Aromatic ring compound as well as preparation method and application thereof

Abstract

The invention discloses an aromatic ring compound, which can be used for treating related diseases mediated by HPK1.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to an aromatic ring compound and a preparation method and use thereof. Technical Background

[0002] Hematopoietic progenitor cell kinase (HPK1, also known as mitogen-activated protein kinase kinase kinase 1 (MAP4K1)) is a Ste20-related serine / threonine kinase expressed in hematopoietic sites. HPK1 is involved in the regulation of multiple downstream signaling pathways, including JKN (c-Jun N-terminal kinase), AP-1 (activator protein 1) and NF-Kb. These related pathways regulate cell proliferation, apoptosis and immune cell activation, and therefore have an important relationship with the pathogenesis of autoimmune diseases and cancer (Sawasdikosol S, et al, Immunol Res., 2012, 54, 262). In T cells and B cells, 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 function, the HPK1.KO mouse model showed enhanced T cell function when stimulated by antigen, reduced the growth of PGE2-induced cancer, and enhanced the maturation of dendritic cells under 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 an inhibitory effect on tumor growth and a synergistic effect with PD-L1 antibodies. (Hernandez S, et al. Cell Rep. 2018, 25, 80; Liu J, et al. PLoS One 2019, 14, e0212670) Moreover, unlike knocking out some other negative regulatory factors such as CTLA4, which will produce lethal inflammation, there is no obvious autoimmune disease in the HKP1.KO or HPK1.KD models. Further analysis of immune cells in the tumor microenvironment found that the loss of HPK1 activity enhances the function of effector T cells and reduces the number of immunosuppressive Foxp3+ regulatory T cells. At present, there are no drugs targeting the HPK1 target on the market. In order to better meet the huge clinical needs, more effective HPK1 inhibitors need to be developed. Summary of the invention

[0004] The present invention provides a novel and efficient HPK1 inhibitor, which has the advantages of high activity, good selectivity, low toxicity and side effects, and good physical and chemical properties and drug-forming properties.

[0005] In one aspect, the present invention provides a compound, which is a compound represented by formula (I), or an isomer, isotopic 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 a N atom, R3 is absent; when Y is a C atom, R6 is selected from H, F and Cl; when Y is a N atom, R6 is absent; preferably, Y is a C atom and Z is a C atom; or Y is a N atom and Z is a C atom; or Y is a C atom and Z is a N atom;

[0008] The Cy1 ring is selected from a 3-20-membered cycloalkyl, a 3-20-membered heterocyclyl, a 5-20-membered aryl and a 5-20-membered heteroaryl; the 3-20-membered heterocyclyl and the 5-20-membered heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; preferably, the Cy1 ring is selected from a 5-12-membered cycloalkyl, a 5-15-membered heterocyclyl, a 5-12-membered aryl and a 5-15-membered heteroaryl, the 5-15-membered heterocyclyl and the 5-15-membered heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; more preferably, the Cy1 ring is selected from a phenyl and a 5-15-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and the heterocycloalkyl and heteroaryl are monocyclic structures, spirocyclic structures, bridged ring structures or condensed ring structures;

[0009] R1 is a substituent at any position on the Cy1 ring, and each occurrence of R1 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, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 Aryl, C 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 S02R c , the C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-20 Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl and C 5-20The heteroaryl group is optionally substituted by 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, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 Aryl, C 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 S02R c , the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-18 Cycloalkyl, C 3-18 Heterocycloalkyl, C 6-18 Aryl and C 5-18 The heteroaryl group is optionally substituted by p independent R 1a replace;

[0011] More preferably, each occurrence of R1 is independently selected from the group consisting of: oxo (=O), halogen, cyano, carboxyl, hydroxyl, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15Aryl, C 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 S02R c , the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-15 Cycloalkyl, C 3-15 Heterocycloalkyl, C 6-15 Aryl and C 5-15 The heteroaryl group is optionally substituted by p independent R 1a replace

[0012] R 1a Each occurrence is independently selected from: C 1-8 Alkyl, C 1-8 Alkoxy, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 Aryl, C 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, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 The heteroaryl group is optionally substituted by 0, 1, 2, 3 or 4 groups 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 occurrence is independently selected from: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 Aryl, C 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, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 The heteroaryl group is optionally substituted by 0, 1, 2, 3 or 4 groups 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 occurrence is independently selected from: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 Aryl, C 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, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-15 The heteroaryl group is optionally substituted by 0, 1, 2, 3 or 4 groups 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 independently selected from: H, hydroxyl, C 1-8 Alkyl, C 1-8 Alkoxy, -CH=C(C 1-8 alkyl), -CH=CH, -C≡C(C 1-8 alkyl), -C≡CH, C3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 Heteroaryl; preferably, R 1b and R 1c Each independently selected from: H, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -CH=C(C 1-6 alkyl), -CH=CH, -C≡C(C 1-6 alkyl), -C≡CH, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 Heteroaryl; More preferably, R 1b and R 1c Each independently selected from: H, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -CH=C(C 1-3 alkyl), -CH=CH, -C≡C(C 1-3 alkyl), -C≡CH, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-15 heteroaryl;

[0016] or R 1b and R 1c Together with the atoms they are connected to form C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 Aryl, C 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 Heterocycloalkyl, C 4-9 Fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 Cyclic lactam, C 3-7 Cyclic lactone and C 3-7 Cyclic ketone, wherein the C3-20 Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl, C 5-20 Heteroaryl, C 3-20 Heterocycloalkyl, C 4-9 Fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 Cyclic lactam, C 3-7 Cyclic lactone and C 3-7 Cyclic ketone, q independently selected from hydroxyl, C 1-8 Alkyl, -SO2, -SO2N(C 1-10 Alkyl)(C 1-10 Alkyl), -SO2N(C 1-10 Alkyl)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)H, -OCONH2, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -N(C 1-10 Alkyl)(C 1-10 Alkyl), -NH(C 1-10 Alkyl), -NH2, -OC 1-10 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heteroaromatic, -O-heteroaromatic and -S-heteroaromatic substituents;

[0017] Preferably, R 1b and R 1c Together with the atoms they are connected to form C3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 Aryl, C 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 Heterocycloalkyl, C 4-9 Fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 Cyclic lactam, C 3-7 Cyclic lactone and C 3-7 Cyclic ketone, wherein the C 3-18 Cycloalkyl, C 3-18 Heterocycloalkyl, C 6-18 Aryl, C 5-18 Heteroaryl, C 3-18 Heterocycloalkyl, C 4-9 Fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 Cyclic lactam, C 3-7 Cyclic lactone and C 3-7 Cyclic ketone, q independently selected from hydroxyl, C 1-6 Alkyl, -SO2, -SO2N(C 1-8 Alkyl)(C 1-8 Alkyl), -SO2N(C 1-8 Alkyl)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(C1-8 alkyl)H, -OCONH2, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -N(C 1-8 Alkyl)(C 1-8 Alkyl), -NH(C 1-8 Alkyl), -NH2, -OC 1-8 Alkyl, -OH, C 3-8 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heteroaromatic, -O-heteroaromatic and -S-heteroaromatic substituents;

[0018] L1 and L2 are each independently selected from a single bond, -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)-, wherein the C 1-8 Alkylene and C 3-8 The cycloalkylene group is optionally substituted with 0, 1, 2, 3 or 4 R h Substitution; preferably, L1 is selected from a single bond, -C=N-, -O-, -C(O)-, -OC 1-8Alkylene-, -C(O)-NH- and -NH-C(O)-; and / or L2 is selected from a 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 heterocyclyl, 6-20-membered aryl and 5-20-membered heteroaryl, wherein the 3-20-membered heterocyclyl and 5-20-membered heteroaryl each independently contain 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 heterocyclyl, 6-12-membered aryl and 5-15-membered heteroaryl, wherein the 5-12-membered heterocyclyl and 5-15-membered heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The aryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and the 5-12 membered heterocycloalkyl and 5-15 membered heteroaryl groups are monocyclic structures, bridged ring structures, spirocyclic structures or condensed ring structures; more preferably, the Cy2 ring is selected from phenyl and a 5-15 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and the 5-15 membered heteroaryl group is a monocyclic structure, bridged ring structure, spirocyclic structure or condensed ring structure;

[0020] R4 is a substituent at any position on the Cy2 ring, and each occurrence of R4 is independently selected from: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 Aryl, C 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, C 3-20 Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl and C 5-20 The heteroaryl group is optionally substituted by r independent R 4a Substitution, wherein the heterocycloalkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure or a condensed ring structure;

[0021] Preferably, R4 is independently selected from the group consisting of: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-20 Aryl, C 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, C 3-18 Cycloalkyl, C 3-18 Heterocycloalkyl, C 6-18 Aryl and C 5-18 The heteroaryl group is optionally substituted by r independent R 4a Substitution, wherein the heterocycloalkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure or a condensed ring structure;

[0022] More preferably, R4 is independently selected from the group consisting of: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Haloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 Aryl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 5-15 Heteroaryl, -C 1-3 Alkylene-N(Ri )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, C 3-15 Cycloalkyl, C 3-15 Heterocycloalkyl, C 6-15 Aryl and C 5-15 The heteroaryl group is optionally substituted by r independent R 4a Substitution, wherein the heterocycloalkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure or a condensed ring structure;

[0023] R 4a Each occurrence is independently selected from: halogen, oxo (=O), -C(O)R j , cyano, amino, hydroxyl, carboxyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, -C 1-8 Alkylene -CN, C3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 Heteroaryl, wherein the C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 The heteroaryl group is independently selected from hydroxy, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -SO2, C 1-8 Alkyl, -SO2N(C 1-10 Alkyl)(C 1-10 Alkyl), -SO2N(C 1-10 Alkyl)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), -NH2, -OC 1-10 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heterocycloaryl, -O-heterocycloaryl and -S-heterocycloaryl;

[0024] Preferably, R 4aEach occurrence is independently selected from: halogen, oxo (=O), -C(O)R j , cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene -CN, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 The heteroaryl group is independently selected from hydroxy, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -SO2, C 1-6 Alkyl, -SO2N(C 1-6 Alkyl)(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)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), -NH2, -OC1-6 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heterocycloaryl, -O-heterocycloaryl and -S-heterocycloaryl;

[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 halogen;

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

[0028] R e and R f are each 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, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 Heteroaryl; preferably, R e and R f Each independently selected from H and C 1-8 alkyl;

[0029] When R2 is connected to B and the atoms connected thereto form a ring structure, L1 is not a single bond, A is a C atom, and B is selected from CR a and N, preferably, B is CR a ; R2 is independently selected from CR at each occurrence a R b and NR c , preferably, R2 is NR c ; e is 0, 1, 2, 3, or 4, preferably, e is 1 or 2;

[0030] R a , R b , R c , R d , R g , R h , R i , R j, R k and R m Each occurrence 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, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 Heteroaryl, the C 3-20 Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl, and C 5-20 The heteroaryl group is optionally substituted by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxy, amino, nitro, C 1-8 Alkyl and C 1-8 The substituents of the alkoxy group are substituted; preferably, R a , R b , R c , R d , R g , R h , R i , R j , R k and R m Each occurrence 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, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 Heteroaryl, the C 3-18 Cycloalkyl, C 3-18 Heterocycloalkyl, C 6-18 Aryl, and C 5-18 The heteroaryl group is optionally substituted by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxy, amino, nitro, C 1-6 Alkyl and C 1-6 The substituent of the alkoxy group is substituted; more preferably, R a , R b , R c , R d , R g, R h , R i , R j , R k and R m Each occurrence 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, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-15 Heteroaryl, the C 3-15 Cycloalkyl, C 3-15 Heterocycloalkyl, C 6-15 Aryl, and C 5-15 The heteroaryl group is optionally substituted by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxy, amino, nitro, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups;

[0031] When Y is a nitrogen atom, Z is a carbon atom, R2 is -NH2, R3 is H, and L1 is -CONH-, R4 is not -NH2, and -C 1-4 Alkoxy-NH2; or Partially not Partially not

[0032] When Y is a N atom, Z is a C atom, R2 is -NH2, R3 is H, L2 is a single bond, Cy1 is selected from a 3- to 9-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur as one or more ring members, Cy2 is not

[0033] When Y is a nitrogen atom, Z is a carbon atom, R2 is -NH2, R3 is H, L2 is a single bond, L1 is -O-, and Cy1 is When , Cy2 is not a benzene ring;

[0034] When Y is a 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 C atom, Z is a C atom, R3 is H, and L2 is a single bond, Partially 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 C atom, Z is a C atom, R2 is -NH2, R3 is H, R6 is H, L1 is a single bond, and Cy2 is a benzene ring, Partially 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 cyano, -SO2R j R k 、-NR j S02R k ,

[0040] when

[0041] When m=1, R4 is not halogen or methoxy; when m=2, not all R4 are halogen;

[0042] When Y is a C atom or a 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

[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 is methoxy and

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

[0048] in, represents the connection site, Indicates the position of the substitution 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, C 3-6 Cycloalkyl, C 1-8 Alkoxy, C containing N, O and S atoms 3-6 Heterocycloalkyl, -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, -S(O)2-NH-C 1-8 Alkyl, -C 1-8 Alkylene-OH, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, 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 Haloalkoxy, 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, Selected from:

[0063]

[0064]

[0065]

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

[0067]

[0068] In one of the technical solutions, 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 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 compound described above and a pharmaceutically acceptable carrier or excipient.

[0097] Another aspect of the present invention provides use of the compound as described above or the pharmaceutical composition as described above for preparing a drug for treating HPK1-mediated related diseases; preferably, the HPK1-mediated related 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, which comprises the following preparation steps:

[0099]

[0100] Among them, R1, R2, R3, R4, R e , R f , Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are defined as above.

[0101] R o and R o’ is selected from halogen atoms, tin reagents, boronic acid groups or boric acid esters: provided that: R o When it is a halogen or tin reagent, R o’ is a boronic acid group or a boronic acid ester; R o When it is a boronic acid group or a boronic acid 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 , Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are defined as above.

[0105] R p and R p’ is selected from a halogen atom, a tin reagent, or a boronic acid group or a boronic ester group: provided that: R p When it is a halogen or tin reagent, R p’ is a boronic acid group or a boronic ester group; R p When it is a boronic acid group or a boronic acid ester, R p’ It is a halogen or tin reagent.

[0106] The boronic acid group or boronic 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 , Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are defined as above.

[0110] R q and R q’ is selected from a halogen atom, a tin reagent, or a boronic acid group or a boronic ester group: provided that: R q When it is a halogen or tin reagent, R q’ is a boronic acid group or a boronic ester group; Rq When it is a boronic acid group or a boronic acid ester, R q’ It is a halogen or tin reagent.

[0111] The boronic acid group or boronic 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 , Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are defined as above.

[0115] R r and R r’ is selected from a halogen atom, a tin reagent, or a boronic acid group or a boronic ester group: provided that: R r When it is a halogen or tin reagent, R r’ is a boronic acid group or a boronic ester group; R r When it is a boronic acid group or a boronic acid ester, R r’ It is a halogen or tin reagent.

[0116] The boronic acid group or boronic 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 , Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are defined as above.

[0120] R s and R s’ is selected from a halogen atom, a tin reagent, or a boronic acid group or a boronic ester group: provided that: R s When it is a halogen or tin reagent, R s’ is a boronic acid group or a boronic ester group; R s When it is a boronic acid group or a boronic acid ester, R s’ It is a halogen or tin reagent.

[0121] The boronic acid group or boronic 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 , Cy1 ring, Cy2 ring, L1, L2, m, n, and Y are defined as above.

[0125] R t and R t’ is selected from a halogen atom, a tin reagent, or a boronic acid group or a boronic ester group: provided that: R t When it is a halogen or tin reagent, R t’ is a boronic acid group or a boronic ester group; R t When it is a boronic acid group or a boronic acid ester, R t’ It is a halogen or tin reagent.

[0126] The boronic acid group or boronic 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 , Cy1 ring, Cy2 ring, L2, m, n, and Y are defined as above.

[0130] R u and R u’ is selected from a halogen atom, a tin reagent, or a boronic acid group or a boronic ester group: provided that: R u When it is a halogen or tin reagent, R u’ is a boronic acid group or a boronic ester group; R u When it is a boronic acid group or a boronic acid ester, R u’ It is a halogen or tin reagent.

[0131] The boronic acid group or boronic ester group is selected from Definition and detailed description

[0132] The term "alkyl" as contemplated herein refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain 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 various branched chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0133] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by heteroatoms selected from NH, O and S or one or more -CH- 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 substituents may be substituted at any available attachment point, and the substituents are preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

[0134] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl is as defined herein. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

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

[0136] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent, the cycloalkyl ring 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, more preferably 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.

[0137] The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0138] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1-3 are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0139] The heterocycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0140] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently and optionally selected from one or more substituents of hydrogen atoms, halogens, alkyls, alkoxys, haloalkyls, hydroxyls, hydroxyalkyls, cyano groups, aminos, nitros, cycloalkyls, heterocycloalkyls, aryls, heteroaryls.

[0141] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocycloalkyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring. Heteroaryl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents in hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, 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 substituted with one or more hydroxy groups, wherein alkyl 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 subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted cyclopropyl" means that cyclopropyl may but need not be substituted, and the description includes instances where cyclopropyl is substituted and instances where cyclopropyl is not substituted.

[0147] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort.

[0148] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

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

[0150] The present invention is described in detail below by way of examples, but it is not intended to limit the present invention in any adverse way. The present invention has been described in detail herein, and its specific embodiments are also disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0151] Example 1 Synthesis of Compound 2

[0152]

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

[0154] To a solution of 5-bromopyridine-3-ol (300 mg, 1.72 mmol) in H2SO4 (2 mL), cooled to 0 ° C, HNO3 (0.5 mL) was added and the reaction mixture was stirred at RT for 5 hours. The solution was diluted with water (5 mL) 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-nitropyridine-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)pyridin-2-amine (2)

[0156] To a solution of 5-bromo-2-nitropyridine-3-ol (200 mg, 0.9136 mmol) and (2-aminopyridin-4-yl)methanol (147 mg, 1.187 mmol) in THF (3 mL) was added PPh3 (287 mg, 1.096 mmol), DIAD (221 mg, 1.096 mmol) under N2. 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-nitropyridine-3-yl)oxy)methyl)pyridine-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-tetrahydroisoquinolin-7-yl)-2-nitropyridin-3-yl)oxy)methyl)pyridin-2-amine

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

[0159] To a solution of 4-(((5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-nitropyridin-3-yl)oxy)methyl)pyridin-2-amine (100 mg, 0.246 mmol) in EtOH:H2O=5:1 (2 mL) were added Fe (41 mg, 0.74 mmol), NH4Cl (66 mg, 1.234 mmol), the reaction mixture was stirred at 70°C for 3 h, concentrated in vacuo, and the residue was purified by preparative HPLC to give 3-(((2-aminopyridin-4-yl)methoxy)-5-(2,5-dimethyl-1,2,3,4-trihydroxyisoquinolin-7-yl)pyridin-2-amine (2 mg, 2%) as a solid. MS (ESI): [M+H]+ =376.48. 1 H NMR (600 MHz, DMSO-d6) δ7.89 (d, J = 5.2 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.24-7.19 (m, 1H), 7.11-7.07 (m, 1H), 6.60 (dd, J = 5.2, 1.4 Hz, 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 was stirred at 0°C for one day and monitored by TLC. The solvent was concentrated under reduced pressure to obtain a 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, bistriphenylphosphine 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 reactants were stirred at room temperature for 4 hours. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain 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, 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) and 5-bromo-2-nitropyridine-3-ol (282.5 mg, 1.29 mmol) and triphenylphosphine (401.3 mg, 1.53 mmol) in tetrahydrofuran (15 mL) in an ice bath. The reactants were 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 distillation under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain 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, 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) and 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (168.9 mg, 0.21 mmol). The solution was heated at 80° C. for 5 h. 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 distillation under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain the 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-tetrahydroisoquinolin-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-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), and zinc powder (353 mg, 5.40 mmol) and a catalytic amount of p-toluenesulfonic acid were added to the mixture. The reactants were 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 a 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)-carboxylate

[0173] To a mixture of tert-butyl 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (50 mg, 0.164 mmol), trimethylcyclotriboroxane (16 uL, 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) was added tetrakistriphenylphosphine palladium (19 mg, 0.016 mmol). The resulting mixture was stirred at 90 ° C for 3 hours. The reaction solution 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 tert-butyl 2-chloro-4-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (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 obtain the product (10 mg, 52% yield). MS (ESI): m / z found 184 [M+H] + 3.3 Synthesis of 2-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), sodium cyanoborohydride (5.2 mg, 0.0825 mmol) was slowly added to a solution of formaldehyde aqueous solution (6 uL, 0.0825 mmol, 40% aqueous solution) in methanol (1 mL), and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The reaction mixture was quenched with water, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated. 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] + 3.4 Synthesis of 3-(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), hexamethylditin (413 mg, 1.263 mmol) in tetrahydrofuran (6 mL) was added bistriphenylphosphinepalladium dichloride (30 mg, 0.042 mmol). The resulting solution was stirred under nitrogen at 60 °C for 13 hours. The solution was concentrated in vacuo to give the product (300 mg) without purification. MS (ESI): m / z found 459 [M+H] + .

[0178] 3.5 Synthesis of 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-tetrahydropyrido[3,4-d]pyrimidine

[0179] The compound obtained in the previous step (300 mg, 0.42 mmol, crude product) and 2-chloro-4,7-dimethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (105 mg, 0.63 mmol) obtained in the third step were added to a solution of 1,4-dioxane (4 mL) with tetrakistriphenylphosphine palladium (46 mg, 0.042 mmol). The resulting solution was stirred under a nitrogen atmosphere at 100 ° 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 in vacuo, and the resulting residue was purified by Prep-TLC (dichloromethane: methanol = 15: 1) to obtain 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)pyridin-2-amine

[0181] Iron powder (49 mg, 0.86 mmol) and ammonium chloride (23 mg, 0.43 mmol) were added to a mixed solution of the compound (80 mg, 0.14 mmol) obtained in the previous step in 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 in vacuo. The residue was purified by Prep-TLC (dichloromethane: methanol = 10: 1) to obtain 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-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-yl

[0183] The compound obtained in the previous step (20 mg, 0.038 mmol) was added to 4-methylbenzenesulfonate pyridinium (15 mg, 0.057 mmol) in ethanol (1.5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated in vacuo, and the resulting residue was purified by Prep-TLC (dichloromethane: methanol = 5: 1) to obtain 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 to 6-amino-3-bromo-2-fluorobenzoic acid (300 mg, 1.3 mmol) and dimethylamine in dichloromethane (5 mL) in sequence, and the mixture was reacted at room temperature for 1 h. The mixture was quenched with water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to give the product (150 mg, 45%) as a yellow oil. 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-dioxaborolan-2-yl)benzamide

[0189] BPin2 (291 mg, 1.15 mmol), KOAC (169 mg, 1.72 mmol) and Pd(dppf)2Cl2 (46 mg, 0.06 mmol) were added to 6-amino-3-bromo-2-fluoro-N, N-dimethylbenzamide (150 mg, 0.57 mmol) in dioxane (5 mL). The resulting solution was stirred at 100 ° C for 3 hours. The solution was diluted with water (5 mL) and extracted with EA (10 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-2-fluoro-N, N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 56%) as a yellow oil. 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-dioxaborolan-2-yl)benzamide (100 mg, 0.32 mmol) 5-Bromo-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine (100 mg) 0.32 mmol, K3PO4 (100 mg, 0.49 mmol), Pd(dppf)Cl2·CH2Cl2 (53 mg, 0.064 mmol) were added to a mixed solution of dioxane (2 mL) and water (2 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 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%) as a yellow oil. 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] 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) were added Fe (28 mg, 0.52 mmol), NH4Cl (46 mg, 0.86 mmol). 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 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%) as a yellow oil. 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] To a 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) in MeOH (1 mL) was added PPTS (41 mg, 0.17 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 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%) as a yellow oil. 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] Under an ice-water bath, 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). After 16 hours of reaction at room temperature, 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 solution of 6-amino-3-bromo-2-fluorobenzoic acid (1 g, 4.3 mmol) in DCM (30 mL). The resulting solution was stirred at room temperature for 0.5 hours. Dimethylamine (0.8 mL) and DIEA (1.4 mL, 8.54 mmol) were added. The resulting solution was stirred at room temperature for 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 (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) were added (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), Pd(dppf)Cl2·CH2Cl2 (62 mg, 0.0777 mmol). 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 6-amino-3-(5-((2-aminopyridin-4-yl)methoxy)-6-nitropyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide (40 mg, 12%) as a yellow oil. 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] To a 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) in ethanol (0.8 mL) were added Fe (16 mg, 0.3 mmol), H2O (0.4 mL), NH4Cl (27 mg, 0.5 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 obtain 6-amino-3-(6-amino-5-((2-aminopyridin-4-yl)methoxy)pyridin-3-yl)-2-fluoro-N,N-dimethylbenzamide (25 mg, 40%) as a yellow solid.

[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) in sulfuric acid (12 mL) and 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. A crude product (5.7, 94% yield) was obtained.

[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 DMF (8 mL) and stirred at room temperature for 15 minutes, and 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 by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) gave 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 raw 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 in vacuo. 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] 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), bispinacol borate (1.82 g, 7.15 mmol) and potassium acetate (700 g, 7.15 mmol) in 1,4-dioxane (15 mL) was added [1,1'-bis(diphenylmethane] 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 in vacuo. 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] 6.5 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

[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) with tetrakistriphenylphosphine 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 in vacuo. The residue was purified by Pre-p (dichloromethane: methanol = 15: 1) to obtain 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-tetrahydroisoquinolin-7-yl)-3-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-2-amine

[0219] Zinc powder (92 mg, 1.38 mmol) and p-toluenesulfonic acid (20 mg) were added to a mixed solution of the raw material (80 mg, 0.138 mmol) in acetic acid (5 mL). 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 in vacuo. 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, to a mixture solution of 5-bromo-3-((3-(3-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine (250 mg, 0.53 mmol) and biboronic acid pinacol ester (160.8 mg, 0.63 mmol) and potassium acetate (77.6 mg, 0.79 mmol) in dioxane (5 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (76.8 mg, 0.11 mmol). The reactants were heated at 80°C for 2 hours. After the reaction was completed 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] 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), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (342.7 mg, 0.42 mmol) were added to a mixture of tetrahydrofuran (6 mL) and water (6 mL) of the product of the previous step (1.14 mg, 2.52 mmol). The solution was heated at 80°C for 3 h. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH=15:1) to obtain 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]isoquinolin-7-yl)-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-ynyl)benzyl)oxy)pyridin-2-amine

[0227] Under nitrogen protection, reduced iron powder (522 mg, 9.33 mmol) was added to a mixture of the product from the previous step (1.3 g, 1.86 mmol) and ammonium chloride (346 mg, 6.53 mmol) in ethanol (10 mL) and water (12 mL). The reactants were heated at 50 ° C for 6 hours. After the reaction was completed as monitored by LCMS, the filtrate was filtered and concentrated by vacuum distillation to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM: MeOH = 5: 1) to obtain the 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]isoquinolin-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-ol

[0229] PPTS (94 mg, 0.38 mmol) was added to a solution of the product from the previous step (100 mg, 0.15 mmol) in methanol (3.5 mL). 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 by vacuum distillation to obtain a crude product. The crude product was purified by thin layer chromatography (DCM: MeOH = 5: 1) to obtain the product (60 mg, 69.0%). MS (ESI): 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]isoquinolin-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-ol

[0231] Tetrabutylammonium fluoride (0.4 mL, 0.39 mmol) and ethylenediamine (40 μL, 0.59 mmol) were added to a DMF (1.5 mL) solution of the product from the previous step (75 mg, 0.13 mmol). The solution was stirred at 80°C for 8 hours. After the reaction was completed 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-oxopentanonitrile

[0235] A mixture of 2-chloro-4-iodo-3-methylpyridine (2 g, 7.9 mmol) and tert-butyl 2-cyanoacetate (2.2 ml, 15.8 mmol) CuI (15 mg, 0.079 mmol) 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 2-(2-chloro-3-methylpyridin-4-yl)-4,4-dimethyl-3-oxopentanonitrile (1.4 g, 58%) as an oil. 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-methylpyridine-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 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM and washed with saturated aqueous solution. Sodium bicarbonate. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the compound as a beige solid (0.6 g, 42%). MS (ESI):, m / z found 167 [M+H] + .

[0238] 8.3 Synthesis of 2-(5'-chloro-3-methyl-[2,3'-bipyridyl]-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) was added (5-chloropyridin-3-yl)boric acid (380 mg, 0.24 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol), 2N K2CO3 (0.45 mL). 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 (MgSO4) and concentrated in vacuo. 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'-bipyridyl]-5'-yl)boronic acid

[0241] A solution of raw material 1 (200 mg, 0.823 mmol), raw 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 in vacuo. 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'-tripyridine]-4-yl)acetonitrile

[0243] To a solution of raw material 1 (300 mg, 1.1857 mmol) in dioxane (3 mL) was added raw material 2 (675 mg, 1.4229 mmol) and K3PO4 (754 mg, 3.557 mmol) and Pd(dppf). DCM (96 mg, 0.118 mmol) was stirred at 100 ° C for 2 hours under nitrogen. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The solution was concentrated under vacuum and purified by preparative TLC (EA: PE = 1: 1) to give the title compound (240 mg, 50%) as a solid. MS (ESI):, m / z found 502 [M-100 + H] + .

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

[0245] Zn (18 mg, 0.2 mmol) and P-TsOH (17 mg, 0.03 mmol) were added to a solution of the raw material (70 mg, 0.116 mmol) and AcOH (1 mL). 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 in vacuo. The solution was concentrated and the residue was purified by preparative TLC (DCM: MeOH = 15: 1) to give the title compound (4 mg, 5%) as a solid. 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 raw material (1 g, 3.96 mmol) in ACN (20 mL) was added K2CO3 (1.6 g, 11.9 mmol) and 1-(bromomethyl)-3-iodobenzene (1.18 g, 3.96 mmol). 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 the product (650 mg, 35%) as a yellow oil. 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] 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) was added CuI (61 mg, 0.32 mmol) and Pd(PPh)3Cl2 (75 mg, 0.11 mmol). The resulting solution was stirred at 90°C under N2 atmosphere for 6 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 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-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (56 mg, 0.20 mol) in THF (1 mL) and H2O (1 mL) were added K3PO4 (64 mg, 0.30 mmol) and Pd(dppf)Cl2CH2Cl2 (16 mg, 0.02 mmol). The resulting solution was stirred at 80°C for 3 hours under 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-tetrahydroisoquinolin-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-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) were added Zn (20 mg, 0.3 mmol) and TsOH.H2O (5 mg, 0.03 mmol). 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-isobutyrylphenethyl)carbamate

[0259] Under ice bath, isopropylmagnesium bromide (1.2mL, 2.40mmol) was added to a mixture solution of tert-butyl 7-bromo-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (500mg, 1.53mmol) in tetrahydrofuran (8mL) under nitrogen protection. The reactants were stirred at room temperature for 9 hours. After the reaction was completed as monitored by LCMS, the solvent was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (PE:EA=20:1) to give the product (300mg, 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 (4mL) was added to a solution of the raw material (770mg, 2.09mmol) in dichloromethane (15mL). The solution was stirred at room temperature for 3h. After the reaction was completed by LCMS monitoring, it was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was added with sodium cyanoborohydride (328.3mg, 5.23mmol) and a catalytic amount of glacial acetic acid and dissolved in methanol (15mL). The mixture was stirred for 5h and detected by LCMS. The resulting solution was filtered and concentrated under reduced pressure to give a crude product. (500mg)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 catalytic amount of glacial acetic acid were added to the mixture solution of the raw material (506 mg, 2 mmol) in methanol (10 mL). The reaction was stirred at room temperature for 6 hours and fully detected by LCMS. The solvent was filtered and concentrated under reduced pressure to obtain a crude product. (350 mg) MS (ESI): m / z found 268 [M+H] + .

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

[0265] To a mixed solution of the raw material (350 mg, 1.30 mmol) and biboronic acid pinacol ester (394 mg, 1.56 mmol) and potassium acetate (190.2 mg, 1.94 mmol) in dioxane (7.5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (212 mg, 0.26 mmol) under nitrogen. The solvent was filtered and concentrated under reduced pressure. The reaction was heated at 80°C for 2.5 hours and detected by LCMS. The reaction solution was filtered and concentrated under reduced pressure to give a 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] To a mixed solution of the starting material (300 mg, 1.30 mmol), 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 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (212 mg, 0.26 mmol) under nitrogen. The solution was heated at 80°C for 3 h and then completely detected by LCMS. The solvent was extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH=10:1) to give 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-tetrahydroisoquinolin-7-yl)-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxypyridin-2-amine

[0268] Under nitrogen protection, reduced iron powder (239.5 mg, 4.29 mmol) was added to a solution of raw material (500 mg, 0.86 mmol) and ammonium chloride (159 mg, 3.00 mmol) in ethanol (7.5 mL) and water (1.5 mL). The reaction was heated at 50 ° C for 6 hours and fully detected by LCMS. The solvent was filtered and concentrated under reduced pressure to obtain a 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-tetrahydroisoquinolin-7-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-ol

[0270] PPTS (181 mg, 0.72 mmol) was added to a solution of the raw material (160 mg, 0.289 mmol) in methanol (5 mL). The solution was stirred at room temperature for 12 h. LCMS detected that the reaction was complete. The solvent was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM: MeOH = 5: 1) to obtain 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), 7,2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (120 mg, 0.41 mmol) and potassium phosphate (110.2 mg, 0.52 mmol) in tetrahydrofuran (0.7 ml) and H2O (0.7 ml) were added to a molten salt solution of ... [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (56mg, 0.07mmol) was added to the mixture solution in .7ml. The solution was heated at 80°C for 3h. The solution was heated at 80°C for 8h. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain the product (101.6mg, 53.5%). MS (ESI): m / z found 557 [M+H] + .

[0275] 11.2 Synthesis of 5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-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 raw 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 reactants were 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 a crude product. The crude product was purified by thin layer chromatography (DCM: MeOH = 10: 1) to obtain the product (30 mg, 79.2%). MS (ESI): m / z found 527 [M + H] + .11.3 Synthesis of 4-(((2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-3-yl)oxy)methyl)pyridin-2-yl)-2-methylbut-3-yn-2-ol

[0277] PPTS (43.3 mg, 0.171 mmol) was added to a mixture of the raw 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 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)pyridin-2-amine

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

[0282] Under nitrogen protection, triethylamine (0.5 mL) was added to a mixture of the raw 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 bistriphenylphosphine 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 LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 12.3 Synthesis of (E)-4-(((2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-3-yl)methylene)amino)phenyl)-2-methylbut-3-yn-2-ol

[0284] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (56.7 mg, 0.069 mmol) was added to a mixture solution of the raw material (124.9 mg, 0.347 mmol), 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 a 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-tetrahydroisoquinolin-7-yl)-2-(methylamino)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-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 solution of 4-(3-(((2-amino-5-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-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 reactants were stirred at room temperature for 1 h and completely detected by LCMS. 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 obtain a crude product. The crude product was purified by preparative thin layer chromatography (DCM: MeOH = 5: 1) to obtain 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] To a mixture of 5-bromo-3-fluoro-2-aminopyridine (1.0 g, 5.23 mmol) in sulfuric acid (5 mL) was added dropwise hydrogen peroxide (5 mL, 30% in H2O). The resulting mixture was stirred at room temperature for 16 hours, but the reaction was not complete. The solution was added with saturated sodium bicarbonate solution, 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 = 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 raw 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), and the resulting mixture was stirred at 80° C. for 1.5 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 (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] To the raw material (40 mg, 0.085 mmol) was added hydrochloric acid-dioxane solution (2.0 mL, 4 mmol / L), and the mixture was stirred at room temperature for hours under nitrogen. The reaction mixture was concentrated to give 45 mg of crude product without 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] Sodium cyanoborohydride (10 mg, 0.127 mmol) was slowly added to a solution of the compound obtained in the previous step (45 mg, 0.055 mmol) and formaldehyde aqueous solution (10 uL, 0.127 mmol, 40% aqueous solution) in methanol (1.5 mL), and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with water, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated. 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, 52% yield). MS (ESI): m / z found 382 [m+H] +. Synthesis of 14.55-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 raw 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 in vacuo, and the residue was purified by Prep-TLC (dichloromethane: methanol = 10: 1) to obtain the product (15 mg, 83% yield). MS (ESI): m / z found 352 [m+H] +.

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

[0301] To a solution of (R)-3-bromo-N-methyl-5-(2-methylpyrrolidin-1-yl)benzenesulfonamide (360 mg, 1.08 mmol), bis-pinacol boronate (360 mg, 1.4 mmol) and potassium acetate (213 mg, 2.16 mmol) in 1,4-dioxane (5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (80 mg, 0.108 mmol) and 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 in vacuo, and 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] 14.7 Synthesis of (R)-3-(6-amino-5-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-3-yl)-N-methyl-5-(2-methylpyrrolidin-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) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (32 mg, 0.042 mmol) and 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 in vacuo, and the residue was purified by Pre-p (dichloromethane: methanol = 10: 1) to obtain 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 checked by TLC. The solvent was concentrated under reduced pressure to give the crude product.

[0308] 15.2 Synthesis of N-(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 raw material (2.5 mg, crude product, 10.08 mmol) in dichloromethane (10 mL). The solution was stirred at room temperature for 1 d and then completely detected by LCMS. The solvent was extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 15.3 Synthesis of N-(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 solution of the raw 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 reactants were stirred at 70 ° C for 4 hours and completely detected by LCMS. The solvent was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography (DCM: MeOH = 10: 1) to obtain the product (50 mg, 43.5%). MS (ESI): m / z found 404 [M+H] + .

[0312] 15.4 Synthesis of N-(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 raw 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 reactant was heated at 50 ° C for 3 h and fully detected by LCMS. The solvent was filtered and concentrated under reduced pressure to obtain a crude product. (50 mg) MS (ESI): m / z found 374 [M+H] + .

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

[0315] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium 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-dioxaborolan-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 LCMS. The solvent was extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] To a 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 mmmol) and HATU (875 mg, 2.30 mm) in DMF (15 mL) was added DIEA (0.48 mL, 2.76 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-tetrahydroisoquinolin-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) were added 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (154 mg, 0.536 mmol), K3PO4 (175 mg, 0.804 mmol), Pd(dppf)Cl2·CH2Cl2 (50 mg, 0.053 mmol). 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 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%) as a yellow oil. 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-pyrrol-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-dibromopyrazine-2-amine (1.35 g, 5.35 mmol) in DMF (10 mL). The reactants were stirred at 100 ° C for 6 hours. After the reaction was completed as monitored by LCMS, 20 ml of water was added and filtered to obtain a solid crude product. MS (ESI): m / z found 284 [M+H] + .

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

[0327] Under nitrogen protection, reduced iron powder (188 mg, 3.52 mmol) was added to a mixture of raw material (200 mg, 0.70 mmol) and ammonium chloride (118 mg, 2.11 mmol) in ethanol (8 mL) and water (4 mL). The reactants were 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 a crude product. MS (ESI): m / z found 254 [M+H] + .

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

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

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

[0331] Under nitrogen protection, 2,5-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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(diphenylphosphino)ferrocene] dichloropalladium (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, it was 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 a crude product. The crude product was purified by silica gel column chromatography (EA:MeOH=1:1) to obtain the 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] To a mixture of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.325 mmol) in tetrahydrofuran (12 mL) was added sodium hydroxide (106 mg, 2.65 mmol) The resulting mixture was stirred at room temperature for 5 minutes, hydrogen peroxide (270 uL, 2.65 mmol, 30% inH2O) was added dropwise and stirred at room temperature for 1.5 hours. The reaction solution was adjusted to Ph 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 tert-butyl 4-(4-hydroxy-1H-pyrazol-1-yl)piperidine-1-carboxylate (200 mg, 71% yield). MS (ESI): m / z found 212.2 [m+H] + .

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

[0337] The compound obtained in the previous step (800 mg, 2.98 mmol) was added to a solution of hydrochloric acid-dioxane (5Ml, 4 mol / L in dioxane), and the resulting mixture was stirred at room temperature for 1 hour. The solution was concentrated to obtain a crude product (700 mg) without purification. MS (ESI): m / z found 168.2 [m+H] + .

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

[0339] Sodium cyanoborohydride (282 mg, 4.47 mmol) was slowly added to a solution of the compound obtained in the previous step (700 mg, 2.98 mmol) and formaldehyde aqueous solution (310 uL, 4.47 mmol, 40% aqueous solution) in methanol (5 mL), and the mixture was stirred at room temperature for 5 hours under nitrogen. The reaction mixture was concentrated. The crude product (550 mg) was obtained 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), potassium carbonate (820 mg, 5.96 mmol) were added to dimethyl sulfoxide (5 mL), and the resulting solution was stirred under a nitrogen atmosphere at 80°C for 1.5 hours. The solution was extracted with ethyl acetate, the organic phases were combined, the combined organic phases were washed with brine, the combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 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-dioxaborolan-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) with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane 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 in vacuo. The residue was purified by 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-tetrahydroisoquinolin-7-yl)-3-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)oxy)pyridin-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 raw 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 in vacuo. 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-yn-2-ol

[0349] 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) was added TEA (10 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 19.2 Synthesis of (E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide To a mixture solution of the starting material (2 g, 11.43 mmol) and 2-amino-5-bromonicotinic acid (2.48 g, 11.43 mmmol) and HATU (3.5 g, 11.42 mmol) in DMF (20 mL) was added DIEA (2.4 ml, 13.72 mmol). The reaction was allowed to proceed at room temperature for 2 hours and was completely checked by LCMS. The solvent was filtered and the solid (3.6 g, 84.2%) was collected. MS (ESI): 375 [m+H] + .

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

[0352] 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-dioxaborol-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) was added Pd(dppf)Cl2 DCM (43.6 mg, 0.0535 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 20.1 Synthesis of (E)-4-(3-aminophenyl)-2-methylbut-3-yn-2-ol

[0356] 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) was added TEA (10 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 20.2 Synthesis of (E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

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

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

[0360] To a mixed solution of raw material (350 mg, 0.933 mmol), 2,5-dimethyl-7-(4,4,4,5,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1,2,3,4-tetrahydroisoisoquinoline (322 mg, 1.12 mmol) and K3PO4 (275 mg, 2.88 mmol) in dioxane (8 mL) and H2O (1.6 mL) under nitrogen, the solution was heated at 80°C for 4 hours. Then the detection was completed by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative TLC (DCM:MeOH=5:1) to give 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]isoquinolin-5(1H)-one

[0364] Under ice bath, sodium hydride (60 mg, 1.36 mmol) was added to a solution of 7-bromo-4-methyl-3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5(1H)-one (240 mg, 0.909 mmol) in DMF (5 mL). After 30 minutes, iodomethane (90 μL, 1.36 mmol) was added. The reaction was stirred at room temperature for 3 hours and completely detected by LCMS. The solvent was quenched with saturated aqueous NH4Cl 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 solution of the raw material (200 mg, 0.72 mmol) in tetrahydrofuran (5 mL) under an ice bath. The solution was stirred at room temperature for 0.5 h and then completely detected by LCMS. The solvent was quenched with 2M aqueous sodium hydroxide solution and washed with ethyl acetate. The resulting solution was filtered and concentrated to obtain a 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(diphenylphosphino)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)picolinamide (600 mg, 1.60 mmol) and biboric acid pinacol ester (486 mg, 1.92 mmol) and potassium acetate (237 mg, 2.41 mmol) in dioxane (7.5 mL). The reactants were heated at 80 ° C for 2.5 h and completely detected by LCMS. The solvent was filtered and concentrated under reduced pressure to give a 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]isoquinolin-7-yl)-N-(3-(3-hydroxy-3-methylbut-1-ynyl)phenyl)picolinamide

[0369] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (111 mg, 0.15 mmol) was added to a mixed solution of raw material 1 (300 mg, 0.88 mmol), raw material 2 (200 mg, 0.76 mmol) and potassium phosphate (242 mg, 1.14 mmol) in tetrahydrofuran (3 mL) and water (3 mL) under N2. The solution was heated at 80°C for 3 h and then completely detected by LCMS. The solvent was extracted with EA. The organic layer was dried over Na2SO4 and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM: MeOH = 10: 1) to obtain 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-(thiazol-2-yl)piperidine-1-carboxylate

[0373] 2-Bromo-1,1-diethoxyethane (1.6 g, 8.18 mmol) and TsOH·H2O (3 g, 16.36 mmol) were added to a solution of tert-butyl 4-carbamoylpiperidine-1-carboxylate (2 g, 8.18 mmol) in ethanol (50 mL). The resulting solution was stirred at 80 ° C overnight, 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 tert-butyl 4-(thiazol-2-yl)piperidine-1-carboxylate (1.2 g, 55%) as a yellow oil. MS (ESI): m / z found 269.4 [M+H] + .

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

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

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

[0377] To a mixture of 2-(piperidin-4-yl)thiazole (1 g, 5.92 mmol) in THF (40 mL) was added TEA (822 mg, 5.92 mmol), CH2O (0.67 mL, 8.88 mmol), STAB (1.8 g, 8.88 mmol). 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 2-(1-methylpiperidin-4-yl)thiazole (600 mg, 60%) as a yellow oil. 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) was added n-butyl lithium (0.5 mL, 0.82 mol). 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 2-(1-methylpiperidin-4-yl)-5-(tributyltinyl)thiazole (200 mg, 52%) as a yellow oil. 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] To a mixture of 2-(1-methylpiperidin-4-yl)-5-(tributyltinyl)thiazole (200 mg, 1.0 mmol) and 5-bromo-3-((3-(3-methyl-3-((tetrahydro-2H-pyran-2-yl)oxy)but-1-yn-1-yl)benzyl)oxy)-2-nitropyridine (200 mg, 1.0 mmol) dissolved in dioxane (5 mL) was added CuI (25 mg, 0.3 mmol) and Pd(PPh)Cl (35 mg, 0.1 mmol). Under N atmosphere, the resulting solution was stirred at 90 ° C for 6 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 NaSO and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (20% MeOH in DCM) to give 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%) as a yellow oil. MS (ESI): m / z found 577.7 [M+H] + .22.6 Synthesis of 4-(3-((2-amino-5-(5-(1-methylpiperidin-4-yl)thiazol-2-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-ol

[0382] To a mixture of 2-(1-methylpiperidin-4-yl)-5-(tributyltinyl)thiazole (100 mg, 0.17 mmol) in ACOH (2 mL) was added Zn (113 mg, 1.7 mmol) and TsOH HO (5 mg, 0.1 mmol). 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 4-(3-(((2-amino-5-(5-(1-methylpiperidin-4-yl)thiazol-2-yl)pyridin-3-yl)oxy)methyl)phenyl)-2-methylbut-3-yn-2-ol (100 mg, 41%) as a yellow oil. 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-methylpyrrolidin-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-methylpyrrolidin-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] 23.2 Synthesis of (R)-N-methyl-3-(2-methylpyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

[0388] To a solution of (R)-3-bromo-N-methyl-5-(2-methylpyrrolidin-1-yl)benzenesulfonamide (360 mg, 1.08 mmol), bis-pinacol boronate (360 mg, 1.4 mmol) and potassium acetate (213 mg, 2.16 mmol) in 1,4-dioxane (5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (80 mg, 0.108 mmol) and 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 in vacuo, and 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] 23.3 Synthesis of (R)-2-amino-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-5-(3-(2-methylpyrrolidin-1-yl)-5-(N-methylsulfamoyl)phenyl)nicotinamide

[0390] To a solution of 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) in dioxane (6 mL) and water (1.2 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (50 mg, 0.053 mmol), and the resulting 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-yn-2-ol

[0394] 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) was added TEA (10 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 24.2 Synthesis of (E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

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

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

[0398] 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-dioxaborolane (406 mg. 1.61 mmol) and KoAc (200 mg, 2.01 mmol) in dioxane (5 mL) was added Pd(dppf)Cl2 (196 mg, 0.268 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then N2 was passed through. LCMS was completely detected. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 24.4 Synthesis of (E)-7-bromo-2-(2,2-difluoroethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline

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

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

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

[0403] Example 25 Synthesis of Compound 141

[0404]

[0405] 25.1 Synthesis of (S)-4-(6-amino-5-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)-N-(2-(3-fluoropyrrolidin-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-tetrahydroisoquinolin-6-yl)pyridin-3-yl)boric acid (50 mg, 0.13 mmol), (S)-4-bromo-N-(2-(3-fluoropyrrolidin-1-yl)ethyl)-2,6-dimethylbenzamide (54 mg, 0.16 mmol) and potassium carbonate (54 mg, 0.39 mmol) dioxane (3 mL) and water (0.6 ml). The reactants were stirred at 80 ° C overnight and the reaction was completed by TLC monitoring. After concentration under reduced pressure, 2 ml of TFA was added. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-yn-2-ol

[0410] 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) was added TEA (10 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 26.2 Synthesis of (E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

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

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

[0414] 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-dioxaborolane (406 mg. 1.61 mmol) and KoAc (200 mg, 2.01 mmol) in dioxane (5 mL) was added Pd(dppf)Cl2 (196 mg, 0.268 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then N2 was passed through. LCMS was completely detected. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 26. Synthesis of 4(E)-2-(7-bromo-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethyl-1-ol

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

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

[0418] To a mixed solution of starting material 1 (75 mg, 0.22 mmol), starting material 2 (60 mg, 0.242 mmol) and K2CO3 (85 mg, 0.66 mmol) in dioxane (2 mL) and H2O (0.4 mL) was added Pd(dppf)Cl2 (16 mg, 0.022 mmol) under N2. 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 (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-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline

[0422] 7-Bromo-2,5-dimethyl-1,2,3,4-tetrahydroisoquinoline (400 mg, 1.67 mmol), biboric acid pinacol ester (420 mg, 1.67 mmol), potassium acetate (204 mg, 2.08 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (203 mg, 0.28 mmol) were added to the reaction vessel and dissolved in 1,4-dioxane (5 mL). Under nitrogen protection, the mixture was reacted at 80 ° C for 3 hours. After the reaction was completed by LCMS monitoring, the crude product was filtered and concentrated by vacuum distillation to obtain a 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), DMAP (33 mg, 0.26 mmol) were added to the reaction vessel and dissolved in DCM (15 mL). The mixture was reacted at room temperature for 4 hours. After the reaction was completed by monitoring by LCMS, it was 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 a crude product. Purification by column chromatography (PE:EA=6:1) gave 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-tetrahydroisoquinolin-7-yl)-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)pyridazine-4-carboxamide

[0425] Add raw material 1 (500 mg, 1.43 mmol), raw material 2 (500 mg), potassium phosphate (455 mg, 2.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (209 mg, 0.29 mmol) to the reaction vessel and dissolve in tetrahydrofuran (5 mL) and water (5 mL). Under nitrogen protection, the mixture was reacted at 80 ° C for 3 hours. After the reaction was completed by LCMS monitoring, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 5: 1) gave the title compound (120 mg, 17.7%). MS (ESI): m / z found 475 [M + H] + .

[0426] Example 28 Synthesis of Compound 37

[0427]

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

[0429] 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) was added TEA (10 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 28.2 Synthesis of (E)-2-amino-5-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)nicotinamide

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

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

[0433] 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-dioxaborolane (406 mg. 1.61 mmol) and KoAc (200 mg, 2.01 mmol) in dioxane (5 mL) was added Pd(dppf)Cl2 (196 mg, 0.268 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then N2 was passed through. LCMS was completely detected. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 28. Synthesis of 4-(E)-7-bromo-5-methyl-2-(3-methyloxetan-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline

[0435] Under N2, 7-bromo-5-methyl-1,2,4-tetrahydroisoquinoline (345 mg, 1.53 mmol), 3-bromomethyl-3-methyloxetane (212 uL, 2.3 mmol) and K2CO3 (520 mg, 4,6 mmol) were added to a mixed solution in ACN (6 mL). The solution was heated at 65 ° C overnight and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 28.5 Synthesis of (E)-2-amino-N-(3-hydroxy-3-methylbut-1-ynyl)phenyl)-5-(5-methyl-2-(3-methyloxetan-3-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)nicotinamide

[0437] To a mixed solution of starting material 1 (200 mg, 0.59 mmol), starting material 2 (224 mg, 0.73 mmol) and Na2CO3 (136 mg, 1.77 mmol) in dioxane (4 mL) and H2O (0.8 mL) was added Pd(pph3)4 (68 mg, 0.06 mmol) under N2. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative TLC (DCM:MeOH=5:1) to give 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, 9.14 mmol), DMAP (279 mg, 2.29 mmol) were added to the reaction vessel and dissolved in DCM (15 mL). The mixture was reacted at room temperature for 4 hours. After the reaction was completed by monitoring by LCMS, it was 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 a crude product. Purification by column chromatography (PE:EA=6:1) gave 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)pyridazine-4-carboxamide

[0443] The raw 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(diphenylphosphino)ferrocene]palladium dichloride (83 mg, 0.11 mmol) were added to the reaction vessel and dissolved in tetrahydrofuran (5 mL) and water (5 mL). Under nitrogen protection, the mixture was reacted at 80°C for 3 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM:MeOH=5:1) gave the title compound (100 mg, 64.5%). MS (ESI): m / z found 518 [M+H] + .

[0444] Example 30 Synthesis of Compound 41

[0445]

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

[0447] 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) was added TEA (10 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 30.2 Synthesis of (E)-2-methyl-4-(3-(methylamino)phenyl)but-3-yn-2-ol (0000676-DLY-054R1) 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), reacted at room temperature for 2 hours, and completely detected by LCMS. The solvent was filtered and the solid (110 mg, 28.9%) was collected. MS (ESI): 189.3 [m+H] + .

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

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

[0451] 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-dioxaborol-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) was added Pd(dppf)Cl2 (28.3 mg, 0.039 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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-yn-2-ol

[0455] 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) was added TEA (10 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 31.2 Synthesis of (E)-3-amino-6-bromo-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)pyrazine-2-carboxamide To the starting material (200 mg, 1.14 mmol) and 3-amino-6-bromopyrazine-2-carboxylic acid (250 mg, 1.14 mmol) and HATU

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

[0458] 31.3 Synthesis of (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] 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-dioxaborol-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) was added Pd(dppf)Cl2 (19.5 mg, 0.027 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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)propan-1-one

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

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

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

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

[0467] To a solution of compound 3 (1.05 g, 3.2 mmol) in THF (10 mL) was added triisobutyl lithium borohydride (6.7 mL, 6.7 mmol) at -78 ° C. The resulting solution was stirred at -78 ° C for 3 hours. The solution was quenched by adding methanol, diluted with brine, and the mixture was extracted with dichloromethane (3 × 100 ml), the organic phases were combined, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a yellow oily compound 4 (872 mg, 83%).

[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 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (49 mg, 0.1 mmol) were added to a mixed solution of compound 4 (200 mg, 0.6 mmol) and compound 5 (246 mg, 0.7 mmol) in ultra-dry 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 in vacuo. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give compound 6 (89 mg, yield: 26%).

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

[0471] To a stirred solution of compound 6 (89 mg, 0.2 mmol) in methanol (4.5 ml) was added hydrochloric acid (1,4-dioxane 4M solution) (0.1 ml, 0.5 mmol). The resulting solution was stirred at room temperature for 16 hours. The pH of the solution was adjusted with sodium bicarbonate, and the mixture was extracted with ethyl acetate (3×100 ml). After drying with anhydrous sodium sulfate, the organic phase was concentrated in vacuo and purified by Prep-TLC (dichloromethane: methanol = 5:1) to obtain 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)propan-1-one

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

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

[0477] Sodium borohydride (817 mg, 21.6 mmol) and aluminum chloride (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, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3×100 ml). The organic phases were combined, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain a white solid compound 3 (846 mg, 83%).

[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 a mixed solution of compound 3 (200 mg, 0.9 mmol) and compound 4 (355 mg, 1.0 mmol) in ultra-dry 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 in vacuo. The residue was purified by Prep-TLC (dichloromethane: methanol = 10: 1) to obtain 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-yn-2-ol

[0483] 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) was added TEA (10 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 34.2 Synthesis of (E)-2-methyl-4-(3-(methylamino)phenyl)but-3-yn-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), reacted at room temperature for 2 hours, and completely detected by LCMS. The solvent was filtered and the solid (110 mg, 28.9%) was collected. MS (ESI): 189.3 [m+H] + .

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

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

[0488] 34.4 Synthesis of (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] 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-dioxaborol-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) was added Pd(dppf)Cl2 (30 mg, 0.041 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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)propan-1-one

[0493] The Grignard reagent (12 ml, 85.7 mmol) was slowly added to a solution of compound 1 (3 g, 15.3 mmol) in ether (30 mL), and the mixture was stirred at room temperature for 16 hours. The solution was quenched with saturated aqueous 4M hydrochloric acid (18 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, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain compound 2 (3.2 g, 92%) as a yellow oil.

[0494] 35.2 Synthesis of 3-(3-bromo-5-methylphenyl)pentan-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, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain a white solid compound 3 (442 mg, 39%).

[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 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (69 mg, 0.1 mmol) were added to a mixed solution of compound 3 (220 mg, 0.9 mmol) and compound 4 (348 mg, 1.0 mmol) in ultra-dry 1,4-dioxane and water (4:1 ml) under nitrogen. 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 in vacuo, and 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] 36.1 Synthesis of (E)-3-(1-methylpyrazol-4-yl)ethynylaniline

[0501] 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) was added TEA (0.195 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 36.2 Synthesis of (E)-3-amino-6-bromo-N-(3-(1-methylpyrazol-4-yl)ethynyl)phenyl)pyrazine-2-carboxamide To a mixture solution of starting material (64 mg, 0.32 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (106 mg, 0.48 mmol) and HATU (184 mg, 0.48 mmol) in DMF (1 mL) was added DIEA (0.16 ml, 0.96 mmol). The reaction was allowed to react at room temperature for 12 hours and was completely detected by LCMS. The solvent was filtered and the solid was collected (74 mg, 57.4%). MS (ESI): 397.2 [m+H] + .

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

[0504] 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-dioxaborol-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) was added Pd(dppf)Cl2 (18 mg, 0.025 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 37.1 Synthesis of (E)-3-(1-methylpyrazol-3-yl)ethynyl)aniline

[0508] 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) was added TEA (0.195 mL) under N2. 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 over Na2SO4 and concentrated to give a 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] 37.2 Synthesis of (E)-3-amino-6-bromo-N-(3-(1-methylpyrazol-3-yl)ethynyl)phenyl)pyrazine-2-carboxamide To a mixture solution of starting material (58 mg, 0.29 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (96 mg, 0.44 mmol) and HATU (167 mg, 0.44 mmol) in DMF (2 mL) was added DIEA (0.145 ml, 0.87 mmol). The reaction was allowed to react at room temperature for 12 hours and was completely detected by LCMS. The solvent was filtered and the solid (34 mg, 29.1%) was collected. MS (ESI): 397.2 [m+H] + .

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

[0511] 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-dioxaborol-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) was added Pd(dppf)Cl2 (6 mg, 0.009 mmol) under N2. The solution was heated at 80 degrees Celsius for 4 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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] 38.1 Synthesis of (E)-4-(5-aminopyridin-3-yl)-2-methylbut-3-yn-2-ol

[0515] 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) was added diisopropylamine (1.5 ml, 11.5 mmol) under N2. The solution was heated to 100 degrees Celsius 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 over Na2SO4 and concentrated to give a 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] 38.2 Synthesis of (E)-2-amino-5-bromo-N-(5-(3-hydroxy-3-methylbut-1-ynyl)pyridin-3-yl)nicotinamide

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

[0518] 38.3 Synthesis of (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] To a mixed solution of raw material (88 mg, 0.24 mmol), 2,5-dimethyl-7-(4,4,4,5,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,2,3,4-tetrahydroisoisoquinoline (90 mg, 0.29 mmol) and K2CO3 (97 mg, 0.71 mmol) in dioxane (1 mL) and H2O (0.2 mL) under nitrogen, the solution was heated at 80°C for 4 hours. Then the detection was completed by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative TLC (DCM:MeOH=5:1) to give 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) was added chloroform hydrochloride (1.3 g, 6.7 mmol). 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 a purple oily compound 2 (913 mg, 72%).

[0524] 39.2 Synthesis of 4-(3-aminophenyl)-2-methylbut-3-yn-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) were added cuprous iodide (1.3 g, 6.9 mmol), triethylamine (10.5 ml, 75.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.6 g, 2.3 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The solution was washed with ethyl acetate, brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 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'-tetramethyluronium hexafluorophosphate (3.0g, 8.0mmol) was added to a solution of 2-amino-5-bromonicotinic acid (2.1g, 9.6mmol) in N,N-dimethylformamide (10mL) under nitrogen. The mixture was stirred at room temperature for 15 minutes. Compound 4 (1.4g, 8.0mmol) and N,N-diisopropylethylamine (1.7ml, 9.6mmol) were then added respectively and stirred at room temperature for 6 hours. The reaction mixture was washed with ethyl acetate, brine, and dried over anhydrous sodium sulfate to obtain compound 5 (3.4g), 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) was added diboric acid pinacol ester (815 mg, 3.2 mmol), potassium acetate (394 mg, 4.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (218 mg, 0.1 mmol). The resulting solution was stirred under a nitrogen atmosphere at 85°C for 6 hours. The solution was extracted with ethyl acetate (3×100 ml), the organic phases were combined, the combined organic phases were washed with brine, the combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a crude product 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 a mixed solution of compound 2 (810 mg, 2.9 mmol) and compound 6 (1.2 g, 3.4 mmol) in ultra-dry 1,4-dioxane and water (5:1 mL) under nitrogen. 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 in vacuo. 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] 40.1 Synthesis of (E)-3-amino-6-bromo-N-(2-(3-hydroxy-3-methylbut-1-ynyl)pyridin-4-yl)pyrazine-2-carboxamide

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

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

[0537] To a mixed solution of raw material (270 mg, 0.72 mmol), 2,5-dimethyl-7-(4,4,4,5,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,2,3,4-tetrahydroisoisoquinoline (275 mg, 0.88 mmol) and K2CO3 (299 mg, 2.16 mmol) in dioxane (4 mL) and H2O (0.8 mL) under nitrogen, the solution was heated at 80°C for 4 hours. Then the detection was completed by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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 the reaction vessel, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 20: 1) gave 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 raw 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(diphenylphosphino)ferrocene]palladium dichloride (150 mg, 0.184 mmol) were added to the reaction vessel and dissolved in tetrahydrofuran (5 mL) and water (5 mL). Under nitrogen protection, the mixture was reacted at 80 ° C for 2.5 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 5: 1) gave the title compound (120 mg, 31.3%). MS (ESI): m / z 417 [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-carboxylate

[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 into a flask, and the mixture was stirred at room temperature for 1 hour, then concentrated and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 2 (6.2 g, 95%) as a light 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 mixed solution of compound 2 (416 mg, 1.58 mmol) and 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (479 mg, 1.45 mmol) in ultra-dry 1,4-dioxane and water (5:1 mL) were added potassium carbonate (600 mg, 4.35 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (105 mg, 0.14 mmol) under nitrogen. The mixture was heated to 80°C and then stirred for 3 hours. The reaction mixture was cooled to room temperature and filtered, and the filtrate was washed with ethyl acetate and brine, and dried over anhydrous sodium sulfate after vacuum concentration. The residue was separated and purified using column chromatography to obtain 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 ultra-dry tetrahydrofuran (7 mL) solution, and the mixture was stirred for 3 hours at room temperature under nitrogen protection. The reaction mixture was filtered, and the filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was separated and purified by column chromatography (dichloromethane: methanol = 30: 1) to obtain 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-carboxylate

[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, and the mixture was stirred at room temperature for 1 hour, then concentrated and the residue was purified by column chromatography (dichloromethane: methanol = 15: 1) to obtain 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-carboxylate

[0555] 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) was added cesium carbonate (130 mg, 0.20 mmol) and benzylbis(triphenylphosphine)palladium chloride (21 mg, 0.02 mmol) under nitrogen. The mixture was heated to 85°C and then 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 in vacuo, and the residue was separated and purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain 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]pyridin-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, the pH value of the reaction solution was adjusted to neutral with sodium bicarbonate solution, the neutral mixed solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained residue was separated and 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)propiolate

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

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

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

[0564] 43.3 Synthesis of methyl 3-(3-(2-amino-5-bromonicotinamido)phenyl)propiolate

[0565] 2-Amino-5-bromonicotinic acid (300 mg, 1.38 mmol), HATU (650 mg, 1.71 mmol) and DIEA (3 ml) were added to a mixture of the raw material (200 mg, 1.14 mmol) in DMF (7.5 mL). The reaction was stirred at room temperature for 4 hours and completely detected by LCMS. The solvent was extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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)nicotinamido)phenyl)propiolate

[0567] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (47 mg, 0.06 mmol) was added to a mixture solution of the raw material (120 mg, 0.32 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 reactants were stirred at 70 ° C for 1 hour and completely detected by LCMS. The solvent was extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a 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)nicotinamido)phenyl)propiolic acid

[0569] LiOH·H2O (51 mg, 1.21 mmol) was added to a mixed solution of the raw material (60 mg, 0.12 mmol) in tetrahydrofuran (4 ml), methanol (1 ml) and H2O (4 ml). The reaction was stirred at room temperature for 3 hours and completely detected by LCMS. The pH value of the solvent was adjusted to 5-6 with 4M aqueous hydrochloric acid. The organic layer was extracted with a mixed solvent of chloroform and isopropanol (3:1), dried over Na2SO4, and concentrated to give a crude product. The crude product was purified by preparative thin layer chromatography (DCM: MeOH = 2:1) to give 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)pyrimidin-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) and then triethylamine (7.15 ml, 50.95 mmol), triphenylphosphine (1.2 g, 4.63 mmol), benzylbis(triphenylphosphine)palladium chloride (1 g, 1.54 mmol), cuprous iodide (884 ml, 4.64 mmol) were added, and the mixture was stirred at 140°C for 12 hours, then concentrated and the residue was 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-chloronicotinyl chloride

[0575] Compound 3 (1 g, 4.24 mmol) was dissolved in ultra-dry dichloromethane (10 ml), thionyl chloride (5 ml) was added, and the reactant was refluxed and stirred at 50° C. for 2 hours to obtain compound 4. The compound was dried and used without purification.

[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 dichloromethane (5 ml) solution of compound 4 (1.1 g, 4.24 mmol), and then the dichloromethane (4 ml) solution of compound 4 was slowly added thereto at 0°C, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature and filtered, and the filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue was separated and purified by Prep-TLC (dichloromethane: methanol = 30: 1) to obtain 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 super dry dioxane (5 ml), triethylamine (260 μl, 1.87 mmol) and p-methoxybenzylamine (313 μl, 2.53 mmol) were added, and the reactants were refluxed and stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and filtered, and the filtrate was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was separated and 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), and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and the pH value was adjusted to 7 with sodium bicarbonate. The mixed solution was washed with ethyl acetate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was separated and 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] 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-dioxaborol-2-yl)phenyl)-4-methylpiperazine (122 mg, 0.37 mmol) in ultra-dry 1,4-dioxane (2 mL) and deionized water (0.5 mL) was added sodium carbonate (98 mg, 0.924 mmol), and tetrakis[triphenylphosphine]palladium (25.6 mg, 0.0308 mmol) under nitrogen. 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] Triethylamine (600uL, 4.3mmol) and 1-propylphosphonic anhydride (1.3mL, 2.15mmol, 50% in ethyl acetate) were added to 5-bromo-2-chloronicotinic acid (340mg, 1.43mmol) in DMF (15mL). 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 (450mg, 1.71mmol) was added and reacted at room temperature for 5 hours. 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 obtain the product (250mg, 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 uL, 1.4 mmol) and triethylamine (145 uL, 1.04 mmol) were added to dioxane (5 mL), and the mixture was stirred at 100 ° C for 4 hours. The solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain 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 in vacuo and 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 obtain 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-dioxaborol-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) with tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol), and 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 in vacuo, and the residue was purified by 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] 46.1 Synthesis of (E)-1-ethynylcyclobutane-1-ol

[0597] At 0 degrees Celsius, cyclobutanone (500 mg, 7.14 mmol) was slowly added dropwise to ethynylmagnesium bromide (19.5 ml, 9.29 mmol), nitrogen was evacuated, and the mixture was reacted for 15 minutes, and then quenched with saturated ammonium chloride. The product (480 mg, 69.8%) was obtained. MS (ESI): 96.1 [m+H] + .

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

[0599] 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) was added TEA (0.75 ml) under N2. The solution was heated to 80 degrees Celsius for 5 h and then completely detected by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative TLC (PE:EA=1:1) to give the product (250 mg, 97.7%). MS (ESI): 187.2 [m+H] + .

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

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

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

[0603] To a mixed solution of raw material (231 mg, 0.6 mmol), 2,5-dimethyl-7-(4,4,4,5,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1,2,3,4-tetrahydroisoisoquinoline (229 mg, 0.74 mmol) and K2CO3 (248 mg, 1.48 mmol) in dioxane (4 mL) and H2O (0.8 mL) under nitrogen, the solution was heated at 80°C for 4 hours. Then the detection was completed by LCMS. The solvent was quenched with NaCl and extracted with EA. The organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative TLC (DCM:MeOH=5:1) to give 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] Dissolve 6-fluoroimidazo[1,2-a]pyridine (600 mg, 4.4 mmol) in concentrated sulfuric acid (4 mL), add concentrated nitric acid (0.8 ml) under ice bath, and stir at room temperature for 1.5 hours. After the reaction is completed by LCMS monitoring, water is added to quench, and the solid is filtered and dried to obtain the title compound (800 mg, 99.7%). MS (ESI): m / z 182 [M+H] + .

[0608] 47.2 Synthesis of 6-fluoroimidazo[1,2-a]pyridin-3-amine

[0609] Add the raw material (800 mg, 4.4 mmol), reduced iron powder (1.2 g, 22.0 mmol), ammonium chloride (816 mg, 15.4 mmol) to the reaction vessel and dissolve 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 by LCMS monitoring, it was filtered, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purify by column chromatography (DCM: MeOH = 10: 1) to obtain 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-fluoroimidazo[1,2-a]pyridin-3-yl)nicotinamide

[0611] Add the raw 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) to the reaction vessel. The mixture was reacted at room temperature for 3 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 10: 1) gave 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-fluoroimidazo[1,2-a]pyridin-3-yl)nicotinamide

[0613] The raw 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(diphenylphosphino)ferrocene]dichloropalladium (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). Under nitrogen protection, the mixture was reacted at 80°C for 1 hour. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM:MeOH=10:1) gave the product (124 mg, 30.1%). MS (ESI): 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), sodium hydride (246 mg, 6.14 mmol) was added under ice bath, and the mixture was stirred under ice bath for 0.5 hours. After 0.5 hours, iodomethane (654 mg, 4.61 mmol) was added. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (PE:EA=3:1) gave the title compound (519 mg, 95.4%). MS (ESI): m / z 177 [M+H] + .

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

[0619] Add the raw material (519 mg, 2.93 mmol), reduced iron powder (1.15 g, 19.8 mmol), ammonium chloride (734 mg, 13.8 mmol) to the reaction vessel and dissolve 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 by LCMS monitoring, it was filtered, dried over anhydrous sodium sulfate and concentrated by vacuum distillation to obtain a crude product. Purify by column chromatography (DCM: MeOH = 10: 1) to obtain 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 dried, and the raw material (360 mg, 2.43 mmol), triethylamine (2.5 ml) and dichloromethane (7.5 ml) were added, and the mixture was reacted at 45°C for 2 hours. After the reaction was completed by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 15: 1) gave 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] Add the raw material (315 mg, 0.87 mmol), 4-methoxybenzylamine (411 mg, 3 mmol), potassium carbonate (414 mg, 3 mmol) and acetonitrile (7.5 ml) to the reaction vessel. The mixture was reacted at 80 ° C for 6 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 20: 1) gave a crude product (526 mg). 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] 0000772-CW-063R1 (526 mg) and trifluoroacetic acid (5 ml) were added to the reaction vessel. The mixture was reacted at 80°C for 2.5 hours. After the reaction was completed by monitoring by LCMS, the crude product was obtained by distillation under reduced pressure and concentration. The crude product (400 mg) was obtained by column chromatography (D CM: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 raw 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(diphenylphosphino)ferrocene]dichloropalladium (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). Under nitrogen protection, the mixture was reacted at 80°C for 3 hours. After the reaction was completed, it was monitored by LCMS and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM:MeOH=10:1) gave the product (220 mg, 54.8%). MS (ESI): m / z470[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 (1g, 5.0mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.32g, 5.9mmol), sodium carbonate (780mg, 7.35mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (720mg, 1.0mmol) were dissolved in a mixed solvent of tetrahydrofuran (10ml) and water (10ml). Under nitrogen protection, the mixture was reacted at 80°C for 3 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (PE:EA=3:1) gave a crude product (1.7g). MS (ESI): m / z 220 [M+H] + .

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

[0633] Add the raw material (1.7 g,), palladium carbon (2 g) and methanol (10 mL) to the reaction vessel. Under hydrogen, the mixture was reacted at 40 ° C for 3 hours. After the reaction was completed by LCMS monitoring, it was filtered, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purify by column chromatography (DCM: MeOH = 5: 1) to obtain 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, raw materials (660 mg, 3.5 mmol), hydrobromic acid (15 ml) and sodium nitrite (357 mg, 5.1 mmol) aqueous solution were added to the reaction vessel. The mixture was reacted at -20 ° C for 3 hours. After 3 hours of reaction, sodium bromide (533 mg, 5.1 mmol) aqueous solution was added. The reaction was allowed to react overnight at room temperature. After the reaction was completed by LCMS monitoring, saturated sodium bicarbonate solution was added to quench, and the mixture was extracted with a mixed solvent of chloroform / isopropanol. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 5: 1) gave 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 raw 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(diphenylphosphino)ferrocene]dichloropalladium 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). Under nitrogen protection, the mixture was reacted at 80 ° C for 2 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification was performed on a TLC preparation plate (DCM: MeOH = 5: 1) to obtain the product (25 mg, 38.0%). MS (ESI): m / z 471 [M+H] + .

[0638] Example 50 Synthesis of Compound 82

[0639]

[0640] 50.1 Synthesis of (S)-(2'-amino-5'-bromo-[2,3'-bipyridyl]-5-yl)(3-hydroxypyrrolidin-1-yl)methanone

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

[0642] 50.2 Synthesis of (S)-(2'-amino-5'-(3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)-[2,3'-bipyridyl]-5-yl)(3-hydroxypyrrolidin-1-yl)methanone

[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-dioxaborolan-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) and Pd(dppf)2Cl2 (3 mg, 0.003 mmol) was added, and 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 in vacuo, and 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] 51. Synthesis of tert-butyl 1(R)-(1-(3-bromophenyl)pyrrolidin-3-yl)carbamate

[0647] Pd2(dba)3 (160 mg, 0.17 mmol) was added to a solution of 1-bromo-3-iodobenzene (760 mg, 2.68 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg, 2.68 mmol), sodium tert-butoxide (516 mg, 5.36 mmol) and XantPhos (310 mg, 0.54 mmol) in toluene (20 mL), and the temperature was raised to 120°C and stirred for 4 hours under nitrogen atmosphere. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo, and 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-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)carbamate

[0649] To the compound obtained in the previous step (200 mg, 0.586 mmol), bis-pinacol borate (300 mg, 1.17 mmol) and potassium acetate (116 mg, 1.17 mmol) in a solution of 1,4-dioxane (8 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (43 mg, 0.058 mmol) was added and 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 in vacuo, and the residue was purified by liquid chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain the product (220 mg, 95% yield). MS (ESI): m / z 389 [m+H] + 51.3 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)pyrrolidin-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) with tetrakistriphenylphosphine palladium (21 mg, 0.018 mmol), and 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 in vacuo, and 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] 51.5 Synthesis of (R)-2-amino-5-(3-(3-aminopyrrolidin-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 in vacuo, and the obtained residue was purified by reverse phase column chromatography to obtain 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-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1 g, 4.5 mmol), potassium phosphate (1.1.9 g, 8.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (658 mg, 0.9 mmol) were added to the reaction vessel and dissolved in a mixed solvent of tetrahydrofuran (7.5 ml) and water (1.5 ml). Under nitrogen protection, the mixture was reacted at 80 ° C for 12 hours. After the reaction was completed by monitoring by LCM S, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 25: 1) gave 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] Add the raw material (1 g, 4.1 mmol), palladium carbon (2 g) and methanol (10 mL) to the reaction vessel. Under the protection of hydrogen, the mixture was reacted at 40 ° C for 2 hours. After the reaction was completed by LCMS monitoring, it was filtered, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purify by column chromatography (DCM: MeOH = 20: 1) to obtain 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 raw material (600 mg, 2.7 mmol), cuprous bromide (1.2 g) and isoamyl nitrite (500 μL) were added to the reaction vessel and dissolved in acetonitrile (15 mL). The mixture was reacted at room temperature for 3 hours. After the reaction was completed by LCMS monitoring, the crude product was obtained by filtration and concentrated by pressure distillation. The title compound (175 mg, 19.9%) was obtained by column chromatography (DCM: MeOH = 50: 1). 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-dioxaborolan-2-yl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine

[0662] Add the raw material (75 mg, 0.27 mmol), biboronic acid pinacol ester (82 mg, 0.32 mmol), potassium acetate (53 mg, 0.54 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (40 mg, 0.06 mmol) and dioxane (5 ml) to the reaction vessel. The mixture was reacted at 80 ° C for 12 hours. After the reaction was completed by LCMS monitoring, the filtrate was filtered and concentrated by vacuum distillation. The crude product (80 mg) was obtained. 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 raw 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(diphenylphosphino)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). Under nitrogen protection, the mixture was reacted at 80°C for 2 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification was performed by TLC preparation plate (D CM:MeOH=10:1) to obtain the product (15 mg, 23.3%). MS (ESI): m / z 496 [M+H] + .

[0665] Example 53 Synthesis of Compound 88

[0666]

[0667] 53.1 Synthesis of tert-butyl ((R)-(1-(2-bromopyridin-4-yl)pyrrolidin-3-yl)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)-tert-butyl pyrrolidin-3-ylcarbamate (762 mg, 2.68 mmol), sodium tert-butoxide (516 mg, 5.36 mmol) and XantPhos (310 mg, 0.54 mmol) in toluene (20 mL), and the temperature was raised to 120°C and stirred for 4 hours under nitrogen atmosphere. The mixture was filtered, washed with ethyl acetate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo, and 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] [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (51 mg, 0.07 mmol) was added 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-pinacol boronate (213 mg, 0.84 mmol) and potassium acetate (137 mg, 1.39 mmol) in 1,4-dioxane (8 mL) and 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 in vacuo, and 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] 53.3 Synthesis of tert-butyl (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'-bipyridyl]-4-yl)pyrrolidin-3-yl)carbamate

[0672] The compound obtained in the previous step (58 mg, 0.135 mmol), tert-butyl ((R)-(1-(2-bromopyridin-4-yl)pyrrolidin-3-yl)carbamate (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) and tetrakistriphenylphosphine palladium (15 mg, 0.012 mmol), 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 in vacuo, and 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] 53. Synthesis of 4(R)-6'-amino-4-(3-aminopyrrolidin-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 in vacuo, and the obtained residue was purified by reverse phase column chromatography to obtain 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-oxybutyl)-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. Stirred in an ice bath for 20 minutes, followed by dropwise addition of hydrogen peroxide (10 ml). The mixture was refluxed for 2 days. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purified by column chromatography (PE:EA=1:1) to obtain the product (1 g, 47.2%). MS (ESI): m / z 300 / 302 [M+H] + .

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

[0680] Add the raw material (1g, 3.3mmol), pyridine (1.6ml) and acetonitrile (20mL) to the reaction vessel. Dissolve 1.3ml of p-toluenesulfonyl chloride in 5ml of acetonitrile and add it dropwise to the reaction solution. After the mixture reacts at room temperature for 5 hours, the reaction temperature is lowered to 10°C and 3ml of ethanolamine is added. Extract with ethyl acetate. Combine the organic phases, wash with brine, dry over anhydrous sodium sulfate and concentrate by distillation under reduced pressure to obtain a crude product. Purify by column chromatography (PE:EA=10:1) to obtain the title compound (480mg, 48%). MS (ESI): m / z 299 / 301[M+H] + .

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

[0682] Add the raw material (480mg, 1.6mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (287mg, 1.3mmol), potassium phosphate (1g, 4.8mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (235mg, 0.3mmol) to the reaction vessel and dissolve in a mixed solvent of dioxane (10ml) and water (2ml). Under nitrogen protection, the mixture was reacted at 80°C for 2.5 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by column chromatography (DCM: MeOH = 10: 1) gave the product (250mg, 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 raw 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(diphenylphosphino)ferrocene]dichloropalladium (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). Under nitrogen protection, the mixture was reacted at 80° C. for 2.5 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification was performed by TLC preparation plate (DCM:MeOH=5:1) to obtain the product (18 mg, 31.1%). MS (ESI): m / z 484 [M+H] + .

[0685] Example 55 Synthesis of Compound 91

[0686]

[0687] 55. Synthesis of tert-butyl 1(R)-(1-(2-chloropyrimidin-4-yl)pyrrolidin-3-yl)carbamate

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

[0689] 55.2 Synthesis of tert-butyl 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)pyrrolidin-3-yl)carbamate

[0690] To 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 tetrakistriphenylphosphine palladium (12 mg, 0.01 mmol) in 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 in vacuo, and 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] 55.3 Synthesis of (R)-2-amino-5-(4-(3-aminopyrrolidin-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 in vacuo, and the obtained residue was purified by reverse phase column chromatography to obtain 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 tert-butyl (2-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)carbamoyl)-[2,3'-bipyridyl]-6-yl)pyrrolidine-3-carbamate

[0696] To the reaction vessel, tert-butyl (R)-(1-(6-bromopyridin-2-yl)pyrrolidin-3-yl)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-boric acid (40 mg, 0.12 mmol), sodium carbonate (30 mg, 0.28 mmol) and tetrakistriphenylphosphine palladium (20 mg, 0.02 mmol) were added and dissolved in a mixed solvent of dioxane (5 ml) and water (1 ml). Under nitrogen protection, the mixture was reacted at 80 ° C for 3 hours. After the reaction was completed by monitoring by LCMS, it was extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. Purification by TLC preparative plate (DCM: MeOH = 20: 1) gave the product (30 mg, 44.8%). MS (ESI): m / z 558 [M+H] + .

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

[0698] Add the raw material (30 mg, 0.05 mmol), methanol (1 ml) and hydrochloric acid-dioxane solution (3 mL) to the reaction vessel. The mixture is reacted at room temperature for 3 hours. After the reaction is completed by monitoring by LCMS, the mixture is filtered, dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure to obtain a crude product. The title compound (22 mg, 96.3%) is obtained. MS (ESI): m / z 458 [M+H] + .

[0699] Example 57 Synthesis of Compound 93

[0700]

[0701] 57. Synthesis of tert-butyl 1(R)-(1-(4-chloropyrimidin-2-yl)pyrrolidin-3-yl)carbamate

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

[0703] 57.2 Synthesis of tert-butyl (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)pyrrolidin-3-yl)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) with tetrakistriphenylphosphine palladium (9 mg, 0.0076 mmol), 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 in vacuo, and 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] 57.3 Synthesis of (R)-2-amino-5-(2-(3-aminopyrrolidin-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 in vacuo, and the obtained residue was purified by reverse phase column chromatography to obtain 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] Place 6-chloroisoquinolin-1(2H)-one (1g, 5.59mmol) in a microwave tube, add POBr3 (5ml), heat to 180℃ and react overnight. After the reaction is complete, cool to room temperature and quench with ice water. Add EA to extract 3 times, and combine the organic phases. Concentrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain the product (587mg, 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, bistriphenylphosphine 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 reactants were stirred at 80 ° C for 4 hours. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column chromatography (PE: EA = 2: 1) to obtain 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)isoquinolin-6-yl)boronic acid 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) in dioxane (10 mL) under nitrogen protection. The reactants were stirred at 80°C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column 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)isoquinolin-6-yl)pyridin-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)isoquinolin-6-yl)boric acid (210 mg, 0.62 mmol), 5-bromo-3-iodopyridin-2-amine (277 mg, 0.93 mmol) and sodium carbonate (98 mg, 0.93 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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 (2-( ...

[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)isoquinolin-6-yl)pyridin-2-amine (85 mg, 0.18 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (90 mg, 0.27 mmol) and potassium carbonate (58 mg, 0.55 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column 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)isoquinolin-1-yl)

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

[0721] Under nitrogen protection, 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)isoquinolin-6-yl)pyridin-2-amine (35 mg) was dissolved in DCM (2 ml), TFA (1 ml) was added, and the reaction solution was stirred at room temperature for 1 h. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified on a silica gel column to obtain the 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) in dioxane (250 mL). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the product (7.6 g, 100%). MS (ESI): [M+H]+=217.

[0726] 59.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-2,7-naphthyridin-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)boric acid (436 mg, 2.09 mmol), 6-bromo-2,7-naphthyridine-1(2H)-one (300 mg, 1.34 mmol) and sodium carbonate (213 mg, 4.02 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-naphthyridin-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-naphthyridin-1(2H)-one (104 mg, 0.33 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (163 mg, 0.49 mmol) and potassium carbonate (105 mg, 0.99 mmol) dioxane (5 mL) and water (1 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the product (40 mg, 27.6%). MS (ESI): [M+H]+=441.

[0729] Example 60 Synthesis of Compound 98

[0730]

[0731] 60.1 Synthesis of (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) and KOAc (9.63 g, 100.33 mmol) in dioxane (250 mL). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it 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 a crude product. The product (7.6 g, 100%) was obtained. MS (ESI): [M+H]+=217.

[0733] 60.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)isoquinolin-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-bromoisoquinolin-1(2H)-one (400 mg, 1.79 mmol) and sodium carbonate (568 mg, 5.36 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the product (210 mg, 37.2%). MS (ESI): [M+H] + = 316.60.3 Synthesis of (6-amino-5-(1-oxo-1,2-dihydroisoquinolin-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)isoquinolin-1(2H)-one (1.4 g, 4.43 mmol), B2Pin2 (1.72 g, 6.65 mmol) and KoAc (1.3 g, 13.29 mmol) in dioxane (10 mL). The reactants were stirred at 80°C overnight. 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 distillation under reduced pressure to obtain a crude product. The crude product was purified by silica gel column to obtain the 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'-bipyridyl]-5'-yl)isoquinolin-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-dihydroisoquinolin-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) and potassium carbonate (59 mg, 4.26 mmol) dioxane (5 mL) and water (1 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the product (25 mg, 39.7%). MS (ESI): [M+H]+=441.2.

[0738] Example 61 Synthesis of Compound 97

[0739]

[0740] 61. Synthesis of tert-butyl 1(R)-(1-(3-bromo-6-chloropyridin-2-yl)pyrrolidin-3-yl)carbamate

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

[0742] 61.2 Synthesis of tert-butyl (R)-(1-(6-chloro-1'-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-2-yl)pyrrolidin-3-yl)carbamate

[0743] Pd(dppf)Cl2 (30 mg, 0.0398 mmol) was added to the compound obtained in the previous step (150 mg, 0.399 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (89 mg, 0.399 mmol) and potassium carbonate (110 mg, 0.798 mmol) in 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 in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain the product (140 mg, 90% yield). MS (ESI): m / z 393 [m+H] + .

[0744] 61.3 Synthesis of tert-butyl (R)-(1-(6-amino-1'-methyl-5-(1-oxo-1,2-dihydroisoquinolin-6-yl)-1'-, 2"-, 3"-, 6'-tetrahydro-[3,2'-:5'-, 4'-bipyridyl]-6'-yl)pyrrolidin-3-yl)carbamate

[0745] To the compound obtained in the previous step (50 mg, 0.127 mmol), (6-amino-5-(1-oxo-1,2-dihydroisoquinolin-6-yl)pyridin-3-yl)boronic acid (36 mg, 0.127 mmol) and sodium carbonate (27 mg, 0.255 mmol) were added tetrakistriphenylphosphine palladium (15 mg, 0.012 mmol) in a solution of dioxane (5 mL) and water (1 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 in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain the product (25 mg, 33.3% yield). MS (ESI): m / z 594.2 [m+H] + .

[0746] 61.4 Synthesis of (R)-2-amino-5-(2-(3-aminopyrrolidin-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 in vacuo, and the obtained residue was purified by reverse phase column chromatography to obtain 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] Pd2(dba)3 (887 mg, 0.968 mmol) and XantPhos (1.12 g, 1.93 mmol) were added to a solution of 3-bromo-6-chloro-2-methylpyridine (2.0 g, 9.68 mmol), 1-methylpiperazine (950 uL, 8.52 mmol) and sodium tert-butoxide (1.86 g, 19.37 mmol) in toluene (20 mL), and 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 in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain a crude product (1.12 g) and then reversed phase (8%) to obtain 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'-bipyridyl]-5'-yl)isoquinolin-1(2H)-one

[0753] The compound obtained in the previous step (60 mg, 0.21 mmol), (6-amino-5-(1-oxo-1,2-dihydroisoquinolin-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 tetrakistriphenylphosphine palladium (25 mg, 0.021 mmol), 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 in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to obtain 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, using 6-bromo-3-chloro-2-methylpyridine instead of 3-bromo-6-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] Pd2(dba)3 (445 mg, 0.48 mmol) and XantPhos (560 mg, 0.968 mmol) were added to a solution of 5-bromo-2-chloro-4-methylpyridine (1.0 g, 4.84 mmol), 1-methylpiperazine (484 uL, 4.35 mmol) and sodium tert-butoxide (930 mg, 9.68 mmol) in toluene (15 mL), and 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 in vacuo, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain a crude product, which was then subjected to reverse phase (8%) to obtain 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'-bipyridyl]-5'-yl)isoquinolin-1(2H)-one

[0762] The compound obtained in the previous step (60 mg, 0.21 mmol), (6-amino-5-(1-oxo-1,2-dihydroisoquinolin-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 tetrakistriphenylphosphine palladium (25 mg, 0.021 mmol), 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 in vacuo, and 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, using 2-bromo-5-chloro-4-methylpyridine instead of 5-bromo-2-chloro-4-methylpyridine.

[0766] Example 66 Synthesis of Compound 104

[0767]

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

[0769] Dissolve 6-bromoisoquinolin-1(2H)-one (50 mg, 0.23 mmol) in DMF, and add cesium carbonate (219 mg, 0.67 mmol) and iodomethane (21 ul, 0.34 mmol) to the mixed solvent in turn. Stir at room temperature for 4 h, detect the reaction completion, add water and EA to extract, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column to obtain the product (52 mg, 97%). MS (ESI): [M+H]+=238.2.

[0770] 66.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-2-methylisoquinolin-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-methylisoquinolin-1(2H)-one (52 mg, 0.22 mmol) and sodium carbonate (70 mg, 0.66 mmol) dioxane (3 mL) and water (0.6 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-methylisoquinolin-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-methylisoquinolin-1(2H)-one (61 mg, 0.19 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (92 mg, 0.28 mmol) and potassium carbonate (77 mg, 0.56 mmol) dioxane (5 mL) and water (1 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the product (21 mg, 25%). MS (ESI): [M+H] + =454.

[0773] Example 67 Synthesis of Compound 105

[0774]

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

[0776] Dissolve 6-chloro-3,4-dihydroisoquinolin-1(2H)-one (500mg, 2.21mmol) in THF, add TEA (921ul, 6.64mmol), (Boc)2O (737ul, 3.32mmol), DMAP (14mg, 0.11mml) in turn, and stir the reaction solution at room temperature for 3h. After the reaction is completed as monitored by LCMS, it is concentrated under reduced pressure and extracted with ethyl acetate and water. The organic phases are combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure to obtain a crude product. The product (626mg, 87%) is obtained. 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)-carboxylate

[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) and sodium carbonate (706 mg, 6.66 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80°C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-tetrahydroisoquinolin-6-yl)pyridin-3-yl)boronic acid

[0780] Under nitrogen protection, Pd(dppf)Cl2 (45 mg) was added to a mixture of tert-butyl 6-(2-amino-5-bromopyridin-3-yl)-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (510 mg, 1.22 mmol), B2Pin2 (472 mg, 1.83 mmol) and KoAc (359 mg, 3.66 mmol) in dioxane (10 mL). The reactants were stirred at 80°C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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'-bipyridyl]-5'-yl)-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate

[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-tetrahydroisoquinolin-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) and potassium carbonate (40 mg, 0.31 mmol) dioxane (5 mL) and water (1 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain 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'-bipyridyl]-5'-yl)-3,4-dihydroisoquinolin-1(2H)-one

[0784] Under nitrogen protection, tert-butyl 6-(6'-amino-6-methyl-5-(4-methylpiperazine-1-yl)-[2,3'-bipyridine]-5'-yl)-1-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (22 mg) was dissolved in DCM (2 ml), TFA (1 ml) was added, and the reaction solution was stirred at room temperature for 1 h. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified on a silica gel column to obtain the 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)pyridin-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)boronic acid (126 mg, 0.58 mmol), 6-bromoisoquinoline (100 mg, 0.48 mmol) and sodium carbonate (154 mg, 1.45 mmol) dioxane (3 mL) and water (0.6 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-(isoquinolin-6-yl)pyridin-2-amine

[0790] Under nitrogen protection, Pd(dppf)Cl2 (4 mg) was added to a mixture of 5-bromo-3-(isoquinolin-6-yl)pyridin-2-amine (20 mg, 0.07 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (27 mg, 0.08 mmol) and potassium carbonate (21.2 mg, 0.2 mmol) dioxane (2 mL) and water (0.4 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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)pyridin-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-bromonaphthalene-1-ol (250 mg, 1.13 mmol) and sodium carbonate (358 mg, 3.38 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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)naphthalen-1-ol

[0796] Under nitrogen protection, Pd(dppf)Cl2 (8 mg) was added to a mixture of 5-bromo-3-(isoquinolin-6-yl)pyridin-2-amine (40 mg, 0.13 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (63 mg, 0.19 mmol) and potassium carbonate (41 mg, 0.38 mmol) dioxane (2 mL) and water (0.4 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-fluoroisoquinolin-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-fluoroisoquinolin-1-ol (100 mg, 0.41 mmol) and sodium carbonate (132 mg, 1.24 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-fluoroisoquinolin-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-fluoroisoquinolin-1-ol (44 mg, 0.13 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (52 mg, 0.16 mmol) and potassium carbonate (42 mg, 0.40 mmol) dioxane (2 mL) and water (0.4 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-fluoroisoquinolin-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-fluoroisoquinolin-1(2H)-one (100 mg, 0.41 mmol) and sodium carbonate (132 mg, 1.24 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-fluoroisoquinolin-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-fluoroisoquinolin-1(2H)-one (30 mg, 0.08 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (45 mg, 0.15 mmol) and potassium carbonate (29 mg, 0.30 mmol) dioxane (2 mL) and water (0.4 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-methylisoquinolin-1-amine

[0811] Dissolve 6-bromo-1-chloroisoquinoline (100 mg, 0.41 mmol) in DMSO, add methylamine solution (49 ul, 1.24 mmol) and potassium carbonate (171 mg, 1.24 mmol) to the mixed solution in turn, fill with nitrogen, heat to 80 degrees Celsius to react for 4 hours, and detect that the reaction is complete. Extract with ethyl acetate and water, combine the organic phases, wash with brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified on a silica gel column to obtain the product (82 mg, 84.1%). MS (ESI): [M+H]+=237.72.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-N-methylisoquinolin-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-methylisoquinolin-1-amine (120 mg, 0.51 mmol) and sodium carbonate (162 mg, 1.53 mmol) dioxane (10 mL) and water (2 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-methylisoquinolin-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-methylisoquinolin-1-amine (55 mg, 0.17 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (66 mg, 0.20 mmol) and sodium carbonate (53 mg, 0.50 mmol) dioxane (2 mL) and water (0.4 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified on a silica gel column to obtain the 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-dimethylisoquinolin-1-amine

[0817] Dissolve 6-bromo-1-chloroisoquinoline (100 mg, 0.41 mmol) in DMSO, add dimethylamine solution (70 ul, 1.24 mmol) and sodium bicarbonate (104 mg, 1.24 mmol) to the mixed solution, fill with nitrogen, heat to 80 degrees Celsius for 4 hours, and detect that the reaction is complete. Extract with ethyl acetate and water, combine the organic phases, wash with brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column to obtain the product (55 mg, 52.9%). MS (ESI): [M+H]+=251.

[0818] 73.2 Synthesis of 6-(2-amino-5-bromopyridin-3-yl)-N,N-dimethylisoquinolin-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)boric acid (57 mg, 0.26 mmol), 6-bromo-N, N-dimethylisoquinolin-1-amine (55 mg, 0.22 mmol) and sodium carbonate (70 mg, 0.66 mmol) dioxane (5 mL) and water (1 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-dimethylisoquinolin-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-dimethylisoquinolin-1-amine (72 mg, 0.21 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (83 mg, 0.25 mmol) and sodium carbonate (67 mg, 0.63 mmol) dioxane (2 mL) and water (0.4 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified on a silica gel column to obtain the 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] Dissolve 6-bromoisoquinolin-1-ol (100 mg, 0.45 mmol) in methanol, add sodium methoxide solution (71 ul, 1.434 mmol) to the mixed solution, fill with nitrogen, heat to 80 degrees Celsius for 4 hours, and detect that the reaction is complete. Extract with ethyl acetate and water, combine the organic phases, wash with brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column to obtain the product (64 mg, 60.4%). MS (ESI): [M+H]+=238.

[0825] 74.2 Synthesis of 5-bromo-3-(1-methoxyisoquinolin-6-yl)pyridin-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) and sodium carbonate (86 mg, 0.81 mmol) dioxane (5 mL) and water (1 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-methoxyisoquinolin-6-yl)pyridin-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-dimethylisoquinolin-1-amine (25 mg, 0.08 mmol), 1-(2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine (30 mg, 0.09 mmol) and sodium carbonate (24 mg, 0.22 mmol) dioxane (2 mL) and water (0.4 ml). The reactants were stirred at 80 ° C overnight. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified on a silica gel column to obtain the 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-(piperidine-1-carbonyl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinolin-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-tetrahydroisoquinolin-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (4-bromo-2,6-dimethylphenyl)(piperidin-1-yl)methanone (46 mg, 0.16 mmol) and potassium carbonate (54 mg, 0.39 mmol) dioxane (3 mL) and water (0.6 ml). The reactants were stirred at 80 ° C overnight and the reaction was completed by TLC monitoring. After concentration under reduced pressure, 2 ml of TFA was added. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-(azetidine-1-carbonyl)-3,5-dimethylphenyl)pyridin-3-yl)-3,4-dihydroisoquinolin-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-tetrahydroisoquinolin-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (azetidin-1-yl(4-bromo-2,6-dimethylphenyl)methanone (42 mg, 0.16 mmol) and potassium carbonate (54 mg, 0.39 mmol) dioxane (3 mL) and water (0.6 ml). The reactants were stirred at 80°C overnight and the reaction was completed as monitored by TLC. After concentration under reduced pressure, 2 ml of TFA was added. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-dihydroisoquinolin-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-tetrahydroisoquinolin-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (R)-(4-bromo-2,6-dimethylphenyl)(2-methylpyrrolidin-1-yl)methanone (46 mg, 0.16 mmol) and potassium carbonate (54 mg, 0.39 mmol) dioxane (3 mL) and water (0.6 ml). The reactants were stirred at 80 ° C overnight and the reaction was completed by TLC monitoring. After concentration under reduced pressure, 2 ml of TFA was added. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the 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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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) and potassium carbonate (54 mg, 0.39 mmol) dioxane (3 mL) and water (0.6 ml). The reactants were stirred at 80 ° C overnight and the reaction was completed by TLC monitoring. After concentration under reduced pressure, 2 ml of TFA was added. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the product (35 mg, 64.8%). MS (ESI): [M+H]+=415.2.

[0844] Example 79 Synthesis of Compound 140

[0845]

[0846] 79.1 Synthesis of (S)-6-(2-amino-5-(3,5-dimethyl-4-(2-methylpyrrolidine-1-carbonyl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinolin-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-tetrahydroisoquinolin-6-yl)pyridin-3-yl)boronic acid (50 mg, 0.13 mmol), (S)-(4-bromo-2,6-dimethylphenyl)(2-methylpyrrolidin-1-yl)methanone (46 mg, 0.16 mmol) and potassium carbonate (54 mg, 0.39 mmol) dioxane (3 mL) and water (0.6 ml). The reactants were stirred at 80 ° C overnight and the reaction was completed by TLC monitoring. After concentration under reduced pressure, 2 ml of TFA was added. After the reaction was completed as monitored by LCMS, it was 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 a crude product. The crude product was purified by silica gel column to obtain the product (35 mg, 58.7%). MS(ESI):[M+H] + =455.2.

[0848] Other compounds can be synthesized by the same or similar methods as the above methods.

[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 = 2.3 Hz, 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] The compounds disclosed in the present invention can be prepared by methods similar to the preparation methods described in detail above or by conventional preparation methods in the art.

[1017] Test Example 1 Determination of HPK1 enzyme activity

[1018] Table 1 HPK1 enzyme activity assay reagents

[1019]

[1020] The positive reference drug PF-07265028, its preparation method refers 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% Brij-35, the DMSO solution concentrations of the positive reference drug PF-07265028: 20000nM, 4000nM, 800nM, 160nM, 32nM, 6.4nM, 1.28nM, 0.26nM, 0.05nM, 0nM, among which the compound concentration of 0nM group was the blank group, the DMSO solution concentrations of the test compounds: 20000nM, 4000nM, 800nM, 160nM, 32nM, 6.4nM, 1.28nM, 0.26nM, 0.05nM, 0nM, among which the compound concentration of 0nM group was the blank group.

[1023] Experimental steps: 4 μL kinase was added to a 384-well plate, 2 μL of Cpd solution of each concentration was added to each well, centrifuged at 1000 rpm for 1 min, shaken and incubated at room temperature for 10 min. 4 μL Mix was added to each well, centrifuged at 1000 rpm for 1 min, shaken at 37.5°C and 400 rpm for 60 min, the 384-well plate was taken out and placed at room temperature for 10 min. 10 μL ADP-Glo ​​Maxreagent was added to each well, centrifuged at 1000 rpm for 1 min, shaken at room temperature at 400 rpm for 40 min. 20 μL kinasedetection reagent was added to each well, centrifuged at 1000 rpm for 1 min, shaken at room temperature at 400 rpm for 30 min. Luminescence was read on an ELISA reader, and data was processed by 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 IC was obtained by curve fitting using the software GraphpadPrism8.0. 50 The experimental results of the compounds are shown in Table 2.

[1025]

[1026] Table 2 Inhibition results of compounds on HPK1 enzyme activity

[1027]

[1028]

[1029]

[1030]

[1031] It can be seen from the experimental results that the compounds of the present invention have a high inhibitory activity on HPK1 kinase.

Claims

1. A compound, wherein the compound is a compound represented by formula (I), or an isomer, isotope derivative, polymorph, prodrug, or pharmaceutically acceptable salt or solvate thereof: in: 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 a N atom, R3 is absent; when Y is a C atom, R6 is selected from H, F and Cl; when Y is a N atom, R6 is absent; preferably, Y is a C atom and Z is a C atom; or Y is a N atom and Z is a C atom; or Y is a C atom and Z is a N atom; The Cy1 ring is selected from a 3-20-membered cycloalkyl, a 3-20-membered heterocyclyl, a 6-20-membered aryl and a 5-20-membered heteroaryl; the 3-20-membered heterocyclyl and the 5-20-membered heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; preferably, the Cy1 ring is selected from a 5-12-membered cycloalkyl, a 5-15-membered heterocyclyl, a 6-12-membered aryl and a 5-15-membered heteroaryl, the 5-15-membered heterocyclyl and the 5-15-membered heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; more preferably, the Cy1 ring is selected from a phenyl and a 5-15-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and the heteroaryl is a monocyclic structure, a spirocyclic structure, a bridged ring structure or a condensed ring structure; R1 is a substituent at any position on the Cy1 ring, and each occurrence of R1 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, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 Aryl, C 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 S02R c , the C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-20 Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl and C 5-20 The heteroaryl group is optionally substituted by p independent R 1a replace; 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, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 Aryl, C 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 S02R c , the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-18 Cycloalkyl, C 3-18 Heterocycloalkyl, C 6-18 Aryl and C 5-18 The heteroaryl group is optionally substituted by p independent R 1a replace; More preferably, each occurrence of R1 is independently selected from the group consisting of: oxo (=O), halogen, cyano, carboxyl, hydroxyl, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 Aryl, C 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 S02R c , the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-15 Cycloalkyl, C 3-15 Heterocycloalkyl, C 6-15 Aryl and C 5-15 The heteroaryl group is optionally substituted by p independent R 1a replace R 1a Each occurrence is independently selected from: C 1-8 Alkyl, C 1-8 Alkoxy, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 Aryl, C 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, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 The heteroaryl group is optionally substituted by 0, 1, 2, 3 or 4 groups independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-8 Alkyl, and C 1-8 Substitution of alkoxy groups; Preferably, R 1a Each occurrence is independently selected from: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 Aryl, C 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, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 The heteroaryl group is optionally substituted by 0, 1, 2, 3 or 4 groups independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-6 Alkyl, and C 1-6 Substitution of alkoxy groups; More preferably, R 1a Each occurrence is independently selected from: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 Aryl, C 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, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-15 The heteroaryl group is optionally substituted by 0, 1, 2, 3 or 4 groups independently selected from halogen, cyano, carboxyl, hydroxyl, amino, nitro, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups; R 1b and R 1c Each independently selected from: H, hydroxyl, C 1-8 Alkyl, C 1-8 Alkoxy, -CH=C(C 1-8 alkyl), -CH=CH, -C≡C(C 1-8 alkyl), -C≡CH, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 heteroaryl; Preferably, R 1b and R 1c Each independently selected from: H, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -CH=C(C 1-6 alkyl), -CH=CH, -C≡C(C 1-6 alkyl), -C≡CH, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 heteroaryl; More preferably, R 1b and R 1c Each independently selected from: H, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -CH=C(C 1-3 alkyl), -CH=CH, -C≡C(C 1-3 alkyl), -C≡CH, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-15 heteroaryl; or R 1b and R 1c Together with the atoms they are connected to form C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 Aryl, C 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 Heterocycloalkyl, C 4-9 Fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 Cyclic lactam, C 3-7 Cyclic lactone and C 3-7 Cyclic ketone, wherein the C 3-20 Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl, C 5-20 Heteroaryl, C 3-20 Heterocycloalkyl, C 4-9 Fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 Cyclic lactam, C 3-7 Cyclic lactone and C 3-7 Cyclic ketone, q independently selected from hydroxyl, C 1-8 Alkyl, -SO2, -SO2N(C 1-10 Alkyl)(C 1-10 Alkyl), -SO2N(C 1-10 Alkyl)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)H, -OCONH2, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -N(C 1-10 Alkyl)(C 1-10 Alkyl), -NH(C 1-10 Alkyl), -NH2, -OC 1-10 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heteroaromatic, -O-heteroaromatic and -S-heteroaromatic substituents; Preferably, R 1b and R 1c Together with the atoms they are connected to form C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 Aryl, C 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 Heterocycloalkyl, C 4-9 Fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 Cyclic lactam, C 3-7 Cyclic lactone and C 3-7 Cyclic ketone, wherein the C 3-18 Cycloalkyl, C 3-18 Heterocycloalkyl, C 6-18 Aryl, C 5-18 Heteroaryl, C 3-18 Heterocycloalkyl, C 4-9 Fused cycloalkyl, C 5-10 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 3-7 Cyclic lactam, C 3-7 Cyclic lactone and C 3-7 Cyclic ketone, q independently selected from hydroxyl, C 1-6 Alkyl, -SO2, -SO2N(C 1-8 Alkyl)(C 1-8 Alkyl), -SO2N(C 1-8 Alkyl)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)H, -OCONH2, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -N(C 1-8 Alkyl)(C 1-8 Alkyl), -NH(C 1-8 Alkyl), -NH2, -OC 1-8 Alkyl, -OH, C 3-8 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heteroaromatic, -O-heteroaromatic and -S-heteroaromatic substituents; L1 and L2 are each independently selected from a single bond, -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)-, wherein the C 1-8 Alkylene and C 3-8 The cycloalkylene group is optionally substituted with 0, 1, 2, 3 or 4 R h Substitution; preferably, L1 is selected from a single bond, -C=N-, -O-, -C(O)-, -OC 1-8 Alkylene-, -C(O)-NH- and -NH-C(O)-; and / or L2 is selected from a single bond, -C=N-, -O-, -C(O)-, -OC 1-8 Alkylene-, -C(O)-NH-, and -NH-C(O)-; The Cy2 ring is selected from 3-20-membered cycloalkyl, 3-20-membered heterocyclyl, 6-20-membered aryl and 5-20-membered heteroaryl, wherein the 3-20-membered heterocyclyl and 5-20-membered heteroaryl each independently contain 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 heterocyclyl, 6-12-membered aryl and 5-15-membered heteroaryl, wherein the 5-12-membered heterocyclyl and 5-15-membered heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The aryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and the 5-12 membered heterocycloalkyl and 5-15 membered heteroaryl groups are monocyclic structures, bridged ring structures, spirocyclic structures or condensed ring structures; more preferably, the Cy2 ring is selected from phenyl and a 5-15 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and the 5-15 membered heteroaryl group is a monocyclic structure, bridged ring structure, spirocyclic structure or condensed ring structure; R4 is a substituent at any position on the Cy2 ring, and each occurrence of R4 is independently selected from: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Haloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 Aryl, C 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, C 3-20 Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl and C 5-20 The heteroaryl group is optionally substituted by r independent R 4a Substitution, wherein the heterocycloalkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure or a condensed ring structure; Preferably, R4 is independently selected from the group consisting of: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-20 Aryl, C 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 、-OR j 、-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, C 3-18 Cycloalkyl, C 3-18 Heterocycloalkyl, C 6-18 Aryl and C 5-18 The heteroaryl group is optionally substituted by r independent R 4a Substitution, wherein the heterocycloalkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure or a condensed ring structure; More preferably, R4 is independently selected from the group consisting of: oxo (=O), halogen, cyano, carboxyl, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Haloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 Aryl, C 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, C 3-15 Cycloalkyl, C 3-15 Heterocycloalkyl, C 6-15 Aryl and C 5-15 The heteroaryl group is optionally substituted by r independent R 4a Substitution, wherein the heterocycloalkyl group is a monocyclic structure, a bridged ring structure, a spirocyclic structure or a condensed ring structure; R 4a Each occurrence is independently selected from: halogen, oxo (=O), -C(O)R j , cyano, amino, hydroxyl, carboxyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, -C 1-8 Alkylene -CN, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 Heteroaryl, wherein the C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 The heteroaryl group is independently selected from hydroxy, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -SO2, C 1-8 Alkyl, -SO2N(C 1-10 Alkyl)(C 1-10 Alkyl), -SO2N(C 1-10 Alkyl)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), -NH2, -OC 1-10 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heterocycloaryl, -O-heterocycloaryl and -S-heterocycloaryl; Preferably, R 4a Each occurrence is independently selected from: halogen, oxo (=O), -C(O)R j , cyano, amino, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-6 Alkylene -CN, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 Heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 The heteroaryl group is independently selected from hydroxy, halogen, -CN, -OCH2F, -OCHF2, -OCF3, -SO2, C 1-6 Alkyl, -SO2N(C 1-6 Alkyl)(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)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), -NH2, -OC 1-6 Alkyl, -OH, C 3-10 Substitution of cycloalkyl, -O-heterocycloalkyl, -N-heterocycloalkyl, -N-heterocycloaryl, -O-heterocycloaryl and -S-heterocycloaryl; p, q, r and s are each independently 0, 1, 2, 3 or 4; 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 halogen; When R2 is not connected to B to form a ring, R2 is selected from NR e R f , F, Cl, Br and I, A is a single bond, B does not exist, and e is 1; R e and R f are each 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, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 Heteroaryl; preferably, R e and R f Each independently selected from H and C 1-8 alkyl; When R2 is connected to B and the atoms connected thereto form a ring structure, L1 is not a single bond, A is a C atom, and B is selected from CR a and N, preferably, B is CR a ; R2 is independently selected from CR at each occurrence a R b and NR c , preferably, R2 is NR c ; e is 0, 1, 2, 3, or 4, preferably, e is 1 or 2; R a , R b , R c , R d , R g , R h , R i , R j , R k and R m Each occurrence 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, C 3-20 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-20 Heterocycloalkyl, C 6-20 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-20 Heteroaryl, the C 3-20 Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl, and C 5-20 The heteroaryl group is optionally substituted by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxy, amino, nitro, C 1-8 Alkyl and C 1-8 Substitution of alkoxy groups; Preferably, R a , R b , R c , R d , R g , R h , R i , R j , R k and R m Each occurrence 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, C 3-18 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-18 Heterocycloalkyl, C 6-18 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-18 Heteroaryl, the C 3-18 Cycloalkyl, C 3-18 Heterocycloalkyl, C 6-18 Aryl, and C 5-18 The heteroaryl group is optionally substituted by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxy, amino, nitro, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; More preferably, R a , R b , R c , R d , R g , R h , R i , R j , R k and R m Each occurrence 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, C 3-15 Cycloalkyl, C containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S 3-15 Heterocycloalkyl, C 6-15 The aryl group and the C group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S are 5-15 Heteroaryl, the C 3-15 Cycloalkyl, C 3-15 Heterocycloalkyl, C 6-15 Aryl, and C 5-15 The heteroaryl group is optionally substituted by 0, 1, 2, 3, or 4 groups selected from halogen, cyano, carboxyl, hydroxy, amino, nitro, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups; When Y is a nitrogen atom, Z is a carbon atom, R2 is -NH2, R3 is H, and L1 is -CONH-, R4 is not -NH2, and -C 1-4 Alkoxy-NH2; or Partially not Partially not When Y is a N atom, Z is a C atom, R2 is -NH2, R3 is H, L2 is a single bond, Cy1 is selected from a 3- to 9-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur as one or more ring members, Cy2 is not When Y is a nitrogen atom, Z is a carbon atom, R2 is -NH2, R3 is H, L2 is a single bond, L1 is -O-, and Cy1 is When , Cy2 is not a benzene ring; When Y is a 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 When Y is a C atom, Z is a C atom, R3 is H, and L2 is a single bond, Partially not 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 When Y is a C atom, Z is a C atom, R2 is -NH2, R3 is H, R6 is H, L1 is a single bond, and Cy2 is a benzene ring, Partially not Or R4 is not -SO2R i , and -SO2N(R j )R k ; 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 When R4 is not cyano, -SO2R j R k 、-NR j S02R k , When m=1, R4 is not halogen and methoxy; when m=2, R4 is not all halogen; When Y is a C atom or a N atom, Z is a C atom, R2 is -NH2, R3 is H, and R6 is H, Part of When R4 is not 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 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 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 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 is methoxy and When Y is a C atom, Z is a C atom or a N atom, R2 is -NH2, L1 is a single bond, and the Cy1 ring is When the Cy2 ring is not When m=1, R4 is not cyano or in, represents the connection site, represents the position of the substitution on the ring.

2. The compound according to claim 1, wherein The Cy1 ring is selected from the group consisting of:

3. The compound according to any one of claims 1 to 2, wherein R1 is selected from oxo (=O), F, Cl, O, S, hydroxy, carboxyl, amino, cyano, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, C 1-8 Alkoxy, C containing N, O and S atoms 3-6 Heterocycloalkyl, -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, 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, -C(O)-NH-O-CH3, -C(O)-NH-OH, 4. The compound according to any one of claims 1 to 3, wherein 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, -S(O)2-NH-C 1-8 Alkyl, -C 1-8 Alkylene-OH, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, cyano, -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; 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 Haloalkoxy, 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, -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.

5. The compound according to any one of claims 1 to 4, wherein Selected from:

6. The compound according to any one of claims 1 to 5, wherein Cy2 is selected from:

7. A compound according to any one of claims 1 to 6, wherein Selected from:

8. The compound according to claim 1, wherein The compound is selected from:

9. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier or excipient.

10. Use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 for preparing a medicament for treating HPK1-mediated related diseases; preferably, the HPK1-mediated related diseases are cancer or tumors.

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