 °C for 2 hours. The solution was filtered to obtain a filtrate, which was diluted with water (20 mL) and extracted with EA (25 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow solid of 6-amino-3-(6-amino-5-((2-aminopyridin-4-yl)methoxy)pyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide (25 mg, 40%).

[0205] MS(ESI): m / z found 427.4 [M+H] + .

[0206] Example 6 Synthesis of Compound 9

[0207]

[0208] 6.1 Synthesis of 3-bromo-2-fluoro-5-nitrobenzoic acid

[0209] Nitric acid (1.14 mL, 29.6 mmol) was added to a mixture of 3-bromo-2-fluorobenzoic acid (5 g, 22.8 mmol) and sulfuric acid (12 mL). The resulting mixture was stirred at room temperature for 5 hours. The reaction solution was slowly poured into ice water and stirred for 15 minutes. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product (5.7 g, 94% yield).

[0210] 6.2 Synthesis of 3-bromo-2-fluoro-N,N-dimethyl-5-nitrobenzamide

[0211] The compound obtained in the previous step (2.0 g, 7.57 mmol) and HATU (5.76 g, 15.1 mmol) were added to a solution of DMF (8 mL) and stirred at room temperature for 15 minutes. Then, a solution of dimethylamine hydrochloride (1.85 g, 22.7 mmol) and DIEA (0.65 mL, 37.8 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. Purification was performed by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give the product (1.5 g, 71% yield). MS (ESI): m / z found 291 / 293 [m+H] + .

[0212] 6.3 Synthesis of 5-amino-3-bromo-2-fluoro-N,N-dimethylbenzamide

[0213] Iron powder (2.5 mg, 42.5 mmol) and ammonium chloride (1.2 g, 22.5 mmol) were added to a mixed solution of the starting material (2.5 g, 7.5 mmol) in ethanol (20 mL) and water (2 mL). The mixture was stirred at 50 °C for 4 hours. The reaction mixture was filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product (2.0 g, 89% yield). MS (ESI): m / z found 261 / 263 [m+H] + .

[0214] 6.4 Synthesis of 5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)boronic acid

[0215] Add [1,1'-bis(diphenyl)] to a solution of 5-bromo-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy-2-nitropyridine (1.7 g, 3.58 mmol), bis(pinacol)boronic acid ester (1.82 g, 7.15 mmol), and potassium acetate (700 g, 7.15 mmol) in 1,4-dioxane (15 mL) The [phosphine-ferrocene]palladium dichloride dichloromethane complex (290 mg, 0.357 mmol) was stirred at 80 °C under nitrogen for 3 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 5:1) to give the product (1.5 g, 83% yield). MS (ESI): m / z found 339 [m+H]. + .

[0216] Synthesis of 6,5-dimethyl-7-(5-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)-6-nitropyridin-3-yl)-1,2,4-tetrahydroisoquinoline

[0217] The compound obtained in the previous step (120 mg, 0.23 mmol), 516-ZS-76P (60 mg, 0.23 mmol), and potassium phosphate (96 mg, 0.69 mmol) were added to a solution of tetrahydrofuran (6 mL) and water (1.2 mL), followed by the addition of tetra(triphenylphosphine-palladium) (27 mg, 0.023 mmol). The mixture was stirred at 100 °C under nitrogen for 3 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using Pre-p (dichloromethane:methanol = 15:1) to give the product (82 mg, 89% yield). MS (ESI): m / z found 475.2 [m+H-102]. + .

[0218] 6.6 Synthesis of 5-(2,5-dimethyl-1,2,4-tetrahydroisoquinoline-7-yl)-3-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridine-2-amine

[0219] To a mixture of starting material (80 mg, 0.138 mmol) in acetic acid (5 mL), zinc powder (92 mg, 1.38 mmol) and p-toluenesulfonic acid (20 mg) were added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 10:1) to give the product (28 mg, 43% yield). MS (ESI): m / z found 463.2 [m+H] + .

[0220] Example 7 Synthesis of Compound 10

[0221]

[0222] 7.1 Synthesis of (5-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridine-3-boronic acid)

[0223] Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (76.8 mg, 0.11 mmol) was added to a mixture of 5-bromo-3-((3-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine (250 mg, 0.53 mmol), pinacol diboronate (160.8 mg, 0.63 mmol), and potassium acetate (77.6 mg, 0.79 mmol) in dioxane (5 mL). The reaction mixture was heated at 80 °C for 2 hours. After the reaction was complete as monitored by LCMS, the solvent was filtered and concentrated under reduced pressure. MS (ESI): m / z found 441 [M+H] + .

[0224] 7.2 Synthesis of 4-methyl-7-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,5-tetrahydropyrrolo[4,3,2]isoquinoline

[0225] To a mixture of tetrahydrofuran (6 mL) and water (6 mL) of the product from the previous step (1.14 mg, 2.52 mmol), 7-bromo-4-methyl-1-(2-(trimethylsilyl)ethoxy)methyl)-1,3,4,5-tetrahydropyrrolo[4,3,2]isoquinoline (800 mg, 2.10 mmol), potassium phosphate (667.8 mg, 3.15 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (342.7 mg, 0.42 mmol) were added. The solution was heated at 80 °C for 3 h. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give the product (1.3 g, 89.0%). MS(ESI): m / z found 697[M+H] + .

[0226] 7.3 Synthesis of 5-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,5-tetrahydropyrrolo[4,3,2]isoquinoline-7-yl)-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-ynyl)benzyl)oxy)pyridine-2-amine

[0227] Under nitrogen protection, the product from the previous step (1.3 g, 1.86 mmol) and ammonium chloride (346 mg, 6.53 mmol) were reacted with reduced iron powder (522 mg, 9.33 mmol) in a mixture of ethanol (10 mL) and water (12 mL). The reaction mixture was heated at 50 °C for 6 hours. After the reaction was completed as monitored by LCMS, the filtrate was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 5:1) to give the final product (0.5 g, 40.3%). MS (ESI): m / z found 667 [M+H] + .

[0228] 7.4 Synthesis of 4-(2-amino-5-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,5-tetrahydropyrrolo[4,3,2]isoquinoline-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yne-2-ol

[0229] PPTS (94 mg, 0.38 mmol) was added to a methanol (3.5 mL) solution of the previous step product (100 mg, 0.15 mmol). The mixture was stirred at room temperature for 7 h. After the reaction was completed as monitored by LCMS, the filtrate was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (DCM:MeOH = 5:1) to obtain the final product (60 mg, 69.0%). MS (E SI): m / z found 583 [M+H] + .

[0230] 7.5 Synthesis of 4-(2-amino-5-(4-methyl-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yne-2-ol

[0231] To a DMF (1.5 mL) solution of the previous step product (75 mg, 0.13 mmol), tetrabutylammonium fluoride (0.4 mL, 0.39 mmol) and ethylenediamine (40 μL, 0.59 mmol) were added. The solution was stirred at 80 °C for 8 hours. After the reaction was complete as monitored by LCMS, the resulting solution was extracted with EA to obtain the product (35 mg, 59.6%). MS (ESI): m / z found 453 [M+H] + .

[0232] Example 8 Synthesis of Compound 11

[0233]

[0234] 8.1 Synthesis of 2-(2-chloro-3-methylpyridin-4-yl)-4,4-dimethyl-3-oxopentanilide

[0235] A mixture of 2-chloro-4-iodo-3-methylpyridine (2 g, 7.9 mmol), tert-butyl 2-cyanoacetate (2.2 mL, 15.8 mmol), CuI (15 mg, 0.079 mmol), and K₂CO₃ (4.3 g, 31.6 mmol) in DMF (20 mL) was stirred at 120 °C for 24 hours. The resulting mixture was diluted with water and 10% citric acid and extracted with EA. The solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (5% EA) to give an oily 2-(2-chloro-3-methylpyridin-4-yl)-4,4-dimethyl-3-oxopentanonitrile (1.4 g, 58%). MS (ESI): m / z found 267.0 [M+H] + .

[0236] 8.2 Synthesis of 2-(2-chloro-3-methylpyridin-4-yl)acetonitrile

[0237] A solution of tert-butyl 2-(2-chloro-3-methylpyridin-4-yl)-2-cyanoacetate (1.4 g, 5.24 mmol) and TFA (5 mL) in DCM (5 mL) was stirred at 40 °C for 3.5 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in DCM and washed with saturated aqueous solution containing sodium bicarbonate. The combined organic phases were washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by silica gel chromatography to give a beige solid compound (0.6 g, 42%). MS (ESI): m / z found 167 [M+H] + .

[0238] 8.3 Synthesis of 2-(5'-chloro-3-methyl-[2,3'-bipyridin]-4-yl)acetonitrile

[0239] To a solution of 2-(2-chloro-3-methylpyridin-4-yl)acetonitrile (200 mg, 0.12 mmol) in dioxane (3 mL), (5-chloropyridin-3-yl)boric acid (380 mg, 0.24 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol), and 2N K2CO3 (0.45 mL) were added. The resulting solution was stirred at 100 °C for 1 hour. The solution was extracted with EA. The combined organic fractions were washed with brine, dried over (MgSO4), and concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound (250 mg, 85%). MS (ESI): m / z found 244.0 [M+H] + .

[0240] 8.4 Synthesis of (4-(cyanomethyl)-3-methyl-[2,3'-bipyridin]-5'-yl)boronic acid

[0241] A solution of starting material 1 (200 mg, 0.823 mmol), starting material 2 (270 mg, 1.646 mmol), Xphos-Pd-G2 (91 mg, 0.082 mmol), and potassium acetate (210 mg, 2.13 mmol) in 1,4-dioxane (5 mL) was heated at 100 °C for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by silica gel chromatography (solvent gradient 0-100% EtOAc in cyclohexane) to give the title compound (320 mg, 83%) as a yellow oil. MS (ESI): m / z found 254.0 [M+H] +

[0242] 8.5 Synthesis of 2-(3-methyl-5'-(3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6'-nitro-[2,3':5',3'-tripyridin]-4-yl)acetonitrile

[0243] Add starting material 2 (675 mg, 1.4229 mmol), K3PO4 (754 mg, 3.557 mmol), and Pd (dppf) to a solution of starting material 1 (300 mg, 1.1857 mmol) in dioxane (3 mL). Stir the resulting solution at 100 °C for 2 hours under nitrogen atmosphere using DCM (96 mg, 0.118 mmol). Dilute the reaction mixture with water and extract with EtOAc. Wash the combined organic extracts with brine, dry to (MgSO4), and concentrate under vacuum. Concentrate the solution under vacuum and purify by preparative TLC (EA:PE = 1:1) to give the title compound as a solid (240 mg, 50%). MS (ESI): m / z found 502 [M-100+H] + .

[0244] 8.6 Synthesis of 2-(6'-amino-5'-(3-(3-hydroxy-3-methylbut-1-yl)benzyl)oxy)-3-methyl-[2,3':5',3'-tripyridin]-4-yl)acetonitrile

[0245] Zn (18 mg, 0.2 mmol) and P-TsOH (17 mg, 0.03 mmol) were added to the starting material (70 mg, 0.116 mmol) and AcOH (1 mL) solution. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated under vacuum. The concentrated solution and residue were purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound as a solid (4 mg, 5%). MS (ESI): m / z found 490 [M+H] + .

[0246] Example 9 Synthesis of Compound 12

[0247]

[0248] 9.1 Synthesis of 5-bromo-4-chloro-3-((3-iodobenzyl)oxy)-2-nitropyridine

[0249] To a solution of the starting material (1 g, 3.96 mmol) in 20 mL of ACN, K₂CO₃ (1.6 g, 11.9 mmol) and 1-(bromomethyl)-3-iodobenzene (1.18 g, 3.96 mmol) were added. The resulting solution was stirred at 80 °C for 5 hours. The solution was diluted with water (20 mL) and extracted with EA (40 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oily product (650 mg, 35%). MS (ESI): m / z found 470.5 [M+H] + .

[0250] 9.2 Synthesis of 5-bromo-4-chloro-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine

[0251] CuI (61 mg, 0.32 mmol) and Pd(PPh)3Cl2 (75 mg, 0.11 mmol) were added to a solution of 5-bromo-4-chloro-3-((3-iodobenzyl)oxy)-2-nitropyridine (500 mg, 1.07 mmol) and 2-((2-methylbut-3-yn-2-yl)oxy"tetrahydro-2H-pyran (197 mg, 1.17 mmol) in dioxane (10 mL). The resulting solution was stirred at 90 °C for 6 hours under a nitrogen atmosphere. The solution was diluted with water (20 mL) and extracted with EA (40 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oil (380 mg, 70%). MS (ESI): m / z found 510.8 [M+H] + .

[0252] 9.3 Synthesis of 7-(4-chloro-5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline

[0253] To a mixture of 5-bromo-4-chloro-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine (100 mg, 0.20 mmol) and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline (56 mg, 0.20 mol) in THF (1 mL) and H₂O (1 mL), K₃PO₄ (64 mg, 0.30 mmol) and Pd(dppf)Cl₂CH₂Cl₂ (16 mg, 0.02 mmol) were added. The resulting solution was stirred at 80 °C for 3 hours under a nitrogen atmosphere. The solution was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give a yellow oil (40 mg, 34%), MS (ESI): m / z found 591.1 [M+H]. + .

[0254] 9.4 Synthesis of 4-(3-((2-amino-4-chloro-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yne-2-ol

[0255] To a mixture of 7-(4-chloro-5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline (40 mg, 0.07 mmol) in ACN (1 mL), Zn (20 mg, 0.3 mmol) and TsOH·H₂O (5 mg, 0.03 mmol) were added. The resulting solution was stirred at room temperature for 3 hours. The solution was evaporated to give a yellow oil (35 mg, 88%). MS (ESI): m / z found 477.0 [M+H] + .

[0256] Example 10 Synthesis of Compound 13

[0257]

[0258] 10.1 Synthesis of tert-butyl (4-bromo-2-isobutyrylphenylethyl)carbamate

[0259] Under nitrogen protection, tert-butyl 7-bromo-tert-butyl-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid (500 mg, 1.53 mmol) was added to a mixture of tert-butyl 7-bromo-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid in tetrahydrofuran (8 mL). The reaction mixture was stirred at room temperature for 9 hours. After the reaction was completed as monitored by LCMS, the solvent was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to give the product (300 mg, 53.2%). MS (ESI): m / z found 313 [M+H-56] + .

[0260] 10.2 Synthesis of 7-bromo-1-isopropyl-1,2,3,4-tetrahydroisoquinoline

[0261] Trifluoroacetic acid (4 mL) was added to a solution of the starting material (770 mg, 2.09 mmol) in dichloromethane (15 mL). The solution was stirred at room temperature for 3 h. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. Sodium cyanoborohydride (328.3 mg, 5.23 mmol) and a catalytic amount of glacial acetic acid were added to the crude product and dissolved in methanol (15 mL). The mixture was stirred for 5 h and analyzed by LCMS. The resulting solution was filtered and concentrated under reduced pressure to obtain the crude product. (500 mg) MS (ESI): m / z found 254 [M+H + .

[0262] 10.3 Synthesis of 7-bromo-1-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0263] Under nitrogen protection, formalin (226.6 mg, 3 mmol), sodium cyanoborohydride (186 mg, 3 mol), and a catalytic amount of glacial acetic acid were added to a mixture of the starting material (506 mg, 2 mmol) in methanol (10 mL). The reaction was stirred at room temperature for 6 hours, and the reaction was completely detected by LC-MS. The solvent was filtered and concentrated under reduced pressure to give the crude product. (350 mg) MS (ESI): m / z found 268 [M+H] + .

[0264] 10.4 Synthesis of (1-isopropyl-2-methyl-1,2,4-tetrahydroisoquinoline-7-yl)boronic acid

[0265] Under nitrogen atmosphere, a mixture of the starting material (350 mg, 1.30 mmol), pinacol diboronate (394 mg, 1.56 mmol), and potassium acetate (190.2 mg, 1.94 mmol) in dioxane (7.5 mL) was added to a solution of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (212 mg, 0.26 mmol). The solvent was filtered and the solution was concentrated under reduced pressure. The reaction was heated at 80 °C for 2.5 h and analyzed by LC-MS. The reaction solution was filtered and concentrated under reduced pressure to give the crude product. (300 mg) MS (ESI): m / z found 234 [M+H] + .

[0266] 10.5 Synthesis of 1-Isopropyl-2-methyl-7-(5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy]-6-nitropyridin-3-yl)-1,2,4-tetrahydroisoquinoline

[0267] Under nitrogen atmosphere, a mixture of 300 mg (1.30 mmol) of the starting material, 5-bromo-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine (708 mg (1.56 mmol)) and potassium phosphate (411 mg (1.94 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added to a solution of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (212 mg (0.26 mmol)). The solution was heated at 80 °C for 3 h and then completely detected by LC-MS. The solvent was extracted with EA. The organic layer was dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the product (500 mg, 66.1%). MS (ESI): m / z found 584[M+H] + 10.6 Synthesis of 5-(1-isopropyl-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxypyridine-2-amine

[0268] Reduced iron powder (239.5 mg, 4.29 mmol) was added to a solution of the starting material (500 mg, 0.86 mmol) and ammonium chloride (159 mg, 3.00 mmol) in ethanol (7.5 mL) and water (1.5 mL) under nitrogen protection. The reaction was heated at 50 °C for 6 hours and completely detected by LC-MS. The solvent was filtered and concentrated under reduced pressure to give the crude product. (160 mg) MS (ESI): m / z found 554 [M+H)+ .

[0269] 10.7 Synthesis of 4-(3-(((2-amino-5-(1-isopropyl-2-methyl-1,2,4-tetrahydroisoquinoline-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yne-2-ol

[0270] PPTS (181 mg, 0.72 mmol) was added to a solution of the starting material (160 mg, 0.289 mmol) in methanol (5 mL). The solution was stirred at room temperature for 12 h. The reaction was confirmed to be complete by LC-MS. The solvent was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (130 mg, 95.6%). MS (ESI): m / z found 471 [M+H] + .

[0271] Example 11 Synthesis of Compound 14

[0272]

[0273] 11.1 Synthesis of 2,5-dimethyl-7-(5-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)methoxy)-6-nitropyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline

[0274] Under nitrogen protection, 5-bromo-3-((2-(3-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)but-1-ynyl)pyridin-4-ylmethoxy)-2-nitropyridine (163 mg, 0.34 mmol), 72,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline (120 mg, 0.41 mmol) and potassium phosphate (110.2 mg, 0.52 mmol) were reacted in tetrahydrofuran (0.7 ml) and H2O (0 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (56 mg, 0.07 mmol) was added to a mixture solution of 0.7 ml. The solution was heated at 80 °C for 3 h. The solution was then heated at 80 °C for 8 h. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by thin-layer chromatography (DCM:MeOH = 10:1) to give the product (101.6 mg, 53.5%). MS (ESI): m / z found 557 [M+H] + .

[0275] 11.2 Synthesis of 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-3-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)methoxy)pyridin-2-amine

[0276] Under nitrogen protection, reduced iron powder (21.1 mg, 0.36 mmol) was added to a mixture of the starting material (40 mg, 0.072 mmol) and ammonium chloride (13.5 mg, 0.252 mmol) in ethanol (0.75 mL) and water (0.15 mL). The reaction mixture was heated at 50 °C for 6 hours. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography (DCM:MeOH = 10:1) to obtain the final product (30 mg, 79.2%). MS (ESI): m / z found 527 [M+H] + Synthesis of 2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-2-methylbut-3-yne-2-ol

[0277] PPTS (43.3 mg, 0.171 mmol) was added to a mixture of the starting material (30 mg, 0.057 mmol) in methanol (1.5 mL). The solution was stirred at room temperature for 12 h. The solvent was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 5:1) to give the final product (21 mg, 81.1%). MS (ESI): m / z found 443 [M+H] + .

[0278] Example 12 Synthesis of Compound 16

[0279]

[0280] 12.1 Synthesis of (E)-5-bromo-3-(((3-iodophenyl)imino)methyl)pyridine-2-amine

[0281] Glacial acetic acid (0.5 mL) was added to a mixture of 2-amino-5-bromonicoraldehyde (1.5 g, 7.46 mmol) and 3-iodoaniline (988 μL, 8.21 mmol) in ethanol (40 mL). The reaction mixture was heated at 40 °C for 8 h, and the reaction was completely detected by LC-MS. The solvent was filtered and the solid was collected to give the crude product (2 g, 67%). MS (ESI): m / z found 401 [M+H] +Synthesis of 12.2(E)-4-(2-amino-5-bromopyridin-3-yl)methylene)amino)phenyl)-2-methylbut-3-yne-2-ol

[0282] Under nitrogen protection, triethylamine (0.5 mL) was added to a mixture of the starting material (100 mg, 0.25 mmol), 2-methylbut-3-yn-2-ol (25.9 μL, 0.28 mmol), cuprous iodide (15.2 mg, 0.08 mmol), and bis(triphenylphosphine)palladium dichloride (21 mg, 0.03 mmol) in tetrahydrofuran (3 mL). The solution was heated at 70 °C for 5 h, and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried on Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (PE:EA = 1:1) to give the product (36.6 mg, 40.9%). MS (ESI): m / z found 358 [M+H] + .

[0283] Synthesis of 12.3(E)-4-(((2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)pyridin-3-yl)methylene)amino)phenyl)-2-methylbut-3-yne-2-ol

[0284] Under nitrogen protection, a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (56.7 mg, 0.069 mmol) was added to a mixture of the starting material (124.9 mg, 0.347 mmol), 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline (120 mg, 0.417 mmol), and potassium phosphate (110.5 mg, 0.521 mmol) in tetrahydrofuran (2.5 mL) and water (2.5 mL). The solution was heated at 80 °C for 4 h and then completely detected by LCMS. The product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 5:1) to give the product (50 mg, 32.9%). MS(ESI): m / z found439[M+H] + .

[0285] Example 13 Synthesis of Compound 17

[0286]

[0287] 13.1 Synthesis of 4-(((5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-(methylamino)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yne-2-ol

[0288] Under nitrogen protection, sodium cyanoborohydride (5.0 mg, 0.086 mmol) and a catalytic amount of glacial acetic acid were added to a mixture of 4-(3-(((2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-ol (25 mg, 0.057 mmol) in methanol (0.5 mL). The reaction mixture was stirred at room temperature for 1 h and completely detected by LC-MS. After 1 hour, formalin (10 μL, 0.063 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 5:1) to give the product (20 mg, 77.2%). MS (ESI): m / z found 456 [M+H] + .

[0289] Example 14 Synthesis of Compound 18

[0290]

[0291] 14.1 Synthesis of 5-bromo-3-fluoro-2-nitropyridine

[0292] Hydrogen peroxide (5 mL, 30% in H2O) was added dropwise to a mixture of 5-bromo-3-fluoro-2-aminopyridine (1.0 g, 5.23 mmol) and sulfuric acid (5 mL). The resulting mixture was stirred at room temperature for 16 hours, but the reaction was not complete. The solution was extracted with ethyl acetate in the presence of saturated sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 2-chloropyrimidin-4-yl)methanol (300 mg, 30% yield). MS (ESI): m / z found 221.

[0293] 14.2 Synthesis of tert-butyl 4-(4-((5-bromo-2-nitropyridin-3-yl)oxy)-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0294] Potassium carbonate (125 mg, 0.9 mmol) was added to a solution of the starting material (100 mg, 0.45 mmol) and tert-butyl 4-(4-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate (121 mg, 0.45 mmol) in DMSO (4 mL). The resulting mixture was stirred at 80 °C for 1.5 h. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give the product (140 mg, 61% yield). MS (ESI): m / z found 506 [m+H]+.

[0295] 14.3 Synthesis of 5-bromo-2-nitro-3-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridine

[0296] Add 2.0 mL of hydrochloric acid-dioxane solution (4 mmol / L) to the starting material (40 mg, 0.085 mmol), and stir the mixture at room temperature for hours under nitrogen atmosphere. Concentrate the reaction mixture to give 45 mg of crude product, which does not require further purification. MS (ESI): m / z found 369 [m+H]+.

[0297] 14.4 Synthesis of 5-bromo-3-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-nitropyridine

[0298] The compound obtained in the previous step (45 mg, 0.055 mmol), an aqueous solution of formaldehyde (10 μL, 0.127 mmol, 40% aqueous solution) was slowly added to a solution of sodium cyanoborohydride (10 mg, 0.127 mmol) in methanol (1.5 mL), and the mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. The reaction mixture was quenched with water, washed with ethyl acetate and brine, and concentrated by drying over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product 2-chloro-4,7-dimethyl-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidine (20 mg, 52% yield). MS (ESI): m / z found 382[m+H]+. 14.55 Synthesis of bromo-3-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridine-2-amine

[0299] Iron powder (9 mg, 0.3 mmol) and ammonium chloride (5 mg, 0.15 mmol) were added to a mixed solution of the starting material (20 mg, 0.052 mmol) in ethanol (1 mL) and water (0.2 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 10:1) to give the product (15 mg, 83% yield). MS (ESI): m / z found 352 [m+H]+.

[0300] Synthesis of 14.6(R)-N-methyl-3-(2-methylpyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzenesulfonamide

[0301] To a solution of (R)-3-bromo-N-methyl-5-(2-methylpyrrolidone-1-yl)benzenesulfonamide (360 mg, 1.08 mmol), bis(pinacolborate) (360 mg, 1.4 mmol), and potassium acetate (213 mg, 2.16 mmol) in 1,4-dioxane (5 mL), a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (80 mg, 0.108 mmol) was added. The mixture was stirred at 100 °C under nitrogen for 6 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 2:1) to give the product (300 mg, 73% yield). MS (ESI): m / z found 381 [m+H]+.

[0302] Synthesis of 14.7(R)-3-(6-amino-5-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-3-yl)-N-methyl-5-(2-methylpyrrolidine-1-yl)benzenesulfonamide

[0303] The compound obtained in the previous step (195 mg, 0.51 mmol), 473-ZS-04P (150 mg, 0.42 mmol), and potassium carbonate (118 mg, 0.85 mmol) were added to a solution of tetrahydrofuran (4 mL) and water (0.8 mL), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (32 mg, 0.042 mmol). The mixture was stirred at 80 °C under nitrogen for 3 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using Pre-p (dichloromethane:methanol = 10:1) to give the product (60 mg, 26% yield). MS (ESI): m / z found 526.2 [m+H]+.

[0304] Example 15 Synthesis of Compound 19

[0305]

[0306] 15.1 Synthesis of 3-iodobenzoyl chloride

[0307] A solution of 3-iodobenzoic acid (2.5 g, 10.08 mmol) in SOCl2 (12 mL) was stirred at 60 °C for 2 h and completely detected by TLC. The solvent was concentrated under reduced pressure to obtain the crude product.

[0308] Synthesis of 15.2N-(5-bromo-2-nitropyridin-3-yl)-3-iodobenzamide

[0309] Triethylamine (4.2 mL) and 5-bromo-2-nitropyridine-3-amine (546.8 mg, 2.52 mmol) were added to a solution of the starting material (2.5 mg, crude product, 10.08 mmol) in dichloromethane (10 mL). The solution was stirred at room temperature for 1 day, and then completely analyzed by LC-MS. The solvent was extracted with EA. The organic layer was dried on Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (508 mg, 45.1%). MS (ESI): m / z found 447.9 [M+H] + .

[0310] Synthesis of 15.3N-(5-bromo-2-nitropyridin-3-yl)-3-(3-hydroxy-3-methylbut-1-yn-1-yl)benzamide

[0311] Under nitrogen protection, triethylamine (0.3 ml) was added to a mixture of the starting material (128 mg, 0.287 mmol), 2-methylbut-3-yn-2-ol (30.6 μL, 0.316 mmol), and cuprous iodide (16.4 mg, 0.086 mmol) in tetrahydrofuran (2.5 ml). The reaction mixture was stirred at 70 °C for 4 hours and completely detected by LC-MS. The solvent was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the product (50 mg, 43.5%). MS (ESI): m / z found 404 [M+H] + .

[0312] Synthesis of 15.4N-(2-amino-5-bromopyridin-3-yl)-3-(3-hydroxy-3-methylbut-1-yn-1-yl)benzamide

[0313] Under nitrogen protection, reduced iron powder (138.6 mg, 2.319 mmol) was added to a solution of the starting material (190 mg, 0.474 mmol) and ammonium chloride (88.7 mg, 1.658 mmol) in ethanol (7.5 mL) and water (1.5 mL). The reaction mixture was heated at 50 °C for 3 h and completely detected by LC-MS. The solvent was filtered and concentrated under reduced pressure to obtain the crude product. (50 mg) MS (ESI): m / z found 374 [M+H) + .

[0314] Synthesis of 15.5N-(2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)pyridin-3-yl)-3-(3-hydroxy-3-methylbut-1-yn-1-yl)benzamide

[0315] Under nitrogen protection, a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (20 mg, 0.027 mmol) was added to a solution of 0000641-CW-054R1 (50 mg, 0.134 mmol), 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline (46 mg, 0.161 mmol) and potassium phosphate (43 mg, 0.201 mmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL). The solution was heated at 80 °C for 3 h and then completely detected by LC-MS. The solvent was extracted with EA. The organic layer was dried on Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (42 mg, 69.4%). MS(ESI): m / z found 455.2 [M+H] + .

[0316] Example 16 Synthesis of Compound 20

[0317]

[0318] 16.1 Synthesis of 2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0319] DIEA (0.48 mL, 2.76 mmol) was added to a DMF (15 mL) solution of 2-amino-5-bromonicotinic acid (500 mg, 2.30 mmol), 4-(3-aminophenyl)-2-methylbut-3-yn-2-ol (403 mg, 2.30 mmol), and HATU (875 mg, 2.30 mmol). The resulting solution was stirred at room temperature for 2 hours. The solution was diluted with water (20 mL) and extracted with DCM (25 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20% EA in DCM) to give 2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide (500 mg, 58%) as a yellow solid. MS (ESI): m / z found 375.2 [M+H] + .

[0320] 16.2 Synthesis of 2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0321] To a solution of 2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide (200 mg, 0.536 mmol) in THF (3 mL) and H₂O (3 mL), 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline (154 mg, 0.536 mmol), K₃PO₄ (175 mg, 0.804 mmol), and Pd(dppf)Cl₂·CH₂Cl₂ (50 mg, 0.053 mmol) were added. The resulting solution was stirred at 80 °C for 2 hours. The solution was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (10% methanol in DCM) to give a yellow oily 2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide (50 mg, 28%). MS (ESI): m / z found 455.6 [M+H] + .

[0322] Example 17 Synthesis of Compound 21

[0323]

[0324] 17.1 Synthesis of 5-bromo-3-(3-nitro-1H-pyrrolo-1-yl)pyrazin-2-amine

[0325] Potassium carbonate (925 mg, 8.03 mmol) was added to a mixture of 3-nitro-1H-pyrrole (500 mg, 4.46 mmol) and 3,5-dibromopyrazin-2-amine (1.35 g, 5.35 mmol) in DMF (10 mL). The reaction mixture was stirred at 100 °C for 6 hours. After the reaction was complete as monitored by LCMS, 20 mL of water was added, and the mixture was filtered to obtain a solid crude product. MS (ESI): m / z found 284 [M+H] + .

[0326] 17.2 Synthesis of 3-(3-amino-1H-pyrrolo-1-yl)-5-bromopyrazine-2-amine

[0327] Under nitrogen protection, reduced iron powder (188 mg, 3.52 mmol) was added to a mixture of the starting material (200 mg, 0.70 mmol) and ammonium chloride (118 mg, 2.11 mmol) in ethanol (8 mL) and water (4 mL). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. MS (ESI): m / z found 254 [M+H] + .

[0328] Synthesis of 17.3N-(1-(3-amino-6-bromopyrazin-2-yl)-1H-pyrrolo-3-yl)ethanesulfonamide

[0329] Under nitrogen protection and an ice bath, ethanesulfonyl chloride (219.8 mg, 1.75 mmol) was added dropwise to a mixture of tetrahydrofuran (5 mL) containing the starting material (540 mg, crude product, 0.70 mmol) and pyridine (276.9 mg, 3.50 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. After the reaction was completed as monitored by LCMS, the reaction was quenched with water. The mixture was extracted with a mixture of chloroform and isopropanol (3:1). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the product (228.2 mg, 94.2%). MS (ESI): m / z found 346 [M+H] + .

[0330] Synthesis of 17.4N-(1-(3-amino-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)pyrazin-2-yl)-1H-pyrrole-3-yl)ethanesulfonamide

[0331] Under nitrogen protection, 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline (129.6 mg, 0.45 mmol) and potassium phosphate (143.1 mg, 0.68 mmol) [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (65.7 mg, 0.09 mmol) were added to a mixed solution of 0000472-CW-043R1 (220 mg, 0.52 mmol) in tetrahydrofuran (6 mL) and water (6 mL). The solution was heated at 80 °C for 8 h. After the reaction was completed as monitored by LCMS, the solution was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:MeOH = 1:1) to give the final product (110 mg, 49.8%). MS (ESI): m / z found 427 [M+H] + .

[0332] Example 18 Synthesis of Compound 22

[0333]

[0334] 18.1 Synthesis of tert-butyl 4-(4-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0335] Sodium hydroxide (106 mg, 2.65 mmol) was added to a mixture of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.325 mmol) in tetrahydrofuran (12 mL). The resulting mixture was stirred at room temperature for 5 minutes, and hydrogen peroxide (270 μL, 2.65 mmol, 30% inH2O) was added dropwise while stirring at room temperature for 1.5 hours. The pH of the reaction mixture was adjusted to 7 with 1 mol / L hydrochloric acid solution. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give 4-(4-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 71% yield). MS(ESI): m / z found 212.2[m+H] + .

[0336] 18.2 Synthesis of 1-(piperidin-4-yl)-1H-pyrazole-4-ol

[0337] The compound obtained in the previous step (800 mg, 2.98 mmol) was added to a solution of dioxane hydrochloride (5 M, 4 mol / L in dioxane), and the resulting mixture was stirred at room temperature for 1 hour. The solution was concentrated to give a crude product (700 mg), which did not require purification. MS (ESI): m / z found 168.2 [m+H] + .

[0338] 18.3 Synthesis of 1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-ol

[0339] The compound obtained in the previous step (700 mg, 2.98 mmol), an aqueous solution of formaldehyde (310 μL, 4.47 mmol, 40% aqueous solution), and sodium cyanoborohydride (282 mg, 4.47 mmol) in methanol (5 mL) were slowly added. The mixture was stirred at room temperature for 5 hours under nitrogen atmosphere. The reaction mixture was concentrated to give a crude product (550 mg) without purification. MS (ESI): m / z found 182.2 [m+H]+.

[0340] 18.4 Synthesis of 5-bromo-3-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)-2-nitropyridine

[0341] The compound obtained in the previous step (550 mg, 2.98 mmol), 5-bromo-3-fluoro-2-nitropyridine (650 mg, 2.98 mmol), and potassium carbonate (820 mg, 5.96 mmol) were added to dimethyl sulfoxide (5 mL). The resulting solution was stirred at 80 °C under nitrogen for 1.5 hours. The solution was extracted with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product (390 mg, 34% yield). MS (ESI): m / z found 382 / 384 [m+H]+.

[0342] 18.5 Synthesis of 2,5-dimethyl-7-(5-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)-6-nitropyridin-3-yl)-1,2,4-tetrahydroisoquinoline

[0343] The compound obtained in the previous step (190 mg, 0.5 mmol), 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline (172 mg, 0.59 mmol), and potassium phosphate (212 mg, 0.99 mmol) were added to a solution of tetrahydrofuran (6 mL) and water (1.2 mL) along with a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (41 mg, 0.05 mmol). The mixture was stirred at 80 °C under nitrogen for 3 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using Pre-p (dichloromethane:methanol = 5:1) to give the product (50 mg, 21% yield). MS (ESI): m / z found 463.2 [m+H]+.

[0344] 18.6 Synthesis of 5-(2,5-dimethyl-1,2,4-tetrahydroisoquinoline-7-yl)-3-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridine-2-amine

[0345] Iron powder (37 mg, 0.65 mmol) and ammonium chloride (20 mg, 0.32 mmol) were added to a mixed solution of the starting material (50 mg, 0.1 mmol) in ethanol (3 mL) and water (0.6 mL). The mixture was stirred at 50 °C for 4 hours. The reaction mixture was filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 5:1) to give the product (12 mg, 28% yield). MS (ESI): m / z found 433.2 [m+H] + .

[0346] Example 19 Synthesis of Compound 23

[0347]

[0348] 19.1 Synthesis of (E)-4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0349] TEA (10 mL) was added to a mixed solution of 3-iodoaniline (5 g, 22.83 mmol), 2-methylbut-3-yn-2-ol (5.07 mL, 68.49 mmol), CuI (1.31 g, 6.85 mmol), and PdCl2(PPh3)2 (1.6 g, 2.28 mmol) in dioxane (50 mL) under N2 conditions. The solution was heated at room temperature for 5 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (3.5 g, 87.5%). MS (ESI): 176 [m+H]+.

[0350] Synthesis of 19.2(E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide: DIEA (2.4 mL, 13.72 mmol) was added to a mixture of starting material (2 g, 11.43 mmol), 2-amino-5-bromonicotinic acid (2.48 g, 11.43 mmol), and HATU (3.5 g, 11.42 mmol) in DMF (20 mL). The reaction was carried out at room temperature for 2 hours and completely detected by LC-MS. The solvent was filtered and the solid (3.6 g, 84.2%) was collected. MS (ESI): 375 [m+H] + .

[0351] Synthesis of 19.3(E)-2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)benzene)nicotinamide

[0352] Under N2 atmosphere, Pd(dppf)Cl2 DCM (43.6 mg, 0.0535 mmol) was added to a mixed solution of the starting material (200 mg, 0.535 mmol), 1-(2,6-dimethyl-4-(4,4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)-4-methylpiperazine (220 mg, 0.642 mmol), and K3PO4 (180 mg, 1.604 mmol) in dioxane (4 mL) and H2O (0.8 mL). The solution was heated at 80 °C for 4 h and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (57 mg, 20.4%). MS (ESI): 497.6 [m+H] + .

[0353] Example 20 Synthesis of Compound 24

[0354]

[0355] Synthesis of 20.1(E)-4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0356] TEA (10 mL) was added to a mixed solution of 3-iodoaniline (5 g, 22.83 mmol), 2-methylbut-3-yn-2-ol (5.07 mL, 68.49 mmol), CuI (1.31 g, 6.85 mmol), and PdCl2(PPh3)2 (1.6 g, 2.28 mmol) in dioxane (50 mL) under N2 conditions. The solution was heated at room temperature for 5 h, and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (3.5 g, 87.5%). MS (ESI): 176 [m+H] + .

[0357] Synthesis of 20.2(E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0358] DIEA (0.31 mL, 1.371 mmol) was added to a mixture of the starting material (200 mg, 1.143 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (250 mg, 1.143 mmol), and HATU (522 mg, 3.43 mmol) in DMF (4 mL). The reaction was allowed to proceed for 2 hours at room temperature and the reaction was completely detected by LC-MS. The solvent was filtered and the solid (350 mg, 81.4%) was collected. MS (ESI): 376 [m+H]+.

[0359] Synthesis of 20.3(E)-3-amino-6-(2,5-dimethyl-1,2,4-tetrahydroisoquinoline-7-yl)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)pyrazine-2-carboxamide

[0360] A solution of the starting material (350 mg, 0.933 mmol), 2,5-dimethyl-7-(4,4,4,5,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1,2,3,4-tetrahydroisoquinoline (322 mg, 1.12 mmol), and K3PO4 (275 mg, 2.88 mmol) in dioxane (8 mL) and H2O (1.6 mL) was heated at 80 °C for 4 hours under nitrogen. The solution was then analyzed by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to obtain the product (160 mg, 37.6%). MS (ESI): 455.6 [m+H] + .

[0361] Example 21 Synthesis of Compound 25

[0362]

[0363] 21.1 Synthesis of 7-bromo-1,4-dimethyl-3,4-dihydropyrrolo[4,3,2-de]isoquinoline-5(1H)-one

[0364] Sodium hydride (60 mg, 1.36 mmol) was added to a solution of 7-bromo-4-methyl-3,4-dihydropyrrolo[4,3,2-de]isoquinoline-5(1H)-one (240 mg, 0.909 mmol) in DMF (5 mL) under ice bath conditions. After 30 minutes, methyl iodide (90 μL, 1.36 mmol) was added. The reaction was stirred at room temperature for 3 hours and completely detected by LC-MS. The solvent was quenched with saturated NH4Cl aqueous solution and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to give the product (200 mg, 79.1%). MS (ESI): m / z found 279 / 281 [M+H-56] + .21.2 Synthesis of 7-bromo-1,4-dimethyl-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline

[0365] Under nitrogen protection, lithium aluminum hydride (1.3 mL) was added to a tetrahydrofuran (5 mL) solution of the starting material (200 mg, 0.72 mmol) in an ice bath. The solution was stirred at room temperature for 0.5 h, and then completely analyzed by LC-MS. The solvent was quenched with 2 M sodium hydroxide aqueous solution and washed with ethyl acetate. The resulting solution was filtered and concentrated to obtain the crude product. MS (ESI): m / z found 265 / 267 [M+H] + .

[0366] 21.3 Synthesis of (5-amino-6-((3-hydroxy-3-methylbut-1-ylbut-1-ynyl)phenyl)carbamoyl)pyridine-2-boronic acid

[0367] Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (234 mg, 0.32 mmol) was added to a solution of 3-amino-6-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)pyridinecarboxamide (600 mg, 1.60 mmol), pinacol diboronate (486 mg, 1.92 mmol), and potassium acetate (237 mg, 2.41 mmol) in dioxane (7.5 mL). The reaction mixture was heated at 80 °C for 2.5 h and completely detected by LC-MS. The solvent was filtered and concentrated under reduced pressure to give the crude product. (300 mg) MS (ESI): m / z found 340 [M+H] + .

[0368] 21.4 Synthesis of 3-amino-6-(1,4-dimethyl-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline-7-yl)-N-(3-(3-hydroxy-3-methylbut-1-ynyl)phenyl)pyridinecarboxamide

[0369] Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (111 mg, 0.15 mmol) was added to a mixed solution of starter 1 (300 mg, 0.88 mmol), starter 2 (200 mg, 0.76 mmol), and potassium phosphate (242 mg, 1.14 mmol) in tetrahydrofuran (3 mL) and water (3 mL) under N2 atmosphere. The solution was heated at 80 °C for 3 h, and then completely detected by LC-MS. The solvent was extracted with EA. The organic layer was dried on Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (220 mg, 60.4%). MS (ESI): m / z found 480 [M+H] + .

[0370] Example 22 Synthesis of Compound 27

[0371]

[0372] 22.1 Synthesis of tert-butyl 4-(thiazolyl-2-yl)piperidine-1-carboxylate

[0373] To a solution of tert-butyl 4-carbamoylpiperidin-1-carboxylate (2 g, 8.18 mmol) in ethanol (50 mL), 2-bromo-1,1-diethoxyethane (1.6 g, 8.18 mmol) and TsOH·H₂O (3 g, 16.36 mmol) were added. The resulting solution was stirred overnight at 80 °C, and then (BoC)₂ (2.7 g, 12.27 mmol) was added at room temperature. The resulting solution was stirred at room temperature for 5 hours. The solution was diluted with water (20 mL) and extracted with DCM (40 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (50% EA in PE) to give a yellow oily tert-butyl 4-(thiazol-2-yl)piperidin-1-carboxylate (1.2 g, 55%). MS (ESI): m / z found 269.4 [M+H] + .

[0374] 22.2 Synthesis of 2-(piperidin-4-yl)thiazole

[0375] 4-(thiazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester (1.2 g, 3.73 mmol) in a mixture of HCl, dioxane (15 mL), and dioxane. The resulting solution was stirred at room temperature for 0.5 hours. The solution was evaporated to give a yellow oily 2-(piperidin-4-yl)thiazolium (1 g, 83%). MS (ESI): m / z found 169.3 [M+H] + .

[0376] 22.3 Synthesis of 2-(1-methylpiperidin-4-yl)thiazole

[0377] TEA (822 mg, 5.92 mmol), CH2O (0.67 mL, 8.88 mmol), and STAB (1.8 g, 8.88 mmol) were added to a mixture of 2-(piperidin-4-yl)thiazole (1 g, 5.92 mmol) in THF (40 mL). The resulting solution was stirred at room temperature for 3 hours. The solution was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (50% EA in PE) to give a yellow oily 2-(1-methylpiperidin-4-yl)thiazole (600 mg, 60%). MS (ESI): m / z found 183.3 [M+H] + .

[0378] 22.4 Synthesis of 2-(1-methylpiperidin-4-yl)-5-(tributyltinyl)thiazole

[0379] To a mixture of 2-(1-methylpiperidin-4-yl)thiazole (150 mg, 0.82 mmol) in THF (3 mL), n-butyllithium (0.5 mL, 0.82 mol) was added. The resulting solution was stirred at -78 °C for 1 hour, and then Bu3SnC (0.3 mL, 0.82 mmol) was added. The resulting solution was stirred at -78 °C for 1 hour. The solution was diluted with NH4.Cl (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20% MeOH in DCM) to give a yellow oily 2-(1-methylpiperidin-4-yl)-5-(tributyltinyl)thiazole (200 mg, 52%). MS (ESI): m / z found 472.3 [M+H] + .

[0380] 22.5 Synthesis of 2-(5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)-5-(1-methylpiperidin-4-yl)thiazole

[0381] CuI (25 mg, 0.3 mmol) and Pd(PPh)3Cl2 (35 mg, 0.1 mmol) were added to a mixture of 2-(1-methylpiperidin-4-yl)-5-(tributyltinyl)thiazole (200 mg, 1.0 mmol) dissolved in dioxane (5 mL). The resulting solution was stirred at 90 °C for 6 hours under a nitrogen atmosphere. The solution was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20% MeOH in DCM) to give a yellow oily 2-(5-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-6-nitropyridin-3-yl)-5-(1-methylpiperidin-4-yl)thiazole (100 mg, 41%). MS (ESI): m / z found 577.7 [M+H] + 22.6 Synthesis of 4-(3-((2-amino-5-(5-(1-methylpiperidin-4-yl)thiazolyl-2-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yne-2-ol

[0382] Zn (113 mg, 1.7 mmol) and TsOH·H₂O (5 mg, 0.1 mmol) were added to a mixture of 2-(1-methylpiperidin-4-yl)-5-(tributyltinyl)thiazole (100 mg, 0.17 mmol) in ACOH (2 mL). The resulting solution was stirred at room temperature for 1 hour. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20% MeOH in DCM) to give a yellow oily 4-(3-(((2-amino-5-(5-(1-methylpiperidin-4-yl)thiazole-2-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-ol (100 mg, 41%). MS (ESI): m / z found 463.6 [M+H] + .

[0383] Example 23 Synthesis of Compound 28

[0384]

[0385] 23.1 Synthesis of (R)-3-bromo-N-methyl-5-(2-methylpyrrolidone-1-yl)benzenesulfonamide

[0386] Methylamine (3.84 mL, 7.68 mmol, 2 mol / L in THF) was added to a solution of (R)-3-bromo-5-(2-methylpyrrolidone-1-yl)benzenesulfonyl chloride (0.5 mL, 3.4 mmol) in pyridine (10 mL), and the resulting mixture was stirred at room temperature for 3 hours. The solution was quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give the product (650 mg, 67% yield). MS (ESI): m / z found 268 [m+H]+.

[0387] Synthesis of 23.2(R)-N-methyl-3-(2-methylpyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzenesulfonamide

[0388] To a solution of (R)-3-bromo-N-methyl-5-(2-methylpyrrolidone-1-yl)benzenesulfonamide (360 mg, 1.08 mmol), bis(pinacolborate) (360 mg, 1.4 mmol), and potassium acetate (213 mg, 2.16 mmol) in 1,4-dioxane (5 mL), a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (80 mg, 0.108 mmol) was added. The mixture was stirred at 100 °C under nitrogen for 6 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 2:1) to give the product (300 mg, 73% yield). MS (ESI): m / z found 381 [m+H]+.

[0389] Synthesis of 23.3(R)-2-amino-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-5-(3-(2-methylpyrrolidin-1-yl)-5-(N-methylaminosulfonyl)phenyl)nicotinamide

[0390] The compound obtained in the previous step (240 mg, 0.64 mmol) and 2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide (200 mg, 0.53 mmol) and potassium carbonate (150 mg, 1.07 mmol) were added to a solution of dioxane (6 mL) and water (1.2 mL) along with a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (50 mg, 0.053 mmol). The mixture was stirred at 95 °C for 3 hours. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give the product (106 mg, 36% yield). MS (ESI): m / z found 548.6 [m+H]+.

[0391] Example 24 Synthesis of Compound 29

[0392]

[0393] 24.1 Synthesis of (E)-4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0394] TEA (10 mL) was added to a mixed solution of 3-iodoaniline (5 g, 22.83 mmol), 2-methylbut-3-yn-2-ol (5.07 mL, 68.49 mmol), CuI (1.31 g, 6.85 mmol), and PdCl2(PPh3)2 (1.6 g, 2.28 mmol) in dioxane (50 mL) under N2 conditions. The solution was heated at room temperature for 5 h, and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (3.5 g, 87.5%). MS (ESI): 176 [m+H] + .

[0395] Synthesis of 24.2(E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0396] DIEA (2.4 mL, 13.72 mmol) was added to a mixed solution of the starting material (2 g, 11.43 mmol), 2-amino-5-bromonicotinic acid (2.48 g, 11.43 mmol), and HATU (3.5 g, 11.42 mmol) in DMF (20 mL). The reaction was allowed to proceed for 2 hours at room temperature, and the sample was completely detected by LC-MS. The solvent was filtered off, and the solid (3.6 g, 84.2%) was collected. MS (ESI): 375 [m+H] + .

[0397] Synthesis of 24.3(E)-(6-amino-5-((3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)carbamoyl)pyridin-3-yl)boronic acid

[0398] Under N2, Pd(dppf)Cl2 (196 mg, 0.268 mmol) was added to a mixed solution of starting material (500 mg, 1.34 mmol), 4,4,4',4',4',4',5,5,5',5',5'-octamethyl-2,2'-bis(1,3,2-dioxaboron (406 mg, 1.61 mmol) and KoAc (200 mg, 2.01 mmol) in dioxane (5 mL). The solution was heated at 80 °C for 4 h and then purged with N2. LC-MS was used for complete detection. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (734 mg). MS (ESI): 340 [m+H] + .

[0399] Synthesis of 24,4(E)-7-bromo-2-(2,2-difluoroethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline

[0400] Under N2 atmosphere, a mixture of 7-bromo-5-methyl-1,2,4-tetrahydroisoquinoline (250 mg, 1.06 mmol), 1,1-difluoro-2-iodoethane (425 μL, 4.24 mmol), and K2CO3 (306 mg, 2.12 mmol) in DMF (5 mL) was added. The solution was heated overnight at 100 °C and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC to give the product (170 mg, 53.1%). MS (ESI): 290 [m+H] + .

[0401] Synthesis of 24.5(E)-2-amino-5-(2-(2,2-difluoroethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0402] To a mixed solution of feedstock 1 (180 mg, 0.529 mmol), feedstock 2 (138 mg, 0.582 mmol), and K₂CO₃ (160 mg, 1.59 mmol) in dioxane (2 mL) and H₂O (0.4 mL), Pd(dp pf)Cl₂ (39 mg, 0.0529 mmol) was added under N₂. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to obtain the product (30 mg, 11.3%). MS (ESI): 504.6 [m+H] + .

[0403] Example 25 Synthesis of Compound 141

[0404]

[0405] Synthesis of 25.1(S)-4-(6-amino-5-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)-N-(2-(3-fluoropyrrolidone-1-yl)ethyl)-2,6-dimethylbenzamide

[0406] Under nitrogen protection, S-phos PdG2 (5 mg) was added to a mixture of (6-amino-5-(2-(tert-butoxycarbonyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (S)-4-bromo-N-(2-(3-fluoropyrrolidone-1-yl)ethyl)-2,6-dimethylbenzamide (54 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), dioxane (3 mL), and water (0.6 mL). The reaction mixture was stirred overnight at 80 °C, and the reaction was monitored by TLC until completion. After concentration under reduced pressure, 2 mL of TFA was added, and the reaction was monitored by LCMS until completion. The mixture was then extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (20 mg, 30.6%). MS(ESI):[M+H] + =502.2.

[0407] Example 26 Synthesis of Compound 30

[0408]

[0409] 26.1 Synthesis of (E)-4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0410] TEA (10 mL) was added to a mixed solution of 3-iodoaniline (5 g, 22.83 mmol), 2-methylbut-3-yn-2-ol (5.07 mL, 68.49 mmol), CuI (1.31 g, 6.85 mmol), and PdCl2(PPh3)2 (1.6 g, 2.28 mmol) in dioxane (50 mL) under N2 conditions. The solution was heated at room temperature for 5 h, and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (3.5 g, 87.5%). MS (ESI): 176 [m+H] + .

[0411] Synthesis of 26.2(E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0412] DIEA (2.4 mL, 13.72 mmol) was added to a mixed solution of the starting material (2 g, 11.43 mmol), 2-amino-5-bromonicotinic acid (2.48 g, 11.43 mmol), and HATU (3.5 g, 11.42 mmol) in DMF (20 mL). The reaction was heated at room temperature for 2 hours and completely detected by LC-MS. The solvent was filtered and the solid (3.6 g, 84.2%) was collected. MS (ES I): 375 [m+H] + .

[0413] Synthesis of 26.3(E)-(6-amino-5-((3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)carbamoyl)pyridin-3-yl)boronic acid

[0414] Under N2, Pd(dppf)Cl2 (196 mg, 0.268 mmol) was added to a mixed solution of starting material (500 mg, 1.34 mmol), 4,4,4',4',4',4',5,5,5',5',5'-octamethyl-2,2'-bis(1,3,2-dioxaboron (406 mg, 1.61 mmol) and KoAc (200 mg, 2.01 mmol) in dioxane (5 mL). The solution was heated at 80 °C for 4 h and then purged with N2. LC-MS was used for complete detection. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (734 mg). MS (ESI): 340 [m+H] + .

[0415] Synthesis of 26,4(E)-2-(7-bromo-5-methyl-3,4-dihydroisoquinoline-2(1H)-yl)ethyl-1-ol

[0416] Under N2 atmosphere, a mixture of 7-bromo-5-methyl-1,2,4-tetrahydroisoquinoline (150 mg, 0.66 mmol), bromoethanol (75 μL, 1 mmol), and K2CO3 (185 mg, 1.32 mmol) in DMF (3 mL) was added. The solution was heated overnight at 100 °C and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC to give the product (125 mg, 64.8%). MS (ESI): 270 [m+H] + .

[0417] Synthesis of 26.5(E)-2-amino-N-(3-(3-hydroxy-3-methylbut-1-ynyl)phenyl)-5-(2-hydroxyethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)nicotinamide

[0418] To a mixed solution of feedstock 1 (75 mg, 0.22 mmol), feedstock 2 (60 mg, 0.242 mmol), and K₂CO₃ (85 mg, 0.66 mmol) in dioxane (2 mL) and H₂O (0.4 mL), Pd(dppf)Cl₂ (16 mg, 0.022 mmol) was added under N₂. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to obtain the product (20 mg, 18.7%). MS (ESI): 485 [m+H]⁺.

[0419] Example 27 Synthesis of Compound 33

[0420]

[0421] 27.1 Synthesis of 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydroisoquinoline

[0422] 7-Bromo-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline (400 mg, 1.67 mmol), pinacol diboronate (420 mg, 1.67 mmol), potassium acetate (204 mg, 2.08 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (203 mg, 0.28 mmol) dissolved in 1,4-dioxane (5 mL) were added to a reaction vessel. The mixture was reacted at 80 °C for 3 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the mixture was filtered and concentrated under reduced pressure by distillation to obtain the crude product (500 mg). MS (ESI): m / z found 288 [M+H] + .

[0423] 27.2 Synthesis of 3,6-dichloro-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)pyridazine-4-carboxamide

[0424] 3,6-Dichloropyridazine-4-carboxylic acid (1 g, 5.21 mmol), 4-(3-aminophenyl)-2-methylbut-3-yn-2-ol (0.45 g, 2.60 mmol), EDCI (1 g, 5.21 mmol), and DMAP (33 mg, 0.26 mmol) dissolved in DCM (15 mL) were added to the reaction vessel. The mixture was reacted at room temperature for 4 hours. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. The crude product was purified by column chromatography (PE:EA = 6:1) to give the title compound (500 mg, 27.5%). MS (ESI): m / z found 350 [M+H] + .27.3 Synthesis of 3-chloro-6-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)pyridazine-4-carboxamide

[0425] Starting material 1 (500 mg, 1.43 mmol), starting material 2 (500 mg), potassium phosphate (455 mg, 2.1 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (209 mg, 0.29 mmol) dissolved in tetrahydrofuran (5 mL) and water (5 mL) were added to the reaction vessel. The mixture was reacted at 80 °C for 3 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. Purification was performed by column chromatography (DCM:MeOH = 5:1) to give the title compound (120 mg, 17.7%). MS (ESI): m / zfound 475 [M+H] + .

[0426] Example 28 Synthesis of Compound 37

[0427]

[0428] 28.1 Synthesis of (E)-4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0429] TEA (10 mL) was added to a mixed solution of 3-iodoaniline (5 g, 22.83 mmol), 2-methylbut-3-yn-2-ol (5.07 mL, 68.49 mmol), CuI (1.31 g, 6.85 mmol), and PdCl2(PPh3)2 (1.6 g, 2.28 mmol) in dioxane (50 mL) under N2 conditions. The solution was heated at room temperature for 5 h, and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (3.5 g, 87.5%). MS (ESI): 176 [m+H] + .

[0430] Synthesis of 28.2(E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0431] DIEA (2.4 mL, 13.72 mmol) was added to a mixed solution of the starting material (2 g, 11.43 mmol), 2-amino-5-bromonicotinic acid (2.48 g, 11.43 mmol), and HATU (3.5 g, 11.42 mmol) in DMF (20 mL). The reaction was heated at room temperature for 2 hours and completely detected by LC-MS. The solvent was filtered and the solid (3.6 g, 84.2%) was collected. MS (ES I): 375 [m+H] + .

[0432] Synthesis of 28.3(E)-(6-amino-5-((3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)carbamoyl)pyridin-3-yl)boronic acid

[0433] Under N2, Pd(dppf)Cl2 (196 mg, 0.268 mmol) was added to a mixed solution of starting material (500 mg, 1.34 mmol), 4,4,4',4',4',4',5,5,5',5',5'-octamethyl-2,2'-bis(1,3,2-dioxaboron (406 mg, 1.61 mmol) and KoAc (200 mg, 2.01 mmol) in dioxane (5 mL). The solution was heated at 80 °C for 4 h and then purged with N2. LC-MS was used for complete detection. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (734 mg). MS (ESI): 340 [m+H] + .

[0434] Synthesis of 28.4(E)-7-bromo-5-methyl-2-(3-methyloxetane-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline

[0435] Under N2 atmosphere, a mixed solution of 7-bromo-5-methyl-1,2,4-tetrahydroisoquinoline (345 mg, 1.53 mmol), 3-bromomethyl-3-methyloxetane (212 μL, 2.3 mmol), and K2CO3 (520 mg, 4.6 mmol) in ACN (6 mL) was added. The solution was heated at 65 °C overnight and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC to give the product (224 mg, 47.4%). MS (ESI): 310.2 [m+H] + .

[0436] Synthesis of 28.5(E)-2-amino-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)-5-(5-methyl-2-(3-methyloxetane-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)nicotinamide

[0437] To a mixed solution of feedstock 1 (200 mg, 0.59 mmol), feedstock 2 (224 mg, 0.73 mmol), and Na₂CO₃ (136 mg, 1.77 mmol) in dioxane (4 mL) and H₂O (0.8 mL), Pd(pph₃)₄ (68 mg, 0.06 mmol) was added under N₂. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to obtain the product (103 mg, 33.5%). MS (ESI): 524.7 [m+H] + .

[0438] Example 29 Synthesis of Compound 40

[0439]

[0440] 29.1 Synthesis of 6-dichloro-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)pyridazine-4-carboxamide

[0441] 3,6-Dichloropyridazine-4-carboxylic acid (800 mg, 4.57 mmol), 4-(3-aminophenyl)-2-methylbut-3-yn-2-ol (1.75 g, 9.14 mmol), EDCI (1.75 g, 9.14 mmol), and DMAP (279 mg, 2.29 mmol) dissolved in DCM (15 mL) were added to the reaction vessel. The mixture was reacted at room temperature for 4 hours. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. The crude product was purified by column chromatography (PE:EA = 6:1) to give the title compound (420 mg, 26.3%). MS (ESI): m / z found 350 [M+H] + .

[0442] 29.2 Synthesis of 3-chloro-6-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)pyridazin-4-carboxamide

[0443] The starting material (200 mg, 0.57 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-4-methylpiperazine (100 mg, 0.30 mmol), potassium phosphate (181 mg, 0.86 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (83 mg, 0.11 mmol) dissolved in tetrahydrofuran (5 mL) and water (5 mL) were added to the reaction vessel. The mixture was reacted at 80 °C for 3 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. Purification was performed by column chromatography (DCM:MeOH = 5:1) to give the title compound (100 mg, 64.5%). MS (ESI): m / z found 518 [M+H] + .

[0444] Example 30 Synthesis of Compound 41

[0445]

[0446] Synthesis of 30.1(E)-4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0447] TEA (10 mL) was added to a mixed solution of 3-iodoaniline (5 g, 22.83 mmol), 2-methylbut-3-yn-2-ol (5.07 mL, 68.49 mmol), CuI (1.31 g, 6.85 mmol), and PdCl2(PPh3)2 (1.6 g, 2.28 mmol) in dioxane (50 mL) under N2 conditions. The solution was heated at room temperature for 5 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (3.5 g, 87.5%). MS (ESI): 176 [m+H]+.

[0448] Synthesis of 30.2(E)-2-methyl-4-(3-(methylamino)phenyl)but-3-yn-2-ol (0000676-DLY-054R1): Starting material (350 mg, 2 mmol), (CH₂O)n (332 mg, 8 mmol), and NaBH₄ (154 mg, 4 mmol) were placed in MeOH (5 mL) and reacted at room temperature for 2 hours, with complete detection by LC-MS. The solvent was filtered and the solid (110 mg, 28.9%) was collected. MS (ESI): 189.3 [m+H] + .

[0449] Synthesis of 30.3(E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-N-methylnicotinamide: DIEA (0.59 mL, 3.33 mmol) was added to a mixture of starting material (210 mg, 1.11 mmol), 2-amino-5-bromonicotinic acid (288 mg, 1.332 mmol), and HATU (630 mg, 1.66 mmol) in DMF (4 mL). The reaction was carried out at room temperature for 12 hours and completely detected by LC-MS. The solvent was filtered and the solid (260 mg, 60.6%) was collected. MS (ESI): 388.3 [m+H] + .

[0450] Synthesis of 30.4(E)-2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-N-methylnicotinamide

[0451] Under N2 atmosphere, Pd(dppf)Cl2 (28.3 mg, 0.039 mmol) was added to a mixed solution of the starting material (150 mg, 0.39 mmol), 1-(2,6-dimethyl-4-(4,4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)-4-methylpiperazine (147 mg, 0.48 mmol), and K2CO3 (160 mg, 1.17 mmol) in dioxane (2 mL) and H2O (0.4 mL). The solution was heated at 80 °C for 4 h and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (58 mg, 29.3%). MS (ESI): 511.7 [m+H] + .

[0452] Example 31 Synthesis of Compound 43

[0453]

[0454] 31.1 Synthesis of (E)-4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0455] TEA (10 mL) was added to a mixed solution of 3-iodoaniline (5 g, 22.83 mmol), 2-methylbut-3-yn-2-ol (5.07 mL, 68.49 mmol), CuI (1.31 g, 6.85 mmol), and PdCl2(PPh3)2 (1.6 g, 2.28 mmol) in dioxane (50 mL) under N2 conditions. The solution was heated at room temperature for 5 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (3.5 g, 87.5%). MS (ESI): 176 [m+H]+.

[0456] Synthesis of 31.2(E)-3-amino-6-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)pyrazin-2-carboxamide: The reaction proceeded from a starting material (200 mg, 1.14 mmol) and 3-amino-6-bromopyrazin-2-carboxylic acid (250 mg, 1.14 mmol) and HATU.

[0457] DIEA (0.31 mL, 1.37 mmol) was added to a mixture of 522 mg (1.14 mmol) in DMF (4 mL). The reaction was allowed to proceed for 12 hours at room temperature, and the mixture was completely detected by LC-MS. The solvent was filtered and the solid (414 mg, 95.4%) was collected. MS (ESI): 375.2 [m+H] + .

[0458] Synthesis of 31.3(E)-3-amino-6-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)pyrazine-2-carboxamide

[0459] Under N2 atmosphere, Pd(dppf)Cl2 (19.5 mg, 0.027 mmol) was added to a mixed solution of the starting material (100 mg, 0.27 mmol), 1-(2,6-dimethyl-4-(4,4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)-4-methylpiperazine (99.2 mg, 0.32 mmol), and K2CO3 (110 mg, 0.81 mmol) in dioxane (2 mL) and H2O (0.4 mL). The solution was heated at 80 °C for 4 h and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (110 mg, 82.7%). MS (ESI): 498.6 [m+H] + .

[0460] Example 32 Synthesis of Compound 44

[0461]

[0462] 32.1 Synthesis of 1-(3-bromo-5-methylphenyl)prop-1-one

[0463] Grignard reagent (4 mL, 28.5 mmol) was slowly added to a solution of compound 1 (1 g, 5.1 mmol) in ether (10 mL), and the mixture was stirred at room temperature for 16 hours. The resulting solution was quenched with saturated aqueous solution of 4 M hydrochloric acid (6 mL), stirred at room temperature for 6 hours, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product (petroleum ether:ethyl acetate = 20:1) was purified by silica gel column chromatography to give compound 2 (1.03 g, 89%) as a yellow oil.

[0464] 32.2 Synthesis of (S,E)-N-(1-(3-bromo-5-methylphenyl)propylidene)-2-methylpropane-2-sulfinamide

[0465] Tetraisopropyl titanate (4.8 mL, 22.6 mmol) was added to a mixture of compound 2 (1.03 g, 4.5 mmol) and (S)-(-)-2-methyl-2-propanesulfonamide (1.1 g, 9.1 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at 90 °C for 4 hours. The solution was diluted with dichloromethane, and an aqueous sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (3 × 100 mL), and the organic phases were combined. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product (petroleum ether:ethyl acetate = 5:1) was purified by silica gel column chromatography to give compound 3 (1.2 g, 80%) as a yellow oil.

[0466] Synthesis of 32.3(S)-N-(1-(3-bromo-5-methylphenyl)propyl)-2-methylpropane-2-sulfinamide

[0467] Lithium triisobutylborate (6.7 mL, 6.7 mmol) was added dropwise to a solution of compound 3 (1.05 g, 3.2 mmol) in THF (10 mL) at -78 °C. The resulting solution was stirred at -78 °C for 3 hours. The solution was quenched with methanol, diluted with brine, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the combined organic phases were purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound 4 (872 mg, 83%) as a yellow oil.

[0468] 32.4 Synthesis of 2-amino-5-(3-(1-((S)-tert-butylsulfinylamino)propyl)-5-methylphenyl)-N-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0469] Potassium phosphate (384 mg, 1.8 mmol) and the [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (49 mg, 0.1 mmol) were added to an ultradry mixed solution of compound 4 (200 mg, 0.6 mmol) and compound 5 (246 mg, 0.7 mmol) in water (4:1 mL) under nitrogen atmosphere. The mixture was stirred at 110 °C for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound 6 (89 mg, yield: 26%).

[0470] Synthesis of 32.5(S)-2-amino-5-(3-(1-aminopropyl)-5-methylphenyl)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

[0471] Hydrochloric acid (0.1 mL, 0.5 mmol) was added to a stirred solution of compound 6 (89 mg, 0.2 mmol) in methanol (4.5 mL). The resulting solution was stirred at room temperature for 16 hours. The pH of the solution was adjusted with sodium bicarbonate, the mixture was extracted with ethyl acetate (3 × 100 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated under vacuum, and purified by Prep-TLC (dichloromethane:methanol = 5:1) to give compound 7 (82 mg) as a yellow oil.

[0472] Example 33 Synthesis of Compound 45

[0473]

[0474] 33.1 Synthesis of 1-(3-bromo-5-methylphenyl)prop-1-one

[0475] Grignard reagent (12 mL, 85.7 mmol) was slowly added to a solution of compound 1 (3 g, 15.3 mmol) in diethyl ether (30 mL), and the mixture was stirred at room temperature for 16 hours. The solution was quenched with 4 M hydrochloric acid (18 mL) in saturated aqueous solution, stirred at room temperature for 6 hours, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product (petroleum ether:ethyl acetate = 20:1) was purified by silica gel column chromatography to give compound 2 (3.2 g, 92%) as a yellow oil.

[0476] 33.2 Synthesis of 1-(3-bromo-5-methylphenyl)prop-1-ol

[0477] Sodium borohydride (817 mg, 21.6 mmol) and aluminum trichloride (1.6 g, 1.9 mmol) were added to a mixture of compound 2 (1.0 g, 4.4 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at 80 °C for 2 hours. The solution was cooled to room temperature, and an aqueous solution of ammonium chloride was added. The mixture was extracted with ethyl acetate (3 × 100 mL), and the organic phases were combined. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product (petroleum ether:ethyl acetate = 10:1) was purified by silica gel column chromatography to give compound 3 (846 mg, 83%) as a white solid.

[0478] 33.3 Synthesis of 2-amino-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-5-(3-(1-hydroxypropyl)-5-methylphenyl)nicotinamide

[0479] Sodium carbonate (278 mg, 2.6 mmol) and tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol) were added to an ultradry mixed solution of compound 3 (200 mg, 0.9 mmol) and compound 4 (355 mg, 1.0 mmol) in N,N-dimethylformamide and water (4:1 mL). The mixture was stirred at 130 °C for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 10:1) to give the compound (100 mg, yield: 26%).

[0480] Example 34 Synthesis of Compound 48

[0481]

[0482] 34.1 Synthesis of (E)-4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0483] TEA (10 mL) was added to a mixed solution of 3-iodoaniline (5 g, 22.83 mmol), 2-methylbut-3-yn-2-ol (5.07 mL, 68.49 mmol), CuI (1.31 g, 6.85 mmol), and PdCl2(PPh3)2 (1.6 g, 2.28 mmol) in dioxane (50 mL) under N2 conditions. The solution was heated at room temperature for 5 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (3.5 g, 87.5%). MS (ESI): 176 [m+H]+.

[0484] Synthesis of 34.2(E)-2-methyl-4-(3-(methylamino)phenyl)but-3-yne-2-ol

[0485] The starting material (350 mg, 2 mmol), (CH₂O)n (332 mg, 8 mmol), and NaBH₄ (154 mg, 4 mmol) were placed in MeOH (5 mL) and reacted at room temperature for 2 hours. The reaction was completely detected by LC-MS. The solvent was filtered and the solid (110 mg, 28.9%) was collected. MS (ESI): 189.3 [m+H] + .

[0486] Synthesis of 34.3(E)-3-amino-6-bromo-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)-N-methylpyrazine-2-carboxamide: Starting material (100 mg, 0.53 mmol) and 3-amino-6-bromopyrazine-2-carboxylic acid (138 mg, 0.64 mmol) and HATU

[0487] DIEA (0.26 mL, 1.59 mmol) was added to a mixture of 300 mg (0.8 mmol) and DMF (2 mL). The reaction was allowed to proceed for 12 hours at room temperature, and the mixture was completely detected by LC-MS. The solvent was filtered and the solid (160 mg, 78.1%) was collected. MS (ESI): 389.3 [m+H] + .

[0488] Synthesis of 34.4(E)-3-amino-6-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)-N-methylpyrazine-2-carboxamide

[0489] Under N2 conditions, Pd(dppf)Cl2 (30 mg, 0.041 mmol) was added to a mixed solution of the starting material (160 mg, 0.41 mmol), 1-(2,6-dimethyl-4-(4,4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)-4-methylpiperazine (157 mg, 0.5 mmol), and K2CO3 (170 mg, 1.23 mmol) in dioxane (2 mL) and H2O (0.4 mL). The solution was heated at 80 °C for 4 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (140 mg, 66.4%). MS (ESI): 512.7 [m+H] + .

[0490] Example 35 Synthesis of Compound 49

[0491]

[0492] 35.1 Synthesis of 1-(3-bromo-5-methylphenyl)prop-1-one

[0493] Grignard reagent (12 mL, 85.7 mmol) was slowly added to a solution of compound 1 (3 g, 15.3 mmol) in diethyl ether (30 mL), and the mixture was stirred at room temperature for 16 hours. The solution was quenched with 4 M hydrochloric acid (18 mL) in saturated aqueous solution, stirred at room temperature for 6 hours, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product (petroleum ether:ethyl acetate = 20:1) was purified by silica gel column chromatography to give compound 2 (3.2 g, 92%) as a yellow oil.

[0494] 35.2 Synthesis of 3-(3-bromo-5-methylphenyl)pentane-3-ol

[0495] Ethyl magnesium bromide (1.7 mL, 13.3 mmol) was added to a mixture of compound 2 (1.0 g, 4.4 mmol) and tetrahydrofuran (10 mL). The resulting mixture was stirred at 0 °C for 3 hours. An aqueous solution of ammonium chloride was added to the solution, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the combined organic phases were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 3 (442 mg, 39%) as a white solid.

[0496] 35.3 Synthesis of 2-amino-N-(3-(3-hydroxy-3-methylbut-1-ynyl)phenyl)-5-(3-(3-hydroxypent-3-yl)-5-methylphenyl)nicotinamide

[0497] Potassium phosphate (544 mg, 2.6 mmol) and the [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (69 mg, 0.1 mmol) were added to an ultradry mixed solution of compound 3 (220 mg, 0.9 mmol) and compound 4 (348 mg, 1.0 mmol) in 1,4-dioxane and water (4:1 mL) under nitrogen atmosphere. The mixture was stirred at 110 °C for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 10:1) to give compound 5 (104 mg, yield: 26%).

[0498] Example 36 Synthesis of Compound 50

[0499]

[0500] Synthesis of 36.1(E)-3-(1-methylpyrazol-4-yl)ethynylaniline

[0501] TEA (0.195 mL) was added to a mixed solution of 3-ethynylaniline (50 mg, 0.43 mmol), 4-iodo-1-methylpyrazole (178 mg, 0.85 mmol), CuI (25 mg, 0.13 mmol), and PdCl2(PPh3)2 (29 mg, 0.04 mmol) in THF (2 mL) under N2 conditions. The solution was heated at room temperature for 5 h, and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (64 mg, 75.2%). MS (ESI): 197.2 [m+H] + .

[0502] Synthesis of 36.2(E)-3-amino-6-bromo-N-(3-(1-methylpyrazol-4-yl)ethynyl)phenyl)pyrazin-2-carboxamide: A mixture of starting material (64 mg, 0.32 mmol), 3-amino-6-bromopyrazin-2-carboxylic acid (106 mg, 0.48 mmol), and HATU (184 mg, 0.48 mmol) in DMF (1 mL) was added to DIEA (0.16 mL, 0.96 mmol). The reaction was carried out at room temperature for 12 hours and completely detected by LC-MS. The solvent was filtered and the solid (74 mg, 57.4%) was collected. MS (ESI): 397.2 [m+H] + .

[0503] Synthesis of 36.3(E)-3-amino-6-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-(1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)pyrazin-2-carboxamide (0000720-DLY-068R1)

[0504] Under N2 atmosphere, Pd(dppf)Cl2 (18 mg, 0.025 mmol) was added to a mixed solution of the starting material (100 mg, 0.25 mmol), 1-(2,6-dimethyl-4-(4,4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)-4-methylpiperazine (96 mg, 0.31 mmol), and K2CO3 (104 mg, 0.75 mmol) in dioxane (2 mL) and H2O (0.4 mL). The solution was heated at 80 °C for 4 h and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (87 mg, 66.4%). MS (ESI): 520.7 [m+H] + .

[0505] Example 37 Synthesis of Compound 51

[0506]

[0507] 37. Synthesis of 1(E)-3-(1-methylpyrazol-3-yl)ethynyl)aniline

[0508] TEA (0.195 mL) was added to a mixed solution of 3-ethynylaniline (50 mg, 0.43 mmol), 3-iodo-1-methylpyrazole (0.13 mL, 0.85 mmol), CuI (25 mg, 0.13 mmol), and PdCl2(PPh3)2 (29 mg, 0.04 mmol) in THF (2 mL) under N2 conditions. The solution was heated at room temperature for 5 h, and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (58 mg, 68.2%). MS (ESI): 197.2 [m+H] + .

[0509] Synthesis of 37.2(E)-3-amino-6-bromo-N-(3-(1-methylpyrazol-3-yl)ethynyl)phenyl)pyrazin-2-carboxamide: A mixture of starting material (58 mg, 0.29 mmol), 3-amino-6-bromopyrazin-2-carboxylic acid (96 mg, 0.44 mmol), and HATU (167 mg, 0.44 mmol) in DMF (2 mL) was added to DIEA (0.145 mL, 0.87 mmol). The reaction was carried out at room temperature for 12 hours and completely detected by LC-MS. The solvent was filtered and the solid (34 mg, 29.1%) was collected. MS (ESI): 397.2 [m+H] + .

[0510] Synthesis of 37.3(E)-3-amino-6-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-(1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)pyrazin-2-carboxamide

[0511] Under N2 atmosphere, Pd(dppf)Cl2 (6 mg, 0.009 mmol) was added to a mixed solution of the starting material (34 mg, 0.085 mmol), 1-(2,6-dimethyl-4-(4,4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)-4-methylpiperazine (33 mg, 0.105 mmol), and K2CO3 (37 mg, 0.26 mmol) in dioxane (1 mL) and H2O (0.2 mL). The solution was heated at 80 °C for 4 h and then completely detected by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (32 mg, 71.1%). MS (ESI): 520.7 [m+H] + .

[0512] Example 38 Synthesis of Compound 52

[0513]

[0514] Synthesis of 38.1(E)-4-(5-aminopyridin-3-yl)-2-methylbut-3-yn-2-ol

[0515] Diisopropylamine (1.5 mL, 11.5 mmol) was added to a mixed solution of 5-iodopyridin-3-amine (600 mg, 3.47 mmol), 2-methylbut-3-yn-2-ol (0.96 mL, 10.41 mmol), CuI (180 mg, 1.04 mmol), and PdCl2(PPh3)2 (220 mg, 0.35 mmol) in DMSO (6 mL) under N2 conditions. The solution was heated to 100 °C and reacted for 5 h at room temperature, followed by complete detection by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to give the product (125 mg, 20.4%). MS (ESI): 176.2 [m+H] + .

[0516] Synthesis of 38.2(E)-2-amino-5-bromo-N-(5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-3-yl)nicotinamide

[0517] DIEA (0.35 mL, 2.13 mmol) was added to a mixture of the starting material (125 mg, 0.71 mmol), 2-amino-5-bromonicotinic acid (230 mg, 1.07 mmol), and HATU (403 mg, 1.07 mmol) in DMF (2 mL). The reaction was allowed to proceed for 12 hours at room temperature, and the reaction was completely detected by LC-MS. The solvent was filtered and the solid (187 mg, 70.6%) was collected. MS (E SI): 375.2 [m+H] + .

[0518] Synthesis of 38.3(E)-2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-3-yl)nicotinamide

[0519] The starting material (88 mg, 0.24 mmol), 2,5-dimethyl-7-(4,4,4,5,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1,2,3,4-tetrahydroisoquinoline (90 mg, 0.29 mmol), and K₂CO₃ (97 mg, 0.71 mmol) were heated at 80 °C for 4 hours under nitrogen atmosphere in a mixed solution of dioxane (1 mL) and H₂O (0.2 mL). The solution was then analyzed by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to obtain the product (100 mg, 85.5%). MS (ESI): 498.6 [m+H] + .

[0520] Example 39 Synthesis of Compound 53

[0521]

[0522] 39.1 Synthesis of 1-(6-bromo-2,4-dimethylpyridin-3-yl)-4-methylpiperazine

[0523] To a mixture of compound 1 (900 mg, 4.5 mmol) in ethylene glycol ethyl ether (4.5 mL), chloromethane hydrochloride (1.3 g, 6.7 mmol) was added. The resulting mixture was stirred at 130 °C for 16 hours. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound 2 (913 mg, 72%) as a purple oil.

[0524] 39.2 Synthesis of 4-(3-aminophenyl)-2-methylbut-3-yne-2-ol

[0525] To a solution of compound 3 (5 g, 22.8 mmol) and 2-methylbut-3-yn-2-ol (5.8 g, 68.5 mmol) in 1,4-dioxane (50 mL), cuprous iodide (1.3 g, 6.9 mmol), triethylamine (10.5 mL, 75.3 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.6 g, 2.3 mmol) were added under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The solution was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 4 (3.8 g, 95%) as a yellow solid.

[0526] 39.3 Synthesis of 2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-ynyl)phenyl)nicotinamide

[0527] 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.0 g, 8.0 mmol) was added to a solution of 2-amino-5-bromonicotinic acid (2.1 g, 9.6 mmol) in N,N-dimethylformamide (10 mL) under nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes. Then, compound 4 (1.4 g, 8.0 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.6 mmol) were added separately and stirred at room temperature for 6 hours. The reaction mixture was washed with ethyl acetate and brine, and dried over anhydrous sodium sulfate to give compound 5 (3.4 g), which was used in the next step without further purification.

[0528] 39.4 Synthesis of (6-amino-5-((3-hydroxy-3-methylbut-1-ylbut-1-yn-1-yl)phenyl)carbamoyl)pyridine-3-boronic acid

[0529] To a solution of compound 5 (1 g, 2.6 mmol) in 1,4-dioxane (10 mL), pinacol diboronate (815 mg, 3.2 mmol), potassium acetate (394 mg, 4.0 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (218 mg, 0.1 mmol) were added. The resulting solution was stirred at 85 °C under nitrogen for 6 hours. The solution was extracted with ethyl acetate (3 × 100 mL), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give crude compound 6 (1.5 g) as a yellow solid.

[0530] 39.5 Synthesis of 6'-amino-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-4,6-dimethyl-5-(4-methylpiperazin-1-yl)-[2,3'-bipyridine]-5'-carboxamide

[0531] Potassium carbonate (1.2 mg, 8.6 mmol) and tetrakis(triphenylphosphine)palladium (329 mg, 0.1 mmol) were added to an ultradry solution of compound 2 (810 mg, 2.9 mmol) and compound 6 (1.2 g, 3.4 mmol) in a mixed solution of 1,4-dioxane and water (5:1 mL) under nitrogen atmosphere. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 10:1) to give compound 7 (130 mg, yield: 9.1%).

[0532] Example 40 Synthesis of Compound 56

[0533]

[0534] Synthesis of 40.1(E)-3-amino-6-bromo-N-(2-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-yl)pyrazin-2-carboxamide

[0535] DIEA (0.15 mL, 0.87 mmol) was added to a mixture of 4-(4-aminopyridin-2-yl)-2-methylbut-3-yn-2-ol (50 mg, 0.29 mmol), 3-amino-6-bromopyrazin-2-carboxylic acid (94 mg, 0.44 mmol), and HATU (164 mg, 0.44 mmol) in DMF (2 mL). The reaction was allowed to proceed for 12 hours at room temperature and was completely detected by LC-MS. The solvent was filtered and the solid (100 mg, 92.6%) was collected. MS (ESI): 376.2 [m+H] + .

[0536] Synthesis of 40.2(E)-3-amino-6-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(2-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-yl)pyrazin-2-carboxamide

[0537] A solution of the starting material (270 mg, 0.72 mmol), 2,5-dimethyl-7-(4,4,4,5,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1,2,3,4-tetrahydroisoquinoline (275 mg, 0.88 mmol), and K₂CO₃ (299 mg, 2.16 mmol) in dioxane (4 mL) and H₂O (0.8 mL) was heated at 80 °C for 4 hours under nitrogen. The solution was then analyzed by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to give the product (64 mg, 17.8%). MS (ESI): 499.6 [m+H] + .

[0538] Example 41 Synthesis of Compound 58

[0539]

[0540] 41.1 Synthesis of 2-amino-5-bromo-N-(4-pyridyl)nicotinamide

[0541] 4-Aminopyridine (500 mg, 5.32 mmol), 2-amino-5-bromonicotinic acid (1.2 g, 5.32 mmol), HATU (3 g, 7.98 mmol), DIEA (1.3 mL), and DMF (10 mL) were added to a reaction vessel, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to give the title compound (330 mg, 21.2%). MS (ESI): m / z 293 / 295 [M+H] + .

[0542] 41.2 Synthesis of 2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-pyridin-4-ylnicotinamide

[0543] The starting material (270 mg, 0.922 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-4-methylpiperazine (365 mg, 1.106 mmol), potassium phosphate (293 mg, 1.382 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (150 mg, 0.184 mmol) dissolved in tetrahydrofuran (5 mL) and water (5 mL) were added to the reaction vessel. The mixture was reacted at 80 °C for 2.5 h under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. Purification by column chromatography (DCM:MeOH = 5:1) gave the title compound (120 mg, 31.3%). MS(ESI): m / z417[M+H] + .

[0544] Example 42 Synthesis of Compound 59

[0545]

[0546] 42.1 Preparation of tert-butyl 5-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid

[0547] Compound 1 (4.31 g, 21.87 mmol), di-tert-butyl dicarbonate (9.01 ml, 39.37 mmol), 4-dimethylaminopyridine (267 mg, 2.19 mmol), triethylamine (8.24 ml, 59 mmol), and tetrahydrofuran (30 ml) were added to a flask. The mixture was stirred at room temperature for 1 hour, then concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2 (6.2 g, 95%) as a pale yellow solid.

[0548] 42.2 Preparation of 5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine

[0549] To a mixture of compound 2 (416 mg, 1.58 mmol) and 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-4-methylpiperazine (479 mg, 1.45 mmol) in an ultradry solution of 1,4-dioxane and water (5:1 mL), potassium carbonate (600 mg, 4.35 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (105 mg, 0.14 mmol) were added under nitrogen. The mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with ethyl acetate and brine, concentrated under vacuum, and dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give compound 3 (200 mg, 40%).

[0550] 42.3 Preparation of 3-bromo-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine

[0551] Compound 3 (157 mg, 0.49 mmol) and bromosuccinimide (83.7 mg, 0.49 mmol) were added to an ultradry tetrahydrofuran (7 mL) solution, and the mixture was stirred at room temperature under nitrogen protection for 3 hours. The reaction mixture was filtered, and the filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane:methanol = 30:1) to give compound 4 (80 mg, yield: 41%).

[0552] 42.4 Preparation of tert-butyl 3-bromo-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid

[0553] Compound 4 (70 mg, 0.174 mmol), di-tert-butyl dicarbonate (72.1 μl, 0.314 mmol), 4-dimethylaminopyridine (2.1 mg, 0.0174 mmol), triethylamine (73.4 μl, 59 mmol), and tetrahydrofuran (3 mL) were added to a flask. The mixture was stirred at room temperature for 1 hour, then concentrated and purified by column chromatography (dichloromethane:methanol = 15:1) to give compound 5 (85 mg, 98%).

[0554] 42.5 Preparation of tert-butyl 5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-3-(3-ethynylphenyl)amino-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid

[0555] Cesium carbonate (130 mg, 0.20 mmol) and benzylbis(triphenylphosphine)palladium chloride (21 mg, 0.02 mmol) were added to a mixed solution of compound 5 (85 mg, 0.17 mmol) and 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol (29.6 mg, 0.17 mmol) in ultra-dry toluene (2 mL) under nitrogen atmosphere. The mixture was heated to 85 °C and stirred overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give compound 6 (30 mg, yield: 41%).

[0556] 42.6 5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-ethynylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-amine

[0557] Compound 6 (30 mg, 0.056 mmol) and trifluoroacetic acid (1 ml) were stirred at room temperature for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to neutral with sodium bicarbonate solution. The neutral mixture was extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 7 (20 mg, 82%).

[0558] Example 43 Synthesis of Compound 61

[0559]

[0560] 43.1 Synthesis of methyl 3-(3-nitrophenyl)propynate

[0561] Under nitrogen protection, triethylamine (3 mL) was added to a mixture of 1-iodo-3-nitrobenzene (1.5 g, 6.02 mmol), methyl propynate (1.5 mL, 15.06 mmol), CuI (344 mg, 1.81 mmol), and bis(triphenylphosphine)palladium dichloride (420 mg, 0.60 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at 70 °C for 4 h. After 4 h, the mixture was analyzed by LCMS. The solvent was filtered and extracted with EA. The organic layer was dried on Na₂SO₄ and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to give the product (800 mg, 64.5%). MS (ESI): m / z 207 [M+H] + .

[0562] 43.2 Synthesis of methyl 3-(3-aminophenyl)propynate

[0563] Under nitrogen protection, reduced iron powder (1.14 g, 19.5 mmol) was added to a mixture of the starting material (800 mg, 3.9 mmol) and ammonium chloride (726 mg, 13.7 mmol) in ethanol (10 mL) and water (2.5 mL). The reaction mixture was stirred at 50 °C for 5 hours and completely detected by LC-MS. The solvent was filtered and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to give the product (500 mg, 73.3%). MS (ESI): m / z 176 [M+H] + .

[0564] 43.3 Synthesis of methyl 3-(3-(2-amino-5-bromonicotinamide)phenyl)propynate

[0565] To a mixture of starting material (200 mg, 1.14 mmol) and DMF (7.5 mL), 2-amino-5-bromonicotinic acid (300 mg, 1.38 mmol), HATU (650 mg, 1.71 mmol), and DIEA (3 mL) were added. The reaction mixture was stirred at room temperature for 4 hours and completely detected by LC-MS. The solvent was extracted with EA. The organic layer was dried on Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (180 mg, 42.3%). MS (ESI): m / z 376 [M+H] + .

[0566] 43.4 Synthesis of methyl 3-(3-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)nicotinamide)phenyl)propynate

[0567] Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (47 mg, 0.06 mmol) was added to a mixture of the starting material (120 mg, 0.32 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-methylpiperazine (129 mg, 0.39 mmol), and potassium phosphate (102 mg, 0.48 mmol) in tetrahydrofuran (2.5 mL) and water (2.5 mL). The reaction mixture was stirred at 70 °C for 1 hour and completely detected by LC-MS. The solvent was extracted with EA. The organic layer was dried on Na2SO4 and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 5:1) to give the product (60 mg, 37.7%). MS (ESI): m / z 249.6,498 [M+H] + .

[0568] 43.5 Synthesis of 3-(3-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)nicotinamide)phenyl)propynic acid

[0569] The starting material (60 mg, 0.12 mmol) was added to a mixed solution of tetrahydrofuran (4 ml), methanol (1 ml), and H₂O (4 ml) with LiOH·H₂O (51 mg, 1.21 mmol). The reaction was stirred at room temperature for 3 hours and completely detected by LC-MS. The pH of the solvent was adjusted to 5-6 with 4M hydrochloric acid aqueous solution. The organic layer was extracted with a mixed solvent of chloroform and isopropanol (3:1), dried over Na₂SO₄, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 2:1) to obtain the product (60 mg, 92.0%). MS (ESI): m / z 249.6, 498 [M+H] + .

[0570] Example 44 Synthesis of Compound 62

[0571]

[0572] 44.1 Preparation of 6-(3-methyl-3-(tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyrimidine-4-amine

[0573] Compound 1 (2 g, 15.44 mmol) and 2-methylbut-3-yn-2-ol (3.86 ml, 23.16 mmol) were dissolved in N,N-dimethylformamide (20 ml), followed by the addition of triethylamine (7.15 ml, 50.95 mmol), triphenylphosphine (1.2 g, 4.63 mmol), benzylbis(triphenylphosphine)palladium chloride (1 g, 1.54 mmol), and cuprous iodide (884 ml, 4.64 mmol). The mixture was stirred at 140 °C for 12 hours, then concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give compound 2 (1.62 g, 40%) as a brown solid.

[0574] 44.2 Preparation of 5-bromo-2-chloronicotinamide chloride

[0575] Compound 3 (1 g, 4.24 mmol) was dissolved in ultradry dichloromethane (10 ml), and thionyl chloride (5 ml) was added. The reaction mixture was refluxed and stirred at 50 °C for 2 hours to obtain compound 4. No purification was required; the mixture was then evaporated to dryness for later use.

[0576] 44.3 Preparation of 5-bromo-2-chloro-N-(6-(3-methyl-3-(tetrahydro-2H-pyran-2-oxy)but-1-ynyl)pyrimidin-4-yl)nicotinamide

[0577] Triethylamine (4 ml) was added to a 5 ml solution of compound 4 in dichloromethane, followed by the slow addition of another 4 ml solution of compound 4 in dichloromethane at 0 °C. The mixture was stirred at 50 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane:methanol = 30:1) to give compound 5 (723 mg, yield: 35%).

[0578] 44.4 Preparation of 5-bromo-2-(4-methoxybenzyl)amino-N-(6-(3-methyl-3-(tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyrimidin-4-yl)nicotinamide

[0579] Compound 5 (450 mg, 0.937 mmol) was dissolved in ultra-dry dioxane (5 ml), and triethylamine (260 μl, 1.87 mmol) and p-methoxybenzylamine (313 μl, 2.53 mmol) were added. The reaction mixture was refluxed and stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate = 5:1) to give compound 6 (280 mg, yield: 50%).

[0580] 44.5 Preparation of 2-amino-5-bromo-N-(6-(3-hydroxy-3-methylbut-1-ynyl)pyrimidin-4-yl)nicotinamide

[0581] Compound 6 (280 mg, 0.482 mmol) was dissolved in trifluoroacetic acid (3 ml). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and the pH was adjusted to 7 with sodium bicarbonate. The mixture was washed with ethyl acetate and brine, dried with anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by Prep-TLC (petroleum ether: ethyl acetate = 1:1) to give compound 7 (108 mg, yield: 60%).

[0582] 44.6 Preparation of 2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(6-(3-hydroxy-3-methylbut-1-ynyl)pyrimidin-4-yl)nicotinamide

[0583] Sodium carbonate (98 mg, 0.924 mmol) and tetra[triphenylphosphine]palladium (25.6 mg, 0.0308 mmol) were added to a solution of compound 7 (108 mg, 0.290 mmol) and 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)-4-methylpiperazine (122 mg, 0.37 mmol) in ultradry 1,4-dioxane (2 mL) and deionized water (0.5 mL) under nitrogen atmosphere. The resulting mixture was stirred at 85 °C for 3 hours. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give compound 8 (100 mg, 69%) as a yellow oil.

[0584] Example 45 Synthesis of Compound 63

[0585]

[0586] 45.1 Synthesis of 5-bromo-2-chloro-N-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyrimidin-4-yl)nicotinamide

[0587] 5-Bromo-2-chloronicotinic acid (340 mg, 1.43 mmol) was added to DMF (15 mL) along with triethylamine (600 μL, 4.3 mmol) and 1-propylphosphonic anhydride (1.3 mL, 2.15 mmol, 50% in ethyl acetate). The resulting mixture was stirred at room temperature for 20 minutes, and then 2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyrimidin-4-amine (450 mg, 1.71 mmol) was added. The reaction was carried out at room temperature for 5 hours, but the reaction was incomplete. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give the product (250 mg, 38% yield). MS (ESI): m / z found 479 / 481 [m+H] + .

[0588] 45.2 Synthesis of 5-bromo-2-((4-methoxybenzyl)amino)-N-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyrimidin-4-yl)nicotinamide

[0589] The compound obtained in the previous step (250 mg, 0.52 mmol), (4-methoxyphenyl)methylamine (180 μL, 1.4 mmol), and triethylamine (145 μL, 1.04 mmol) were added to dioxane (5 mL), and the mixture was stirred at 100 °C for 4 hours. The solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to give the product (245 mg, 80% yield). MS (ESI): m / z 580 / 582 [m+H]+.

[0590] 45.3 Synthesis of 2-amino-5-bromo-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)nicotinamide

[0591] The compound obtained in the previous step (245 mg, 0.42 mmol) was added to trifluoroacetic acid (72 mg, 4 mL) and stirred at 60 °C for 3 hours. The solution was concentrated under vacuum, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give the product (132 mg, 83% yield). MS (ESI): m / z found 376 / 378 [m+H] + .

[0592] 45.4 Synthesis of 2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)nicotinamide

[0593] The compound obtained in the previous step (90 mg, 0.24 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)phenyl)-4-methylpiperazine (95 mg, 0.18 mmol), and sodium carbonate (51 mg, 0.48 mmol) were added to a solution of dioxane (4 mL) and water (0.8 mL), followed by the addition of tetraphenylphosphine palladium (28 mg, 0.024 mmol). The mixture was stirred at 85 °C under nitrogen for 5 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using Pre-p (dichloromethane:methanol = 10:1) to give the product (30 mg, 25% yield). MS (ESI): m / z found 500.2 [m+H] + .

[0594] Example 46 Synthesis of Compound 54

[0595]

[0596] 46. ​​Synthesis of 1(E)-1-ethynylcyclobutane-1-ol

[0597] Cyclobutanone (500 mg, 7.14 mmol) was slowly added dropwise to acetylenyl magnesium bromide (19.5 mL, 9.29 mmol) at 0°C. Nitrogen gas was drawn, and the mixture was allowed to react for 15 min, followed by quenching with saturated ammonium chloride. The product was obtained (480 mg, 69.8%). MS (ESI): 96.1 [m+H] + .

[0598] 46.2 Synthesis of (E)-1-((3-aminophenyl)ethynyl)cyclobutane-1-ol

[0599] TEA (0.75 mL) was added to a mixed solution of 3-iodoaniline (300 mg, 3.13 mmol), starting material (480 mg, 69.19 mmol), CuI (94 mg, 0.94 mmol), and PdCl2(PPh3)2 (96 mg, 0.31 mmol) in dioxane (4 mL) under N2 conditions. The solution was heated to 80 °C and reacted for 5 h, followed by complete detection by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by preparative TLC (PE:EA = 1:1) to obtain the product (250 mg, 97.7%). MS (ESI): 187.2 [m+H] + .

[0600] Synthesis of 46.3(E)-2-amino-5-bromo-N-(3-((1-hydroxycyclobutyl)ethynyl)phenyl)nicotinamide

[0601] DIEA (0.52 mL, 4.02 mmol) was added to a mixture of the starting material (250 mg, 1.34 mmol), 2-amino-5-bromonicotinic acid (435 mg, 2.01 mmol), and HATU (762 mg, 2.01 mmol) in DMF (6 mL). The reaction was carried out at room temperature for 12 hours and completely detected by LC-MS. The solvent was filtered and the solid (231 mg, 44.9%) was collected. MS (E SI): 386.2 [m+H] + .

[0602] Synthesis of 46.4(E)-2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-(1-hydroxycyclobutyl)ethynyl)phenyl)nicotinamide

[0603] The starting material (231 mg, 0.6 mmol), 2,5-dimethyl-7-(4,4,4,5,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-1,2,3,4-tetrahydroisoquinoline (229 mg, 0.74 mmol), and K₂CO₃ (248 mg, 1.48 mmol) were heated at 80 °C for 4 hours under nitrogen atmosphere in a mixed solution of dioxane (4 mL) and H₂O (0.8 mL). The solution was then analyzed by LC-MS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM:MeOH = 5:1) to obtain the product (82 mg, 26.8%). MS (ESI): 509.7 [m+H] + .

[0604] Example 47 Synthesis of Compound 70

[0605]

[0606] 47.1 Synthesis of 6-fluoro-3-nitroimidazo[1,2-a]pyridine

[0607] 6-Fluorimidazolo[1,2-a]pyridine (600 mg, 4.4 mmol) was dissolved in concentrated sulfuric acid (4 mL), and concentrated nitric acid (0.8 mL) was added under ice bath conditions. The mixture was stirred at room temperature for 1.5 hours. After the reaction was completed as monitored by LCMS, the mixture was quenched with water, filtered to obtain a solid, and dried to give the title compound (800 mg, 99.7%). MS (ESI): m / z 182 [M+H] + .

[0608] 47.2 Synthesis of 6-Fluorimidazolo[1,2-a]pyridine-3-amine

[0609] The starting material (800 mg, 4.4 mmol), reduced iron powder (1.2 g, 22.0 mmol), and ammonium chloride (816 mg, 15.4 mmol) were added to the reaction vessel and dissolved in ethanol (10 mL) and water (2 mL). Under nitrogen protection, the mixture was reacted at 50 °C for 3 hours. After the reaction was completed as monitored by LCMS, the mixture was filtered, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. Purification was performed by column chromatography (DCM:MeOH = 10:1) to give the title compound (220 mg, 33.2%). MS (ESI): m / z 152 [M+H] + .

[0610] 47.3 Synthesis of 2-amino-5-bromo-N-(6-fluoroimidazolo[1,2-a]pyridin-3-yl)nicotinamide

[0611] The starting material (250 mg, 1.6 mmol), 2-amino-5-bromonicotinic acid (518 mg, 2.4 mmol), HAT U (912 mg, 2.4 mmol), DIEA (309 mg, 2.4 mmol), and DMF (7.5 mL) were added to the reaction vessel. The mixture was reacted at room temperature for 3 hours. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to give the title compound (250 mg, 44.8%). MS (ESI): m / z 350 [M+H] + .

[0612] 47.4 Synthesis of 2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(6-fluoroimidozopo[1,2-a]pyridin-3-yl)nicotinamide

[0613] The starting material (315 mg, 0.87 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-4-methylpiperazine (353 mg, 1.1 mmol), potassium phosphate (227 mg, 1.1 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (117 mg, 0.14 mmol) were added to the reaction vessel and dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (3 mL). The mixture was reacted at 80 °C for 1 hour under nitrogen protection. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to give 124 mg, 30.1%. MS(E SI): m / z 474 [M+H] + .

[0614] Example 48 Synthesis of Compound 72

[0615]

[0616] 48.1 Synthesis of 1-methyl-4-nitropyrrolo[2,3-b]pyridine

[0617] 4-Nitropyrrolo[2,3-b]pyridine (500 mg, 3.07 mmol) was dissolved in DMF (5 mL), and sodium hydride (246 mg, 6.14 mmol) was added under ice bath conditions. The mixture was stirred under ice bath conditions for 0.5 h. After 0.5 h, iodomethane (654 mg, 4.61 mmol) was added. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 3:1) to give the title compound (519 mg, 95.4%). MS (ESI): m / z 177 [M+H] + .

[0618] 48.2 Synthesis of 1-methylpyrrolo[2,3-b]pyridine-4-amine

[0619] The starting material (519 mg, 2.93 mmol), reduced iron powder (1.15 g, 19.8 mmol), and ammonium chloride (734 mg, 13.8 mmol) were added to the reaction vessel and dissolved in ethanol (12 mL) and water (3 mL). Under nitrogen protection, the mixture was reacted at 50 °C for 3 hours. After the reaction was completed as monitored by LCMS, the mixture was filtered, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. Purification was performed by column chromatography (DCM:MeOH = 10:1) to give the title compound (420 mg, 96.6%). MS (ESI): m / z 148 [M+H] + .

[0620] 48.3 Synthesis of 2-chloro-5-bromo-N-(1-methylpyrrolo[2,3-b]pyridin-4-yl)nicotinamide

[0621] 5-Bromo-2-chloronicotinic acid (1.2 g, 5 mmol) and thionyl chloride (7.5 mL) were added to the reaction vessel. The mixture was reacted at 65 °C for 3 hours. After the reaction was completed by thin-layer chromatography, the solvent was evaporated to dryness, and the starting material (360 mg, 2.43 mmol), triethylamine (2.5 mL), and dichloromethane (7.5 mL) were added. The mixture was reacted at 45 °C for 2 hours. After the reaction was completed by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 15:1) to give the title compound (315 mg, 35.6%). MS (ESI): m / z 364 [M+H] + .

[0622] 48.4 Synthesis of 5-bromo-2-(4-methoxybenzyl)amino-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)nicotinamide

[0623] The starting material (315 mg, 0.87 mmol), 4-methoxybenzylamine (411 mg, 3 mmol), potassium carbonate (414 mg, 3 mmol), and acetonitrile (7.5 mL) were added to the reaction vessel. The mixture was reacted at 80 °C for 6 hours. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to give 526 mg of crude product. MS (ESI): m / z 466 [M+H] + .

[0624] 48.5 Synthesis of 2-amino-5-bromo-N-(1-methylpyrrolo[2,3-b]pyridin-4-yl)nicotinamide

[0625] Add 526 mg of 0000772-CW-063R1 and 5 ml of trifluoroacetic acid to the reaction vessel. React the mixture at 80 °C for 2.5 hours. After the reaction is complete, as monitored by LCMS, concentrate the crude product by vacuum distillation. Purify the crude product (400 mg) by column chromatography (DCM:MeOH = 10:1). MS (ESI): m / z 346 [M+H] + .

[0626] 48.6 Synthesis of 2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)nicotinamide (0000772-CW-071R1)

[0627] The starting material (400 mg mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-4-methylpiperazine (330 mg, 1.0 mmol), potassium phosphate (267 mg, 1.26 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (123 mg, 0.17 mmol) were added to the reaction vessel and dissolved in a mixed solvent of tetrahydrofuran (7.5 mL) and water (3.5 mL). The mixture was reacted at 80 °C for 3 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to give 220 mg, 54.8%. MS (E SI): m / z 470 [M+H] + .

[0628] Example 49 Synthesis of Compound 76

[0629]

[0630] 49.1 Synthesis of 1-methyl-6-nitro-1,2,3,6-tetrahydro-3,4-bipyridine

[0631] 5-Bromo-2-nitropyridine (1 g, 5.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (1.32 g, 5.9 mmol), sodium carbonate (780 mg, 7.35 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (720 mg, 1.0 mmol) were dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (10 mL). The mixture was reacted at 80 °C for 3 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product (1.7 g) was purified by column chromatography (PE:EA = 3:1). MS (ESI): m / z 220 [M+H] + .

[0632] 49.2 Synthesis of 1-methylpyrrolo[2,3-b]pyridine-4-amine

[0633] The starting material (1.7 g), palladium on carbon (2 g), and methanol (10 mL) were added to the reaction vessel. The mixture was reacted at 40 °C for 3 hours under hydrogen atmosphere. After the reaction was completed as monitored by LCMS, the mixture was filtered, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. Purification was performed by column chromatography (DCM:MeOH = 5:1) to give the title compound (800 mg, 83.8%). MS (ESI): m / z 192 [M+H] + .

[0634] 49.3 Synthesis of 2-bromo-5-(1-methylpiperidin-4-yl)pyridine

[0635] Under nitrogen protection, the starting material (660 mg, 3.5 mmol), hydrobromic acid (15 mL), and an aqueous solution of sodium nitrite (357 mg, 5.1 mmol) were added to the reaction vessel. The mixture was reacted at -20 °C for 3 hours. After 3 hours of reaction, an aqueous solution of sodium bromide (533 mg, 5.1 mmol) was added. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed as monitored by LCMS, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with a chloroform / isopropanol mixture. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 5:1) to give the title compound (290 mg, 23.4). MS (ESI): m / z 255 / 257 [M+H] + .

[0636] 49.4 Synthesis of 6-amino-N-(2-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)-5-(1-methylpiperidin-4-yl)-[2,3'-bipyridine]-5-carboxamide

[0637] The starting material (36 mg, 0.14 mmol), 6-amino-5-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridine-3-boronic acid (40 mg, 0.14 mmol), potassium phosphate (45 mg, 0.21 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (23 mg, 0.03 mmol) were added to the reaction vessel and dissolved in a mixed solvent of tetrahydrofuran (0.75 mL) and water (0.75 mL). The mixture was reacted at 80 °C for 2 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by TLC (DCM:MeOH = 5:1) to give 25 mg, 38.0%. MS(ESI): m / z 471[M+H] + .

[0638] Example 50 Synthesis of Compound 82

[0639]

[0640] Synthesis of 50.1(S)-(2'-amino-5'-bromo-[2,3'-bipyridine]-5-yl)(3-hydroxypyrrolidone-1-yl) methyl ketone

[0641] To a solution of 2'-amino-5'-bromo-[2,3'-bipyridine]-5-carboxylic acid (23 mg, 0.078 mmol) in DMF (3 mL), HATU (60 mg, 0.156 mmol) and DIEA (55 μL, 0.31 mmol) were added. After stirring at room temperature for 10 minutes, (S)-pyrrolidine-3-ol (12 mg, 0.093 mmol) was added, and the mixture was stirred under nitrogen for 2 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (dichloromethane:methanol = 10:1) to give the product (13 mg, 46% yield). MS (ESI): m / z 363 / 365 [m+H] + .

[0642] Synthesis of 50.2(S)-(2'-amino-5'-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-[2,3'-bipyridine]-5-yl)(3-hydroxypyrrolidine-1-yl) methyl ketone

[0643] The compound obtained in the previous step (13 mg, 0.035 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-4-methylpiperazine (14 mg, 0.43 mmol), and potassium phosphate (16 mg, 0.071 mmol) were added to a solution of dioxane (2 mL) and water (0.4 mL) with Pd(dppf)₂Cl₂ (3 mg, 0.003 mmol). The mixture was stirred at 80 °C under nitrogen for 3 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 5:1) to give the product (0.61 mg). MS (ESI): m / z found 487.2 [m+H] + .

[0644] Example 51 Synthesis of Compound 83

[0645]

[0646] Synthesis of 51.1(R)-(1-(3-bromophenyl)pyrrolidone-3-yl)tert-butyl carbamate

[0647] A solution of 1-bromo-3-iodobenzene (760 mg, 2.68 mmol), (R)-pyrrolidone-3-ylcarbamate tert-butyl ester (500 mg, 2.68 mmol), sodium tert-butoxide (516 mg, 5.36 mmol), and XantPhos (310 mg, 0.54 mmol) in toluene (20 mL) was added to Pd₂(dba)₃ (160 mg, 0.17 mmol), and the mixture was heated to 120 °C and stirred under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 5:1) to give the product (570 mg, 63% yield). MS (ESI): m / z 341 / 343 [m+H] + .

[0648] 51.2 Synthesis of tert-butyl(R)-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyrrolidine-3-yl)carbamate

[0649] The compound obtained in the previous step (200 mg, 0.586 mmol), bis(pinacolborate) (300 mg, 1.17 mmol), and potassium acetate (116 mg, 1.17 mmol) were added to a solution of 1,4-dioxane (8 mL) along with [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (43 mg, 0.058 mmol). The mixture was stirred at 80 °C under nitrogen for 7 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 5:1) to give the product (220 mg, 95% yield). MS (ESI): m / z 389 [m+H] + Synthesis of tert-butyl((3R)-1-(3-(6-amino-5-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridin-3-yl)phenyl)pyrrolidine-3-yl)carbamate.

[0650] The compound obtained in the previous step (70 mg, 0.18 mmol), 2-amino-5-bromo-N-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)nicotinamide (100 mg, 0.21 mmol), and sodium carbonate (39 mg, 0.36 mmol) were added to a solution of dioxane (2 mL) and water (0.4 mL), followed by the addition of tetraphenylphosphine palladium (21 mg, 0.018 mmol). The mixture was stirred at 80 °C under nitrogen for 3 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product (95 mg, 82% yield). MS (ESI): m / z 642.2 [m+H] + .

[0651] Synthesis of 51.5(R)-2-amino-5-(3-(3-aminopyrrolidone-1-yl)phenyl)-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)nicotinamide

[0652] The compound obtained in the previous step (95 mg, 0.148 mmol) was added to trifluoroacetic acid (2.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under vacuum, and the residue was purified by reversed-phase column chromatography to give the product (6.1 mg). MS (ESI): m / z found 457.2 [m+H] + .

[0653] Example 52 Synthesis of Compound 87

[0654]

[0655] 52.1 Synthesis of 4-(2,6-dimethyl-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine

[0656] 2-Bromo-1,3-dimethyl-5-nitrobenzene (1 g, 4.4 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (1 g, 4.5 mmol), potassium phosphate (1.19 g, 8.8 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (658 mg, 0.9 mmol) were added to a reaction vessel and dissolved in a mixed solvent of tetrahydrofuran (7.5 mL) and water (1.5 mL). The mixture was reacted at 80 °C for 12 hours under nitrogen protection. After the reaction was complete as monitored by LCM SS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. The crude product was purified by column chromatography (DCM:MeOH = 25:1) to give the product (1 g, 92.4%). MS(ESI): m / z 247[M+H] + .

[0657] 52.2 Synthesis of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

[0658] The starting material (1 g, 4.1 mmol), palladium on carbon (2 g), and methanol (10 mL) were added to the reaction vessel. Under hydrogen protection, the mixture was reacted at 40 °C for 2 hours. After the reaction was completed as monitored by LCMS, the mixture was filtered, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. Purification was performed by column chromatography (DCM:MeOH = 20:1) to give the title compound (600 mg, 67.8%). MS (ESI): m / z 217 [M+H] + .

[0659] 52.3 Synthesis of 4-(4-bromo-2,6-dimethylphenyl)-1-methyl-1,2,3,6-tetrahydropyridine

[0660] Under nitrogen protection, the starting material (600 mg, 2.7 mmol), cuprous bromide (1.2 g), and isoamyl nitrite (500 μL) dissolved in acetonitrile (15 mL) were added to the reaction vessel. The mixture was reacted at room temperature for 3 hours. After the reaction was completed as monitored by LCMS, the crude product was obtained by reduced-pressure filtration and distillation. Purification was performed by column chromatography (DCM:MeOH = 50:1) to give the title compound (175 mg, 19.9%). MS (ESI): m / z 280 / 282 [M+H] + .

[0661] 52.4 Synthesis of 4-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine

[0662] The starting material (75 mg, 0.27 mmol), pinacol diboronate (82 mg, 0.32 mmol), potassium acetate (53 mg, 0.54 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (40 mg, 0.06 mmol), and dioxane (5 mL) were added to the reaction vessel. The mixture was reacted at 80 °C for 12 hours. After the reaction was completed as monitored by LCMS, the mixture was filtered, and the filtrate was concentrated by vacuum distillation to obtain the crude product (80 mg). MS (ESI): m / z 328 [M+H] + .

[0663] 52.5 Synthesis of 2-amino-5-(3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-(2-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-yl)nicotinamide

[0664] The starting material (30 mg), 2-amino-5-bromo-N-(2-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-yl)nicotinamide (27 mg, 0.07 mmol), potassium carbonate (25 mg, 0.18 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (15 mg, 0.02 mmol) were added to the reaction vessel and dissolved in a mixed solvent of dioxane (1 mL) and water (0.2 mL). The mixture was reacted at 80 °C for 2 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by TLC (DCM:MeOH = 10:1) to give 15 mg, 23.3%. MS (ESI): m / z 496 [M+H] + .

[0665] Example 53 Synthesis of Compound 88

[0666]

[0667] 53.1 Synthesis of (R)-(1-(2-bromopyridin-4-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0668] Pd₂(dba)₃ (246 mg, 0.16 mmol) was added to a solution of 2-bromo-4-iodopyridine (500 mg, 2.68 mmol), (R)-pyrrolidine-3-ylcarbamate tert-butyl ester (762 mg, 2.68 mmol), sodium tert-butoxide (516 mg, 5.36 mmol), and XantPhos (310 mg, 0.54 mmol) in toluene (20 mL). The mixture was heated to 120 °C and stirred under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 2:1) to give the product (230 mg, 25% yield). MS (ESI): m / z 342 / 344 [m+H] + .

[0669] 53.2 Synthesis of (6-amino-5-((2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridin-3-yl)boronic acid

[0670] To a solution of 2-amino-5-bromo-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)nicotinamide (320 mg, 0.7 mmol), bis-pinacolborate (213 mg, 0.84 mmol), and potassium acetate (137 mg, 1.39 mmol) in 1,4-dioxane (8 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (51 mg, 0.07 mmol) was added. The mixture was stirred at 80 °C under nitrogen for 7 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 5:1) to give the product (100 mg, 34% yield). MS (ESI): m / z 425.2 [m+H] + .

[0671] Synthesis of 53.3(3R)-1-(6'-amino-5'-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)carbamoyl)-[2,3'-bipyridin]-4-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0672] The compound obtained in the previous step (58 mg, 0.135 mmol), ((R)-(1-(2-bromopyridin-4-yl)pyrrolidine-3-yl)carbamate tert-butyl ester (42 mg, 0.122 mmol), and sodium carbonate (26 mg, 0.249 mmol) were added to a solution of dioxane (2 mL) and water (0.4 mL) with tetraphenylphosphine palladium (15 mg, 0.012 mmol). The mixture was stirred at 80 °C under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 5:1) to give the product (25 mg, 37% yield). MS (ESI): m / z 558.2 [m+H] + .

[0673] Synthesis of 53.4(R)-6'-amino-4-(3-aminopyrrolidone-1-yl)-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)-[2,3'-bipyridine]-5'-carboxamide

[0674] The compound obtained in the previous step (25 mg, 0.045 mmol) was added to trifluoroacetic acid (2.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under vacuum, and the residue was purified by reversed-phase column chromatography to give the product (10.6 mg). MS (ESI): m / z 458.2 [m+H] + .

[0675] Example 54 Synthesis of Compound 90

[0676]

[0677] 54.1 Synthesis of 2-bromo-5-iodo-1-(λ1-butyloxy)-λ4-pyridine (0000798-CW-049R1)

[0678] 2-Bromo-5-iodopyridine (2 g, 7.5 mmol) and trifluoroacetic acid (6 mL) were added to the reaction vessel. The mixture was stirred in an ice bath for 20 minutes, followed by the dropwise addition of hydrogen peroxide (10 mL). The mixture was refluxed for 2 days. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to give 1 g, 47.2%. MS (ESI): m / z 300 / 302 [M+H] + .

[0679] 54.2 Synthesis of 6-bromo-3-iodopyridine-2-amine

[0680] The starting material (1 g, 3.3 mmol), pyridine (1.6 mL), and acetonitrile (20 mL) were added to the reaction vessel. 1.3 mL of p-toluenesulfonyl chloride was dissolved in 5 mL of acetonitrile and added dropwise to the reaction mixture. After reacting the mixture at room temperature for 5 hours, the reaction temperature was lowered to 10 °C, and 3 mL of ethanolamine was added. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. Purification was performed by column chromatography (PE:EA = 10:1) to give the title compound (480 mg, 48%). MS (ESI): m / z 299 / 301 [M+H] + .

[0681] 54.3 Synthesis of 6-bromo-1-methyl-1,2,3,6-tetrahydrobipyridine-2-amine

[0682] The starting material (480 mg, 1.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (287 mg, 1.3 mmol), potassium phosphate (1 g, 4.8 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (235 mg, 0.3 mmol) were added to the reaction vessel and dissolved in a mixed solvent of dioxane (10 mL) and water (2 mL). The mixture was reacted at 80 °C for 2.5 h under nitrogen protection. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to give 250 mg, 58.5%. MS(ESI):m / z fou nd 268 / 270[M+H] + .

[0683] 54.4 Synthesis of 6,6-diamino-N-(2-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)-1-methyl-1,2,3,6-tetrahydro-3,2:5,4-tripyridine-5-carboxamide

[0684] The starting material (40 mg, 0.15 mmol), 6-amino-5-(2-(3-methyl-3-(tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridine-3-boronic acid (50 mg, 0.12 mmol), potassium phosphate (30 mg, 0.14 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20 mg, 0.03 mmol) were added to the reaction vessel and dissolved in a mixed solvent of dioxane (2 mL) and water (0.4 mL). The mixture was reacted at 80 °C for 2.5 h under nitrogen protection. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by TLC (DCM:MeOH = 5:1) to give 18 mg, 31.1%. MS(ESI): m / z 484 [M+H] + .

[0685] Example 55 Synthesis of Compound 91

[0686]

[0687] Synthesis of 55.1(R)-(1-(2-chloropyrimidin-4-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0688] A solution of 2,4-dichloropyrimidine (246 mg, 1.64 mmol), (R)-pyrrolidine-3-ylcarbamate tert-butyl ester (300 mg, 1.64 mmol), sodium tert-butoxide (320 mg, 3.29 mmol), and XantPhos (190 mg, 0.33 mmol) in toluene (10 mL) was added to Pd2(dba)3 (150 mg, 0.16 mmol), and the mixture was heated to 120 °C and stirred under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 2:1) to give the product (150 mg, 38.5% yield). MS (ESI): m / z 299 / 301 [m+H] + .

[0689] Synthesis of 55.2(3R)-1-(2-(6-amino-5-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridin-3-yl)pyrimidin-4-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0690] The compound obtained in the previous step (30 mg, 0.1 mmol), (6-amino-5-((2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridin-3-yl)boronic acid (51 mg, 0.12 mmol), and sodium carbonate (21 mg, 0.2 mmol) were added to a solution of dioxane (2 mL) and water (0.4 mL), and the mixture was stirred at 80 °C under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 5:1) to give the product (18 mg, 32% yield). MS (ESI): m / z 559.2 [m+H] + .

[0691] Synthesis of 55.3(R)-2-amino-5-(4-(3-aminopyrrolidone-1-yl)pyrimidin-2-yl)-N-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)nicotinamide

[0692] The compound obtained in the previous step (18 mg, 0.039 mmol) was added to trifluoroacetic acid (2.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under vacuum, and the residue was purified by reversed-phase column chromatography to give the product (3.1 mg). MS (ESI): m / z 459.2 [m+H] + .

[0693] Example 56 Synthesis of Compound 92

[0694]

[0695] 56.1 Synthesis of (2-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)carbamoyl)-[2,3'-bipyridin]-6-yl)pyrrolidine-3-carbamate tert-butyl ester

[0696] (R)-(1-(6-bromopyridin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate (40 mg, 0.12 mmol), 6-amino-5-(2-(3-methyl-3-(tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridine-3-boronic acid (40 mg, 0.12 mmol), sodium carbonate (30 mg, 0.28 mmol), and tetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol) were added to the reaction vessel and dissolved in a mixed solvent of dioxane (5 ml) and water (1 ml). The mixture was reacted at 80 °C for 3 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. Purification was performed using TLC (DCM:MeOH = 20:1) to obtain the product (30 mg, 44.8%). MS (ESI): m / z 558 [M+H] + .

[0697] Synthesis of 56.2(R)-6'-amino-6-(3-aminopyrrolidone-1-yl)-N-(2-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)-[2,3'-bipyridine]-5'-carboxamide

[0698] The starting material (30 mg, 0.05 mmol), methanol (1 mL), and dioxane hydrochloride solution (3 mL) were added to the reaction vessel. The mixture was reacted at room temperature for 3 hours. After the reaction was completed as monitored by LCMS, the mixture was filtered, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The title compound was given (22 mg, 96.3%). MS (ESI): m / z 458 [M+H] + .

[0699] Example 57 Synthesis of Compound 93

[0700]

[0701] Synthesis of 57.1(R)-(1-(4-chloropyrimidin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0702] A solution of 2,4-dichloropyrimidine (246 mg, 1.64 mmol), (R)-pyrrolidine-3-ylcarbamate tert-butyl ester (300 mg, 1.64 mmol), sodium tert-butoxide (320 mg, 3.29 mmol), and XantPhos (190 mg, 0.33 mmol) in toluene (10 mL) was added to Pd2(dba)3 (150 mg, 0.16 mmol), and the mixture was heated to 120 °C and stirred under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 2:1) to give the product (23 mg, 4.6% yield). MS (ESI): m / z 299 / 301 [m+H] + .

[0703] Synthesis of 57.2(3R)-1-(4-(6-amino-5-(2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridin-3-yl)pyrimidin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0704] The compound obtained in the previous step (23 mg, 0.076 mmol), (6-amino-5-((2-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)pyridin-4-yl)carbamoyl)pyridin-3-yl)boronic acid (40 mg, 0.092 mmol), and sodium carbonate (16 mg, 0.15 mmol) were added to a solution of dioxane (2 mL) and water (0.4 mL), and the mixture was stirred at 80 °C under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 5:1) to give the product (12 mg, 28% yield). MS (ESI): m / z found 559.2 [m+H] + .

[0705] Synthesis of 57.3(R)-2-amino-5-(2-(3-aminopyrrolidone-1-yl)pyrimidin-4-yl)-N-(2-(-3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)nicotinamide

[0706] The compound obtained in the previous step (12 mg, 0.026 mmol) was added to trifluoroacetic acid (2.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under vacuum, and the residue was purified by reversed-phase column chromatography to give the product (0.5 mg). MS (ESI): m / z 459.2 [m+H] + .

[0707] Example 58 Synthesis of Compound 94

[0708]

[0709] 58.1 Synthesis of 1-bromo-6-chloroisoquinoline

[0710] 6-Chloroisoquinoline-1(2H)-one (1 g, 5.59 mmol) was placed in a microwave-safe tube, POBr3 (5 ml) was added, and the mixture was heated to 180 °C and reacted overnight. After confirming the reaction was complete, the mixture was cooled to room temperature and quenched with ice water. Extraction was performed three times with EA, and the organic phases were combined. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the product (587 mg, 43.2%). MS (ESI): [M+H]+=244.

[0711] 58.2 Synthesis of 6-chloro-1-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)isoquinoline

[0712] Under nitrogen protection, bis(triphenylphosphine)palladium dichloride (85 mg, 0.12 mmol) was added to a mixture of 1-bromo-6-chloroisoquinoline (587 mg, 2.43 mmol), 2-((2-methylbut-3-yn-2-yl)oxy)tetrahydro-2H-pyran (815 mg, 4.85 mmol), and cuprous iodide (23 mg, 0.12 mmol) in triethylamine (1 mL) and dioxane (10 mL). The reaction mixture was stirred at 80 °C for 4 hours. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give the product (200 mg, 25%). MS (ESI): [M+H]+ = 330.

[0713] 58.3 Synthesis of 1-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)isoquinoline-6-yl)boronic acid: Under nitrogen protection, Pd(dppf)Cl2 (22 mg, 0.006 mmol) was added to a mixture of 6-chloro-1-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)isoquinoline (200 mg, 0.61 mmol), B2Pin2 (235 mg, 0.91 mmol), and KoAc (175 mg, 1.82 mmol) dioxane (10 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. The crude product was purified by silica gel column chromatography to obtain the product (210 mg, 100%). MS (ESI): [M+H]+ = 340.

[0714] 58.4 Synthesis of 5-bromo-3-(1-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)isoquinoline-6-yl)pyridine-2-amine

[0715] Under nitrogen protection, Pd(pph3)4 (36 mg, 0.006 mmol) was added to a mixture of 1-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)isoquinoline-6-yl)boronic acid (210 mg, 0.62 mmol), 5-bromo-3-iodopyridin-2-amine (277 mg, 0.93 mmol), sodium carbonate (98 mg, 0.93 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (85 mg, 29.5%). MS (ESI): [M+H]+ = 466.

[0716] 58.5 5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-3-(1-(3-methyl-3-((tetrahydro-2H-pyran-2-yl))

[0717] Synthesis of (oxy)but-1-yn-1-yl)isoquinoline-6-yl)pyridine-2-amine

[0718] Under nitrogen protection, Pd(pph3)4 (36 mg, 0.006 mmol) was added to a mixture of 5-bromo-3-(1-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)isoquinoline-6-yl)pyridin-2-amine (85 mg, 0.18 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)-4-methylpiperazine (90 mg, 0.27 mmol), potassium carbonate (58 mg, 0.55 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. The crude product was purified by silica gel column chromatography to obtain the product (35 mg, 32.4%). MS (ESI): [M+H]+ = 590.

[0719] 58.6 4-(6-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)pyridin-3-yl)isoquinoline-1-yl)

[0720] Synthesis of 2-methylbut-3-yn-2-ol

[0721] Under nitrogen protection, 35 mg of 5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-3-(1-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)isoquinoline-6-yl)pyridine-2-amine was dissolved in 2 ml of DCM, and 1 ml of TFA was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (24 mg, 80%). MS (ESI): [M+H]+=506.3.

[0722] Example 59 Synthesis of Compound 95

[0723]

[0724] 59.1 Synthesis of (2-amino-5-bromopyridin-3-yl)boronic acid

[0725] Under nitrogen protection, Pd2(dba)3 (1.53 mg, 1.67 mmol) was added to a mixture of 5-bromo-3-iodopyridin-2-amine (10 g, 33.45 mmol), B2Pin2 (10.36 g, 40.13 mmol), and KoAc (9.63 g, 100.33 mmol) and dioxane (250 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (7.6 g, 100%). MS (ESI): [M+H]+=217.

[0726] 59.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-2,7-naphthidium-1(2H)-one

[0727] Under nitrogen protection, Pd(pph3)4 (77 mg, 0.007 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (436 mg, 2.09 mmol), 6-bromo-2,7-naphthidium-1(2H)-one (300 mg, 1.34 mmol), sodium carbonate (213 mg, 4.02 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (104 mg, 24.6%). MS(ESI): [M+H]+=317.59.3 Synthesis of 6-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)pyridin-3-yl)-2,7-naphthidium-1(2H)-one

[0728] Under nitrogen protection, Pd(pph3)4 (19 mg) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)-2,7-naphthidium-1(2H)-one (104 mg, 0.33 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (163 mg, 0.49 mmol), potassium carbonate (105 mg, 0.99 mmol), dioxane (5 mL), and water (1 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the product (40 mg, 27.6%). MS (ESI): [M+H]+=441.

[0729] Example 60 Synthesis of Compound 98

[0730]

[0731] Synthesis of 60.1 (2-amino-5-bromopyridin-3-yl)boronic acid

[0732] Under nitrogen protection, Pd2(dba)3 (1.53 mg, 1.67 mmol) was added to a mixture of 5-bromo-3-iodopyridin-2-amine (10 g, 33.45 mmol), B2Pin2 (10.36 g, 40.13 mmol), KOAc (9.63 g, 100.33 mmol), and dioxane (250 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the crude product. The product was given (7.6 g, 100%). MS (ESI): [M+H]+=217.

[0733] 60.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)isoquinoline-1(2H)-one

[0734] Under nitrogen protection, Pd(pph3)4 (103 mg, 0.009 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (581 mg, 2.68 mmol), 6-bromoisoquinoline-1(2H)-one (400 mg, 1.79 mmol), sodium carbonate (568 mg, 5.36 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the product (210 mg, 37.2%). MS (ESI): [M+H]+=316.60.3 (Synthesis of 6-amino-5-(1-oxo-1,2-dihydroisoquinoline-6-yl)pyridin-3-yl)boronic acid

[0735] Under nitrogen protection, Pd(dppf)Cl2 (162 mg, 0.22 mmol) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)isoquinoline-1(2H)-one (1.4 g, 4.43 mmol), B2Pin2 (1.72 g, 6.65 mmol), and KoAc (1.3 g, 13.29 mmol) dioxane (10 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (689 mg, 55.12%). MS (ESI): [M+H]+ = 282.

[0736] 60.4 Synthesis of 6-(6'-amino-4,6-dimethyl-5-(4-methylpiperazin-1-yl)-[2,3'-bipyridin]-5'-yl)isoquinoline-1(2H)-one

[0737] Under nitrogen protection, Pd(pph3)4 (8 mg) was added to a mixture of (6-amino-5-(1-oxo-1,2-dihydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (40 mg, 1.42 mmol), 1-(6-bromo-2,4-dimethylpyridin-3-yl)-4-methylpiperazine (60 mg, 2.13 mmol), potassium carbonate (59 mg, 4.26 mmol), dioxane (5 mL), and water (1 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (25 mg, 39.7%). MS (ESI): [M+H]+ = 441.2.

[0738] Example 61 Synthesis of Compound 97

[0739]

[0740] Synthesis of 61.1(R)-(1-(3-bromo-6-chloropyridin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate

[0741] DIEA (690 μL, 3.96 mmol) was added to a solution of 3-bromo-2,6-dichloropyridine (300 mg, 1.3 mmol) and (R)-pyrrolidine-3-ylcarbamate tert-butyl ester (270 mg, 1.45 mmol) in acetonitrile (6 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by liquid chromatography (petroleum ether:ethyl acetate = 10:1) to give the product (180 mg, 36% yield). MS (ESI): m / z 376 / 378 [m+H]+.

[0742] Synthesis of tert-butyl(R)-(1-(6-chloro-1'-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridin]-2-yl)pyrrolidine-3-yl)carbamate

[0743] The compound obtained in the previous step (150 mg, 0.399 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine (89 mg, 0.399 mmol), and potassium carbonate (110 mg, 0.798 mmol) were added to a solution of dioxane (2 mL) and water (0.4 mL) with Pd(dppf)Cl2 (30 mg, 0.0398 mmol). The mixture was stirred at 80 °C under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product (140 mg, 90% yield). MS (ESI): m / z 393 [m+H] + .

[0744] Synthesis of 61.3 tert-butyl(R)-(1-(6-amino-1'-methyl-5-(1-oxo-1,2-dihydroisoquinoline-6-yl)-1'-,2'-,3'-,6'-tetrahydro-[3,2'-:5'-,4'-bipyridine]-6'-yl)pyrrolidine-3-yl)carbamate

[0745] The compound obtained in the previous step (50 mg, 0.127 mmol), (6-amino-5-(1-oxo-1,2-dihydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (36 mg, 0.127 mmol), and sodium carbonate (27 mg, 0.255 mmol) were added to a solution of dioxane (5 mL) and water (1 mL) with tetraphenylphosphine palladium (15 mg, 0.012 mmol). The mixture was stirred at 80 °C under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product (25 mg, 33.3% yield). MS (ESI): m / z 594.2 [m+H] + .

[0746] Synthesis of 61.4(R)-2-amino-5-(2-(3-aminopyrrolidone-1-yl)pyrimidin-4-yl)-N-(2-(-3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)nicotinamide

[0747] The compound obtained in the previous step (25 mg, 0.042 mmol) was added to trifluoroacetic acid (2.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under vacuum, and the residue was purified by reversed-phase column chromatography to give the product (8.2 mg). MS (ESI): m / z 494.2 [m+H] + .

[0748] Example 62 Synthesis of Compound 99

[0749]

[0750] 62.1 Synthesis of 1-(6-chloro-2-methylpyridin-3-yl)-4-methylpiperazine

[0751] To a solution of 3-bromo-6-chloro-2-methylpyridine (2.0 g, 9.68 mmol), 1-methylpiperazine (950 μL, 8.52 mmol), and sodium tert-butoxide (1.86 g, 19.37 mmol) in toluene (20 mL), Pd₂(dba)₃ (887 mg, 0.968 mmol) and XantPhos (1.12 g, 1.93 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a crude product (1.12 g), which was then subjected to reversed-phase chromatography (8%) to give the product (800 mg, 36.5% yield). MS (ESI): m / z 226 / 228 [m+H] + .

[0752] 62.2 Synthesis of 6-(6'-amino-6-methyl-5-(4-methylpiperazin-1-yl)-[2,3'-bipyridin]-5'-yl)isoquinoline-1(2H)-one

[0753] The compound obtained in the previous step (60 mg, 0.21 mmol), (6-amino-5-(1-oxo-1,2-dihydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (49 mg, 0.21 mmol), and sodium carbonate (46 mg, 0.42 mmol) were added to a solution of dioxane (5 mL) and water (1 mL) with tetraphenylphosphine palladium (25 mg, 0.021 mmol). The mixture was stirred at 80 °C under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product (2.3 mg). MS (ESI): m / z 427.2 [m+H] + .

[0754] Example 63 Synthesis of Compound 100

[0755]

[0756] Compound 100 was synthesized according to the method of Synthesis Example 62, replacing 3-bromo-6-chloro-2-methylpyridine with 6-bromo-3-chloro-2-methylpyridine.

[0757] Example 64 Synthesis of Compound 102

[0758]

[0759] 64.1 Synthesis of 1-(6-chloro-4-methylpyridin-3-yl)-4-methylpiperazine

[0760] To a solution of 5-bromo-2-chloro-4-methylpyridine (1.0 g, 4.84 mmol), 1-methylpiperazine (484 μL, 4.35 mmol), and sodium tert-butoxide (930 mg, 9.68 mmol) in toluene (15 mL), Pd₂(dba)₃ (445 mg, 0.48 mmol) and XantPhos (560 mg, 0.968 mmol) were added. The mixture was stirred overnight at 100 °C under nitrogen. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a crude product, which was then subjected to reversed-phase chromatography (8%) to give the product (300 mg, 27.4% yield). MS (ESI): m / z 226 / 228 [m+H] + .

[0761] 64.2 Synthesis of 6-(6'-amino-4-methyl-5-(4-methylpiperazin-1-yl)-[2,3'-bipyridin]-5'-yl)isoquinoline-1(2H)-one

[0762] The compound obtained in the previous step (60 mg, 0.21 mmol), (6-amino-5-(1-oxo-1,2-dihydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (49 mg, 0.21 mmol), and sodium carbonate (46 mg, 0.42 mmol) were added to a solution of dioxane (5 mL) and water (1 mL) with tetraphenylphosphine palladium (25 mg, 0.021 mmol). The mixture was stirred at 80 °C under nitrogen for 4 hours. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the product (4.12 mg). MS (ESI): m / z found 427 [m+H] + .

[0763] Example 65 Synthesis of Compound 101

[0764]

[0765] Compound 101 was synthesized according to the method of Synthesis Example 64, replacing 5-bromo-2-chloro-4-methylpyridine with 2-bromo-5-chloro-4-methylpyridine.

[0766] Example 66 Synthesis of Compound 104

[0767]

[0768] 66.1 Synthesis of 6-bromo-2-methylisoquinoline-1(2H)-one

[0769] 6-Bromoisoquinoline-1(2H)-one (50 mg, 0.23 mmol) was dissolved in DMF, and cesium carbonate (219 mg, 0.67 mmol) and methyl iodide (21 μL, 0.34 mmol) were added sequentially to the mixed solvent. The mixture was stirred at room temperature for 4 h, and the reaction was checked for completion. Water and EA were added for extraction, and the crude product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the final product (52 mg, 97%). MS (ESI): [M+H]+ = 238.2.

[0770] 66.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-2-methylisoquinoline-1(2H)-one

[0771] Under nitrogen protection, Pd(PPh3)4 (13 mg, 0.002 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (72 mg, 0.33 mmol), 6-bromo-2-methylisoquinoline-1(2H)-one (52 mg, 0.22 mmol), sodium carbonate (70 mg, 0.66 mmol), dioxane (3 mL), and water (0.6 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (61 mg, 84.7%). MS(ESI): [M+H]+=330.66.3 Synthesis of 6-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)pyridin-3-yl)-2-methylisoquinoline-1(2H)-one

[0772] Under nitrogen protection, Pd(PPh3)4 (11 mg) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)-2-methylisoquinoline-1(2H)-one (61 mg, 0.19 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (92 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol), dioxane (5 mL), and water (1 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (21 mg, 25%). MS (ESI): [M+H] + =454.

[0773] Example 67 Synthesis of Compound 105

[0774]

[0775] 67.1 Synthesis of tert-butyl 6-chloro-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid

[0776] 6-Chloro-3,4-dihydroisoquinoline-1(2H)-one (500 mg, 2.21 mmol) was dissolved in THF, and TEA (921 μL, 6.64 mmol), (Boc)₂O (737 μL, 3.32 mmol), and DMAP (14 mg, 0.11 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed as monitored by LCMS, the mixture was concentrated under reduced pressure and extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was obtained (626 mg, 87%). MS (ESI): [M+H]⁺ = 282.

[0777] 67.2 Synthesis of tert-butyl 6-(2-amino-5-bromopyridin-3-yl)-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid

[0778] Under nitrogen protection, Pd(pph3)4 (128 mg, 0.11 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (723 mg, 3.33 mmol), (6-chloro-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (626 mg, 2.22 mmol), sodium carbonate (706 mg, 6.66 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (510 mg, 55.2%). MS (ESI): [M+H]+ = 418.

[0779] 67.3 Synthesis of 6-amino-5-(2-(tert-butoxycarbonyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)boronic acid

[0780] Under nitrogen protection, Pd(dppf)Cl2 (45 mg) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (510 mg, 1.22 mmol), B2Pin2 (472 mg, 1.83 mmol), and KoAc (359 mg, 3.66 mmol) dioxane (10 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (190 mg, 40.7%). MS (ESI): [M+H]+=383.

[0781] 67.4 Synthesis of tert-butyl 6-(6'-amino-6-methyl-5-(4-methylpiperazin-1-yl)-[2,3'-bipyridin]-5'-yl)-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid

[0782] Under nitrogen protection, Pd(dppf)Cl2 (6 mg) was added to a mixture of (6-amino-5-(2-(tert-butoxycarbonyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (40 mg, 0.11 mmol), 1-(6-chloro-2-methylpyridin-3-yl)-4-methylpiperazine (36 mg, 0.16 mmol), potassium carbonate (40 mg, 0.31 mmol), dioxane (5 mL), and water (1 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the product (22 mg, 36.2%). MS (ESI): [M+H]+=529.2.

[0783] 67.5 Synthesis of 6-(6'-amino-6-methyl-5-(4-methylpiperazin-1-yl)-[2,3'-bipyridin]-5'-yl)-3,4-dihydroisoquinoline-1(2H)-one

[0784] Under nitrogen protection, 22 mg of 6-(6'-amino-6-methyl-5-(4-methylpiperazin-1-yl)-[2,3'-bipyridin]-5'-yl)-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester was dissolved in 2 ml of DCM, and 1 ml of TFA was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (16 mg, 89.9%). MS (ESI): [M+H] + =429.2.

[0785] Example 68 Synthesis of Compound 106

[0786]

[0787] 68.1 Synthesis of 5-bromo-3-(isoquinolin-6-yl)pyridine-2-amine

[0788] Under nitrogen protection, Pd(PPh3)4 (28 mg, 0.002 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boric acid (126 mg, 0.58 mmol), 6-bromoisoquinoline (100 mg, 0.48 mmol), sodium carbonate (154 mg, 1.45 mmol), dioxane (3 mL), and water (0.6 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (84 mg, 57.9%). MS (ESI): [M+H] + =300.

[0789] 68.2 Synthesis of 5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-3-(isoquinoline-6-yl)pyridine-2-amine

[0790] Under nitrogen protection, Pd(dppf)Cl2 (4 mg) was added to a mixture of 5-bromo-3-(isoquinoline-6-yl)pyridin-2-amine (20 mg, 0.07 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (27 mg, 0.08 mmol), potassium carbonate (21.2 mg, 0.2 mmol), dioxane (2 mL), and water (0.4 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (10 mg, 35.5%). MS (ESI): [M+H] + =424.2.

[0791] Example 69 Synthesis of Compound 107

[0792]

[0793] 69.1 Synthesis of 5-bromo-3-(isoquinolin-6-yl)pyridine-2-amine

[0794] Under nitrogen protection, Pd(PPh3)4 (65 mg, 0.006 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (293 mg, 1.35 mmol), 6-bromonaphth-1-ol (250 mg, 1.13 mmol), sodium carbonate (358 mg, 3.38 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (170 mg, 48%). MS (ESI): [M+H]+ = 315.

[0795] 69.2 Synthesis of 6-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)pyridin-3-yl)naphthalene-1-ol

[0796] Under nitrogen protection, Pd(dppf)Cl2 (8 mg) was added to a mixture of 5-bromo-3-(isoquinoline-6-yl)pyridin-2-amine (40 mg, 0.13 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (63 mg, 0.19 mmol), potassium carbonate (41 mg, 0.38 mmol), dioxane (2 mL), and water (0.4 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (30 mg, 53.6%). MS (ESI): [M+H] + =439.2.

[0797] Example 70 Synthesis of Compound 110

[0798]

[0799] 70.1 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-7-fluoroisoquinoline-1-ol

[0800] Under nitrogen protection, Pd(PPh3)4 (24 mg, 0.002 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (108 mg, 0.50 mmol), 6-bromo-7-fluoroisoquinoline-1-ol (100 mg, 0.41 mmol), sodium carbonate (132 mg, 1.24 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (44 mg, 31.9%). MS(ESI): [M+H]+=334.70.2 Synthesis of 6-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)pyridin-3-yl)-7-fluoroisoquinoline-1-ol

[0801] Under nitrogen protection, Pd(dppf)Cl2 (8 mg) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)-7-fluoroisoquinoline-1-ol (44 mg, 0.13 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (52 mg, 0.16 mmol), potassium carbonate (42 mg, 0.40 mmol), dioxane (2 mL), and water (0.4 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (21 mg, 34.8%). MS (ESI): [M+H] + =458.2.

[0802] Example 71 Synthesis of Compound 111

[0803]

[0804] 71.1 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-8-fluoroisoquinoline-1(2H)-one

[0805] Under nitrogen protection, Pd(PPh3)4 (24 mg, 0.002 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (108 mg, 0.50 mmol), 6-bromo-8-fluoroisoquinoline-1(2H)-one (100 mg, 0.41 mmol), sodium carbonate (132 mg, 1.24 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (71 mg, 51.5%). MS (ESI): [M+H]+ = 334.

[0806] 71.2 Synthesis of 6-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)pyridin-3-yl)-8-fluoroisoquinoline-1(2H)-one

[0807] Under nitrogen protection, Pd(dppf)Cl2 (5 mg) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)-8-fluoroisoquinoline-1(2H)-one (30 mg, 0.08 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (45 mg, 0.15 mmol), potassium carbonate (29 mg, 0.30 mmol), dioxane (2 mL), and water (0.4 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (19 mg, 46.34%). MS (ESI): [M+H] + =458.2.

[0808] Example 72 Synthesis of Compound 135

[0809]

[0810] 72.1 Synthesis of 6-bromo-N-methylisoquinoline-1-amine

[0811] 6-Bromo-1-chloroisoquinoline (100 mg, 0.41 mmol) was dissolved in DMSO. Methylamine solution (49 μL, 1.24 mmol) and potassium carbonate (171 mg, 1.24 mmol) were added sequentially to the mixture. Nitrogen gas was introduced, and the mixture was heated to 80°C for 4 h. The reaction was then checked for completeness. The product was extracted with ethyl acetate and water, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (82 mg, 84.1%). MS (ESI): [M+H]+=237.72.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-N-methylisoquinoline-1-amine

[0812] Under nitrogen protection, Pd(PPh3)4 (30 mg, 0.003 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (133 mg, 0.61 mmol), 6-bromo-N-methylisoquinoline-1-amine (120 mg, 0.51 mmol), sodium carbonate (162 mg, 1.53 mmol), dioxane (10 mL), and water (2 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (55 mg, 32.9%). MS(ESI): [M+H]+=329.72.3 Synthesis of 6-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)pyridin-3-yl)-N-methylisoquinoline-1-amine

[0813] Under nitrogen protection, Pd(PPh3)4 (10 mg) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)-N-methylisoquinoline-1-amine (55 mg, 0.17 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (66 mg, 0.20 mmol), sodium carbonate (53 mg, 0.50 mmol), dioxane (2 mL), and water (0.4 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (56 mg, 73.7%). MS (ESI): [M+H] + =453.3.

[0814] Example 73 Synthesis of Compound 134

[0815]

[0816] 73.1 Synthesis of 6-bromo-N,N-dimethylisoquinoline-1-amine

[0817] 6-Bromo-1-chloroisoquinoline (100 mg, 0.41 mmol) was dissolved in DMSO. Dimethylamine solution (70 μL, 1.24 mmol) and sodium bicarbonate (104 mg, 1.24 mmol) were added sequentially to the mixture. Nitrogen gas was introduced, and the mixture was heated to 80°C for 4 h. The reaction was then checked for completeness. The product was extracted with ethyl acetate and water, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure by distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (55 mg, 52.9%). MS (ESI): [M+H]+ = 251.

[0818] 73.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-N,N-dimethylisoquinoline-1-amine

[0819] Under nitrogen protection, Pd(PPh3)4 (13 mg, 0.001 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (57 mg, 0.26 mmol), 6-bromo-N,N-dimethylisoquinoline-1-amine (55 mg, 0.22 mmol), sodium carbonate (70 mg, 0.66 mmol), dioxane (5 mL), and water (1 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (72 mg, 96%). MS(ESI): [M+H]+=342.73.3 Synthesis of 6-(2-amino-5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)pyridin-3-yl)-N,N-dimethylisoquinoline-1-amine

[0820] Under nitrogen protection, Pd(PPh3)4 (12 mg) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)-N,N-dimethylisoquinoline-1-amine (72 mg, 0.21 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (83 mg, 0.25 mmol), sodium carbonate (67 mg, 0.63 mmol), dioxane (2 mL), and water (0.4 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (36 mg, 36.7%). MS (ESI): [M+H] + =467.3.

[0821] Example 74 Synthesis of Compound 128

[0822]

[0823] 74.1 Synthesis of 6-bromo-1-methoxyisoquinoline

[0824] 6-Bromoisoquinoline-1-ol (100 mg, 0.45 mmol) was dissolved in methanol. Sodium methoxide solution (71 μL, 1.434 mmol) was added sequentially to the mixture. Nitrogen gas was introduced, and the mixture was heated to 80°C for 4 h. The reaction was then checked for completion. The product was extracted with ethyl acetate and water, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (64 mg, 60.4%). MS (ESI): [M+H]+ = 238.

[0825] 74.2 Synthesis of 5-bromo-3-(1-methoxyisoquinoline-6-yl)pyridine-2-amine

[0826] Under nitrogen protection, Pd(PPh3)4 (16 mg, 0.001 mmol) was added to a mixture of (2-amino-5-bromopyridin-3-yl)boronic acid (70 mg, 0.32 mmol), 6-bromo-1-methoxyisoquinoline (64 mg, 0.27 mmol), sodium carbonate (86 mg, 0.81 mmol), dioxane (5 mL), and water (1 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was completed as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (25 mg, 28.1%). MS(ESI): [M+H]+=330.74.3 Synthesis of 5-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-3-(1-methoxyisoquinoline-6-yl)pyridine-2-amine

[0827] Under nitrogen protection, Pd(PPh3)4 (4 mg) was added to a mixture of 6-(2-amino-5-bromopyridin-3-yl)-N,N-dimethylisoquinoline-1-amine (25 mg, 0.08 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)-4-methylpiperazine (30 mg, 0.09 mmol), sodium carbonate (24 mg, 0.22 mmol), dioxane (2 mL), and water (0.4 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete as monitored by LCMS, the mixture was extracted with ethyl acetate and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to give the final product (20 mg, 58.1%). MS (ESI): [M+H] + =454.3.

[0828] Example 75 Synthesis of Compound 136

[0829]

[0830] 75.1 Synthesis of 6-(2-amino-5-(3,5-dimethyl-4-(piperidin-1-carbonyl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinoline-1(2H)-one

[0831] Under nitrogen protection, S-phos PdG2 (5 mg) was added to a mixture of (6-amino-5-(2-(tert-butoxycarbonyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (4-bromo-2,6-dimethylphenyl)(piperidin-1-yl) methyl ketone (46 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), dioxane (3 mL), and water (0.6 mL). The reaction mixture was stirred overnight at 80 °C, and the reaction was monitored by TLC until completion. After concentration under reduced pressure, 2 mL of TFA was added, and the reaction was monitored by LCMS until completion. The mixture was then extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (25 mg, 42.1%). MS (ESI): [M+H] + =455.2.

[0832] Example 76 Synthesis of Compound 137

[0833]

[0834] 76.1 Synthesis of 6-(2-amino-5-(4-(azacyclobutane-1-carbonyl)-3,5-dimethylphenyl)pyridin-3-yl)-3,4-dihydroisoquinoline-1(2H)-one

[0835] Under nitrogen protection, S-phos PdG2 (5 mg) was added to a mixture of (6-amino-5-(2-(tert-butoxycarbonyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (azacyclobutane-1-yl(4-bromo-2,6-dimethylphenyl) methyl ketone (42 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), dioxane (3 mL), and water (0.6 mL). The reaction mixture was stirred overnight at 80 °C, and the reaction was monitored by TLC until completion. After concentration under reduced pressure, 2 mL of TFA was added, and the reaction was monitored by LCMS until completion. The mixture was then extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (30 mg, 54%). MS (ESI): [M+H]+ = 427.2.

[0836] Example 77 Synthesis of Compound 138

[0837]

[0838] 77.1 Synthesis of (R)-6-(2-amino-5-(3,5-dimethyl-4-(2-methylpyrrolidine-1-carbonyl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinoline-1(2H)-one

[0839] Under nitrogen protection, S-phos PdG2 (5 mg) was added to a mixture of (6-amino-5-(2-(tert-butoxycarbonyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (R)-(4-bromo-2,6-dimethylphenyl)(2-methylpyrrolidone-1-yl) methyl ketone (46 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), dioxane (3 mL), and water (0.6 mL). The reaction mixture was stirred overnight at 80 °C, and the reaction was monitored by TLC until completion. After concentration under reduced pressure, 2 mL of TFA was added, and the reaction was monitored by LCMS until completion. The mixture was then extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (32 mg, 53.9%). MS(ESI):[M+H] + =455.2.

[0840] Example 78 Synthesis of Compound 139

[0841]

[0842] 78.1 Synthesis of N-(4-(6-amino-5-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)-2,6-dimethylphenyl)-N-methylacetamide

[0843] Under nitrogen protection, S-phos PdG2 (5 mg) was added to a mixture of (6-amino-5-(2-(tert-butoxycarbonyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), N-(4-bromo-2,6-dimethylphenyl)-N-methylacetamide (40 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), dioxane (3 mL), and water (0.6 mL). The reaction mixture was stirred overnight at 80 °C, and the reaction was monitored by TLC until completion. After concentration under reduced pressure, 2 mL of TFA was added, and the reaction was monitored by LCMS until completion. The mixture was then extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (35 mg, 64.8%). MS(ESI):[M+H]+=415.2.

[0844] Example 79 Synthesis of Compound 140

[0845]

[0846] 79. Synthesis of (S)-6-(2-amino-5-(3,5-dimethyl-4-(2-methylpyrrolidine-1-carbonyl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinoline-1(2H)-one

[0847] Under nitrogen protection, S-phos PdG2 (5 mg) was added to a mixture of (6-amino-5-(2-(tert-butoxycarbonyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (S)-(4-bromo-2,6-dimethylphenyl)(2-methylpyrrolidone-1-yl) methyl ketone (46 mg, 0.16 mmol), potassium carbonate (54 mg, 0.39 mmol), dioxane (3 mL), and water (0.6 mL). The reaction mixture was stirred overnight at 80 °C, and the reaction was monitored for completion by TLC. After concentration under reduced pressure, 2 mL of TFA was added, and the reaction was monitored for completion by LCMS. The mixture was then extracted with ethyl acetate and water. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the final product (35 mg, 58.7%). MS(ESI):[M+H] + =455.2.

[0848] Other compounds can be synthesized using methods that are the same as or similar to those described above.

[0849] Example 80 Compound 123

[0850]

[0851] 1 H NMR (600MHz, DMSO) δ11.24(d,J=5.7Hz,1H),9.80(s,1H),8.29(d,J=2.0Hz,1H) ,8.14(s,1H),7.98(s,1H),7.95(d,J=7.9Hz,1H),7.77(s,1H),7.50(d,J=8.2Hz ,2H),7.48(s,1H),6.39(d,J=17.0Hz,2H),3.18–3.20(m,2H),3.10–3.06(m,2H ),2.31(s,6H),1.89(t,J=6.5Hz,2H),1.75(t,J=9.0Hz,2H),1.68–1.60(m,2H).

[0852] Example 81 Compound 124

[0853]

[0854] 1 H NMR (400MHz, DMSO-d6) δ11.25(d,J=5.7Hz,1H),8.27(d,J=2.7Hz,2H),8.24(s,1H),7.80(d,J=1.7Hz,1H),7.66–7.60(m,2H),7.27 –7.17(m,3H),6.91(d,J=7.4Hz,1H),6.60(d,J=7.1Hz,1H),3.02(t,J=6.1Hz,2H),2.42(t,J=6.3Hz,2H),2.27(s,6H),2.22(s,6H).

[0855] Example 82 Compound 125

[0856]

[0857] 1 H NMR (600MHz, DMSO-d6) δ11.24(s,1H),10.99(s,1H),8.26(d,J=8.3Hz,1H),8.23(d ,J=2.3Hz,1H),7.86(d,J=1.7Hz,1H),7.71(dd,J=8.3,1.7Hz,1H),7.60(d,J=2.3H z,1H),7.23–7.19(m,2H),7.00(d,J=7.7Hz,1H),6.59(d,J=7.1Hz,1H),6.55(d,J= 7.8Hz,1H),6.46–6.44(m,1H),5.85(s,2H),3.14(s,4H),2.56(s,4H),2.27(s,3H).

[0858] Example 83 Compound 145

[0859]

[0860] 1H NMR(400MHz, DMSO-d6)δ8.41(s,1H),8.36(dd,J=5.1,2.4Hz,2H),7.97(d,J=2.9Hz,1H),7.94(s,1H),7.92(s,1H),7.77–7.74(m,1H),5.95(s,2H), 5.18(s,2H),4.50(s,2H),2.98(t,J=6.5Hz,2H),2.10–2.03(m,2H),1.98– 1.86(m,3H),1.75–1.69(m,2H),1.61–1.52(m,2H),1.26(d,J=6.3Hz,3H).

[0861] Example 84 Compound 151

[0862]

[0863] 1 H NMR (400MHz, DMSO) δ8.37(d,J=2.4Hz,1H),7.97–7.91(m,2H),7.71(d,J=2.4Hz,1H),7.50(t,J=7.4Hz,4H),5. 91(s,2H),3.03(s,3H),2.97(t,J=6.5Hz,2H),2.35–2.28(m,2H),2.19(s,6H),1.70–1.49(m,7H),1.37(s,2H).

[0864] Example 85 Compound 152

[0865]

[0866] 1 H NMR (600MHz, DMSO) δ8.41(s,1H),7.96(s,1H),7.93(d,J=7.9Hz,2H),7.75(s,1H),7.54–7.47(m,4H),6.02(s,2H),3.91–3.75( m,2H),3.74–3.53(m,2H),3.46–3.40(m,2H),2.26(dd,J=15.8,5.3Hz,2H),2.22–2.08(m,2H),2.18(s,3H),1.82–1.78(m,4H).

[0867] Example 86 Compound 153

[0868]

[0869] 1H NMR (600MHz, DMSO) δ9.80(s,1H),8.29(d,J=2.0Hz,1H),8.14(s,1H),7.98(s,1H),7.95(d,J=7.9Hz,1H),7.77(s,1H),7.50(d,J=8.2Hz,1 H),7.48(s,1H),6.39(d,J=17.0Hz,2H),3.18–3.20(m,4H),3.10–3.06(m,4H),2.98(t,J=6.5Hz,2H),2.91(d,J=9.0Hz,2H),2.31(s,6H).

[0870] Example 87 Compound 156

[0871]

[0872] 1 H NMR (400MHz, DMSO) δ8.36(d,J=2.4Hz,1H),7.97–7.90(m,2H),7.70(d,J=2.4Hz,1H),7.50(t,J=7.4Hz,4H),5. 91(s,2H),3.03(s,3H),2.97(t,J=6.5Hz,2H),2.35–2.28(m,2H),2.19(s,6H),1.70–1.49(m,7H),1.37(s,3H).

[0873] Example 88 Compound 158

[0874]

[0875] 1 H NMR (400MHz, DMSO) δ8.37(d,J=2.3Hz,1H),7.97–7.92(m,2H),7.73(d,J=2. 3Hz,1H),7.60(s,1H),7.56–7.47(m,3H),7.21(d,J=7.9Hz,1H),6.01(s,2H) ,4.02(dd,J=9.4,5.7Hz,1H),3.84(s,1H),3.69(d,J=12.8Hz,1H),3.42(td ,J=6.5,2.4Hz,4H),3.27(d,J=13.6Hz,5H),3.00–2.88(m,4H),2.28(s,3H).

[0876] Example 89 Compound 164

[0877]

[0878] 1 H NMR (600MHz, DMSO) δ8.41(s,1H),7.96(s,1H),7.93(d,J=7.9Hz,1H),7.75(s,1H),7.54–7.47(m,4H),6.02(s,2H),5.35(dd,J=76.7,52.5 Hz,1H),3.91–3.75(m,2H),3.74–3.53(m,2H),3.46–3.40(m,3H),2.98(t,J=6.5Hz,2H),2.26(dd,J=15.8,5.3Hz,3H),2.22–2.08(m,2H).

[0879] Example 90 Compound 248

[0880]

[0881] 1 H NMR (400MHz, DMSO) δ9.60–9.52(m,1H),7.98(s,1H),7.92(d,J=7.9Hz,1H),7.88(d,J=6.3H z,1H),7.64(d,J=10.0Hz,1H),7.52–7.44(m,1H),7.45(d,J=3.6Hz,1H),7.37(d,J=8.1Hz,1 H),7.28–7.24(m,1H),6.63(s,1H),6.34(s,1H),6.14(s,2H),3.49–3.43(m,4H),3.38–3.30 (m,1H),3.25–3.21(m,2H),3.18–3.15(m,2H),1.03(d,J=2.5Hz,3H),1.01(d,J=2.5Hz,3H).

[0882] Example 91 Compound 165

[0883]

[0884] 1H NMR (600MHz, DMSO) δ8.45(d,J=2.4Hz,1H),8.05(d,J=7.3Hz,2H),7.97–7.92(m,2H),7.82(d,J=2.4Hz,1H),7.54(dt,J=15.2,7.8Hz,2H),7.50( s,1H),6.08(s,2H),5.45–5.21(m,1H),3.84–3.67(m,2H),3.55–3.50(m ,1H),3.45–3.40(m,3H),3.26(d,J=25.1Hz,2H),2.98(t,J=6.5Hz,2H).

[0885] Example 92 Compound 166

[0886]

[0887] 1 H NMR(600MHz,DMSO)δ8.34(d,J=2.3Hz,1H),7.98–7.91(m,2H),7.68(d,J=2.1Hz,1H),7 .50(t,J=7.9Hz,1H),7.48(s,1H),7.40(s,2H),5.90(s,2H),5.33(dd,J=88.2,52.4Hz ,1H),3.85(dd,J=24.6,14.5Hz,1H),3.76–3.66(m,1H),3.66–3.54(m,2H),3.46–3.41 (m,2H),3.14(dd,J=8.5,5.7Hz,2H),2.98(t,J=6.5Hz,2H),2.22(s,3H),2.19(s,3H).

[0888] Example 93 Compound 171

[0889]

[0890] 1H NMR (600MHz, DMSO) δ8.34(d,J=2.4Hz,1H),7.95(s,1H),7.93–7.90(m,2H),7.85(d,J=2.0Hz,1H),7.70(d,J=2.4Hz,1H),7.58(d,J=8.4Hz,1H),7 .51(d,J=7.9Hz,1H),7.48(s,1H),5.95(s,2H),3.43–3.40(m,4H),2.97 (t,J=6.5Hz,2H),2.89(t,J=4.6Hz,4H),2.49–2.47(m,2H),2.24(s,3H).

[0891] Example 94 Compound 172

[0892]

[0893] 1 H NMR (600MHz, DMSO) δ8.47(d,J=2.1Hz,1H),7.96(s,1H),7.93(d,J=7.9Hz,1H),7. 82(d,J=2.0Hz,1H),7.64(dd,J=9.9,2.0Hz,2H),7.53(d,J=8.1Hz,1H),7.50(s,1 H),6.15(s,2H),5.37(dd,J=58.0,55.0Hz,1H),3.85–3.72(m,2H),3.66–3.51(m, 2H), 3.43 (ddd, J=12.7, 9.9, 7.1Hz, 2H), 2.98 (t, J=6.5Hz, 2H), 2.27–2.11 (m, 2H).

[0894] Example 95 Compound 175

[0895]

[0896] 1 H NMR (600MHz, DMSO) δ8.27(d,J=2.3Hz,1H),8.14(s,1H),7.96(s,1H),7.93(d,J=7.9Hz,1H),7.61(d,J=2.3Hz,1H),7.49(dd,J=13.1,5.6H z,3H),7.46–7.40(m,1H),7.07(d,J=8.3Hz,1H),5.79(d,J=28.6Hz,2H),3.37–3.27(m,4H),2.93–2.90(m,4H),2.56(s,3H),2.30(s,3H).

[0897] Example 96 Compound 177

[0898]

[0899] 1 H NMR (400MHz, DMSO) δ8.29(t,J=3.5Hz,1H),8.27(s,1H),7.99–7.90(m,1H),7.64(d,J=2.4Hz,1H),7.52–7.45(m,2H),7.40–7.3 4(m,1H),7.16(s,1H),7.12(d,J=8.4Hz,1H),5.87(s,2H),3.00–2.95(dd,J=14.5,5.7Hz,6H),2.48–2.44(m,7H),2.23(s,3H).

[0900] Example 97 Compound 178

[0901]

[0902] 1 H NMR (400MHz, DMSO) δ8.36(d,J=2.2Hz,1H),7.96(s,1H),7.93(d,J=7.9Hz,1H),7.71(dd,J=10.2,5.1Hz,3H),7.52(dd,J=11.1 ,3.1Hz,2H),7.37(d,J=8.1Hz,2H),5.93(s,2H),3.42(td,J=6.6,2.6Hz,2H),3.17(s,3H),2.97(t,J=6.5Hz,2H),1.82(s,3H).

[0903] Example 98 Compound 179

[0904]

[0905] 1 H NMR (400MHz, DMSO) δ8.39(d,J=2.4Hz,1H),7.98–7.92(m,2H),7.75(d,J=2.4Hz,1H),7.51(d,J=8.0Hz,1H),7.49(s,1H),7.36(d,J=1. 1Hz,1H),7.31–7.26(m,2H),5.91(d,J=16.7Hz,2H),3.91(s,3H),3.44–3.40(m,2H),3.04(s,3H),2.97(t,J=6.5Hz,2H),1.70(s,3H).

[0906] Example 99 Compound 180

[0907]

[0908] 1 H NMR (400MHz, DMSO) δ8.42(d,J=2.3Hz,1H),7.96(s,1H),7.93(d,J=7.9Hz,1H),7.75(dd,J=9.3,2.0Hz,2H),7.61(dd,J =8.3,1.5Hz,1H),7.55–7.47(m,3H),6.04(s,2H),3.46–3.39(m,2H),3.12(s,3H),2.97(t,J=6.5Hz,2H),1.79(s,3H).

[0909] Example 100 Compound 181

[0910]

[0911] 1 H NMR (400MHz, DMSO) δ8.46(d,J=2.4Hz,1H),8.09(s,2H),7.98–7.92(m,2H),7.83(d,J=2.4Hz,1H),7.64(d,J=8.0Hz,1H),7. 53(d,J=8.0Hz,1H),7.50(s,1H),6.09(s,2H),3.42(td,J=6.6,2.6Hz,2H),3.09(s,3H),2.97(t,J=6.5Hz,2H),1.69(s,3H).

[0912] Example 101 Compound 182

[0913]

[0914] 1 H NMR (400MHz, DMSO-d6) δ8.46(d,J=2.4Hz,1H),8.27(d,J=2.7Hz,2H),8.24(s,1H),7.80(d,J=1.7Hz,1H),7.66–7.60(m,2H),7.27–7.17(m,2H),6 .91(d,J=7.4Hz,1H),6.60(d,J=7.1Hz,1H),3.46–3.38(m,2H),3.23(t, J=6.3Hz, 2H), 3.02 (t, J=6.1Hz, 2H), 2.42 (t, J=6.3Hz, 2H), 2.22 (s, 6H).

[0915] Example 102 Compound 183

[0916]

[0917] 1 H NMR (400MHz, DMSO) δ8.21(s,1H),7.95(s,1H),7.92(d,J=7.9Hz,1H),7.55(d,J=2.3Hz,1H),7.52–7.44(m,2H),7.31(d,J=8.6Hz,2H),6.61(d ,J=8.1Hz,1H),5.66(s,2H),3.46–3.38(m,2H),3.23(t,J=6.3Hz,2H),2.97(t,J=6.4Hz,2H),2.65(t,J=6.3Hz,2H),2.30(s,6H),2.12(s,3H).

[0918] Example 103 Compound 184

[0919]

[0920] 1 H NMR (400MHz, DMSO) δ11.28(d,J=5.2Hz,1H),9.77–9.69(m,1H),8.73(d,J=2.3H z,1H),8.28(d,J=8.3Hz,1H),8.23(d,J=9.0Hz,1H),8.06(d,J=2.2Hz,1H),7.80 (d,J=9.0Hz,1H),7.60(dd,J=8.3,1.7Hz,1H),7.26–7.19(m,1H),6.63(d,J=7.0 Hz,1H),6.33(s,2H),3.72(s,2H),3.58(s,2H),3.28–3.19(m,4H),2.91(s,3H).

[0921] Example 104 Compound 185

[0922]

[0923] 1H NMR (400MHz, DMSO) δ11.25(d,J=5.1Hz,1H),8.33(d,J=2.4Hz,1H),8.28–8.23(m,1H),7. 81(d,J=1.5Hz,1H),7.70(d,J=2.4Hz,1H),7.64(dd,J=8.3,1.7Hz,1H),7.50(dd,J=14.5, 2.1Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),7.22–7.19(m,1H),7.04(d,J=8.9Hz,1H),6.60(d ,J=7.0Hz,1H),5.89(s,2H),3.07–2.99(m,4H),2.49–2.45(m,4H),2.22(d,J=8.6Hz,3H).

[0924] Example 105 Compound 186

[0925]

[0926] 1 H NMR(400MHz,DMSO)δ11.26(d,J=5.2Hz,1H),9.70–9.64(m,1H),8.73(d,J=2.3 Hz,1H),8.26(d,J=8.2Hz,1H),8.24(d,J=9.3Hz,1H),8.04(d,J=2.4Hz,1H),7 .81(d,J=8.5Hz,1H),7.61(dd,J=8.3,1.7Hz,1H),7.26–7.16(m,1H),6.61(d, J=6.8Hz,1H),6.31(s,2H),3.75–3.61(m,4H),3.28–3.19(m,4H),2.90(s,3H).

[0927] Example 106 Compound 187

[0928]

[0929] 1H NMR (400MHz, DMSO) δ11.28(d,J=4.9Hz,1H),8.64(d,J=2.4Hz,1H),8.31(s,2H ),8.26(d,J=8.3Hz,1H),7.95(d,J=2.4Hz,1H),7.80–7.76(m,2H),7.60(dd,J= 8.3,1.7Hz,1H),7.50(dd,J=11.1,8.2Hz,1H),7.25–7.19(m,1H),6.62(d,J=7 .1Hz,1H),6.10(s,2H),3.11–3.03(m,5H),2.48(s,3H),2.24(d,J=7.7Hz,3H).

[0930] Example 107 Compound 188

[0931]

[0932] 1 H NMR (400MHz, DMSO) δ11.25(d,J=5.5Hz,1H),8.38(d,J=2.4Hz,1H),8.25(d,J =8.3Hz,1H),7.81(d,J=1.4Hz,1H),7.76(d,J=2.4Hz,1H),7.63(dd,J=8.3,1. 7Hz,1H),7.45–7.42(m,1H),7.41(d,J=4.6Hz,1H),7.24–7.18(m,1H),6.60(d ,J=7.0Hz,1H),6.01(s,2H),3.12(d,J=4.4Hz,4H),2.43(s,4H),2.23(s,3H).

[0933] Example 108 Compound 190

[0934]

[0935] 1H NMR (400MHz, DMSO) δ8.37(d,J=2.3Hz,1H),7.99(s,1H),7.95(d,J=7.9Hz,1H),7.86(d,J=2.1Hz,1H),7.71(d,J=1.7Hz,1H),7.60(dd,J=8.1,2.0Hz, 1H),7.52(dd,J=11.1,3.1Hz,2H),7.30(d,J=8.2Hz,1H),6.42(s,2H),3.4 5–3.42(m,4H),3.08(d,J=11.8Hz,3H),2.98(t,J=6.5Hz,3H),2.23(s,3H).

[0936] Example 109 Compound 195

[0937]

[0938] 1 H NMR (600MHz, DMSO) δ11.25(d,J=4.8Hz,1H),8.67(d,J=2.1Hz,1H),8.26(d,J=8.2Hz,1H),7.98(d,J=2.1Hz,1 H),7.78(s,1H),7.59(d,J=8.2Hz,1H),7.28(dd,J=17.6,8.1Hz,2H),7.23–7.19(m,1H),6.61(d,J=7.0Hz,1H ),5.92(s,2H),5.39(d,J=54.7Hz,1H),3.86–3.81(m,1H),3.75(dd,J=20.1,10.7Hz,2H),3.68(dd,J=13.2,3 .6Hz,1H),3.57(dd,J=13.2,5.7Hz,2H),2.97(s,3H),2.77(s,3H),2.23(d,J=22.0Hz,3H),2.18–2.07(m,2H).

[0939] Example 110 Compound 196

[0940]

[0941] 1H NMR (600MHz, DMSO) δ11.26(d,J=4.8Hz,1H),8.79(t,J=2.9Hz,1H),8.27(d,J=8.2Hz,1H),8.25( s,1H),8.19(d,J=2.1Hz,1H),8.15(s,1H),7.80(d,J=7.0Hz,1H),7.73(d,J=9.0Hz,1H),7.66–7 .62(m,1H),7.54(d,J=8.3Hz,1H),7.51(d,J=8.4Hz,1H),7.24–7.20(m,1H),7.01(d,J=6.4Hz,1 H),6.63–6.58(m,1H),6.03(d,J=5.1Hz,1H),3.54–3.49(m,4H),3.48–3.45(m,4H),2.19(s,3H).

[0942] Example 111 Compound 197

[0943]

[0944] 1 H NMR (600MHz, DMSO) δ11.25(d,J=5.0Hz,1H),8.67(d,J=2.2Hz,1H),8.26(d,J=8.2Hz,1H),7.98(d,J=2.2Hz ,1H),7.78(s,1H),7.59(dd,J=8.2,1.5Hz,1H),7.29(d,J=8.1Hz,1H),7.26(dd,J=7.1,4.8Hz,1H),7.23–7. 20(m,1H),6.61(d,J=7.1Hz,1H),5.92(s,2H),5.39(d,J=55.3Hz,1H),3.86–3.80(m,1H),3.80–3.72(m,2H) ,3.71–3.66(m,1H),3.61–3.55(m,1H),2.97(s,3H),2.77(s,3H),2.23(d,J=4.9Hz,3H),2.17–2.08(m,3H).

[0945] Example 112 Compound 199

[0946]

[0947] 1H NMR (400MHz, DMSO) δ11.26(d,J=5.3Hz,1H),8.42(d,J=2.4Hz,1H),8.26(d,J=8.3Hz,1H),7.81(d,J=2.6Hz,2H),7.64(dd,J=8.3,1.6Hz,1H),7.38(s,1 H),7.29(t,J=4.5Hz,2H),7.24–7.19(m,1H),6.60(d,J=7.0Hz,1H),5.98(s ,2H),3.91(d,J=2.7Hz,3H),3.05(d,J=11.8Hz,3H),1.70(d,J=3.0Hz,3H).

[0948] Example 113 Compound 201

[0949]

[0950] 1 H NMR (600MHz, DMSO) δ9.61 (s, 1H), 8.39 (d, J = 2.4Hz, 1H), 8.00 (s, 1H), 7.95 (d, J = 7.9Hz, 1H), 7.86 (s, 1H), 7.53 (dd, J = 13. 0,10.1Hz,2H),7.49(s,1H),6.55–6.42(m,2H),3.54–3.46(m,6H),3.20–3.15(m,4H),2.98(t,J=6.6Hz,2H),2.89(s,3H).

[0951] Example 114 Compound 202

[0952]

[0953] 1 H NMR (600MHz, DMSO) δ11.26(s,1H),8.64(d,J=2.2Hz,1H),8.29(s,1H),8.25(t,J=8.7Hz ,1H),7.95(d,J=2.2Hz,1H),7.77(s,1H),7.59(d,J=8.2Hz,1H),7.25(s,1H),7.21(d,J =5.1Hz,1H),6.63–6.58(m,1H),5.92(s,2H),4.61(s,1H),3.72(dd,J=10.6,6.4Hz,2H) ,3.55–3.47(m,6H),2.41(d,J=19.7Hz,5H),2.37–2.29(m,2H),2.21(d,J=47.4Hz,4H),

[0954] 1.79 (dd, J = 16.8, 10.2 Hz, 2H).

[0955] Example 115 Compound 205

[0956]

[0957] 1 H NMR (600MHz, DMSO) δ11.26(s,1H),8.63(d,J=2.2Hz,1H),8.29(s,1H),8.23(t,J=8.7Hz, 1H),7.95(d,J=2.2Hz,1H),7.77(s,1H),7.60(d,J=8.1Hz,1H),7.25(s,1H),7.21(d,J=5. 1Hz,1H),6.63–6.58(m,1H),5.92(s,2H),3.44(dd,J=15.3,9.6Hz,4H),3.07(d,J=13.4Hz ,2H),2.99–2.94(m,1H),2.90(m,1H),2.31(s,3H),2.25–2.14(m,1H),1.79–1.68(m,4H).

[0958] Example 116 Compound 212

[0959]

[0960] 1 H NMR (400MHz, DMSO) δ8.67(d,J=2.3Hz,1H),8.14(s,1H),7.98–7.91(m,2H),7.73(d,J=8.5Hz,1H),7.50–7.41(m,3H),6.85(s,1H),6.66(s,1H ),6.10–6.07(m,1H),5.97(s,2H),3.75(s,2H),3.42(dd,J=9.5,6.7Hz,3H),3.01–2.94(m,3H),2.84(s,4H),2.45–2.38(m,3H),2.24(s,3H).

[0961] Example 117 Compound 213

[0962]

[0963] 1H NMR (400MHz, DMSO) δ8.73(d,J=2.3Hz,1H),8.26(d,J=8.6Hz,1H),8.14(s,1H),8.04( d,J=2.3Hz,1H),7.99–7.92(m,1H),7.84(d,J=6.8Hz,1H),7.75(d,J=8.6Hz,1H),7.63 (d,J=8.5Hz,1H),7.47(d,J=8.8Hz,1H),7.40(dd,J=6.9,3.1Hz,1H),6.66(dd,J=3.3, 1.8Hz,1H),6.04(s,2H),3.43(dd,J=8.1,5.8Hz,4H),3.09–2.93(m,8H),2.23(s,3H).

[0964] Example 118 Compound 214

[0965]

[0966] 1 H NMR (600MHz, DMSO) δ8.67(d,J=2.3Hz,1H),8.17(s,1H),7.96(s,1H),7.94(dd,J=5.0,2.7Hz,1H),7.47(d,J=8.0Hz,1H),7.45(s,1H), 7.41(d,J=8.0Hz,1H),7.20(d,J=8.0Hz,1H),5.92(s,2H),3.95(s,3H),3.03(s,4H),2.97(t,J=6.5Hz,4H),2.48(s,4H),2.24(s,3H).

[0967] Example 119 Compound 215

[0968]

[0969] 1H NMR (600MHz, DMSO) δ11.24(d,J=59.3Hz,1H),8.88(dd,J=12.1,2.2Hz,1H),8.18(d,J=2.3Hz,1 H),7.95(d,J=8.0Hz,1H),7.64(d,J=8.5Hz,1H),7.55(d,J=8.5Hz,1H),7.54–7.51(m,1H),7.5 1–7.49(m,1H),7.48(s,1H),7.18(s,1H),6.89(s,1H),6.19–6.09(m,1H),5.94(d,J=13.0Hz,2 H),3.42(d,J=6.6Hz,3H),3.03–2.96(m,3H),2.90(d,J=41.9Hz,4H),2.29(m,2H),2.19(s,3H).

[0970] Example 120 Compound 216

[0971]

[0972] 1 H NMR (600MHz, DMSO) δ8.79(s,1H),8.05(s,1H),7.97(s,1H),7.94(d,J=7.7Hz,1H),7.75(d,J=7.9Hz,1H),7.60(d,J=7. 9Hz,1H),7.49–7.46(m,2H),6.14(s,2H),3.99(s,2H),3.42(s,3H),3.04(s,2H),3.00–2.96(m,3H),2.22–2.16(m,3H).

[0973] Example 121 Compound 222

[0974]

[0975] 1 H NMR (600MHz, DMSO) δ8.86(s,1H),8.34(s,1H),8.00–7.93(m,2H),7.85(d,J=8.5Hz,2H),7.63(d,J=30.2Hz,2H),7.51(d ,J=8.0Hz,1H),7.48(s,1H),7.15(s,1H),5.97(s,2H),3.48–3.40(m,6H),3.02–2.97(m,2H),2.90(s,4H),2.26(s,3H).

[0976] Example 122 Compound 227

[0977]

[0978] 1 H NMR (400MHz, DMSO) δ8.29(d,J=2.4Hz,1H),8.19(s,1H),7.96(s,1H),7.93(d,J=7.9 Hz,1H),7.63(d,J=2.4Hz,1H),7.52–7.48(m,1H),7.47(s,1H),7.16–7.11(m,1H),6. 94–6.88(m,1H),5.79(s,2H),3.85(s,3H),3.44–3.39(m,4H),3.01–2.92(m,4H),2. 74–2.67(m,2H),2.60(d,J=4.4Hz,4H),1.03(d,J=2.5Hz,3H),1.01(d,J=2.5Hz,3H).

[0979] Example 123 Compound 229

[0980]

[0981] 1 H NMR (600MHz, DMSO) δ11.43(s,1H),8.33(d,J=2.4Hz,1H),7.91(d,J=10.2Hz,1H),7.80(d,J=7.1Hz,1H),7.65(d,J=2.4Hz,1H),7.25 (s,2H),7.23–7.18(m,1H),6.63(d,J=7.1Hz,1H),5.86(s,2H),3.02(d,J=4.4Hz,4H),2.44–2.39(m,4H),2.31(s,6H),2.23(s,3H).

[0982] Example 124 Compound 234

[0983]

[0984] 1H NMR (600MHz, DMSO) δ8.29(d,J=2.3Hz,1H),8.16(s,1H),7.95(s,1H),7.92(s,1H),7.64(d,J=2.2Hz,1H),7.50(d,J=8.0Hz,1H),7.47(s,1H), 7.14(dd,J=11.4,3.3Hz,1H),6.92(d,J=8.1Hz,1H),5.78(s,2H),3.86(s,3H),3.46–3.40(m,6H),2.98(dd,J=13.3,6.7Hz,6H),2.26(s,3H).

[0985] Example 125 Compound 235

[0986]

[0987] 1 H NMR (600MHz, DMSO) δ11.18(s,1H),8.30(dd,J=9.6,5.6Hz,1H),7.85(s,1H),7.76(d,J =8.2Hz,1H),7.70(d,J=2.3Hz,1H),7.66(d,J=9.9Hz,1H),7.45–7.41(m,1H),7.30(s,

[0988] 1H),6.53(s,1H),5.94(s,2H),3.32–3.29(m,4H),2.33(s,6H),2.24(s,3H),2.08(s,3H).

[0989] Example 126 Compound 236

[0990]

[0991] 1 H NMR(400MHz,DMSO)δ8.39(d,J=2.3Hz,1H),7.98–7.91(m,2H),7.75(d,J=2.3H z,1H),7.51(dd,J=12.1,4.1Hz,2H),7.35(s,1H),7.27(d,J=8.5Hz,2H),5.93( s,2H),3.89(s,3H),3.04(s,3H),3.34–3.32(m,2H),2.97(t,J=6.5Hz,2H),2.0 0(dd,J=15.7,7.6Hz,1H), 1.87(dd,J=15.7,7.6Hz,1H), 0.90(t,J=7.5Hz,3H).

[0992] Example 127 Compound 237

[0993]

[0994] 1 H NMR(400MHz,DMSO)δ8.37(d,J=2.3Hz,1H),7.97–7.90(m,2H),7.74(d,J=2.2Hz,1H ),7.50(dd,J=12.1,4.1Hz,2H),7.34(s,1H),7.24(d,J=8.4Hz,2H),5.92(s,2H),3. 87(s,3H),3.06(s,3H),3.37–3.34(m,2H),2.95(t,J=6.5Hz,2H),2.01(dd,J=15.7, 7.6Hz,1H),1.87(dd,J=15.7,7.6Hz,1H),1.12–1.10(m,2H),0.91(t,J=7.5Hz,3H).

[0995] Example 128 Compound 239

[0996]

[0997] 1 H NMR (400MHz, DMSO) δ11.26–11.23(m,1H),8.24(d,J=8.3Hz,1H),8.17(s,1H),7.77(s,1H),7.70(d,J=10.1Hz,1H),7.60(d,J=8.2Hz,1H),7.23–7 .18(m,1H),7.08(s,1H),6.92(d,J=8.8Hz,1H),6.57(s,1H),6.54(s,1H) ,6.27(s,1H),3.81(s,3H),2.99(s,4H),2.48–2.45(m,4H),2.23(s,3H).

[0998] Example 129 Compound 240

[0999]

[1000] 1H NMR (400MHz, DMSO) δ8.32(d,J=2.4Hz,1H),7.96(s,1H),7.92(d,J=7.9Hz,1H),7.66(d,J=2.4Hz,1H),7.51(d,J=8.1Hz,1H),7.49(s,1H),7.38(dd,J=8 .4,1.9Hz,1H),7.33(d,J=1.9Hz,1H),7.19(d,J=8.4Hz,1H),5.89(s,2H),4 .68(s,2H),3.42(dd,J=6.4,4.0Hz,2H),3.30(s,3H),2.97(t,J=6.4Hz,2H).

[1001] Example 130 Compound 246

[1002]

[1003] 1 H NMR (400MHz, DMSO) δ9.61–9.52(m,1H),7.96(s,1H),7.92(d,J=8.0Hz,1H),7.88( d,J=6.3Hz,1H),7.66(d,J=10.1Hz,1H),7.54–7.47(m,1H),7.46(d,J=3.5Hz,1H) ,7.37(d,J=8.1Hz,1H),7.28–7.25(m,1H),6.64(s,1H),6.35(s,1H),6.16(s,2H) ,3.49–3.45(m,4H),3.27(s,3H),3.25–3.21(m,2H),2.93(dd,J=14.3,7.4Hz,6H).

[1004] Example 131 Compound 264

[1005]

[1006] 1H NMR (400MHz, DMSO) δ9.60–9.52(m,1H),7.95(s,1H),7.91(d,J=8.1Hz,1H),7.88(d,J =6.3Hz,1H),7.66(d,J=10.1Hz,1H),7.53–7.47(m,1H),7.45(d,J=3.5Hz,1H),7.36( d,J=8.1Hz,1H),7.29–7.25(m,1H),6.64(s,1H),6.35(s,1H),6.14(s,2H),3.48–3.4 5(m,4H),3.26(s,3H),3.25–3.21(m,2H),2.93(dd,J=14.3,7.4Hz,6H),2.24(s,3H).

[1007] Example 132 Compound 265

[1008]

[1009] 1 H NMR (400MHz, DMSO) δ9.60–9.51(m,1H),7.93(s,1H),7.90(d,J=8.0Hz,1H),7.88(d,J=6. 3Hz,1H),7.64(d,J=10.1Hz,1H),7.53–7.45(m,1H),7.43(d,J=3.3Hz,1H),7.37(d,J=8. 1Hz,1H),7.29–7.25(m,1H),6.64(s,1H),6.35(s,1H),6.15(s,2H),3.46–3.43(m,4H),3 .25(s,3H),3.24–3.21(m,2H),3.23–3.20(m,1H),3.19–3.17(m,1H),1.71–1.68(m,2H).

[1010] Example 133 Compound 267

[1011]

[1012] 1H NMR (400MHz, DMSO) δ9.60–9.51(m,1H),7.96(s,1H),7.90(d,J=8.0Hz,1H),7.88(d,J=6. 3Hz,1H),7.65(d,J=10.0Hz,1H),7.54–7.46(m,1H),7.45(d,J=3.5Hz,1H),7.37(d,J=8. 1Hz,1H),7.28–7.24(m,1H),6.64(s,1H),6.36(s,1H),6.15(s,2H),3.46–3.40(m,4H),3 .25(s,3H),3.25–3.21(m,2H),3.20–3.18(m,2H),2.25–2.21(m,1H),1.75–1.63(m,4H).

[1013] Example 134 Compound 268

[1014]

[1015] 1 H NMR (600MHz, DMSO) δ9.60–9.52(m,1H),7.93(s,1H),7.90(d,J=8.2Hz,1H),7.86(d,J=6. 1Hz,1H),7.63(d,J=10.0Hz,1H),7.54–7.46(m,1H),7.42(d,J=3.7Hz,1H),7.37(d,J=8. 1Hz,1H),7.28–7.21(m,1H),6.62(s,1H),6.34(s,1H),6.12(s,2H),3.44–3.40(m,4H),3 .22(s,3H),3.25–3.21(m,2H),3.20–3.18(m,2H),2.25–2.21(m,4H),1.75–1.63(m,2H).

[1016] All compounds disclosed in this invention can be prepared by methods similar to those described in detail above, or by conventional methods in the art.

[1017] Test Example 1: Determination of HPK1 enzyme activity

[1018] Table 1. Reagents for HPK1 enzyme activity assay

[1019]

[1020] The positive reference drug PF-07265028 is prepared according to patent CN115698004A.

[1021]

[1022] Experimental system: HPK1 protein solution concentration: 2.5 ng / μL, ATP concentration: 100 μM, substrate solution concentration: 0.2 μg / μL, enzyme buffer: 40 mM Tris, 7.5, 20 mM MgCl2, 0.1 mg / ml BSA, 50 μM DTT, 1% The DMSO solution concentrations of Brij-35 and the positive reference drug PF-07265028 were: 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, 0.05 nM, and 0 nM, with the group containing the compound at a concentration of 0 nM serving as the blank group. The DMSO solution concentrations of the test compound were: 20000 nM, 4000 nM, 800 nM, 160 nM, 32 nM, 6.4 nM, 1.28 nM, 0.26 nM, 0.05 nM, and 0 nM, with the group containing the compound at a concentration of 0 nM serving as the blank group.

[1023] Experimental Procedure: Add 4 μL of kinase to each well of a 384-well plate. Add 2 μL of Cpd solution of various concentrations to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 10 min using a trigger. Add 4 μL of Mix to each well, centrifuge at 1000 rpm for 1 min, and mix at 37.5℃ and 400 rpm for 60 min. Remove the 384-well plate and incubate at room temperature for 10 min. Add 10 μL of ADP-Glo ​​Maxreagent to each well, centrifuge at 1000 rpm for 1 min, and mix at room temperature and 400 rpm for 40 min using a trigger. Add 20 μL of kinase detection reagent to each well, centrifuge at 1000 rpm for 1 min, and mix at room temperature and 400 rpm for 30 min using a trigger. Read the luminescence using a microplate reader and process the data using Graphpad Prism 8.0.

[1024] Data processing: The inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC50 was obtained by curve fitting using GraphpadPrism 8.0 software. 50 Values. The experimental results for the compounds are shown in Table 2.

[1025]

[1026] Table 2 shows the inhibitory effects of the compounds on HPK1 enzyme activity.

[1027]

[1028]

[1029]

[1030]

[1031] The experimental results show that the compound of the present invention has high inhibitory activity against HPK1 kinase.

Claims

1. A compound, in which, The compounds are selected from: 。 2. A pharmaceutical composition comprising a therapeutically effective dose of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

3. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating HPK1-mediated diseases.

4. The use as described in claim 3, wherein, The HPK1-mediated diseases mentioned are tumors.

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