Quinazoline macrocyclic compound serving as HPK1 kinase inhibitor as well as preparation method and application of quinazoline macrocyclic compound

Abstract

The invention relates to the field of biological medicine, in particular to a plurality of macrocyclic compounds serving as HPK1 kinase inhibitors as well as a preparation method and application of the macrocyclic compounds.

Description

[0001] This application claims the priority benefit of application number 202310804741.4 filed on July 1, 2023, the contents of which are incorporated herein in their entirety. Technical Field

[0002] The present application relates to the field of biomedicine, and specifically to a quinazoline macrocyclic compound as an HPK1 kinase inhibitor, and a preparation method and use thereof. Background Art

[0003] Cancer immunotherapy is a treatment approach that harnesses the body’s own immune system to help fight cancer. In recent years, such unique approaches have achieved remarkable clinical success in treating a variety of tumor types, particularly with the application of immune checkpoint inhibitors and chimeric antigen T cell therapy. The two most studied classes of checkpoint blockers, namely CTLA4 and PD-1 inhibitors, have demonstrated significant antitumor activity by overcoming immunosuppressive mechanisms at the tumor site. CTLA4 blockade enhances T cell activation primarily during the initiation phase of the immune response, while PD-1 inhibitors release activated effector T cell populations and reduce regulator T cell function. While these monoclonal antibody-based T cell interventions have proven effective, the utility of this approach is limited because they can only target receptors on the cell surface. In contrast, small molecule T cell activators offer the opportunity to target both extracellular and intracellular immune targets, including kinases. In addition, inhibition of immunosuppressive kinases has the potential to directly activate T cells, thereby bypassing checkpoint inhibitory pathways and overcoming intrinsic and acquired resistance to checkpoint receptor blockers. Hematopoietic progenitor kinase 1 (HPK1; also known as mitogen-activated protein kinase 1 (MAP4K1)) is a member of the germinal center kinase family of serine / threonine kinases and is expressed primarily by hematopoietic cells in T cells. In T cells, HPK1 has been reported to phosphorylate SLP76 (serine 376) after triggering the T cell receptor (TCR) and inducing binding of SLP76 to 14-3-3 proteins. Knockout of HPK1 expression in Jurkat T cells has been reported to increase TCR-induced IL2 gene activation. Furthermore, antigen-stimulated T cells from HPK1-deficient mice proliferate more vigorously and produce more cytokines than antigen-stimulated T cells from wild-type mice. Importantly, HPK1-deficient mice develop a more severe form of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. HPK1-knockout dendritic cells (DCs) have shown enhanced antigen presentation function both in vitro and in vivo. In particular, both HPK1 knockout T cells and HPK1 knockout DC cells were associated with tumor rejection in a mouse model of lung cancer. These findings confirm HPK1 as a new target for anticancer immunotherapy. Therefore, inhibiting HPK1 with small molecule inhibitors has the potential to be a treatment for cancer and other diseases. The compounds disclosed herein can be used for the potential treatment or prevention of HPK1-related diseases. Summary of the invention

[0004] The present application provides a class of quinazoline macrocyclic compounds or pharmaceutically acceptable salts thereof, which are inhibitors of hematopoietic progenitor kinase 1 (HPK1). The present application also discloses the use of these compounds in the potential treatment or prevention of HPK1-related diseases or conditions. The present application also discloses compositions comprising one or more compounds. The present application further discloses the use of these compositions in the potential prevention or treatment of HPK1-related diseases.

[0005] In one aspect, the present application provides a compound of formula I:

[0006]

[0007] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein,

[0008] X 1 is -O-, -NH- or -S-;

[0009] X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene;

[0010] Ring A and Ring B are each independently selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl;

[0011] R1, R2, R3 and R4 are each independently selected from:

[0012] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0013] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0014] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following:1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0015] iv. Alternatively, R1 and R2 together with the ring A to which they are connected, or R3 and R4 together with the ring B to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0016] Preferably, the fused ring group has any of the following structures:

[0017]

[0018] R5, R6 and R7 are each independently selected from:

[0019] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0020] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0021] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0022] L is selected from -(CH2) p-C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、

[0023] and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from:

[0024] i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0025] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0026] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0027] L or selected from:

[0028] R 20Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

[0029] In one aspect, the present application provides a compound of formula II:

[0030]

[0031] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein:

[0032] X 1 is -O-, -NH- or -S-;

[0033] X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene;

[0034] A ring is selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl;

[0035] R1, R2, R3 and R4 are each independently selected from:

[0036] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0037] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0038] iii.C 3-8 Cycloalkyl, C 3-8Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0039] iv. Alternatively, R1 and R2 together with the ring A to which they are connected, or R3 and R4 together with the benzene ring to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0040] Preferably, the fused ring group has any of the following structures:

[0041]

[0042] R5, R6 and R7 are each independently selected from:

[0043] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0044] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0045] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0046] L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、

[0047] and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from:

[0048] i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0049] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0050] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0051] L or selected from:

[0052] R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

[0053] In one aspect, the present application provides a compound of formula III:

[0054]

[0055] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein:

[0056] X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene;

[0057] A ring is selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl;

[0058] R1, R2, R3 and R4 are each independently selected from:

[0059] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0060] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0061] iii.C3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0062] iv. Alternatively, R1 and R2 together with the ring A to which they are connected, or R3 and R4 together with the benzene ring to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0063] Preferably, the fused ring group has any of the following structures:

[0064]

[0065]

[0066] R5, R6 and R7 are each independently selected from:

[0067] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0068] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0069] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0070] L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、

[0071] and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from:

[0072] i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0073] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0074] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0075] L or selected from:

[0076] R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

[0077] In one aspect, the present application provides a compound of formula IV:

[0078]

[0079] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein:

[0080] X 1 is -O-, -NH- or -S-;

[0081] X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene;

[0082] B ring is selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl;

[0083] R1, R2, R3 and R4 are each independently selected from:

[0084] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0085] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0086] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0087] iv. Alternatively, R1 and R2 together with the benzene ring to which they are connected, or R3 and R4 together with the ring B to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0088] Preferably, the fused ring group has any of the following structures:

[0089]

[0090] R5, R6 and R7 are each independently selected from:

[0091] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0092] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0093] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0094] L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、

[0095] and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from:

[0096] i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0097] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0098] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0099] L or selected from:

[0100] R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

[0101] In one aspect, the present application provides a compound of formula V:

[0102]

[0103] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein:

[0104] X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene;

[0105] B ring is selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl;

[0106] R1, R2, R3 and R4 are each independently selected from:

[0107] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0108] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0109] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0110] iv. Alternatively, R1 and R2 together with the benzene ring to which they are connected, or R3 and R4 together with the ring B to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0111] Preferably, the fused ring group has any of the following structures:

[0112]

[0113] R5, R6 and R7 are each independently selected from:

[0114] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0115] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0116] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0117] L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、

[0118] and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from:

[0119] i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0120] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0121] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0122] L or selected from:

[0123] R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

[0124] In one aspect, the present application provides a compound of formula VI:

[0125]

[0126] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein:

[0127] X 1 is -O-, -NH- or -S-;

[0128] X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene;

[0129] R1, R2, R3 and R4 are each independently selected from:

[0130] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0131] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0132] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0133] iv. Alternatively, R1 and R2 together with the benzene ring to which they are connected, or R3 and R4 together with the benzene ring to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0134] Preferably, the fused ring group has any of the following structures:

[0135]

[0136] R5, R6 and R7 are each independently selected from:

[0137] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0138] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0139] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0140] L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、

[0141] and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from:

[0142] i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0143] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0144] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0145] L or selected from:

[0146] R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

[0147] In one aspect, the present application provides a compound of formula VII:

[0148]

[0149] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein:

[0150] X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene;

[0151] R1, R2, R3 and R4 are each independently selected from:

[0152] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0153] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0154] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0155] iv. Alternatively, R1 and R2 together with the benzene ring to which they are connected, or R3 and R4 together with the benzene ring to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0156] Preferably, the fused ring group has any of the following structures:

[0157]

[0158] R5, R6 and R7 are each independently selected from:

[0159] i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0160] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0161] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0162] L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、

[0163] and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from:

[0164] i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy;

[0165] ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy;

[0166] iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3;

[0167] L or selected from:

[0168] R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

[0169] In certain embodiments, -X in the above formula I to formula VII 2 -L-Selected from-C 1-6 Alkylene-N(R 16 )-C(O)-、-C 1-6 Alkenylene-N(R 16 )-C(O)-、-OC 1-6 Alkylene- and -OC 1-6 Alkenylene-, where R 16 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

[0170] In certain embodiments, -X in the above formula I to formula VII 2 -L-Selected from-C 1-6 Alkylene-NH-C(O)-, -C 1-6 Alkenylene-NH-C(O)-, -OC 1-6 Alkylene- and -OC 1-6 Alkenylene-.

[0171] In certain embodiments, -X in the above formula I to formula VII 2 -L- is selected from -CH2-CH2-NH-C(O)-, -CH2-CH2-CH2-NH-C(O)-, -CH=CH-CH2-NH-C(O)-, -O-CH2-CH2-CH2-CH2- and -O-CH2-CH2-CH-CH-.

[0172] In certain embodiments, R1, R2, R3 and R4 in the above formula I to formula VII are each independently selected from hydrogen, halogen, -C(O)-NR a R b, optionally substituted with C 1-6 alkyl, heteroaryl, optionally substituted with hydroxyl 1-6 Alkyl and Where R a and R b Each independently selected from H and C 1-6 alkyl, m and n are each independently selected from: 0, 1, 2, 3, 4, 5 or 6, R8 and R9 are each independently selected from H, di(C 1-6 alkyl)amino or mono(C 1-6 Alkyl)amino.

[0173] In certain embodiments, R1 and R2 in the above formula I to formula VII are each independently selected from halogen, -C(O)-NR a R b and C optionally substituted with a hydroxyl group 1-6 Alkyl, where R a and R b Each independently selected from H and C 1-6 Alkyl; R3 and R4 are each independently selected from hydrogen, -C(O)-NR a R b , optionally substituted with C 1-6 Alkyl heteroaryl and Where R a and R b Each independently selected from H and C 1-6 alkyl, m and n are each independently selected from: 0, 1, 2, 3, 4, 5 or 6, R8 and R9 are each independently selected from H, di(C 1-6 alkyl)amino or mono(C 1-6 Alkyl)amino.

[0174] In certain embodiments, R1 in the above formula I to formula VII is halogen; R2 is -C(O)NR a R b or optionally substituted with hydroxyl C 1-6 Alkyl, where R a and R b Each independently selected from H and C 1-6 Alkyl; R3 is Optionally substituted with C 1-6 Alkyl heteroaryl and -C(O)-NR a R b , wherein m and n are each independently selected from: 0, 1, 2, 3, 4, 5 or 6, R8 and R9 are each independently selected from H, di(C 1-6 alkyl)amino or mono(C 1-6 alkyl)amino; R4 is H.

[0175] In certain embodiments, R5, R6 and R7 in the above formula I to formula VII are each independently selected from hydrogen, halogen, -C(O)-NR a R b , optionally substituted with C 1-6 alkyl, heteroaryl, optionally substituted with hydroxyl 1-6 Alkyl and Where R a and R b Each independently selected from H and C 1-6 alkyl, m and n are each independently selected from: 0, 1, 2, 3, 4, 5 or 6, R8 and R9 are each independently selected from H, di(C 1-6 alkyl)amino or mono(C 1-6 Alkyl)amino.

[0176] In certain embodiments, R5 and R7 in the above formula I to formula VII are hydrogen; R6 is selected from halogen, -C(O)-NR a R b , optionally substituted with C 1-6 alkyl, heteroaryl, optionally substituted with hydroxyl 1-6 Alkyl and Where R a and R b Each independently selected from H and C 1-6 alkyl, m and n are each independently selected from: 0, 1, 2, 3, 4, 5 or 6, R8 and R9 are each independently selected from H, di(C 1-6 alkyl)amino or mono(C 1-6 Alkyl)amino.

[0177] In certain embodiments, R5 and R7 in the above formula I to formula VII are hydrogen; and R6 is halogen.

[0178] In certain embodiments, the present invention provides the following compounds:

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186] or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof.

[0187] On the other hand, the present application provides a pharmaceutical composition comprising the compound described in the present application, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof; and a pharmaceutically acceptable carrier.

[0188] On the other hand, the present application provides the use of the compound in the preparation of a medicament for preventing and / or treating HPK1-mediated diseases, including various HPK1-related diseases including autoimmune diseases, inflammatory diseases, tumors, pathogenic infectious diseases, etc.

[0189] Preferably, the drug is used to prevent, diagnose or treat HPK1-mediated tumors, including at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, colorectal cancer, ovarian cancer, pancreatic cancer, hematological malignancies, renal cell carcinoma, malignant melanoma, neuroblastoma and mammary secretory carcinoma.

[0190] Preferably, the administration of the drug includes at least one of oral, intradermal injection, subcutaneous injection, application to the skin, parenteral, and rectal administration.

[0191] Those skilled in the art can easily discern other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of the present application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which the present application relates. Accordingly, the description in the present application specification is merely exemplary and not restrictive. DETAILED DESCRIPTION

[0192] Unless otherwise indicated, the following terms are used throughout the disclosure of the present invention:

[0193] The term "prodrug" refers to any derivative that can be converted into a corresponding active pharmaceutical compound in vivo. Prodrugs of the compounds described herein are easily chemically changed under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0194] The term "pharmaceutically acceptable salt", unless otherwise indicated, includes salts of acidic groups (such as, but not limited to, potassium, sodium, magnesium, calcium, etc.) or basic groups (such as, but not limited to, formates, acetates, citrates, tartrates, methanesulfonates, malates or sulfates, hydrochlorides, phosphates, nitrates, carbonates, etc.) which may be present in the compounds of the invention.

[0195] The term "solvate" refers to a complex molecular compound formed in a solution when solute molecules or ions attract adjacent solvent molecules through intermolecular forces such as Coulomb force, van der Waals force, charge transfer force, hydrogen bond, etc. In one embodiment, the solvent is water, that is, the compound of the present invention forms a hydrate.

[0196] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms, defined as (R)- or (S)-, or as (D)- or (L)- configurations in terms of the absolute stereochemical configuration of the amino acids. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be obtained using chiral synthesis or chiral preparation, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors, resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). The present invention provides pure isomers and isomer mixtures, as well as methods for their preparation and use, and compositions comprising them.

[0197] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetautomers) include interconversions performed by the reorganization of some bonding electrons.

[0198] The term "halogen" herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0199] The term "alkyl" herein refers to a hydrocarbon group selected from a straight chain saturated hydrocarbon group and a branched chain saturated hydrocarbon group, which contains 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8 or 1 to 6 or 1 to 4) carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0200] The term "alkenyl" herein refers to a hydrocarbon group selected from a straight chain hydrocarbon group and a branched hydrocarbon group, which contains at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Examples of alkenyl groups are, for example, C 2-6 Alkenyl groups include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0201] The term "cycloalkyl" herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, which includes monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, cycloalkyl may contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4) carbon atoms. Even further, for example, cycloalkyl may be selected from monocyclic groups containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, examples of saturated monocyclic cycloalkyl groups are C 3-8Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, cycloalkyl is a monocyclic ring (abbreviated as C 3-6 Cycloalkyl) including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyls include those having 7 to 12 ring atoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, or a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Other examples of bicyclic cycloalkyls include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems, such as wherein the wavy line indicates the point of attachment. The ring may be saturated or have at least one double bond (ie, partially unsaturated), but is not fully conjugated and is not aromatic as aromatic is defined herein.

[0202] The term "aryl", used alone or in combination with other terms, refers to a group selected from:

[0203] a. 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0204] b. a bicyclic ring system, such as a 7- to 12-membered bicyclic ring system, in which at least one ring is carbocyclic and aromatic, such as naphthyl; and

[0205] c. A tricyclic ring system, such as a 10- to 15-membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0206] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a benzene ring. In some embodiments, the aromatic hydrocarbon ring is a benzene ring.

[0207] The term "heteroaryl" herein refers to a group selected from:

[0208] a. a 5-, 6- or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S) and oxygen (O) (as one or more ring atoms), the remaining ring atoms being carbon;

[0209] b. a 7- to 12-membered bicyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O and S (as one or more ring atoms), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0210] c. an 11- to 14-membered tricyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O and S (as one or more ring atoms), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0211] In a preferred embodiment, the heteroaryl group is a 5- to 6-membered heteroaryl group comprising one nitrogen atom and 0 or 1 additional heteroatom selected from N, O and S, including but not limited to pyridyl, isoxazolyl and oxazolyl.

[0212] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not greater than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group can be oxidized to form N-oxides.

[0213] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5-6 membered heteroaryl ring, which is a monocyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8-10 membered heteroaryl ring, which is a bicyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[0214] Examples of heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (numbered from the attachment position designated as priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, yl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3, 4-triazolyl), quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thiazolyl -2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzophenylthio, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

[0215] The term "heterocyclic" or "heterocycle" or "heterocyclyl" herein refers to a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered monocyclic, bicyclic and tricyclic saturated and partially unsaturated rings, which contains at least one carbon atom and at least one heteroatom, such as 1 to 4 heteroatoms, further such as 1 to 3 heteroatoms or further such as 1 or 2 heteroatoms, these heteroatoms are selected from nitrogen (N), sulfur (S), oxygen (O), -SO- or -SO2 (as one or more ring atoms).

[0216] In some embodiments, the heterocyclic group is a 4, 5, 6, 7 or 8-membered monocyclic ring with at least one heteroatom selected from N, O and S. In some preferred embodiments, the heterocyclic group is a 4, 5, 6, 7 or 8-membered saturated monocyclic ring containing a nitrogen heteroatom. Exemplary heterocyclic groups are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl and azocyclooctanyl. In other embodiments, the heterocyclic group is a 5, 6, 7 or 8-membered saturated monocyclic ring containing a nitrogen atom and 1 additional heteroatom selected from -NH, -O-, -S-, -SO- or -SO2-. Exemplary heterocyclic groups are morpholino, morpholinyl or piperazinyl rings. In some embodiments, the heterocyclic group is a 7 to 12-membered saturated bicyclic ring containing a nitrogen atom and 0 or 1 or 2 additional heteroatoms selected from -NH, -O-, -S-, -SO- or -SO2-. In some preferred embodiments, the heterocyclic group is a bicyclic bridged ring or a spiro ring.

[0217] "Heterocycle" herein also refers to a 5- to 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S fused to a 5, 6 and / or 7-membered cycloalkyl, carbocyclic aromatic ring or heteroaromatic ring, provided that the entire ring structure is non-aromatic. The heterocyclic ring is not a heteroaryl as defined herein. In a preferred embodiment, the heterocyclic group is a 5- to 6-membered heterocyclic group containing one nitrogen atom and 0 or 1 additional heteroatoms selected from N, O and S, including but not limited to pyrrolyl, dihydropyridine, morpholino, morpholinyl and tetrahydropyranyl.

[0218] Examples of heterocycles include, but are not limited to (numbered from the attachment position designated as priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thioethanethiol, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thiooxanyl, piperazinyl, homopiperazinyl, homo piperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiinyl, 1,4-oxathiinyl, 1,4-oxazepanyl, 1,4-dithiinyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepanyl, diazepinyl, thiazepinyl, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolazinyl, 2-pyrrolazinyl, 3-pyrrolazinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, 1,1-dioxo-thiomorpholinyl, 3-azabis(1,4-dioxo- ... cyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, tetrahydro-1H-pyrrolazin-7-yl, tetrahydro-1H-furo[3,4-b]pyrrol-3a-yl, tetrahydro-1H-furo[3,4-c]pyrrol-3a-yl, tetrahydro-1H-furo[3,4-b]pyrrol-6a-yl\octahydrocyclopenta[b]pyrrol-6a-yl, octahydrocyclopenta[c]pyrrol-3a-yl, octahydrocyclopenta[b]pyrrol-3a-yl, 3-azabicyclo[3.1.0]hexan-1-yl or 2-azabicyclo[3.1.0]hexan-1-yl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0219] In some embodiments, the heterocyclyl is a non-aromatic fused bicyclic heterocyclyl, such as the fused bicyclic heterocycles listed above; and such as the non-aromatic fused bicyclic heterocyclyls below.

[0220] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0221] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0222] The term "integer from 0 to 10" refers to 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0223] When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and R in each case has independent options. In addition, combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds. The term "one or more" disclosed herein includes, for example, 1 to 5 (e.g., 1 to 4, further such as 1, 2 or 3) substituents, provided that valence permits.

[0224] Embodiment 1:

[0225] Step 1: Preparation of intermediate TM1-5A

[0226]

[0227] Synthesis of compound TM1-9: Compound TM1-8 (4.50 g, 18.1 mmol, 1.00 eq) was dissolved in tetrahydrofuran (45 mL), and then 45 mL of an aqueous solution of sodium hydroxide (2.18 g, 54.4 mmol, 3.00 eq) was added, and the mixture was reacted at room temperature for 20 hours. After the reaction monitoring was completed, 4 M aqueous hydrochloric acid solution was added to adjust the pH to 4, and then ethyl acetate and water were added for extraction. The organic layer was dried and concentrated to obtain compound TM1-9 (4.2 g, yield: 98.93%, yellow solid) LCMS: (M+1) +:233.8, directly used in the next reaction.

[0228] Synthesis of compound TM1-10: Compound TM1-9 (4.20 g, 18.0 mmol, 1.00 eq) and compound 9A (3.64 g, 53.8 mmol, 3.00 eq) were dissolved in N,N-dimethylformamide (80 mL), and then N,N-diisopropylethylamine (9.28 g, 71.8 mmol, 4.00 eq) was added. 1-hydroxybenzotriazole (2.67 g, 19.7 mmol, 1.10 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.47 g, 23.3 mmol, 1.30 eq) were added under ice bath, and the temperature was slowly raised to room temperature for 16 hours. After the reaction monitoring was completed, ethyl acetate and water were added for extraction. The organic phase was back-extracted twice with saturated brine, concentrated, and purified by normal phase (petroleum ether: ethyl acetate = 1:1) to obtain compound TM1-10 (4.1 g, yield: 92.46%, yellow solid), LCMS: (M+1) + :247.0.

[0229] Synthesis of compound TM1-5A: Compound TM1-10 (1.50 g, 6.07 mmol, 1.00 eq), 10A (1.68 g, 6.68 mmol, 1.10 eq), cesium carbonate (5.93 g, 18.2 mmol, 3.00 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (579 mg, 1.21 mmol, 0.200 eq), palladium acetate (136 mg, 0.607 mmol, 0.100 eq) were added to 1,4-dioxane (45 mL) and water (4.5 mL), and the atmosphere was replaced with nitrogen three times. The reaction was carried out at 100°C for 12 hours. After the reaction monitoring was completed, ethyl acetate and water were added for extraction. After the organic phase was dried, the sample was mixed and purified by normal phase (petroleum ether: ethyl acetate = 1:2) to obtain compound TM1-5A (1 g, yield: 53%, yellow solid), LCMS: (M+1) + :312.2.

[0230] Step 2: Preparation of the final product TM1

[0231]

[0232] Synthesis of compound TM1-2: 2-fluoro-5-nitrobenzoic acid (5.0 g, 27.0 mmol, 1.00 eq) and Boc anhydride (14.7 g, 67.5 mmol, 2.50 eq) were dissolved in tetrahydrofuran (20 mL) and tert-butyl alcohol (20 mL), 4-dimethylaminopyridine (1.65 g, 13.5 mmol, 0.50 eq) was added in batches under an ice bath, nitrogen was replaced three times, and the reaction was carried out at room temperature for 4 hours. After the reaction monitoring was completed, ice water was added to the reaction solution to quench, ethyl acetate was extracted three times, the organic phase was spin-dried, the sample was mixed, and normal phase purification (petroleum ether: ethyl acetate = 10:1) was obtained to obtain compound TM1-2 (3.67 g, yellow liquid, yield 56%), LCMS: (M-100) + :141.1.

[0233] Synthesis of compound TM1-3: 2-fluoro-5-nitrobenzoic acid tert-butyl ester (3.76 g, 15.6 mmol, 1.00 eq) was dissolved in 40 mL of acetonitrile, and N1, N1, N2-trimethylethane-1,2-diamine (2.39 g, 23.4 mmol, 1.50 eq) and potassium carbonate (5.39 g, 39.0 mmol, 2.50 eq) were added under stirring in a water bath, and nitrogen was replaced three times, and the reaction was carried out at 30°C for 2 hours. After the reaction monitoring was completed, water and ethyl acetate were added to the reaction solution, extracted three times, and back-extracted once with saturated brine. After the organic phase was dried over anhydrous sodium sulfate, compound TM1-3 (4.50 g, orange liquid, yield 89%) was obtained, LCMS: (M+1) + :324.3.

[0234] Synthesis of compound TM1-4: Dissolve tert-butyl 2-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitrobenzoate (4.67 g, 14.4 mmol, 1.00 eq) in ethyl acetate (60 mL), add palladium carbon (1.50 g, 14.1 mmol, 10% content, 0.976 eq), replace with hydrogen three times, and react at room temperature for 6 hours. After the reaction monitoring is completed, the reaction solution is filtered through diatomaceous earth and dried to obtain compound TM1-4 (3.90 g, yellow solid, yield 92%), LCMS: (M+1) + :294.4.

[0235] Synthesis of compound TM1-5: 8-bromo-2-chloro-6-fluoroquinazoline (637 mg, 2.43 mmol, 1.00 eq) was dissolved in ethanol (6 mL) and water (6 mL), p-toluenesulfonic acid (463 mg, 2.43 mmol, 1.00 eq) was added, and the mixture was stirred at 90 °C for 30 minutes. After cooling to room temperature, tert-butyl 5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoate (750 mg, 2.56 mmol, 1.05 eq) in ethanol (6 mL) and water (6 mL) was added, and the mixture was reacted at 90 °C for 14 hours. After the reaction monitoring was completed, the reaction mixture was cooled to room temperature, the reaction solution was spin-dried, ethyl acetate was used for slurrying, and the obtained filter cake was dissolved in 15 mL of sodium bicarbonate (204 mg, 2.43 mmol, 1.00 eq) aqueous solution and allowed to stand for 1 hour under an ice bath. A large amount of yellow solid precipitated. After filtration, the filter cake was freeze-dried to obtain compound TM1-5 (550 mg, orange solid, yield 44%), LCMS: (M+1) + :462.1.

[0236] Synthesis of compound TM1-6: 5-((8-bromo-6-fluoroquinazolin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoic acid (300 mg, 0.579 mmol, 1.00 eq), tert-butyl (2-amino-3-fluoro-5-(methylcarbamoyl)phenethyl)carbamate (295 mg, 1.24 mmol, 1.50 eq), cesium carbonate (566 mg, 1.74 mmol, 3.00 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (72.1 mg, 0.116 mmol, 0.200 eq) and tris(dibenzylideneacetone)dipalladium (53.0 mg, 0.0579 mmol, 0.1 eq) were dissolved in 1,4-dioxane (6 mL), replaced with nitrogen three times, and reacted at 120°C for 22 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was spin-dried, mixed, and purified by normal phase purification (dichloromethane (0.1% triethylamine): methanol = 5:1) to obtain the product TM1-6 (300 mg, yellow solid, yield 69%), LCMS: (M+1) + :693.4.

[0237] Synthesis of compound TM1-7: 5-((8-((2-(2-((tert-butoxycarbonyl)amino)ethyl)-6-fluoro-4-(methylcarbamoyl)phenyl)amino)-6-fluoroquinazolin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoic acid (150 mg, 0.216 mmol, 1.00 eq) was dissolved in 1 mL of 1,4-dioxane, 4 M hydrochloric acid dioxane solution (7 mL) was added, and the mixture was reacted at room temperature for 1 hour. After the reaction monitoring was completed, the reaction solution was dried to obtain compound TM1-7 (150 mg, hydrochloride, orange solid, yield 99%), LCMS: (M+1) + :593.6.

[0238] Synthesis of compound TM1: 5-((8-((2-(2-aminoethyl)-6-fluoro-4-(methylcarbamoyl)phenyl)amino)-6-fluoroquinazolin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoic acid (150 mg, 0.238 mmol, 1.00 eq) was dissolved in N,N-dimethylformamide (15 mL), replaced with nitrogen three times, and N,N-diisopropylethylamine (0.197 mL, 1.19 mmol, 5.00 eq) and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (99.3 mg, 0.191 mmol, 0.800 eq) in N,N-dimethylformamide (1 mL) were added dropwise under ice bath, and the reaction was carried out at room temperature for 16 hours. After the reaction monitoring was completed, the reaction solution was purified by high pressure preparation (water (0.225% formic acid): acetonitrile = 3:1)) to obtain compound TM1 (22.0 mg, yellow solid, 97% purity, yield 14.1%). LCMS: (M+1) + :593.6. 1 H NMR (400MHz, DMSO-d6) δ9.96(s,1H),9.21(s,1H),8.88(d,J=2.7Hz,1H),8.49(dd,J=9.0,4.4Hz,1H),8.22(s,1H),7.93(s,1H),7.74(d,J=

[0239] 1.4Hz,1H),7.56(dd,J=12.4,1.8Hz,1H),7.11(dd,J=8.7,2.7Hz,1H),7.04(dd,J=8.7,2.6Hz,1H),6.95(d,J=8.8Hz,1H),6.49(ddd,J=11.0 ,5.0,2.6Hz,1H),3.12(d,J=7.2Hz,2H),3.00(s,2H),2.80(d,J=4.5Hz,3H),2.71(s,3H),2.55–2.52(m,2H),2.46–2.41(m,3H),2.17(s,6H).

[0240] Embodiment 2:

[0241] Step 1: Preparation of intermediate TM2-5A

[0242]

[0243] Synthesis of compound TM2-8: Compound TM1-10 (3.00 g, 12.1 mmol, 1.0 eq) and compound 8A (3.44 g, 12.1 mmol, 1.0 eq) were dissolved in 1,4-dioxane (60 mL) and water (12 mL), potassium carbonate (5.03 g, 36.4 mmol, 3.0 eq) and Pd(dppf)Cl2 (888 mg, 1.21 mmol, 0.1 eq) were added, nitrogen was replaced three times, and the mixture was reacted at 90°C for 14 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was filtered using diatomaceous earth, the filtrate was concentrated under reduced pressure, silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) was performed to obtain compound TM2-8 (4.20 g, yellow solid, yield 79%), LCMS: (M+1) + :324.1.

[0244] Synthesis of compound TM2-5A: Compound TM2-8 (1.20 g, 3.71 mmol, 1.0 eq) was dissolved in tetrahydrofuran (60 mL), and then palladium carbon (600 mg, 5.64 mmol, 1.5 eq) was added, and hydrogen was replaced three times, and the reaction was carried out at room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered using diatomaceous earth, and the filtrate was dried under vacuum to obtain compound TM2-5A (1.10 g, white solid, yield 91%), LCMS: (M+1) + :326.5.

[0245] Step 2: Preparation of the final product TM2

[0246]

[0247] Synthesis of compound TM2-2: Dissolve compound TM2-1 (5.00 g, 25.9 mmol, 1.0 eq) in tetrahydrofuran (15 mL), replace with nitrogen, and add dimethylamine (2M tetrahydrofuran solution) (25.9 mL, 51.8 mmol, 2.0 eq) dropwise under ice bath. After the addition is complete, react at room temperature for 3 hours. After the reaction monitoring is completed, the reaction solution is dried under vacuum, tetrahydrofuran (30 mL) is added, stirred for 5 minutes, filtered, and the filter cake is dried to obtain a crude compound TM2-2 (3.90 g, yellow liquid, yield 63%).

[0248] Synthesis of compound TM2-3: Compound TM2-2 (3.75 g, 6.30 mmol, 1.0 eq) was dissolved in tetrahydrofuran (15 mL) and tert-butyl alcohol (15 mL), and 4-dimethylaminopyridine (385 mg, 3.15 mmol, 0.5 eq) and di-tert-butyl dicarbonate (3.44 g, 15.7 mmol, 2.5 eq) were added under stirring in a water bath, and nitrogen was replaced, and stirred at room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was concentrated under reduced pressure, silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) were performed to obtain compound TM2-3 (850 mg, white solid, yield 46%), LCMS: (M-100+1) + :238.9.

[0249] Synthesis of compound TM2-4: Compound TM2-3 (400 mg, 1.36 mmol, 1.0 eq) was dissolved in ethyl acetate (15 mL), palladium carbon (200 mg, 1.88 mmol, 1.4 eq) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was dried under vacuum to obtain compound TM2-4 (320 mg, white solid, yield 89%), LCMS: (M+1) + :265.2.

[0250] Synthesis of compound TM2-5: Compound TM2-4 (578 mg, 2.19 mmol, 1.1 eq) and compound TM1-4A (520 mg, 1.99 mmol, 1.0 eq) were added to isopropanol (13 mL), and trifluoroacetic acid (1.13 g, 9.94 mmol, 5.0 eq) was added thereto. After nitrogen replacement three times, the reaction was carried out at 90 ° C for 4 hours. After the reaction monitoring was completed, ethyl acetate (50 mL) was added to the reaction solution, and after concentrating under reduced pressure, ethyl acetate (15 mL) was added thereto, and stirred at room temperature for half an hour. The precipitated solid was collected by filtration, and the filtrate was repeated with the above pulping operation. The collected solid was dried under vacuum to obtain compound TM2-5 (440 mg, yellow solid, yield 45%), LCMS: (M+1)+ :433.1.

[0251] Synthesis of compound TM2-6: Compound TM2-5 (300 mg, 0.613 mmol, 1.0 eq) and compound TM2-5A (219 mg, 0.674 mmol, 1.1 eq) were added to 1,4-dioxane (15 mL), and cesium carbonate (499 mg, 1.53 mmol, 2.5 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (76.4 mg, 0.122 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (56.1 mg, 0.061 mmol, 0.1 eq) were added thereto in sequence. After nitrogen replacement three times, the reaction was carried out at 110°C for 3 hours. After the reaction monitoring was completed, silica gel was added to the reaction solution to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) were performed to obtain compound TM2-6 (360 mg, yellow solid, yield 80%), LCMS: (M+1) + :734.4.

[0252] Synthesis of compound TM2-7: Add compound TM2-6 (200 mg, 0.272 mmol, 1.0 eq) to 1,4-dioxane (3 mL), and add 4M hydrochloric acid dioxane solution (4 mL, 16.3 mmol). After the addition is complete, react at room temperature for 2 hours. After the reaction monitoring is completed, the reaction solution is dried under vacuum to obtain compound TM2-7 (150 mg, yellow solid, yield 95%), LCMS: (M+1) + :578.6.

[0253] Synthesis of TM2: Compound TM2-7 (150 mg, 0.259 mmol, 1.0 eq) was dissolved in N, N-dimethylformamide (18 mL), and N, N-diisopropylethylamine (168 mg, 1.30 mmol, 5.0 eq) was added thereto. 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (135 mg, 0.259 mmol, 1.0 eq) was added thereto under ice bath conditions. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was stirred for 16 hours. After the reaction monitoring was completed, the reaction solution was directly filtered, and the filtrate was subjected to reverse phase preparation purification (water (0.225% formic acid)-acetonitrile) to obtain compound TM2 (58.14 mg, yellow solid, yield 39%, purity 98%), LCMS: (M+1) + :560.3. 1H NMR (400MHz, DMSO-d6) δ12.45–12.14(m,1H),10.32(s,1H),9.29(s,1H),9.26(d,J=2.0Hz,1H),8.73(t,J =5.4Hz,1H),8.57(q,J=4.4Hz,1H),8.12(s,1H),7.79(s,1H),7.63(dd,J=11.5,1.5Hz,1H),7.33(dd,J=8. 3,2.1Hz,1H),7.20(d,J=8.2Hz,1H),7.04(dd,J=8.4,2.6Hz,1H),6.29(ddd,J=11.3,5.0,2.6Hz,1H),3.1 1–2.99(m,2H),2.91(s,3H),2.82(d,J=4.5Hz,3H),2.79(s,3H),2.54(d,J=4.6Hz,2H),2.09–1.81(m,2H).

[0254] Embodiment 3:

[0255] Experimental procedures: Preparation of TM3

[0256]

[0257] Synthesis of compound TM3-2: 5-((8-bromo-6-fluoroquinazolin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoic acid (200 mg, 0.433 mmol, 1.00 eq), tert-butyl (3-(2-amino-3-fluoro-5-(methylcarbamoyl)phenyl)propyl)carbamate (172 mg, 0.476 mmol, 1.10 eq) , cesium carbonate (423 mg, 1.30 mmol, 3.00 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (53.9 mg, 0.0865 mmol, 0.200 eq) and tris(dibenzylideneacetone)dipalladium (39.6 mg, 0.0433 mmol, 0.100 eq) were dissolved in 1,4-dioxane (6 mL), replaced with nitrogen three times, and reacted at 120°C for 14 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was concentrated and mixed, and normal phase purification (dichloromethane (0.1% triethylamine): methanol) was performed.

[0258] =5:1) to obtain compound TM3-2 (265 mg, yellow solid, yield 80%), LCMS: (M+1) + :707.4.

[0259] Synthesis of compound TM3-3: 5-((8-((2-(3-((tert-butoxycarbonyl)amino)propyl)-6-fluoro-4-(methylcarbamoyl)phenyl)amino)-6-fluoroquinazolin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoic acid (107 mg, 0.14 mmol, 1.00 eq) was dissolved in 1,4-dioxane (1 mL), 4M hydrochloric acid dioxane solution (8 mL) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction monitoring was completed, the reaction solution was spin-dried to obtain compound TM3-3 (90 mg, hydrochloride, orange solid, yield 99%), LCMS: (M+1) + :607.4.

[0260] Synthesis of TM3: 5-((8-((2-(3-aminopropyl)-6-fluoro-4-(methylcarbamoyl)phenyl)amino)-6-fluoroquinazolin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)benzoic acid (45 mg, 0.0700 mmol, 1.00 eq) was dissolved in N,N-dimethylformamide (5 mL), replaced with nitrogen three times, and N,N-diisopropylethylamine (0.058 mL, 0.350 mmol, 5.00 eq) and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (36.4 mg, 0.0700 mmol, 1.00 eq) in N,N-dimethylformamide (0.6 mL) were added dropwise under ice bath, and the reaction was carried out at room temperature for 16 hours. After the reaction monitoring was completed, the reaction solution was purified by high pressure preparation (water (0.225% formic acid): acetonitrile = 3:1)) to obtain TM3 (8.89 mg, yellow solid, purity: 96%, yield: 19.4%), LCMS: (M+1) + :589.3. 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.22(s,1H),8.81–

[0261] 8.71(m,1H),8.55(q,J=4.4Hz,1H),8.20(s,1H),7.92(s,1H),7.78(s,1H),7.6 3(d,J=11.2Hz,1H),7.23(dd,J=8.7,2.2Hz,1H),7.13(d,J=8.6Hz,1H),7.00(dd ,J=8.5,2.5Hz,1H),6.26(ddd,J=11.2,5.2,2.7Hz,1H),3.17–3.14(m,4H),2.82 (d, J = 4.4Hz, 3H), 2.69 (s, 3H), 2.55 (d, J = 6.3Hz, 4H), 2.30 (s, 6H), 2.07 (s, 2H).

[0262] Example 4: Experimental procedures: Preparation of TM4

[0263]

[0264] Synthesis of compound TM4-2: Compound TM4-1 (5 g, 21.7 mmol, 1.0 eq), 1A (6.78 g, 327 mmol, 1.5 eq), potassium carbonate (9.01 g, 65.2 mmol, 3 eq) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (1.77 g, 2.17 mmol, 1 eq) were added to 1,4-dioxane (100 mL) and water (20 mL), nitrogen was replaced three times, and the reaction temperature was raised to 90 ° C for 3 hours. After the reaction monitoring was completed, the reaction solution was concentrated, and the normal phase separation (petroleum ether: ethyl acetate = 1:10) was used to obtain compound TM4-2 (3.5 g, yield: 70%, gray solid), LCMS: (M+1) + :232.3.

[0265] Synthesis of compound TM4-3: Compound TM4-2 (2.47 g, 10.7 mmol, 1 eq) was added to methanol (20 mL) and water (20 mL) under an ice bath, and then sodium hydroxide (2.14 g, 53.5 mmol, 5 eq) was added to the reaction solution, and the temperature was automatically raised to room temperature for 20 hours. After the reaction monitoring was completed, impurities were extracted with ethyl acetate, and the aqueous phase was adjusted to pH 6 with 6M hydrochloric acid, and the compound TM4-3 (2 g, yield: 86%, gray solid) was obtained after filtration and drying, LCMS: (M+1) + :217.3.

[0266] Synthesis of compound TM4-4: Compound TM4-3 (499 mg, 2.29 mmol, 1.2 eq), TM1-4A (500 mg, 1.91 mmol, 1.0 eq), and trifluoroacetic acid (327 mg, 2.87 mmol, 1.5 eq) were added to isopropanol (10 mL). The reaction temperature was raised to 90°C for 12 hours. After the reaction monitoring was completed, ethyl acetate (10 mL) was added to the reaction solution, and then filtered. The solid on the filter cake was washed with ethyl acetate and dried to obtain compound TM4-4 (550 mg, yield: 65%, yellow solid), LCMS: (M+1) + :442.3.

[0267] Synthesis of compound TM4-5: Compound TM4-4 (350 mg, 678 μmol, 1.0 eq), TM2-5A (265 mg, 814 μmol, 1.2 eq), sodium tert-butoxide (81.3 mg, 949 μmol, 1.5 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (84.5 mg, 135 μmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (62.1 mg, 67.8 μmol, 0.1 eq) were added to 1,4-dioxane (15 mL), nitrogen was replaced three times, and the reaction temperature was raised to 120 ° C for 13 hours. After the reaction monitoring was completed, the reaction solution was concentrated and prepared by high pressure to obtain compound TM4-5 (75 mg, yield: 16%, yellow solid), LCMS: (M-100+1) + :587.3.

[0268] Synthesis of compound TM4-6: Compound TM4-5 (60 mg, 87.8 μmol, 1.0 eq) was added to 1,4-dioxane hydrochloride (1.5 mL) and reacted at 25°C for 0.5 hours. After the reaction monitoring was completed, the reaction solution was concentrated to obtain compound TM4-6 (50 mg, yield: 98%, orange solid), LCMS: (M+1) + :587.2.

[0269] Synthesis of TM4: Compound TM4-6 (50 mg, 85.2 μmol, 1.0 eq) was added to N, N-dimethylformamide (5 mL) under ice bath, and then N, N-diisopropylethylamine (55.1 mg, 426 μmol, 5.0 eq) and 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (35.5 mg, 68.2 μmol, 0.8 eq) were added, and the temperature was automatically raised to room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was prepared under high pressure to obtain the final product TM4 (20.9 mg, yield: 43%, yellow solid, purity: 99%). LCMS: (M+1) + :569.2. 1H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.26(s,1H),8.83(d,J=2.4Hz,1H),8.68(t,J=5.2Hz,1H),8.57(dd,J=8.6,4.0 Hz,1H),7.98(s,1H),7.83(d,J=0.8Hz,1H),7.79(s,1H),7.63(dd,J=11.5,1.8Hz,1H),7.59(d,J=0.8Hz,1H),7.46(d ,J=8.4Hz,1H),7.27(dd,J=8.5,2.4Hz,1H),7.02(dd,J=8.5,2.6Hz,1H),6.27(ddd,J=11.3,5.3,2.6Hz,1H),3.83(s, 3H),3.15–3.05(m,2H),2.82(d,J=4.5Hz,3H),2.67(dt,J=3.7,1.8Hz,1H),2.33(dt,J=3.6,1.7Hz,1H),2.08(s,2H).

[0270] Example 5 and Example 13:

[0271] Experimental procedures: Preparation of TM5 and TM13

[0272]

[0273] Synthesis of compound TM5-2: Compound TM5-1 (5.5 g, 32.2 mmol, 1.0 eq), TM5-1A (6.18 g, 48.3 mmol, 1.5 eq), triethylamine (326 mg, 3.22 mmol, 0.1 eq) and zirconocene hydrochloride (830 mg, 3.22 mmol, 0.1 eq) were added to a single-mouth bottle, replaced with nitrogen three times, and the reaction temperature was raised to 65 ° C for 12 hours. After the reaction monitoring was completed, the reaction solution was concentrated and the normal phase separation (petroleum ether: ethyl acetate = 1:1) was used to obtain compound TM5-2 (5.1 g, yield: 56%, colorless oily liquid

[0274] ), LCMS:(M+1) + :284.3.

[0275] Synthesis of compound TM5-3: Compound TM5-2 (3.2 g, 11.3 mmol, 1.0 eq), TM5-2A (3.06 g, 12.4 mmol, 1.2 eq), potassium carbonate (4.69 g, 33.9 mmol, 3.0 eq) and tetrakis(triphenylphosphine)palladium (1.31 g, 1.13 mmol, 0.1 eq) were added to 1,4-dioxane (18 mL) and water (4.5 mL), nitrogen was replaced three times, and the reaction temperature was raised to 80 ° C for 5 hours. After the reaction monitoring was completed, the reaction solution was filtered and concentrated, and the compound TM5-3 (2.68 g, yield: 74%, yellow solid) was obtained after normal phase separation (petroleum ether: ethyl acetate = 3:1), LCMS: (M+1) + :323.2.

[0276] Synthesis of compound TM5-4: Compound TM5-3 (262 mg, 814 mmol, 1.3 eq), TM5-3A (300 mg, 678 μmol, 1.0 eq), cesium carbonate (663 mg, 162 μmol, 2.5 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (845 mg, 136 μmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (62.2 mg, 68.8 μmol, 0.1 eq) were added to 1,4-dioxane (15 mL), nitrogen was replaced three times, and the reaction temperature was raised to 120 ° C for 5 hours. After the reaction monitoring was completed, the reaction solution was concentrated and the compound TM5-4 (125 mg, yield: 27%, yellow solid) was obtained after high pressure preparation separation, LCMS: (M+1) + :684.4.

[0277] Synthesis of compound TM5-5: Compound TM5-4 (125 mg, 183 μmol, 1.0 eq) was added to 1,4-dioxane hydrochloride (4 mL) and reacted at 25°C for 4 hours. After the reaction monitoring was completed, the reaction solution was concentrated to obtain compound TM5-5 (95 mg, yield: 89%, orange solid), LCMS: (M+1) + :584.2.

[0278] Synthesis of compound TM13: Compound TM5-5 (95 mg, 165 μmol, 1.0 eq) was added to N, N-dimethylformamide (9 mL) under ice bath, and then N, N-diisopropylethylamine (106 mg, 823 μmol, 5 eq) and 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (68.5 mg, 132 μmol, 0.8 eq) were added, and then the temperature was automatically raised to room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was subjected to high pressure preparative separation to obtain compound TM13 (55 mg, yield: 59%, yellow solid), LCMS: (M+1) + :566.1. 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),9.30(s,1H),8.95(d,J=2.3Hz,1H),8.87(t,J=5.9Hz,1H),8.26(s,1H ),8.19(s,1H),7.82(s,1H),7.79(d,J=1.5Hz,1H),7.60(s,1H),7.46(d,J=8.5Hz,1H),7.34(dd,J=8.5,2.3 Hz,1H),7.14(dd,J=8.4,2.6Hz,1H),7.06(d,J=15.9Hz,1H),6.87(dt,J=16.3,3.6Hz,1H),6.55(ddd,J=11. 1,8.3,2.6Hz,1H),3.99(d,J=23.4Hz,2H),3.84(s,3H),3.15(dd,J=14.3,7.1Hz,2H),1.12(t,J=7.1Hz,3H).

[0279] Synthesis of compound TM5: Compound TM13 (50 mg, 88.4 μmol, 1.0 eq) was added to methanol (2.5 mL) and tetrahydrofuran (2.5 mL), followed by addition of hydrochloric acid (16.2 mg, 442 μmol, 5 eq) and palladium carbon (282 mg, 265 μmol, 3 eq), hydrogen replacement three times, and reaction at room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered, and the filtrate was separated by high pressure preparation to obtain compound TM5 (10.3 mg, yield: 20%, yellow solid), LCMS: (M+1) + :570.3. 1H NMR (400MHz, DMSO-d6) δ8.58(s,1H),8.53(t,J=4.5Hz,2H),8.15(s,1H),7.81(d,J=1.6Hz,1H),7.77(s,1 H),7.68(dd,J=11.6,1.8Hz,1H),7.54(d,J=0.6Hz,1H),7.36(d,J=8.4Hz,1H),7.10(s,1H),6.93(dd,J=8 .4,2.4Hz,1H),6.26(s,1H),6.22(dd,J=8.9,2.7Hz,1H),5.82(ddd,J=11.3,5.6,2.7Hz,1H),4.40(s,1H) ,3.82(s,3H),3.08(dd,J=14.3,7.1Hz,4H),2.91–2.79(m,2H),2.10–2.00(m,2H),1.09(t,J=7.1Hz,3H).

[0280] Embodiment 6:

[0281] Experimental step 1: Preparation of intermediate TM6-5A

[0282]

[0283] Synthesis of compound TM6-9: Compound TM6-8 (12.5 g, 73.5 mmol, 1.0 eq), Ag2CO3 (2.03 g, 7.35 mmol, 0.1 eq), and NaN3 (14.33 g, 220.38 mmol, 3.0 eq) were dissolved in N,N-dimethylformamide (100 mL). The reaction solution was stirred at 120 ° C for 12 hours. After the reaction monitoring was completed, water and ethyl acetate were added for extraction, the aqueous layer was quenched with sodium hypochlorite, and the organic layer was dried and concentrated to obtain a crude compound TM6-9 (12.0 g, brown oil, yield 98%), LCMS: (M+1) + :229.3. It can be directly used in the next reaction.

[0284] Synthesis of compound TM6-10: Compound TM6-9 (12.0 g, 71.8 mmol, 1.0 eq) was dissolved in acetonitrile (100 mL), and N-bromosuccinimide (12.8 g, 71.8 mmol, 1.0 eq) was added under ice bath conditions. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 2 hours. After the reaction monitoring was completed, silica gel was added to the reaction solution to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 5:1) were performed to obtain compound TM6-10 (6.10 g, brown oil, yield 35%), LCMS: (M+1) + :246.0.

[0285] Synthesis of compound TM6-11: Compound TM6-10 (2.60 g, 10.6 mmol, 1.0 eq), 10A (4.02 g, 15.9 mmol, 1.5 eq), potassium acetate (3.11 g, 31.7 mmol, 3.0 eq) and tetrakis(triphenylphosphine)palladium (1.22 g, 1.06 mmol, 0.1 eq) were added to 1,4-dioxane (50 mL), replaced with nitrogen three times, and reacted at 80 ° C for 12 hours. After the reaction monitoring was completed, the reaction solution was filtered, and the filtrate was dried under vacuum to obtain a crude compound TM6-11 (3.00 g, yellow oily liquid, yield 97%), LCMS: (M+1) + :293.4. It can be directly used in the next reaction.

[0286] Synthesis of compound TM6-12: Add compound TM6-11 (3.00 g, 10.2 mmol, 1.0 eq) to tetrahydrofuran (50 mL), and add hydrogen peroxide (346 mg, 10.2 mmol, 1.0 eq) under ice bath. After the addition is completed, slowly warm up to room temperature and stir to react for 2 hours. After the reaction monitoring is completed, add sodium sulfite aqueous solution and ethyl acetate to the reaction bottle and extract. After the organic layer is concentrated under vacuum, add silica gel to mix the sample, and purify by normal phase separation (petroleum ether: ethyl acetate = 3:1) to obtain compound TM6-12 (2.03 g, yellow oily liquid, yield 97%), LCMS: (M+1) + :184.2.

[0287] Synthesis of compound TM6-5A: Add compound TM6-12 (2.00 g, 10.9 mmol, 1.0 eq) to acetonitrile (40 mL), then add TM6-12A (1.76 g, 13.1 mmol, 1.2 eq) and potassium carbonate (4.53 g, 32.7 mmol, 3.0 eq). Stir the reaction at 80 °C for 7 hours. After the reaction detection is completed, the reaction solution is concentrated under vacuum and silica gel is added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 2:1) are performed to obtain compound TM6-5A (660 mg, white solid, yield 26%), LCMS: (M+1) + :238.3.

[0288] Experimental step 2: Preparation of compound TM6

[0289]

[0290] Synthesis of compound TM6-2: Compound TM6-1 (5.00 g, 21.7 mmol, 1.0 eq) was added to a mixed solution of 1,4-dioxane solution (50 mL) and water (10 mL), and potassium carbonate (9.01 g, 65.2 mmol, 3.0 eq), compound TM6-1A (5.02 g, 32.6 mmol, 1.5 eq) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.59 g, 2.17 mmol, 0.1 eq) were added thereto in sequence. Nitrogen was replaced three times and the reaction was carried out at 90 ° C for 3 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature and extracted with water and a large amount of ethyl acetate. The organic phase was dried and filtered using anhydrous sodium sulfate. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample. The mixture was separated and purified by normal phase separation (petroleum ether: ethyl acetate = 3:1) to obtain compound TM6-2 (3.00 g, yellow oily liquid, yield 78%), LCMS: (M+1) + :178.0.

[0291] Synthesis of compound TM6-3: Compound TM6-2 (3.00 g, 16.9 mmol, 1.0 eq) was added to a mixed solution of methanol (15 mL) and water (15 mL), and sodium hydroxide (1.69 g, 42.3 mmol, 2.5 eq) was added thereto. The reaction solution was stirred at room temperature for 16 hours. After the reaction monitoring was completed, the reaction solution was concentrated under vacuum. 1 M hydrochloric acid was added to adjust the pH of the solution to 5, and water and a large amount of ethyl acetate were added for extraction. The collected organic phase was spin-dried under vacuum to obtain compound TM6-3 (2.50 g, yellow solid, yield 90%), LCMS: (M+1) + :164.0.

[0292] Synthesis of compound TM6-4: Compound TM6-3 (2.60 g, 15.9 mmol, 1.0 eq) was dissolved in N, N-dimethylformamide (50 mL), and N, N-diisopropylethylamine (8.24 g, 63.7 mmol, 4.0 eq) was added thereto. N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (9.09 g, 23.9 mmol, 1.5 eq) was added thereto under ice bath conditions, and after stirring the reaction for 15 minutes, dimethylamine hydrochloride (3.90 g, 47.8 mmol, 3.0 eq) was added under ice bath conditions. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 1 hour. After the reaction monitoring was completed, water and a large amount of ethyl acetate were added for extraction. The extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and then silica gel was added to mix the sample and purified by normal phase separation (petroleum ether: ethyl acetate).

[0293] =1:1), to obtain the crude product of compound TM6-4 (4.00 g, yellow oily liquid), LCMS: (M+1) + :191.1.

[0294] Synthesis of compound TM6-5: Compound TM6-4 (4.95 g, 26.0 mmol, 4.0 eq) and compound TM1-4A (1.70 g, 6.50 mmol, 1.0 eq) were dissolved in isopropanol (50 mL), and trifluoroacetic acid (3.71 g, 32.51 mmol, 5.0 eq) was added thereto. Nitrogen was replaced three times, and the reaction was stirred at 90 ° C for 16 hours. After the reaction monitoring was completed, it was cooled to room temperature, ethyl acetate (50 ml) was added, and it was spin-dried under vacuum. Ethyl acetate (20 ml) was added thereto and stirred at room temperature for half an hour. The precipitated solid was collected by filtration, and the filtrate was repeated again. The collected solid was dried under vacuum to obtain compound TM6-5 (2.00 g, yellow solid, yield 74%), LCMS: (M+1) + :415.1.

[0295] Synthesis of compound TM6-6: Compound TM6-5 (500 mg, 1.20 mmol, 1.0 eq) and compound TM2-5A (314 mg, 1.32 mmol, 1.1 eq) were dissolved in 1,4-dioxane (10 mL). Cesium carbonate (1.18 g, 3.61 mmol, 3.0 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (149 mg, 0.240 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (110 mg, 0.120 mmol, 0.1 eq) were added thereto in sequence. Nitrogen was replaced three times and the reaction was carried out at 110°C for 16 hours. After the reaction monitoring was completed, the mixture was filtered using diatomaceous earth. The filtrate was concentrated under vacuum and then silica gel was added to mix the sample. Normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM6-6 (600 mg, yellow solid, yield 80%), LCMS: (M+1) + :572.3.

[0296] Synthesis of compound TM6-7: Compound TM6-6 (150 mg, 0.262 mmol, 1.0 eq) was dissolved in toluene (5 mL), and Grubbs second-generation catalyst (89.1 mg, 0.104 mmol, 0.4 eq) was added thereto. Nitrogen was replaced three times, and the reaction was carried out at 65 ° C for 4 hours. After the reaction monitoring was completed, it was cooled to room temperature and filtered using diatomaceous earth. The filtrate was concentrated under vacuum and then silica gel was added to mix the sample. The normal phase separation and purification (petroleum ether: ethyl acetate = 0: 1) was performed to obtain compound TM6-7 (130 mg, dark brown solid, yield 91%), LCMS: (M+1)+ :544.2.

[0297] Synthesis of TM6: Compound TM6-7 (140 mg, 0.257 mmol, 1.0 eq) was dissolved in methanol (3 mL), and palladium carbon (137 mg, 0.128 mmol, 0.5 eq) was added thereto. The mixture was replaced with hydrogen three times, and the reaction was stirred at room temperature for 5 hours. After the reaction, diatomaceous earth was used for filtration, and the filtrate was dried under vacuum and subjected to reverse phase preparation and purification (water (0.225% formic acid)-acetonitrile) to obtain compound TM6 (8.54 mg, yellow solid, yield of 6.1%, purity of 95%), LCMS: (M+1) + :548.3. 1 H NMR (400MHz, DMSO-d6) δ10.17(d,J=34.8Hz,1H),8.53(d,J=8.1Hz,1H),8.24(d,J=82.7Hz,1H),7.79(s ,1H),7.63–7.43(m,2H),7.25–7.14(m,1H),7.09(s,1H),7.01(d,J=8.2Hz,1H),6.82–6.68(m,1H),6.35 (dd,J=8.6,2.3Hz,1H),6.20(dd,J=17.2,4.7Hz,1H),4.42(t,J=14.4Hz,3H),3.10–3.02(m,2H),2.99(d ,J=7.9Hz,3H),2.78(d,J=9.8Hz,3H),2.62–2.52(m,2H),1.76(d,J=25.1Hz,4H),1.09(q,J=7.2Hz,3H).

[0298] Embodiment 7:

[0299] Experimental procedure: Preparation of compound TM7

[0300]

[0301] Synthesis of compound TM7-2: Compound TM7-1 (5.00 g, 26.6 mmol, 1.00 eq) was added to a mixed solution of water (80 mL) and 1,4-dihexacyclopentane (16 mL), and compound TM6-1A (6.14 g, 39.9 mmol, 1.50 eq), potassium carbonate (11.0 g, 79.8 mmol, 3.00 eq) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.17 g, 2.66 mmol, 0.1 eq) were added thereto in sequence, nitrogen was replaced three times, and the reaction was carried out at 90°C for 3 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was spin-dried under vacuum conditions, silica gel was added to mix the sample, and normal phase separation (petroleum ether: ethyl acetate = 3:1) was performed to obtain compound TM7-2 (2.4 g, yellow oily liquid, yield 67%), LCMS: (M+1) + :136.1.

[0302] Synthesis of compound TM7-3: Compound TM7-2 (2.4 g, 17.8 mmol, 1.00 eq) was added to acetonitrile (25 mL), and triethylamine (5.39 g, 53.3 mmol, 3.00 eq) and 4-methylaminopyridine (217 mg, 1.78 mmol, 0.100 eq) were added under stirring. The mixed solution was cooled to 0 ° C, and N-phenylbis(trifluoromethanesulfonyl)imide (7.61 g, 21.3 mmol, 1.20 eq) was added under stirring. The mixture was slowly warmed to room temperature and reacted for 1 hour. After the reaction monitoring was completed, silica gel was added to the reaction solution to mix the sample, and normal phase separation (petroleum ether: ethyl acetate = 3:1) was performed to obtain compound TM7-3 (3.9 g, yellow solid, yield 82%), LCMS: (M+1) + :268.0.

[0303] Synthesis of compound TM7-4: Compound TM7-3 (3.80 g, 14.2 mmol, 1.00 eq) and compound TM7-3A (4.44 g, 21.3 mmol, 1.50 eq) were added to 1,4-dioxane (30 mL) and water (6 mL), and potassium carbonate (5.90 g, 42.7 mmol, 3.00 eq) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.04 g, 1.42 mmol, 0.100 eq) were added under stirring. After nitrogen replacement three times, the reaction was carried out at 90 ° C for 3 hours. After the reaction monitoring was completed, silica gel was added to the reaction solution to mix the sample, and normal phase separation (petroleum ether: ethyl acetate = 3:1) was performed to obtain compound TM7-4 (2.2 g, brown solid, yield 78%), LCMS: (M+1) + :200.2.

[0304] Synthesis of compound TM7-5: Compound TM7-4 (838 mg, 4.21 mmol, 1.10 eq) and compound TM1-4A (1.00 g, 3.82 mmol, 1.00 eq) were added to isopropanol (10 mL), and trifluoroacetic acid (2.18 g, 19.1 mmol, 5.00 eq) was added under stirring. After nitrogen replacement three times, the reaction was carried out at 90 ° C for 4 hours. After the reaction monitoring was completed, ethyl acetate (10 mL) was added and stirred at room temperature for half an hour. A large amount of solid precipitated, filtered, and the filter cake was collected. After the filter cake was spin-dried, compound TM7-5 (580 mg, yellow solid, yield 36%) was obtained, LCMS: (M+1) + :423.9.

[0305] Synthesis of compound TM7-6: Compound TM7-5 (250 mg, 0.589 mmol, 1.00 eq) and compound TM2-5A (175 mg, 0.737 mmol, 1.25 eq), cesium carbonate (576 mg, 1.77 mmol, 3.00 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (73.4 mg, 0.118 mmol, 0.200 eq) and tris(dibenzylideneacetone)dipalladium (54.0 mg, 0.589 mmol, 0.100 eq) were dissolved in 1,4-dioxane (10 mL), replaced with nitrogen three times, and then reacted at 110 ° C for 1.5 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was spin-dried and mixed, and normal phase purification (petroleum ether: ethyl acetate = 1:1) was performed to obtain compound TM7-6 (270 mg, yellow solid, yield 79%), LCMS: (M-100+1) + :581.3.

[0306] Synthesis of compound TM7-7: Compound TM7-6 (270 mg, 0.465 mmol, 1.00 eq) was dissolved in 1,2-dichloroethane (27 mL), Grubbs second-generation catalyst (158 mg, 0.186 mmol, 0.400 eq) was added, nitrogen was replaced three times, and then reacted at 60°C for 4 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was concentrated and mixed, and normal phase purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM7-7 (140 mg, yellow solid, yield 55%), LCMS: (M-100+1) + :553.0.

[0307] Synthesis of TM7: Compound TM7-7 (120 mg, 0.217 mmol, 1.00 eq) was dissolved in tetrahydrofuran (2 mL) and methanol (10 mL), and concentrated hydrochloric acid (0.033 mL, 1.09 mmol, 5.00 eq) and palladium carbon (10% content) (400 mg, 3.76 mmol, 17.3 eq) were added. After hydrogen replacement three times, the mixture was reacted at room temperature for 3 hours. After the reaction monitoring was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated and purified by high pressure preparation (water (0.225% formic acid): acetonitrile = 1:1) to obtain TM7 (36.51 mg, yellow solid, yield 29.1%), LCMS: (M+1) + :557.2. 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.36(d,J=2.2Hz,1H),7.76(s,1H),7.54(dd,J=12.2,1.5Hz, 1H),7.48(d,J=0.6Hz,2H),7.18(s,1H),7.13(d,J=8.2Hz,1H),6.72(dd,J=8.3,2.3Hz,1H),6.35( dd,J=8.9,2.7Hz,1H),6.19(ddd,J=11.0,8.3,2.7Hz,1H),6.15(s,1H),4.45–4.36(m,4H),3.87(s ,3H),3.04(q,J=7.2Hz,2H),2.68(dd,J=7.7,5.9Hz,2H),1.79–1.70(m,4H),1.08(t,J=7.2Hz,3H).

[0308] Embodiment 8:

[0309] Experimental procedures: Preparation of compound TM8

[0310]

[0311] Synthesis of compound TM8-2: Compound TM8-1 (5.00 g, 20.2 mmol, 1.0 eq) and diboric acid pinacol ester (6.14 g, 24.2 mmol, 1.2 eq) were dissolved in 1,4-dioxane (110 mL), potassium acetate (5.93 g, 60.5 mmol, 3.0 eq) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.47 g, 2.02 mmol, 0.1 eq) were added thereto, nitrogen was replaced three times, and the reaction was carried out at 80 ° C for 16 hours. After the reaction monitoring was completed, it was concentrated under vacuum, ethyl acetate was added and filtered, and the filtrate was spin-dried under vacuum to obtain a crude compound TM8-2 (6.00 g, black solid), LCMS: (M+1) +:296.2. It can be directly used in the next reaction.

[0312] Synthesis of compound TM8-3: Compound TM8-2 (5.00 g, 16.9 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), and hydrogen peroxide solution (9.60 g, 84.7 mmol, 5.0 eq) was added under ice bath conditions. The reaction solution was stirred at room temperature for 1 hour. After the reaction monitoring was completed, sodium sulfite was added to quench, and then ethyl acetate and water were added for extraction. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and silica gel was added to mix the sample. The normal phase separation and purification (petroleum ether: ethyl acetate = 3:1) was obtained to obtain compound TM8-3 (3.00 g, yellow oily liquid, yield 96%), LCMS: (M+1) + :185.8.

[0313] Synthesis of compound TM8-4: Compound TM8-3 (3.00 g, 16.2 mmol, 1.0 eq) and potassium carbonate (6.72 g, 48.6 mmol, 3.0 eq) were added to acetonitrile (40 mL), and then 4-bromobutene (2.62 g, 19.4 mmol, 1.2 eq) was added, and the reaction solution was stirred at 80 ° C for 16 hours. After the reaction monitoring was completed, silica gel was added to the reaction solution to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 3:1) were performed to obtain compound TM8-4 (1.40 g, white solid, yield 36%), LCMS: (M+1) + :240.1.

[0314] Synthesis of compound TM8-5: Compound TM8-4 (1.30 g, 5.43 mmol, 1.0 eq) was dissolved in tetrahydrofuran (13 mL), and 13 mL of an aqueous solution of sodium hydroxide (652 mg, 16.3 mmol, 3.0 eq) was added. After the addition was completed, the reaction was carried out at 65°C for 2 hours. After the reaction monitoring was completed, 4 M aqueous hydrochloric acid was added to adjust the pH to 4, and ethyl acetate and water were added for extraction. The organic phase was dried and concentrated to obtain compound TM8-5 (1.20 g, yellow solid, yield 98%), LCMS: (M+1) + :226.0. It can be used directly in the next reaction.

[0315] Synthesis of compound TM8-6: Compound TM8-5 (1.20 g, 5.33 mmol, 1.0 eq) and methylamine hydrochloride (1.08 g, 16.0 mmol, 3.0 eq) were added to N, N-dimethylformamide (25 mL), and then N, N-diisopropylethylamine (2.75 g, 21.3 mmol, 4.0 eq) was added. 1-hydroxybenzotriazole (0.79 g, 5.86 mmol, 1.1 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.33 g, 6.93 mmol, 1.3 eq) were added under ice bath. After the addition was completed, the temperature was slowly raised to room temperature and reacted for 24 hours. After the reaction monitoring was completed, ethyl acetate and water were added for extraction, and the mixed organic phase was washed twice with saturated brine. The organic phase was dried and concentrated, and then silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) were performed to obtain compound TM8-6 (1.20 g, yellow solid, yield 95%), LCMS: (M+1) + :239.1.

[0316] Synthesis of compound TM8-7: Compound TM8-6 (300 mg, 0.707 mmol, 1.0 eq) and compound TM8-6A (185 mg, 0.778 mmol, 1.1 eq) were dissolved in 1,4-dioxane (6 mL), and cesium carbonate (691 mg, 2.12 mmol, 3.0 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (88.1 mg, 0.141 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (64.8 mg, 0.071 mmol, 0.1 eq) were added thereto in sequence. Nitrogen was replaced three times and the mixture was reacted at 110°C for 3 hours. After the reaction monitoring was completed, the product was filtered using diatomaceous earth. The filtrate was concentrated under vacuum and then silica gel was added to mix the sample. Normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM8-7 (400 mg, yellow solid, yield 97%), LCMS: (M+1) + :582.2.

[0317] Synthesis of compound TM8-8: Compound TM8-7 (400 mg, 0.688 mmol, 1.0 eq) was dissolved in dichloroethane (40 mL), and Grubbs second-generation catalyst (234 mg, 0.275 mmol, 0.4 eq) was added thereto. After nitrogen replacement three times, the reaction was stirred at 65 ° C for 4 hours. After the reaction monitoring was completed, the catalyst was filtered using diatomaceous earth. The collected filtrate was concentrated under vacuum and silica gel was added to mix the sample, and the normal phase separation and purification (dichloromethane: methanol = 10: 1) was performed to obtain compound TM8-8 (290 mg, reddish brown solid, yield 76%), LCMS: (M+1) + :554.1.

[0318] Synthesis of TM8: Compound TM8-8 (240 mg, 0.433 mmol, 1.0 eq) was dissolved in tetrahydrofuran (24 mL), and palladium carbon (461 mg, 0.433 mmol, 1.0 eq) was added thereto. Hydrogen was replaced three times and reacted at room temperature for 12 hours. After the reaction monitoring was completed, the catalyst was filtered using diatomaceous earth. The filtrate was spin-dried under vacuum and subjected to reverse phase preparation purification (water (0.1% formic acid)-acetonitrile). Compound TM8 (49.54 mg, yellow solid, yield 20%, purity 98%) was obtained, LCMS: (M+1) + :556.1. 1 H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.27(s,1H),8.55–8.47(m,2H),7.80(s,1H),7.70( s,1H),7.58–7.50(m,2H),7.45(dd,J=12.3,1.3Hz,1H),7.21(d,J=8.3Hz,1H),7.16(dd,J= 8.4,2.6Hz,1H),7.07(dd,J=8.3,2.2Hz,1H),6.68(ddd,J=10.5,7.6,2.6Hz,1H),4.44(t,J =4.0Hz,2H),3.88(s,3H),2.81(d,J=4.5Hz,3H),2.75(t,J=6.3Hz,2H),1.88–1.75(m,4H).

[0319] Embodiment 9 and embodiment 11:

[0320] Experimental procedures: Preparation of compounds TM9 and TM11

[0321]

[0322] Synthesis of compound TM9-2: 2-bromo-1-fluoro-4-nitrobenzene (7.0 g, 31.8 mmol, 1.00 eq) and N1, N1, N2-trimethylethane (3.41 g, 33.4 mmol, 1.05 eq) were dissolved in acetonitrile (85 mL), replaced with nitrogen three times, and potassium carbonate (11.0 g, 79.6 mmol, 2.50 eq) was added under stirring in an ice bath, and reacted at room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was dried and dissolved in ethyl acetate, saturated brine (80 mL) was added, extracted, dried over anhydrous sodium sulfate, and dried to obtain compound TM9-2 (8.9 g, orange liquid, yield 93%), LCMS: (M+1) + :302.3.

[0323] Synthesis of compound TM9-3: N1-(2-bromo-4-nitrophenyl)-N1, N2, N2-trimethylethane-1,2-diamine (4.1 g, 13.6 mmol, 1.00 eq) was dissolved in 40 mL of methanol, and 10 mL of water, ammonium chloride (7.26 g, 136 mmol) and reduced iron powder (5.30 g, 95.0 mmol, 7.00 eq) were added under stirring. After nitrogen replacement three times, the mixture was reacted at 72 ° C for 48 hours. After the reaction monitoring was completed, 100 mg of potassium carbonate was added to the reaction solution after cooling to room temperature. The mixed solution was filtered through diatomaceous earth, the filtrate was dried, the sample was mixed, and the normal phase was purified (dichloromethane (0.1% triethylamine): methanol = 5:1) to obtain compound TM9-3 (5.0 g, gray solid), LCMS: (M+1) + :272.3.

[0324] Synthesis of compound TM9-4: 2-Bromo-N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,4-diamine (1.26 g, 4.13 mmol, 1.00 eq), potassium carbonate (2.86 g, 20.7 mmol, 5.00 eq) and Pd(dppf)Cl2 (454 mg, 0.62 mmol, 0.15 eq) were dissolved in 10 mL of dioxane and 2 mL of water, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (1.27 g, 8.27 mmol, 2.00 eq) was added, and after nitrogen replacement three times, the reaction was carried out at 90 °C for 14 hours (parallel reaction × 4). After the reaction monitoring was completed, the reaction solution was cooled to room temperature, and the sample was dried and purified by normal phase (dichloromethane (0.1% triethylamine): methanol = 5:1) to obtain compound TM9-4 (2.0 g, brown solid, yield 55%), LCMS: (M+1) + :220.4.

[0325] Synthesis of compound TM9-5: 8-bromo-2-chloro-6-fluoro-4a,8a dihydroquinazoline (697 mg, 2.67 mmol, 1.00 eq) was dissolved in isopropanol (8 mL), trifluoroacetic acid (0.792 mL, 10.7 mmol, 4.00 eq) and N1-(2-(dimethylamino)ethyl)-N1-methyl-2-vinylbenzene-1,4-diamine (950 mg, 3.47 mmol, 1.30 eq) in isopropanol (8 mL) were added, and the mixture was reacted at 90 °C for 5 hours (parallel reaction × 2). After the reaction monitoring was completed, the reaction solution was cooled to room temperature, and then dried by rotary evaporation, dissolved in N,N-dimethylformamide (25 mL), purified by reverse phase (water (0.225% formic acid): acetonitrile = 3:1), and lyophilized to obtain compound TM9-5 (1.0 g, yellow solid, yield 42%), LCMS: (M+1) + :444.1.

[0326] Synthesis of compound TM9-6: N4-(8-bromo-6-fluoroquinazolin-2-yl)-N1-(2-(dimethylamino)ethyl)-N1-methyl-2-vinylbenzene-1,4-diamine (500 mg, 1.13 mmol, 1.00 eq), 4-amino-5-(but-3-ene-1-oxy)-2-fluoro-N-methylbenzamide (295 mg, 1.24 mmol, 1.10 eq) were added. q), cesium carbonate (1.10g, 3.38mmol, 3.00eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (140mg, 0.225mmol, 0.200eq) and tris(dibenzylideneacetone)dipalladium (103mg, 0.113mmol, 0.100eq) were dissolved in 1,4-dioxane (15mL), replaced with nitrogen three times, and reacted at 120°C for 2 hours. After the reaction monitoring was completed, the reaction solution was cooled to room temperature, and the reaction solution was dried and mixed, and the normal phase was purified (dichloromethane (0.1% triethylamine): methanol = 5:1) to obtain compound TM9-6 (470mg, yellow solid, yield 69%), LCMS: (M+1) + :602.4.

[0327] Synthesis of TM11: 3-(But-3-ene-1-oxy)-4-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-vinylphenyl)amino)-6-fluoroquinazolin-8-yl)amino)-5-fluoro-N-methylbenzamide (100 mg, 0.166 mmol, 1.00 eq) was dissolved in 1,2-dichloroethane (15 mL), and p-toluenesulfonic acid (28.6 mg, 0.166 mmol, 1.00 eq) and Grubbs second-generation catalyst (169 mg, 0.199 mmol, 1.20 eq) were added in sequence. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 60 °C for 4.5 hours. After the reaction monitoring was completed, the reaction solution was cooled to room temperature, and then directly mixed and purified under high pressure (water (0.225% formic acid): acetonitrile = 1:1)) to obtain compound 7 (3.52 mg, yellow solid, yield 3.54%), LCMS: (M+1) + :574.3. 1H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 9.24 (s, 1H), 8.98 (d, J = 2.5Hz, 1H), 8.51 (q, J = 4.4Hz, 1H), 7.61 (s, 1H),7.49–7.40(m,1H),7.33(s,1H),7.16(dd,J=8.4,2.6Hz,1H),7.10(dd,J=8.7,2.6Hz,1H),7.03(d,J =8.6Hz,1H),6.86(d,J=16.0Hz,1H),6.72(ddd,J=10.6,7.8,2.6Hz,1H),6.48–6.38(m,1H),4.46(t,J=4 .7Hz,2H),3.00–2.94(m,2H),2.82(d,J=4.5Hz,3H),2.68–2.62(m,5H),2.47–2.40(m,2H),2.17(s,6H).

[0328] Synthesis of TM9: (E)-14-((2-(dimethylamino)ethyl)(methyl)amino)-36,56-difluoro-N-methyl-6-oxa-2,4-diaza-3(2,8)-quinazoline-1(1,3),5(1,2)-diphenylcyclododeca-9ene-54-carboxamide (55 mg, 0.096 mmol) was dissolved in tetrahydrofuran (20 mL), wet palladium carbon (120 mg, 1.13 mmol) was added, and the mixture was replaced with hydrogen three times, and the mixture was reacted at room temperature for 6 hours. After the reaction monitoring was completed, the reaction solution was filtered through diatomaceous earth, the filtrate was dried, dissolved in N,N-dimethylformamide (2.5 mL), and purified by high pressure preparation (water (0.225% formic acid): acetonitrile = 3:1)), and 3.02 mg of yellow solid was obtained, with a yield of 5.20%, LCMS: (M+1) + :576.2.

[0329] 1H NMR (400MHz, DMSO-d6) δ9.86 (s, 1H), 9.23 (s, 1H), 8.52 (q, J = 4.5Hz, 1H), 8.40 (d, J = 2.5Hz, 1H), 7.6 6(s,1H),7.53(s,1H),7.44(d,J=12.2Hz,1H),7.17–7.10(m,2H),7.02(dd,J=8.6,2.5Hz,1H),6.66( ddd,J=10.6,7.9,2.6Hz,1H),4.43(s,2H),2.91(dd,J=8.2,6.4Hz,2H),2.81(d,J=4.5Hz,3H),2.74 (dd,J=17.2,10.4Hz,2H),2.59(s,3H),2.33(dt,J=7.9,3.8Hz,2H),2.11(s,6H),1.85–1.76(m,4H).

[0330] Example 10 and Example 12:

[0331] Experimental procedures: Preparation of compounds TM10 and TM12

[0332]

[0333] Synthesis of compound TM10-2: Compound TM6-5 (500 mg, 1.20 mmol, 1.0 eq) and compound TM2-5A (316 mg, 1.32 mmol, 1.1 eq) were dissolved in 1,4-dioxane (12 mL), and cesium carbonate (981 mg, 3.01 mmol, 2.5 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (150 mg, 0.24 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (110 mg, 0.12 mmol, 0.1 eq) were added thereto in sequence. After nitrogen replacement three times, the mixture was reacted at 110°C for 4 hours. After the reaction monitoring was completed, silica gel was added to the reaction solution to mix the sample, and the normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM10-2 (600 mg, yellow solid, yield 87%), LCMS: (M+1) + :573.3.

[0334] Synthesis of compound TM12: Compound TM10-2 (470 mg, 0.697 mmol, 1.0 eq) was dissolved in dichloroethane (40 mL), and Grubbs second-generation catalyst (237 mg, 0.279 mmol, 0.4 eq) was added thereto. Nitrogen was replaced three times, and the reaction was stirred at 65 ° C for 4 hours. After the reaction monitoring was completed, the catalyst was filtered using diatomaceous earth. The filtrate was spin-dried under vacuum and purified by reverse phase separation (water (0.1% formic acid)-acetonitrile). Compound TM12 (180 mg, yellow solid, yield 47%) was obtained, LCMS: (M+1) + :545.3. 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.31(s,1H),9.22(d,J=1.8Hz,1H),8.51(d,J=4.7Hz ,1H),7.60(s,1H),7.44(dd,J=12.5,1.7Hz,1H),7.36(s,1H),7.21(dd,J=8.3,2.7Hz,1H),7 .19–7.09(m,2H),6.85–6.75(m,1H),6.71(dd,J=15.6,7.6Hz,1H),6.54(d,J=15.8Hz,1H), 4.40(s,3H),3.01(s,3H),2.81(d,J=4.5Hz,2H),2.78(s,3H),2.66(dt,J=11.9,3.6Hz,2H).

[0335] Synthesis of TM10: Compound TM12 (180 mg, 0.323 mmol, 1.0 eq) was dissolved in tetrahydrofuran (18 mL), and palladium carbon (517 mg, 0.485 mmol, 1.5 eq) was added thereto. The hydrogen gas was replaced three times, and the reaction was stirred at room temperature for 12 hours. After the reaction, the catalyst was filtered using diatomaceous earth. The filtrate was spin-dried under vacuum and subjected to reverse phase preparation purification (water (0.1% formic acid)-acetonitrile). Compound TM10 (63.8 mg, yellow solid, yield 36%, purity 99%) was obtained, LCMS: (M+1) + :547.2. 1H NMR (400MHz, DMSO-d6) δ10.13(s,1H),9.29(s,1H),8.54(s,1H),8.52(d,J=4.6 Hz,1H),7.71(s,1H),7.54(s,1H),7.45(d,J=12.5Hz,1H),7.18(dd,J=8.4,2.6H z,1H),7.09(s,2H),6.69(ddd,J=10.6,7.9,2.5Hz,1H),4.42(s,2H),3.00(s,3H ),2.81(d,J=4.5Hz,3H),2.79(s,3H),2.59(t,J=6.3Hz,2H),1.87–1.70(m,4H).

[0336] Embodiment 14

[0337] Experimental step 1: Preparation of intermediate TM14-2

[0338]

[0339] Synthesis of compound TM14-2: Compound TM14-1 (1 g, 5.08 mmol, 1 eq) was dissolved in 1.4-dioxane (12 mL) and water (3 mL). Then, vinylboronic acid pinacol ester (1.95 g, 2.15 mL, 12.69 mmol, 2.5 eq), potassium carbonate (1.75 g, 721.67 μL, 12.69 mmol, 2.5 eq), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (622 mg, 761.31 μmol, 0.15 eq) were added at 25 °C. After the addition was completed, the temperature was slowly raised to 100 °C and stirred for 3 hours. After the reaction monitoring was completed, the mixture was filtered, and water and dichloromethane were added to the filtrate for extraction. The extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and then silica gel was added to stir the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 5:1) was performed to obtain compound TM14-2 (900 mg, yellow solid, yield: 96%). Mass spectrum LCMS: (M+H)+: 145.1.

[0340] Experimental step 2: Preparation of compound TM14

[0341]

[0342] Synthesis of compound TM14-4: Compound TM14-2 (1.67 g, 11.56 mmol, 1 eq) and compound TM14-3 (3.0 g, 11.56 mmol, 1 eq) were dissolved in N-methylpyrrolidone (15 mL). Then, p-toluenesulfonic acid (3.98 g, 23.12 mmol) was added thereto at 25 °C. After the addition was completed, the temperature was raised to 95 °C and stirred for 18 hours. After the reaction monitoring was completed, the reaction solution was cooled to room temperature and slowly poured into ice water to quench. Then water and dichloromethane were added thereto for extraction, and the extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain compound TM14-4 (1.85 g, yellow solid, yield 43.58%). Mass spectrum LCMS: (M+H)+: 367.1.

[0343] Synthesis of compound TM14-5: Compound TM14-4 (1.0 g, 2.72 mmol, 1 eq) was dissolved in N,N-dimethylformamide (15 mL). Then, bromomethylbenzene (442.4 mg, 95%, 288.97 μL, 3.54 mmol, 1.3 eqq) was slowly added to the reaction bottle at 0°C. After the addition was completed, the temperature was slowly raised to 25°C and stirred for 18 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was collected and dried under vacuum, and then silica gel was added to the sample, and the sample was separated and purified by normal phase separation (petroleum ether: ethyl acetate = 1:1) to obtain compound TM14-5 (800 mg, yellow solid, yield (71.4%). Mass spectrum LCMS of compound TM14-5: (M+H)+: 411.1.

[0344] Synthesis of compound TM14-6: Compound TM14-5 (700 mg, 1.70 mmol, 1 eq) and compound TM2-5A (406 mg, 1.70 mmol, 1 eq) were dissolved in 1.4-dioxane (15 mL). Then, tris(dibenzyl-BASE acetone)dipalladium(0) (312 mg, 340.42 μmol, 0.2 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (424 mg, 98%, 680.83 μmol, 0.4 eq) and cesium carbonate (1.39 g, 99.9%, 4.26 mmol, 2.5 eq) were added to the reaction flask at 25°C. After the addition was completed, the mixture was protected by nitrogen, heated to 110°C and stirred for 4 hours. After the reaction, the reaction solution was filtered, the filtrate was collected and dried under vacuum, and then silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1: 1) were performed to obtain compound TM14-6 (500 mg, yellow solid, yield (51.7%). LCMS of compound TM14-6: (M+H) +: 569.3

[0345] Synthesis of compound TM14-7: Compound TM14-6 (300 mg, 527.60 μmol, 1 eq) was dissolved in dichloroethane (30 mL), and Grubbs second-generation catalyst (179 mg, 97%, 211.04 μmol, 0.4 eq) was added thereto. Nitrogen was replaced three times, and the reaction solution was stirred at 85 ° C for 4 hours. After the reaction monitoring was completed, it was cooled to room temperature and the catalyst was filtered using diatomaceous earth. The filtrate was spin-dried under vacuum and purified by normal phase separation (ethyl acetate: methanol = 10: 1) to obtain compound TM14-7 (25.9 mg, yellow solid, yield 10.8%, purity 98.51%). Mass spectrum LCMS of compound TM14-7: (M+H) +: 541.3.

[0346] Synthesis of compound TM14-8: Compound TM14-7 (90 mg, 166.50 μmol, 1 eq) was dissolved in dichloromethane (2 mL), and then hydrochloric acid / 1.4-dioxane (0.2 mL) was added thereto at 0°C. Nitrogen was replaced three times, and the reaction solution was stirred at room temperature for 4 hours. After the reaction monitoring was completed, the filtrate was spin-dried under vacuum to obtain compound TM14-8 (80 mg, yellow solid, crude). The mass spectrum of compound 8 LCMS: (M+H)+: 497.3.

[0347] Synthesis of compound TM14-9: Compound TM14-8 (80 mg, 161.13 μmol, 1 eq) and triethylamine (82 mg, 805.64 μmol, 5 eq) were dissolved in dichloromethane (10 mL). Trifluoromethanesulfonic anhydride (0.1 mL) was added thereto. Nitrogen was replaced, and the reaction solution was stirred at 25 °C for 2 hours. After the reaction monitoring was completed, the reaction solution was spin-dried. Then saturated sodium carbonate aqueous solution and ethyl acetate were added thereto for extraction, and the extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain compound 9 (100 mg, Crude, yellow solid, yield: 98.74%). Mass spectrum LCMS of compound TM14-9: (M+H)+: 629.1.

[0348] Synthesis of compound TM14: Compound TM14-9 (100 mg, 159.09 μmol, 1 eq), compound TM14-10 (93.6 mg, 98%, 318.19 μmol, 2 eq), 1,1-bis(diphenylphosphine)diiron palladium dichloride (46.6 mg, 98%, 63.64 μmol, 0.4 eq), and potassium carbonate (66 mg, 477.28 μmol, 3 eq) were dissolved in dioxane (4 mL) and water (0.5 mL). The reaction solution was stirred at 90 °C for 18 hours. After the reaction monitoring was completed, the reaction mixture was cooled to room temperature, and the reaction solution was filtered. The filtrate was concentrated under vacuum and then silica gel was added to mix the sample. Normal phase separation and purification (ethyl acetate: methanol = 10:1) was performed to obtain the crude compound ND-H2-001, and then reverse phase separation and purification (water (0.1% formic acid) - acetonitrile) was performed to obtain compound ND-H2-001 (9 mg, yellow solid, yield was 9.55%, purity was 95.12%). 1 H NMR (400MHz, DMSO-d6) δ13.02(s,1H),10.55(s,1H),9.47(d,J=1.8Hz,1H),9.33(s,1 H),8.48(dd,J=8.9,4.3Hz,2H),8.24(s,1H),7.94(s,1H),7.72–7.67(m,2H),7.60(s ,1H),7.43(dd,J=12.7,1.2Hz,1H),7.32–7.24(m,2H),7.19(s,1H),7.00–6.90(m,1H ), 6.86 (d, J = 15.8Hz, 1H), 4.35 (s, 2H), 2.82 (d, J = 4.5Hz, 3H), 2.77 (d, J = 6.2Hz, 2H). LCMS:(M+H)+:547.2.

[0349] Embodiment 15

[0350] Experimental steps:

[0351]

[0352] Synthesis of compound TM15-1A: Compound TM15-0 (10 g, 52.6 mmol, 1.0 eq) and vinylboronic acid pinacol ester (16.2 g, 105.3 mmol, 2.0 eq) were dissolved in dioxane (60 mL) and water (10 mL), and (1,1'-bis(diphenylphosphino)ferrocene) palladium dichloride (116 g, 650 mmol, 1.1 eq) and potassium carbonate (21.8 g, 157.9 mmol, 3.0 eq) were added thereto. The reaction solution was stirred at 90°C for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered and dried, mixed with silica gel, and purified by normal phase separation (petroleum ether: ethyl acetate = 5:1) to obtain compound 1A (5.7 g, yellow oily liquid, yield 79%). Mass spectrum LCMS of compound TM15-1A: (M+1) + :138.0.

[0353]

[0354] Synthesis of compound TM15-2: Compound TM15-1 (1.0 g, 385 mmol, 1.0 eq) and compound TM15-1A (529 mg, 385 mmol, 1.0 eq) were dissolved in N-methylpyrrolidone (30 mL), and p-toluenesulfonic acid (1.33 g, 7.71 mmol, 2.0 eq) was added thereto. The reaction solution was stirred at 95 ° C for 16 hours. After the reaction monitoring was completed, a saturated bicarbonate solution was added to the reaction solution for quenching, and then ethyl acetate and water were added thereto for extraction. The extracted organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) was performed to obtain compound TM15-2 (410 mg, yellow solid, yield 30%). Mass spectrum LCMS of compound TM15-2: (M+1)+: 360.0, 362.0.

[0355] Synthesis of compound TM15-3: Compound TM15-2 (923 mg, 1.64 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL), and tert-butyldimethylsilyl chloride (371 mg, 2.46 mmol, 1.5 eq) and 1H-imidazole (223 mg, 3.28 mmol, 2.0 eq) were added thereto. The reaction solution was stirred at 25 °C for 16 hours. After the reaction monitoring was completed, ethyl acetate and water were added thereto for extraction. The extracted organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and then silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 5:1) was performed to obtain compound TM15-3 (420 mg, yellow solid, yield 54%). Mass spectrum LCMS of compound TM15-3: (M+1)+: 474.2, 476.1.

[0356] Synthesis of compound TM15-4: Compound TM15-3 (787 mg, 1.66 mmol, 1.0 eq) and TM2-5A (514 mg, 2.16 mmol, 1.3 eq) were dissolved in 1,4-dioxane (20 mL), and tridibenzylideneacetone dipalladium (152 mg, 0.17 mmol, 0.1 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (207 mg, 0.33 mmol, 0.2 eq) and cesium carbonate (1.62 g, 4.98 mmol, 3.0 eq) were added thereto. The reaction solution was stirred at 100 ° C for 6 hours under nitrogen protection. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under vacuum, and silica gel was added to the sample, and the normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) was obtained to obtain compound TM15-4 (0.6 g, yellow solid, yield 57%). Mass spectrum LCMS of compound TM15-4: (M+1)+: 632.3.

[0357] Synthesis of compound TM15-5: Compound TM15-4 (600 mg, 0.95 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (100 mL), 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinyl) (dichlorobenzylidene) (tricyclohexylphosphine) ruthenium (322 mg, 0.38 mmol, 0.4 eq) was added thereto, and the mixture was stirred at 60°C for 16 hours under nitrogen protection. After the reaction monitoring was completed, the reaction solution was spin-dried under vacuum. Silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) were performed to obtain compound TM15-5 (180 mg, yellow-black solid, yield 31%). Mass spectrum LCMS of compound TM15-5: (M+1)+: 604.3.

[0358] Synthesis of compound TM15-6: Compound TM15-5 (180 mg, 0.3 mmol, 1.0 eq) was dissolved in tetrahydrofuran (140 mL). Tetrabutylammonium fluoride (0.6 mL, 0.6 mmol, 2.0 eq) was added thereto. The reaction was stirred at 25 °C for 1 hour. After the reaction monitoring was completed, water and ethyl acetate were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain a crude compound TM15-6 (145 mg, yellow solid). Mass spectrum LCMS of compound TM15-6: (M+1)+: 490.1.

[0359] Synthesis of compound TM15-7: Compound TM15-6 (135 mg, 0.28 mmol, 1.0 eq) and triethylamine (55.8 mg, 0.55 mmol, 2.0 eq) were dissolved in dichloromethane (20.0 mL), and trifluoromethanesulfonic anhydride (93 mg, 0.33 mmol, 1.2 eq) was added thereto at 0°C. Then the reaction was stirred at 25°C for 3 hours. After the reaction monitoring was completed, the reaction solution was concentrated and silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) were performed to obtain compound TM15-7 (60 mg, yellow-black solid, yield: 35%). Mass spectrum LCMS of compound TM15-7: (M+1)+: 622.0.

[0360] Synthesis of compound TM15-8: Compound TM15-7 (55 mg, 0.088 mmol, 1.0 eq) and compound TM15-7A (63 mg, 0.13 mmol, 1.5 eq) were dissolved in a mixed solution of 1,4-dioxane (50.0 mL) and water (10.0 mL). Potassium carbonate (25 mg, 0.18 mmol, 2.0 eq) and DPPF palladium dichloride (6.5 mg, 0.0088 mmol, 0.1 eq) were added thereto. The reaction solution was stirred at 90 ° C for 0.5 hours. After the reaction monitoring was completed, it was cooled to room temperature and the reaction solution was concentrated under vacuum. Then water and ethyl acetate were added thereto for extraction, and the extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and then silica gel was added to stir the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) was performed to obtain compound TM15-8 (47 mg, yellow colloid, yield 65%). The mass spectrum of compound TM15-8 LCMS: (M+1)+: 823.3.

[0361] Synthesis of compound TM15: Compound TM15-8 (47 mg, 0.057 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL). Tetrabutylammonium fluoride (0.11 mL, 0.11 mmol, 2.0 eq) was added thereto. The reaction was stirred at 25 °C for 0.5 hours. After the reaction monitoring was completed, water and ethyl acetate were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain a crude compound, which was then separated and purified by reverse phase separation (water (0.1% formic acid)-acetonitrile) to obtain compound TM15 (10.2 mg, yellow solid, yield of 31%, purity of 98.9%). Mass spectrum LCMS of compound TM15: (M+1)+: 584.3. 1 H NMR(400MHz, DMSO-d6)δ10.08(s,1H),9.28(dd,J=7.0,2.2Hz,1H),9.25(s,1H),8.48(q, J=4.4Hz,1H),8.16(s,1H),7.88(s,1H),7.62(d,J=1.6Hz,1H),7.60(s,1H),7.43(dd,J= 12.7,1.0Hz,1H),7.21–7.09(m,4H),6.83–6.69(m,2H),4.93(t,J=5.2Hz,1H),4.16(t,J =5.6Hz,2H),3.76(q,J=5.5Hz,2H),2.81(d,J=4.5Hz,3H),2.71(dd,J=11.8,5.7Hz,2H).

[0362] Example 16

[0363] Experimental steps:

[0364]

[0365] Synthesis of compound TM16-2: Compound TM16-1 (24 g, 104.3 mmol, 1.0 eq), TM6-1A (24.1 g, 156.5 mmol, 1.5 eq), potassium carbonate (43.2 g, 314 mmol, 3 eq) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (4.3 g, 5.3 mmol, 0.05 eq) were added to 1,4-dioxane (500 mL) and water (100 mL), and nitrogen was replaced three times. The reaction temperature was raised to 90 ° C for 6 hours. After the reaction monitoring was completed, the reaction solution was concentrated, and compound TM16-2 (17 g, yield: 91%, yellow oily liquid) was obtained after forward separation (PE: EA = 5: 1). Mass spectrum LCMS of compound TM16-2: (M+1) + :178.1.

[0366] Synthesis of compound TM16-3: Compound TM16-2 (6.5 g, 36.7 mmol, 1.2 eq), TM1-4A (8 g, 1 mmol, 1.0 eq), trifluoroacetic acid (5.2 g, 46 mmol, 1.5 eq) were added to isopropanol (160 mL). The reaction temperature was raised to 90 ° C for 12 hours. After the reaction monitoring was completed, ethyl acetate (50 mL) was added to the reaction solution, filtered, and the solid on the filter cake was washed with ethyl acetate. After drying, compound TM16-3 (8.4 g, yield: 68%, yellow solid) was obtained. Mass spectrum LCMS of compound TM16-3: (M+1)+: 402.0.

[0367] Synthesis of compound TM16-4: Compound TM16-3 (5 g, 12.5 mol, 1.0 eq), TM2-5A (3.3 g, 13.7 mol, 1.1 eq), cesium carbonate (12.2 g, 37.3 mol, 3 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.55 g, 2.5 mol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (1.14 g, 1.2 mol, 0.1 eq) were added to 1,4-dioxane (100 mL), replaced with nitrogen three times, and the reaction temperature was raised to 110 ° C for 3 hours. After the reaction monitoring was completed, the reaction solution was concentrated, and compound TM16-4 (4.5 g, yield: 65%, yellow solid) was obtained after forward separation (PE: EA = 1: 1). The mass spectrum of compound TM16-4 LCMS: (M+1) +: 560.2.

[0368] Synthesis of compound TM16-5: Compound TM16-4 (4.5 g, 6.3 mol, 1.0 eq) and Grubbs second-generation catalyst (2.8 g, 2.5 mol, 0.4 eq) were added to 1,2-dichloromethane (450 mL), replaced with nitrogen three times, and the reaction temperature was raised to 65 ° C for 5 hours. After the reaction monitoring was completed, the reaction solution was concentrated, and compound TM16-5 (1.6 g, yield: 37.4%, yellow solid) was obtained after forward separation (PE: EA = 2: 3). The mass spectrum of compound TM16-5 LCMS: (M+1) +: 532.1.

[0369] Synthesis of compound TM16-6: Compound TM16-5 (1.6 g, 3.0 mmol, 1 eq) was added to tetrahydrofuran (10 mL), methanol (5 mL) and water (10 mL) under an ice bath, and then lithium hydroxide (2.27 g, 54.2 mmol, 18 eq) was added to the reaction solution, and then the temperature was raised to 55°C for 20 hours. After the reaction monitoring was completed, impurities were extracted with ethyl acetate, the aqueous phase was adjusted to a pH of about 6 with 6M hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried and concentrated to obtain compound TM16-6 (1.2 g, yield: 77%, yellow solid). Mass spectrum LCMS of compound TM16-6: (M+1)+: 518.1.

[0370] Synthesis of compound TM16: Compound TM16-6 (70 mg, 135.3 μmol, 1.0 eq) was added to N, N-dimethylformamide (1.5 mL) under ice bath, and then N, N-diisopropylethylamine (53 mg, 67.1 μmol, 3 eq), (7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (77 mg, 203 μmol, 1.5 eq) and 6A (27.6 mg, 270 μmol, 2 eq) were added, and the temperature was automatically raised to room temperature for 2 hours. After the reaction monitoring was completed, water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution, the aqueous layer was extracted three times, the organic layer was concentrated, and the concentrated mixture was prepared under high pressure to obtain the final product TM16 (29 mg, yield: 35.6%, yellow solid, purity 99%). LCMS of TM16: (M+1)+: 602.3. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.30(s,1H),9.22(d,J=8.1Hz,1H),8.52–8.47 (t,1H),8.17(s,1H),7.60(s,1H),7.43(d,J=12.4Hz,1H),7.35(s,1H),7.23–7.11(m, 3H),6.79–6.52(m,3H),4.41(s,2H),3.58(s,2H),3.16(d,J=6.7Hz,3H),2.99(s,1H), 2.81(d,J=4.5Hz,3H),2.75(s,2H),2.65(d,J=13.5Hz,2H),2.24(s,6H),1.91(s,2H).

[0371] Embodiment 17

[0372] Experimental steps:

[0373]

[0374] Synthesis of TM17: Compound TM16-6 (70 mg, 135.3 μmol, 1.0 eq) was added to N, N-dimethylformamide (1.5 mL) under ice bath, and then N, N-diisopropylethylamine (53 mg, 67.1 μmol, 3 eq), (7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (77 mg, 203 μmol, 1.5 eq) and TM17-1A (21.74 mg, 185 μmol, 1.2 eq) were added, and the temperature was automatically raised to room temperature for 2 hours. After the reaction monitoring was completed, water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution, the aqueous layer was extracted three times, the organic layer was concentrated, and the concentrated mixture was prepared under high pressure to obtain the final product TM17 (63 mg, yield: 76.3%, yellow solid, purity 99%). Mass spectrum LCMS: (M+1)+: 617.3. 1 HNMR (400MHz, DMSO-d6) δ10.23(d,J=4.0Hz,1H),9.30(s,1H),9.22(s,1H),8.50(d,J=4.6Hz,1H),7.60(s,1H) ,7.44(dd,J=12.5,1.2Hz,1H),7.35(d,J=2.6Hz,1H),7.21(dd,J=8.3,2.5Hz,1H),7.13(dt,J=8.3,7.0Hz,2H), 6.81–6.64(m,2H),6.52(d,J=15.8Hz,1H),4.34(s,2H),4.13(s,1H),3.56–3.49(t,1H),3.20–3.09(t,2H),2.9 6(d,J=6.0Hz,2H),2.81(d,J=4.4Hz,3H),2.73(s,1H),2.66(d,J=13.2Hz,2H),1.71–1.64(t,1H),1.57–1.50(t 1H),1.16(s,3H),0.84(s,3H).

[0375] Embodiment 18

[0376] Experimental steps:

[0377]

[0378] Synthesis of compound TM18-2: Compound TM16-6 (150 mg, 289.9 μmol, 1.0 eq) was added to N, N-dimethylformamide (3 mL) under ice bath, and then N, N-diisopropylethylamine (112.4 mg, 869.6 μmol, 3 eq), (7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (165.4 mg, 434.8 μmol, 1.5 eq) and TM18-1A (75 mg, 434.9 μmol, 1.5 eq) were added, and the temperature was automatically raised to room temperature for 2 hours. After the reaction monitoring was completed, water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution, the aqueous layer was extracted three times, the organic layer was concentrated, and the concentrated mixture was prepared under high pressure to obtain compound TM18-2 (180 mg, yield: 92%, yellow solid, purity 99%). Mass spectrum LCMS of compound TM18-2: (M+1)+: 672.4.

[0379] Synthesis of compound TM18: Compound TM18-1 (130 mg, 193.5 μmol, 1.0 eq) was added to 1,4-dioxane hydrochloride (4 mL) and reacted at 25°C for 0.5 hours. After the reaction monitoring was completed, the reaction solution was concentrated and the final product TM18 (30 mg, yield: 27.1%, yellow solid, purity 99%) was prepared under high pressure. The mass spectrum of compound TM18 LCMS: (M+1)+: 572.2. 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.32(s,1H),9.16(d,J=2.1Hz,1H),8.83(d,J=7.0Hz,1H),8.55–8.49 (dd,1H),8.37(s,1H),7.61(s,1H),7.47–7.40(m,2H),7.36(s,1H),7.19(ddd,J=17.2,8.3,2.4Hz,2H),7.0 4(d,J=15.8Hz,1H),6.77(ddd,J=10.7,7.8,2.6Hz,1H),6.60–6.49(m,1H),4.73(dd,J=14.7,7.1Hz,1H),4. 43(s,2H),3.88(t,J=8.4Hz,2H),3.78(t,J=8.2Hz,2H),2.82(d,J=4.5Hz,3H),2.63(dd,J=12.4,5.6Hz,2H).

[0380] Embodiment 19

[0381] Experimental steps:

[0382]

[0383] Synthesis of compound TM19-2: Compound TM19-1 (1.00 g, 5.02 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10.0 mL). Methylmagnesium bromide (1.80 g, 15.1 mmol, 3.0 eq) was slowly added thereto at 0 °C. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was stirred for 1 hour. After the reaction monitoring was completed, ammonium chloride solution was slowly added to the reaction solution for quenching. Ethyl acetate and water were added thereto for extraction, and the extracted organic phase was dried and filtered using anhydrous sodium sulfate. The filtrate was spin-dried under vacuum to obtain a crude product of compound TM19-2 (1.00 g, yellow oily liquid, yield 93%). Mass spectrum LCMS of compound 2: (M+1-100)+: 116.0.

[0384] Synthesis of compound TM19-3: Compound TM19-2 (900 mg, 4.18 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2.00 mL), and 4M dioxane hydrochloride solution (1.31 g, 36.0 mmol) was added thereto. The reaction solution was stirred at 25°C for 1 hour. The reaction was completed when a large amount of red solid precipitated from the reaction solution. The reaction solution was spin-dried under vacuum to obtain a crude product of compound TM19-3 (470 mg, yellow jelly solid, yield 98%).

[0385] Synthesis of compound TM19: Compound TM19-3 (44.5 mg, 0.386 mmol, 2.0 eq) and compound TM16-6 (100 mg, 0.193 mmol, 1.0 eq) were dissolved in N,N-dimethylformamide (1.50 mL), N,N-diisopropylethylamine (125 mg, 0.966 mmol, 5.0 eq) and 1-hydroxybenzotriazole (28.7 mg, 0.213 mmol, 1.1 eq) were added thereto in sequence, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48.2 mg, 0.251 mmol, 1.3 eq) was added thereto at 0°C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for reaction for 1 hour. After the reaction monitoring was completed, the reaction solution was filtered and subjected to reverse phase separation and purification (water (0.1% formic acid)-acetonitrile) to obtain compound TM19 (38.4 mg, yellow solid, yield 32%, purity 99%). The mass spectrum LCMS of compound TM19: (M+1)+: 615.3. 1H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.31(s,1H),9.23(s,1H),8.50(q,J=4.5Hz,1H),7.60(s,1H),7.44(dd,J=12.5,1.7Hz, 1H),7.35(s,1H),7.21(dd,J=8.3,2.6Hz,1H),7.16(dd,J=8.3,2.1Hz,1H),7.07(d,J=8.5Hz,1H),6.78(ddd,J=10.7,7.8,2.6H z,1H),6.69(dt,J=15.3,7.5Hz,1H),6.48(d,J=15.8Hz,1H),5.06(d,J=13.6Hz,1H),4.48(d,J=51.7Hz,2H),3.77–3.52(t,1H) ,2.99(s,2H),2.81(d,J=4.4Hz,3H),2.66(dd,J=26.9,11.2Hz,3H),2.21(s,3H),1.93(s,1H),1.34–1.24(s,1H),0.95(s,2H).

[0386] Embodiment 20

[0387] Experimental steps:

[0388]

[0389] Synthesis of compound TM20-2: Compound TM20-1 (9.00 g, 36.0 mmol, 1.00 eq) and N,N,N'-trimethylethylenediamine (3.97 g, 38.9 mmol, 1.08 eq) were dissolved in acetonitrile (220 mL), replaced with nitrogen three times, and potassium carbonate (12.56 g, 90.9 mmol, 2.00 eq) was added under stirring in a water bath, and reacted at room temperature for 14 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was dried and dissolved in ethyl acetate, saturated brine (100 mL) was added, extracted, and the organic phase was dried over anhydrous sodium sulfate and dried to obtain compound TM20-2 (12.0 g, yellow oil, yield 100%). Compound TM20-2 mass spectrum LCMS: (M+1)+: 332.1.

[0390] Synthesis of compound TM20-3: Compound TM20-2 (7.00 g, 21.1 mmol, 1.00 eq), vinylboronic acid pinacol ester (6.49 g, 42.1 mmol, 2.00 eq), potassium carbonate (8.74 g, 63.2 mmol, 3.00 eq) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (771 mg, 1.05 mmol, 0.05 eq) were dissolved in 1,4-dioxane (80 mL) and water (16 mL), replaced with nitrogen three times, and reacted at 80 ° C for 5 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was filtered through diatomaceous earth, the filtrate was extracted with water and ethyl acetate, the organic phases were combined, dried, and spin-dried to obtain a crude compound TM20-3 (12.8 g, red oil, yield 217%). Compound TM20-3 mass spectrum LCMS: (M+1)+: 280.1.

[0391] Synthesis of compound TM20-4: Compound TM20-3 (12.8 g, 45.8 mmol, 1.00 eq) was dissolved in methanol (120 mL) and water (24 mL), and ammonium chloride (24.5 g, 458 mmol, 10.00 eq) was added. Zinc powder (15.0 g, 229 mmol, 5.00 eq) was added in portions under an ice bath, and the mixture was reacted at room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered, potassium carbonate was added to the filtrate under an ice bath until the pH was 8, and a large amount of methanol was removed by rotary evaporation. Water and ethyl acetate were added for extraction, the organic phases were combined, dried by rotary evaporation, mixed, and purified by normal phase (petroleum ether: ethyl acetate = 1:5) to obtain compound TM20-4 (2.80 g, yellow oil, yield 24.5%). Compound 4 mass spectrum LCMS: (M+1)+: 250.2.

[0392] Synthesis of compound TM20-5: Compound TM20-4 (1.70 g, 6.82 mmol, 1.15 eq) and compound TM1-4A (1.55 g, 5.93 mmol, 1.00 eq) were dissolved in isopropanol (35 mL), trifluoroacetic acid (1.76 mL, 23.7 mmol, 4.00 eq) was added dropwise under ice bath, and the mixture was reacted at 90°C for 14 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was spin-dried, dissolved in N,N-dimethylformamide (25 mL), and purified by reverse phase (water (0.1% trifluoroacetic acid): acetonitrile) to obtain compound TM20-5 (1.67 g, brown solid, yield 44.5%). Compound 5 mass spectrum LCMS: (M+1)+: 474.1.

[0393] Synthesis of compound TM20-6: Compound TM20-5 (591 mg, 1.16 mmol, 1.00 eq), compound TM2-5A (304 mg, 1.28 mmol, 1.10 eq), cesium carbonate (1.32 g, 4.06 mmol, 3.50 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (144 mg, 0.232 mmol, 0.200 eq) and tris(dibenzylideneacetone)dipalladium (106 mg, 0.116 mmol, 0.100 eq) were dissolved in 1,4-dioxane (15 mL), replaced with nitrogen three times, and reacted at 110° C. for 15 hours. After the reaction monitoring was completed, the reaction solution was cooled to room temperature, the reaction solution was spin-dried, the sample was mixed, and the normal phase was purified (petroleum ether: ethyl acetate = 0:1) to obtain compound TM20-6 (150 mg, yellow solid, yield 20.5%). Mass spectrum LCMS of compound TM20-6: (M+1)+: 632.4.

[0394] Synthesis of compound TM20: Compound TM20-6 (145 mg, 0.230 mmol, 1.00 eq) was dissolved in 1,2-dichloroethane (14.5 mL), p-toluenesulfonic acid (98.8 mg, 0.574 mmol, 2.50 eq) and Grubbs second-generation catalyst (78.0 mg, 0.0918 mmol, 0.400 eq) were added, nitrogen was replaced three times, and the reaction was carried out at 80°C for 8 hours. After the reaction monitoring was completed, the reaction solution was cooled to room temperature, and the reaction solution was directly mixed and purified by normal phase (ethyl acetate: methanol = 10:1) to obtain 75 mg of crude product. The crude product was purified by high pressure preparation (water (0.225% formic acid): acetonitrile = 1:1)) to obtain TM20 (10.9 mg, yellow solid, yield 7.53%). TM20 spectrum LCMS: (M+1)+: 604.4. 1H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.93(s,1H),8.53–8.48(dd,1H),8.41(s,1H),8.19(s,1H),7.61(d,J=0. 6Hz,1H),7.43(dd,J=12.4,1.3Hz,1H),7.33(s,1H),7.18(dt,J=7.7,2.1Hz,1H),6.80–6.71(m,3H),6.36–6.2 7(m,1H),4.46(t,J=5.4Hz,2H),3.91(s,3H),3.02–2.98(t,2H),2.81(d,J=4.5Hz,3H),2.70(s,3H),2.67(dt, J=3.8,1.9Hz,1H),2.61(dd,J=12.6,6.5Hz,2H),2.42–2.37(t,2H),2.33(dt,J=3.7,1.9Hz,1H),2.12(s,6H).

[0395] Embodiment 21

[0396] Experimental steps:

[0397]

[0398] Synthesis of compound TM21-2: Compound TM21-1 (10.0 g, 45.4 mmol, 1.00 eq) and methyl (2-(methylamino)ethyl) carbamic acid tert-butyl ester (9.58 g, 50.9 mmol, 1.12 eq) were dissolved in acetonitrile (200 mL), replaced with nitrogen three times, and potassium carbonate (12.56 g, 90.9 mmol, 2.00 eq) was added under stirring in a water bath, and reacted at room temperature for 14 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was dried and dissolved in ethyl acetate, saturated brine (100 mL) was added, extracted, dried over anhydrous sodium sulfate, and dried to obtain compound TM21-2 (19.0 g, yellow liquid). LCMS of compound TM21-2: (M+1)+: 388.1.

[0399] Synthesis of compound TM21-3: Compound TM21-2 (10.0 g, 25.8 mmol, 1.00 eq), compound vinylboronic acid pinacol ester (7.93 g, 51.5 mmol, 2.00 eq), potassium carbonate (10.7 g, 77.3 mmol, 3.00 eq) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (943 mg, 1.29 mmol, 0.05 eq) were dissolved in 1,4-dioxane (100 mL) and water (20 mL), replaced with nitrogen three times, and reacted at 80°C for 3 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was filtered through diatomaceous earth, the filtrate was extracted with water and ethyl acetate, the organic phases were combined, dried, and spin-dried to obtain a crude compound TM21-3 (14.3 g, orange oil). Compound TM21-3 mass spectrum LCMS: (M+1)+: 336.1.

[0400] Synthesis of compound TM21-4: Compound TM21-3 (12.8 g, 38.0 mmol, 1.00 eq) was dissolved in methanol (130 mL) and water (20 mL), and ammonium chloride (20.3 g, 380 mmol, 10.00 eq) was added. Zinc powder (12.4 g, 190 mmol, 5.00 eq) was added in portions under an ice bath, and the mixture was reacted at room temperature for 3 hours. After the reaction monitoring was completed, the reaction solution was filtered, potassium carbonate was added to the filtrate under an ice bath until pH = 8, a large amount of methanol was removed by rotary evaporation, and water and ethyl acetate were added for extraction. The organic phases were combined and dried by rotary evaporation, mixed, and purified by normal phase (petroleum ether: ethyl acetate = 5:1) to obtain compound TM21-4 (4.24 g, orange oil, yield 36.5%). Compound TM21-4 mass spectrum LCMS: (M+1)+: 306.2.

[0401] Synthesis of compound TM21-5: Compound TM21-4 (750 mg, 2.46 mmol, 1.10 eq) and compound TM1-4A (584 mg, 2.23 mmol, 1.00 eq) were dissolved in N, N-dimethylformamide (15 mL), potassium carbonate (617 mg, 4.46 mmol, 2.00 eq) and 4A molecular sieve (810 mg, 3.35 mmol, 1.50 eq) were added, and the mixture was reacted at 80°C for 18 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was filtered, the filtrate was extracted with water and ethyl acetate, the organic phases were combined, back-extracted twice with saturated brine, dried, spin-dried, mixed, and purified by normal phase (petroleum ether: ethyl acetate = 1:1) to obtain compound TM21-5 (300 mg, yellow solid, yield 12.7%). Compound TM21-5 mass spectrum LCMS: (M+1)+: 530.2.

[0402] Synthesis of compound TM21-6: Compound TM21-5 (260 mg, 0.490 mmol, 1.00 eq), compound TM2-5A (128 mg, 0.539 mmol, 1.10 eq), cesium carbonate (479 mg, 1.47 mmol, 3.00 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (61.0 mg, 0.0980 mmol, 0.200 eq) and tris(dibenzylideneacetone)dipalladium (44.9 mg, 0.0490 mmol, 0.100 eq) were dissolved in 1,4-dioxane (8 mL), replaced with nitrogen three times, and reacted at 110° C. for 2.5 hours. After the reaction monitoring was completed, the reaction solution was cooled to room temperature, the reaction solution was spin-dried, the sample was mixed, and the normal phase was purified (petroleum ether: ethyl acetate = 1:1) to obtain compound TM21-6 (300 mg, yellow solid, yield 89.0%). Mass spectrum LCMS of compound TM21-6: (M+1)+: 688.4.

[0403] Synthesis of compound TM21-7: Compound TM21-6 (155 mg, 0.225 mmol, 1.00 eq) was dissolved in 1,2-dichloroethane (15.5 mL), Grubbs second-generation catalyst (76.5 mg, 0.0901 mmol, 0.400 eq) was added, nitrogen was replaced three times, and the reaction was carried out at 80°C for 15 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was directly mixed with a sample, and normal phase purification (petroleum ether: ethyl acetate = 1:1) was performed to obtain compound TM21-7 (140 mg, brown solid, yield 47.1%). Compound TM21-7 mass spectrum LCMS: (M+1)+: 660.3.

[0404] Synthesis of compound TM21: Compound TM21-7 (110 mg, 0.167 mmol) was dissolved in dioxane (0.5 mL), and 4 M hydrochloric acid dioxane solution (5 mL) was added under ice bath, and the reaction was carried out at room temperature for 0.5 hours. After the reaction monitoring was completed, the reaction solution was spin-dried, and the crude product was purified by high pressure preparation (water (0.225% formic acid): acetonitrile = 3:1)) to obtain TM21 (44.7 mg, yellow solid, yield 41.4%). TM21 spectrum LCMS: (M+1)+: 560.3. 1H NMR (400MHz, DMSO-d6) δ9.99(s,1H),9.25(s,1H),9.00(d,J=2.4Hz,1H),8.52(q,J=4.3Hz,1H),8.30(s,1H),7. 62(s,1H),7.44(dd,J=12.0,0.9Hz,1H),7.33(s,1H),7.17(dd,J=8.4,2.6Hz,1H),7.12(dd,J=8.6,2.3Hz,1H),7 .07(d,J=8.6Hz,1H),6.94(d,J=16.0Hz,1H),6.73(ddd,J=10.5,7.7,2.5Hz,1H),6.51–6.41(dd,1H),4.46(s,2 H),3.04(t,J=6.5Hz,3H),2.80(dd,J=12.0,5.5Hz,6H),2.66(dd,J=11.8,5.0Hz,2H),2.61(s,3H),2.38(s,3H).

[0405] Embodiment 22

[0406] Experimental steps:

[0407]

[0408] Synthesis of compound TM22-2: Compound TM21-1 (22.0 g, 100 mmol, 1.00 eq) and TM22-1A (22.4 g, 16.9 mL, 120 mmol, 1.20 eq) were added to ACN (400 mL) and K2CO3 (41.5 g, 17.1 mL, 300 mmol, 3.00 eq) was reacted at 90°C for 72 hours. After the reaction monitoring was completed, water and ethyl acetate were added for extraction three times, the organic layers were combined and extracted once with saturated brine, and the organic layers were dried and concentrated to obtain a crude compound TM22-2 (38.0 g, yellow solid, yield 99%), which can be directly used in the next step. The mass spectrum of compound TM22-2 LCMS: (M+23)+: 408.1.

[0409] Synthesis of compound TM22-3: Add HCl (29.2 g, 200 mL, 800 mmol, 8.35 eq, 4 M / 1,4-dioxane) to compound TM22-2 (37.0 g, 95.8 mmol, 1.00 eq) in a 1,4-dioxane (50 mL) solution and react at room temperature for 1 hour. After the reaction monitoring is completed, the reaction solution is concentrated to obtain compound TM22-3 (27.0 g, yellow solid, yield 98%). LCMS of compound TM22-3: (M+1) + :286.0.

[0410] Synthesis of compound TM22-4: Compound TM22-3 (15.0 g, 52.4 mmol, 1.00 eq) and K2CO3 (21.7 g, 8.95 mL, 157 mmol, 3.00 eq) were added to ACN (300 mL) solution, and TM22-3A (15.1 g, 13.5 mL, 62.9 mmol, 1.20 eq) was added, and the mixture was reacted at 90°C for 16 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was concentrated, and then ethyl acetate (500 mL) and water (200 mL) were added for extraction, and then extracted three times with ethyl acetate (100 mL). The mixed organic layer was washed once with saturated brine (100 mL), dried and filtered with Na2SO4, and concentrated to obtain compound TM22-4 (23.1 g, yellow solid, yield 99%). Mass spectrum LCMS of compound TM22-4: (M+1)+: 444.2.

[0411] Synthesis of compound TM22-5: Compound TM22-4 (23.0 g, 51.8 mmol, 1.00 eq), vinylboronic acid pinacol ester (9.56 g, 10.5 mL, 62.1 mmol, 1.20 eq) and K2CO3 (21.5 g, 8.83 mL, 155 mmol, 3.00 eq) were added to H2O (60 mL) and 1,4-dioxane (300 mL) and Pd(dppf)Cl2 (2.11 g, 2.59 mmol, 0.05 eq). After nitrogen replacement three times, the reaction was carried out at 90°C for 6 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was concentrated, and then ethyl acetate (300 mL) and water (200 mL) were added for extraction, and then ethyl acetate (50 mL) was used for extraction three times. The mixed organic layer was washed once with saturated brine (100 mL), dried and filtered with Na2SO4, and the organic layer was concentrated under vacuum to obtain compound TM22-5 (20.0 g, brown oily liquid, yield 98%). It can be directly used in the next step without purification. The mass spectrum of compound TM22-5 LCMS: (M+1)+: 392.3.

[0412] Synthesis of compound TM22-6: Compound TM22-5 (20.0 g, 51.1 mmol, 1.00 eq) and NH4Cl (13.7 g, 8.99 mL, 255 mmol, 5.00 eq) were added to MeOH (200 mL) and H2O (100 mL) in batches, and Zn powder (16.7 g, 2.34 mL, 255 mmol, 5.00 eq) was added in an ice bath. After the addition was completed, the reaction solution was slowly returned to room temperature and reacted for 16 hours. After the reaction detection was completed, the reaction solution was filtered, the filtrate was concentrated, and then a saturated sodium carbonate solution was added to adjust the pH to 8, and extracted three times with ethyl acetate (200 mL). The mixed organic layer was washed once with saturated brine (100 mL), dried with Na2SO4 and filtered, the reaction solution was concentrated under vacuum, silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 2:1) was performed to obtain compound TM22-6 (6.0 g, yellow oily liquid, yield 32%). The mass spectrum of compound TM22-6 LCMS: (M+1)+: 362.3.

[0413] Synthesis of compound TM22-7: Compound TM1-4 (694 mg, 2.65 mmol, 1.20 eq) and TM22-6 (800 mg, 2.21 mmol, 1.00 eq) were added to an isopropanol (15 mL) solution with AcOH (664 mg, 634 μL, 11.1 mmol, 5.00 eq). The mixture was replaced with nitrogen three times and stirred at 90°C for 48 hours. After the reaction monitoring was completed, a saturated sodium carbonate solution was added to adjust the pH to 8, and the mixture was extracted three times with ethyl acetate (50 mL). The mixed organic layer was washed once with saturated brine (30 mL), dried and filtered with Na2SO4, the reaction solution was concentrated under vacuum, and silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) was performed to obtain compound TM22-7 (1.15 g, yellow solid, yield 44%). The mass spectrum of compound TM22-7 LCMS: (M+1)+: 586.2.

[0414] Synthesis of compound TM22-8: Compound TM22-7 (490 mg, 835 umol, 1.00 eq) and compound TM2-5A (219 mg, 919 umol, 1.10 eq) were dissolved in 1,4-dioxane (10 mL). Cesium carbonate (816 mg, 2.51 mmol, 3.00 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (104 mg, 0.167 mmol, 0.200 eq) and tris(dibenzylideneacetone)dipalladium (76.5 mg, 0.084 mmol, 0.100 eq) were added thereto in sequence. After nitrogen replacement three times, the mixture was reacted at 110°C for 3 hours. After the reaction monitoring was completed, the reaction solution was concentrated under vacuum, silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM22-8 (530 mg, yellow solid, yield 85%). LCMS of compound TM22-8: (M+1)+: 744.4.

[0415] Synthesis of compound TM22: Compound TM22-8 (300 mg, 0.403 mmol, 1.00 eq) and p-toluenesulfonic acid (174 mg, 1.01 mmol, 2.50 eq) were dissolved in DCE (30 mL), and Grubbs second-generation catalyst (137 mg, 0.161 mmol, 0.400 eq) was added thereto. After nitrogen replacement three times, the reaction was carried out at 60°C for 4 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, saturated sodium carbonate solution was added to adjust the pH to 8, and extracted three times with ethyl acetate (50 mL). The mixed organic layer was washed once with saturated brine (30 mL), dried and filtered with Na2SO4, the reaction solution was concentrated under vacuum, and then silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 0: 1) was performed, and then reverse phase preparative purification (water (0.225% formic acid)-acetonitrile) was performed to obtain compound TM22 (39.99 mg, yellow solid, yield 15%, purity 97%). LCMS spectrum of compound TM22: (M+1)+: 602.2. 1H NMR (400MHz, DMSO-d6) δ9.97(s,1H),9.24(s,1H),9.01(d,J=2.4Hz,1H),8.51(q,J=4.3Hz,1H),8.17(s, 1H),7.62(s,1H),7.42(dd,J=12.0,0.9Hz,1H),7.35(s,1H),7.15(dd,J=8.4,2.6Hz,1H),7.13(dd,J=8. 6,2.3Hz,1H),7.05(d,J=8.6Hz,1H),6.94(d,J=16.0Hz,1H),6.71(ddd,J=10.5,7.7,2.5Hz,1H),6.52–6 .40(dd,1H),4.45(s,3H),3.54(q,J=6.5Hz,2H),2.78(dd,J=12.0,5.5Hz,6H),2.65(m,6H),2.43(t,2H).

[0416] Embodiment 23

[0417] Experimental steps:

[0418]

[0419] Synthesis of compound TM23-2: Compound TM23-1 (20.00 g, 110.38 mmol, 1 eq) was dissolved in chloroform (200.0 mL). Then, N-bromosuccinimide (23.57 g, 132.46 mmol, 1.2 eq) was added thereto at 0°C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 16 hours. After the reaction monitoring was completed, water and dichloromethane were added to the reaction solution for extraction. The extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and silica gel was added to mix the sample. Normal phase separation and purification (petroleum ether: ethyl acetate = 5:1) was performed to obtain compound TM23-2 (17.50 g, yellow solid, yield: 60.96%). Mass spectrum LCMS of compound TM23-2: (M-31) + :228.1.

[0420] Synthesis of compound TM23-3: Compound TM23-2 (17.50 g, 67.29 mmol, 1 eq) was dissolved in tetrahydrofuran (100.0 mL). Then, lithium borohydride (67.29 mL, 134.57 mmol, 2 eq, 2M inTHF) was added at 0 °C. After the addition was completed, the temperature was slowly raised to 50 °C and stirred for 2 hours. After the reaction monitoring was completed, the reaction solution was cooled to room temperature and slowly poured into ice water to quench. Then water and dichloromethane were added to extract the organic phase, and the extracted organic phase was washed three times with water, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain compound TM23-3 (13.5 g, yellow solid, yield 86.45%).

[0421] Synthesis of compound TM23-4: Compound TM23-3 (4.50 g, 19.39 mmol, 1.0 eq) was dissolved in chloroform (100 mL). Then, manganese dioxide (16.86 g, 193.90 mmol, 10.0 eq) was slowly added to the reaction bottle at 0°C. After the addition was completed, the temperature was slowly raised to 40°C and stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was collected and dried under vacuum, and then silica gel was added to the sample, and the sample was separated and purified by normal phase separation (petroleum ether: ethyl acetate = 5:1) to obtain compound TM23-4 (3.8 g, yellow solid, yield (85.19%). Mass spectrum LCMS of compound TM23-4: (M+H) + :230.1.

[0422] Synthesis of compound TM23-5: Compound TM23-4 (3 g, 13.04 mmol, 1 eq) and urea (7.83 g, 130.4 mmol, 10 eq) were stirred evenly and reacted at 180°C for 2 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, slurried with dichloromethane and methanol, and the solid was collected by filtration and dried under vacuum to obtain compound TM23-5 (3 g, white solid, yield 90.20%). LCMS of compound TM23-5: (M+H)+: 254.9.

[0423] Synthesis of compound TM23-6: Compound TM23-5 (3 g, 11.76 mmol, 1 eq) was dissolved in phosphorus oxychloride (75 mL). Nitrogen was replaced three times, and the reaction solution was stirred at 110 ° C for 16 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was dried, and then poured into ice water and extracted with dichloromethane. The extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain compound TM23-6 (2 g, yellow solid, yield 62.17%). Mass spectrum LCMS of compound TM23-6: (M+H) +: 272.9.

[0424] Synthesis of compound TM23-7: Compound TM23-6 (3 g, 10.97 mmol, 1.0 eq) was dissolved in dichloromethane (35 mL), and then aluminum chloride (4.39 g, 32.91 mmol, 3 eq) was added thereto at 0 °C. Nitrogen was replaced three times, and the reaction solution was stirred at 45 °C for 16 hours. After the reaction monitoring was completed, it was cooled to room temperature, and then water and dichloromethane were added thereto for extraction. The extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 1:1) was performed to obtain compound TM23-7 (2.3 g, yellow solid, yield: 80.81%). Mass spectrum LCMS of compound TM23-7: (M+H)+: 259.1.

[0425] Synthesis of compound TM23-8: Compound TM23-7 (1g, 3.85mmol, 1.0eq), compound TM23-1A (466mg, 4.05mmol, 1.05eq) and triphenylphosphine (1.52g, 5.78mmol, 1.5eq) were dissolved in dichloromethane (35mL), and then diisopropyl azodicarboxylate (1.17g, 5.78mmol, 1.5eq) was added thereto at 0°C. Nitrogen was replaced three times, and the reaction solution was stirred at room temperature for 2 hours. After the reaction monitoring was completed, silica gel was added to mix the sample, and normal phase separation and purification (dichloromethane: methanol = 10:1) were performed to obtain compound TM23-8 (800mg, yellow solid, yield: 58.21%). Mass spectrum LCMS of compound TM23-8: (M+H)+: 356.0.

[0426] Synthesis of compound TM23-9: Compound TM23-8 (840 mg, 2.36 mmol, 1.0 eq), compound TM23-2A (537.7 mg, 2.83 mmol, 1.2 eq) and trifluoroacetic acid (805.6 mg, 7.07 mmol, 3 eq) were dissolved in isopropanol (10 mL). Nitrogen was replaced three times, and the reaction solution was stirred at 90 ° C for 2 hours. After the reaction monitoring was completed, it was cooled to room temperature and the reaction solution was spin-dried. Then saturated sodium carbonate aqueous solution and ethyl acetate were added thereto for extraction, and the extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and silica gel was added to mix the sample, and normal phase separation and purification (dichloromethane: methanol = 10: 1) was performed to obtain compound TM23-9 (330 mg, yellow solid, yield: 27.45%). Mass spectrum LCMS of compound TM23-9: (M+H) +: 510.2.

[0427] Synthesis of compound TM23-10: Compound TM23-9 (230 mg, 0.45 mmol, 1 eq), compound TM2-5A (128.8 mg, 0.54 mmol, 1.2 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (56.1 mg, 0.09 mmol, 0.2 eq), cesium carbonate (440.4 mg, 1.35 mmol, 3 eq) and tris(dibenzylideneacetone)dipalladium (41.3 mg, 0.045 mmol, 0.1 eq) were dissolved in dioxane (10 mL) and the reaction solution was stirred at 110°C for 6 hours. After the reaction monitoring was completed, the reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under vacuum, and silica gel was added to the sample, and the sample was separated and purified by normal phase separation (dichloromethane: methanol = 6:1) to obtain compound TM23-10 (230 mg, yellow solid, yield 76.44%). Mass spectrum LCMS of compound TM23-10: (M+H)+: 668.4.

[0428] Synthesis of compound TM23: Compound TM23-10 (230 mg, 0.34 mmol, 1.0 eq) and p-toluenesulfonic acid (88.9 mg, 0.52 mmol, 1.5 eq) were dissolved in dichloroethane (23 mL), and Grubbs second-generation catalyst (116.9 mg, 0.14 mmol) was added thereto. Nitrogen was replaced three times, and the reaction solution was stirred at 85 ° C for 4 hours. After the reaction monitoring was completed, it was cooled to room temperature and the catalyst was filtered using diatomaceous earth. The filtrate was spin-dried under vacuum and purified by normal phase separation (ethyl acetate: methanol = 10: 1) to obtain the crude product of compound ND-H2-014, and then reverse phase separation and purification (water (0.1% formic acid)-acetonitrile) was performed to obtain compound TM23 (25.9 mg, yellow solid, yield 10.8%, purity 98.51%). LCMS of compound TM23: (M+H) +: 640.4. 1H NMR (400MHz, DMSO-d6) δ9.78(s,1H),9.24(s,1H),8.86(d,J=2.4Hz,1H),8.24(q,J=4.3Hz,1H),8.12(s,1 H),7.52(s,1H),7.31(dd,J=12.0,0.9Hz,1H),7.35(s,1H),7.15(dd,J=8.4,2.6Hz,1H),7.13(dd,J=8.6,2 .3Hz,1H),7.05(d,J=8.6Hz,1H),6.94(d,J=16.0Hz,1H),6.56(ddd,J=10.5,7.7,2.5Hz,1H),6.42–6.30( dd,1H),4.25(q,2H),4.15(m,2H),3.12(s,6H),2.80(d,J=7.4Hz,6H),2.64(q,2H),J=8.6Hz,2.64(t,2H).

[0429] Embodiment 24

[0430] Experimental steps:

[0431]

[0432] Synthesis of compound TM24-2: Compound TM24-1 (3.00 g, 10.1 mmol, 1.00 eq), compound N,N,N'-trimethylethylenediamine (1.34 g, 13.1 mmol, 1.30 eq), Cs2CO3 (9.87 g, 30.3 mmol, 3.00 eq), Xantphos (1.17 g, 2.02 mmol, 0.20 eq) and Pd2(dba)3 (0.92 g, 1.01 mmol, 0.10 eq) were dissolved in 1,4-dioxane (45 mL). After nitrogen replacement 3 times, the mixture was reacted at 110 °C for 4 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was concentrated and added to silica gel for mixing, and the product TM24-2 (1.50 g, yellow oil, yield 59%) was obtained by column chromatography purification (petroleum ether: ethyl acetate = 0:1). LCMS mass spectrum of compound TM24-2: (M+1) + :250.2.

[0433] Synthesis of compound TM24-3: Compound TM24-2 (1.50 g, 6.02 mmol, 1.00 eq) was dissolved in methanol (15 mL), and then a solution of ammonium chloride (1.61 g, 30.1 mmol, 5.00 eq) in water (7.50 ml) was added. Zinc powder (1.97 g, 30.1 mmol, 5.0 eq) was slowly added under ice bath conditions. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered, the organic phase was concentrated, silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM24-3 (850 mg, yellow oil, yield 64%). Mass spectrum LCMS of compound TM24-3: (M+1) + :220.1.

[0434] Synthesis of compound TM24-4: Compound TM24-3 (692 mg, 3.16 mmol, 1.10 eq) and compound TM1-A4 (750 mg, 2.87 mmol, 1.00 eq) were dissolved in isopropanol (16 mL), and then trifluoroacetic acid (654 mg, 5.74 mmol, 2.00 eq) was added, and the mixture was reacted at 90°C for 16 hours. After the reaction monitoring was completed, the reaction solution was concentrated, adjusted to pH = 9 with sodium carbonate solution, extracted with ethyl acetate three times, and then the organic phase was concentrated and mixed, and forward separation (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM24-4 (630 mg, yellow oily liquid, yield 49%). Mass spectrum LCMS of compound TM24-4: (M+1) + :444.1.

[0435] Synthesis of compound TM24-5: Compound TM24-4 (530 mg, 1.19 mmol, 1.00 eq) and compound TM2-5A (312 mg, 1.31 mmol, 1.10 eq), cesium carbonate (1.17 g, 3.58 mmol, 3.00 eq), BINAP (148 mg, 2.04 mmol, 0.20 eq), Pd2dba3 (110 mg, 0.12 mmol, 0.10 eq) were dissolved in 1,4-dioxane (10 ml), replaced with nitrogen three times, and reacted at 110 ° C for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered. The filtrate was concentrated under vacuum and silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 0: 1) were performed to obtain compound TM24-5 (650 mg, yellow solid, yield 91%). Mass spectrum LCMS of compound TM24-5: (M+1) + :602.3.

[0436] Synthesis of compound TM24: Compound TM24-5 (300 mg, 0.50 mmol, 1.00 eq) and p-toluenesulfonic acid (215 mg, 1.25 mmol, 2.50 eq) were dissolved in DCE (30 mL), and Grubbs 2nd (169 mg, 0.19 mmol, 0.40 eq) was added thereto. After nitrogen replacement 3 times, the reaction was carried out at 80°C for 16 hours. After the reaction was completed, the pH was adjusted to 9 with Na2CO3 solution, and then extracted with dichloromethane. The mixed organic phase was spin-dried under vacuum and subjected to reverse phase preparation purification (water (0.1% formic acid)-acetonitrile) to obtain compound TM24 (22.55 mg, yellow solid, yield of 7.3%, purity of 96%). LCMS of compound TM24: (M+1)+: 574.3. 1 H NMR(400MHz,DMSO-d6)δ9.86(s,1H),9.25(s,1H),8.54(s,1H),8.50(q,J=4.9Hz,1H),7 .59(s,1H),7.43(d,J=11.8Hz,1H),7.31(s,1H),7.18(dd,J=8.4,2.6Hz,1H),6.76(ddd, J=10.6,8.4,2.4Hz,1H),6.68–6.53(m,2H),6.50(s,1H),6.26(s,1H),4.44(s,2H),2.89 (s,3H),2.81(d,J=4.4Hz,3H),2.65(d,J=17.5Hz,2H),2.46–2.25(dd,4H),2.19(s,6H).

[0437] Embodiment 25

[0438] Experimental steps:

[0439]

[0440] Synthesis of compound TM25-2: Compound TM25-1 (5.00 g, 20.3 mmol, 1.0 eq) and compound dimethylamine (4.97 g, 61.0 mmol, 3.0 eq) were dissolved in N, N-dimethylformamide (80.0 mL), and N, N-diisopropylethylamine (10.5 g, 81.3 mmol, 4.0 eq) and 1-hydroxybenzotriazole (3.02 g, 22.4 mmol, 1.1 eq) were added thereto. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.07 g, 26.4 mmol, 1.3 eq) was added thereto at 0°C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for reaction for 1 hour. After the reaction monitoring was completed, water and ethyl acetate were added to the reaction solution for extraction, and the extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample, and then separated and purified by normal phase (petroleum ether: ethyl acetate = 3:1) to obtain compound TM25-2 (5.00 g, red solid, yield: 90%). LCMS of compound TM25-2: (M+1) + :273.0.

[0441] Synthesis of compound TM25-3: Compound TM25-2 (4.9 g, 18.0 mmol, 1.0 eq) and compound vinylboronic acid pinacol ester (3.32 g, 21.5 mmol, 1.2 eq) were dissolved in a mixed solution of 1,4-dioxane (50.0 mL) and water (10.0 mL). Potassium carbonate (7.44 g, 53.8 mmol, 3.0 eq) and DPPF palladium dichloride (1.05 g, 1.44 mmol, 0.08 eq) were added thereto. The reaction solution was stirred at 90 ° C for 1 hour. After the reaction monitoring was completed, it was cooled to room temperature and concentrated under vacuum. Then water and ethyl acetate were added thereto for extraction, and the extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample, and then purified by normal phase separation (petroleum ether: ethyl acetate = 3:1) to obtain compound TM25-3 (3.90 g, yellow solid, yield 99%). LCMS of compound TM25-3: (M+1) + :220.9.

[0442] Synthesis of compound TM25-4: Compound TM25-3 (3.50 g, 15.9 mmol, 1.0 eq) was dissolved in a mixed solution of water (25.0 mL) and methanol (50.0 mL), and ammonium chloride (4.25 g, 79.5 mmol, 5.0 eq) was added thereto. Then, zinc powder (5.20 g, 79.5 mmol, 5.0 eq) was slowly added to the reaction bottle at 0°C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected and dried under vacuum. After ethyl acetate was added to dilute it, a saturated sodium carbonate solution was used to adjust the pH of the solution to about 9. Then a large amount of ethyl acetate and water were added for extraction, and the extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample, and then purified by normal phase separation (petroleum ether: ethyl acetate = 0:1) to obtain compound TM25-4 (1.45 g, yellow solid, yield 48%). LCMS of compound TM25-4: (M+1) + :191.1.

[0443] Synthesis of compound TM25-5: Compound TM25-4 (698 mg, 3.67 mmol, 1.2 eq) and compound TM1-4A (800 mg, 3.06 mmol, 1.0 eq) were dissolved in isopropanol (15.0 mL), and trifluoroacetic acid (523 mg, 4.59 mmol, 1.5 eq) was added thereto. The reaction solution was stirred at 90 °C for 16 hours. After the reaction monitoring was completed, it was cooled to room temperature and the reaction solution was dried under vacuum. Methanol (15.0 mL) was added thereto and stirred at room temperature for one hour. The precipitated solid was collected by filtration and dried under vacuum to obtain compound TM25-5 (600 mg, yellow solid, yield 24%). Mass spectrum LCMS of compound TM25-5: (M+1) + :415.0.

[0444] Synthesis of compound TM25-6: Compound TM25-5 (550 mg, 1.32 mmol, 1.0 eq) and compound TM2-5A (379 mg, 1.59 mmol, 1.2 eq) were dissolved in 1,4-dioxane (10.0 mL). Cesium carbonate (1.08 g, 3.31 mmol, 2.5 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (165 mg, 0.265 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (121 mg, 0.132 mmol, 0.1 eq) were added thereto in turn. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 110°C for 2 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under vacuum, silica gel was added and the sample was mixed, and normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM25-6 (700 mg, yellow solid, yield 92%). LCMS of compound TM25-6: (M+1) + :573.2.

[0445] Synthesis of compound TM25: Compound TM25-6 (350 mg, 0.611 mmol, 1.0 eq) was dissolved in dichloroethane (35 mL), and Grubbs second-generation catalyst (208 mg, 0.244 mmol) was added thereto. Nitrogen was replaced three times, and the reaction solution was stirred at 65 ° C for 4 hours. After the reaction monitoring was completed, it was cooled to room temperature and the catalyst was filtered using diatomaceous earth. The filtrate was spin-dried under vacuum and purified by normal phase separation (petroleum ether: ethyl acetate = 0: 1) to obtain the crude product of compound ND-H2-017, and then reverse phase separation and purification (water (0.1% formic acid)-acetonitrile) was performed to obtain compound TM25 (35.6 mg, yellow solid, yield 11%, purity 98%). LCMS of compound TM25: (M+1) + :545.3.

[0446] 1 H NMR (400MHz, DMSO) δ10.20(s,1H),9.30(s,1H),9.27(s,1H),8.50(q,J=4.1Hz,1H),7.59(s,1H),7.43(dd,J=12.5,1.7Hz, 1H),7.32(s,1H),7.21(dd,J=8.3,2.7Hz,1H),7.11(s,1H),6.85(s,1H),6.82–6.71(m,2H),6.66(d,J=15.9Hz,1H),4.61–

[0447] 4.23(t,2H),2.96(d,J=22.8Hz,6H),2.81(d,J=4.5Hz,3H),2.72–2.61(t,2H).

[0448] Embodiment 26

[0449] Experimental steps:

[0450]

[0451] Synthesis of compound TM26-2: Compound TM26-1 (10.0 g, 40.7 mmol, 1.0 eq) was dissolved in acetonitrile (100 mL), and N,N-diisopropylethylamine (26.3 g, 203 mmol, 5.0 eq) was added thereto. Then, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (18.6 g, 48.8 mmol, 1.2 eq) was added thereto at 0°C, and after stirring for 15 minutes, compound dimethylamine (9.94 g, 122 mmol, 3.0 eq) was added at 0°C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 1 hour. After the reaction monitoring was completed, the reaction solution was spin-dried under vacuum, and ethyl acetate and water were added thereto for extraction. The extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was dried under vacuum to obtain a crude compound TM26-2 (11.0 g, red oily liquid, yield 99%). LCMS of compound TM26-2: (M+1) + :273.0.

[0452] Synthesis of compound TM26-3: Compound TM26-2 (10.0 g, 36.6 mmol, 1.0 eq) and compound vinylboronic acid pinacol ester (5.64 g, 36.6 mmol, 1.0 eq) were dissolved in a mixed solution of 1,4-dioxane (120 mL) and water (25.0 mL), and potassium carbonate (15.2 g, 110 mmol, 3.0 eq) and DPPF palladium dichloride (1.34 g, 1.83 mmol, 0.05 eq) were added thereto. The reaction solution was stirred at 90 ° C for 2 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was dried under vacuum, and water and ethyl acetate were added thereto for extraction. The extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was dried under vacuum to obtain a crude product of compound TM26-3 (8.00 g, red oily liquid, yield 99%). LCMS mass spectrum of compound TM26-3: (M+1) + :220.9.

[0453] Synthesis of compound TM26-4: Compound TM26-3 (5.30 g, 24.1 mmol, 1.0 eq) was dissolved in a mixed solution of methanol (50.0 mL) and water (25.0 mL), and ammonium chloride (6.44 g, 120 mmol, 5.0 eq) was added thereto. Zinc powder (7.87 g, 120 mmol, 5.0 eq) was slowly added to the reaction bottle at 0 °C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was collected and dried under vacuum. After ethyl acetate was added to dilute it, a saturated sodium carbonate solution was used to adjust the pH of the solution to about 9. Ethyl acetate and water were then added for extraction, and the extracted organic phase was washed three times with water, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample, and then separated and purified by normal phase (petroleum ether: ethyl acetate = 0:1) to obtain compound TM26-4 (1.80 g, red oily liquid, yield 39%). LCMS of compound TM26-4: (M+1) + :191.3.

[0454] Synthesis of compound TM26-5: Compound TM26-4 (1.02 g, 5.34 mmol, 1.3 eq) and compound TM1-4A (1.00 g, 4.11 mmol, 1.0 eq) were dissolved in isopropanol (12.0 mL), and acetic acid (370 mg, 6.16 mmol, 1.5 eq) was added thereto. The reaction solution was stirred at 90 °C for 8 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was spin-dried under vacuum, ethyl acetate was added thereto for dilution, and the pH of the solution was adjusted to about 9 using a saturated sodium carbonate solution. Ethyl acetate and water were then added for extraction, and the extracted organic phase was washed three times with water, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel for sample mixing, and normal phase separation and purification (dichloromethane: ethyl acetate = 1:1) was performed to obtain compound TM26-5 (640 mg, yellow solid, yield 39%). Mass spectrum LCMS of compound TM26-5: (M+1) + :397.1.

[0455] Synthesis of compound TM26-6: Compound TM26-5 (600 mg, 1.51 mmol, 1.0 eq) and compound TM2-5A (396 mg, 1.66 mmol, 1.1 eq) were dissolved in 1,4-dioxane (10.0 mL). Cesium carbonate (1.23 g, 3.78 mmol, 2.5 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (188 mg, 0.302 mmol, 0.2 eq,) and tris(dibenzylideneacetone)dipalladium (138 mg, 0.151 mmol, 0.1 eq) were added thereto in turn. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 110°C for 5 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under vacuum, silica gel was added and the sample was mixed, and normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM26-6 (830 mg, yellow solid, yield 99%). LCMS of compound TM26-6: (M+1) + :555.3.

[0456] Synthesis of compound TM26: Compound TM26-6 (800 mg, 1.44 mmol, 1.0 eq) was dissolved in dichloroethane (80.0 mL), and Grubbs second-generation catalyst (490 mg, 0.577 mmol, 0.4 eq) was added thereto. Nitrogen was replaced three times, and the reaction solution was stirred at 65 ° C for 4 hours. After the reaction monitoring was completed, it was cooled to room temperature and the catalyst was filtered using diatomaceous earth. The filtrate was spin-dried under vacuum and purified by normal phase separation (petroleum ether: ethyl acetate = 0: 1) to obtain the crude product of compound TM26, and then reverse phase separation and purification (water (0.1% formic acid)-acetonitrile) was performed to obtain compound TM26 (122 mg, yellow solid, yield 16%. Purity 98%). LCMS spectrum of compound ND-H2-018: (M+1) + :527.2. 1H NMR (400MHz, DMSO) δ10.23(s,1H),9.34(s,1H),9.31(d,J=1.9Hz,1H),8.50–8.43(m,1H),7. 60(s,1H),7.45(d,J=7.9Hz,1H),7.41(d,J=12.6Hz,1H),7.32(t,J=7.8Hz,1H),7.17(dt,J=1 4.2,5.2Hz,3H),7.01(t,J=8.0Hz,1H),6.71(dt,J=15.3,7.5Hz,1H),6.55(d,J=15.8Hz,1H) ,4.41(s,2H),3.01(s,3H),2.81(d,J=4.4Hz,3H),2.78(s,3H),2.65(dd,J=12.9,6.2Hz,2H).

[0457] Embodiment 27

[0458] Experimental steps:

[0459]

[0460] Synthesis of compound TM27-2: Compound TM27-1 (2.00 g, 12.0 mmol, 1.0 eq) and compound TM27-1A (1.78 g, 13.2 mmol, 1.1 eq) were dissolved in acetonitrile (30.0 mL), and potassium carbonate (4.96 g, 35.9 mmol, 3.0 eq) was added thereto. The reaction solution was stirred at 90°C for 16 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under vacuum, and silica gel was added to mix the sample, and normal phase separation and purification (petroleum ether: ethyl acetate = 3:1) were performed to obtain compound TM27-2 (1.56 g, yellow oily liquid, yield 59%). Mass spectrum LCMS of compound TM27-2: (M+1) + :222.1.

[0461] Synthesis of compound TM27-3: Compound TM27-2 (1.86 g, 8.41 mmol, 1.0 eq) was dissolved in methanol (10.0 mL), and a solution of sodium hydroxide (1.01 g, 25.2 mmol, 3.0 eq) dissolved in water (10.0 mL) was slowly added thereto. The reaction solution was stirred and reacted at 50°C for 3 hours. After the reaction monitoring was completed, it was cooled to room temperature, the reaction solution was filtered, and the filtrate was dried under vacuum. Ethyl acetate was added to dilute it, and the pH was adjusted to about 5 using a 6M hydrochloric acid solution. Ethyl acetate and water were then added for extraction, and the extracted organic phase was washed three times with water, dried with anhydrous sodium sulfate, and filtered. The filtrate was dried under vacuum to obtain a crude product of compound TM27-3 (1.70 g, yellow oily liquid, with a yield of 99%). Mass spectrum LCMS of compound TM27-3: (M+1) + :208.0.

[0462] Synthesis of compound TM27-4: Compound TM27-3 (1.50 g, 7.24 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (18.0 mL), and N,N-diisopropylethylamine (3.74 g, 29.0 mmol, 4.0 eq) was added thereto. Then, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (3.30 g, 8.69 mmol, 1.2 eq) was added thereto at 0°C, and after stirring for 15 minutes, methylamine hydrochloride (1.47 g, 21.7 mmol, 3.0 eq) was added at 0°C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 1 hour. After the reaction monitoring was completed, the reaction solution was dried under vacuum, and ethyl acetate and water were added thereto for extraction. The extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample, and then purified by normal phase separation (petroleum ether: ethyl acetate = 3:1) to obtain compound TM27-4 (1.55 g, yellow oily liquid, yield 98%). LCMS of compound TM27-4: (M+1) + :221.2.

[0463] Synthesis of compound TM27-5: Compound TM27-4 (398 mg, 1.81 mmol, 1.5 eq) and compound TM25-5 (500 mg, 1.20 mmol, 1.0 eq) were dissolved in 1,4-dioxane (15.0 mL). Cesium carbonate (981 mg, 3.01 mmol, 2.5 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (150 mg, 0.241 mmol, 0.2 eq,) and tris(dibenzylideneacetone)dipalladium (110 mg, 0.120 mmol, 0.1 eq) were added thereto in turn. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 110°C for 3 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under vacuum, silica gel was added and the sample was mixed, and normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM27-5 (600 mg, yellow solid, yield 90%). LCMS of compound TM27-5: (M+1) + :555.3.

[0464] Synthesis of compound TM27: Compound TM27-5 (550 mg, 0.992 mmol, 1.0 eq) was dissolved in dichloroethane (50 mL), and Grubbs second-generation catalyst (337 mg, 0.397 mmol, 0.4 eq) was added thereto. Nitrogen was replaced three times, and the reaction solution was stirred at 65 ° C for 4 hours. After the reaction monitoring was completed, it was cooled to room temperature and the catalyst was filtered using diatomaceous earth. The filtrate was spin-dried under vacuum and purified by normal phase separation (petroleum ether: ethyl acetate = 0: 1) to obtain the crude product of compound TM27, and then reverse phase separation and purification (water (0.1% formic acid)-acetonitrile) was performed to obtain compound TM27 (113 mg, yellow solid, yield 22%, purity 97%). LCMS of compound TM27: (M+1) + :527.3. 1 H NMR (400MHz, DMSO) δ10.26(s,1H),9.32(s,1H),9.20(d,J=2.1Hz,1H),8.33(q,J=4.4Hz,1H),7.64–7.56(m,3H),7.49–7.44(m,2H),7.29(dd,J=

[0465] 8.0,2.7Hz,1H),7.20(dd,J=8.4,2.0Hz,1H),7.14(d,J=8.2Hz,1H),6.73(dt,J=

[0466] 15.5,7.6Hz,1H),6.55(d,J=15.8Hz,1H),4.35(t,J=5.9Hz,2H),3.01(s,3H),2.81

[0467] –2.75(t,6H),2.68(dd,J=12.9,6.5Hz,2H).

[0468] Embodiment 28

[0469] Experimental steps:

[0470]

[0471] Synthesis of compound TM28-2: Compound TM28-1 (5 g, 1.0 eq) was dissolved in acetonitrile (20 mL), cooled to 0°C, triethylamine (11.06 mL, 3.5 eq) and methylamine hydrochloride (1.53 g, 1.0 eq) were added, and the temperature was raised to 25°C and stirred for 16 hours. After the reaction monitoring was completed, the reaction solution was filtered and the filtrate was concentrated to obtain crude compound 2 (5.8 g), which was directly used in the next step. LCMS of compound TM28-2: (M+1) + :230.9.

[0472] Synthesis of compound TM28-3: Compound TM28-2 (8.25 g, 1.0 eq) was dissolved in toluene (100 mL), compound TM28-2A (5.68 mL, 2.0 eq) was added, and the mixture was heated to 120°C and stirred for 16 hours. After the reaction monitoring was completed, the reaction solution was directly concentrated to obtain crude compound TM28-3 (10.3 g, 93.8% yield), which was directly used in the next step. LCMS of compound TM28-3: (M+1) + :308.9.

[0473] Synthesis of compound TM28-4: Compound TM28-3 (8.0 g, 1.0 eq) was dissolved in acetonitrile (100 mL), potassium carbonate (10.8 g, 3.0 eq) and potassium iodide (432 mg, 0.1 eq) and compound TM28-3A (2.61 g, 1.0 eq) were added, and the mixture was stirred at 25°C for 16 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, the residue was added to silica gel, and the sample was mixed and purified by normal phase separation (dichloromethane: methanol = 10:1) to obtain compound TM28-4 (8 g, yield 83%). Mass spectrum LCMS of compound TM28-4: (M+1) + :371.1.

[0474] Synthesis of compound TM28-5: Compound TM28-4 (5.0 g, 1.0 eq) and compound vinylboronic acid pinacol ester (1.37 mL, 1.5 eq) were dissolved in dioxane (15 mL) and water (5 mL), potassium carbonate (2.23 g, 3.0 eq) and Pd(dppf)Cl2 (118 mg, 0.03 eq) were added, and the mixture was stirred at 90°C under nitrogen protection for 16 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, the residue was added to silica gel and mixed, and normal phase separation and purification (petroleum ether: ethyl acetate = 10:1) was performed to obtain compound TM28-5 (2.6 g), which was directly used in the next step. Mass spectrum LCMS of compound TM28-5: (M+1) + :319.2.

[0475] Synthesis of compound TM28-6: Compound TM28-5 (2.5 g, 1.0 eq) was dissolved in acetonitrile (30 mL), and ammonium chloride (2.94 g, 7.0 eq) and zinc powder (2.57 g, 5.0 eq) and water (15 mL) were added, and the mixture was stirred at 25°C for 2 hours. After the reaction monitoring was completed, the reaction solution was filtered, and the filtrate was concentrated. Dichloromethane (60 mL) and 50 ml of water were added to the residue, and the pH was adjusted to 9-10 with sodium carbonate solution. The organic phase was collected, washed with saturated brine, washed with water, dried, and concentrated to obtain a crude compound TM28-6 (2 g, yield 88%), which was directly used in the next step. Mass spectrum LCMS of compound TM28-6: (M+1) + :289.2.

[0476] Synthesis of compound TM28-7: Compound TM28-6 (1.8 g, 1.1 eq) and compound TM1-4A (1.48 g, 1.0 eq) were dissolved in isopropanol (30 mL), trifluoroacetic acid (2.17 mL, 5.0 eq) was added, and the mixture was heated to 90 ° C and stirred for 16 hours. After the reaction monitoring was completed, the reaction solution was concentrated, ethyl acetate (50 mL) was added to the residue, and then slurried for 1 hour. Filter, collect the solid and dry it. The obtained solid was dissolved in 50 mL of 10% sodium carbonate aqueous solution and 100 mL of dichloromethane, stirred and separated, the organic phase was collected, the aqueous phase was extracted once with dichloromethane, the organic phases were combined, washed once with saturated brine, washed with water, dried and concentrated to obtain the crude compound TM28-7 (900 mg, 31% yield) which was directly used in the next step reaction. Mass spectrum LCMS of compound TM28-7: (M+1) + :513.2.

[0477] Synthesis of compound TM28-8: Compound TM28-7 (800 mg, 1.0 eq) was dissolved in anhydrous dioxane (30 mL), and compound TM2-5A (408 mg, 1.1 eq) and cesium carbonate (1.52 g, 3.0 eq), BINAP (194 mg, 0.2 eq) and Pd2(dba)3 (142.7 mg, 0.1 eq) were added, and the mixture was stirred at 110°C for 16 hours under nitrogen protection. After the reaction monitoring was completed, the reaction solution was filtered, and the residue was added to silica gel after the filtrate was concentrated and mixed with the sample, and normal phase separation and purification (dichloromethane: methanol = 10:1) was performed to obtain compound TM28-8 (800 mg, yellow solid, yield 76.5%). LCMS spectrum of compound TM28-8: (M+1) + :671.4

[0478] Synthesis of compound TM28: Compound TM28-8 (500 mg, 1.0 eq) and p-toluenesulfonic acid (321 mg, 2.5 eq) were dissolved in dichloroethane (50 mL), and the catalyst Grubbs 2 nd (253mg, 0.4eq) was added to the reaction solution and stirred at 80°C for 10 hours under nitrogen protection. After the reaction monitoring was completed, dichloromethane (20mL) and methanol (15mL) were added to the reaction solution and stirred to make the reaction solution clear. The solution was then washed twice with 10% potassium carbonate aqueous solution (25mL), washed once with saturated brine, dried and concentrated. The residue was added with silica gel and mixed with the sample. The sample was separated and purified by normal phase separation (containing petroleum ether: ethyl acetate = 3:1 to 0:1) to obtain a crude compound TM28. The crude product was then subjected to reverse phase preparation and purification (water (0.225% formic acid)-acetonitrile) to obtain compound TM28 (50.8mg, yellow solid, yield 10.6%, purity 98.25%). LCMS spectrum of compound TM28: (M+1) + :643.4. 1 H NMR (400MHz, DMSO) δ10.25(s,1H),9.31(s,1H),9.23(s,1H),8.50(d,J=4.7Hz,1H),8.14(s,1H),7.61(s,1H),7. 43(dd,J=12.5,1.7Hz,1H),7.35(s,1H),7.21(dd,J=8.3,2.7Hz,1H),7.19(s,2H),6.88–6.61(m,3H),6.53(d,J=

[0479] 15.8Hz,1H),4.44(s,2H),3.06(s,3H),2.89–2.73(m,6H),2.77(s,2H),2.68(d,J=6.7Hz,2H),2.31–2.19(t,4H),2.03(t,4H).

[0480] Embodiment 29

[0481] Experimental steps:

[0482]

[0483] Synthesis of compound TM29-2: Compound TM29-1 (3.00 g, 10.1 mmol, 1.0 eq) and compound N-methylpiperazine (1.21 g, 12.1 mmol, 1.2 eq) were dissolved in 1,4-dioxane (50.0 mL), and cesium carbonate (8.22 g, 25.2 mmol, 2.5 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.26 g, 2.02 mmol, 0.2 eq,) and tris(dibenzylideneacetone)dipalladium (924 mg, 1.01 mmol, 0.1 eq) were added thereto in turn. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 100°C for 2 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under vacuum, silica gel was added and the sample was mixed, and normal phase separation and purification (petroleum ether: ethyl acetate = 0:1) was performed to obtain compound TM29-2 (1.00 g, yellow solid, yield 40%). LCMS of compound TM29-2: (M+1) + :248.1.

[0484] Synthesis of compound TM29-3: Compound TM29-2 (900 mg, 3.64 mmol, 1.0 eq) was dissolved in a mixed solution of water (5.00 mL) and methanol (10.0 mL), and ammonium chloride (973 mg, 18.2 mmol, 5.0 eq) was added thereto. Then, zinc powder (1.19 g, 18.2 mmol, 5.0 eq) was slowly added to the reaction bottle at 0°C. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 1 hour. After the reaction monitoring was completed, the reaction solution was filtered, and the filtrate was collected and dried under vacuum. After ethyl acetate was added to dilute it, a saturated sodium carbonate solution was used to adjust the pH of the solution to about 9. Then a large amount of ethyl acetate and water were added for extraction, and the extracted organic phase was washed with water three times, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample, and then separated and purified by normal phase (petroleum ether: ethyl acetate = 0:1) to obtain compound TM29-3 (410 mg, yellow solid, yield 52%). LCMS of compound TM29-3: (M+1) +:218.2.

[0485] Synthesis of compound TM29-4: Compound TM29-3 (360 mg, 1.66 mmol, 1.0 eq) and compound TM1-4A (520 mg, 1.99 mmol, 1.2 eq) were dissolved in isopropanol (10.0 mL), and trifluoroacetic acid (283 mg, 2.48 mmol, 1.5 eq) was added thereto. The reaction solution was stirred at 90 °C for 16 hours. After the reaction monitoring was completed, it was cooled to room temperature and the reaction solution was spin-dried under vacuum. Ethyl acetate was added to dilute it, and the pH was adjusted to about 9 with a saturated sodium carbonate solution. Ethyl acetate and water were then added for extraction, and the extracted organic phase was washed three times with water, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample, and the normal phase was separated and purified (petroleum ether: ethyl acetate = 1:1) to obtain compound TM29-4 (280 mg, yellow solid, yield 38%). Mass spectrum LCMS of compound TM29-4: (M+1) + :442.1.

[0486] Synthesis of compound TM29-5: Compound TM29-4 (230 mg, 0.520 mmol, 1.0 eq) and compound TM2-5A (149 mg, 0.624 mmol, 1.2 eq) were dissolved in 1,4-dioxane (15.0 mL). Cesium carbonate (424 mg, 1.30 mmol, 2.5 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (64.8 mg, 0.104 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium (47.6 mg, 0.052 mmol, 0.1 eq) were added thereto in sequence. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 110°C for 3 hours. After the reaction monitoring was completed, the mixture was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under vacuum, silica gel was added and the sample was mixed, and normal phase separation and purification (dichloromethane: ethyl acetate = 0:1) was performed to obtain compound TM29-5 (300 mg, yellow solid, yield 96%). LCMS of compound TM29-5: (M+1) + :600.2.

[0487] Synthesis of compound TM29: Compound TM29-5 (250 mg, 0.417 mmol, 1.0 eq) and p-toluenesulfonic acid (179 mg, 1.04 mmol, 2.5 eq) were dissolved in dichloroethane (25 mL), and Grubbs second-generation catalyst (142 mg, 0.167 mmol, 0.4 eq) was added thereto. Nitrogen was replaced three times, and the reaction solution was stirred at 80 ° C for 4 hours. After the reaction monitoring was completed, it was cooled to room temperature and the pH of the reaction solution was adjusted to about 9 using a saturated sodium carbonate solution. Ethyl acetate and water were then added for extraction, and the extracted organic phase was washed three times with water, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and then added with silica gel to mix the sample, and then separated and purified by normal phase (petroleum ether: ethyl acetate = 0:1) to obtain the crude product of compound ND-H2-021, and then separated and purified by reverse phase (water (0.1% formic acid)-acetonitrile) to obtain compound TM29 (20.91 mg, yield 9%, purity 99%). LCMS spectrum of compound TM29: (M+1) + :572.3. 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.26(s,1H),8.70(s,1H),8.51(q,J=4.5Hz,1H) ,8.17(d,J=7.1Hz,1H),7.60(s,1H),7.43(d,J=12.6Hz,1H),7.30(s,1H),7.18(dd,J=

[0488] 8.4,2.7Hz,1H),6.87–6.49(m,4H),4.58–4.16(m,2H),3.58(s,1H),3.14–3.08(m,3 H),2.81(d,J=4.5Hz,3H),2.63(s,2H),2.49–2.42(m,4H),2.36(s,1H),2.22(s,3H).

[0489] Embodiment 30

[0490] Experimental steps:

[0491]

[0492] Synthesis of compound TM30-2: Compound TM16-6 (150 mg, 289.9 μmol, 1.0 eq) was added to N, N-dimethylformamide (3 mL) under ice bath, and then N, N-diisopropylethylamine (112.4 mg, 869.6 μmol, 3 eq), (7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (165.4 mg, 434.8 μmol, 1.5 eq) and TM30-1A (87 mg, 434.8 μmol, 1.5 eq) were added, and the temperature was automatically raised to room temperature for 2 hours. After the reaction monitoring was completed, water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution, the aqueous layer was extracted three times, the organic layer was concentrated, and the concentrated mixture was prepared under high pressure to obtain TM30-2 (120 mg, yield: 59%, yellow solid, purity 99%). LCMS mass spectrum of compound TM30-2: (M+1) + :700.3.

[0493] Synthesis of compound TM30: Compound TM30-2 (100 mg, 87.8 μmol, 1.0 eq) was added to 1,4-dioxane hydrochloride (2 mL) and reacted at 25°C for 2 hours. After the reaction monitoring was completed, the reaction solution was concentrated and the final product TM30 (50 mg, yield: 57.7%, yellow solid, purity 99%) was prepared under high pressure. LCMS of TM30: (M+1) + :600.3. 1 HNMR(400MHz,DMSO-d6)δ10.24(s,1H),9.31(s,1H),9.22(s,1H),8.51(d,J=4.6Hz,1H),8.24(s,1H ),7.60(s,1H),7.44(dd,J=12.5,1.6Hz,1H),7.35(s,1H),7.23–7.13(m,3H),6.84–6.73(m,1H),6. 72–6.60(m,2H),4.40(s,2H),3.34(s,1H),3.30–3.23(m,2H),3.17–3.10(m,1H),2.98(dd,J=10.7, 4.4Hz,1H),2.82(d,J=4.5Hz,3H),2.64(d,J=6.5Hz,2H),2.27(d,J=61.1Hz,3H),2.02–1.72(m,2H).

[0494] Embodiment 31

[0495] Experimental steps:

[0496]

[0497] Synthesis of compound TM31-2: Compound TM31-1 (12.0 g, 1.0 eq) and compound N-methylpiperazine (5.79 mL, 1.0 eq) were dissolved in anhydrous dichloroethane (100 mL), cooled to 0 ° C, and then sodium triacetoxyborohydride (16.6 g, 1.5 eq) was added, and the reaction was stirred at 30 ° C for 16 hours. After the reaction monitoring was completed, dichloromethane (100 mL) and saturated sodium bicarbonate aqueous solution (100 mL) were added to the reaction solution, stirred and separated, and the organic phase was collected. The aqueous phase was extracted three times with dichloromethane (25 mL), the organic phases were combined, washed with saturated brine, dried and concentrated to obtain the crude compound TM31-2 (15 g), which was directly used in the next step. Mass spectrum LCMS of compound TM31-2: (M+1) + :314.1.

[0498] Synthesis of compound TM31-3: Under nitrogen protection, compound TM31-2 (15g, 1.0eq) and vinylboronic acid pinacol ester (12.1mL, 1.5eq) were dissolved in dioxane (100mL) and water (40mL), potassium carbonate (19.8g, 3.0eq) and catalyst Pd(dppf)Cl2 (0.35g, 0.01eq) were added, heated to 100°C and stirred for 4 hours. After the reaction monitoring was completed, the reaction solution was quenched with 3M dilute hydrochloric acid solution, Ph was adjusted to 3, stirred and separated, the aqueous phase was extracted once with dichloromethane (60mL), the organic phases were combined, washed with saturated brine, dried and concentrated to obtain the crude compound TM31-3 (12.9g), which was directly used in the next step. Mass spectrum LCMS of compound TM31-3: (M+1) + :262.2.

[0499] Synthesis of compound TM31-4: Compound TM31-3 (12.9 g, 1.0 eq) was dissolved in methanol (60 mL) and water (60 mL), and ammonium chloride (18.4 g, 7.0 eq) and zinc powder (16.14 g, 5.0 eq) were added, and the mixture was heated to 55 ° C and stirred for 1 hour. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, sodium carbonate solution was added to the residue to adjust the pH to 9, and then ethyl acetate (100 mL) and water (100 mL) were added, stirred and separated, the aqueous phase was extracted three times with ethyl acetate (50 mL), the organic phases were combined, dried and concentrated, the residue was added to silica gel and mixed, and normal phase separation and purification (dichloromethane: methanol = 10: 1) obtained Compound TM31-4 (4.3 g, yield 38%) Mass spectrum LCMS of compound TM31-4: (M+1) + :232.1.

[0500] Synthesis of compound TM31-5: Compound TM31-4 (4.3 g, 1.0 eq) and compound TM1-4A (4.86 g, 1.0 eq) were dissolved in isopropanol (40 mL), trifluoroacetic acid (10.6 g, 5.0 eq) was added under ice bath, and the mixture was heated to 90°C and stirred for 6 hours. After the reaction monitoring was completed, the reaction solution was concentrated to dryness, ethyl acetate (50 mL) was added to the residue, and the mixture was stirred for half an hour after the solid was precipitated, filtered, and the filter cake was stirred in a mixture of sodium carbonate aqueous solution and ethyl acetate, and the organic phase was collected and concentrated to dryness to obtain compound TM31-5 (2.8 g, yield 33%). LCMS of compound TM31-5: (M+1) + :456.1.

[0501] Synthesis of compound TM31-6: Under nitrogen protection, compound TM31-5 (900 mg, 1.0 eq) and compound TM2-5A (517 mg, 1.1 eq) were dissolved in dioxane (20 mL), cesium carbonate (1.93 g, 3.0 eq) and BINAP (245.6 mg, 0.2 eq) and catalyst Pd2(dba)3 (181 mg, 0.1 eq) were added, and then heated to 110°C and stirred for 16 hours. After the reaction monitoring was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, the residue was added to silica gel and mixed, and normal phase separation and purification (dichloromethane: methanol = 10:1) were performed to obtain compound TM31-6 (1 g, yield 83%). Mass spectrum LCMS of compound TM31-6: (M+1) + :614.4.

[0502] Synthesis of compound TM31: Compound TM31-6 (350 mg, 1.0 eq) and p-toluenesulfonic acid (245 mg, 2.5 eq) were dissolved in dichloroethane (40 mL), and the catalyst Grubbs 2 nd (193mg, 0.4eq) was added to the reaction solution and stirred at 80°C for 10 hours under nitrogen protection. After the reaction monitoring was completed, dichloromethane (20mL) and methanol (15mL) were added to the reaction solution and stirred to make the reaction solution clear. The solution was washed twice with 10% potassium carbonate aqueous solution (25mL) and once with saturated brine, dried and concentrated. The residue was added with silica gel and mixed with the sample. The sample was separated and purified by normal phase separation (petroleum ether: ethyl acetate = 3:1 to 0:1) to obtain a crude compound TM31 (140mg). The crude product was further subjected to reverse phase preparative purification (water (0.225% formic acid)-acetonitrile) to obtain compound TM31 (56.2mg, yellow solid, yield 16.8%, purity 97.17%).

[0503] LCMS spectrum of compound TM31: (M+1) + :586.3. 1H NMR (400MHz, DMSO-d6) δ10.04(s,1H),9.27(s,1H),9.09(s,1H),8.50(q,J=3.7Hz, 1H),7.59(s,1H),7.43(dd,J=12.5,1.7Hz,1H),7.30(s,1H),7.19(dd,J=8.4,2.6Hz ,1H),7.07(s,1H),6.80–6.71(m,2H),6.68(t,J=7.1Hz,1H),6.62(d,J=15.9Hz,1H ),4.81–3.98(m,4H),2.81(d,J=4.5Hz,3H),2.64(s,2H),2.33(t,8H),2.15(s,3H).

[0504] Embodiment 32

[0505] Experimental steps:

[0506]

[0507] Synthesis of compound TM32-2: Under nitrogen protection, compound TM32-1 (19.0 g, 1.0 eq) and compound vinylboronic acid pinacol ester (22.1 mL, 1.5 eq) were dissolved in a mixed solution of dioxane (100 mL) and water (40 mL), potassium carbonate (36.1 g, 3.0 eq) and Pd(dppf)2Cl2 (0.6 g, 0.01 eq) were added, and then heated to 90°C and stirred for 6 hours. After the reaction monitoring was completed, the reaction solution was directly concentrated to dryness, and the residue was added to silica gel and mixed, and the compound TM32-2 (17.5 g, crude yield 121%) was obtained by normal phase separation and purification (petroleum ether: ethyl acetate = 3:1), which was directly used in the next step. Mass spectrum LCMS of compound TM32-2: (M+1) + :166.0.

[0508] Synthesis of compound TM32-3: In an ice bath, compound TM32-2 (15g, 1.0eq) and compound TM32-2A (40.6g, 1.25eq) were dissolved in dichloromethane (200mL), triethylamine (19ml, 1.5eq) was added dropwise, and then the temperature was raised to room temperature and stirred for 16 hours. After the reaction monitoring was completed, dichloromethane (100mL) was added to the reaction solution for dilution, and the organic phase was washed once with saturated sodium bicarbonate aqueous solution (150mL) and brine (150mL) in sequence, and the organic phase was concentrated, and the residue was added with silica gel and mixed, and the normal phase was separated and purified (petroleum ether: ethyl acetate = 1:0) to obtain compound TM32-3 (15g, yield 56%), which was directly used in the next step. Mass spectrum LCMS of compound TM32-3: (M+1) +:297.9.

[0509] Synthesis of compound TM32-4: Under nitrogen protection, compound TM24-1 (5g, 1.0eq) and compound TM32-3A (6.53g, 2.0eq) were dissolved in dioxane (50mL) and water (20mL), and sodium carbonate (8.92g, 5.0eq) and Pd(PPh3)4 (1.36g, 0.07eq) were added and heated to 100°C and stirred for 5 hours. After the reaction monitoring was completed, the reaction solution was concentrated to dryness, and the residue was added to silica gel and mixed. The compound TM32-4 (2.8g, yield 77%) was obtained by normal phase separation and purification (petroleum ether: ethyl acetate = 10:1), which was directly used in the next step. Mass spectrum LCMS of compound TM32-4: (M+1) + :216.1.

[0510] Synthesis of compound TM32-5: Under nitrogen protection, compound TM32-4 (2.6g, 1.0eq) and compound TM32-4A (2.62g, 2.0eq) were dissolved in anhydrous DMF (50mL), cesium carbonate (7.87g, 2.0eq) and potassium iodide (200mg, 0.1eq) were added, heated to 120°C and stirred for 16 hours. After the reaction monitoring was completed, the reaction solution was filtered, water (60mL) and ethyl acetate (60mL) were added to the filtrate, stirred and allowed to stand, the organic phase was collected, the aqueous phase was extracted once with ethyl acetate (60mL), the organic phases were combined, washed with water, washed with saturated brine, dried and concentrated. The residue was added with silica gel and mixed, and the normal phase was separated and purified (petroleum ether: ethyl acetate = 3:1) to obtain compound TM32-5 (2g, yield 58%). Mass spectrum LCMS of compound TM32-5: (M+1) + :288.2.

[0511] Synthesis of compound TM32-6: Compound TM32-5 (1.8 g, 1.0 eq) was dissolved in acetonitrile (20 mL) and water (10 mL), and zinc powder (2.05 g, 5.0 eq) and ammonium chloride (2.35 g, 7.0 eq) were added and heated to 50 ° C and stirred for 2 hours. After the reaction monitoring was completed, the reaction solution was concentrated to remove acetonitrile, and dichloromethane (50 mL) and water (30 mL) were added thereto. After stirring, the organic phase was collected, and the aqueous phase was extracted once more with dichloromethane (20 mL). The organic phases were combined, dried, and concentrated to dryness to obtain a crude compound TM32-6 (1.61 g), which was directly used in the next step. LCMS of compound TM32-6: (M+1) + :258.2.

[0512] Synthesis of compound TM32-7: Compound TM32-6 (1.61 g, 1.1 eq) and compound TM1-4A (1.49 g, 1.0 eq) were dissolved in isopropanol (25 mL), trifluoroacetic acid (2.1 mL, 5.0 eq) was added, and the temperature was raised to 90 ° C and stirred for 16 hours. After the reaction monitoring was completed, the reaction solution was concentrated to dryness, the residue was dissolved in dichloromethane (50 mL), and washed once with saturated sodium carbonate solution (20 mL). The organic phase was dried and concentrated, and the residue was added to silica gel and mixed. The sample was separated and purified by normal phase separation (petroleum ether: ethyl acetate = 3:1 to 1:1) to obtain compound TM32-7 (1.21 g, yield 44%), a yellow solid. Mass spectrum LCMS of compound TM32-7: (M+1) + :482.1.

[0513] Synthesis of compound TM32-8: Under nitrogen protection, compound TM32-7 (1g, 1.0eq) and compound TM2-5A (543mg, 1.1eq) were dissolved in dioxane (20mL), cesium carbonate (2.03g, 3.0eq) and BINAP (258mg, 0.2eq) and catalyst Pd2(dba)3 (190mg, 0.1eq) were added, and then heated to 110°C and stirred for 16 hours. After the reaction monitoring was completed, the reaction solution was concentrated to dryness, and the residue was added with silica gel and mixed. The compound was separated and purified by normal phase (dichloromethane: methanol = 20:1) to obtain compound TM32-8 (1g, yield 75%), a brown solid. Mass spectrum LCMS of compound TM32-8: (M+1) + :640.3.

[0514] Synthesis of compound TM32: Under nitrogen protection, compound TM32-8 (800 mg, 1.0 eq) was dissolved in dichloroethane (160 mL), and the catalyst Grubbs 2 nd (425 mg, 0.4 eq) was then heated to 65 ° C and stirred for 2 hours. After the reaction monitoring was completed, the reaction solution was concentrated to dryness, and the residue was added to silica gel for sample mixing. Normal phase separation and purification (dichloromethane: methanol = 20:1 to 10:1) was performed to obtain a crude compound TM32 (600 mg). The crude product was further subjected to reverse phase preparation and purification (water (0.225% formic acid)-acetonitrile) to obtain compound TM32 (42.1 mg, yellow solid, yield 5.5%, purity 98.8%). LCMS spectrum of compound TM32: (M+1) + :612.3. 1H NMR (400MHz, DMSO-d6) δ10.03(s,1H),9.28(s,1H),9.10(s,1H),8.50(q,J=3.7 Hz,1H),7.76(s,1H),7.60(s,1H),7.45(d,J=8.6,1H),7.35(s,1H),7.20(s,1H ),7.13(d,J=6.6,1H),6.85–6.65(m,3H),6.65(d,J=7.2Hz,1H),4.75(s,1H),4 .71–4.15(m,2H),4.10(s,2H),2.80(d,J=4.5Hz,3H),2.64(s,2H),1.21(s,6H).

[0515] Embodiment 33

[0516] Experimental steps:

[0517]

[0518] Synthesis of compound TM33: Compound TM16-6 (100 mg, 192.2 μmol, 1.0 eq) was added to N, N-dimethylformamide (1.5 mL) under ice bath, and then N, N-diisopropylethylamine (75 mg, 98.8 μmol, 3 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (48 mg, 251.2 μmol, 1.3 eq), 1-hydroxybenzotriazole (26 mg, 193.2 μmol, 1.0 eq) and TM33-1A (19 mg, 193.3 μmol, 2 eq) were added, and the temperature was automatically raised to room temperature for 2 hours. After the reaction monitoring was completed, the reaction solution was added dropwise to water (10 mL), extracted with ethyl acetate (10 mL) 3 times, and the organic layer was concentrated and then prepared under high pressure to obtain the final product TM33 (25.1 mg, yield: 19.7%, yellow solid, purity 99%). LCMS mass spectrum of TM33: (M+1) + :597.3. 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.33(s,1H),9.21(s,1H),8.51(d,J=4.6Hz,1H),7.59(s,1H),7 .44(d,J=8.7Hz,2H),7.38(s,1H),7.20(ddd,J=22.6,8.4,2.4Hz,2H),6.83–6.74(m,1H),6.65(dd,J=

[0519] 11.4,3.8Hz,4H),5.25(s,1H),4.40(s,2H),2.81(d,J=4.4Hz,3H),2.61(d,J=5.7Hz,2H),1.95(s,3H).

[0520] Embodiment 34

[0521] Experimental steps:

[0522]

[0523] Synthesis of compound TM34-2: Sodium hydrogen (3.83 g, 96.13 mmol, 1.5 eq) was added to a mixture of but-3-ene-1-ol TM34-1A (5.54 g, 76.90 mmol, 1.2 eq) in DMF. The mixture was then stirred at 0°C for 30 minutes. 3-Fluoro-4-nitroaniline TM34-1 (10 g, 64.09 mmol, 1.0 eq) was added and the mixture was stirred at zero°C for 1 hour. The mixture was poured into water, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain a yellow oily product TM34-2 (9.5 g, 45.49 mmol, 67.49% yield). LCMS of TM34-2: (M+1) + :209.2.

[0524] Synthesis of compound TM34-3: A mixture of 3-(but-3-ene-1-oxy)-4-nitroaniline TM34-2 (9.5 g, 45.49 mmol, 1 eq), TEA (9.2 g, 90.99 mmol, 2.0 eq), DMAP (2.77 g, 22.74 mmol, 0.5 eq) and Boc2O (11.91 g, 54.59 mmol, 1.2 eq) in tetrahydrofuran was stirred at room temperature for 16 hours. The mixture was then concentrated and purified by column chromatography to give a yellow solid product TM34-3 (7.3 g, 23.69 mmol, 52.14% yield). LC-MS: [ESI] [M+H] + =331.4, t R =1.414min.

[0525] Synthesis of compound TM34-4: To a mixture of TM34-3 (7.3 g, 23.6 mmol, 1 eq) in DMF (80 mL) was added NaH (1.13 g, 47.38 mmol, 2 eq), and the mixture was stirred at room temperature for 30 minutes. Then MeI (4.50 g, 35.53 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain a yellow oily product TM34-4 (6.0 g, 18.62 mmol, yield 78.62%). LCMS: m / z (ES + )[M+H] + =267.4,Rt=1.460min.

[0526] Synthesis of compound TM34-5: To a solution of compound TM34-4 (6.0 g, 18.62 mmol, 1 eq) in tetrahydrofuran (40 mL) were added water (20 mL), zinc powder (6.05 g, 93.1 mmol, 5 eq), ammonium chloride (4.98 g, 93.1 mmol, 5 eq), and the mixture was stirred at room temperature for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give tert-butyl 6-amino-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate TM34-5 (3 g, 45% yield) as a yellow oil. LCMS: m / z (ES + )[M+H] + =293.4,Rt=1.174min.

[0527]

[0528] Synthesis of compound TM34-7: To a solution of compound 6-nitro-1,2,3,4-tetrahydroisoquinoline TM34-6 (5 g, 28.1 mmol, 1.0 eq) in trifluoromethanesulfonic acid (50 mL) was added N-iodosuccinimide (12.6 g, 56.2 mmol, 2.0 eq). It was stirred at room temperature for 2 hours. The reactant was partitioned between water (200 mL) and ethyl acetate (200 ml) and extracted with ethyl acetate (200 mL×2). The combined organic layers were dried over sodium sulfate and filtered. The organic layer was filtered and concentrated to give crude 8-iodo-6-nitro-1,2,3,4-tetrahydroisoquinoline TM34-7 (12 g, yield 140%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =305.0,Rt=0.296min.

[0529] Synthesis of compound TM34-8: To a solution of compound 8-iodo-6-nitro-1,2,3,4-tetrahydroisoquinoline TM34-7 (12 g, 39.47 mmol, 1.0 eq) in tetrahydrofuran (100 mL) was added di-tert-butyl dicarbonate (25.8 g, 118.4 mmol, 3.0 eq). It was stirred at room temperature for 12 hours. After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give 8-iodo-6-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM34-8 (7.1 g, 44% yield) as a yellow solid. LCMS: m / z (ES + )[M+H] + =349.0,Rt=0.859min.

[0530] Synthesis of compound TM34-9: To a solution of compound 8-iodo-6-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM34-8 (3 g, 7.42 mmol, 1.0 eq) in 1,4-dioxane (30 mL) was added water (6 mL) potassium trifluoro(vinyl)borate (2.98 g, 22.26 mmol, 3.0 eq), K2CO3 (3.07 g, 22.26 mmol, 3.0 eq), Pd(dppf)Cl2 (0.542 g, 0.742 mmol, 0.1 eq), and the mixture was stirred at 100° C. for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give tert-butyl 6-nitro-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate TM34-9 (2.1 g, 95% yield) as a yellow solid. LCMS: m / z (ES + )[M+H] + =249.2,Rt=0.839min.

[0531] Synthesis of compound TM34-10: To a solution of compound 6-nitro-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM34-9 (2.1 g, 6.9 mmol, 1.0 eq) in tetrahydrofuran (10 mL) were added water (10 mL), zinc powder (4.5 g, 69 mmol, 10.0 eq), NH4Cl (3.7 g, 69 mmol, 10.0 eq), and the mixture was stirred at room temperature for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give 6-amino-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM34-10 (850 mg, 45% yield) as a yellow oil. LCMS: m / z (ES + )[M+H] + =275.2,Rt=1.385min.

[0532]

[0533] Synthesis of compound TM34-12: TM34-5 (2.48 g, 10.26 mmol, 1.0 eq), Xantphos (1.18 g, 2.04 mmol, 0.2 eq), cesium carbonate (6.69 g, 20.52 mmol, 2.0 eq), palladium acetate (0.23 g, 1.02 mmol, 0.1 eq) were added to a solution of compound 8-bromo-2-chloroquinazoline TM34-11 (3 g, 10.26 mmol, 1.0 eq) in 1,4-dioxane (30 mL), and the mixture was stirred at 100 ° C for 3 hours. After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give tert-butyl 6-((8-((2-(but-3-en-1-oxy)-4-((tert-butoxycarbonyl)(methyl)amino)-6-fluorophenyl)amino)quinazolin-2-yl)amino)-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate TM34-12 (1.3 g, 2.86 mmol, 67.35% yield) as a yellow solid.

[0534] Synthesis of compound TM34-13: TM34-10 (301 mg, 1.1 mol, 1.0 eq) was added to a solution of compound TM34-12 (500 mg, 1.1 mmol, 1.0 eq) in 1,4-1,4-dioxane (10 mL). After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give 6-((8-((2-(but-3-ene-1-oxy)-4-((tert-butoxycarbonyl)(methyl)amino)-6-fluorophenyl)amino)quinazolin-2-yl)amino)-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM34-13 (110 mg, 0.15 mmol, 14.4% yield) as a yellow solid.

[0535] Synthesis of compound TM34-14: To a solution of compound TM34-13 (110 mg, 0.15 mmol, 1.0 eq) in 1,2-dichloroethane (10 mL) was added Grubbs II (35 mg, 0.056 mmol, 1.0 eq), and the mixture was stirred at 40 ° C for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography to give a yellow solid TM34-14 (100.0 mg, 0.15 mmol, 94.78% yield). LCMS: m / z (ES + )[M+H] + =665.2,Rt=6.852min.

[0536] Synthesis of compound TM34: trifluoroacetic acid (1 mL) was added to a solution of compound TM34-14 (100 mg, 0.15 mmol, 1.0 eq) in DCM (3 mL). The mixture was stirred at 25°C for 1 hour. The residue was purified by preparative HPLC to obtain TM34-14 as a yellow solid (11.3 mg, yield 13%). LCMS: m / z (ES + )[M+H] + =465.2,Rt=0.580min. 1H NMR (400MHz, DMSO-d6) δ9.91(d,J=15.3Hz,1H),9.27(s,1H),8.96(d,J=1.7Hz,1H),7.47(dd,J=8. 6,4.6Hz,1H),7.32(d,J=8.6Hz,1H),7.29–7.22(m,2H),6.96(s,2H),6.76(d,J=15.6Hz,1H),6.63– 6.51(m,1H),6.48(d,J=2.3Hz,1H),6.20(dd,J=8.6,2.3Hz,1H),5.50(d,J=4.7Hz,1H),4.30(t,J=5 .8Hz,2H),3.93(s,2H),3.00(t,J=5.6Hz,2H),2.74(d,J=4.2Hz,5H),2.68(dd,J=12.4,5.8Hz,2H).

[0537] Embodiment 35

[0538] Experimental steps:

[0539]

[0540] Synthesis of compound TM35-2: Sodium hydrogen (3.83 g, 96.13 mmol, 1.5 eq) was added to a mixture of but-3-ene-1-ol TM34-1A (5.54 g, 76.90 mmol, 1.2 eq) in DMF. The mixture was then stirred at 0°C for 30 minutes. 3-Fluoro-4-nitroaniline TM35-1 (10 g, 64.09 mmol, 1.0 eq) was added and the mixture was stirred at zero°C for 1 hour. The mixture was poured into water, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain a yellow oily product TM35-2 (9.7 g, 45.49 mmol, 67.49% yield). LCMS of TM35-2: (M+1) + :228.3.

[0541] Synthesis of compound TM35-3: A mixture of 5-fluoro-3-(but-3-ene-1-oxy)-4-nitroaniline TM35-2 (9.5 g, 45.49 mmol, 1 eq), TEA (9.2 g, 90.99 mmol, 2.0 eq), DMAP (2.77 g, 22.74 mmol, 0.5 eq) and Boc2O (11.91 g, 54.59 mmol, 1.2 eq) in tetrahydrofuran was stirred at room temperature for 16 hours. The mixture was then concentrated and purified by column chromatography to give a yellow solid product TM35-3 (7.5 g, 23.69 mmol, 52.3% yield). LC-MS: [ESI] [M+H]+ =349.4, t R =1.414min.

[0542] Synthesis of compound TM35-4: To a mixture of TM35-3 (7.3 g, 23.6 mmol, 1 eq) in DMF (80 mL) was added NaH (1.13 g, 47.38 mmol, 2 eq), and the mixture was stirred at room temperature for 30 minutes. Then MeI (4.50 g, 35.53 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain a yellow oily product TM35-4 (6.4 g, 18.62 mmol, yield 78.6%). LCMS: m / z (ES + )[M+H] + =276.4,Rt=1.460min.

[0543] Synthesis of compound TM35-5: To a solution of compound TM35-4 (6.0 g, 18.62 mmol, 1 eq) in tetrahydrofuran (40 mL) were added water (20 mL), zinc powder (6.05 g, 93.1 mmol, 5 eq), ammonium chloride (4.98 g, 93.1 mmol, 5 eq), and the mixture was stirred at room temperature for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give 5-fluoro-6-amino-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM35-5 (3.2 g, 45.1% yield) as a yellow oil. LCMS: m / z (ES + )[M+H] + =312.4,Rt=1.174min.

[0544] Synthesis of compound TM35-6: TM35-5 (2.48 g, 10.26 mmol, 1.0 eq), Xantphos (1.18 g, 2.04 mmol, 0.2 eq), cesium carbonate (6.69 g, 20.52 mmol, 2.0 eq), palladium acetate (0.23 g, 1.02 mmol, 0.1 eq) were added to a solution of compound 8-bromo-2-chloroquinazoline TM34-11 (3 g, 10.26 mmol, 1.0 eq) in 1,4-dioxane (30 mL), and the mixture was stirred at 100 ° C for 3 hours. After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. The residue was purified by flash silica gel chromatography to give tert-butyl 5-fluoro-6-((8-((2-(but-3-en-1-oxy)-4-((tert-butoxycarbonyl)(methyl)amino)-6-fluorophenyl)amino)quinazolin-2-yl)amino)-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate TM35-6 (1.4 g, 2.9 mmol, 67.6% yield) as a yellow solid.

[0545] Synthesis of compound TM35-7: To a solution of compound tert-butyl (3-(but-3-ene-1-oxy)-4-((2-chloroquinazolin-8-yl)amino)-5-fluorophenyl(methyl)carbamate TM35-6 (300 mg, 0.63 mmol, 1.0 eq) in 1,4-dioxane (30 mL) were added tert-butyl 6-amino-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (175 mg, 0.63 mol, 1.0 eq), Xantphos (73 mg, 0.126 mmol), cesium carbonate (410 mg, 1.26 mmol, 2.0 eq) and palladium acetate (1 5mg, 0.063mmol, 0.1eq), and the mixture was stirred at 100°C for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give 6-((8-((2-(but-3-ene-1-oxy)-4-(((tert-butoxycarbonyl)(methyl)amino)-6-fluorophenyl)amino)quinazolin-2-yl)amino)-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM35-7 (400mg, 89% yield) as a yellow solid. LCMS: m / z (ES + )[M+H] + =711.4,Rt=2.17min.

[0546] Synthesis of compound TM35-8: To a DCE (10 mL) solution of compound 6-((8-((2-(but-3-ene-1-oxy)-4-((tert-butoxycarbonyl)(methyl)amino)-6-fluorophenyl)amino)quinazolin-2-yl)quinazolin-2-yl)amino)-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate TM35-7 (400 mg, 0.56 mmol, 1.0 eq) was added Grubbs II (35 mg, 0.056 mmol, 0.1 eq) After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give tert-butyl (E)-54-((tert-butyloxycarbonyl)(methyl)amino)-56-fluoro-11,12,12,13,14-tetrahydro-6-oxa-2,4-diaza-3(2,8)-quinazoline-1(6,8)-isoquinoline-5(1,2)-benzocyclohexanone-9-ene-2-carboxylate TM35-8 (300 mg, yield 78%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =683.2,Rt=1.01min.

[0547] Synthesis of compound TM35: Compound (E)-54-((tert-butoxycarbonyl)(methyl)amino)-56-fluoro-11,12,13,14-tetrahydro-6-oxo-2,4-diaza-3(2,8)-quinazoline-1(6,8)-isoquinoline-5(1,2)-benzocyclohexanone-9-ene-2-carboxylic acid tert-butyl ester TM35-8 (300 mg, 0.44 mmol, 1.0 eq) was added to DCM (3 mL). TFA (1 mL) was added to the solution and the mixture was stirred at 25°C for 1 hour. The residue was purified by preparative HPLC to obtain (E)-56-fluoro-N-methyl-11,12,13,14-tetrahydro-6-oxa-2,4-diaza-3(2,8)-quinazoline-1(6,8)-isoquinoline-5(1,2)-benzocyclohexanone-9-en-54amine TM35 (50 mg, yield 23.5%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =483.4,Rt=0.675min. 1H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 9.21 (s, 1H), 8.85 (d, J = 1.9Hz, 1H), 7.20 –7.14(m,2H),6.84(d,J=1.5Hz,1H),6.78(s,1H),6.71–6.63(m,2H),6.49–6. 39(m,1H),6.30(s,1H),6.07(dd,J=13.7,2.2Hz,1H),5.87(q,J=4.8Hz,1H),4 .29(s,2H),3.83(s,2H),2.91(d,J=5.3Hz,2H),2.66(dd,J=30.8,25.0Hz,8H).

[0548] Embodiment 36

[0549] Experimental steps:

[0550]

[0551] Synthesis of compound TM36-2: To a solution of compound 7-nitro-1,2,3,4-tetrahydroisoquinoline TM36-1 (5 g, 28.1 mmol, 1.0 eq) in trifluoromethanesulfonic acid (50 mL) was added NIS (12.6 g, 56.2 mmol, 2.0 eq). It was stirred at room temperature for 2 hours. The reactant was partitioned between water (200 mL) and ethyl acetate (200 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layers were dried over sodium sulfate and filtered. The organic layer was filtered and concentrated to give crude 8-iodo-6-nitro-1,2,3,4-tetrahydroisoquinoline TM36-2 (12 g, yield 140%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =305.0,Rt=0.296min.

[0552] Synthesis of compound TM36-3: To a solution of compound 8-iodo-7-nitro-1,2,3,4-tetrahydroisoquinoline TM36-2 (12 g, 39.47 mmol, 1.0 eq) in THF (100 mL) was added di-tert-butyl dicarbonate (25.8 g, 118.4 mmol, 3.0 eq). It was stirred at room temperature for 12 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give 8-iodo-6-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM36-3 (7.1 g, 44% yield) as a yellow solid. LCMS: m / z (ES + )[M+H]+ =349.0,Rt=0.859min.

[0553] Synthesis of compound TM36-4: To a solution of compound 8-iodo-7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM36-3 (3 g, 7.42 mmol, 1.0 eq) in 1,4-dioxane (30 mL) was added water (6 mL) potassium trifluoro(vinyl)borate (2.98 g, 22.26 mmol, 3.0 eq), potassium carbonate (3.07 g, 22.26 mmol, 3.0 eq), Pd(dppf)Cl2 (0.542 g, 0.742 mmol, 0.1 eq), and the mixture was stirred at 100° C. for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give tert-butyl 6-nitro-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate TM36-4 (2.1 g, yield 95%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =249.2,Rt=0.521min.

[0554] Synthesis of compound TM36-5: To a solution of compound 7-nitro-5-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM36-4 (2.1 g, 6.9 mmol, 1.0 eq) in THF (10 mL) were added water (10 mL), zinc powder (4.48 g, 69 mmol, 10.0 eq), ammonium chloride (3.7 g, 69 mol, 10.0 eq), and the mixture was stirred at room temperature for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give 6-amino-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM36-5 (850 mg, 45% yield) as a yellow solid. LCMS: m / z (ES + )[M+H] + =275.2,Rt=0.661min.

[0555] Synthesis of compound TM36-6: To a solution of compound (3-(but-3-ene-1-oxy)-4-((2-chloroquinazolin-8-yl)amino)-5-fluorophenyl)(methyl)carbamic acid tert-butyl ester TM36-5 (300 mg, 0.63 mmol, 1.0 eq) in 1,4-dioxane (30 mL) was added tert-butyl 7-amino-5-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate TM35-6 (175 mg, 0.63 mol, 1.0 eq), Xantphos (73 mg, 0.126 mmol, 0.1 eq), cesium carbonate (410 mg, 1.26 mmol, 2.0 eq) and palladium acetate (15 mg, 0.063 mmol, 0.1 eq), and the mixture was stirred at 100° C. for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give 6-((8-((2-(but-3-ene-1-oxy)-4-((tert-butoxycarbonyl)(methyl)amino)-6-fluorophenyl)amino)quinazolin-2-yl)amino)-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM36-6 (400 mg, 89% yield) as a yellow solid.

[0556] Synthesis of compound TM36-7: To a DCE (10 mL) solution of compound 7-((8-((2-(but-3-ene-1-oxy)-4-((tert-butoxycarbonyl)(methyl)amino)-6-fluorophenyl)amino)quinazolin-2-yl)amino)-5-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester TM36-6 (400 mg, 0.56 mmol, 1.0 eq) was added Grubbs II (35 mg, 0.056 mmol, 0.1 eq). After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography to give tert-butyl (E)-54-((tert-butoxycarbonyl)(methyl)amino)-56-fluoro-11,12,13,14-tetrahydro-6-oxa-2,4-diaza-3(2,8)-quinazoline-1(7,5)-isoquinoline-5(1,2)-benzocyclohexanone-9-ene-2-carboxylate TM36-7 (300 mg, yield 78%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =683.2,Rt=1.005min.

[0557] Synthesis of compound TM36: To a solution of compound (E)-54-((tert-butoxycarbonyl)(methyl)amino)-56-fluoro-11,12,13,14-tetrahydro-6-oxo-2,4-diaza-3(2,8)-quinazoline-1(7,5)-isoquinoline-5(1,2)-benzocyclohexanone-9-ene-2-carboxylic acid tert-butyl ester TM36-7 (300 mg, 0.44 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25°C for 1 hour and the residue was purified by preparative HPLC to give (E)-56-fluoro-N-methyl-11,12,13,14-tetrahydro-6-oxa-2,4-diaza-3(2,8)-quinazoline-1(7,5)-isoquinoline-5(1,2)-benzocyclohexanone-9-en-54amine TM36 (50 mg, yield 23.5%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =483.2,Rt=0.502min. 1 H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 9.21 (s, 1H), 8.89 (d, J = 2.0Hz, 1H), 7.24–7.1 1(m,2H),6.83–6.70(m,3H),6.65(td,J=6.1,3.2Hz,1H),6.46(dd,J=15.3,7.7Hz, 1H),6.30(s,1H),6.07(dd,J=13.7,2.1Hz,1H),5.87(d,J=5.1Hz,1H),4.29(s,2H) ,3.81(s,2H),2.97(t,J=5.8Hz,2H),2.70(d,J=5.0Hz,3H),2.57(d,J=24.4Hz,4H).

[0558] Embodiment 37

[0559] Experimental steps:

[0560]

[0561] Synthesis of compound TM37-2: TM37-1 (4 g) was added to 20 mL of pyridine, 5 g of hydroxylamine was added to 5 mL of ethanol and 2 mL of water, and the mixture was stirred at room temperature for 5 min, and then stirred for 3 h. 100 mL of water was added to the flask and stirred for half an hour. The mixture was then filtered to obtain yellow crystals. The crude product was recrystallized from ethanol / water (60%) to obtain the product TM37-2 (3.7 g, yield 72.7%).

[0562] Synthesis of compound TM37-3: Add 2.5 g of phosphorus pentachloride to a solution of 2.4 g of raw material TM37-2 and 80 ml of a large amount of anhydrous chloroform after cooling, and stir vigorously at -20 ° C for 40 min. The reaction mixture was stirred at -20 ° C for another 20 minutes, and then stirred at 25 ° C for another 2 hours. Add 80 ml of ice water at 0 ° C-5 ° C, and then add 10% sodium hydroxide ice solution to adjust the pH to 7. The organic layer was separated, and the aqueous layer was extracted with chloroform (2*50 mL). The combined organic layer was washed with saturated brine (2*50 mL), dried over anhydrous magnesium sulfate, decolorized with activated carbon, and evaporated in vacuo to obtain a yellow solid. Column chromatography was performed with ethyl acetate as the eluent to obtain 800 mg of the product with a yield of 31.8%.

[0563] Synthesis of compound TM37-4: To a solution of compound TM37-3 (5 g, 28.1 mmol, 1.0 eq) in trifluoroacetic acid (50 mL) was added NBS (11.2 g, 56.2 mmol, 2.0 eq). It was stirred at room temperature for 2 hours. The reactant was partitioned between water (200 mL) and ethyl acetate (200 ml) and extracted with ethyl acetate (200 mL×2). The combined organic layers were dried over sodium sulfate and filtered. The organic layer was filtered and concentrated to give a crude 7-nitro-5-bromo-1,4-dihydroisoquinoline-3(2H)-1 product TM37-4 (11 g, yield 120%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =305.0,Rt=0.296min.

[0564] Synthesis of compound TM37-5: Compound TM37-4 (3 g, 7.42 mmol, 1.0 eq) was added to a 1,4-dioxane (30 mL) solution, and water (4 mL) potassium trifluoro(vinyl)borate (2.98 g, 22.26 mmol, 3.0 eq), potassium carbonate (3.07 g, 22.26 mmol, 3.0 eq), Pd(dppf)Cl2 (0.542 g, 0.742 mmol, 0.1 eq) were added, and stirred at 100 ° C for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave 7-nitro-5-vinyl-1,4-dihydroisoquinoline-3(2H)-1 product TM37-5 (2.1 g, yield 95%) as a yellow solid.

[0565] Synthesis of compound TM37-6: Compound TM37-5 (2.1 g, 6.9 mmol, 1.0 eq) was added to THF (50 mL) solution, and water (40 mL), zinc powder (4.5 g, 69 mmol, 10.0 eq), and ammonium chloride (3.7 g, 69 mmol, 10.0 eq) were added, and stirred at room temperature for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave a buttery product TM37-6 (850 mg, 45% yield).

[0566] Synthesis of compound TM37-7: Compound TM37-6 (300 mg, 0.63 mmol, 1.0 eq) was added to a 1,4-dioxane (30 mL) solution, and tert-butyl 6-amino-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (175 mg, 0.63 mmol, 1.0 eq), Xantphos (73 mg, 0.126 mmol, 2.0 eq), cesium carbonate (410 mg, 1.26 mmol, 10.0 eq), palladium acetate (15 mg, 0.063 mmol, 0.1 eq) were added, and stirred at 100°C for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, the combined organic layers were collected together, and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave a yellow solid product (400 mg, 89% yield).

[0567] Synthesis of compound TM37-8: TM37-7 (400 mg, 0.56 mmol, 1.0 eq) and Grubbs II (35 mg, 0.056 mmol, 0.1 eq) were added to DCE (50 mL) and stirred at 40 ° C for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography gave a yellow solid product (300 mg, yield 78%).

[0568] Synthesis of compound TM37: TFA (3.5 mL) was added to DCM (10 mL) solution, and TM37-7 (150 mg, 0.21 mmol, 1.0 eq) was slowly added under ice bath conditions. Stir at 25°C for 1 hour. Column chromatography purification gave a yellow solid product TM37 (25 mg, yield 15.5%). LCMS: m / z (ES + )[M+H] + =497.1,Rt=1.692min. 1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.21(s,1H),9.04-8.99(m,1H),8.02– 7.97(m,1H),7.20-7.18(m,2H),6.98-6.92(m,1H),6.85-6.74(m,2H),6.67 -6.64(m,1H),6.55–6.49(m,1H),6.30(s,1H),6.09-6.04(m,1H),5.90-5.8 6(m,1H)4.33-4.31(m,2H),3.40(s,2H),2.79(d,J=9.2Hz,3H),2.59(s,2H).

[0569] Embodiment 38

[0570] Experimental steps:

[0571]

[0572] Synthesis of compound TM38-2: Compound 2-(2-bromophenyl)acetic acid methyl ester TM38-1 (1 g, 4.37 mmol, 1.0 eq) was dissolved in concentrated sulfuric acid (5 mL) at -20°C, and concentrated nitric acid (1 mL) was added to react at this temperature for half an hour. The reaction system was poured into a large amount of ice, and the organic phase was extracted with ethyl acetate (50 mL × 2), and the organic phase was combined and neutralized with sodium bicarbonate, and the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-(2-bromo-5-nitrobenzene)acetic acid methyl ester TM38-2 (1.1 g, yield 92%).

[0573] Synthesis of compound TM38-3: 2-(2-bromo-5-nitrophenyl)acetic acid methyl ester TM38-2 (1.1 g, 4.01 mmol, 1.0 eq) solution was added to 1,4-dioxane (30 mL) and water (2 mL), potassium (tert-butylcarbonylamino) methyl-trifluoroborate amide (1.43 g, 6.03 mmol, 1.5 eq) di-(1-adamantyl)-n-butylphosphine (283 mg, 0.802 mmol, 0.2 eq), cesium carbonate (2.63 g, 8.03 mmol, 2.0 eq), palladium acetate (90 mg, 0.401 mmol, 0.1 eq), and stirred at 100 ° C for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, the combined organic layers were collected together, and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave a yellow solid product TM38-3 (1.1 g, yield 85%).

[0574] Synthesis of compound TM38-4: TM38-3 (2.0 g, 6.17 mmol, 1.0 eq) was added to 1,4-dioxane (10 mL) and HCl solution was added, and the mixture was stirred at 40°C for 1 hour. After the reaction was quenched, the mixture was concentrated under reduced pressure to obtain a crude product. The residue was added with NaHCO3 (1.55 g, 18.5 mmol, 1.0 eq) and stirred at 60°C for 3 hours. After the reaction was quenched, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain a white solid product (1.2 g, yield 70%).

[0575] Synthesis of compound TM38-5: NIS (4.68 g, 20.8 mmol, 1.0 eq) was added to a solution of TM38-4 (2 g, 10.4 mmol, 1.0 eq) in TfOH (50 mL) and stirred at room temperature for 2 hours. The reaction was partitioned between water (100 mL) and ethyl acetate (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were dried over sodium sulfate and filtered, and the organic layer was filtered and concentrated to obtain a yellow solid crude product (1.65 g, 50% yield).

[0576] Synthesis of compound TM38-6: Compound TM38-5 (1.6 g, 5.0 mmol, 1.0 eq) was added to a 1,4-dioxane (30 mL) solution, and water (4 mL) potassium trifluoro(vinyl)borate (2.0 g, 10.0 mmol, 3.0 eq), potassium carbonate (1.5 g, 10.0 mmol, 3.0 eq), Pd(dppf)Cl2 (0.27 g, 0.5 mmol, 0.1 eq) were added, and stirred at 100 ° C for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave a yellow solid product TM38-6 (1.5 g, 98% yield).

[0577] Synthesis of compound TM38-7: Compound TM38-6 (1.65 g, 5.2 mmol, 1.0 eq) was added to a tetrahydrofuran (50 mL) solution, and water (40 mL), Zn (4.5 g, 69 mmol, 13.0 eq), and ammonium chloride (3.7 g, 69 mmol, 13.0 eq) were added, and stirred at room temperature for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave a buttery product (850 mg, 45% yield).

[0578] Synthesis of compound TM38-8: In 1,4-dioxacyclopentane (30 mL), TM38-7 (350 mg, 1.86 mmol, 1.0 eq), Xantphos (219 mg, 0.33 mmol, 0.2 eq), cesium carbonate (1.1 g, 5.5 mmol, 3.0 eq), palladium acetate (15 mg, 0.186 mmol, 0.1 eq) in TM35-6 (800 mg, 1.69 mmol, 0.9 eq) were added and stirred at 100 ° C for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave a yellow solid product (650 mg, yield 73%).

[0579] Synthesis of compound TM38-9: TM38-8 (650 mg, 1.1 mmol, 1.0 eq) and Grubbs II (69 mg, 0.11 mmol, 0.1 eq) were added to DCE (50 mL) and stirred at 40 ° C for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave a yellow solid product TM38-8 (400 mg, yield 78%).

[0580] Synthesis of compound TM38: Add trifluoroacetic acid (3.5 mL) to a dichloromethane (10 mL) solution, and slowly add compound TM38-9 (400 mg, 1.2 mmol). Stir at 25°C for 1 hour. Purify by column chromatography to obtain a yellow solid final product TM38 (27.8 mg, yield 11.5%). LCMS: m / z (ES + )[M+H] + =497.1,Rt=1.694min. 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.23(s,1H),8.980-8.985(m,1H),8 .02(s,1H),7.19-7.18(m,2H),6.93(s,1H),6.78-6.74(m,2H),6.66-6.6 4(m,1H),6.56–6.49(m,1H),6.30(s,1H),6.08-6.05(m,1H),5.88-5.87( m,1H)4.33-4.21(m,2H),3.40(s,2H),2.69(d,J=5.2Hz,3H),2.58(s,2H).

[0581] Embodiment 39

[0582] Experimental steps:

[0583]

[0584] Synthesis of compound TM39-2: Water (120 mL) and ethanol (30 mL) were added to a flask containing sodium sulfide (9.0 g) and sulfur (3.672 g). The mixture was heated at 80 ° C for 1 hour. The solution was then added to a flask of water (120 mL) and ethanol (210 mL) containing 2-bromo-4,6-dinitroaniline (30 g) and ammonium chloride (9.18 g). The reaction mixture was heated at 80 ° C for 30 minutes. 2N NaOH (120 mL) solution was added dropwise to the reaction mixture, which was then heated at 80 ° C for 30 min. After cooling to room temperature, the reaction mixture was poured into ice water, neutralized to pH = 7 with 2N HCl solution, and then extracted with ethyl acetate (2x 300 mL). The combined organic layer was washed with brine (100 mL), dried with sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product TM39-2 (30 g) as a rust-colored solid. The crude product was used directly in the next step. LCMS: m / z(ES + )[M+H] + =232.2,Rt=0.657min.

[0585] Synthesis of compound TM39-3: A mixture of compound TM39-2 (30 g, 129 mmol, 1.0 eq) and di(1H-imidazol-1-yl)methylthione (27.6 g, 155.2 mmol, 1.25 eq) in dioxane (300 mL) was stirred at 100° C. overnight. The mixture was then poured into water, and the solid was filtered to give a brown solid product (20 g, yield 56%). LCMS: m / z (ES + )[M+H] + =274.2,Rt=0.631min.

[0586] Synthesis of compound TM39-4: To a solution of compound TM39-3 (17.5 g, 63.86 mmol, 1.0 eq) and K2CO3 (26.44 g, 191.6 mmol, 3.0 eq) in 1,4-dioxane (300 mL) was added MeI (27.02 g, 191.6 mmol, 3.0 eq), and the mixture was stirred at 50°C for 3 hours. The mixture was poured into water, and the solid was filtered to give a crude product of a yellow solid (20 g, yield 100%). LCMS: m / z (ES + )[M+H] + =289.0,Rt=0.748min.

[0587] Synthesis of compound TM39-5: To a solution of compound TM39-4 (20 g, 69.9 mmol, 1.0 eq) and Cs2CO3 (22.8 g, 69.9 mmol, 1.0 eq) in DMF (10 mL) was added tert-butyl (2-bromoethyl)carbamate (15.66 g, 69.9 mmol, 1.0 eq), and the mixture was stirred at 100°C for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography to give a yellow solid product (6 g, 20% yield). LCMS: m / z (ES + )[M+H] + =431.2,Rt=5.004min.

[0588] Synthesis of compound TM39-6: m-CPBA (2.82 g, 13.92 mmol, 1.0 eq) was added to a solution of compound TM39-5 (6 g, 13.92 mmol, 1.0 eq) in DCM (100 mL), and the mixture was stirred at 50 ° C for 3 hours. The mixture was filtered and the filtrate was concentrated to give a yellow solid product (7 g, yield 100%). LCMS: m / z (ES + )[M+H] + =463.2,Rt=0.553min.

[0589] Synthesis of compound TM39-7: To a solution of compound TM39-6 (7 g, 15.12 mmol, 1.0 eq) in THF (100 mL) was added tBuOK (1.69 g, 15.12 mmol, 1.0 eq), and the mixture was stirred at 50° C. for 1 hour. The mixture was poured into water and filtered to give a yellow solid product (2 g, yield 46.8%). 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=2.2Hz,1H),8.08(d,J=2.2Hz,1H),7.97(s,1H),4.27(dd,J=9.7,6.9Hz,2H),4.09(t,J=8.2Hz,2H).

[0590] Synthesis of compound TM39-8: DMAP (869 mg, 7.06 mol, 1.0 eq) and Boc2O (1.54 g, 7.06 mmol, 1.0 eq) were added to a solution of compound TM39-7 (2.0 g, 7.06 mmol, 1.0 eq) in THF (30 mL), and the mixture was stirred at 25° C. for 1 hour. The residue was poured into water and filtered to give the product as a yellow solid (2 g, yield 74%). 1H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.21(s,1H),4.46(s,2H),4.35(s,2H),1.55(s,9H).

[0591] Synthesis of compound TM39-9: To a solution of compound TM39-8 (2 g, 5.22 mmol, 1.0 eq) in 1,4-dioxane (30 mL) was added H2O (6 mL), potassium trifluoro(vinyl)borate (2.98 g, 22.26 mmol, 3.8 eq), potassium carbonate (3.07 g, 22.26 mmol, 3.8 eq), Pd(dppf)Cl2 (0.542 g, 0.742 mmol, 0.15 eq), and the mixture was stirred at 100° C. under N2 for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave a yellow solid product (2 g, 100% yield).

[0592] Synthesis of compound TM39-10: Water (10 mL), zinc powder (4.48 g, 69 mmol, 10.0 eq), ammonium chloride (3.7 g, 69 mol, 10.0 eq) were added to a solution of compound TM39-9 (2.1 g, 6.9 mmol, 1.0 eq) in THF (10 mL), and the mixture was stirred at room temperature for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave the product (850 mg, 45% yield) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δ6.88(dd,J=17.7,11.2Hz,1H),6.49(d,J=1.9Hz,1H),6.32(d,J=17.6Hz,1 H),5.32(dd,J=11.2,2.2Hz,1H),4.34(dd,J=9.0,6.7Hz,2H),4.17–4.07(m,2H),1.55–1.52(m,9H).

[0593] Synthesis of compound TM39-11: In 1,4-dioxacyclic ring (30 mL), TM35-6 (300 mg, 0.63 mmol, 1.0 eq), Xantphos (73 mg, 0.126 mmol, 0.2 eq), cesium carbonate (616 mg, 1.89 mmol, 3.0 eq), palladium acetate (6 mg, 0.063 mmol, 0.1 eq) and TM39-10 (189 mg, 0.63 mmol, 1.0 eq) were added, and the solution was stirred at 100 ° C for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave a yellow solid product TM39-11 (400 mg, yield 89%). LCMS: m / z (ES + )[M+H] + =719.4,Rt=0.852min.

[0594] Synthesis of compound TM39-12: Grubbs II (35 mg, 0.056 mmol, 1.0 eq) was added to a DCE (10 mL) solution of compound TM39-11 (400 mg, 0.56 mmol, 1.0 eq). After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave TM39-12 (300 mg, 78% yield) as a yellow solid.

[0595] Synthesis of compound TM39: Compound TM39-11 was dissolved in a solution of dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was slowly added under ice bath. The mixture was stirred at 25°C for 1 hour. The crude residue was purified by preparative HPLC to obtain a yellow solid product (50 mg, yield 23.5%). LCMS: m / z (ES + )[M+H] + =491.2,Rt=0.637min. 1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.20(s,1H),8.97(s,1H),8.14(s,1H),7.45– 7.36(m,1H),7.23(dd,J=17.0,6.0Hz,3H),6.99(d,J=16.1Hz,1H),6.89(d,J=13.5 Hz,2H),6.77(dd,J=15.9,8.0Hz,1H),6.41(s,1H),6.14(d,J=6.7Hz,1H),4.22(d, J=5.6Hz,2H),4.12(d,J=8.3Hz,2H),4.02(d,J=7.2Hz,2H),2.67(d,J=10.6Hz,5H).

[0596] Embodiment 40

[0597] Experimental steps:

[0598]

[0599] Synthesis of compound TM40-2: Dissolve compound 8-bromoquinolin-2-ol TM40-1 (10 g, 44.85 mmol, 1.0 eq) in TFA (100 mL), add fuming HNO3 (15 mL) to the solution. Stir at 70°C for 12 hours. Extract the reaction solution with water (200 mL) and ethyl acetate (200 mL×2). Dry the combined organic layers with sodium sulfate and filter. Filter the organic layer and concentrate and filter to obtain a yellow solid crude product 8-bromo-6-nitroquinolin-2-ol TM40-2 (11 g, yield 91.6%). LCMS: m / z (ES + )[M+Na] + =293.0,Rt=0.42min.

[0600] Synthesis of compound TM40-3: Compound 8-bromo-6-nitroquinoline-2-ol TM40-2 (5.5 g, 20.5 mmol, 1.0 eq) was dissolved in POCl3 (30 ml). It was stirred at 70°C for 1 hour. After quenching the reaction, it was extracted with ethyl acetate (200 ml) and water (150 ml). The combined organic layers were collected together and concentrated under reduced pressure to obtain a yellow solid crude product 8-bromo-2-chloro-6-nitroquinoline TM40-3 (6 g, yield 103%).

[0601] LCMS: m / z(ES + )[M+H] + =287.0,Rt=0.793min.

[0602] Synthesis of compound TM40-4: Compound 8-bromo-2-chloro-6-nitroquinoline TM40-3 (6 g, 20.98 mmol, 1.0 eq) was dissolved in methylamine ethanol solution (40 ml), and the mixture was stirred at 60°C for 12 hours. After quenching the reaction, it was extracted with ethyl acetate (150 ml) and water (150 ml). The combined organic layers were collected together and concentrated under reduced pressure to give a yellow solid crude product 8-bromo-N-methyl-6-nitroquinoline-2-amine TM40-4 (6.6 g, yield 112%). LCMS: m / z (ES + )[M+H] + =282.0,Rt=0.563min.

[0603] Synthesis of compound TM40-5: Compound 8-bromo-N-methyl-6-nitroquinoline-2-amine TM40-4 (6.6 g, 23.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran (60 ml), di-tert-butyl dicarbonate (10.25 g, 47 mmol, 2.0 eq), triethylamine (11.32 g, 112.1 mmol, 4.8 eq) and DMAP (2.74 g, 22.42 mmol, 0.96 eq) were added to the solution, and the mixture was stirred at room temperature for 12 hours. After quenching the reaction, it was extracted with ethyl acetate (150 ml) and water (150 ml). The combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave tert-butyl (8-bromo-6-nitroquinoline-2-yl) (methyl) carbamate TM40-5 (6.0 g, 67% yield) as a yellow solid. LCMS: m / z(ES + )[M-56+H] + =326.2,Rt=0.93min.

[0604] Synthesis of compound TM40-6: Compound (8-bromo-6-nitroquinolin-2-yl)(methyl)carbamic acid tert-butyl ester TM40-5 (3.57 g, 9.37 mmol, 1.0 eq) was added to 1,4-dioxane (30 mL), H2O (6 mL), potassium trifluoro(vinyl)borate (2.98 g, 22.26 mmol, 2.4 eq), potassium carbonate (3.07 g, 22.26 mmol, 2.4 eq), Pd(dppf)Cl2 (0.542 g, 0.742 mmol, 0.08 eq) were added to the solution, and the mixture was stirred at 100 ° C for 3 hours. After quenching the reaction, it was extracted with EA (150 ml) and water (150 ml). The combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography gave a yellow solid product, methyl (6-nitro-8-vinylquinolin-2-yl) carbamic acid tert-butyl ester TM40-6 (3 g, yield 97%). LCMS: m / z (ES + )[M-56+H] + =274.2,Rt=0.92min.

[0605] Synthesis of compound TM40-7: Water (10 ml), Zn (2.37 g, 36.5 mmol, 10.0 eq), and ammonium chloride (1.95 g, 36.5 mmol, 10.0 eq) were added to a solution of compound methyl (6-nitro-8-vinylquinolin-2-yl) carbamic acid tert-butyl ester TM40-6 (1.2 g, 3.65 mmol, 1.0 eq) in THF (10 ml), and the mixture was stirred at room temperature for 3 hours. After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave yellow oily (6-amino-8-vinylquinolin-2-yl) (methyl) carbamic acid tert-butyl ester TM40-7 (960 mg, 87% yield). LCMS: m / z (ES + )[M+H] + =300.2,Rt=0.559min.

[0606] Synthesis of compound TM40-8: Compound (6-amino-8-vinylquinolin-2-yl) (methyl) carbamic acid tert-butyl ester TM40-8 (450 mg, 1.5 mmol, 1.0 eq) was added to 1,4-dioxane (15 mL), tert-butyl (3-(but-3-ene-1-oxy)-4-((2-chloroquinazoline-8-yl) amino)-5-fluorophenyl) (methyl) carbamate (849 mg, 1.8 mmol, 1.3 eq), Xantphos (173 mg, 0.3 mmol, 0.2 eq), cesium carbonate (1.467 g, 4.5 mmol, 3.0 eq) and palladium acetate (34 mg, 0.15 mmol, 0.1 eq), and the mixture was stirred at 100 ° C for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave tert-butyl (3-(but-3-en-1-oxy)-4-((2-(((tert-butoxycarbonyl)(methyl)amino)-8-vinylquinolin-6-yl)amino)quinazolin-8-yl)aminoamino)-5-fluorophenyl)(methyl ester)carbamate TM40-8 (420 mg, yield 38%) as a red solid. LCMS: m / z (ES + )[M+H] + =736.2,Rt=1.621min.

[0607] Synthesis of compound TM40-9: Compound tert-butyl (3-(but-3-ene-1-oxy)-4-((2-(((tert-butoxycarbonyl)(methyl)amino)-8-vinylquinolin-6-yl)amino)quinazolin-8-yl)aminoamino)-5-fluorophenyl)(methyl ester)carbamate TM40-8 (320 mg, 0.43 mmol, 1.0 eq) was dissolved in DCE (10 mL), Grubbs II (27 mg, 0.043 mmol, 0.1 eq) was added to the solution, and the mixture was stirred at 25 ° C for 6 hours. After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave di-tert-butyl (56-fluoro-6-oxa-2,4-diaza-3(2,8)-quinazoline-1(6,8)-quinoline-5(1,2)-benzocyclohexanone-9-ene-12,54-diyl) (E)-bis(methylcarbamate) TM40-9 as a yellow solid (120 mg, yield 39.5%). LCMS: m / z (ES + )[M+H] + =708.2,Rt=1.05min.

[0608] Synthesis of compound TM40: trifluoroacetic acid (1 mL) was added to a solution of compound di-tert-butyl (56-fluoro-6-oxa-2,4-diaza-3 (2,8)-quinazoline-1 (6,8)-quinoline-5 (1,2)-benzocyclohexanone-9-ene-12,54-diyl) (E)-bis ​​(methylcarbamate) TM40-9 (120 mg, 0.17 mmol, 1.0 eq) in dichloromethane (3 mL). The mixture was stirred at 25° C. for 1 hour and purified by column chromatography to obtain a white solid product TM40 (16.8 mg, yield 19.5%). LCMS: m / z (ES + )[M+H] + =508.2,Rt=0.129min. 1 H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H), 9.38 (d, J = 2.3Hz, 1H), 9.22 (s, 1H), 7.75 (d, J = 9.0Hz ,1H),7.58(d,J=16.3Hz,1H),7.29(d,J=2.3Hz,1H),7.21–7.13(m,2H),6.86(t,J=4.8Hz, 1H),6.80–6.62(m,4H),6.31(s,1H),6.07(dd,J=13.7,2.1Hz,1H),5.89(d,J=5.0Hz,1H), 4.44(s,1H),4.16(s,1H),2.94(d,J=4.7Hz,3H),2.70(d,J=5.0Hz,3H),2.69–2.63(m,2H).

[0609] Embodiment 41

[0610] Experimental steps:

[0611]

[0612] Synthesis of compound TM41-2: To a concentrated solution of 2-chloro-6-nitrobenzo[d]thiazole TM41-1 (10.0 g, 46.73 mmol, 1.0 eq). Concentrated sulfuric acid (50 mL) NBS (8.32 g, 46.73 mmol, 1.0 eq) was added. The reaction mixture was stirred at 60°C for 16 hours. LCMS showed that the reaction was complete. The reaction flask was poured into ice water and basified with 2M NaOH aqueous solution. The organic material was extracted with ethyl acetate (3×200 mL) and dried over anhydrous sodium sulfate. The mixture was purified on silica gel to obtain a yellow solid 4-bromo-2-chloro-6-nitrobenzo[d]thiazole TM41-2 (10.0 g, 34.24 mmol, yield 73.28%). 1H NMR (400MHz, DMSO-d6) δ9.19 (d, J = 2.2 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H).

[0613] Synthesis of compound TM41-3: To a solution of compound 4-bromo-2-chloro-6-nitrobenzo[d]thiazole TM41-2 (10.0 g, 34.24 mmol, 1.0 eq) in ethanol (100 ml) was added hydrazine hydroxide solution (1.09 g, 34.23 mmol, 1.0 eq). The reaction mixture was then stirred at 25 °C for 3 hours. LCMS showed that the reaction was complete. The organic material was extracted with ethyl acetate (3×100 mL) and dried over anhydrous sodium sulfate. The mixture was purified on silica gel to give (E)-4-bromo-2-hydrazine-6-nitro-2,3-dihydrobenzo[d]thiazole TM41-3 (8.9 g, 30.90 mmol, yield 90.25%) as a light yellow solid. 1 HNMR (400MHz, DMSO-d6) δ10.68(s,1H),7.85(d,J=2.4Hz,1H),7.49(d,J=2.4Hz,1H),6.16(s,2H).

[0614] Synthesis of compound TM41-4: To a solution of (E)-4-bromo-2-hydrazine-6-nitro-2,3-dihydrobenzo[d]thiazole TM41-3 (8.9 g, 30.90 mmol, 1.0 eq) in formic acid (90 mL), the reaction mixture was stirred at 110 ° C for 16 h. LCMS showed that the reaction was complete. The mixture was purified by column chromatography to give a white solid 5-bromo-7-nitrobenzo[4,5]thiazolo[2,3-c][1,2,4]triazole TM41-4 (9.0 g, 31.14 mmol, yield 100.5%). LCMS: (ES+) [M+H] + =300.9,Rt=1.25min.

[0615] Synthesis of compound TM41-5: To a solution of TM41-4 (9.0 g, 31.14 mmol, 1.0 eq) in THF (90 mL) and water (9 mL) were added potassium trifluoroborate (4.2 g, 31.14 mm mol, 1.0 eq), potassium carbonate (8.59 g, 62.28 mmol, 2.0 eq) and (PPh3)PdCl2 (1.36 g, 3.11 mmol, 0.1 eq). The reaction mixture was stirred at 85 ° C for 4 hours. LCMS showed that the reaction was complete. The resulting mixture was diluted with water (50 mL) and extracted with EA (80 mL×3). The organic phase was concentrated under reduced pressure. Column chromatography purification gave 7-nitro-5-vinylbenzo[4,5]thiazo[2,3-c][1,2,4]triazole TM41-5 (2.2 g, 8.94 mmol, yield 28.72%) as a white solid. LC-MS: (ES+) [M+41] + =287.6,Rt=1.14min.

[0616] Synthesis of compound TM41-6: Fe (4.97 g, 89.4 mmol, 10.0 eq) was added to a THF (20 mL) solution of TM41-5 (2.2 g, 8.94 mmol, 1.0 eq). Column chromatography was used to purify the mixture to obtain 5-vinylbenzo[4,5]thiazolo[2,3-c][1,2,4]triazole-7-amine TM41-6 (1.0 g, 4.63 mmol, yield 51.78%) as a white solid. LC-MS: (ES+) [M+H] + =216.8,Rt=0.90min.

[0617] Synthesis of compound TM41-7: TM35-6 (874 mg, 1.05 mmol, 1.0 eq), TM41-6 (400 mg, 1.85 mmol, 1.0 eq), Xantphos (141 mg, 0.21 mmol, 0.2 eq), cesium carbonate (1.24 g, 3.15 mmol, 3.0 eq) and palladium acetate (26 mg, 0.105 mmol, 0.1 eq) were added to a dioxane (10 mL) solution, and the mixture was stirred at 100 ° C for 3 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave the product TM41-7 (120 mg, 0.18 mmol, 10%) as a white solid. LC-MS: (ES+) [M+H] + =652.6,Rt=2.92min.

[0618] Synthesis of compound TM41-8: Grubbs II (27 mg, 0.043 mmol, 0.1 eq) was added to a DCE (10 mL) solution of compound TM35-7 (320 mg, 0.43 mmol, 1.0 eq) and the mixture was stirred at 25 ° C for 6 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave the product TM41-8 (120 mg, yield 39.5%) as a yellow solid. LCMS: m / z (ES+) [M+H]+ = 625.2, Rt = 0.937 min.

[0619] Synthesis of compound TM41: Trifluoroacetic acid (1 mL) was added to a solution of compound TM41-8 (120 mg, 0.17 mmol, 1.0 eq) in dichloromethane (3 mL). The mixture was stirred at 25°C for 1 hour, and the crude product was purified by preparative HPLC to obtain the product TM41 (5.48 mg, yield 3%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =525.2,Rt=0.804min. 1 H NMR (400MHz, TFA) δ10.34(s,1H),10.03(d,J=5.3Hz,1H),9.76(d,J=2.0Hz,1H),8.27(d,J=2.0Hz,1H),8.18–8.11(m,2H),7.88(s,1H), 7.71(d,J=16.0Hz,2H),7.59(d,J=10.7Hz,1H),7.41(dd,J=15.3,7.8Hz,1H),5.03(s,2H),3.81(d,J=4.5Hz,3H),3.43(d,J=6.0Hz,2H).

[0620] Embodiment 42

[0621] Experimental steps:

[0622]

[0623] Synthesis of compound TM42-2: TM42-1 (50 g, 274.7 mmol, 1.0 eq) was dissolved in ethanol (750 mL), HCl (27.5 mL) was slowly added at 0°C, and then TM42-1A (55 mL) was added dropwise to the reaction solution, and the mixture was reacted at 0°C for 3 hours. After the reaction, ethyl acetate (200 mL) was added, and the mixture was stirred at room temperature for 1 hour, and filtered to obtain a light yellow solid, which was stirred with methyl tert-butyl ether, and the solid was filtered and dried in vacuo to obtain a light yellow solid compound TM42-2 (48 g, yield 76.3%). LC-MS: [ESI] [M+H] + =228.0,t R =0.60min.

[0624] Synthesis of compound TM42-3: TM42-2 (50 g, 152.8 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (200 mL), and then TM42-2A (25.5 g, 152.8 mmol, 1.0 eq) was slowly added, stirred for 20 minutes, TM42-2B (25 mL) was dissolved in 1,4-dichloromethane (100 mL), and slowly added dropwise to the reaction solution, and the temperature was slowly raised to 80°C, and the reaction was carried out for 3 hours. After the reaction, the silica gel powder was directly concentrated and mixed with petroleum ether / ethyl acetate in a ratio of 3 / 1 to obtain a brown oily compound TM42-3 (28 g, yield 65.4%). LC-MS: [ESI] [M+H] + =233.0,t R =1.10min.

[0625] Synthesis of compound TM42-4: TM42-3 (28 g, 100 mmol, 1.0 eq) and RhCl(PPh3)3 (3.7 g, 4.0 mmol, 0.04 eq) were dissolved in tetrahydrofuran (250 mL), and then H2 (0.4 MPa) was introduced and reacted at 35°C for 24 hours. After the reaction, the silica gel powder was directly concentrated and mixed with petroleum ether / ethyl acetate in a ratio of 5 / 1 to obtain a yellow solid compound TM42-4 (6 g, yield 20.6%). LC-MS: [ESI] [M+H] + =191.2,t R =0.78min.

[0626] Synthesis of compound TM42-5: TM42-4 (3 g, 152.8 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (20 mL) at room temperature and reacted for 3 hours. After the reaction, compound TM42-5 (3 g, brown solid, yield 100%) was directly concentrated and used for the next reaction without further purification. LC-MS: [ESI] [M+H]+ =191.2,t R =0.42min.

[0627] Synthesis of compound TM42-6: TM42-5 (3 g, 10.3 mmol, 1.0 eq) was dissolved in pyridine (20 mL), and TFAA (4.3 g, 20.6 mmol, 2.0 eq) was added. The reaction was carried out at 80°C for 3 hours. After the reaction, the reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (40 mL*3), the organic phase was collected, dried with anhydrous sodium sulfate, and concentrated to obtain compound TM42-6 (1.6 g, brown solid, yield 54.3%). No further purification was required, but it was directly used in the next step of the reaction.

[0628] Synthesis of compound TM42-7: TM42-6 (1.6 g, 5.6 mmol, 1.0 eq) and NBS (2.99 g, 16.8 mmol, 3.0 eq) were dissolved in trifluoromethanesulfonic acid (12 mL) and reacted at 80 ° C for 3 hours. After the reaction was completed, the reaction solution was slowly poured into a saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (50 mL * 3), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain compound TM42-7 (500 mg, brown solid, yield 24.5%). No further purification is required and it is directly used in the next step of the reaction. LC-MS: [ESI] [M + H] + = 335.2, t R =1.23min.

[0629] Synthesis of compound TM42-8: TM42-7 (500 mg, 1.37 mmol, 1.0 eq), TM42-7A (550 mg, 4.11 mmol, 3.0 eq), potassium carbonate (283 mg, 2 mmol, 1.5 eq), Pd(dppf)Cl2 (100 mg, 0.137 mmol, 0.1 eq) were dissolved in 1,4-dioxane (5 mL) and reacted at 100° C. for 12 hours. After the reaction, the silica gel powder was directly concentrated and mixed with a mixture of petroleum ether / ethyl acetate = 5 / 1 to obtain compound TM42-8 (300 mg, yellow solid, yield 70%).

[0630] Synthesis of compound TM42-9: TM42-8 (300 mg, 0.96 mmol, 1.0 eq), zinc powder (312 mg, 4.8 mmol, 5.0 eq) and ammonium chloride (254 mg, 4.8 mol, 5.0 eq). React at 60 ° C for 4 hours. After the reaction is completed, the reaction solution is cooled to room temperature, filtered with a Buchner funnel, and the organic phase is extracted with ethyl acetate (20 mL * 3). The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated to obtain compound TM42-9 (130 mg, brown solid, yield 48%). No further purification is required and it is directly used in the next step of the reaction. LC-MS: [ESI] [M+Na] + =307.2,t R =1.27min.

[0631] Synthesis of compound TM42-10: TM42-9 (130 mg, 0.46 mmol, 1.0 eq), TM35-6 (217 mg, 0.46 mmol, 1.0 eq), cesium carbonate (299 mg, 0.92 mmol, 2.0 eq), Pd(OAc)2 (10.2 mg, 0.046 mmol, 0.1 eq) and Xantphos (53 mg, 0.092 mmol, 0.2 eq) were dissolved in 1,4-dioxane (10 mL) and reacted in a nitrogen environment at 100 ° C for 12 hours. After the reaction, compound TM42-10 (100 mg, yellow solid, yield 30%) was obtained by purification.

[0632] Synthesis of compound TM42-11: TM42-10 (100 mg, 0.139 mmol, 1.0 eq) and Grubbs-2 (23.6 mg, 0.0278 mmol, 0.2 eq) were dissolved in 1,2-dichloroethane (6 mL) and reacted in nitrogen at 80 ° C for 12 hours. After the reaction, column chromatography purification gave compound TM42-11 (40 mg, yellow solid, yield 41.7%).

[0633] Synthesis of compound TM42-12: TM42-11 (40 mg, 0.057 mmol, 1.0 eq) and K2CO3 (11.7 mg, 0.076 mmol, 1.5 eq) were dissolved in methanol (5 mL) and reacted at room temperature for 2 hours. After the reaction, the solid was filtered and the solution was dried in vacuo to obtain compound TM42-12 (35 mg, yellow solid, yield 100%), which was used directly in the next step without further purification.

[0634] Synthesis of compound TM42: TM42-12 (35 mg, 0.057 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL) and reacted at room temperature for 2 hours. After the reaction was complete, the solution was vacuum-rotated and dried, and HPLC was used to prepare compound TM42. 0.5 mL of ammonia was added for freeze drying to remove most of the trifluoroacetic acid to obtain compound TM42 (10 mg, yellow solid, yield 33.8%). LCMS: m / z (ES + )[M+H] + =495.4,Rt=1.61min. 1 H NMR(400MHz,MeOD)δ9.27(d,J=24.8Hz,1H),9.13(s,1H),7.21(dt,J=8.0,7.2H z,2H),7.10(s,1H),6.93(dd,J=15.5,7.7Hz,1H),6.83–6.75(m,2H),6.33(s,1H ),6.10(dd,J=13.4,2.3Hz,1H),5.36(s,1H),5.15(s,1H),4.60(s,2H),2.80(s ,3H),2.71(s,2H),2.31(d,J=10.1Hz,2H),1.62(d,J=11.4Hz,2H),1.32(s,4H).

[0635] Embodiment 43

[0636] Experimental steps:

[0637]

[0638] Synthesis of compound TM43-2: Dissolve the compound 2-bromo-1-fluoro-4-nitrobenzene TM43-1 (10 g, 45.66 mmol, 1.0 eq) in ethanol (100 mL), and add hydrazine hydrate (80%, 15 mL) to the solution. Stir at 25°C for 6 hours. Partition the reactant between water (200 mL) and EA (200 ml) and extract with ethyl acetate (200 mL×2). Dry the combined organic layers over sodium sulfate and filter. Filter the organic layer and concentrate and filter to obtain the crude product (2-bromo-4-nitrophenyl)hydrazine TM43-2 (10.1 g, yield 96.2%) as a yellow solid. LCMS: m / z (ES + )[M+Na] + =232.0,Rt=1.335min.

[0639] Synthesis of compound TM43-3: Compound (2-bromo-4-nitrophenyl) hydrazine TM43-2 (10.1 g, 43.7 mmol, 1.0 eq) was dissolved in ethanol (150 mL), and ethyl 2-oxopropanoate (5.7 g, 43.7 mm mol, 1.0 eq) was added to the solution. It was stirred at 70 ° C for 1 hour. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude yellow solid (E)-ethyl 2-(2-(2-bromo-4-nitrophenyl) hydrazine) propionate TM43-3 (10.0 g, yield 69%). LCMS: m / z (ES + )[M+H] + =332.0,Rt=1.510min.

[0640] Synthesis of compound TM43-4: Compound TM43-3 (10.0 g, 30.4 mmol, 1.0 eq) was dissolved in polyphosphoric acid (100 mL), and the mixture was stirred at 100 ° C for 4 hours. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave TM43-4 (3.4 g, yield 36%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =315.0,Rt=0.787min.

[0641] Synthesis of compound TM43-5: Compound TM43-4 (3.4 g, 10.9 mmol, 1.0 eq) was dissolved in methylamine ethanol solution (30 mL), and the mixture was stirred under microwave at 50 ° C for 1 hour. After quenching the reaction, the aqueous phase was extracted with EtOAc. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave TM43-5 (1.7 g, yield 53%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =300.0,Rt=0.685min.

[0642] Synthesis of compound TM43-6: Compound TM43-5 (1.7 g, 5.68 mmol, 1.0 eq) was placed in 1,4-dioxane (15 mL), water (3 mL), potassium trifluoro(vinyl)borate (2.3 g, 17.04 mmol, 3.0 eq), potassium carbonate (2.3 g, 17.04 mmol, 3.0 eq), Pd(dppf)Cl2 (415 mg, 0.57 mmol, 0.1 eq) were added to the solution, and the mixture was stirred at 100 ° C for 3 hours. After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave TM43-6 (630 mg, yield 45%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =246.2,Rt=0.687min.

[0643] Synthesis of compound TM43-7: Compound TM43-6 (630 mg, 2.57 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), water (2 ml), Zn (1.67 g, 25.7 mmol, 10.0 eq), ammonium chloride (1.37 g, 25.7 mmol, 10.0 eq) were added to the solution, and the mixture was stirred at room temperature for 3 hours. After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave TM43-7 (340 mg, 61%) as a yellow oil. LCMS: m / z (ES + )[M+H] + =216.2,Rt=0.470min.

[0644] Synthesis of compound TM43-8: Compound TM43-7 (340 mg, 1.6 mmol, 1.0 eq) was dissolved in 1,4-dioxane (5 mL), TM35-6 (849 mg, 1.8 mmol, 1.2 eq), Xantphos (173 mg, 0.3 mmol, 0.2 eq), cesium carbonate (1.467 g, 4.5 mmol, 3.0 eq) and palladium acetate (34 mg, 0.16 mmol, 0.1 eq) were added to the solution, and the mixture was stirred at 100 ° C for 3 hours. After quenching the reaction, the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to give a crude product. Column chromatography purification gave TM43-8 (430 mg, yield 41%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =652.2,Rt=0.866min.

[0645] Synthesis of compound TM43-9: Compound TM43-8 (430 mg, 0.66 mmol, 1.0 eq) was dissolved in DCE (10 mL), Grubbs II (42 mg, 0.066 mmol, 0.1 eq) was added to the solution, and the mixture was reacted in nitrogen at 80 ° C for 12 hours. After the reaction was complete, the reaction was quenched and the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave TM43-9 (110 mg, yield 26.8%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =624.4,Rt=5.700min.

[0646] Synthesis of compound TM43: Compound TM43-9 (110 mg, 0.17 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added to the solution, and the mixture was stirred at 25°C for 1 hour. The residue was purified by preparative HPLC to obtain TM43 (10 mg, yield 11.2%) in the form of a white solid. LCMS: m / z (ES + )[M+H] + =524.2,Rt=0.751min. 1 H NMR (400MHz, MeOD) δ9.19(d,J=1.8Hz,1H),9.07(s,1H),7.26(d,J=1.9Hz,1H),7.14(t,J=11.0Hz,3H),7.01(s,1H),6.91(dt,J=15.5,7.5H z,1H),6.74(s,1H),6.33(s,1H),6.09(d,J=12.4Hz,1H),4.57–4.37(m,1H),4.28(s,1H),2.96(s,3H),2.80(s,3H),2.74(d,J=6.5Hz,2H).

[0647] Embodiment 44

[0648] Experimental steps:

[0649]

[0650] Synthesis of compound TM44-2: Add compound 3,5-difluoro-4-nitrobenzonitrile TM44-1 (5 g, 27.16 mmol, 1.0 eq) solution to DMF (100 mL), add potassium carbonate (7.51 g, 54.32 mmol, 2.0 eq) and but-3-ene-1-ol (1.96, 27.16 mmol, 1.0 eq). The reaction mixture was stirred at 60 ° C for 12 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure. The raw material was purified by silica gel column chromatography (10% ethyl acetate / hexane) to obtain compound TM44-2 as butter (5.3 g, yield 81%).

[0651] Synthesis of compound TM44-3: Compound TM44-2 (1.65 g, 5.2 mmol, 1.0 eq) was added to tetrahydrofuran (50 mL) solution, and water (40 mL), zinc powder (4.5 g, 69 mmol, 1.0 eq), and ammonium chloride (3.7 g, 69 mmol, 1.0 eq) were added, and stirred at room temperature for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave a buttery product TM44-3 (850 mg, yield 45%).

[0652] Synthesis of compound TM44-4: Compound TM44-3 (2.0 g, 9.7 mmol, 1.0 eq) was added to 1,4-dioxane (30 mL), and 8-bromo-2-chloroquinazoline (2.83 g, 11.64 mmol, 1.2 eq), Xantphos (1.12 g, 1.94 mmol, 1.0 eq), cesium carbonate (6.23 g, 19.40 mmol, 2.0 eq), palladium acetate (217 mg, 0.97 mmol, 0.1 eq) were added, and stirred at 100 ° C for 3 hours. After the reaction was quenched, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were collected together and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography gave a yellow solid product TM44-4 (1.3 g, yield 50%).

[0653] Synthesis of compound TM44-5: Compound TM44-4 (1.3 g, 3.52 mmol, 1.0 eq) and tert-butyl 6-amino-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.16 g, 4.23 mmol, 1.2 eq), Xantphos (407 mg, 0.705 mmol, 0.2 eq), cesium carbonate (2.3 g, 7.05 mmol, 2.0 eq) and palladium acetate (79 mg, 0.35 mmol, 0.1 eq) were added to 1,4-dioxane (30 mL) and stirred at 100 ° C for 3 hours. After the reaction was complete, the reaction was quenched, the aqueous phase was extracted with ethyl acetate, the combined organic layers were collected together, and the crude product was concentrated under reduced pressure. Purification by column chromatography gave a yellow solid product TM44-5 (1.1 g, yield 53%).

[0654] Synthesis of compound TM44-6: Add compound TM44-5 (1.16 g, 1.91 mmol, 1.0 eq) solution to DCE (50 mL), add Grubbs II (179 mg, 0.191 mmol, 0.1 eq), and stir at 40 ° C for 3 hours. After the reaction is complete, quench, extract the aqueous phase with ethyl acetate, collect the combined organic layers together, and concentrate under reduced pressure to obtain a crude product. Purify by column chromatography to obtain a yellow solid product TM44-6 (850 mg, yield 68%).

[0655] Synthesis of compound TM44-7: Palladium carbon (33 mg, 0.296 mmol, 0.2 eq) was added to a solution of TM44-6 (858 mg, 1.48 mmol, 1.0 eq) in tetrahydrofuran (50 mL), and stirred at 40° C. for 3 hours. The catalyst was removed by filtration through bluestone, and the filtrate was concentrated in vacuo to obtain the product TM44-7 (752 mg, yield 78%) as a yellow solid.

[0656] Synthesis of compound TM44-8: Trifluoroacetic acid (5 mL) was added to a dichloromethane (50 mL) solution, and compound TM44-7 (752 mg, 1.3 mmol) was stirred at room temperature for 3 hours. The crude product was obtained after concentration under reduced pressure. The product TM44-8 (496 mg, yield 72%) was purified by column chromatography as a yellow solid.

[0657] Synthesis of compound TM44: Formaldehyde (418 mg, 5.16 mmol, 37%) was mixed with methanol (1 mL), stirred at 0°C for 1 h, acetic acid (3 drops) and compound TM44-8 (496 mg, 1.03 mmol, 1.0 eq) were added, and then NaBH(OAc)3 (437 mg, 2.06 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 1 h, then filtered and concentrated in vacuo to obtain a residue. Column chromatography purification gave TM44 (25.6 mg, yield 18.5%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =495.2,Rt=1.709min. 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.23(s,1H),8.980-8.985(m,1H),8 .02(s,1H),7.19-7.18(m,2H),6.93(s,1H),6.78-6.74(m,2H),6.66-6.6 4(m,1H),6.56–6.49(m,1H),6.30(s,1H),6.08-6.05(m,1H),5.88-5.87( m,1H)4.33-4.21(m,2H),3.40(s,2H),2.69(d,J=5.2Hz,3H),2.58(s,2H).

[0658] Embodiment 45

[0659] Experimental steps:

[0660]

[0661] Synthesis of compound TM45-2: Add compound 3,5-difluoro-4-nitrobenzonitrile TM45-1 (3 g, 18.86 mmol, 1.0 eq) solution to DMF (50 mL), add potassium carbonate (3.47 g, 25.14 mmol, 1.34 eq) and but-3-ene-1-ol (1.81 g, 25.14 mmol, 1.34 eq). The reaction mixture was stirred at 60 ° C for 12 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The raw material was purified by silica gel column chromatography (10% ethyl acetate / hexane) to obtain compound 1-(but-3-ene-1-oxy)-3-fluoro-2-nitrobenzene as a yellow butter product TM45-2 (2.65 g, yield 66%).

[0662] Synthesis of compound TM45-3: Compound TM45-2 (2.65 g, 12.57 mmol, 1.0 eq) was added to tetrahydrofuran (50 mL) solution, and water (40 mL), zinc powder (4.5 g, 69 mmol, 5.0 eq), and ammonium chloride (3.7 g, 69 mmol, 5.0 eq) were added, and stirred at room temperature for 3 hours. After the reaction was complete, the reaction was quenched, the aqueous phase was extracted with ethyl acetate, the combined organic layers were collected together, and the crude product was concentrated under reduced pressure. Column chromatography purification was performed to obtain a yellow butter product TM45-3 (2.1 g, yield 80%).

[0663] Synthesis of compound TM45-4: Compound TM45-3 (2.1 g, 11.59 mmol, 1.0 eq) was added to a solution of 1,4-dioxane (30 mL), and 8-bromo-2-chloroquinazoline (3.39 g, 13.91 mmol, 1.2 eq), Xantphos (1.34 g, 2.32 mmol, 1.0 eq), cesium carbonate (7.55 g, 23.18 mmol, 2.0 eq), palladium acetate (260 mg, 1.16 mmol, 0.1 eq) were added, and stirred at 100 ° C for 3 hours. After the reaction was complete, the reaction was quenched and the aqueous phase was extracted with ethyl acetate. The combined organic layers were collected and concentrated under reduced pressure to obtain a crude product. Column chromatography purification gave TM45-4 (3.04 mg, yield 72%) as a yellow solid.

[0664] Synthesis of compound TM45-5: Compound TM45-4 (3.04 g, 8.84 mmol, 1.0 eq) was added to 1,4-dioxane (30 mL) with tert-butyl 6-amino-8-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.91 g, 10.61 mmol, 1.3 eq), Xantphos (1.02 g, 1.77 mmol, 0.2 eq), cesium carbonate (5.76 g, 17.69 mmol, 2.0 eq) and Pd(OAc)2 (198 mg, 0.88 mmol, 0.1 eq), and stirred at 100 °C for 3 hours. After the reaction was complete, the reaction was quenched, the aqueous phase was extracted with ethyl acetate, the combined organic layers were collected together, and the crude product was concentrated under reduced pressure. Column chromatography purification gave TM45-5 (3.38 g, yield 67%) as a yellow solid.

[0665] Synthesis of compound TM45-6: Add TM45-5 (3.38 g, 5.81 mmol, 1.0 eq) solution to 1,2-dichloroethane (50 mL), add Grubbs II (35 mg, 0.058 mmol, 0.1 eq), and stir at 40 ° C for 3 hours. After the reaction is complete, quench, extract the aqueous phase with ethyl acetate, collect the combined organic layers together, and concentrate under reduced pressure to obtain a crude product. Purify by column chromatography to obtain TM45-6 (950 mg, 34%) as a yellow solid.

[0666] Synthesis of compound TM45-7: Palladium carbon (38 mg, 0.36 mmol, 0.2 eq) was added to a solution of TM45-6 (950 mg, 1.72 mmol, 1.0 eq) in tetrahydrofuran (50 mL), and stirred at 40° C. for 3 hours. The catalyst was removed by filtration through diatomaceous earth, and the filtrate was concentrated in vacuo to obtain the product TM45-7 (700 mg, yield 78%) as a yellow solid.

[0667] Synthesis of compound TM45-8: Add TFA (5 mL) to dichloromethane (50 mL), stir compound TM45-7 (700 mg, 1.26 mmol, 1.0 eq) at room temperature for 3 hours, and concentrate under reduced pressure to obtain crude product TM45-8 (510 mg, yield 78%) as a yellow solid.

[0668] Synthesis of compound TM45: HCHO (445 mg, 5.5 mmol, 5.0 eq) was mixed with methanol (2 mL), stirred at 0°C for 1 h, AcOH (5 drops) and TM45-8 (500 mg, 1.1 mmol, 1.0 eq) were added, and sodium triacetoxyborohydride (465 mg, 2.2 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 1 h, then filtered and concentrated in vacuo to obtain a residue. Column chromatography purification gave TM45 (360 mg, yield 96.5%) as a yellow solid. LCMS: m / z (ES + )[M+H] + =471.2,Rt=1.290min. 1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),9.23(s,1H),8.26(s,1H),7.40(s,1H),7.30-7.28(m,2H),7.21(t,4.0Hz,1H),7.15-7.11(m,1H),7.06 -7.04(m,1H),6.95-6.91(m,1H),6.81–6.76(m,2H),4.33-4.21(m,2H),3.45(s,2H),2.79(d,J=5.2Hz,3H),2.59-2.54(m,4H),2.37(s,3H).

[0669] Example 46: In vitro test of the inhibition of HPK1 kinase activity by compounds

[0670] 46.1 Compound Testing

[0671] a) Using Echo 655, transfer the dilutions of each compound TM1 to TM45 to each well of an assay plate (6007290, PerkinElmer); b) seal the assay plate and centrifuge the compound plate at 1000 g for 1 minute.

[0672] c) Prepare 2x HPK1 in 1x kinase buffer.

[0673] d) 2x HPK1 was added to a 384-well assay plate (6007290, PerkinElmer).

[0674] e) Centrifuge the plate at 1000 g for 30 seconds and leave at room temperature for 15 minutes.

[0675] f) Prepare 2x MBP and ATP mix in 1x kinase buffer.

[0676] g) Add 5uL of 2x MBP and ATP mixture to start the reaction.

[0677] h) Centrifuge the plate at 100 g for 30 seconds, seal the assay plate, and leave at room temperature for 1 hour.

[0678] i) Add ADP-Glo ​​reagent and incubate at room temperature for 1 hour.

[0679] k) Add kinase detection reagent and incubate at room temperature for 1 hour.

[0680] l) Read the luminescent signal on an Envision 2104 plate reader.

[0681] 46.2 Data Analysis

[0682] a) Detect the luminescent signal of each well.

[0683] b) Inhibition was calculated as follows: %inhibition=100-(Signalcmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100.

[0684] c) The logarithm of inhibition rate and compound concentration was fitted to a nonlinear regression (dose response-variable slope) by GraphPad 6.0 to calculate IC 50 .

[0685] Table 1. Inhibitory ability of compounds on HPK1 kinase

[0686]

[0687]

Claims

1. Compounds of formula I: or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein, X 1 is -O-, -NH- or -S-; X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene; Ring A and Ring B are each independently selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl; R1, R2, R3 and R4 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; iv. Alternatively, R1 and R2 together with the ring A to which they are connected, or R3 and R4 together with the ring B to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; Preferably, the fused ring group has any of the following structures: R5, R6 and R7 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、 and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13， R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L or selected from: R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

2. The compound according to claim 1, characterized in that The compound of formula (I) has the following compound structure: or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein: X 1 is -O-, -NH- or -S-; X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene; A ring is selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl; R1, R2, R3 and R4 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; iv. Alternatively, R1 and R2 together with the ring A to which they are connected, or R3 and R4 together with the benzene ring to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; Preferably, the fused ring group has any of the following structures: R5, R6 and R7 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、 and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13， R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L or selected from: R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

3. The compound according to claim 2, characterized in that The compound of formula (II) has the following compound structure of formula (III): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein: X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene; A ring is selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl; R1, R2, R3 and R4 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; iv. Alternatively, R1 and R2 together with the ring A to which they are connected, or R3 and R4 together with the benzene ring to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; Preferably, the fused ring group has any of the following structures: R5, R6 and R7 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、 and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13， R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L or selected from: R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

4. The compound according to claim 1, characterized in that The compound of formula (I) has the following compound structure of formula (IV): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein: X 1 is -O-, -NH- or -S-; X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene; B ring is selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl; R1, R2, R3 and R4 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; iv. Alternatively, R1 and R2 together with the benzene ring to which they are connected, or R3 and R4 together with the ring B to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; Preferably, the fused ring group has any of the following structures: R5, R6 and R7 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、 and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13， R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L or selected from: R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

5. The compound according to claim 4, characterized in that The compound of formula (IV) has the following compound structure of formula (V): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein: X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene; B ring is selected from C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl; R1, R2, R3 and R4 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; iv. Alternatively, R1 and R2 together with the benzene ring to which they are connected, or R3 and R4 together with the ring B to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; Preferably, the fused ring group has any of the following structures: R5, R6 and R7 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、 and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13， R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L or selected from: R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

6. The compound according to claim 1, characterized in that The compound of formula (I) has the following compound structure of formula (VI): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein: X 1 is -O-, -NH- or -S-; X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene; R1, R2, R3 and R4 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; iv. Alternatively, R1 and R2 together with the benzene ring to which they are connected, or R3 and R4 together with the benzene ring to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; Preferably, the fused ring group has any of the following structures: R5, R6 and R7 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、 and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13， R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L or selected from: R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

7. The compound according to claim 6, characterized in that The compound of formula (VI) has the following compound structure of formula (VII): or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof, wherein: X 2 -O-, -N(CH3)-, C 1-6 Alkylene or C 1-6 alkenylene; R1, R2, R3 and R4 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R8 and R9 are each independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; iv. Alternatively, R1 and R2 together with the benzene ring to which they are connected, or R3 and R4 together with the benzene ring to which they are connected form a fused ring group, a bridged ring group, a heterobridged ring group, a spiro ring group or a heterospiro ring group, wherein the fused ring group, the bridged ring group, the heterobridged ring group, the spiro ring group or the heterospiro ring group is optionally substituted with one or more groups selected from the following: C 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; Preferably, the fused ring group has any of the following structures: R5, R6 and R7 are each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amide, C 1-6 Alkoxy, or m and n are each independently selected from: an integer of 0-10; R 10 and R 11 Each is independently selected from: hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, oxo, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L is selected from -(CH2) p -C(R 12 )=C(R 13 )-、-CH(R 14 )-(CH(R 15 )) p -、-N(R 16 )-C(O)-、-(CH(R 17 )) p -N(R 18 )-、 and -(CH(R 19 )) p -O-, wherein p is independently selected from: an integer of 0-10; R 12 , R 13， R 14 , R 15 , R 16 , R 17 , R 18 and R 19 Each independently selected from: i. Hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy; ii. Branched or linear C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted with one or more groups selected from the group consisting of hydroxy, halogen, cyano, amino, amide, -CHF2, -CF3, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino, C 3-6 Cycloalkyl or C 1-6 Alkoxy; iii.C 3-8 Cycloalkyl, C 3-8 Heterocyclic group, C 6-10 Aryl or C 5-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from the following: 1-6 Alkyl, hydroxy, halogen, cyano, amino, amide, -CHF2 or -CF3; L or selected from: R 20 Selected from hydrogen, hydroxyl, halogen, cyano, amino, amide, di(C 1-6 Alkyl)amino, mono(C 1-6 Alkyl)amino or C 1-6 Alkoxy.

8. The compound according to claims 1-7, characterized in that Selected from the following compounds: or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof; and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotope-labeled substance, metabolite or prodrug thereof in the preparation of a medicament for preventing and / or treating a disease mediated by HPK1, wherein the disease mediated by HPK1 is selected from autoimmune diseases, inflammatory diseases, tumors, and pathogenic infectious diseases; preferably, the disease mediated by HPK1 is a tumor, and the tumor is selected from non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, colorectal cancer, ovarian cancer, pancreatic cancer, hematological malignancies, renal cell carcinoma, malignant melanoma, neuroblastoma and mammary secretory carcinoma.

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