Polycyclic compounds, methods of preparation and medical uses thereof

Abstract

Disclosed are compounds of Formula (I) useful as cancer therapeutics, methods of making the same, pharmaceutical compositions containing the same, and pharmaceutical uses for treating certain diseases or conditions.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to nitrogen-containing polycyclic compounds, their preparation methods, pharmaceutical compositions comprising said compounds, and their pharmaceutical uses. Background Technology

[0002] Kirsten rat sarcoma 2 virus oncogene homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas acts as a molecular switch that cycles between an inactive (GDP-binding) state and an active (GTP-binding) state to transduce upstream cellular signals received from a variety of tyrosine kinases to downstream effectors, thereby regulating a variety of processes, including cell proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignant tumors has been observed for over 30 years. Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25% to 30% of lung adenocarcinomas (e.g., see Samatar and Poulikakos (2014) Nat RevDrug Disc 13(12): 928–942). Single nucleotide substitutions that produce missense mutations at codons 12 and 13 of the KRas primary amino acid sequence constitute approximately 40% of these KRas-driven mutations in lung adenocarcinomas. KRAS G12C mutations were found in 25.0% of all patients with pancreatic ductal adenocarcinoma, 13.3% of all patients with colorectal cancer, 10.1% of all patients with rectal cancer, 4.1% of all patients with non-small cell lung cancer, and 1.7% of all patients with small cell lung cancer (e.g., see The AACRProjectGENIE Consortium, (2017) Cancer Discovery;7(8):818-831. Dataset Version 4).

[0004] The well-known role of KRas in malignant tumors and the discovery of frequent KRas mutations across various tumor types make KRas a highly attractive target for the pharmaceutical industry in cancer treatment. Despite the development of KRas inhibitors for cancer treatment based on a three-decade-long discovery effort targeting patent WO 2021 / 041671, no KRas inhibitor has yet demonstrated sufficient safety and / or efficacy to warrant regulatory approval.

[0005] Compounds that inhibit KRas activity remain in high demand and are under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143) and recent advances in covalent targeting of the allosteric pocket of KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234). Clearly, there remains ongoing interest and effort in developing inhibitors of KRas, particularly inhibitors of activated KRas mutants, especially KRas Gl2D inhibitors. Therefore, there is a need to develop novel KRas G12C inhibitors that demonstrate adequate efficacy for the treatment of KRas G12C-mediated cancers. Summary of the Invention

[0006] The inventions disclosed herein present a novel scaffold for selectively inhibiting KRAS G12C. These compounds are advantageous due to their unique chemotype, which has the potential to provide KRAS G12C inhibitors with improved biochemical properties.

[0007] In one aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, or prodrugs thereof, including tautomers, cis or trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, and mixtures thereof: in, Ring A is aryl, heteroaryl, cycloalkyl, or heterocyclic, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic. Ring B is aryl, heteroaryl, cycloalkyl, or heterocyclic; L1 is a key or -NR a (CR a R b ) n -; L2 is a bond, -C(O)- or -C(O)NR a -; L3 is a key or -(CR) a R b ) n -; R a and Rb Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxyl, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; Or, R a and R b Together with the atoms they are attached to, they form cycloalkyl or heterocyclic groups; R1 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, alkyl-SO2-, alkyl-N-, haloalkyl-O-, alkylamide, R a1 R b1 N-, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and heteroaryl substituted or unsubstituted by alkylene; R a1 and R b1 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, or cycloalkyl; R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkynyl, alkylthio, haloalkyl, hydroxyalkyl, amide-alkyl, cycloalkyl-O-alkyl, R a2 R b2 NL a2 - substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; R a2 and R b2 Each group is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, cycloalkyl, or substituted or unsubstituted heterocyclic groups; L a2 Selected from bonds, alkyl groups, or alkyl C(O); Alternatively, R1 and R2 together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, deuterated alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl or heterocyclic group. R4 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkynyl, alkylthio, haloalkyl, and hydroxyalkyl; R5 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Alternatively, R4 and R5 together with the atoms they are attached to form a heterocyclic group, which is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; x is 1, 2, 3, or 4; and y is 1, 2 or 3.

[0008] In the implementation plan, ring A is C6-C. 10 The aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, or 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O, optionally, ring A is substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; In the embodiments, ring A is phenyl, C3-C8 cycloalkyl, or a 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O. Optionally, ring A is substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl.

[0009] In the implementation plan, ring A is... , , , , , , , , , , , or .

[0010] In the implementation plan, ring B is C6-C. 10Aryl, 5- to 10-membered heteroaryl, C5-C8 cycloalkyl or 5- to 10-membered heterocyclic.

[0011] In the embodiments, ring B is a phenyl group, a 5- to 10-membered fused heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered fused heteroaryl group containing one or two heteroatoms selected from N, O or S. In the embodiments, ring B is a phenyl, a C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S.

[0012] In the implementation plan, ring B is... , , , , , , , , or .

[0013] In the implementation scheme, L1 represents bonds such as NH, -NHCH2-, -N(CH2)3OH, and -N(CH2)3CONH2-. .

[0014] In the implementation scheme, L2 is a bond, -C(O)- or -C(O)NH-.

[0015] In the implementation scheme, L3 is a bond, -CH2-, or .

[0016] In the embodiments, R1 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl-SO2-, C1-C6 alkyl-N-, C1-C6 haloalkyl-O-, C1-C6 alkylamide, R a1 R b1 N-, C3-C 12 cycloalkyl, 3 to 12-membered heterocyclic groups, C6-C 14 aryl and 6 to 14-membered heteroaryl, wherein the C3-C 12 cycloalkyl, 3 to 12-membered heterocyclic groups, C6-C 14The aryl and 6- to 14-membered heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C3-C8 cycloalkyl, wherein R a1 and R b1 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl or C3-C6 cycloalkyl.

[0017] In the implementation scheme, R1 is a halogen, a C1-C3 alkyl, a C1-C3 alkoxyalkyl, a C1-C3 haloalkyl, a C1-C3 alkylthio, a C1-C3 alkylSO2-, a C1-C6 haloalkyl-O-, or R. a1 R b1 N-, where R a1 and R b1 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl or C3-C6 cycloalkyl, wherein preferably, the C3-C6 cycloalkyl is cyclopropyl.

[0018] In the implementation scheme, R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, amide-C1-C6 alkyl, C3-C6 cycloalkyl-O-C1-C6 alkyl, R a2 R b2 NL a2 -、C3-C 12 cycloalkyl, 3 to 12-membered heterocyclic groups, C6-C 14 aryl and 6 to 14-membered heteroaryl, wherein the C3-C 12 cycloalkyl, 3 to 12-membered heterocyclic groups, C6-C 14 The aryl group and the 6- to 14-membered heteroaryl group are optionally separated by one or more groups selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 10 Substitution of aryl, 6- to 10-membered heteroaryl groups, wherein R a2 and R b2 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S.

[0019] In the embodiments, R2 is a halogen, a C1-C3 alkyl group, or a 9- to 10-membered heteroaryl group containing 1, 2, or 3 N heteroatoms. Optionally, the 9- to 10-membered heteroaryl group containing 1, 2, or 3 N heteroatoms is selected from one or more of hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, amide-C1-C3 alkyl, C3-C6 cycloalkyl-O-C1-C3 alkyl, or R a2 R b2 NL a2 - Substituents in - where R a2 and R b2 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C3-C3 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S.

[0020] In the implementation scheme, R4 is hydrogen.

[0021] In the embodiments, R5 is a C3-C8 cycloalkyl group, a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and -CONH. Preferably, R5 is , , It is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, and -CONH.

[0022] In the implementation scheme, R4 and R5, together with the atoms to which they are attached, form a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S.

[0023] In the implementation scheme, the compound of formula (I) may be a compound of formula (II), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: in, Ring A is a C3-C8 cycloalkyl group, containing one or two heteroatoms selected from N or O, and is a 5- to 8-membered heterocyclic group, C6-C 10 The aryl group or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C2-C6 cyanoalkyl. L1 is a bond, NH or -NHCH2-; R1, R2 and R3 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl; R5 is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. m can be 0, 1, 2, 3, or 4; x is 1, 2, 3, or 4; and y is 1, 2 or 3.

[0024] In the implementation scheme, in the compound of formula (II) above, wherein: Ring A is a C3-C8 cycloalkyl group or a 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O; L1 is a bond, NH or -NHCH2-; R1, R2 and R3 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl; R5 is a C3-C8 cycloalkyl group, a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. Alternatively, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S. m can be 0, 1, 2, 3, or 4; x is 1, 2, 3, or 4; and y is 1, 2 or 3.

[0025] In the implementation scheme, the compound of formula (I) may be a compound of formula (III), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: in, Ring B is phenyl, C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S; L3 is a bond, -CH2- or ; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; Alternatively, R1 and R2, together with the atoms they are attached to, form C7-C. 10 Cycloalkyl groups or 7- to 10-membered heterocyclic groups containing 1, 2, or 3 N heteroatoms; R5 is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. m is 0 or 1.

[0026] In the implementation scheme, the compound of formula (I) may be a compound of formula (IV), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: in, Ring B is phenyl, C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S; The ring C is a 5- or 6-membered heterocyclic group containing one or two heteroatoms selected from N, O or S. Optionally, the ring C is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. L3 is a bond, -CH2- or ; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; Alternatively, R1 and R2, together with the atoms they are attached to, form C7-C. 10 Cycloalkyl groups or 7- to 10-membered heterocyclic groups containing 1, 2, or 3 N, O, or S heteroatoms; m is 0 or 1.

[0027] In the implementation scheme, the compound of formula (I) may be a compound of formula (III-A), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: in, Ring B is phenyl, C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S; The ring C is a 5- or 6-membered heterocyclic group containing one or two heteroatoms selected from N, O or S. Optionally, the ring C is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. L3 is a bond, -CH2- or ; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; Alternatively, R1 and R2, together with the atoms they are attached to, form C7-C. 10 Cycloalkyl groups or 7- to 10-membered heterocyclic groups containing 1, 2, or 3 N heteroatoms; R5 is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; m is 0 or 1.

[0028] In the implementation scheme, the compound of formula (I) may be a compound of formula (V), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: in, Ring A is a C3-C8 cycloalkyl group, containing one or two heteroatoms selected from N or O, and is a 5- to 8-membered heterocyclic group, C6-C 10 The aryl group, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O, is optionally substituted with one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C2-C6 cyanoalkyl; L1 is a bond, NH or -NHCH2-; R1, R2 and R3 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl; R5 is a C3-C8 cycloalkyl group, a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. Alternatively, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S. R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; m can be 0, 1, 2, 3, or 4; x is 1, 2, 3, or 4; and y is 1, 2 or 3.

[0029] In the implementation scheme, the compound of formula (I) may be a compound of formula (VI), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: in, Ring A is a C3-C8 cycloalkyl group, containing one or two heteroatoms selected from N or O, and is a 5- to 8-membered heterocyclic group, C6-C 10 The aryl group, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O, is optionally substituted with one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C2-C6 cyanoalkyl; L1 is a bond, NH or -NHCH2-; R2, R3, R7 and R8 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl; R5 is a C3-C8 cycloalkyl group, a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. Alternatively, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S. R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; m can be 0, 1, 2, 3, or 4; x is 1, 2, 3 or 4; y is 1, 2 or 3, and z can be 1, 2, or 3.

[0030] In the implementation scheme, the compound of formula (I) may be a compound of formula (VII), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: in, Ring B is phenyl, C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S; L1 is -NR a (CR a R b ) n -; L3 is a key or -(CR) a R b ) n -; R a and R b It is independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxyl, alkyl, alkoxy, haloalkyl and hydroxyalkyl; Or, R a and R bTogether with the atoms to which they are attached, they form a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O, or S, optionally substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; L3 is a bond, -CH2- or ; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl. Alternatively, R1 and R2, together with the atoms they are attached to, form C7-C. 10 The cycloalkyl or 7- to 10-membered heterocyclic group containing 1, 2 or 3 N, O or S heteroatoms, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, deuterated alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl or heterocyclic group. R5 is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; x is 1, 2, 3 or 4; y is 1, 2 or 3, and n is 0 or 1.

[0031] In the implementation scheme, the compound of formula (I) may be a compound of formula (VIII), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: in, Ring B is phenyl, C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S; L1 is -NR a (CR a R b ) n -; L3 is a key or -(CR) a R b ) n -; R a and R b It is independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxyl, alkyl, alkoxy, haloalkyl and hydroxyalkyl; Or, R a and R b Together with the atoms to which they are attached, they form a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O, or S, optionally substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; L3 is a bond, -CH2- or ; K is selected from C(O) or S(O)2; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl. Alternatively, R1 and R2, together with the atoms they are attached to, form C7-C. 10 The cycloalkyl or 7- to 10-membered heterocyclic group containing 1, 2 or 3 N, O or S heteroatoms, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, deuterated alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl or heterocyclic group. R5 is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; x is 1, 2, 3 or 4; y is 1, 2 or 3, and n is 0 or 1.

[0032] In the implementation scheme, compound (I) may be a compound of formula (IX), (X) or (IX-A), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof. in, A1, A2, and A4 are each independently selected from C, CH, N, NH, S, and O; A3 is selected from C, CH, N, NH, S, O, and bonds; B1 is selected from C, CH, and N; B2 is selected from C, CH, N, and bonds; B3 is selected from CH, N, S, and O; E1 and E2 are each independently selected from CH, CH2, N, NH, S, O, and C. 1-3 Alkoxy group, -*N(CH3)C 1-3 Alkylene#, -*NH-C 1-3 Alkylene#, wherein * can be oriented toward the D1 side or toward the B1 side, and correspondingly, # can be oriented toward the B1 side or the D1 side; D1 is selected from C and CR. d1 N, S and O; D2 is selected from CR d1 C(R) d1 )2, N, NR d1 It may not exist; if D2 does not exist, the key connected to D2 also does not exist. D3 is selected from C and CR. d1 C(R) d1 2. N; Each R d1 Independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, and amino groups. X1 is selected from C, CR d1 C(R) d1 )2, N, NR d1 ; X2 is selected from CR d1 C(R)d1 )2, N, NR d1 The key may not exist; X3 is selected from CR d1 C(R) d1 )2, N, NR d1 The key may not exist; X4 is selected from CR d1 C(R) d1 )2, N, NR d1 The key may not exist; When X1, X2, or X3 does not exist, the keys they are connected to also do not exist; Double or single bonds can be represented as needed to meet valence requirements; R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; R2, R 34 Independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, deuterated alkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, -NR 2a R 2b , cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents selected from alkyl, alkoxy, and halogen. Alternatively, the two atoms in R2 together with the two adjacent atoms they are attached to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R 2a and R 2b Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl, and is optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, ynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. L2 is selected from bond, *C(O), *CR 3a R 3b *C=R 3d *C=NR 3e 、*O、*S、NR3f ; R 3a and R 3b Each is independently selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, amino, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, aryl, and heteroaryl; Or R 3a and R 3b Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which may optionally be substituted by one or more substituents selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino. R 3d Selected from C1-C3 alkyl groups; R 3e Selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino; R 3f Selected from C1-C3 alkyl groups; L4 is selected from *C(O) and *CH2; J is selected from *CH2, *CH, and *C(O); L5 is selected from *CH2 and *C(O); * Indicates a connection point with the parent structure; R4 can be hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, or amino. R5 is selected from (i) hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl; and (ii) cycloalkyl, heterocyclic, aryl, heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; m can be 0, 1, 2, 3, or 4; t is 0, 1, or 2.

[0033] In the implementation scheme, for compounds of formulas (IX) and (X) above, or their tautomers, cis or trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, solvates, or prodrugs, wherein: A1, A2, and A4 are each independently selected from C, CH, N, NH, S, and O; A3 is selected from C, CH, N, NH, S, O, and bonds; B1 is selected from CH and N; B2 is selected from CH, N, and bonds; B3 is selected from CH, N, S, and O; E1 and E2 are each independently selected from CH, CH2, N, NH, S, and O; D1 is selected from C and CR. d1 N, S and O; D2 is selected from CH, CH2, N or does not exist. When D2 does not exist, the bond that D2 is connected to also does not exist. D3 is selected from CH, CH2, N, and NH; R d1 Selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, and amino groups. X1 is selected from C, CH, CH2, N, and NH; X2 is selected from CH, CH2, CH3, N, NH, NH2, or may not exist; X3 is selected from CH, CH2, N, NH, bonds, or does not exist; X4 is selected from CH, CH2, CH3, N, NH, NH2, bonds, or does not exist; When X1, X2, or X3 does not exist, the keys they are connected to also do not exist; Double or single bonds can be represented as needed to meet valence requirements; R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkynyl, alkylthio, haloalkyl, hydroxyalkyl, -NR 2a R 2b , cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents selected from alkyl, alkoxy, and halogen. Alternatively, the two atoms in R2 together with the two adjacent atoms they are attached to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R 2a and R 2bEach is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups, and is optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, ynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, and aminoalkyl groups, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. L2 is selected from bond, *C(O), *CR 3a R 3b *C=R 3d *C=NR 3e 、*O、*S、NR 3f ; R 3a and R 3b Each is independently selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, amino, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, aryl, and heteroaryl; Or R 3a and R 3b Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which may optionally be substituted by one or more substituents selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino. R 3d Selected from C1-C3 alkyl groups; R 3e Selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino; R 3f Selected from C1-C3 alkyl groups; L4 is selected from *C(O) and *CH2; J is selected from *CH2, *CH, and *C(O); L5 is selected from *CH2 and *C(O); * Indicates a connection point with the parent structure; R4 can be hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, or amino. R5 is selected from (i) hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl; and (ii) cycloalkyl, heterocyclic, aryl, heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; m can be 0, 1, 2, 3, or 4. t is 0, 1, or 2.

[0034] In a preferred embodiment, ring A is C6-C. 10 The aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, or 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O, optionally, ring A is substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; Preferably, ring A is phenyl, C3-C8 cycloalkyl, or a 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O. Optionally, ring A is substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. More preferably, ring A is Preferred More preferably * indicates the position connected to N; More preferably, ring A is , , , , , , , , , , , or .

[0035] In a preferred embodiment, Selected from phenyl or 5- to 6-membered heteroaryl groups containing no more than 2 heteroatoms selected from N, O or S.

[0036] In a preferred embodiment, Selected from phenyl or 5- to 6-membered heteroaryl groups containing no more than 2 heteroatoms selected from N, O or S.

[0037] In a preferred embodiment, R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkoxy, and C1-C6 halo-alkylthio; (ii) -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl, C3-C8 cycloalkyl, and 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, and C1-C6 alkyl.

[0038] In a preferred embodiment, R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 halo-alkylthio; (ii) -O-C3-C6 cycloalkyl, -S-C3-C6 cycloalkyl, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 cyanoalkyl, C1-C3 alkyl; x is 0, 1, 2 or 3.

[0039] In a preferred embodiment, Selected from , , , , ; Selected from Preferred ; in, R 11 R 12 and R 14Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. R 13 The group is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 halo-alkylthio, C1-C6 haloalkoxy, (ii) -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl, 3 to 6-membered cycloalkyl, 5 to 8-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl; In a preferred embodiment, R 11 R 12 and R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C4 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. R 13 The group is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 halo-alkylthio, C1-C3 haloalkoxy, (ii) -O-C3-C6 cycloalkyl, -S-C3-C6 cycloalkyl, 3 to 6-membered cycloalkyl, 5 to 8-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl.

[0040] In a preferred embodiment, Selected from , , , , , , , , , , , ; Selected from .

[0041] In a preferred embodiment, Selected from , , , , , , , , , , , , ,in, R 21 R 22 and R 23 Each is independently selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -NR 2a R 2b (ii) 3- to 8-membered cycloalkyl groups, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, C6-C 10 Aryl, C5-C containing one or two heteroatoms selected from N, O, and S 10 The heteroaryl group is optionally substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, amino, cyano, hydroxyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. Or, R 22 and R 23 Together with the atoms they are attached, they form 3- to 8-membered cycloalkyl groups, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, C6-C 10 Aryl, 5 to 8-membered heteroaryl containing one or two heteroatoms selected from N, O and S; R 2a and R 2b Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, amino, 3- to 6-membered cycloalkyl, 5- to 8-membered heterocyclic, C6-C 10 Aryl, 5 to 8-membered heteroaryl.

[0042] In a preferred embodiment, Selected from , , , , , , , , , , , , , ,in R 21 R 22 and R 23 Each is independently selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 cyanoalkyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -NR 2a R 2b (ii) C3-C6 cycloalkyl, 3- to 6-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N, O and S, optionally substituted by one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl; Or, R 22 and R 23 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, C6-C8 aryl, and 5- to 8-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S; optionally substituted by one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. R 2a R 2b Each of the following is independently selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, (ii) C3-C8 cycloalkyl, C3-C6 heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, C5-C8 heteroaryl, and optionally substituted by one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; In the preferred embodiment, R 21 R 22 and R 23 Each is independently selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 cyanoalkyl, C1-C3 alkyl, C1-C3 deuterated alkyl, -NR2a R 2b (ii) , , , , , , , , Optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxy, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; or, R 22 and R 23 Together with the atoms they are attached to, they form , , Optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxy, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; R 2a and R 2b Each is independently selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, and (ii) , , , , , , , , Optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl.

[0043] In a preferred embodiment, Selected from , , , , , , ,in, D1 is selected from C and CR. d1 N, S and O; D2 is selected from CH, CH2, and N; D3 is selected from CH, CH2, N, and NH; R d1 Selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, and amino; X1 is selected from CH, CH2, N, and NH; X2 is selected from CH, CH2, CH3, N, NH, and NH2; X3 is selected from CH, CH2, N, and NH; X4 is selected from CH, CH2, N, NH, and NH2.

[0044] In a preferred embodiment, Selected from , , , , , , , .

[0045] In a preferred embodiment, ring A is selected from phenyl, C3-C8 cycloalkyl, 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O, or 5- to 8-membered heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 alkylamino, C1-C3 alkylcyano, and C1-C3 hydroxyalkyl, wherein the cycloalkyl and heterocyclic group are saturated or partially unsaturated.

[0046] In a preferred embodiment, ring A is selected from... , , , , , , , , , , Optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 alkylamino, C1-C3 alkylcyano, and C1-C3 hydroxyalkyl.

[0047] In a preferred embodiment, ring A is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0048] In a preferred embodiment, L2 is selected from bonds, *C=O, *CF2, *C-OH, *C(F)CH3, *C(OH)CH3, *C=CH2, *C=NH, *C=N-OH, *CO-CH3, *O, *S, , , *NCH3; L4 is selected from *C(O) and *CH2; J is selected from *CH2, *CH, and *C(O); L5 is selected from *CH2 and *C(O).

[0049] In a preferred embodiment, R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl.

[0050] R5 is selected from branched or straight-chain C1-C3 alkyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic groups containing one or two heteroatoms selected from N, O or S, or 5- to 8-membered heteroaryl groups containing one or two heteroatoms selected from N or O, optionally substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, wherein the cycloalkyl or heterocyclic group is saturated or partially unsaturated; Alternatively, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S. m is 0, 1, or 2.

[0051] In a preferred embodiment, R5 is selected from... , , , , , , , , , , , , , .

[0052] Each R 28 R 281 R 282 Independently absent or selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, HC(O)-, alkyl-C(O)-, alkoxy, alkoxyalkyl, deuterated alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, alkylcarbonyl, cycloalkyl, heterocyclic, cycloalkyloxy, aryl, heteroaryl, methylidene (=CH2), wherein the alkyl, hydroxyl, alkenyl, alkynyl, amino, HC(O)-, alkyl-C(O)-, alkoxy, alkoxyalkyl, deuterated alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, alkylcarbonyl, cycloalkyl, heterocyclic, cycloalkyloxy, aryl, heteroaryl, methylidene (=CH2) is optionally surrounded by 1, 2, 3, 4 or 5 R 29 replace; Each R 29 Independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, deuterated alkyl, alkenyl, alkoxy, deuterated alkoxy, alkoxyalkyl, deuterated alkoxyalkyl, alkylthio, haloalkyl, cyano, oxo (=O), cycloalkyl, cycloalkyloxy, heterocyclic, aryl, heteroaryl, and hydroxyalkyl; preferably selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; Or R4 and R 5a Together with the atoms they are attached to, they form 3- to 6-membered heterocyclic groups, which are selected from... , , Preferred , , n5 is 0, 1, 2, 3, or 4.

[0053] In a preferred embodiment, R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl.

[0054] R5 is selected from -C(CH3)2. , , , , , , , , , , , These groups are optionally substituted by 1, 2, 3, 4 or 5 substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, and oxo. Alternatively, R4 and R5 together with the atoms they are attached to form , , , .

[0055] In the implementation scheme, compound (I) may be a compound of formula (XI), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. in, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S. R4 and R5 together with the atoms they are attached to form , .

[0056] In the implementation scheme, compound (I) may be a compound of formula (XII), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. in, R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkoxy, C1-C6 halo-alkylthio, -NR 2a R 2b(ii) -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl, C3-C8 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl; R 2a R 2b Each of the following is independently selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, (ii) C3-C8 cycloalkyl, C3-C6 heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, C5-C8 heteroaryl, and optionally substituted by one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; D1 is selected from C, CH, CH2, and N; D2 is selected from CH, CH2, NH, and N. D3 is selected from C, CH, and N; R d1 Selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, -NH-C1-C3 alkyl, -CONH3, X1 is selected from C, CH, CH2, N, and NH; X2 is selected from CH, CH2, N, NH and bonds; X3 is selected from CH, CH2, N, and NH; X4 is selected from CH, CH2, N, and NH; R 15 The group is selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, and (ii) C1-C3 alkyl-C3-C8 cycloalkyl, C1-C3 alkyl-5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl; R 16 Selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, and amino. x is 2, 3 or 4.

[0057] In the implementation scheme, compound (I) may be a compound of formula (XIII), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (XIII). in, R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkoxy, C1-C6 halo-alkylthio, -NR 2a R 2b (ii) -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl, C3-C8 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl; Cycle D is selected from C3-C8 cycloalkyl groups, 5- to 12-membered fused heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl group and the 5- to 10-membered fused heterocyclic group are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, C1-C6 cyanoalkyl, and C1-C6 alkyl. R 15 The group is selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, and (ii) C1-C3 alkyl-C3-C8 cycloalkyl, C1-C3 alkyl-5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl; R 16 Selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, and amino. x is 2, 3 or 4.

[0058] In a preferred embodiment, ring D is selected from... , Optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, C1-C6 cyanoalkyl, and C1-C6 alkyl.

[0059] In the implementation scheme, compound (I) may be a compound of formula (XIV) or (XV), or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. in, R 17 R 18 and R 19 The group is independently selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; and (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic groups are optionally substituted by 1, 2, 3, 4, or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, and alkyl. E1 is selected from CH, CH2, N, NH, S, and O; E2 is selected from N, NH, S, and O; R 20 and R 20 a is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; R 21 and R 22 It is independently selected from hydrogen, deuterium, F, Cl, Br, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano and C1-C6 hydroxyalkyl; R 23 Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl. r can be 0, 1, 2 or 3.

[0060] In the implementation scheme, in a compound of formula (XIV) or (XV) above, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R 17 R 18 and R 19 It is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; E1 is selected from CH, CH2, N, NH, S, and O; E2 is selected from N, NH, S, and O; R 20 and R 20 a is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; R 21 and R 22 It is independently selected from hydrogen, deuterium, F, Cl, Br, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano and C1-C6 hydroxyalkyl; R 23 Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; r can be 0, 1, 2, or 3; Preferably, the C1-C6 deuterated alkyl group is selected from -CD3, -CHD2, -CH2D, -CD2CH3, and -CH2CD3.

[0061] The present invention also provides a pharmaceutical composition comprising a compound of any form or embodiment of the present invention, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the amount of said compound is from about 0.1% to 95% by weight of the free base; preferably, from about 0.5% to 85% by weight of the free base; more preferably, from about 1% to 70% by weight of the free base; preferably, from about 1% to 60% by weight of the free base; more preferably, from about 1% to 15% by weight of the free base; or from about 15% to 30% by weight of the free base; or from about 30% to 45% by weight of the free base; or from about 15% to 30% by weight of the free base; or from about 45% to 60% by weight of the free base.

[0062] The present invention also provides a pharmaceutical composition comprising a compound of any form or embodiment of the present invention, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, solvate or prodrug thereof, wherein the unit dose of said compound, its tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is about 1 to 1000 mg by weight of free base; Preferably, the amount is about 1 to 500 mg based on the weight of the free base; More preferably, the amount is about 3 to 300 mg based on the weight of the free base; More preferably, the amount is about 5 to 200 mg based on the weight of the free base; More preferably, the amount is about 10 to 100 mg based on the weight of the free base; More preferably, the free base is 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg by weight.

[0063] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of any of formulas (I), (II) and (III) or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0064] In some embodiments, in the above-described pharmaceutical composition, the amount of the compound, its tautomers, cis or trans isomers, meso, racemic, enantiomers, diastereomers or mixtures, or pharmaceutically acceptable salts thereof, is about 0.1% to 95% by weight of the free base, preferably about 5% to 70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%.

[0065] In some embodiments, the above-mentioned pharmaceutical composition is formulated as tablets, capsules, liquids, or injections.

[0066] In some embodiments, the amount of the compound, its tautomers, cis or trans isomers, meso, racemic, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, in the above-described pharmaceutical composition is from about 1 to 1000 mg, preferably from about 1 to 500 mg, more preferably from about 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0067] In some embodiments, the compound, its tautomers, cis or trans isomers, meso, racemic, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, may be administered via any suitable route of administration, such as oral, parenteral, oral, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition may be modified accordingly.

[0068] In some embodiments, the compound, its tautomers, cis or trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers or mixtures, or pharmaceutically acceptable salts are formulated in solid or liquid form, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules or lozenges.

[0069] In another aspect, the present invention relates to a method for treating a disease mediated by a KRAS mutation, the method comprising administering to a subject in need an effective amount of a compound of any formula (I), (II), and (III) or a tautomer thereof, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising thereof.

[0070] In another aspect, the present invention relates to a method for treating cancer, the method comprising administering to a subject in need an effective amount of a compound of any formula (I), (II), and (III) or a tautomer thereof, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising thereof.

[0071] In the implementation plan, cancer is associated with KRAS G12C(ON) mutations.

[0072] In a preferred embodiment, the cancer is selected from: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, and chondromatous hamartoma of the lung. Hamartoma), mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (tumor, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet tumor, glucagonoma, gastrinoma, carcinoid tumor, vasodilator intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, Sarcoma), testis (seminomatous sarcoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenocarcinoma-like tumor, lipoma); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastic carcinoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochronfroma) (osteocartilaginous exostosis) Exostoses), benign chondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; Nervous system: Skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), Meninges (meningiomas, meningiosarcomas, gliomas), Brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pineal tumors), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (Endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor) Tumors: dysgerminoma, malignant teratoma; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma); fallopian tube (cancer); blood: myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands: neuroblastoma.

[0073] The present invention also provides compounds of formula (XVI), or tautomers, cis or trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein: A1, A2, and A4 are each independently selected from C, CH, N, NH, S, and O; A3 is selected from C, CH, N, NH, S, O, and bonds; B1 is selected from CH and N; B2 is selected from CH, N, and bonds; B3 is selected from CH, N, S, and O; E1 and E2 are each independently selected from CH, CH2, N, NH, S, O, and C. 1-3 Alkoxy group, -*N(CH3)C 1-3 Alkylene#, -*NH-C 1-3 Alkylene-#, wherein * can be oriented toward the D1 side or toward the B1 side, and correspondingly, # can be oriented toward the B1 side or the D1 side; D1 is selected from C and CR. d1 N, S and O; D2 is selected from CR d1 CH2, N, or none of them exist. When D2 does not exist, the bond connected to D2 also does not exist. D3 is selected from CR d1 CH2, N and NH; Each R d1 Independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, and amino groups. X1 is selected from C, CRd1 CH2, N, NH; X2 is selected from CR d1 CH2, CH3, N, NH, NH2, bonds may or may not exist; X3 is selected from CR d1 CH2, N, NH bonds may or may not exist; X4 is selected from CR d1 CH2, CH3, N, NH, NH2, bonds may or may not exist; When X1, X2, or X3 does not exist, the keys they are connected to also do not exist; Double or single bonds can be represented as needed to meet valence requirements; R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, deuterated alkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, -NR 2a R 2b , cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents selected from alkyl, alkoxy, and halogen. Alternatively, the two atoms in R2 together with the two adjacent atoms they are attached to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R 2a and R 2b Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl, and is optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, ynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. L2 is selected from bond, *C(O), *CR 3a R 3b *C=R 3d *C=NR 3e 、*O、*S、NR 3f ; R3a and R 3b Each is independently selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, amino, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, aryl, and heteroaryl; Or R 3a and R 3b Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which may optionally be substituted by one or more substituents selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino. R 3d Selected from C1-C3 alkyl groups; R 3e Selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino; R 3f Selected from C1-C3 alkyl groups; R 30 R 31 Independently selected from: (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkylthio, alkoxyalkyl, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio; (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the amino, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkylthio, alkoxyalkyl, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; or (iii) a nitrogen protecting group, preferably Boc; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; t is 0, 1, or 2.

[0074] The present invention also provides a method for preparing a compound of formula (X) or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising: A A1, A2, and A4 are each independently selected from C, CH, N, NH, S, and O; A3 is selected from C, CH, N, NH, S, O, and bonds; B1 is selected from CH and N; B2 is selected from CH, N, and bonds; B3 is selected from CH, N, S, and O; E1 and E2 are each independently selected from CH, CH2, N, NH, S, O, and C. 1-3 Alkoxy group, -*N(CH3)C 1-3 Alkylene#, -*NH-C 1-3 Alkylene-#, wherein * can be oriented toward the D1 side or toward the B1 side, and correspondingly, # can be oriented toward the B1 side or the D1 side; D1 is selected from C and CR. d1 N, S and O; D2 is selected from CR d1 CH2, N, or none of them exist. When D2 does not exist, the bond connected to D2 also does not exist. D3 is selected from CR d1 CH2, N and NH; Each R d1 Independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, and amino groups. X1 is selected from C, CR d1 CH2, N, NH; X2 is selected from CR d1 CH2, CH3, N, NH, NH2, bonds may or may not exist; X3 is selected from CR d1 CH2, N, NH bonds may or may not exist; X4 is selected from CR d1 CH2, CH3, N, NH, NH2, bonds may or may not exist; When X1, X2, or X3 does not exist, the keys they are connected to also do not exist; Double or single bonds can be represented as needed to meet valence requirements; R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, deuterated alkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, -NR 2a R 2b , cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents selected from alkyl, alkoxy, and halogen. Alternatively, the two atoms in R2 together with the two adjacent atoms they are attached to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R 2a and R 2b Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl, and is optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, ynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. L2 is selected from bond, *C(O), *CR 3a R 3b *C=R 3d *C=NR 3e 、*O、*S、NR 3f ; R 3a and R 3b Each is independently selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, amino, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, aryl, and heteroaryl; Or R 3a and R 3b Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which may optionally be substituted by one or more substituents selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino. R 3d Selected from C1-C3 alkyl groups; R 3e Selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino; R 3f Selected from C1-C3 alkyl groups; L4 is selected from *C(O) and *CH2; J is selected from *CH2, *CH, and *C(O); L5 is selected from *CH2 and *C(O); * Indicates a connection point with the parent structure; R4 can be hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, or amino. R5 is selected from (i) hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl; and (ii) cycloalkyl, heterocyclic, aryl, heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. R 34 Halogens are preferred as leaving groups; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; m can be 0, 1, 2, 3, or 4; t is 0, 1, or 2. Detailed Implementation

[0075] The following are definitions of the terms used in this application. Any term not defined herein shall be interpreted as such by those skilled in the art.

[0076] "Alkyl" refers to a compound containing C1-C2. 20Saturated aliphatic hydrocarbon groups with straight and branched chains. Preferably, the alkyl group is an alkyl group having 1 to 12, sometimes more preferably 1 to 6, and sometimes more preferably 1 to 4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2 -Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-ethylpentyl, 2-Methyl-3-ethylpentyl, n-Nonyl, 2-Methyl-2-ethylhexyl, 2-Methyl-3-ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their branched isomers. More preferably, the alkyl group is a lower alkyl group having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point. Preferably, the substituent is one or more groups independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclol, cycloalkylthio, heterocycloalkylthio, and oxo.

[0077] "Alkenyl" refers to an alkyl group as defined above, having at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, preferably C10. 2-20Alkenyl, more preferably C2-12 Alkenyl group, C is the most preferred. 2-6 Alkenyl. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes one to five, and sometimes more preferably one to three groups independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclol, cycloalkylthio, heterocycloalkylthio, and oxo groups.

[0078] "Alynyl" refers to an alkyl group as defined above that has at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, preferably C10. 2-20 Alkyne group, more preferably C 2-12 Alkyne group, C is the preferred group 2-6 Alkynyl. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes one to five, and sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0079] "Alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. Straight-chain or branched groups containing 1 to 20 carbon atoms preferably have 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylene (-CH2CH2CH2CH2-). Alkylenes may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes one to five, and sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0080] "Alkenyl" refers to an alkylene group as defined above, having at least two carbon atoms and at least one carbon-carbon double bond, preferably C. 2-20 alkenyl, more preferably C 2-12alkenyl groups, with C being the most preferred. 2-6 Alkenyl group. Non-limiting examples of alkenyl groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, etc. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0081] "Immyneyl" refers to an ynyl group as defined above, having at least two carbon atoms and at least one carbon-carbon triple bond, preferably C. 2-20 Ethyne group, more preferably C 2-12 alkyne group, C is the preferred group 2-6 Alynyl group. Non-limiting examples of alynyl groups include, but are not limited to, -CH≡CH-, -CH≡CHCH2-, -CH≡CHCH2CH2-, -CH2CH≡CHCH2-, etc. Alynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0082] "Cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc. Polycyclic cycloalkyl groups include cycloalkyl groups having spirocyclic, fused, or bridged rings.

[0083] "Spirocycloalkyl" refers to a 5- to 20-membered polycyclic cyclone whose rings are connected by a shared carbon atom (called a spiro atom), wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spirocycloalkyl is 6- to 14-membered, more preferably 7- to 10-membered. Based on the number of shared spiro atoms, spirocycloalkyl is classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. Representative examples of spirocycloalkyl include, but are not limited to, the following substituents: and .

[0084] "Fused cycloalkyl" refers to a 5- to 20-membered polycyclic hydrocarbon group, wherein each ring in the system shares a pair of adjacent carbon atoms with another ring, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused cycloalkyl is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, fused cycloalkyl is classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyl include, but are not limited to, the following substituents: and .

[0085] "Bridged cycloalkyl" refers to a 5- to 20-membered polycyclic hydrocarbon group, wherein each pair of rings in the system shares two non-directly bonded carbon atoms. The rings may have one or more double bonds, but do not have a fully conjugated π-electron system. Preferably, the bridged cycloalkyl group is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, bridged cycloalkyl groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Representative examples of bridged cycloalkyl groups include, but are not limited to, the following substituents: and .

[0086] The cycloalkyl group can be fused with the rings of aryl, heteroaryl, or heterocycloalkyl groups, wherein the ring bonded to the parent structure is a cycloalkyl group. Representative examples include, but are not limited to, indanylacetic, tetrahydronaphthalene, and benzocycloheptyl. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three, independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloyl, cycloalkylthio, heterocycloalkylthio, and oxo-substituents.

[0087] "Heterocyclic group" refers to a group having one or more (sometimes preferably one to five, sometimes more preferably one to three) groups selected from N, O, and S(O). mThe heteroatom (where m is 0, 1, or 2) is a 3- to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group, but its ring does not contain -OO-, -OS-, or -SS-, and the remaining ring atoms are C. Preferably, the heterocyclic group is a 3- to 12-membered heterocyclic group having 1 to 4 heteroatoms; more preferably, a 3- to 10-membered heterocyclic group having 1 to 3 heteroatoms; even more preferably, a 4- to 8-membered heterocyclic group having 1 to 3 heteroatoms; and most preferably, a 5- to 6-membered heterocyclic group having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclic groups include, but are not limited to, oxo-heterocyclic butyl, aza-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, sulfomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include heterocyclic groups having spirocyclic, fused, or bridged rings.

[0088] "Spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group, in which the rings are connected by a common carbon atom (called a spiro atom), wherein the rings have one or more (sometimes preferably one to five, sometimes more preferably one to three) selected from N, O, and S(O). m (Where m is 0, 1, or 2) heteroatoms serve as ring atoms, and the remaining ring atoms are carbon atoms. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spiroheterocyclic group is 6 to 14 quinary, more preferably 7 to 10 quinary. Based on the number of shared spiroatoms, spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups, preferably monospirocyclic or bispirocyclic, more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic. Representative examples of spiroheterocyclic groups include, but are not limited to, the following substituents: and .

[0089] "Fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent carbon atoms with another ring, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system, wherein said rings have one or more (sometimes preferably one to five, sometimes more preferably one to three) selected from N, O, and S(O). pThe heteroatom (where p is 0, 1, or 2) serves as the ring atom, and the remaining ring atoms are carbon. Preferably, the fused heterocyclic group is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, fused heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Representative examples of fused heterocyclic groups include, but are not limited to, the following substituents: and .

[0090] "Bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group in which each pair of rings shares two atoms that are not directly connected. The rings may have one or more double bonds, but do not have a fully conjugated π-electron system. The rings have one or more atoms selected from N, O, and S(O). m (Where m is 0, 1, or 2) heteroatoms are used as ring atoms, and the remaining ring atoms are carbon. Preferably, the bridging heterocyclic group is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, bridging heterocyclic groups are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic bridging heterocyclic groups, more preferably bicyclic or tricyclic bridging heterocyclic groups. Representative examples of bridging heterocyclic groups include, but are not limited to, the following substituents: and .

[0091] The ring of the heterocyclic group may be fused with the ring of an aryl, heteroaryl, or cycloalkyl group, wherein the ring bonded to the parent structure is a heterocyclic group. Representative examples include, but are not limited to, the following substituents: and wait.

[0092] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0093] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic fused-ring group (a "fused" ring system means that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) and has a fully conjugated π-electron system. Preferably, the aryl group is 6- to 10-membered, such as phenyl and naphthyl, with phenyl being the most preferred. The aryl group can be fused with a ring of a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring bonded to the parent structure is an aryl group. Representative examples include, but are not limited to, the following substituents: and .

[0094] The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes one to five, and sometimes more preferably one to three substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0095] "Heteroaryl" refers to an aryl system having 1 to 4 heteroatoms selected from O, S, and N as ring atoms and having 5 to 14 ring atoms. Preferably, the heteroaryl group is 5 to 10-membered, more preferably 5- or 6-membered, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl group can be fused with the ring of an aryl, heterocyclic, or cycloalkyl group, wherein the ring bonded to the parent structure is a heteroaryl group. Representative examples include, but are not limited to, the following substituents: and .

[0096] The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes one to five, and sometimes more preferably one to three, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and -NR. 9 R 10 Substituents.

[0097] "Alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl) groups, where the alkyl group is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc. Alkoxy groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, sometimes preferably one to five, and sometimes more preferably one to three substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0098] A "bond" refers to a covalent bond with the symbol "-".

[0099] The term "hydrogen" includes protons (¹H), deuterium (²H or D), tritium (³H), and / or mixtures thereof. In specific embodiments, one or more sites in the compound occupied by hydrogen may be enriched with deuterium and / or tritium. Isotopically enriched analogs may be prepared from suitable isotopically labeled starting materials obtained from commercial sources or by known literature steps, and the hydrogen or hydrogen atoms described in this patent include their isotopes (¹H), deuterium (²H), tritium (³H), and / or mixtures thereof.

[0100] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0101] "Hydroxy group" refers to the -OH group.

[0102] "Halogen" refers to fluorine, chlorine, bromine, or iodine atoms.

[0103] "Amino" refers to the -NH2 group.

[0104] "Cyano" refers to the -CN group.

[0105] "Nitro" refers to the -NO2 group.

[0106] "Oxide group" refers to the =O group.

[0107] "Carboxyl group" refers to the -C(O)OH group.

[0108] "Alkoxycarbonyl" refers to a -C(O)O (alkyl) or -C(O)O (cycloalkyl) group, where alkyl and cycloalkyl are as defined above.

[0109] "Optional" or "optionally" means that the event or situation described thereafter may, but is not required to, occur, including situations where the event or situation may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may, but is not required to be present, including cases where the heterocyclic group is alkyl-substituted and cases where the heterocyclic group is not alkyl-substituted.

[0110] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, independently substituted by the corresponding number of substituents. It goes without saying that substituents exist in their only possible chemical positions. Those skilled in the art can determine, experimentally or theoretically, whether substitution is possible or impossible without much effort. For example, the combination of an amino or hydroxyl group with free hydrogen and a carbon atom with an unsaturated bond (e.g., an alkene) may be unstable.

[0111] "Pharmaceutical composition" refers to one or more compounds described in this invention, or a physiologically / pharmaceutical acceptable salt or prodrug thereof, mixed with other chemical components (e.g., physiologically / pharmaceutical acceptable carriers and excipients). The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism, which is beneficial for the absorption of the active ingredient and thus for the expression of biological activity.

[0112] "Pharmaceutically acceptable salt" means a salt of the compound of the present invention that is safe and effective and has the corresponding biological activity when used in mammals.

[0113] Synthesis program Synthesis of 5-bromo-4,6-dichloro-1-methyl-1H-benzo[d]imidazolium BB1 Step 1: Methylamine (2M THF solution, 36 mL) was added to a solution of 1,3,5-trichloro-2-nitrobenzene (5.00 g) in THF (60 mL). After stirring at 50ºC for 16 hours, the reaction mixture was concentrated under reduced pressure to obtain crude 3,5-dichloro-N-methyl-2-nitrobenzene. MS: m / z = 221.0, 222.9 (M+H, ESI+).

[0114] Synthesize the compounds listed in the table below as described above. Step 2: Add N-bromosuccinimide (2.02 g, 11.36 mmol) to a solution of 3,5-dichloro-N-methyl-2-nitroaniline (2.50 g, 11.36 mmol) in DMF (15 mL) at 0°C, and heat to 25°C and stir under N2 for 2 hours. Quench the mixture with a saturated ammonium chloride solution and extract with ethyl acetate (30 x 2 mL). Dry the organic phase with anhydrous Na2SO4. After filtration, remove the solvent under vacuum and purify by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 1:4) on silica gel to give 4-bromo-3,5-dichloro-N-methyl-2-nitroaniline (3.20 g, yield: 94%) as a yellow solid. MS: m / z = 298.8, 301.0 (M+H, ESI+).

[0115] Synthesize the compounds listed in the table below as described above. Step 3: The suspension of crude 4-bromo-3,5-dichloro-N-methyl-2-nitroaniline (6.63 g) and iron powder (6.19 g) obtained in Step 2 in 2M ammonium chloride aqueous solution (55 mL), THF (110 mL), and methanol (110 mL) was stirred at 70°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting mixture was diluted with water and ethyl acetate, and then the insoluble substances were filtered off. The organic layer was separated and washed with saturated sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate) to give 4-bromo-3,5-dichloro-N1-methylphenyl-1,2-diamine (5.25 g) as a yellow solid. MS: m / z = 268.9, 270.9 (M+H, ESI+).

[0116] Synthesize the compounds listed in the table below as described above. Step 4: Concentrated hydrochloric acid (0.30 mL) was added to a suspension of 4-bromo-3,5-dichloro-N1-methylphenyl-1,2-diamine (5.25 g) obtained in Step 3 in 1,1,1-triethoxypropane (30 mL), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate) to give 5-bromo-4,6-dichloro-1-methyl-1H-benzi[d]imidazole, BB1 (5.22 g). MS: m / z = 278.9, 280.9 (M+H, ESI+).

[0117] Synthesize the compounds listed in the table below as described above. Synthesis of 5-bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazolium 371 IntAii T3P (18.33 g, 28.8 mmol) was added to a solution of 375 Aii (3.51 g, 13.05 mmol) and 2-methoxyacetic acid (1.29 g, 14.34 mmol) in DMF (8.14 mL). After stirring at room temperature for 15 min, triethylamine (5.22 g, 51.62 mmol, 7.2 mL) was added to the reaction mixture and stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate, washed with aqueous NaHCO3 solution, water, and NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. Acetic acid was added to the residue, and the mixture was stirred at 50°C for 2 h. The mixture was diluted with ethyl acetate, washed with aqueous NaHCO3 solution, water, and NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 371 Int Aii (2.4 g, 56.9% yield).

[0118] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.20 (s, 1H), 8.12 (s, 1H), 4.75 (s, 2H), 3.90 (s, 3H), 3.32 (s, 3H).

[0119] Synthesis of 5-(8-bromoindazine-3-carbonyl)-2-((2,4-dimethoxybenzyl)amino)benzylnitrile BB2 Step 1: Copper dibromo (37.6 g) was added to a solution of 5-acetyl-2-fluorobenzonitrile (25.0 g) in ethyl acetate (380 mL), and the mixture was stirred at 70°C for 16 hours. Another batch of copper dibromo (37.6 g) was added to the reaction mixture, and the mixture was stirred at 70°C for 2 hours. The reaction mixture was filtered through diatomaceous earth and washed with saturated sodium bicarbonate solution and brine. After drying the organic layer with sodium sulfate and concentrating it, diisopropyl ether was added to the resulting residue, and the mixture was stirred at ambient temperature for 30 minutes. The precipitated solid was collected by filtration to obtain 5-(2-bromoacetyl)-2-fluorobenzonitrile (32.0 g). MS: m / z = 241.9, 243.9 (M+H, ESI+).

[0120] Step 2: 3-Bromo-2-methylpyridine (30 mL) was added to a solution of 5-(2-bromoacetyl)-2-fluorobenzonitrile (32.0 g) obtained in Step 1 in THF (130 mL), and the mixture was stirred at 85°C for 16 hours. Heptane was added to the reaction mixture at ambient temperature and stirred for 30 minutes. The precipitated solid was collected by filtration to obtain 3-bromo-1-(2-(3-cyano-4-fluorophenyl)-2-oxoethyl)-2-methyl-1-pyridinium bromide (55.0 g). MS: m / z = 332.9, 335.9 (M+H, ESI+).

[0121] Step 3: The mixture of DMF (41 mL) and dimethyl sulfate (50 mL) was stirred at 80°C for 3 hours. After cooling the mixture to room temperature, it was added to a solution of 3-bromo-1-(2-(3-cyano-4-fluorophenyl)-2-oxoethyl)-2-methyl-1-pyridinium bromide (14.6 g) in DMF (44 mL) at room temperature. After stirring at room temperature for 30 minutes, N,N-diisopropylethylamine (61 mL) was added to the reaction mixture, and then stirred at room temperature for 1 hour. Water (230 mL) was added to the reaction mixture, and the precipitated solid was collected. The obtained solid was dried under vacuum overnight, ethyl acetate was added to the solid, and then stirred at room temperature for 30 minutes. After adding heptane to the solution, the precipitated solid was collected by filtration to obtain 5-(8-bromoinazine-3-carbonyl)-2-fluorobenzonitrile (9.69 g). MS: m / z =342.8, 344.8 (M+H, ESI+).

[0122] Step 4: 2,4-Dimethoxybenzylamine (100 mL) was added to a solution of 5-(8-bromoindazine-3-carbonyl)-2-fluorobenzonitrile (9.69 g) obtained in Step 3 in 1,4-dioxane (60 mL) and 1,2-dimethoxyethane (10 mL), and the mixture was stirred overnight at 115°C. After cooling to room temperature, water (200 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours, and the precipitated solid was collected. The solid was dried under vacuum at 60°C overnight, and ethyl acetate was added to the solid. After stirring for 30 minutes, heptane was added to the suspension. The mixture was stirred at room temperature for 30 minutes, and the precipitated solid was collected to obtain 5-(8-bromoindazine-3-carbonyl)-2-((2,4-dimethoxybenzyl)amino)benzylnitrile, BB2 (8.06 g). MS: m / z = 489.9, 491.9 (M+H, ESI+).

[0123] Synthesis of (3,4,5-trifluorophenyl)(9,10,12-trimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazin-2-yl) methyl ketone, key Int 375 Step 1: 4-Bromo-N-methyl-2-nitro-5-(trifluoromethyl)aniline, 375-Ai NBS (8.89 g, 50.0 mmol) was added to a solution of N-methyl-2-nitro-5-(trifluoromethyl)aniline (10 g, 45.42 mmol) in dimethylacetamide (100 mL). The mixture was stirred at 50°C for 1 hour. The mixture was quenched with H2O and extracted with ethyl acetate. The organic layer was washed with H2O and brine. The concentrated residue was used directly. 1 H NMR (400 MHz, DMSO-) d 6 ) δ: 8.41 (s, 1H), 8.38 (s, 1H), 7.33 (s, 1H), 3.02-2.99 (m, 3H).

[0124] Step 2: 4-Bromo-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine, 375-Aii A solution of 375-Ai (40 g, 133.76 mmol), iron (37.35 g, 668.80 mmol), and NH4Cl (35.77 g, 668.80 mmol) in a mixture of water (1.4 mL), THF (6 mL), and MeOH (6 mL) was stirred at 60°C for 2 hours. The insoluble precipitate was filtered, and the solvent was evaporated under reduced pressure. After dilution with ethyl acetate, the mixture was washed with water and a saturated sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by column chromatography to give 375-Aii (32 g, 89% yield). Mass spectrometry: C8H8BrF3N2 Calculated values ​​267.98, 269.98 Found values ​​266.95, 268.96 (MH) - ESI. 1 H NMR (400 MHz, DMSO- d 6 ) δ: 6.86 (s, 1H), 6.58 (s, 1H), 5.44 (s, 2H), 5.13 (s, 1H), 2.75-2.73 (m, 3H).

[0125] Step 3: 5-Bromo-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazole, 375-Aiii Concentrated HCl (393 μL, 10.7 mmol) was added to a solution of 375-Aii (29 g, 110 mmol), trimethyl orthoacetate (181 g, 1.51 mol, 192 mL), and acetic acid (6.47 g, 108 mmol, 6.17 mL). The mixture was stirred overnight at room temperature. The reaction mixture was quenched with 5 M NaOH aqueous solution. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, and then dried over Na2SO4 for evaporation. The residue was dissolved in ethyl acetate (40 mL) at 50°C, heptane (150 mL) was added, and the mixture was slowly cooled to room temperature (RT) to give a precipitate. The precipitate was collected by filtration, further washed with heptane, and dried under vacuum at 60°C to give 375-Aiii (28 g, 70% yield). Mass spectrometry: C 10 Calculated values ​​for H8BrF3N2: 291.98, 293.98; Measured values: 292.95, 294.96 (M+H) + ESI. 1 H NMR (400 MHz, DMSO- d 6) δ:8.10 (s, 1H), 7.99 (s, 1H), 3.82 (s, 3H), 2.58 (s, 3H).

[0126] Step 4: 5-Bromo-1,2-dimethyl-4-nitro-6-(trifluoromethyl)-1H-benzo[d]imidazole, 375-Aiv Add KNO3 (11.59 g, 114.64 mmol) to a mixture of 375-Aiii (28 g, 95.54 mmol) and H2SO4 (120 mL) at 0°C. Heat the mixture to room temperature and stir for 2 hours. Carefully pour the mixture into crushed ice and add 30% NH4+. 3· H2O was added until the mixture was neutralized. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum at 50°C to give 375-Aiv (28.5 g, yield 96.8%). 1 HNMR (400 MHz, DMSO- d 6 ) δ: 8.43(s, 1H), 3.89(s, 3H), 2.63(s, 3H).

[0127] Step 5: 5-Bromo-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine, BB-INT 375-A A solution of 375-Aiv (28.5 g, 84.3 mmol), iron (23.54 g, 421.5 mmol), and NH4Cl (22.55 g, 421.50 mmol) in water (2 mL) and ethanol (10 mL) was stirred at 70°C for 30 minutes. The mixture was diluted with ethyl acetate (100 mL), filtered, and concentrated. Water and CHCl3 were added to the filtrate, and the organic layer was separated, washed with brine, dried over Na2SO4, and evaporated. The residue was diluted with isopropyl ether, and the precipitate was collected by filtration to give BB-INT 375-A (21 g, 80.85% yield). 1 HNMR (400 MHz, DMSO- d 6 ) δ: 7.31 (s, 1H), 5.72 (s, 3H), 3.74 (s, 3H), 3.74 (s, 3H), 2.55 (s, 3H).

[0128] Step 6: (8-bromoindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 375-Bi 3-Bromo-2-methylpyridine (91.8 g, 534 mmol) was added to a solution of 2-bromo-1-(3,4,5-trifluorophenyl)ethyl-1-one (45.0 g, 178 mmol) in THF (250 mL). The reaction mixture was heated to 80°C for 16 hours under a nitrogen atmosphere. After cooling, heptane (500 mL) was added, and the resulting precipitate was collected by filtration, washed with heptane, and dried under vacuum to give a pyridinium intermediate (57 g, 75.58% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ:9.02-9.00 (m, 1H), 8.97-8.96 (m, 1H), 8.12-8.09 (m, 2H), 8.06-8.03 (m, 1H), 6.45 (s, 2H), 2.80 (s, 3H).

[0129] A mixture of DMF (78.4 g, 1.07 mol) and dimethyl sulfate (135 g, 1.07 mol) was heated to 80°C for 2 hours. After cooling, this solution was added to a separate solution of pyridinium intermediate (57.0 g, 134 mmol) in DMF, and the reaction mixture was stirred at room temperature for 30 minutes. Then, diisopropylethylamine (139 g, 1.07 mol) was added, and the resulting suspension was stirred for 30 minutes. Water (2.42 g, 134 mmol) was added, and the precipitate was collected by filtration and washed with water. The solid was recrystallized from boiling ethyl acetate (200 mL) to give 375-Bi (30.5 g, 64.2% yield) as a yellow solid. Mass spectrometry: C 15 Calculated values ​​of H7BrF3NO: 352.97, 354.96; Measured values: 354.0, 356.0 (M+H) + ESI. 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.77-9.75 (m, 1H), 7.75-7.71 (m, 3H), 7.56-7.55 (m, 1H), 7.11-7.09 (m, 1H), 6.78-6.77 (m, 1H).

[0130] Step 7: (8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazine-3-yl)(3,4,5-trifluorophenyl)methyl ketone, 375-Bii A solution of 375-Bi (10 g, 28 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronylcyclopentane) (8.61 g, 33.9 mmol), potassium acetate (5.54 g, 56.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (2.29 g, 2.82 mmol) in THF (10 mL) was evacuated and refluxing with N2, then heated to reflux for 4 hours. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 375-Bii (7.1 g, 65% yield).

[0131] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 7.75-7.73 (m, 1H), 7.70-7.66 (m, 2H), 7.46-7.44 (m, 1H), 7.19-7.15 (m, 1H), 7.03-7.02 (m, 1H), 3.84(s, 4H), 1.00(s,6H).

[0132] Step 8: (8-(4-amino-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, Int 375A A solution of BB-INT 375A (17 g, 55 mmol), 375-Bii (33.2 g, 82.8 mmol), SPhos Pd G3 (4.28 g, 5.48 mmol), and K3PO4 (17.5 g, 82.3 mmol) in water (80 mL) and THF (530 mL) was evacuated and refluxing with N2, then heated to 75°C for 2 hours. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (1 / 1 petroleum ether: ethyl acetate) to give Int 375A (16.8 g, 89.5% yield). Mass spectrometry: C 25 H 16 F6N4O Calculated value: 502.12 Measured value: 503.1 (M+H) + ESI. 1 H NMR (400 MHz, CDCl3-d ) δ:9.89-9.87 (m, 1H), 7.94 (s, 1H), 7.71-7.67 (m, 2H), 7.39-7.38 (m, 1H), 7.30-7.25 (m, 3H), 4.96 (s, 2H), 3.80 (s, 3H), 257 (s, 3H).

[0133] Step 9: (8-(4-amino-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-iodoinzidazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, BB-INT 375B NIS (11.6 g, 51.7 mmol) and TFA (13.4 g, 117 mmol) were added to a solution of BB-INT 375A (23.6 g, 47.0 mmol) in THF (250 mL). After stirring at room temperature for 30 min, the mixture was diluted with ethyl acetate, washed with aqueous NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (1 / 1 petroleum ether:ethyl acetate) to give BB-INT 375B (3.5 g, 50% yield). Mass spectrometry: C 25 H 15 F6IN4O Calculated value: 628.02 Measured value: 629.0 (M+H) + ESI. 1 H NMR (400 MHz, DMSO- d 6 ) δ:9.99-9.97 (m, 1H), 7.70-7.66 (m, 2H), 7.55 (s, 1H), 7.31-7.27 (m, 2H), 7.23-7.21 (m, 1H), 4.94 (s, 2H), 3.79 (s, 3H), 2.56 (s, 3H).

[0134] Step 10: (E)-(8-(4-amino-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(2-ethoxyvinyl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, BB-INT 375C A solution of BB-INT 375B (27.3 g, 43.5 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (34.4 g, 174 mmol), Pd(dppf)Cl2 (6.31 g, 8.69 mmol), and an aqueous solution of 2NNa2CO3 (137 mL) in 1,4-dioxane (1.11 L) was evacuated and refilled with N2, then heated to 95°C for 2 hours. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (50:1 dichloromethane / methanol) to give BB-INT 375C (19.4 g, 77.9% yield). Mass spectrometry: C 29 H 22 F6N4O2 Calculated value: 572.16; Measured value: 573.1 (M+H) + ESI. 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.89-9.87 (m, 1H), 7.70-7.66 (m, 2H), 7.40 (s, 1H), 7.32 (s, 1H), 7.20-7.14 (m, 2H), 6.86-6.83 (d, J = 12.8 Hz, 1H), 5.00 (s, 2H), 4.59-4.56 (d, J = 12.8 Hz, 1H), 3.34 (s, 3H), 3.01-2.99 (m, 1H), 2.83-2.80 (m, 1H), 2.51 (s, 3H), 0.86-0.82 (m, 3H).

[0135] Step 11: (9,10-Dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, BB-INT 375D TFA (30.5 g, 267 mmol) and NaBH(OAc)3 (18.88 g, 89.08 mmol) were added to a solution of BB-INT 375C (10.2 g, 17.8 mmol) in dichloromethane (190 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with dichloromethane and quenched with an aqueous solution of NaHCO3 at 0°C. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (50:1 dichloromethane / methanol) to give BB-INT 375D (4.8 g, 51% yield). Mass spectrometry: C 27 H 18 F6N4O Calculated value: 528.14; Measured value: 529.1 (M+H) + ESI. 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.88-9.87 (m, 1H), 7.92 (s,1H), 7.73-7.70 (m, 2H), 7.28 (s, 1H), 7.18-7.17 (m, 1H), 7.10-7.08 (m, 1H), 4.41 (br, 1H), 3.85 (s, 3H), 3.82-3.80 (m, 1H), 3.50-3.47 (m, 1H), 2.97-2.91 (m, 1H), 2.61 (s, 3H), 2.33-2.63 (m, 1H).

[0136] Step 12: (3,4,5-trifluorophenyl)(9,10,12-trimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl) methyl ketone, 375 key Int1 A solution of BB-INT 375D (8.0 g, 15 mmol), 37% methanol aqueous solution (6.14 g, 75.7 mmol), and 0.3 M Zn(BH3CN)2 (147 mL, 45.4 mmol; prepared from NaBH3CN (90.8 mmol) and ZnCl2 (45.4 mmol)) in MeOH in THF (86 mL) was stirred at room temperature for 0.5 h. The resulting suspension was filtered, washed with ethyl acetate, and the filtrate was washed with NaHCO3 aqueous solution, H2O, and brine, then dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (1 / 1 PE / EA) to give 375INT 1 (1.16 g, 70.6% yield). Mass spectrometry: C 28 H 20 F6N4O Calculated value: 542.15 Measured value: 543.1 (M+H) + ESI. 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.84-9.83 (m, 1H), 8.04 (s, 1H), 7.73-7.72 (m, 2H), 7.26 (s, 1H), 7.17-7.15 (m, 1H), 7.07-7.05(m, 1H), 3.88 (s, 3H), 3.03 (s, 3H), 2.82-2.80 (m, 1H), 2.63 (s, 3H), 2.10-2.04 (m, 1H).

[0137] The compounds in the table below were synthesized using a route similar to that used in the key Int 1 of Example 375. Synthetic Int-01 Step 1: 2-Bromo-1-(3,4,5-trifluorophenyl)ethyl-1-one, 01-2 Copper bromide (84.66 g, 379.05 mmol) was added to a solution of 1-(3,4,5-trifluorophenyl)ethyl-1-one (30 g, 172.30 mmol) in EtOAc (450 mL), and the reaction mixture was heated to 70°C overnight. After cooling, the mixture was filtered through diatomaceous earth and washed with aqueous NaHCO3 solution and brine. The reaction mixture (RM) was concentrated under reduced pressure and used without purification.

[0138] 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.01-7.97 (m, 2H), 4.96 (s, 2H).

[0139] Step 2: 3-Bromo-2-methyl-1-[2-oxo-2-(3,4,5-trifluorophenyl)ethyl]-1-pyridinium bromide, 01-3 3-Bromo-2-methylpyridine (91.78 g, 533.56 mmol) was added to a solution of O1-2 (45 g, 177.85 mmol) in THF (250 mL). The reaction mixture was heated to 80°C for 16 hours under a nitrogen atmosphere. After cooling, heptane (500 mL) was added, and the resulting precipitate was collected by filtration, washed with heptane, and dried under vacuum to give O1-3 (57 g, 75.58% yield).

[0140] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.02-9.00 (m, 1H), 8.97-8.96 (m, 1H), 8.12-8.09 (m, 2H), 8.06-8.03 (m, 1H), 6.45 (s, 2H), 2.80 (s, 3H).

[0141] Step 3: (8-bromoindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 01-4 A mixture of DMF (78.41 g, 1.07 mol) and dimethyl sulfate (135.32 g, 1.07 mol) was heated to 80°C for 2 hours. After cooling, this solution was added to a separate solution of O1-3 (57 g, 134.11 mmol) in DMF, and the reaction mixture was stirred at room temperature for 30 minutes. Then, DIEA (138.65 g, 1.07 mol) was added, and the resulting suspension was stirred for another 30 minutes. Water (2.42 g, 134.11 mmol) was added, and the precipitate was collected by filtration and washed with water. The solid was recrystallized from boiling EtOAc (200 mL) to give O1-4 (30.5 g, 64.22% yield) as a yellow solid.

[0142] Mass spectrometry: C 15 Calculated values ​​of H7BrF3NO: 352.97, 354.96; Measured values: 354.0, 356.0 (M+H) + ESI.

[0143] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.77-9.75 (m, 1H), 7.75-7.71 (m, 3H), 7.56-7.55 (m, 1H), 7.11-7.09 (m, 1H), 6.78-6.77 (m, 1H).

[0144] Step 4: (8-(5,5-dimethyl-1,3,2-dioxoborhexane-2-yl)indazin-3-yl)(3,4,5-trifluorophenyl)methyl ketone, 01-5 A solution of 01-4 (10 g, 28.24 mmol), 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxoboronylcyclohexane) (7.65 g, 33.89 mmol), potassium acetate (5.54 g, 56.48 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (2.29 g, 2.82 mmol) in THF (10 mL) was evacuated and refluxing with N2, then heated to reflux temperature for 4 hours. The mixture was diluted with EtOAc and water, extracted once with EtOAc, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 01-5 (7.1 g, 64.94% yield).

[0145] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 7.75-7.73 (m, 1H), 7.70-7.66 (m, 2H), 7.46-7.44 (m, 1H), 7.19-7.15 (m, 1H), 7.03-7.02 (m, 1H), 3.84(s, 4H), 1.00(s,6H).

[0146] Step 5: (8-(4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 01-6 A solution of 5-iodo-4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzi[d]imidazole (5.6 g, 15.13 mmol), O1-5 (8.79 g, 22.70 mmol), Pd(PPh3)4 (1.75 g, 1.51 mmol), and Na2CO3 (3.21 g, 30.26 mmol) in water (14 mL) and 1,4-dioxane (70 mL) was evacuated and refluxing with N2, then heated to 100°C for 12 hours. The mixture was diluted with EtOAc and water, extracted once with EtOAc, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give O1-6 (7.3 g, 83.92% yield).

[0147] Mass spectrometry: C 26 H 17 F6N3O2 Calculated value 517.12 Measured value 518.2 (M+H) + ESI.

[0148] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.86-9.84 (d, J = 6.4 Hz, 1H), 7.80 (s,1H), 7.75-7.71 (m, 2H), 7.37-7.34 (m, 1H), 7.27-7.24 (m, 2H), 6.05-6.04 (m,1H), 4.09 (s, 3H), 3.87 (s, 3H), 2.62 (s, 3H).

[0149] Step 6: (1-Iodo-8-(4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl)methyl ketone, 01-7 NIS (2.77 g, 12.30 mmol) was added to O1-6 (6.7 g, 12.95 mmol) in a solution of HoAc (3 mL) and THF (20 mL). After stirring at room temperature for 30 minutes, the mixture was diluted with EtOAc, washed with aqueous NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give O1-7 (6 g, 72.03% yield).

[0150] Mass spectrometry: C 26 H 16F6IN3O2 Calculated value: 643.02 Measured value: 644.0 (M+H) + ESI.

[0151] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.95-9.93 (m, 1H), 7.80 (s, 1H), 7.75-7.71 (m, 2H), 7.55 (s, 1H), 7.27-7.26 (m, 1H), 7.23-7.20 (m, 1H), 4.17 (s,3H), 3.87 (s, 3H), 2.62 (s, 3H).

[0152] Step 7: (E)-(1-(2-ethoxyvinyl)-8-(4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 01-9 A solution of 01-7 (2.5 g, 3.89 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronyl pentane (2.31 g, 11.66 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (315 mg, 0.38 mmol), and Na₂CO₃ (823.76 mg, 7.77 mmol) in water (1 mL) and 1,4-dioxane (5 mL) was evacuated and refluxing with N₂, then heated to 100°C for 3 hours. The mixture was diluted with EtOAc and water, extracted once with EtOAc, the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 01-9 (2.3 g, 90.67% yield).

[0153] Mass spectrometry: C 30 H 23 F6N3O3 Calculated value: 587.16 Measured value: 588.1 (M+H) + ESI.

[0154] Step 8: 2-(8-(4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-3-(3,4,5-trifluorobenzoyl)indazine-1-yl)acetaldehyde, 01-10 HCl (2 M, 1.11 mL) was added to a solution of O1-9 (1.3 g, 2.21 mmol) in THF (20 mL) at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc and quenched with an aqueous solution of NaHCO3 at 0°C. The organic layer was washed with brine and then dried over Na2SO4. The RM was concentrated under reduced pressure and used without purification.

[0155] Mass spectrometry: C 28 H 19 F6N3O3 Calculated value: 559.13 Measured value: 560.1 (M+H) + ESI.

[0156] Step 9: (1-(2-hydroxyethyl)-8-(4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 01-11 NaBH(OAc)3 (681.9 mg, 3.22 mmol) was added to a solution of O1-10 (1.2 g, 2.14 mmol) and HoAc (12.88 mg, 0.21 mmol) in THF (15 mL). The mixture was stirred at room temperature for 3 hours. The organic layer was washed with brine and then dried over Na2SO4. The residue was purified by column chromatography to give O1-11 (220 mg, 18.27% yield).

[0157] Mass spectrometry: C 28 H 21 F6N3O3 Calculated value: 561.15 Measured value: 562.1 (M+H) + ESI.

[0158] Step 10: (8-(4-hydroxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(2-hydroxyethyl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 01-12 BBr3 (1.47 g, 5.88 mmol) was added to a solution of 01-11 (220 mg, 0.39 mmol) in DCM (10 mL) at 0°C. After stirring at 30°C for 5 hours, an aqueous solution of CHCl3 / MeOH (30%) and NaHCO3 was added to the reaction mixture at 0°C. The aqueous layer was extracted with CHCl3 / MeOH (10%), and the combined organic matter was washed with brine and then dried over Na2SO4 for evaporation. The residue was purified by column chromatography to give 01-12 (190 mg, 88.58% yield).

[0159] Mass spectrometry: C 27 H 19 F6N3O3 Calculated value: 547.13 Measured value: 548.1 (M+H) + ESI.

[0160] Step 11: (9,10-dimethyl-7-(trifluoromethyl)-13,14-dihydro-9H-imidazo[4'',5'':5',6']benzo[1',2':2,3]oxaoctanocyclo[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, INT-01 TMAD (77.84 mg, 0.45 mmol) was added to a solution of 01-12 (165 mg, 0.3 mmol) and P(n-Bu)3 (91.47 mg, 0.45 mmol) in THF (35 mL) at 0°C. After stirring at room temperature for 2 hours, P(n-Bu)3 (91.47 mg, 0.45 mmol) and TMAD (77.84 mg, 0.45 mmol) were added again at 0°C, and stirring was continued at room temperature for 1 hour. The resulting suspension was filtered, washed with EA, and the filtrate was washed with aqueous NaHCO3 solution, H2O, and brine, then dried over Na2SO4 and evaporated. The crude product was purified by column chromatography to give INT-01 (120 mg, 75.2% yield).

[0161] Mass spectrometry: C 27 H 17 F6N3O2 Calculated value: 529.12 Measured value: 530.2 (M+H) + ESI.

[0162] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.89-9.87 (m, 1H), 8.03 (s, 1H), 7.77-7.73 (m, 2H), 7.35 (s, 1H), 7.22-7.18 (m, 2H), 4.62-4.58 (m, 1H), 4.07-4.01(m, 1H), 3.88 (s, 3H), 2.72-2.69 (m, 1H), 2.63 (s, 3H), 2.60-2.58 (m, 1H).

[0163] Synthesis Example 1 (E)-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)indazine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide, Example 1 Step 1: Potassium acetate (663 mg, 6.76 mmol) was added to a mixture of 5-(8-bromoindazine-3-carbonyl)-2-((2,4-dimethoxybenzyl)amino)benzyl nitrile, BB2 (800 mg, 2.25 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,3,2-dioxoborhexacyclopentane (686 mg, 2.70 mmol) and PdCl2(dppf)CH2Cl2 (184 mg, 0.225 mmol) in 1,4-dioxane (11.3 mL). After stirring at 90°C for 90 minutes, the mixture was diluted with EtOAc and water, extracted with EtOAc, washed successively with H2O and brine, dried over sodium sulfate, and evaporated. The residue containing 2-((2,4-dimethoxybenzyl)amino)-5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazine-3-carbonyl)benzylnitrile was used in the next reaction. MS: m / z = 538.2 (M+1, ESI+).

[0164] Step 2: Sodium carbonate (536 mg, 5.06 mmol) was added to a mixture of 5-bromo-4,6-dichloro-1-methyl-1H-benzimidazole, BB1 (649 mg, 1.69 mmol), 2-((2,4-dimethoxybenzyl)amino)-5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazine-3-carbonyl)benzylnitrile (881 mg, 2.19 mmol), and tBu Pd G4 (356 mg, 0.506 mmol) in THF (17.0 mL). After stirring at 80°C for 2 hours, the mixture was diluted with EtOAc and water. Extraction with EtOAc, washing with H2O and brine successively, drying with sodium sulfate, and evaporation were performed. The residue was purified by column chromatography on silica gel (acetone-hexane) to obtain 5-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)inzin-3-carbonyl)-2-((2,4-dimethoxybenzyl)amino)benzylnitrile. MS: m / z = 610.2 (M+1, ESI+).

[0165] Step 3: A solution of 5-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)inazin-3-carbonyl)-2-((2,4-dimethoxybenzyl)amino)benzylnitrile (183 mg, 0.3 mmol) and TFA (5.0 mL) in dichloromethane (10 mL) was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum to give 2-amino-5-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)inazin-3-carbonyl)benzylnitrile (250 mg, crude) as a brown solid, which was used in the next step without purification. MS: m / z = 460.1 (M+1, ESI+).

[0166] Step 4: (E)-4-chlorobut-2-enoic acid (74.5 mg), 1-propanephosphoanhydride cyclic trimer (1.7 M THF solution, 0.5 mL), and triethylamine (0.1 mL) were added to a solution of 2-amino-5-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)inazin-3-carbonyl)benzyl nitrile (0.25 g) obtained in Step 3 in DMF (2.1 mL). The reaction was carried out at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, followed by washing the organic layer with a saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol) to obtain (E)-4-chloro-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)indazine-3-carbonyl)phenyl)but-2-enamide (93.2 mg). MS: m / z = 561.8, 563.8 (M+H, ESI+).

[0167] Step 5: (lr,4r)-4-methoxycyclohexane-l-amine hydrochloride (28.5 mg), potassium carbonate (47.6 mg), and potassium iodide (34.3 mg) were added to a solution of (E)-4-chloro-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)indazine-3-carbonyl)phenyl)but-2-enamide (39.0 mg) in DMF (0.7 mL). The reaction was carried out at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, followed by washing the organic layer with saturated sodium chloride solution. The washed layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative reversed-phase HPLC (water:acetonitrile (0.1% formic acid)). Saturated sodium bicarbonate solution was added to the purified fraction containing the title compound, followed by extraction with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (E)-N-(2-cyano-4-(8-(4,6-dichloro-1-methyl-1H-benzo[d]imidazol-5-yl)inazine-3-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide (8.50 mg).

[0168] MS: m / z = 655.2, 657.1 (M+H, ESI+).

[0169] HNMR (400 MHz, CD3OD) δ 10.00 (d, J = 6.8 Hz, 1H), 8.55-8.45 (brs,1H), 8.32 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.6, 2.0 Hz, 1H),7.98 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.37 (d, J = 4.8 Hz, 1H), 7.32 -7.20(m, 2H), 7.05-6.94 (m, 1H), 6.54 (d, J = 15.3 Hz, 1H), 6.11 (d, J = 4.8 Hz,1H), 3.96 (s, 3H), 3.78 (d, J = 6.4 Hz, 2H), 3.34 (s, 3H), 3.24 -3.14 (m,1H), 2.97-2.87 (m, 1H), 2.21-2.08 (m, 4H), 1.44-1.18 (m, 4H).

[0170] The compounds in the table below were synthesized using a route similar to that in Example 1. Synthesis Example 161 Step 1: (4-Amino-3,5-Difluorophenyl)(9,10-Dimethyl-7-(trifluoromethyl)-13,14-dihydro-9H-imidazo[4'',5'':5',6']benzo[1',2':2,3]oxaoctanocyclo[4,5,6-hi]indazine-2-yl) methyl ketone, 25-1 INT-01 (105 mg, 0.19 mmol) was suspended in THF (1 mL). Then, 30% NH3 aqueous solution (10 mL) was added and the solution was stirred overnight at 130 °C. The mixture was diluted with EtOAc and water, extracted once with EtOAc, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give 25-1 (100 mg, 95.78% yield).

[0171] Mass spectrometry: C 27 H 19 F5N4O2 Calculated value: 526.14; Measured value: 527.1 (M+H) + ESI.

[0172] 1 H NMR (400 MHz, DMSO- d 6) δ: 9.79-9.77 (m, 1H), 8.02 (s, 1H), 7.44-7.41 (m, 2H), 7.37 (s, 1H), 7.11-7.08 (m, 1H), 7.06-7.04 (m, 1H), 5.98 (s, 2H), 4.61-4.56 (m, 1H), 4.07-4.03 (m, 1H), 3.87 (s, 3H), 2.74-2.69 (m, 1H), 2.63 (s, 3H), 2.60-2.59 (m, 1H).

[0173] Step 2: (E)-4-chloro-N-(4-(9,10-dimethyl-7-(trifluoromethyl)-13,14-dihydro-9H-imidazo[4'',5'':5',6']benzo[1',2':2,3]oxaoctanocyclo[4,5,6-hi]indazine-2-carbonyl)-2,6-difluorophenyl)but-2-enamide, 25-2 A solution of 25-1 (100 mg, 0.19 mmol), (E)-4-chlorobutyric acid (27.47 mg, 0.23 mmol), and T3P (120.88 mg, 0.19 mmol) in EtOAc (3 mL) was prepared. TEA (57.66 mg, 0.57 mmol) was then added to the mixture. After stirring at room temperature for 1 hour, the mixture was diluted with EtOAc and water, extracted once with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 25-2 (73 mg, 61.10% yield).

[0174] Mass spectrometry: C 31 H 22 ClF5N4O3 Calculated values: 628.13, 670.13 Measured values: 629.1, 671.2 (M+H) + ESI.

[0175] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 10.09 (s, 1H), 9.91-9.89 (m, 1H), 8.03 (s, 1H), 7.58-7.56 (m, 2H), 7.37 (s, 1H), 7.21-7.17 (m, 2H), 6.49-6.48 (d, J= 7.2 Hz , 1H), 6.17-6.15 (d, J=6.8 Hz , 1H), 4.61-4.57 (m, 1H), 4.08-4.02 (m,1H), 3.88 (s, 3H), 3.44-3.42 (m, 1H), 3.21-3.18 (m, 1H), 2.76-2.73 (m, 1H), 2.67 (s, 3H), 2.60-2.58 (m, 1H).

[0176] Step 3: (E)-4-(((1r,4r)-4-cyanocyclohexyl)amino)-N-(4-(9,10-dimethyl-7-(trifluoromethyl)-13,14-dihydro-9H-imidazo[4'',5'':5',6']benzo[1',2':2,3]oxaoctylcyclo[4,5,6-hi]indazine-2-carbonyl)-2,6-difluorophenyl)but-2-enamide, Example 2 A solution of 25-2 (36 mg, 0.06 mmol), (1r,4r)-4-aminocyclohexane-1-onitrile (8.53 mg, 0.07 mmol), K₂CO₃ (15.82 mg, 0.11 mmol), and KI (57.01 mg, 0.34 mmol) in DMF (2 mL) was stirred at room temperature for 6 hours. The mixture was diluted with EtOAc and water, extracted once with EtOAc, the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase column chromatography (C18 column) to give product Example 161 (10 mg, yield 24.38%).

[0177] Mass spectrometry: C 38 H 33 F5N6O3 Calculated value: 716.25 Measured value: 717.2 (M+H) + ESI.

[0178] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 10.02 (s, 1H), 9.92-9.90 (m, 1H), 8.03 (s, 1H), 7.58-7.56 (d, J=8.0 Hz, 2H), 7.38 (s, 1H), 7.23-7.16 (m, 2H), 6.90-6.84 (m, 1H), 6.37-6.33 (m, 1H), 4.61-4.57 (m, 1H), 4.05-4.02 (m, 2H), 3.88(s, 3H), 3.40-3.39 (m, 2H), 2.76-2.73 (m, 2H), 2.67 (s, 3H), 2.04-2.00 (m,2H), 1.92-1.88 (m, 2H), 1.56-1.47 (m, 2H), 1.19-1.10 (m, 4H).

[0179] Synthesis Example 163 Step 6: (4-Amino-3,5-Difluorophenyl)(8-(4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)methyl ketone, 07A-1 In a sealed tube, a solution of [8-[4-methoxy-1,2-dimethyl-6-(trifluoromethyl)benzimidazol-5-yl]indazine-3-yl]-(3,4,5-trifluorophenyl)methyl ketone (400 mg, 773.06 μmol) in ammonium hydroxide (91.19 mg, 773.06 μmol, 5 mL, 28% purity) and THF (2 mL) was stirred at 135°C for 16 hours. LC-MS analysis showed the desired MS formation. The reactants were extracted with EA and washed with water, and the organic phase was concentrated under vacuum to give crude 07A-1 (300 mg, 75% yield).

[0180] Mass spectrometry: C 26 H 19 F5N4O2 Calculated value: 514.1 Measured value: 515.1 (M+H) + ESI.

[0181] Step 7: (E)-4-chloro-N-(2,6-difluoro-4-(8-(4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-carbonyl)phenyl)but-2-enamide, 07A-2 TEA (540.92 mg, 5.35 mmol, 745.58 μL) was added dropwise to a solution of (4-amino-3,5-difluoro-phenyl)-[8-[4-methoxy-1,2-dimethyl-6-(trifluoromethyl)benzimidazol-5-yl]indazine-3-yl] methyl ketone (250 mg, 485.96 μmol), T3P (927.79 mg, 1.46 mmol, 50% purity) in EA (8 mL), and the mixture was stirred for 1 hour. LC-MS indicated that the reaction was complete. The reactants were extracted with EA and washed with water. The organic phase was concentrated under vacuum to give the crude product. The residue was purified by column chromatography to give 07A-2 (280 mg, 93.40% yield).

[0182] Mass spectrometry: C 30 H 22 F5N4O3Cl Calculated value: 616.1 Measured value: 617.1 (M+H) + ESI.

[0183] Step 8: (E)-4-(((1r,4r)-4-cyanocyclohexyl)amino)-N-(2,6-difluoro-4-(8-(4-methoxy-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-carbonyl)phenyl)but-2-enamide, Example 163 A solution of (E)-4-chloro-N-[2,6-difluoro-4-[8-[4-methoxy-1,2-dimethyl-6-(trifluoromethyl)benzimidazol-5-yl]indazine-3-carbonyl]phenyl]but-2-enamide (200 mg, 324.17 μmol), 4-aminocyclohexanonitrile (80.51 mg, 648.34 μmol), KI (322.87 mg, 1.95 mmol), and K₂CO₃ (134.40 mg, 972.50 μmol) in DMF (5 mL) was stirred at 35°C for 3 hours. LC-MS showed the formation of the desired product. The reactants were extracted with EA and washed with water. The organic phase was concentrated under vacuum to obtain the residue. The residue was purified by TLC to obtain the crude product. The crude product was purified by prep-HPLC to obtain Example 3 (28 mg, yield 12.3%).

[0184] Mass spectrometry: C 37 H 33 F5N6O3 Calculated value: 704.3 Measured value: 705.3 (M+H) + ESI.

[0185] 1 H NMR (400 MHz, DMSO- d 6δ: 9.98 (s, 1H), 9.87 (d, J = 6.4 Hz, 1H),7.80 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 4.8 Hz, 1H),7.24 (m,2H), 6.88 (m, 1H), 6.35 (m, 1H), 6.05 (m, 1H), 4.09 (s, 3H), 3.87 (s, 3H),3.37 (m, 2H), 2.66 (m, 1H) 2.62 (s, 3H), 2.44 (m, 1H), 2.02-1.87 (m, 5H), 1.50 (m, 2H), 1.10 (m, 2H).

[0186] The compounds in the table below were synthesized using routes similar to those in Example 1, Example 161, or Example 163. Synthesis of (E)-4-(((1r,4r)-4-cyanocyclohexyl)amino)-N-(2,6-difluoro-4-(9,10,12-trimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide, Examples 369 and 375 Step 1: 375-B (300 mg, 0.55 mmol) was suspended in 1,4-dioxane (4 mL). Then, 30% NH3 aqueous solution (8 mL) was added and the solution was stirred overnight at 130 °C. The mixture was diluted with ethyl acetate and water, extracted once with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give 375-B (180 mg, 60.33% yield).

[0187] Mass spectrometry: C 28 H 22F5N5O Calculated value: 539.17; Measured value: 540.1 (M+H) + ESI.

[0188] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.75-9.73 (m, 1H), 8.03 (s, 1H), 7.41-7.39 (m, 2H), 7.29 (s, 1H), 7.07-7.03 (m, 1H), 5.94 (s, 2H), 6.95-6.93 (m,1H), 3.86 (s, 3H), 3.30-2.99 (m, 1H), 3.04 (s, 3H), 2.84-2.79 (m, 1H), 2.68-2.67 (m, 1H), 2.63 (s, 3H), 2.12-2.09 (m, 1H).

[0189] Step 2: A solution of 375-B (166 mg, 0.31 mmol) and (E)-4-chlorobutyric acid (55.63 mg, 0.46 mmol) in ethyl acetate (5 mL). Then, T3P (587.45 mg, 0.92 mmol) and triethylamine (342.19 mg, 3.38 mmol) were added to the mixture. After stirring at room temperature for 2 hours, the mixture was diluted with EA and water, extracted once with EA, and the organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give 375-C (100 mg, 50.62% yield).

[0190] Mass spectrometry: C 32 Calculated values ​​for H5ClF5N5O2: 641.16, 643.16; Measured values: 642.2, 644.2 (M+H) + ESI.

[0191] 1 H NMR (400 MHz, DMSO- d 6) δ: 10.08 (s, 1H), 9.87-9.85 (m, 1H), 8.04 (s, 1H), 7.57-7.53 (m, 2H), 7.28 (s, 1H), 7.17-7.14 (m, 1H), 7.06-7.04 (m, 1H), 6.50-6.48 (m, 1H), 6.18-6.13 (m, 1H), 3.86 (s, 3H), 3.42-3.41 (m, 2H), 3.31-3.30 (m, 1H), 3.03 (s, 3H), 2.84-2.79 (m, 1H), 2.79-2.63 (m, 4H), 2.10-2.05 (m, 1H).

[0192] Step 3: Add 375-C (45 mg, 0.07 mmol), KI (34.91 mg, 0.21 mmol), and K₂CO₃ (29.06 mg, 0.21 mmol) to a solution of (1r,4r)-4-aminocyclohexane-1-onitrile (26.21 mg, 0.21 mmol) in DMF (3 mL). The mixture was then stirred at 40 °C for 2 hours. The mixture was diluted with EA and water, extracted once with ethyl acetate, and the organic layer was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18 column) to give a mixture of Examples 369 and 375 (10.5 mg, yield 20.53%).

[0193] Mass spectrometry: C 39 H 36 F5N7O2 Calculated value: 729.29 Measured value: 730.3 (M+H) + ESI.

[0194] 1 H NMR (400 MHz, DMSO- d 6) δ: 10.00 (s, 1H), 9.87-9.85 (m, 1H), 8.04 (s, 1H), 7.56-7.54 (m, 2H), 7.28 (s, 1H), 7.17-7.13 (m, 1H), 7.06-7.04 (m, 1H), 6.91-6.85 (m, 1H), 6.37-6.33 (m, 1H), 3.86 (s, 3H), 3.31-3.28 (m, 2H), 3.03 (s, 3H), 2.81-2.78 (m, 1H), 2.69-2.63 (m, 5H), 2.47-2.44 (m, 1H), 2.10-2.00 (m, 3H), 1.90-1.88 (m, 2H), 1.55-1.49 (m, 2H), 1.16-1.09 (m, 2H).

[0195] The isomers 371 and 375 were separated under the following conditions.

[0196] Column: CHIRALPAK IE-3, 15*0.46cm 5μm; Mobile phase: EtOH / TEA=100 / 0.1(V / V); Flow rate: 0.5 ml / min; Wavelength: UV 254nm; Temperature: 35 ℃ Example 369: Retention time = 6.05 min.

[0197] Example 375: Retention time = 8.36 minutes.

[0198] The compounds in the table below were synthesized using a route similar to that in Example 375. The compounds in the table below were synthesized using a route similar to that in Example 375. Synthesis of (E)-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(2,6-difluoro-4-(8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(methylamino)indazine-3-carbonyl)phenyl)but-2-enamide, Example 437 Step 1: 3-Methoxy-N-methyl-2-nitro-5-(trifluoromethyl)aniline, 1-ib A solution of 1-ia (9.5 g, 37.31 mmol) and CH3ONa (20.16 g, 373.14 mmol) in MeOH (100 mL) was stirred overnight at 80°C under a nitrogen atmosphere. The mixture was quenched with sodium potassium tartrate. The mixture was diluted with EA and water, extracted with EA, the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 1-ib (8.5 g, 91.05% yield).

[0199] Mass spectrometry: C9H9N2O3F3 Calculated value 250.17 Measured value 251.12 (M+H) + ESI Step 2: 4-Iodo-3-methoxy-N-methyl-2-nitro-5-(trifluoromethyl)aniline, 1-iia N-iodosuccinimide (1.78 g, 7.91 mmol) was added to a solution of 1-ib (1.8 g, 7.19 mmol) in acetic acid (15 mL). The mixture was stirred overnight at 40°C. The mixture was poured into water and filtered, yielding a residue. The residue was concentrated under reduced pressure using RM and used without further purification.

[0200] Mass spectrometry: C9H8N2O3IF3 Calculated value 376.07 Measured value 375.14 (MH) - ESI Step 3: 4-Iodo-3-methoxy-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine, 1-iiia Fe (1.86 g, 33.24 mmol) and NH4Cl (888.96 mg, 16.62 mmol) were added to a solution of 1-iia (2.5 g, 6.65 mmol) in a mixture of THF (40 mL), MeOH (40 mL), and water (20 mL). The mixture was stirred at 60°C for 15 minutes. The mixture was diluted with EA and water, extracted with EA, the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. RM was then concentrated under reduced pressure and used without further purification.

[0201] Mass spectrometry: C9H 10 N2OIF3 calculated value 346.09, measured value 347.05 (M+H) + ESI Step 4: 5-Iodo-4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole, 437-1 A solution of 1-iiia (11 g, 31.78 mmol), T3P (50.38 g, 69.92 mmol, 50% purity), 2-methoxyacetic acid (3.15 g, 34.96 mmol), and triethylamine (12.86 g, 127.14 mmol, 17.73 mL) in DMF (40.62 mL) was stirred at room temperature for 2 hours. The mixture was then diluted with EA and water, extracted with EA, the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Acetic acid was added to the residue and stirred at 50°C for 1 hour. The mixture was diluted with EA and water, extracted with EA, the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give 437-1 (6.1 g, 47.96% yield).

[0202] Mass spectrometry: C 12 H 12 O2IN2F3 Calculated value: 400.13 Measured value: 401.10 (M+H) + ESI Step 5: (8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 437-2 A solution of 437-1 (2.00 g, 5.00 mmol), [8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazin-3-yl]-(3,4,5-trifluorophenyl)methyl ketone (3.01 g, 7.50 mmol), PD(PPH3)4 (577.59 mg, 499.83 μmol), and K3PO4 (2.12 g, 10.00 mmol) in water (8 mL) was stirred at 90°C for 18 hours under an Ar atmosphere. The mixture was filtered to remove insoluble substances. The mixture was diluted with EA and water, extracted with EA, the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 437-2 (2.05 g, 74.92% yield).

[0203] Mass spectrometry: C 27 H 19 N3O3F6 Calculated value 547.13, measured value 518.16 (M-CH2CH3) - ESI Step 6: (8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-nitroindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 437-3 KNO3 (70.18 mg, 694.13 μmol) was added to a solution of 437-2 (400 mg, 730.66 μmol) in 5 mL of H2SO4 at 0°C and stirred for 0.5 h. The mixture was poured onto ice and the pH was adjusted to 7 with aqueous NaOH solution. The mixture was diluted with EA and water, extracted with EA, the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 437-3 (210 mg, 48.51% yield).

[0204] Mass spectrometry: C 27 H 18 N4O5F6 Calculated value: 592.45 Measured value: 593.19 (M+H) + ESI Step 7: (1-Amino-8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 437-4 Boronic acid (136.19 mg, 1.52 mmol) and 4,4-bipyridine (7.91 mg, 50.64 μmol) were added to a solution of 437-3 (300 mg, 506.38 μmol) in DMF (5 mL) and stirred at room temperature for 15 minutes. The mixture was diluted with dichloromethane and water, extracted with dichloromethane, the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 1437-4 (170 mg, 59.69% yield).

[0205] Mass spectrometry: C 27 H 20 N4O3F6 Calculated value 562.46 Measured value 563.24 (M+H) + ESI Step 8: (8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(methylamino)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 437-5 Potassium carbonate (522.90 mg, 3.78 mmol) was added to a mixture of 437-4 (1.4 g, 1.89 mmol) and DMA (9.88 mL) and stirred at 0°C. Dimethyl sulfate (167.02 mg, 1.32 mmol, 128.48 μL) was then slowly added and stirred for 3 hours. The reaction mixture was quenched with a saturated aqueous NaCl solution. The mixture was diluted with EA and water, extracted with EA, the organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 437-5 (210 mg, 20.39% yield).

[0206] Mass spectrometry: C 28 H 22 N4O3F6 Calculated value 576.49 Measured value 577.22 (M+H) + ESI Step 9: (4-Azide-3,5-Difluorophenyl)(8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(methylamino)indazine-3-yl) methyl ketone, 437-6 NaN3 (59.20 mg, 910.69 μmol) was added to a solution of 437-5 (500 mg, 867.32 μmol) DMA (10 mL). The mixture was stirred at 80°C for 2 hours. The mixture was diluted with EA and water, extracted once with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. RM was concentrated under reduced pressure and used without purification.

[0207] Mass spectrometry: C 28 H 22 N7O3F5 Calculated value: 599.17 Measured value: 600.34 (M+H) + ESI Step 10: (4-Amino-3,5-Difluorophenyl)(8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(methylamino)indazine-3-yl) methyl ketone, 437-7 Pd / C (105.34 mg, 867.32 μmol) was added to a solution of 437-6 (519.97 mg, 867.32 μmol) in EA (10 mL). The mixture was stirred at room temperature for 1.5 hours under a H2 atmosphere. The mixture was filtered to remove Pd / C, and the solution was concentrated under reduced pressure and used without further purification.

[0208] Mass spectrometry: C28 H 24 N5O3F5 Calculated value: 573.18 Measured value: 574.29 (M+H) + ESI Step 11: (E)-4-chloro-N-(2,6-difluoro-4-(8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(methylamino)indazine-3-carbonyl)phenyl)but-2-enamide, 437-8 A mixture of 437-7 (475 mg, 745.41 μmol), T3P (2.37 g, 3.73 mmol, 50% purity), TEA (377.14 mg, 3.73 mmol), and (E)-4-chlorobutyric acid (89.85 mg, 745.41 μmol) in EA (1.58 mL) was stirred overnight at room temperature for 1.5 h under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reverse-phase column chromatography (C18 column) to give product 437-8 (105 mg, 155.32 μmol, 20.84% ​​yield).

[0209] Mass spectrometry: C 32 H 27 N5O4F5Cl Calculated value: 675.03 Measured value: 676.37 (M+H) + ESI.

[0210] Step 12: (E)-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(2,6-difluoro-4-(8-(4-methoxy-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(methylamino)indazine-3-carbonyl)phenyl)but-2-enamide, Example 437 A solution of 437-8 (100 mg, 147.92 μmol), 4-aminobicyclo[2.2.2]octane-1-onitrile (41.42 mg, 221.88 μmol), K3PO4 (94.20 mg, 443.77 μmol), and KI (24.56 mg, 147.92 μmol) in DMF (1 mL) was stirred overnight at room temperature. The mixture was purified by reverse-phase column (C18 column) to give product Example 437 (50 mg, yield 42.80%).

[0211] Mass spectrometry: C 41 H 40N7F5O5 Calculated value: 789.81 Measured value: 790.32 (M+H) + ESI.

[0212] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.93-9.92 (d, 1H), 9.55 (s, 1H), 7.80 (s,1H), 7.49-7.45 (m, 2H), 7.09-7.06 (m, 1H), 6.83-6.91 (m, 2H), 6.68(s, 1H),6.34-6.30 (d, 1H), 4.85-4.76 (m, 2H), 4.18 (s, 3H), 3.96 (s, 3H), 3.45 (s,3H), 3.33-3.31(m, 2H), 2.52-2.47 (m, 3H), 1.98-1.94 (m, 6H), 1.59-1.61 (m, 6H).

[0213] Synthesis of (E)-N-(2,6-difluoro-4-(9,10,12-trimethyl-7-(trifluoromethyl)-12,13,14,15-tetrahydro-9H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-2-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide, Example 441 Step 1: (8-(4-amino-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, INT 375A A solution of 5-bromo-1,2-dimethyl-6-(trifluoromethyl)benzimidazol-4-amine (9 g, 29.21 mmol), [8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazin-3-yl]-(3,4,5-trifluorophenyl)methyl ketone (17.58 g, 43.82 mmol), K3PO4 (13.37 g, 63.00 mmol), and SPhos Pd G3 (2.28 g, 2.92 mmol) in H2O (15 mL) and THF (90 mL) was stirred at 90°C for 2 hours. The mixture was diluted with EA and water, extracted with EA, washed successively with H2O and brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give INT 375A (12 g, 81.77%).

[0214] Mass spectrometry: C 25 H 16 N4OF6 Calculated value: 502.41; Measured value: 503.2 (M+H) + ESI.

[0215] Step 2: (1-amino-8-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 441-1 KNO3 (201.24 mg, 1.99 mmol) was added to a solution of INT 375A (1 g, 1.99 mmol) in 7.5 mL of H2SO4 at 0°C, and the solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice, the pH of the reaction mixture was adjusted to 8 with NaHCO3, and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was used in the next step without purification.

[0216] Mass spectrometry: C 25 H 15 N5O3F6 Calculated value: 547.41 Measured value: 548.1 (M+H) + ESI.

[0217] Step 3: (8-(1,2-dimethyl-4-(methylamino)-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-nitroindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 441-2 Methyl trifluoromethanesulfonate (1.20 g, 7.31 mmol) was added dropwise to a solution of 441-1 (4 g, 7.31 mmol) in hexafluoroisopropanol (20 mL), and the solution was stirred at room temperature for 2 hours. The concentrated crude product was purified by reverse-phase column (C18 column) to obtain product 441-2.

[0218] Mass spectrometry: C 26 H 17 N5O3F6 Calculated value: 561.43 Measured value: 562.2 (M+H) + ESI.

[0219] Step 4: (8-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-nitroindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 441-3 To a solution of 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (1.86 g, 10.69 mmol), [8-[1,2-dimethyl-4-(methylamino)-6-(trifluoromethyl)benzimidazol-5-yl]-1-nitro-indazine-3-yl]-(3,4,5-trifluorophenyl)methyl ketone (1.2 g, 2.14 mmol), trifluoroacetic acid (24.37 mg, 213.74 μmol) in THF (5 mL), NaBH3CN (470.11 mg, 7.48 mmol) and ZnCl2 (509.80 mg, 3.74 mmol) in MeOH (1 mL) were added dropwise, and the solution was stirred at room temperature for 4 hours. The reaction solution was extracted with EA and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The concentrated crude product was purified by passing it through a reverse-phase column (C18 column) to obtain product 441-3.

[0220] Mass spectrometry: C 34 H 35 N5O4F6Si Calculated value: 719.75 Measured value: 720.3 (M+H) + ESI.

[0221] Step 5: (1-amino-8-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-1,2-dimethyl-6-(trifluoromethyl)-4H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 441-1 A solution of 441-3 (1 g, 1.39 mmol) and Raney nickel (244.64 mg, 4.17 mmol) in MeOH (10 mL) was stirred at room temperature for 4 hours under H2. The filtered solution was concentrated to obtain the crude product. The crude product was used in the next step without purification.

[0222] Mass spectrometry: C 34 H 37 N5O2F6Si Calculated value: 689.76; Measured value: 690.4 (M+H) + ESI.

[0223] Step 6: (3,4,5-trifluorophenyl)(9,10,12-trimethyl-7-(trifluoromethyl)-12,13,14,15-tetrahydro-9H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]indazin-2-yl) methyl ketone, 441-5 A mixture of 441-4 (100 mg, 0.17 mmol), dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (27.69 mg, 0.03 mmol), and K₂CO₃ (24.01 mg, 0.17 mmol) in Tol (3 mL) was stirred at 110°C for 16 hours. RM was purified by reverse-phase column chromatography (C18 column) to give 441-5 (50 mg, 51.62% yield).

[0224] Mass spectrometry: C 28 H 21 F6N5O Calculated value: 557.17; Measured value: 558.2 (M+H) + ESI.

[0225] Step 7: (3,4,5-trifluorophenyl)(9,10,12-trimethyl-7-(trifluoromethyl)-12,13,14,15-tetrahydro-9H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]indazin-2-yl) methyl ketone, 441-6 A solution of 441-5 (450 mg, 781.92 μmol), K₂CO₃ (108.07 mg, 781.92 μmol), and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (124.59 mg, 156.38 μmol) in Tol (45 mL) was stirred at 110°C for 16 hours. The mixture was diluted with EA and water, extracted with EA, the organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was purified by column chromatography to give product 441-6 (320 mg, yield 73.41%).

[0226] Mass spectrometry: C 28 H 21 N5OF6 Calculated value: 557.49; Measured value: 558.1 (M+H) + ESI.

[0227] Step 8: 9,10,12-Trimethyl-2-(3,4,5-trifluorobenzoyl)-7-(trifluoromethyl)-9,12,13,14-tetrahydro-15H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-15-carboxylic acid tert-butyl ester, 441-7 A solution of 441-6 (200 mg, 358.75 μmol), TEA (181.51 mg, 1.79 mmol), and di-tert-butyl dicarbonate (391.48 mg, 1.79 mmol) in DCM (8 mL) was stirred at room temperature for 6 hours. The mixture was diluted with EA and water, extracted with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give product 441-7 (130 mg, yield 55.10%).

[0228] Mass spectrometry: C 33 H 29 N5O3F6 Calculated value: 657.60 Measured value: 658.2 (M+H) + ESI.

[0229] Step 9: 2-(4-amino-3,5-difluorobenzoyl)-9,10,12-trimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydro-15H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inzine-15-carboxylic acid tert-butyl ester, 441-8 A solution of 441-7 (120 mg, 182.48 μmol) and NaN3 (11.86 mg, 182.48 μmol) in DMA (0.5 mL) was stirred at 70°C for 3 hours. The mixture was diluted with EA and water, extracted once with EA, and the organic layer was washed with brine, dried with Na2SO4 and filtered. The solution was then concentrated under reduced pressure by RM and used without further purification.

[0230] Mass spectrometry: C 33 H 29 N8O3F5 Calculated value: 680.63 Measured value: 681.42 (M+H) + ESI.

[0231] Step 10: 2-(4-amino-3,5-difluorobenzoyl)-9,10,12-trimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydro-15H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inzine-15-carboxylic acid tert-butyl ester, 441-9 A solution of 441-8 (120 mg, 176.31 μmol) and Pd (1.88 mg, 17.63 μmol) in MeOH (5 mL) was stirred at room temperature for 6 hours under H2. The mixture was diluted with EA and water, extracted once with EA, and the organic layer was washed with brine, dried with Na2SO4 and filtered. The solution was then concentrated under reduced pressure by RM and used directly for the next step without purification.

[0232] Mass spectrometry: C 33 H 31 N6O3F5 Calculated value: 654.63 Measured value: 655.47 (M+H) + ESI.

[0233] Step 11: (E)-2-(4-(4-chlorobut-2-enamido)-3,5-difluorobenzoyl)-9,10,12-trimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydro-15H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-15-carboxylic acid tert-butyl ester, 441-10 T3P (267.34 mg, 840.17 μmol) was added to a solution of 441-9 (110 mg, 168.03 μmol), TEA (136.03 mg, 1.34 mmol), and (E)-4-chlorobut-2-enoic acid (24.30 mg, 201.64 μmol) in EA (3 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA and water, extracted once with EA, and the organic layer was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and used without purification.

[0234] Mass spectrometry: C 37 H 34 N6O4F5Cl Calculated value: 756.23 Measured value: 757.2 (M+H) + ESI.

[0235] Step 12: 2-(3,5-difluoro-4-((E)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamido)benzoyl)-9,10,12-trimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydro-15H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inzine-15-carboxylic acid tert-butyl ester, 441-11 A solution of 441-10 (120 mg, 158.49 μmol), 4-methoxycyclohexylamine (61.43 mg, 475.47 μmol), KI (131.55 mg, 792.45 μmol), and K₂CO₃ (109.52 mg, 792.45 μmol) in DMF (5 mL) was stirred at room temperature for 4 hours. The mixture was diluted with EA and water, extracted once with EA, the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used in the next step without purification.

[0236] Mass spectrometry: C 44 H 48 N7O5F5 Calculated value 849.89 Measured value 850.3 (M+H)+ ESI.

[0237] Step 13: (E)-N-(2,6-difluoro-4-(9,10,12-trimethyl-7-(trifluoromethyl)-12,13,14,15-tetrahydro-9H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-2-carbonyl)phenyl)-4-(((1r,4r)-4-methoxycyclohexyl)amino)but-2-enamide, Example 441 The solution of 441-11 (80 mg, 94.13 μmol) and TFA (10.73 mg, 94.13 μmol, 1.5 mL) in DMF (4 mL) was stirred at room temperature for 2 hours. The mixture was purified by reverse-phase column (C18 column) to give product Example 441 (27 mg, yield 38.26%).

[0238] Mass spectrometry: C 39 H 40 F5N7O3 Calculated value 749.31, measured value 748.37 [MH] - ESI.

[0239] 1 H NMR: (400 MHz, DMSO- d 6 ) δ: 10.00 (s, 1H), 9.89-9.87 (m, 1H), 7.90 (s, 1H), 7.54-7.52 (d, J=8.0 Hz , 2H), 7.17-7.13 (m, 1H), 7.07-7.03 (m, 2H), 6.89-6.85 (m, 1H), 6.37-6.33 (d, J=16.0 Hz , 1H), 3.85 (s, 3H), 3.60-3.57 (m,5H), 3.39-3.40 (m, 3H), 3.22 (s, 1H), 3.09-3.08 (m, 2H), 2.91-2.86 (m, 1H),2.80-2.77 (m, 3H), 2.62-2.42 (m, 4H), 1.98-1.89 (m, 4H), 1.12-1.07 (m, 4H).

[0240] Synthesis of (E)-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-12,13,14,15-tetrahydro-9H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-2-carbonyl)phenyl)but-2-enamide, Example 445 Step 1: N-methyl-2-nitro-5-(trifluoromethyl)aniline, 445-2 Methylamine (14.83 g, 143.21 mmol, 30% purity) was added to a solution of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (10 g, 47.82 mmol) in THF (100 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with H2O and extracted with EA. The organic layer was washed with H2O and brine. The concentrated residue was used directly.

[0241] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.33 (s, 1H), 8.25-8.23 (m, 1H), 7.22 (s, 1H), 6.95-6.92 (m, 1H), 3.01-2.99 (m, 3H).

[0242] Step 2: 4-Bromo-N-methyl-2-nitro-5-(trifluoromethyl)aniline, 445-3 Add NBS (9.78 g, 54.96 mmol) to a solution of 445-2 (11 g, 49.97 mmol) in DMA (100 mL). Stir the mixture at 50°C for 1 hour. Quench the mixture with H2O and extract with EA. Wash the organic layer with H2O and brine. Use the concentrated residue directly.

[0243] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.41 (s, 1H), 8.37 (s, 1H), 7.32 (s, 1H), 3.02-3.00 (m, 3H).

[0244] Step 3: 4-Bromo-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine, 445-4 A solution of 445-3 (14 g, 46.82 mmol), Fe (13.07 g, 234.08 mmol), and NH4Cl (12.52 g, 234.08 mmol) in a mixture of water (1.4 mL), THF (6 mL), and MeOH (6 mL) was stirred at 60°C for 2 hours. The insoluble substances were filtered off, and the solvent was then evaporated under reduced pressure. After dilution with ethyl acetate, the mixture was washed with water and a saturated sodium chloride solution, and then dried over sodium sulfate. After evaporation, the residue was purified by column chromatography to give 445-4 (11.5 g, 91.3% yield).

[0245] Mass spectrometry: C8H8BrF3N2 Calculated values ​​267.98, 269.98 Measured values ​​269.02, 270.99 (M+H) + ESI.

[0246] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 6.85 (s, 1H), 6.57 (s, 1H), 5.45 (s, 2H), 5.14-5.11 (m, 1H), 2.74-2.73 (m, 3H).

[0247] Step 4: 5-Bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole, 445-5 T3P (18.33 g, 28.8 mmol) was added to a solution of 445-4 (3.51 g, 13.05 mmol) and 2-methoxyacetic acid (1.29 g, 14.34 mmol) in DMF (8.14 mL). After stirring at room temperature for 15 minutes, triethylamine (5.22 g, 51.62 mmol, 7.2 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. The mixture was diluted with EA, washed with aqueous NaHCO3 solution, water, and NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. Acetic acid was added to the residue, and the mixture was stirred at 50°C for 2 hours. The mixture was diluted with EA, washed with aqueous NaHCO3 solution, water, and NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-5 (2.4 g, 56.94% yield).

[0248] 1 H NMR (400 MHz, DMSO- d 6) δ: 8.20 (s, 1H), 8.12 (s, 1H), 4.75 (s, 2H), 3.90 (s, 3H), 3.32 (s, 3H).

[0249] Step 5: 5-Bromo-2-(methoxymethyl)-1-methyl-4-nitro-6-(trifluoromethyl)-1H-benzo[d]imidazole, 445-6 KNO3 (234.68 mg, 2.32 mmol) was added to a mixture of 445-5 (500 mg, 1.55 mmol) in H2SO4 (5 mL) at -5°C. The mixture was stirred at -5°C for 1 hour. The mixture was quenched with H2O and extracted with EA. The organic layer was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-6 (450 mg, 79% yield).

[0250] Mass spectrometry: C 11 H9BrF3N3O3 Calculated values: 366.98, 368.98 Measured values: 368.05, 370.06 (M+H) + ESI.

[0251] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.53 (s, 1H), 4.79 (s, 2H), 3.97 (s, 3H), 3.32 (s, 3H).

[0252] Step 6: 5-Bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine, 445-7 A solution of 445-6 (400 mg, 1.9 mmol), Fe (303.42 mg, 5.43 mmol), and NH4Cl (290.63 mg, 5.43 mmol) in THF (2.3 mL), water (1.5 mL), and EtOH (5.4 mL) was stirred at 60°C for 2 hours. The insoluble substances were filtered off, and the solvent was evaporated under reduced pressure. The mixture was diluted with EA, washed with water and an aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-7 (340 mg, 92.54% yield).

[0253] Mass spectrometry: C 11 H 11BrF3N3O: Calculated values ​​337.00, 339.00; Measured values ​​338.04, 340.03 (M+H) + ESI.

[0254] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 7.37 (s, 1H), 5.88 (s, 2H), 4.71 (s, 2H), 3.82 (s, 3H), 3.34 (s, 3H).

[0255] Step 7: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-8 SPhos Pd G3 (1.38 g, 1.77 mmol) was added to a solution of [8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazin-3-yl]-(3,4,5-trifluorophenyl)methyl ketone (17.80 g, 44.36 mmol), K3PO4 (18.83 g, 88.73 mmol), and 445-7 (10 g, 29.58 mmol) in H2O (20 mL) and THF (100 mL). After stirring overnight at 100°C, the mixture was extracted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-8 (15 g, 28.17 mmol, 95.26% yield).

[0256] Mass spectrometry: C 26 H 18 N4O2F6 Calculated value: 532.44 Measured value: 533.1 (M+H) + ESI.

[0257] Step 8: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-nitroindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-9 KNO3 (3.42 g, 33.81 mmol) was added to a mixture of 445-8 (18 g, 33.81 mmol) in H2SO4 (80 mL) and stirred at -10°C for 0.5 h. The mixture was quenched with ice, and the reaction mixture was adjusted to pH 8 with aqueous NH3H2O ​​and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-9 (740 mg, 1.38 mmol, 94.29% yield).

[0258] Mass spectrometry: C 26 H 17 N5O4F6 Calculated value: 577.43 Measured value: 578.1 (M+H) + ESI.

[0259] Step 9: (8-(2-(methoxymethyl)-1-methyl-4-(methylamino)-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-nitroindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-10 Methyl trifluoromethanesulfonate (2.27 g, 13.85 mmol) was added dropwise to a solution of 445-9 (8 g, 13.85 mmol) in hexafluoroisopropanol (70 mL), and the mixture was stirred at room temperature for 4 hours. The insoluble substance was filtered off, and the solvent was evaporated under reduced pressure. The mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reverse-phase column chromatography (C18 column) to give 445-10 (1 g, 12.2% yield).

[0260] Mass spectrometry: C 27 H 19 N5O4F6 Calculated value: 591.46 Measured value: 592.2 (M+H) + ESI.

[0261] Step 10: (8-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-nitroindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-11 A mixture of 445-10 (860 mg, 1.45 mmol), 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (760.36 mg, 4.36 mmol), and TFA (16.58 mg, 145.40 μmol) in THF (10 mL) was stirred. NaBH3CN (319.81 mg, 5.09 mmol) and ZnCl2 (346.81 mg, 2.54 mmol) were added dropwise to MeOH (3 mL), and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with EA and water, extracted once with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-11 (1 g, 91.73% yield).

[0262] Mass spectrometry: C 35 H 37 N5O5F6Si Calculated value: 749.77 Measured value: 750.3 (M+H) + ESI.

[0263] Step 11: (1-amino-8-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-12 Raney nickel (78.28 mg, 1.33 mmol) was added to a solution of 445-11 (1 g, 1.33 mmol) in MeOH (1 mL). After stirring overnight at room temperature, the mixture was diluted with EA, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used for the next step without purification.

[0264] Mass spectrometry: C 35 H 39 N5O3F6Si Calculated value: 719.79 Ω·cm Measured value: 720.4 Ω·cm (M+H) + ESI.

[0265] Step 12: (1-amino-8-(4-((2-hydroxyethyl)(methyl)amino)-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-13 A solution of 445-12 (950 mg, 1.32 mmol) in DCM (4 mL) and HCl (4 M, 1 mL) was stirred at room temperature for 0.5 h. The mixture was adjusted to pH 9 with aqueous NaHCO3 solution, diluted with EA and water, extracted once with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give 445-13 (400 mg, 88.52% yield).

[0266] Mass spectrometry: C 29 H 25 N5O3F6 Calculated value: 605.53 Measured value: 606.2 (M+H) + ESI.

[0267] Step 13: (10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-12,13,14,15-tetrahydro-9H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-14 A solution of 445-13 (600 mg, 990.87 μmol), K₂CO₃ (136.94 mg, 990.87 μmol), and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (157.88 mg, 198.17 μmol) in Tol (60 mL) was stirred at 110°C for 16 hours. The mixture was diluted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-14 (450 mg, 765.94 μmol, 77.30% yield).

[0268] Mass spectrometry: C 29 H 23 N5O2F6 Calculated value: 587.51 Measured value: 588.2 (M+H) + ESI.

[0269] Step 14: (1-amino-8-(4-((2-hydroxyethyl)(methyl)amino)-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-15 A solution of 445-14 (250 mg, 319.14 μmol), TEA (161.47 mg, 1.60 mmol, 222.56 μL), and di-tert-butyl dicarbonate (348.26 mg, 1.60 mmol) in DCM (4.78 mL) was stirred at room temperature for 3 hours. The mixture was adjusted to pH 9 with aqueous NaHCO3 solution, diluted with EA and water, extracted once with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used in the next step without purification.

[0270] Mass spectrometry: C 34 H 31 N5O4F6 Calculated value: 687.64 Measured value: 688.2 (M+H) + ESI.

[0271] Step 15: 2-(4-azido-3,5-difluorobenzoyl)-10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydro-15H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-15-carboxylic acid tert-butyl ester, 445-16 A solution of 445-15 (170 mg, 222.50 μmol) and NaN3 (14.46 mg, 222.50 μmol) in DMA (5 mL) was stirred at 80°C for 3 hours. The mixture was diluted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used in the next step without purification.

[0272] Mass spectrometry: C 34 H 31 N8O4F5 Calculated value: 710.65 Measured value: 711.3 (M+H) + ESI.

[0273] Step 16: 2-(4-amino-3,5-difluorobenzoyl)-10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydro-15H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-15-carboxylic acid tert-butyl ester, 445-17 A solution of 445-16 (150 mg, 189.97 μmol) and Pd (10.11 mg, 94.98 μmol) in MeOH (5 mL) was stirred at room temperature for 3 hours under a H2 atmosphere. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-17 (80 mg, 61.51% yield).

[0274] Mass spectrometry: C 30 H 27 N6O2F5 Calculated value: 684.65 Measured value: 685.4 (M+H) + ESI.

[0275] Step 17: (E)-2-(4-(4-chlorobut-2-enamido)-3,5-difluorobenzoyl)-10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydro-15H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-15-carboxylic acid tert-butyl ester, 445-18 T3P (74.36 mg, 116.85 μmol, 50% purity) was added dropwise to a solution of 445-17 (80 mg, 116.85 μmol), (E)-4-chlorobut-2-enoic acid (16.90 mg, 140.22 μmol), and TEA (94.59 mg, 934.78 μmol, 130.38 μL) in EA (3 mL), and the solution was stirred at room temperature for 1 hour. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used for the next step without purification.

[0276] Mass spectrometry: C 38 H 36 N6O5F5Cl Calculated value: 787.17 Measured value: 788.32 (M+H) + ESI.

[0277] Step 18: (E)-4-chloro-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12,15-trimethyl-7-(trifluoromethyl)-12,13,14,15-tetrahydro-9H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-2-carbonyl)phenyl)but-2-enamide, 445-19 A solution of 445-18 (70 mg, 88.93 μmol), 4-aminobicyclo[2.2.2]octane-1-nitrile hydrochloride (83.00 mg, 444.63 μmol), K₂CO₃ (61.45 mg, 444.63 μmol), and KI (73.81 mg, 444.63 μmol) in DMF (3 mL) was stirred at 33°C for 4 hours. The mixture was diluted with EA and water, extracted once with EA, and the organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated under reduced pressure, and used without further purification.

[0278] Mass spectrometry: C 47 H 49 N8O5F5 Calculated value: 900.93 Measured value: 901.4 (M+H) + ESI.

[0279] Step 19: (E)-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-12,13,14,15-tetrahydro-9H-imidazo[4'',5'':3',4']benzo[1',2':8,9][1,4]diazanonocyclo[7,6,5-hi]inazine-2-carbonyl)phenyl)but-2-enamide, Example 445 A solution of 445-19 (70 mg, 77.70 μmol) in TFA (8.86 mg, 77.70 μmol, 1 mL) and DCM (2 mL) was stirred at 20°C for 1 hour. The mixture was diluted with EA and water, extracted once with EA, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by passing it through a reversed-phase column (C18 column) to give product Example 445 (15 mg, yield 24.11%).

[0280] Mass spectrometry: C 42 H 41 N8O3F5 Calculated value: 800.82 Measured value: 801.57 (M+H) + ESI.

[0281] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.85-9.83 (m, 1H), 7.94 (s, 1H), 7.50 (d,2H, J=8 Hz), 7.15-7.06 (m, 1H), 7.05 (s, 2H), 6.85-6.82 (m, 1H), 6.32-6.28(d, 1H, J =16 Hz), 4.75 (s, 2H), 3.89 (s, 3H), 3.60-3.56 (m, 1H), 3.35 (s,3H), 3.27 (m, 2H), 2.53 (s, 3H), 1.92(m, 6H), 1.55 (m, 6H).

[0282] The racemic mixtures were purified by chiral SFC on a Chiralpak AD-3 50×4.6mm ID, 3µm column (using 40% isopropanol (0.05% diisopropylethylamine) as mobile phase B) to obtain iso 1 and iso 2 in Example 445. With a flow rate of 3 mL / min, the retention times of isoform 1 and isoform 2 were found to be 1.169 min and 2.898 min, respectively.

[0283] Synthesis Example 440 ISO 1 440-INT-ISO-1 and ISO-2 (E)-4-(((1r,4r)-4-cyanocyclohexyl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide Step 1: N -Methyl-2-nitro-5-(trifluoromethyl)aniline, 440-INT-02 Methylamine (14.8 g, 143 mmol, 30% purity) was added to a solution of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (10.0 g, 47.8 mmol) in tetrahydrofuran (100 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with H2O and extracted with ethyl acetate. The organic layer was washed with H2O and brine. The concentrated residue was used directly in subsequent steps.

[0284] 1 H NMR (400 MHz, DMSO- d 6) δ: 8.33 (s, 1H), 8.25-8.23 (m, 1H), 7.22 (s, 1H), 6.95-6.92 (m, 1H), 3.01-2.99 (m, 3H).

[0285] Step 2: 4-Bromo- N -Methyl-2-nitro-5-(trifluoromethyl)aniline, 440-INT-03 To N-methyl-2-nitro-5-(trifluoromethyl)aniline (11.0 g, 49.9 mmol) in N,N Add to the solution of dimethylacetamide (100 mL) N - Bromosuccinimide (9.78 g, 54.9 mmol). The mixture was stirred at 50°C for 1 hour. The mixture was quenched with H2O and extracted with ethyl acetate. The organic layer was washed with H2O and brine. The concentrated residue was used directly for subsequent steps.

[0286] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.41 (s, 1H), 8.37 (s, 1H), 7.32 (s, 1H), 3.02-3.00 (m, 3H).

[0287] Step 3: 4-Bromo-N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine, 440-INT-04 A solution of 4-bromo-N-methyl-2-nitro-5-(trifluoromethyl)aniline (14.0 g, 46.8 mmol), Fe (13.1 g, 234 mmol), and NH4Cl (12.5 g, 234 mmol) in a mixture of water (1.4 mL), tetrahydrofuran (6 mL), and methanol (6 mL) was stirred at 60°C for 2 hours. The insoluble matter was filtered off, and the solvent was then evaporated under reduced pressure. After dilution with ethyl acetate, the mixture was washed with water and a saturated sodium chloride solution, and then dried over sodium sulfate. After evaporation, the residue obtained was purified by silica gel column chromatography to give 4-bromo- N 1-Methyl-5-(trifluoromethyl)benzene-1,2-diamine (11.5 g, yield 91.3%).

[0288] Mass spectrometry: C8H8BrF3N2 Calculated values ​​267.98, 269.98 Measured values ​​269.02, 270.99 (M+H) + ESI.

[0289] 1H NMR (400 MHz, DMSO- d 6 ) δ: 6.85 (s, 1H), 6.57 (s, 1H), 5.45 (s, 2H), 5.14-5.11 (m, 1H), 2.74-2.73 (m, 3H).

[0290] Step 4: 5-Bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole, 440-INT-05 T3P (18.33 g, 28.8 mmol) was added to 4-bromo-N1-methyl-5-(trifluoromethyl)phenyl-1,2-diamine (3.51 g, 13.1 mmol) and 2-methoxyacetic acid (1.29 g, 14.3 mmol) in... N,N The mixture was added to a solution of dimethylformamide (8.14 mL). After stirring at room temperature for 15 minutes, triethylamine (5.22 g, 51.62 mmol, 7.2 mL) was added to the reaction mixture and stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with aqueous NaHCO3 solution, water and NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. Acetic acid was added to the residue and then stirred at 50°C for 2 hours. The mixture was diluted with ethyl acetate, washed with aqueous NaHCO3 solution, water and NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography to give 5-bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (2.4 g, yield 56.94%).

[0291] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.20 (s, 1H), 8.12 (s, 1H), 4.75 (s, 2H), 3.90 (s, 3H), 3.32 (s, 3H).

[0292] Step 5: 5-Bromo-2-(methoxymethyl)-1-methyl-4-nitro-6-(trifluoromethyl)-1H-benzo[d]imidazole, 440-INT-06 KNO3 (235 mg, 2.32 mmol) was added to a mixture of 5-bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (500 mg, 1.55 mmol) in H2SO4 (5 mL) at -5°C. The mixture was stirred at -5°C for 1 hour. The mixture was quenched with H2O and extracted with ethyl acetate. The organic layer was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 5-bromo-2-(methoxymethyl)-1-methyl-4-nitro-6-(trifluoromethyl)-1H-benzo[d]imidazole (450 mg, 79% yield).

[0293] Mass spectrometry: C 11 H9BrF3N3O3 Calculated values: 366.98, 368.98 Measured values: 368.05, 370.06 (M+H) + ESI.

[0294] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 8.53 (s, 1H), 4.79 (s, 2H), 3.97 (s, 3H), 3.32 (s, 3H).

[0295] Step 6: 5-Bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine, 440-INT-07 A solution of 5-bromo-2-(methoxymethyl)-1-methyl-4-nitro-6-(trifluoromethyl)-1H-benzo[d]imidazole (400 mg, 1.9 mmol), Fe (303.42 mg, 5.43 mmol), and NH4Cl (290.63 mg, 5.43 mmol) in tetrahydrofuran (2.3 mL), water (1.5 mL), and ethanol (5.4 mL) was stirred at 60°C for 2 hours. The insoluble matter was filtered off, and the solvent was evaporated under reduced pressure. The mixture was diluted with ethyl acetate, washed with water and an aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 5-bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole-4-amine (340 mg, 92.5% yield).

[0296] Mass spectrometry: C 11 H 11BrF3N3O: Calculated values ​​337.00, 339.00; Measured values ​​338.04, 340.03 (M+H) + ESI.

[0297] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 7.37 (s, 1H), 5.88 (s, 2H), 4.71 (s, 2H), 3.82 (s, 3H), 3.34 (s, 3H).

[0298] Step 7: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) ketone, 440-INT-08 A solution of 5-bromo-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine (62.0 g, 183 mmol), [8-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)indazin-3-yl]-(3,4,5-trifluorophenyl)methyl ketone (110 g, 275 mmol), SPhos Pd G3 (14.3 g, 18.3 mmol), and K3PO4 (117 g, 550 mmol) in water (100 mL) and 1,4-dioxane (500 mL) was evacuated and refilled with N2, then heated to 80 °C overnight. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzi[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone (97.0 g, 182 mmol, yield 99.4%).

[0299] Mass spectrometry: C 26 H 18 F6N4O2 Calculated value: 532.13 Measured value: 533.16 (M+H) + ESI.

[0300] 1 H NMR (400 MHz, DMSO- d 6) δ: 9.89-9.87 (m, 1H), 7.71-7.67 (m, 2H), 7.39-7.37 (m, 1H), 7.35 (s, 1H), 7.29-7.25 (m, 2H), 6.04-6.03 (m, 1H), 5.13(s, 2H), 4.73 (s, 2H), 3.87 (s, 3H), 3.35 (s, 3H).

[0301] Step 8: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-iodoinzidazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 440-INT-09 NIS (36.13 g, 160.58 mmol) was added to a solution of (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl)methyl ketone (90.0 g, 169 mmol) in acetic acid (38.6 g, 338 mmol, 25.9 mL) and tetrahydrofuran (450 mL). After stirring at room temperature for 4 hours, the mixture was diluted with ethyl acetate, washed with aqueous NaHCO3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-iodoinzidazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone (111 g, 169 mmol, yield 99.75%).

[0302] Mass spectrometry: C 26 H 17 F6IN4O2 Calculated value: 658.03 Measured value: 659.13 (M+H) + ESI.

[0303] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.99-9.97 (m, 1H), 7.70-7.67 (m, 2H), 7.55 (s, 1H), 7.35 (s, 1H), 7.31-7.28 (m, 1H), 7.24-7.22 (m, 1H), 5.13 (s, 2H), 4.78-4.67 (m, 2H), 3.87 (s, 3H), 3.37 (s, 3H).

[0304] Step 9: ( E )-(8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(2-ethoxyvinyl)inzin-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 440-INT-10 (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzi[d]imidazol-5-yl)-1-iodoinzi-3-yl)(3,4,5-trifluorophenyl) methyl ketone (100 g, 152 mmol), ( E A solution of 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (60.2 g, 304 mmol), tetra(triphenylphosphine)palladium (8.78 g, 7.59 mmol), and Na₂CO₃ (32.2 g, 304 mmol) in water (100 mL) and 1,4-dioxane (500 mL) was evacuated and refilled with N₂, then heated to 100°C for 10 hours. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain ( E )-(8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(2-ethoxyvinyl)inzin-3-yl)(3,4,5-trifluorophenyl) methyl ketone (80.0 g, 133 mmol, yield 87.4%).

[0305] Mass spectrometry: C 30 H 24 F6N4O3 Calculated value: 602.18 Measured value: 603.28 (M+H) + ESI.

[0306] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.89-9.87 (m, 1H), 7.70-7.56 (m, 3H), 7.39 (d, J=8.4 Hz , 2H), 7.19-7.15 (m, 2H), 6.87-6.84 (m, 1H), 5.12 (s, 2H), 4.79-4.70 (m, 2H), 3.89 (s, 3H), 0.84-0.81 (m, 3H).

[0307] Step 10: (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 440-INT-11 Add NaBH(OAc)3 (84.42 g, 398.32 mmol) to ( E 3,4,5-Trifluorophenyl) methyl ketone (80.0 g, 133 mmol) and trifluoroacetic acid (242 g, 2.12 mol, 163 mL) were mixed in a solution of dichloromethane (850 mL). The mixture was stirred at room temperature for 3 hours. The mixture was quenched with aqueous NaHCO3 and 5 M NaOH solutions and diluted with dichloromethane. The organic layer was washed with brine and then dried with Na2SO4. The residue was purified by column chromatography to give (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (300 mg, yield 81%).

[0308] Mass spectrometry: C 28 H 20 F6N4O2 Calculated value 558.15, measured value 559.2 (M+H) + ESI.

[0309] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.89-9.87 (m, 1H), 8.01 (s, 1H), 7.74-7.70 (m, 2H), 7.29 (s, 1H), 7.22-7.18 (m, 1H), 7.11-7.10 (m, 1H), 4.79-4.76(m, 2H), 4.48 (s, 1H), 3.94 (s, 3H), 3.75-3.74 (m, 4H), 2.99-2.93 (m, 1H), 2.61-2.58 (m, 1H), 2.31-1.29 (m, 1H).

[0310] Step 11: (10-(methoxymethyl)-9-methyl-12-(methyl-d3)-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 440-INT-12 (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (20.0 g, 35.8 mmol) was dissolved in... N,N - Dimethylformamide (200 mL). Add K₂CO₃ (9.90 g, 71.6 mmol) and CD₃I (6.23 g, 43.0 mmol) to dimethylformamide (200 mL). N,N The solution was prepared in dimethylformamide (10 mL) and stirred at 30°C for 2 hours. The mixture was quenched with water and concentrated under reduced pressure to give crude (10-(methoxymethyl)-9-methyl-12-(methyl-d3)-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (15.0 g, 26.1 mmol, yield 72.8%).

[0311] Mass spectrometry: C 29 H 19 N4O2F6D3 Calculated value 575.18 Measured value 576.1 (M+H) + ESI.

[0312] Step 12: (10-(methoxymethyl)-9-methyl-12-(methyl-d3)-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 440-INT-13 (10.0 g, 17.4 mmol) of (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (50 mL) was suspended in 1,4-dioxane. Then, NH3•H2O (50 mL) was added and the solution was stirred overnight at 130 °C. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, filtered, and the reaction mixture was concentrated under reduced pressure and used without purification.

[0313] Mass spectrometry: C 29 H 21 N5O2F5D3 Calculated value 572.20 Measured value 573.3 (M+H) + ESI.

[0314] Step 13: (10-(methoxymethyl)-9-methyl-12-(methyl-d3)-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 440-INT-ISO-1 and 440-INT-ISO-2 (104 g) was separated by SFC to obtain 440-INT-ISO-1 (44.2 g, RT=2.720 min) and 440-INT-ISO-2 (47.6 g, RT=3.222 min).

[0315] Preparative separation methods: Instrument: Thar 350 preparative SFC (SFC-23); Column: ChiralPak AD, 300×50 mm ID, 10µm; Mobile phase: A is CO2 and B isopropanol; Gradient: B 40%; Flow rate: 200 mL / min; Back pressure: 100 bar; Column temperature: 38℃; Wavelength: 340 nm; Cycle time: ~5 min 440-INT-ISO-1 Mass spectrometry: C 29 H 21 N5O2F5D3 Calculated value 572.20 Measured value 573.3 (M+H) + ESI.

[0316] 440-INT-ISO-2 Mass spectrometry: C29 H 21 N5O2F5D3 Calculated value 572.20 Measured value 573.2 (M+H) + ESI.

[0317] (E)-4-(((1r,4r)-4-cyanocyclohexyl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9-methyl-12-(methyl-d3)-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinnozo[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide (Example 440 ISO 1) Step 1: (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 440-1 Dissolve (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone 440-INT-ISO 01 (0.300 g, 537 μmol) in... N,N- Dimethylformamide (7 mL) was added and stirred at 0 °C for 20 minutes. NaH (38.7 mg, 1.61 mmol) was slowly added to the mixture and stirred at 0 °C for 30 minutes. CD3I (77.9 mg, 537 μmol) was then added to the solution. N,N- The solution was prepared in dimethylformamide (3 mL) and stirred at room temperature for 10 hours. The mixture was diluted with dichloromethane and water, extracted once with dichloromethane, the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (100 mg, yield 28.8%).

[0318] Mass spectrometry: C 29 H 19N4O2F6D3 Calculated value 575.52 Measured value 576.1 (M+H) + ESI.

[0319] Step 2: (10-(methoxymethyl)-9-methyl-12-(methyl-d3)-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 440-2 (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (110 mg, 191 μmol) was suspended in 1,4-dioxane (30 mL). Then, 30% NH3 aqueous solution (30 mL) was added and the solution was stirred overnight at 130 °C. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, the organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure to give (10-(methoxymethyl)-9-methyl-12-(methyl-d3)-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone as a crude residue, which could be used without further purification.

[0320] Mass spectrometry: C 29 H 21 N5O2F5D3 Calculated value: 572.54 Measured value: 573.3 (M+H) + ESI.

[0321] Step 3: ( E )-5-chloro-1-(4-(12-cyclopropyl-9,10-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)-2,6-difluorophenyl)pent-3-en-2-one, 440-3 Prepare (10-(methoxymethyl)-9-methyl-12-(methyl-d3)-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (62.0 mg, 108 μmol) and ( E A solution of 4-chlorobut-2-enoic acid (17.0 mg, 141 μmol) was prepared. Then, propylphosphonic anhydride (138 mg, 217 μmol, 50% purity) and triethylamine (32.87 mg, 324.87 μmol, 45.31 μL) were added to the mixture and stirred at room temperature for 0.5 hours. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain (…). E )-5-chloro-1-(4-(12-cyclopropyl-9,10-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)-2,6-difluorophenyl)pent-3-en-2-one, which can be used without purification.

[0322] Mass spectrometry: C 33 H 24 N5O3F5ClD3 Calculated value: 675.06 ohms Measured value: 673.2 ohms - ESI.

[0323] Step 4: ( E )-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(4-(12-cyclopropyl-9,10-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)-2,6-difluorophenyl)but-2-enamide, Example 440 ISO 1 4-Aminocyclohexane-1-nitrile (CAS: 873651-89-9) (25.8 mg, 207 μmol) and K2CO3 (43.0 mg, 311 μmol) were prepared in... N,N- The solution of dimethylformamide (2 mL) was stirred at room temperature for 10 minutes. Then ( E)-5-chloro-1-(4-(12-cyclopropyl-9,10-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)-2,6-difluorophenyl)pent-3-en-2-one (70.0 mg, 104 μmol) and KI (33.6 mg, 0.200 mmol) were reacted and the mixture was stirred at 40 °C for 3 hours. The mixture was diluted with ethyl acetate and water, extracted once with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase column chromatography (C18 column) to give the product ( E )-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(4-(12-cyclopropyl-9,10-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinnozo[4,5,6-hi]indazine-2-carbonyl)-2,6-difluorophenyl)but-2-enamide (22 mg, yield 27.81%).

[0324] Mass spectrometry: C 40 H 35 D3F5N7O3 Calculated value: 762.3 Measured value: 763.48 (M+H) + ESI.

[0325] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.99 (s, 1H), 9.87-9.85 (m, 1H), 8.13 (s,1H), 7.57 (m, 2H), 7.29 (s, 1H), 7.18-7.15 (m, 1H), 7.07-7.05 (m, 1H), 6.89-6.86 (m, 1H), 6.36-6.32 (m, 1H), 4.79-4.78 (m, 2H), 3.95 (s, 3H), 3.40-3.33(m, 3H), 2.86-2.83 (m, 1H), 2.70-2.63 (m, 2H), 2.45 (s, 1H), 2.09-2.08 (m,1H), 2.04-1.87 (m, 5H), 1.52-1.46 (m, 2H), 1.21-1.04 (m, 2H).

[0326] Synthesis Example 804-ISO 1 (E)-4-(tert-butyl(methyl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-enamide, Step 1: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 445-8 A mixture of 445-7 (8.8 g, 26.03 mmol), [8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazin-3-yl]-(3,4,5-trifluorophenyl)methyl ketone (13.57 g, 33.83 mmol), tripotassium orthophosphate (16.57 g, 78.08 mmol), and SPhox G3 Pd (2.03 g, 2.60 mmol) in 1,4-dioxane (200 mL) and water (40 mL) was stirred at 80 °C for 6 hours under a nitrogen atmosphere. The mixture was quenched with an aqueous solution of NH4Cl. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 445-8 (11.2 g, yield 80.82%).

[0327] Mass spectrometry: C 26 H 18 F6O2N4 Calculated value: 532.13 Measured value: 533.24 (M+H) + ESI.

[0328] Step 2: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-iodoinzidazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 804-1 A mixture of 445-8 (10 g, 18.78 mmol), THF (239.23 mL), TFA (5.35 g, 46.95 mmol, 3.59 mL), and NIS (3.93 g, 17.47 mmol) was stirred at room temperature for 5 hours. The mixture was quenched with saturated NaHCO3 solution. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give 804-1 (10.6 g, 85.73% yield).

[0329] Mass spectrometry: C 26 H 17 N4O2F6I Calculated value: 658.03 Measured value: 659.06 (M+H) + ESI.

[0330] Step 3: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 804-2 A solution of 804-1 (10.6 g, 16.10 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxoborane (12.36 g, 96.61 mmol, 14.05 mL), SPhos Pd G3 (1.01 g, 1.29 mmol), triethylamine (9.78 g, 96.61 mmol, 13.47 mL), and 1,4-dioxane (240 mL) was stirred at 95 °C for 2 hours under a nitrogen atmosphere. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give 804-2 (8.1 g, 76.41% yield).

[0331] Mass spectrometry: C 32 H 29 N4O4F6B Calculated value: 658.22 Measured value: 659.31 (M+H) + ESI.

[0332] Step 4: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-hydroxyindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 804-3 A solution of 804-2 (8.1 g, 12.30 mmol), THF (87.70 mL), NaOH (0.5 M, 49.21 mL), and H2O2 (2.09 g, 61.51 mmol) was stirred at room temperature for 1 hour. Sodium hyposulfite (1 M, 12.30 mL) was added and stirred for 10 minutes. The mixture was adjusted to pH 7 with dilute sulfuric acid. The mixture was diluted with EA and water and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (DCM:MeOH = 98:2) to give 804-3 (6 g, 88.93% yield).

[0333] Mass spectrometry: C 26 H 18 N4O3F6 Calculated value 548.13 Measured value 549.20 (M+H) + ESI.

[0334] Step 5: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-(2-bromoethoxy)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 804-4 A solution of 804-3 (6 g, 10.94 mmol), K2CO3 (7.56 g, 54.7 mmol), 1,2-dibromoethane (16.44 g, 87.52 mmol, 7.54 mL), and DMF (100 mL) was stirred overnight at 50 °C. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (DCM:MeOH = 98:2) to give 804-4 (5 g, 69.73% yield).

[0335] Mass spectrometry: C 28 H 21 N4O3F6Br Calculated value: 654.07 Measured value: 655.1 (M+H) + ESI.

[0336] Step 6: (10-(methoxymethyl)-9-methyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 804-5 A solution of 804-4 (5.4 g, 8.24 mmol), DMF (100 mL), K2CO3 (3.99 g, 28.84 mmol), NaI (1.24 g, 8.24 mmol), and KI (1.37 g, 8.24 mmol) was stirred at 90 °C for 6 hours. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (DCM:MeOH = 98:2) to give 804-5 (4 g, 84.51% yield).

[0337] Mass spectrometry: C 28 H 20 N4O3F6 Calculated value 574.14 Measured value 575.26 (M+H) + ESI.

[0338] Step 7: (10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inzin-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 804-6 804-5 (4 g, 6.96 mmol), formaldehyde (2.09 g, 69.63 mmol), and TFA (1.59 g, 13.93 mmol) were dissolved in THF (60 mL). A solution of sodium cyanoborohydride (875.10 mg, 13.93 mmol) and ZnCl2 (1.71 g, 12.53 mmol) in MeOH (15 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After quenching with aqueous NaHCO3 solution, the mixture was diluted with EA and water and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (DCM:MeOH = 98:2) to give 804-6 (3.7 g, 90.30% yield).

[0339] Mass spectrometry: C 29 H 22 N4O3F6 Calculated value 588.16, measured value 589.2 (M+H) + ESI.

[0340] Step 8: (4-azido-3,5-difluorophenyl)(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inzin-2-yl) methyl ketone, 804-7 A mixture of 804-6 (3.7 g, 6.29 mmol), DMF (60 mL), and NaN3 (531.35 mg, 8.17 mmol) was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give residue 804-7. The residue was used for the next step without purification.

[0341] Mass spectrometry: C 29 H 22 N7O3F5 Calculated value: 611.17 Measured value: 612.2 (M+H) + ESI.

[0342] Step 9: (4-Amino-3,5-Difluorophenyl)(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]indazine-2-yl) methyl ketone, 804-8-ISO 1 A mixture of 804-7 (3.8 g, 6.21 mmol), MeOH (50 mL), and Pd / C (377.36 mg, 3.11 mmol) was stirred at room temperature for 2 hours under a H2 atmosphere. The mixture was filtered through diatomaceous earth and washed with DCM. The organic layer was concentrated under reduced pressure to obtain the residue. The residue was purified by chiral column chromatography to give 804-8-ISO 1 800 mg and 804-8-ISO 2 810 mg.

[0343] Preparation and separation methods: Column: CHIRALPAK IB Column dimensions: 0.46cm × 25cm × 5µm Mobile phase: A: 0.01M CH3COONH4 B: ACN B: 0min(5%)-25min(95%)-25.1min(5%)-30min(5%) Flow rate: 1 mL / min Wavelength: UV 254 nm Temperature: 25 °C HPLC equipment: Shimadzu LC-20 Mass spectrometry: C 29 H 24 N5O3F5 Calculated value: 585.18 Measured value: 586.2 (M+H) + ESI.

[0344] Step 10: (E)-4-chloro-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-enamide, 804-9-ISO 1 804-8-ISO 1 (50 mg, 85.39 μmol) and (E)-4-chlorobutyric acid (12.35 mg, 102.47 μmol) were dissolved in EA (2 mL). After cooling to 0 °C, TEA (86.41 mg, 853.94 μmol, 119.10 μL) and T4P (307.64 mg, 853.94 μmol) were added. The reaction mixture was stirred for 2 hours. The mixture was diluted with EA and water and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 804-9-ISO 1 (56 mg, 95.31% yield).

[0345] Mass spectrometry: C 33 H 27 N5O4F5Cl Calculated value: 687.17 Measured value: 688.2 (M+H) + ESI.

[0346] Step 11: (E)-4-(tert-butyl(methyl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-enamide, Example 804-ISO 1 A mixture of 804-9-ISO 1 (56 mg, 81.39 μmol), DMF (5 mL), N-tert-butylmethylamine (21.28 mg, 244.17 μmol), KI (13.51 mg, 81.39 μmol), and K3PO4 (34.55 mg, 162.78 μmol) was stirred overnight at room temperature. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give Example 804-ISO 1 (12 mg, yield 19.96%).

[0347] Mass spectrometry: C 38 H 39 N6O4F5 Calculated value: 738.74 Measured value: 739.43 (M+H) + ESI.

[0348] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.84-9.82 (m, 1H), 7.97 (s, 1H), 7.51-7.49 (m, 2H), 7.20-7.12 (m, 3H), 6.84-6.77 (m, 1H), 6.34-6.30 (m, 1H), 4.75(s, 2H), 3.95-3.94 (m, 1H), 3.92 (s, 3H), 3.75-3.72 (m, 1H), 3.66-3.60 (m,1H), 3.35 (s, 3H), 3.18-3.16 (m, 2H), 3.13-3.08 (m, 1H), 2.06 (s, 3H), 1.01 (s, 9H).

[0349] Synthetic Example 804 - ISO 2 (E)-4-(tert-butyl(methyl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-enamide, Step 1: (E)-4-chloro-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-enamide, 804-9-ISO 2 804-8-ISO 2 (60 mg, 102.47 μmol) and (E)-4-chlorobutyric acid (14.82 mg, 122.97 μmol) were dissolved in EA (3.86 mL). After cooling to 0 °C, TEA (103.69 mg, 1.02 mmol, 142.92 μL) and T4P (369.17 mg, 1.02 mmol) were added. The reaction mixture was stirred for 2 hours. The mixture was diluted with EA and water and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give 804-9-ISO 2 (58 mg, 82.26% yield).

[0350] Mass spectrometry: C 33 H 27 N5O4F5Cl Calculated value: 687.17 Measured value: 688.2 (M+H) + ESI.

[0351] Step 2: (E)-4-(tert-butyl(methyl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-enamide, Example 804-ISO 2 A mixture of 804-9-ISO 2 (58 mg, 84.30 μmol), DMF (5 mL), N-tert-butylmethylamine (22.04 mg, 252.89 μmol), KI (13.99 mg, 84.30 μmol), and K3PO4 (35.79 mg, 168.59 μmol) was stirred overnight at room temperature. The mixture was diluted with EA and water, and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give Example 804-ISO 2 (12 mg, yield 19.96%).

[0352] Mass spectrometry: C38 H 39 N6O4F5 Calculated value: 738.74 Measured value: 739.30 (M+H) + ESI.

[0353] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 10.00 (s, 1H), 9.88-9.87 (m, 1H), 8.02(s, 1H), 7.56-7.54 (m, 2H), 7.22-7.13 (m, 3H), 6.84-6.77 (m, 1H), 6.38-6.34(m, 1H), 4.78 (s, 2H), 4.00-3.98 (m, 1H), 3.93 (s, 3H), 3.80-3.74 (m, 1H), 3.69-3.63 (m, 1H), 3.38 (s, 3H), 3.19-3.11 (m, 3H), 2.16 (s, 3H), 1.01 (s, 9H).

[0354] Synthesis Example 805 ( E )-4-(((4-cyano-2-oxabicyclo[2.1.1]hexane-1-yl)methyl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazononocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-eneamide Will( E)-4-chloro-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazanonocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-enamide (804-9-ISO 2) (31 mg, 45 μmol), dimethyl sulfoxide (0.450 mL), 1-(aminomethyl)-2-oxabicyclo[2.1.1]hexane-4-onitrile (CAS: 2247107-84-0) (13 mg, 90 μmol), KI (11 mg, 68 μmol), and DIPEA (35 mg, 47 µL, 270 mL). The mixture (μmol) was stirred overnight at 45°C for 16 hours. The crude reaction mixture was purified by C18 column chromatography to obtain ( E )-4-(((4-cyano-2-oxabicyclo[2.1.1]hexane-1-yl)methyl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazononocyclo[7,8,9-hi]inazine-2-carbonyl)phenyl)but-2-enamide (Example 805) (32.9 mg, 91% yield).

[0355] Mass spectrometry: C 40 H 36 F5N7O5 Calculated value: 805.79; Measured value: 806.7 (M+H) + ESI.

[0356] 1 H NMR (400 MHz, CDCl3) δ: 9.98-9.96 (m, 1H), 7.68 (s, 1H), 7.44-7.42(m, 2H), 7.17-7.15 (m, 1H), 7.09-6.98 (m, 3H), 6.25-6.21 (m, 1H), 5.30 (s,2H), 4.81 (s, 2H), 4.06-3.81 (s, 9H), 3.51 (m, 1H), 3.45 (s, 3H), 3.20-3.13(m, 1H), 2.61 (s, 2H), 2.22 (m, 1H), 2.02 (m, 1H), 1.27 (4H, bs) Synthesis Example 806 ( E)-4-((3-cyclopropyloxetane-3-yl)amino)- N -(2,6-Difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazononocyclo[7,8,9- hi Indazine-2-carbonyl)phenyl)but-2-eneamide ( E )-4-((3-cyclopropyloxetane-3-yl)amino)- N -(2,6-Difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(trifluoromethyl)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':5,6][1,4]oxazononocyclo[7,8,9- hi Indazine-2-carbonyl)phenyl)but-2-enamide (Example 806) KI (8.87 mg, 53.41 μmol, 2.84 μL) was added to a solution of 804-9-Iso 2 (35.61 μmol) in DMSO (316.03 μL), followed by 3-cyclopropyloxetane-3-amine hydrochloride (806-1, CAS:2127832-65-7) (6.04 mg, 40.40 μmol), and finally DIPEA (27.61 mg, 213.65 μmol, 37.21 μL). The reaction mixture was heated to 45°C and stirred at that temperature overnight (16 h). The reaction solution was cooled to room temperature, and a saturated aqueous solution of NaHCO3 (3 mL) was added. The mixture was extracted with EtOAc (3 x 3 mL), the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to give crude oil. The crude material was purified by preparative HPLC (Agilent Infinity LabPoroshell 120 4 HPH-C18, 21.2 x 150 mm, 5-95% MeCN + 0.1% FA in H2O) to obtain Example 806 (12.20 mg, 15.95 μmol, yield 44.80%). The product was further purified by LCMS and... 1 ¹H NMR is used to characterize the properties and purity of substances.

[0357] LCMS (ESI-TOF) (m / z): [M+H] + C 39 H 38N6O5F5, calculated value 765; measured value 765.

[0358] 1 H NMR (400 MHz, CDCl3, ): 9.97 (d, J = 6.8 Hz, 1H), 7.68 (s, 1H),7.46 7.41 (m, 2H), 7.22 7.11 (m, 3H), 7.07 6.99 (m, 2H), 6.32 (app d, J = 15.4 Hz, 1H), 4.82 (s, 2H), 4.44 (d, J = 6.5 Hz, 2H), 4.29 (d, J = 6.6Hz, 2H), 4.06 3.98 (m, 1H), 3.96 3.89 (m, 4H), 3.87 3.78 (m, 1H), 3.63 3.60 (m, 2H), 3.45 (s, 3H), 3.21 3.12 (m, 1H), 2.62 (s, 3H), 1.08 0.99 (m, 1H), 0.69 0.60 (m, 2H), 0.52 0.44 (m, 2H).

[0359] Synthesis Example 578 (E)-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide Step 1: (3,5-Difluoro-2-nitrophenyl)carbamate, 578-2 3,5-Difluoro-2-nitroaniline (CAS: 364-30-7) (50.0 g, 287 mmol) was added to a solution of NaH (17.2 g, 430 mmol, 60% purity) in tetrahydrofuran (600 mL), and the mixture was stirred at 0°C for 1 hour. Benzyl chloroformate (53.9 g, 316 mmol) was added to the solution at 0°C and stirred at room temperature. The mixture was diluted with ethyl acetate and water, and the organic layers were separated. The aqueous layer was extracted with ethyl acetate more than twice. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reverse-phase column chromatography (C18 column) to give the product (3,5-difluoro-2-nitrophenyl)carbamate (61.3 g, 69.3%).

[0360] Mass spectrometry: C 14 H 10 N₂F₂O₄ Calculated value: 308.06 mmol / L Measured value: 307.0 mmol / L (MH) - ESI.

[0361] Step 2: (5-fluoro-3-(methylamino)-2-nitrophenyl)carbamate, 578-3 A solution of (3,5-difluoro-2-nitrophenyl)carbamate (61.3 g, 198.87 mmol), tetrahydrofuran (600 mL), and methylamine (41.18 g, 397.75 mmol) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was then purified by column chromatography to give (5-fluoro-3-(methylamino)-2-nitrophenyl)carbamate (55.6 g, 87.6% yield).

[0362] Mass spectrometry: C 15 H 14 Calculated value of FN3O4: 319.10; Measured value: 318.0 (MH) - ESI.

[0363] Step 3: (3-(methylamino)-5-(methylthio)-2-nitrophenyl)carbamate, 578-4 (5-fluoro-3-(methylamino)-2-nitrophenyl)carbamate (31.0 g, 97.1 mmol) and NaSMe (20.4 g, 291 mmol) were mixed in... N,NA solution of dimethylformamide (30 mL) was stirred at room temperature for 2 hours. The mixture was poured into ice water and stirred for 5 minutes, then filtered to obtain a solid. The solid was poured into DMF and water, stirred for 5 minutes, filtered, and dried to obtain a crude product, which was used in subsequent steps.

[0364] Mass spectrometry: C 16 H 17 SN3O4 calculated value 347.09, measured value 348.1 (M+H) + ESI.

[0365] Step 4: ( E )-(8-(4-(2-methoxyvinyl)-1,2-dimethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-1-nitroindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 578-5 (3-(methylamino)-5-(methylthio)-2-nitrophenyl)carbamate (49.6 g, 143 mmol) and N-bromosuccinimide (22.9 g, 129 mmol) were mixed in... N,N The solution in dimethylformamide (150 mL) was stirred at room temperature for 1 hour. The mixture was quenched with an aqueous solution of Na₂S₂O₃, water was added, and the solution was filtered. The residue was collected and dried to give a crude product, which was used in subsequent steps.

[0366] Mass spectrometry: C 16 H 16 BrSN3O4 Calculated value 425.00 Ω, Measured value 423.9 Ω (MH) - ESI.

[0367] Step 5: (2-Amino-6-bromo-3-(methylamino)-5-(methylthio)phenyl)carbamate, 578-6 In an N2 atmosphere, ( E A solution of 3,4,5-trifluorophenyl) methyl ketone (30.0 g, 70.4 mmol), Fe (19.7 g, 352 mmol), and NH4Cl (18.8 g, 352 mmol) in tetrahydrofuran (30 mL), MeOH (30 mL), and H2O (15 mL) was stirred at 68°C for 5 hours. The mixture was filtered and the residue was washed three times with ethyl acetate. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried over Na2SO4, concentrated under vacuum, and dissolved in isopropyl ether to give a crude product as a solution.

[0368] Mass spectrometry: C 16 H 18 Calculated value of N3O2BrS: 395.03; Measured value: 396.0 (M+H) + ESI.

[0369] Step 6: (2-bromo-6-(2-methoxyacetamido)-5-(methylamino)-3-(methylthio)phenyl)carbamate, 578-7 A solution of (2-amino-6-bromo-3-(methylamino)-5-(methylthio)phenyl)carbamate (25.0 g, 63.1 mmol) and 2-methoxyacetic acid (6.25 g, 69.4 mmol) in ethyl acetate (0.8 mL) was stirred. 3-[2,6,8-trioxo-9-[(2R,3R,4R)-2,3,4,5-tetrahydroxypentyl]-3H-purine-7-yl]propyl dihydrogen phosphate (50.0 g, 139 mmol) and triethylamine (25.5 g, 252 mmol) were added to the mixture and stirred for 30 minutes. The mixture was diluted with dichloromethane and H₂O, and the organic phase was separated. The organic phase was washed with brine, dried over Na₂SO₄, concentrated under vacuum, and suspended in isopropyl ether. Filtration yielded a crude residue, which was used in subsequent steps.

[0370] Mass spectrometry: C 19 H 22 N3SBrO3 Calculated value: 467.05 Ω·cm Measured value: 468.1 Ω·cm (M+H) + ESI.

[0371] Step 7: (5-bromo-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzo[d]imidazol-4-yl)carbamate, 578-8 A solution of (2-bromo-6-(2-methoxyacetamyl)-5-(methylamino)-3-(methylthio)phenyl)carbamate (21.0 g, 44.8 mmol) in AcOH (90 mL) was stirred at 50 °C for 1 hour. The mixture was adjusted to pH 9 with an aqueous solution of NaHCO3. The mixture was diluted with ice water and extracted with dichloromethane. The organic phase was dried over Na2SO4, concentrated under vacuum, rapidly stirred with isopropyl ether, and filtered to give a crude product, which was used in subsequent steps.

[0372] Mass spectrometry: C 19 H 20 N3SBrO3 Calculated value: 449.04 Measured value: 450.0 (M+H) + ESI.

[0373] Step 8: (2-(methoxymethyl)-1-methyl-6-(methylthio)-5-(3-(3,4,5-trifluorobenzoyl)indazin-8-yl)-1H-benzo[d]imidazol-4-yl)carbamate, 578-9 A solution of (8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazin-3-yl)(3,4,5-trifluorophenyl) methyl ketone (5.00 g, 11.1 mmol), (5-bromo-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzis[d]imidazol-4-yl)carbamate (6.68 g, 16.7 mmol), RuPhos Pd G3 (929 mg, 1.11 mmol), and K3PO4 (3.54 g, 16.7 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) was degassed three times with N2 and stirred at 85°C for 2 hours. The mixture was diluted with H2O and extracted twice with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and then concentrated under reduced pressure to give the residue. The residue was purified by column chromatography to give (2-(methoxymethyl)-1-methyl-6-(methylthio)-5-(3-(3,4,5-trifluorobenzoyl)inzidin-8-yl)-1H-benzo[d]imidazol-4-yl)carbamate (5.60 g, yield 78.3%).

[0374] Mass spectrometry: C 34 H 27 Calculated value of N4O4SF3: 644.17; Measured value: 645.1 (M+H) + ESI.

[0375] Step 9: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 578-10 A solution of (2-(methoxymethyl)-1-methyl-6-(methylthio)-5-(3-(3,4,5-trifluorobenzoyl)indazin-8-yl)-1H-benzo[d]imidazol-4-yl)carbamate (160 mg, 248 μmol) and TfOH (10.7 g, 71.2 mmol) in acetonitrile (200 mL) was stirred at room temperature for 5 hours. The mixture was adjusted to pH 9 with aqueous NaHCO3 solution. The mixture was diluted with EA and water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was rapidly stirred with isopropyl ether and filtered to give a crude product, which was used in subsequent steps.

[0376] Mass spectrometry: C 26 H 21 Calculated value of N4O2SF3: 510.13; Measured value: 511.1 (M+H) + ESI.

[0377] Step 10: (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzo[d]imidazol-5-yl)-1-iodoinzidazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 578-11 A solution of (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone (3.00 g, 5.88 mmol) in tetrahydrofuran (30 mL) was stirred at 0°C for 5 minutes. N Iodosuccinimide (1.32 g, 5.88 mmol) and trifluoroacetic acid (1.34 g, 11.8 mmol) were added to the mixture and stirred for 1 hour. The mixture was adjusted to pH 9 with aqueous NaHCO3 solution. The mixture was quenched with aqueous Na2S2O3 solution, extracted with ethyl acetate, and the organic phases were combined and concentrated under vacuum to give a crude product. The residue was purified by column chromatography to give (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzo[d]imidazol-5-yl)-1-iodoinziazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone (1.48 g, 49.3% yield).

[0378] Mass spectrometry: C 26 H 20 N4O2SIF3 Calculated value: 636.03 Measured value: 637.1 (M+H) + ESI.

[0379] Step 11: ( E )-(8-(4-amino-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzo[d]imidazol-5-yl)-1-(2-ethoxyvinyl)inzin-3-yl)(3,4,5-trifluorophenyl) methyl ketone, 578-12 A mixture of (8-(4-amino-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzi[d]imidazol-5-yl)-1-iodoinziazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone (500 mg, 785 μmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentane (466.82 mg, 2.36 mmol), Pd(dppf)Cl2 (115 mg, 157 μmol), K3PO4 (333 mg, 1.57 mmol), 1,4-dioxane (45 mL), and H2O (4.5 mL) was stirred at 85 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the crude product. The residue was purified by passing it through a reverse-phase column (C18 column) to obtain ( E )-(8-(4-amino-2-(methoxymethyl)-1-methyl-6-(methylthio)-1H-benzo[d]imidazol-5-yl)-1-(2-ethoxyvinyl)inzin-3-yl)(3,4,5-trifluorophenyl) methyl ketone.

[0380] Mass spectrometry: C 30 H 27 Calculated value of N4O3SF3: 580.18; Measured value: 581.1 (M+H) + ESI.

[0381] Step 12: (10-(methoxymethyl)-9-methyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 578-13 Will( E A solution of 3,4,5-trifluorophenyl) methyl ketone (490 mg, 844 μmol) and NaBH(OAc)3 (894 mg, 4.22 mmol) in DCM (10 mL) and trifluoroacetic acid (1.44 g, 12.66 mmol) was stirred at room temperature for 5 minutes. The mixture was diluted with H2O and extracted twice with ethyl acetate. The organic phase was dried over Na2SO4, concentrated under reduced pressure, and then used for the next step.

[0382] Mass spectrometry: C 28 H 23N4O2SF3 Calculated value 536.15 Measured value 537.0 (M+H) + ESI.

[0383] Step 13: (10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 578-14 A solution of (10-(methoxymethyl)-9-methyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinzo[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (322 mg, 600.11 μmol), formaldehyde (180 mg g, 6.00 mmol), and trifluoroacetic acid (0.137 g, 0.120 mmol) was dissolved in tetrahydrofuran (6 mL). A solution of sodium cyanoborohydride (75.0 mg, 1.20 mmol) and ZnCl2 (163 mg, 1.20 mmol) in methanol (1.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After quenching with aqueous NaHCO3 solution, the mixture was diluted with EA and water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (DCM:MeOH=98:2) to give (10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (301 mg, 91% yield).

[0384] Mass spectrometry: C 29 H 25 N4O2SF3 Calculated value 550.17, measured value 551.1 (M+H) + ESI.

[0385] Step 14: (4-Amino-3,5-Difluorophenyl)(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl) methyl ketone, 578-15 A solution of (10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (300 mg, 545 μmol), 1,4-dioxane (15 mL), and NH3•H2O (188 mg, 5.37 mmol) in pyridine (1 mL) was stirred overnight at 130°C. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted multiple times with ethyl acetate, the organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The crude residue was used in the next step without purification.

[0386] Mass spectrometry: C 29 H 27 Calculated value of N5O2SF2: 547.19; Measured value: 548.2 (M+H) + ESI.

[0387] Step 15: ( E )-4-chloro-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide, 578-16 Phosphorus oxychloride (146 mg, 953 μmol) was added to (4-amino-3,5-difluorophenyl)(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl) methyl ketone (261 mg, 476 μmol) and ( E4-Chlorobut-2-enoic acid (68.94 mg, 571.93 μmol) was added to a solution of pyridine (6 mL), and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was poured into an aqueous solution of NaHCO3, diluted with H2O, and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum to give the crude product. The residue was purified by reversed-phase column chromatography (C18 column) to give (E)-4-chloro-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide (160 mg, yield 51.6%).

[0388] Mass spectrometry: C 33 H 30 N5O3SF2Cl Calculated value: 649.17 Measured value: 650.2 (M+H) + ESI.

[0389] Step 16: ( E )-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide, Example 578 Will( E )-4-chloro-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide (75.0 mg, 115 μmol), 4-aminobicyclo[2.2.2]octane-1-onitrile (CAS: 135908-50-8) (17.3 mg, 115 μmol) and potassium iodide (57.5 mg, 346 μmol) in N,N- The solution of dimethylformamide (5 mL) was stirred at 40 °C for another 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic phase was washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain the crude product. The residue was purified by reversed-phase column chromatography (C18 column) to obtain the product (…). E)-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinnozo[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide (54.1 mg, 34.1%).

[0390] Step 17: Will( E )-4-((4-cyanobicyclo[2.2.2]octane-1-yl)amino)-N-(2,6-difluoro-4-(10-(methoxymethyl)-9,12-dimethyl-7-(methylthio)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-carbonyl)phenyl)but-2-enamide (Example 578) (54.10 mg) was separated by SFC to give 578 iso 1 (21 mg) and 578 iso 2 (23 mg). The retention time of 578 iso 1 was 2.06 min and the retention time of 578 iso 2 was 2.96 min.

[0391] Preparative separation method: Instrument: WATERS 150 preparative SFC (SFC-26), Column: ChiralCel OJ, 250×30mm ID, 10µm, Mobile phase: A is CO2 and B is ethanol (0.1% NH3H2O), Gradient: B 35%, Flow rate: 120 mL / min, Back pressure: 100 bar, Column temperature: 38℃, Wavelength: 220nm 578 ISO 1: Mass spectrometry: C 42 H 43 F2N7O3S Calculated value: 763.31 Measured value: 764.3 ESI (M+H) + ESI.

[0392] 1 H NMR (400 MHz, DMSO- d 6) δ: 9.982-9.961 (m, 1H), 9.870-9.853 (m, 1H), 7.539-7.519 (m, 2H), 7.451 (s, 1H), 7.286-7.258 (m, 2H), 7.171-7.136 (m, 1H),6.893-6.854 (m, 1H), 6.338 (d, J =15.6 Hz, 1H), 4.712 (s, 2H), 3.864 (s, 3H), 3.283-3.275 (m, 6H), 2.999 (s, 3H), 2.825-2.758 (m, 1H), 2.681-2.644 (m, 1H), 2.418 (s, 3H), 2.186-2.115 (m, 1H), 1.952-1.913 (m, 6H), 1.558-1.518 (m, 6H).

[0393] 578 ISO 2: Mass spectrometry: C 42 H 43 F2N7O3S Calculated value: 763.31 Measured value: 764.4 ESI (M+H) + ESI.

[0394] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 9.983-9.961 (m, 1H), 9.872-9.852 (m, 1H), 7.538-7.518 (m, 2H), 7.451 (s, 1H), 7.285-7.257 (m, 2H), 7.171-7.136 (m, 1H),6.905-6.842 (m, 1H), 6.338 (d, J =15.2 Hz, 1H), 4.711 (s, 3H), 3.864 (s, 3H), 3.283-3.274 (m, 5H), 2.999 (s, 3H), 2.824-2.735 (m, 1H), 2.681-2.645 (m, 1H), 2.418 (s, 3H), 2.184-2.115 (m, 1H), 1.952-1.921 (m, 6H), 1.558-1.518 (m, 6H).

[0395] Synthesis Example 402-INT Step 1: 5-Bromo-3-fluoro-N-methyl-2-nitroaniline, 402-2 A mixture of 5-bromo-1,3-difluoro-2-nitrobenzene (CAS: 147808-42-2) (25.0 g, 105 mmol), methylamine HCl salt (7.12 g, 105 mmol), and Cs₂CO₃ (103 g, 316 mmol) in tetrahydrofuran (250 mL) was stirred at 25°C for 2 days under a nitrogen atmosphere. The suspension was separated with water (100 mL), and the aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 5-bromo-3-fluoro-N-methyl-2-nitrobenzene (23 g, 88% yield).

[0396] Mass spectrometry: C7H6BrFN2O2 Calculated value 247.96 Measured value 248.9 (M+H) + ESI.

[0397] Step 2: 5-Cyclopropyl-3-fluoro-N-methyl-2-nitroaniline, 402-3 A solution of 5-bromo-3-fluoro-N-methyl-2-nitroaniline (23.0 g, 92.4 mmol), cyclopropylboronic acid (23.8 g, 277 mmol), K3PO4 (58.8 g, 277 mmol), and Pd(dppf)Cl2 (6.70 g, 9.24 mmol) in 1,4-dioxane (200 mL) and H2O (20 mL) was stirred at 110 °C for 2 h under a nitrogen atmosphere. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (with a gradient of 10% ethyl acetate in dichloromethane) to give 5-cyclopropyl-3-fluoro-N-methyl-2-nitroaniline (16 g, 82% yield) as a yellow solid.

[0398] Mass spectrometry: C 10 H 11 Calculated value of FN2O2: 210.08; Measured value: 211.0 (M+H) + ESI.

[0399] Step 3: 4-Bromo-5-cyclopropyl-3-fluoro-N-methyl-2-nitroaniline, 402-4 5-Cyclopropyl-3-fluoro-N-methyl-2-nitroaniline (16.0 g, 76.2 mmol) was stirred under a nitrogen atmosphere at 0 °C. N,N Add to the solution of dimethylformamide (100 mL) N - Bromosuccinimide (13.6 g, 76.2 mmol). The reaction mixture was heated to room temperature and stirred at 25 °C for 4 hours. The suspension was partitioned between an aqueous solution of NaHCO3 (100 mL) and ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (with a gradient of 10% ethyl acetate in dichloromethane) to give 4-bromo-5-cyclopropyl-3-fluoro-N-methyl-2-nitroaniline (18 g, 82% yield) as a brown solid.

[0400] Mass spectrometry: C 10 H 10 Calculated value of BrFN2O2: 287.99; Measured value: 288.8 (M+H) + ESI.

[0401] Step 4: 4-Bromo-5-cyclopropyl- N 3 , N 3 -bis(2,4-dimethoxybenzyl)- N 1 -Methyl-2-nitrobenzene-1,3-diamine 402-5 Diisopropylethylamine (10.8 g, 83.3 mmol) was added to a solution of 4-bromo-5-cyclopropyl-3-fluoro-N-methyl-2-nitroaniline (8.00 g, 27.8 mmol) in ethanol (80 mL) at 25°C. N -(2,4-Dimethoxybenzyl)-1-(2,5-Dimethoxyphenyl)methylamine (CAS: 20781-23-1) (17.61 g, 55.56 mmol). The mixture was stirred at 80°C for 16 hours. The mixture was cooled to room temperature, diluted with water (80 mL), and extracted with dichloromethane (3 * 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (with a gradient of 10% ethyl acetate in petroleum ether) to give the compound 5-bromo-5-cyclopropyl- as a brown solid. N 3 , N 3 -bis(2,4-dimethoxybenzyl)- N 11,3-Methyl-2-nitrobenzene-1,3-diamine (4.35 g, yield: 27%).

[0402] Mass spectrometry: C 28 H 32 BrN3O6 Calculated value 585.15, measured value 586.2 (M+H) + ESI.

[0403] Step 5: 4-Bromo-5-cyclopropyl-N 3 N 3 -bis(2,4-dimethoxybenzyl)-N1-methylbenzyl-1,2,3-triamine-4-bromo-5-cyclopropyl-N3,N3-bis(2,4-dimethoxybenzyl)-N 1 -Methylbenzene-1,2,3-triamine 402-6 At 25°C under a nitrogen atmosphere, the 4-bromo-5-cyclopropyl group was subjected to oxidation. N 3 , N 3 -bis(2,4-dimethoxybenzyl)- N 1 4-Methyl-2-nitrobenzene-1,3-diamine (4.35 g, 7.42 mmol) was dissolved in methanol (80 mL) with NiCl2 (2.87 g, 22.6 mmol) and NaBH4 (1.41 g, 37.1 mmol). The mixture was stirred at 60°C for 2 hours. The mixture was quenched with water (50 mL) and then extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the compound 4-bromo-5-cyclopropyl- (a brown solid). N 3 , N 3 -bis(2,4-dimethoxybenzyl)- N 1 -Methylbenzene-1,2,3-triamine (4 g, crude).

[0404] Mass spectrometry: C 28 H 34 Calculated value of BrN3O4: 555.17; Measured value: 556.2 (M+H) + ESI.

[0405] Step 6: 5-Bromo-6-cyclopropyl- N , N -bis(2,4-dimethoxybenzyl)-1,2-dimethyl-1H-benzo[d]imidazol-4-amine 402-7 At 25°C under a nitrogen atmosphere, the 4-bromo-5-cyclopropyl group was subjected to oxidation. N3 , N 3 -bis(2,4-dimethoxybenzyl)- N 1 A mixture of 1,2,3-methylbenzene-1,2,3-triamine (4.0 g, 7.2 mmol) and 1,1,1-trimethoxytrimethoxy (12.9 g, 108 mmol) was added with HCl (26 mg, 0.72 mmol). The mixture was stirred at 25°C for 3 hours. The pH of the mixture was adjusted to 8 with an aqueous solution of NaHCO3. The mixture was then diluted with ethyl acetate (100 mL) and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (with a gradient of 10% ethyl acetate in petroleum ether) to give the compound 5-bromo-6-cyclopropyl- as a yellow solid. N , N -bis(2,4-dimethoxybenzyl)-1,2-dimethyl-1H-benzo[d]imidazol-4-amine (3.85 g, yield: 92%).

[0406] Mass spectrometry: C 30 H 34 Calculated value of BrN3O4: 579.17; Measured value: 580.2 (M+H) + ESI.

[0407] Step 7: 5-Bromo-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-4-amine 402-8 5-bromo-6-cyclopropyl- N , N 5-Bis(2,4-dimethoxybenzyl)-1,2-dimethyl-1H-benzo[d]imidazol-4-amine (3.85 g, 6.64 mmol) was dissolved in TFA (34.0 mL, 445 mmol) and stirred at 50°C for 2 hours. The mixture was evaporated under reduced pressure and then poured into water (30 mL). The pH was adjusted to pH=9 with a saturated aqueous solution of NaHCO3. The mixture was then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and filtered. The organic layer was evaporated to give 5-bromo-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-4-amine (2.1 g, crude) as a gray solid.

[0408] Mass spectrometry: C 12 H 14 Calculated value of BrN3: 279.04; Measured value: 280.0 (M+H) + ESI.

[0409] Step 8: (8-(4-amino-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl)methyl ketone 402-9 K3PO4 (2.36 g, 11.25 mmol) and SPhos Pd G3 (656 mg, 0.75 mmol) were added to a solution of 5-bromo-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-4-amine (2.1 g, 7.5 mmol), (8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)indazine-3-yl)(3,4,5-trifluorophenyl)methyl ketone (3 g, 7.5 mmol) in tetrahydrofuran (20 mL) and H2O (2 mL) at 25°C under a nitrogen atmosphere. The mixture was stirred at 75°C for 3 hours. The mixture was cooled, diluted with water (20 mL), and then extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain (8-(4-amino-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone (1.5 g, yield 42%), a yellow solid.

[0410] Mass spectrometry: C 27 H 21 F3N4O Calculated value: 474.17 Measured value: 475.2 (M+H) + ESI.

[0411] Step 9: (8-(4-amino-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-iodoindazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone 402-10 Concentrated HCl (227 mg, 6.32 mmol) was added to a solution of (8-(4-amino-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)indazine-3-yl)(3,4,5-trifluorophenyl)methyl ketone (1.50 g, 3.16 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 25°C for 10 minutes. After 10 minutes, the solution was slowly added at 0°C. N- Iodosuccinimide (711 mg, 3.16 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (10 mL), extracted with EtOAc (3 * 10 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give the compound (8-(4-amino-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-iodoinziazine-3-yl)(3,4,5-trifluorophenyl) methyl ketone (1.35 g, yield: 71%) as a brown solid.

[0412] Mass spectrometry: C 27 H 20 F3IN4O Calculated value: 600.06; Measured value: 601.2 (M+H) + ESI.

[0413] Step 10: ( E )-(8-(4-amino-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2-ethoxyvinyl)inzin-3-yl)(3,4,5-trifluorophenyl)methyl ketone 402-11 A solution of (8-(4-amino-6-cyclopropyl-1,2-dimethyl-1H-benzi[d]imidazol-5-yl)-1-iodoinziazin-3-yl)(3,4,5-trifluorophenyl) methyl ketone (1.35 g, 2.25 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronacecyclopentane (534 mg, 2.70 mmol), and Na₂CO₃ (477 mg, 4.5 mmol) in dioxane (15 mL) and H₂O (1.5 mL) was stirred under nitrogen at 25 °C. Pd(PPh₃)₄ (265 mg, 0.23 mmol) was added, and the reaction mixture was stirred at 95 °C for 3 hours under N₂. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 * 10 mL). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (in heptane with 10% ethyl acetate) to give a compound as a brown solid. E )-(8-(4-amino-6-cyclopropyl-1,2-dimethyl-1H-benzo[d]imidazol-5-yl)-1-(2-ethoxyvinyl)inzin-3-yl)(3,4,5-trifluorophenyl) methyl ketone (1.00 g, 82% yield).

[0414] Mass spectrometry: C 31 H 27F3N4O2 Calculated value: 544.21; Measured value: 545.3 (M+H) + ESI.

[0415] Step 11: (7-Cyclopropyl-9,10-dimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone 402-12 At 25°C ( E 3,4,5-Trifluorophenyl) methyl ketone (1.00 g, 1.84 mmol) was dissolved in dichloromethane (10 mL) with sodium triacetoxyborohydride (334 mg, 3.68 mmol) and trifluoroacetic acid (1.22 mL, 15.8 mmol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (with a gradient of 10% ethyl acetate in DCM) to give a brown solid (7-cyclopropyl-9,10-dimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (620 mg, 67% yield).

[0416] Mass spectrometry: C 29 H 23 F3N4O Calculated value: 500.18 Measured value: 501.2 (M+H) + ESI.

[0417] Step 12: (7-Cyclopropyl-9,10,12-Trimethyl-9,12,13,14-Tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl)methyl ketone 402-13 A solution of compound (7-cyclopropyl-9,10-dimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (400 mg, 0.780 mmol) and formaldehyde (632 mg, 7.80 mmol, 37% aqueous solution) in tetrahydrofuran (10 mL) was added to a solution of sodium cyanoborohydride (193 mg, 3.12 mmol) and ZnCl2 (212 mg, 1.66 mmol) in methanol (10 mL). The mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 * 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (with a gradient of 5% ethyl acetate in dichloromethane) to give a brown solid (7-cyclopropyl-9,10,12-trimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (240 mg, 58% yield). MS: m / z = 515.3 (M+ 1, ESI+).

[0418] Mass spectrometry: C 30 H 25 F3N4O Calculated value: 514.20 Measured value: 515.3 (M+H) + ESI.

[0419] Step 13: (7-Cyclopropyl-9,10,12-Trimethyl-9,12,13,14-Tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl)methyl ketone 402-14 (7-Cyclopropyl-9,10,12-trimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxindo[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (240 mg, 0.470 mmol) and NaN3 (122 mg, 1.88 mmol) were heated under N2. N,N-The solution in dimethylacetamide (2 mL) was stirred at 80°C for 4 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (5 mL) and extracted with ethyl acetate (3 * 5 mL). The combined organic phases were washed with water (20 mL), dried over Na2SO4, filtered, and concentrated to give a brown solid (7-cyclopropyl-9,10,12-trimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (240 mg, crude), MS: m / z = 538.3 (M+ 1, ESI+).

[0420] Mass spectrometry: C 30 H 25 F2N7O calculated value 537.21, measured value 538.3 (M+H) + ESI.

[0421] Step 14: (4-Amino-3,5-Difluorophenyl)(7-Cyclopropyl-9,10,12-Trimethyl-9,12,13,14-Tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)Methyl ketone 402-15 A solution of (7-cyclopropyl-9,10,12-trimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxindo[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (240 mg, 0.450 mmol) and Pd / C (240 mg) in MeOH (2 mL) was stirred at 25°C for 2 hours under H2 atmosphere. The reaction mixture was filtered and concentrated to give the compound (4-amino-3,5-difluorophenyl)(7-cyclopropyl-9,10,12-trimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl) methyl ketone (220 mg, crude).

[0422] Mass spectrometry: C 30 H 25 F2N5O calculated value 511.22, measured value 512.3 (M+H) + ESI.

[0423] Step 15: (4-Amino-3,5-Difluorophenyl)(7-Cyclopropyl-9,10,12-Trimethyl-9,12,13,14-Tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazin-2-yl) methyl ketone (1.30 g) was separated by SFC to yield 402-INT-ISO 1 (647 mg, RT=3.725 min) and 402-INT-ISO 2 (585 mg, RT=4.007 min).

[0424] Preparation and separation methods: Instruments: WATERS 150 preparative SFC (SFC-26); Column: ChiralPak AD, 250×30mm ID, 10µm; Mobile phase: A is CO2 and B isopropanol; Gradient: B 30%; Flow rate: 120 mL / min; Back pressure: 100 bar Column temperature: 38 ℃; Wavelength: 220 nm; Cycle time: ~8 min 402-INT-ISO 1: Mass spectrometry: C 30 H 25 F2N5O calculated value 511.22, measured value 512.3 (M+H) + ESI.

[0425] 402-INT-ISO 1: Mass spectrometry: C 30 H 25 F2N5O calculated value 511.22, measured value 512.3 (M+H) + ESI.

[0426] Synthesize 402-d3-INT-01 and 402-d3-INT-02 (4-Amino-3,5-Difluorophenyl)(7-Cyclopropyl-9,10-Dimethyl-12-(Methyl-d3)-9,12,13,14-Tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)methyl ketone Step 1: (7-Cyclopropyl-9,10-dimethyl-12-(methyl-d3)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone, 402-d3-1 (7-Cyclopropyl-9,10-dimethyl-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxindo[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone 402-12 (1.20 g, 2.40 mmol) and K2CO3 (994.06 mg, 7.19 mmol) were dissolved in... N,N - Dimethylformamide (20 mL). After degassing three times with N2, CD3I (347.54 mg, 2.40 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and then concentrated under reduced pressure to give the crude residue (7-cyclopropyl-9,10-dimethyl-12-(methyl-d3)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinnozo[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone. The residue was used in the next step without purification.

[0427] Mass spectrometry: C 30 H 22 N4F3OD3 Calculated value: 517.22 Measured value: 518.2 (M+H) + ESI.

[0428] Step 2: (4-azido-3,5-difluorophenyl)(7-cyclopropyl-9,10-dimethyl-12-(methyl-d3)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazin-2-yl) methyl ketone, 402-d3-2 (7-Cyclopropyl-9,10-dimethyl-12-(methyl-d3)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxindo[4,5,6-hi]indazine-2-yl)(3,4,5-trifluorophenyl) methyl ketone (1.80 g, 3.48 mmol) and NaN3 (497.41 mg, 7.65 mmol) were dissolved in... N,N-The mixture was stirred in dimethylacetamide (20 mL) at 80 °C for 2 hours. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and then concentrated under reduced pressure to give (4-azido-3,5-difluorophenyl)(7-cyclopropyl-9,10-dimethyl-12-(methyl-d3)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazine-2-yl) methyl ketone as the crude residue. The residue was used in the next step without purification.

[0429] Mass spectrometry: C 30 H 22 N7F2OD3 Calculated value: 540.23 Measured value: 541.3 (M+H) + ESI.

[0430] Step 3: (4-Amino-3,5-Difluorophenyl)(7-Cyclopropyl-9,10-Dimethyl-12-(Methyl-d3)-9,12,13,14-Tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazin-2-yl) methyl ketone, 402-d3-3 (4-Azide-3,5-difluorophenyl)(7-cyclopropyl-9,10-dimethyl-12-(methyl-d3)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinnozo[4,5,6-hi]indazin-2-yl) methyl ketone (1.80 g, 3.33 mmol) and Pd / CaCO3 (688 mg, 3.33 mmol) were dissolved in methanol (40 mL). After degassing with H2 six times, the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give (4-amino-3,5-difluorophenyl)(7-cyclopropyl-9,10-dimethyl-12-(methyl-d3)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazin-2-yl) methyl ketone (1.70 g, crude).

[0431] Step 4: (4-amino-3,5-difluorophenyl)(7-cyclopropyl-9,10-dimethyl-12-(methyl-d3)-9,12,13,14-tetrahydroimidazo[4'',5'':5',6']benzo[1',2':2,3]acoxinno[4,5,6-hi]indazin-2-yl) methyl ketone was separated by SFC to obtain 402-d3-INT-01 (850 mg, RT=3.317 min) and 402-d3-INT-02 (850 mg, RT=4.102 min).

[0432] Preparation and separation methods: Instrument: WATERS 150 preparative SFC (SFC-26); Column: ChiralPak IG, 250×30mm ID, 10µm; Mobile phase: A is CO2 and B is ethanol; Gradient: B 40%; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: 38℃; Wavelength: 220nm; Cycle time: ~4.5 min; 402-d3-INT-01 Mass spectrometry: C 30 H 24 N5F2OD3 Calculated value: 514.24 Measured value: 515.3 (M+H) + ESI.

[0433] 402-d3-INT-02 Mass spectrometry: C 30 H 24 N5F2OD3 Calculated value: 514.24 Measured value: 515.3 (M+H) + ESI.

[0434] The compounds in the table below were synthesized using a route similar to that used in the examples above. The compounds in the table below were synthesized using a route similar to that used in the examples above. The compounds in the table below were synthesized using a route similar to that used in the examples above. Biological assay Biological Experiment 1: KRas G12C or WT isothermal titration calorimetry (ITC) combined with determination Experimental Procedure Prepare 1 L of ITC buffer (50 mM Hepes pH 7.4, 100 mM NaCl, 1 mM TCEP, 5 mM MgCl2, 0.05% Tween 20) and sterilize by filtration using a 0.22 µm top filter. Concentrate the purified KRas G12C or WT to 1 mM using a centrifuge and dialyze thoroughly overnight at room temperature with ITC buffer. After dialyzing, degas 100 mL of ITC buffer and store it for compound dilution, ITC baseline estimation, and rinsing of the ITC cell. All ITC experiments were performed at 20°C using a MicroCal PEAQ-ITC instrument (Malvern Panalytical Inc.) with ITC buffer containing 4% DMSO.

[0435] All compounds were prepared as 10 mM stock solutions in DMSO and then diluted 100-fold in ITC buffer. 1 mM KRas G12C or WT was titrated in a syringe to 50–100 μM of the compound in the measuring cell. Typically, in a single titration, 19 injections of 2 µL each were performed after an initial injection of 0.4 µL, with 150-second intervals between injections. The syringe was stirred at a constant speed of 750 rpm during equilibration and experimentation. The resulting thermograms were analyzed using MicroCal PEAQ-ITC analysis software V.1.40. The binding isotherms were fitted to a standard one-set-of-sites model.

[0436] Conclusion: The compounds of the present invention exhibit a strong binding affinity for human KRas G12C protein.

[0437] Biological Example 2: TR-FRET determination of the interaction between Raf1 Ras-binding domain (RBD) and KRas due to the cleavage of the compound of the present invention (TR-FRET of Raf1 cleavage) Materials and reagents His-labeled recombinant human KRAS G12C / G12C (aa 1-164, His-labeled N-terminus, loaded with GppNHp, prepared internally) FLAG-labeled recombinant human Raf1 Ras-binding domain (aa 54-131, FLAG-labeled C-terminus, prepared internally) LANCE test buffer (10x) (PerkinElmer, CAT#CR97-100) Eu-W1024-labeled anti-6xHis antibody (PerkinElmer, CAT#AD0401) Anti-FLAG IgG conjugated with SureLight-allophycocyanin (PerkinElmer, CAT#AD0059F) GppNHP (non-hydrolyzable GTP analogue) (Abcam, CAT#ab146659) Bovine serum albumin heat shock component (Sigma-Aldrich, CAT#A9647-100G) DMSO (Thermo Fisher Scientific) Compound in DMSO - 10 mM stock solution Victor Nivo Multi-Mode Board Reader (PerkinElmer) OptiPlate-384, white opaque 384-well microplate (PerkinElmer) Experimental Procedure Time-resolved fluorescence resonance energy transfer (TR-FRET) was used to determine the disruption of Raf1-KRAS protein-protein binding induced by the tested compounds. The assay buffer contained 1X LANCE assay buffer supplemented with 5 mM MgCl2, 10 µM GppNHp, and 2.5 µg / mL BSA. His-KRas (loaded with GppNHp) was pre-incubated with a series of 4-fold dilutions of the compound, starting at a final concentration of 10 μM. After 1 hour of incubation at room temperature, mixtures of FLAG-RAF1RBD, anti-His Eu-W1024, and anti-FLAG allophycocyanin were added to the assay wells at final concentrations of 50 nM, 2 nM, and 100 nM, respectively. The reactants were then incubated at room temperature for another 20 hours (for covalent compounds). The TR-FRET signal was read on a plate reader with excitation at 340 nm and detection at 615 nm and 665 nm. The cleavage curves were fitted using sigmoid dose-response curves with a variable slope model in GraphPad Prism. Compounds promoting the cleavage of the Raf1-KRas complex were identified as those inducing a decreased TR-FRET ratio relative to the DMSO control well, IC50. 50 The value (nM) is shown in Table 1 below.

[0438] Table 1 Biological Example 3. Pharmacokinetic Studies in Mice The compounds of the examples were administered orally to SPF-grade Balb / c mice as a suspension in water containing 0.5% MC + 0.5% Tween 80. Plasma samples were collected from mice at each time point: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The concentration of the analytes in the plasma was measured by HPLC-MS / MS at each time point. Chromatographic separation was performed on a Waters BEH C18 column (2.1 × 50 mm, 1.7 µm) (MAC-MOD Analytical, Chadds Ford, PA) using a gradient elution method with water and acetonitrile, both containing 0.1% formic acid. Mass spectrometry measurements with positive electrospray ionization were performed on an API 6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA) to quantify [M+H]... + As a mass transition of precursor ions, relevant pharmacokinetic parameters were estimated using a non-compartmental method with WinNonlin (Enterprise, version 8.2).

[0439] Table 2 Results of PK study in mice (5 mpk PO) Conclusion: The compounds of this invention disrupt the protein-protein binding between Raf1 RBD and KRAS.

[0440] Biological Example 4: Growth inhibitory activity against the KRAS-G12C mutant cell line (H358) (in vitro) H358 cells, the KRAS-G12C mutant human cancer cell line, were suspended in RPMI 1640 medium (manufactured by Gibco) containing 10% fetal bovine serum. 10³ cells were seeded into each well of a PerkinElmer ViewPlate-384 microplate and cultured for 1 day at 37°C in an incubator containing 5% CO₂. The compounds obtained in the "Compound Preparation" section were used as test compounds and dissolved separately in DMSO. Using 1 mM and 10 μM of the compound in DMSO stock solutions, the compounds were directly dispensed into each well of the 384-well plate using a Tecan D300 digital dispenser. The compounds were tested at concentrations from 3 μM to 3 pM. Cells were then cultured for another 3 days at 37°C in an incubator containing 5% CO₂. The cell count after 3 days of culture in the presence of the test compounds was measured using CellTiter-Glo 2.0 reagent (manufactured by Promega Corporation). CellTiter-Glo 2.0 reagent was added to all wells and mixed for 2 minutes. After mixing, the luminescence value was measured using a plate reader. The dose-response curve and the concentration at which the test compound achieved 50% inhibition (IC50 (nM)) were calculated using Prism 10.

[0441] Table 3: Results of H358 cell growth inhibition Biological Example 5. hERG Patch Clamp The inhibitory effect of the compound on the hERG potassium ion channel was detected using a manual patch-clamp method. Table 4 below shows the concentration-effect curves of the tested compounds and hERG channel currents, which were recorded from the HEK293-hERG stable cell line using manual patch-clamp technique. The ratio of the peak hERG current at each concentration to the peak current of the blank control was curve-fitted to the corresponding concentration according to the Hill equation. The results indicate that, within the detected concentration range, the compounds did not significantly inhibit the hERG potassium channel current stably expressed in HEK293 cells.

[0442] Table 4: Results of hERG patch-clamp therapy and H358 cell growth inhibition and hERG patch-clamp IC50 50 ratio Conclusion: The compounds of this invention exhibit very weak hERG inhibition. Therefore, they possess a wider therapeutic window and lower cardiotoxicity potential.

[0443] Biological Example 6. Pharmacokinetic Studies in Mice The compounds of the examples were administered to SPF-grade Balb / c mice via intravenous (IV) and oral gavage in a clear solution of 0.5% DMSO + 40% PEG400 + 59.5% (20% HP-β-CD) (IV in DMAC). Plasma samples were collected from mice at each time point of 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The concentration of the test analytes in plasma was measured by HPLC-MS / MS. Chromatographic separation was performed on a Waters BEH C18 column (2.1 × 50 mm, 1.7 µm) (MAC-MOD Analytical, Chadds Ford, PA) using a gradient elution method with water and acetonitrile, both containing 0.025% formic acid – 1 mM NH4OAc. Mass spectrometry measurements with positive electrospray ionization were performed on an API 6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA) to quantify [M+H] concentrations. + As a mass transition of precursor ions, relevant pharmacokinetic parameters were estimated using a non-compartmental method with WinNonlin (Enterprise, version 8.2).

[0444] Table 5 Results of PK study in mice Biological Example 7. Pharmacokinetic Studies in Preclinical Species The compounds of the examples were administered to Balb / c mice and SD rats via intravenous (IV) and oral gavage as a clear solution in 10% DMSO + 40% PEG400 + 50% (20% HP-β-CD) solution. Plasma samples were collected from mice at each time point of 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The concentration of the test analytes in plasma was measured by HPLC-MS / MS. Chromatographic separation was performed on a Waters BEH C18 column (2.1 × 50 mm, 1.7 µm) (MAC-MODAnalytical, Chadds Ford, PA) using a gradient elution method with water and acetonitrile, both containing 0.025% formic acid – 1 mM NH4OAc. Mass spectrometry measurements with positive electrospray ionization were performed on an API 6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA) to quantify [M+H] concentrations. + As a mass transition of precursor ions, relevant pharmacokinetic parameters were estimated using a non-compartmental method with WinNonlin (Enterprise, version 8.2).

[0445] Results of cross-species PK studies Conclusion: The deuterium-labeled compound 440 iso 1 showed a significant improvement in PK parameters compared to Example 371. The study found that compound 440 iso 1 had a lower in vivo clearance (i.e., IV clearance) and a surprisingly higher C120 concentration. MAX It has a higher oral exposure (AUC), thus enabling therapeutic effects to be achieved with a lower dose.

Claims

1. A compound of formula (I): ， Or its tautomers, cis or trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs, wherein, Ring A is aryl, heteroaryl, cycloalkyl, or heterocyclic, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic. Ring B is aryl, heteroaryl, cycloalkyl, or heterocyclic; L1 is a key or -NR a (CR a R b ) n -; L2 is a bond, -C(O)- or -C(O)NR a -; L3 is a key or -(CR) a R b ) n -; R a and R b Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxyl, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; Or, R a and R b Together with the atoms they are attached to, they form cycloalkyl or heterocyclic groups; R1 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, alkyl-SO2-, alkyl-N-, haloalkyl-O-, alkylamide, R a1 R b1 N-, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and heteroaryl substituted or unsubstituted by alkylene; R a1 and R b1 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, or cycloalkyl; R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkynyl, alkylthio, haloalkyl, hydroxyalkyl, amide-alkyl, cycloalkyl-O-alkyl, R a2 R b2 NL a2 - substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; R a2 and R b2 Each group is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, cycloalkyl, or substituted or unsubstituted heterocyclic groups; L a2 Selected from bonds, alkyl groups, or alkyl C(O); Alternatively, R1 and R2 together with the atoms to which they are attached form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, deuterated alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl or heterocyclic group. R4 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl and cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl and hydroxyalkyl. R5 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Alternatively, R4 and R5 together with the atoms they are attached to form a heterocyclic group, which is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; x is 1, 2, 3, or 4; and y is 1, 2 or 3.

2. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, Ring A is C6-C 10 The aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, or 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O, optionally, ring A is substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; Preferably, ring A is phenyl, C3-C8 cycloalkyl, or a 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O. Optionally, ring A is substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. More preferably, ring A is , , , , , , , , , , , or .

3. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, Ring B is C6-C 10 Aryl, 5- to 10-membered heteroaryl, C5-C8 cycloalkyl or 5- to 10-membered heterocyclic group; Preferably, ring B is a phenyl group, a C5-C7 cycloalkyl group, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S. Preferably, ring B is a phenyl group, a 5- to 10-membered fused heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 10-membered fused heteroaryl group containing one or two heteroatoms selected from N, O, or S; more preferably, ring B is... , , , , , , , , or .

4. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, L1 represents bonds such as NH, -NHCH2-, -N(CH2)3OH, and -N(CH2)3CONH2-. .

5. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, L2 is a bond, -C(O)- or -C(O)NH-.

6. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, L3 is a bond, -CH2- or .

7. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R1 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl-SO2-, C1-C6 alkyl-N-, C1-C6 haloalkyl-O-, C1-C6 alkylamide, R a1 R b1 N-, C3-C 12 cycloalkyl, 3 to 12-membered heterocyclic groups, C6-C 14 aryl and 6 to 14-membered heteroaryl, wherein the C3-C 12 cycloalkyl, 3 to 12-membered heterocyclic groups, C6-C 14 The aryl and 6- to 14-membered heteroaryl groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C3-C8 cycloalkyl, wherein R a1 and R b1 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl or C3-C6 cycloalkyl; Preferably, R1 is a halogen, a C1-C3 alkyl group, a C1-C3 alkoxyalkyl group, a C1-C3 haloalkyl group, a C1-C3 alkylthio group, a C1-C3 alkyl SO2- group, a C1-C6 haloalkyl -O- group, or R a1 R b1 N-, where R a1 and R b1 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl or C3-C6 cycloalkyl, wherein preferably, the C3-C6 cycloalkyl is cyclopropyl.

8. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, amide-C1-C6 alkyl, C3-C6 cycloalkyl-O-C1-C6 alkyl, R a2 R b2 NL a2 -、C3-C 12 cycloalkyl, 3 to 12-membered heterocyclic groups, C6-C 14 aryl and 6 to 14-membered heteroaryl, wherein the C3-C 12 cycloalkyl, 3 to 12-membered heterocyclic groups, C6-C 14 The aryl group and the 6- to 14-membered heteroaryl group are optionally separated by one or more groups selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 10 Substituents in aryl, 6- to 10-membered heteroaryl groups, wherein R a2 and R b2 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S; Preferably, R2 is a halogen, a C1-C3 alkyl group, or a 9- to 10-membered heteroaryl group containing 1, 2, or 3 N heteroatoms. Optionally, the 9- to 10-membered heteroaryl group containing 1, 2, or 3 N heteroatoms is formed by one or more elements selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, amide-C1-C3 alkyl, C3-C6 cycloalkyl-O-C1-C3 alkyl, or R2. a2 R b2 NL a2 - Substituents in - where R a2 and R b2 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C3-C3 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S.

9. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R4 is hydrogen.

10. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, R5 is a C3-C8 cycloalkyl group, a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -CONH; Preferably, R5 is , , It is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, and -CONH. Alternatively, R4 and R5, together with the atoms they are attached to, form 4- to 10-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S.

11. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to any one of claims 1 to 10, having a structure selected from formula (II): ， in, Ring A is a C3-C8 cycloalkyl group, containing one or two heteroatoms selected from N or O, and is a 5- to 8-membered heterocyclic group, C6-C 10 The aryl group, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O, is optionally substituted with one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C2-C6 cyanoalkyl; L1 is a bond, NH or -NHCH2-; R1, R2 and R3 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl; R5 is a C3-C8 cycloalkyl group, a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. Alternatively, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S; m can be 0, 1, 2, 3, or 4; x is 1, 2, 3, or 4; and y is 1, 2 or 3.

12. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to any one of claims 1 to 10, having a structure selected from formula (III) or (IV) or (III-A): , or , in, Ring B is phenyl, C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S; The ring C is a 5- or 6-membered heterocyclic group containing one or two heteroatoms selected from N, O or S. Optionally, the ring C is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. L3 is a bond, -CH2- or ; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; Alternatively, R1 and R2, together with the atoms they are attached to, form C7-C. 10 Cycloalkyl groups or 7- to 10-membered heterocyclic groups containing 1, 2, or 3 N, O, or S heteroatoms; R5 is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; m is 0 or 1.

13. The compound according to any one of claims 1 to 10, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (V): ， in, Ring A is a C3-C8 cycloalkyl group, containing one or two heteroatoms selected from N or O, and is a 5- to 8-membered heterocyclic group, C6-C 10 The aryl group, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O, is optionally substituted with one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C2-C6 cyanoalkyl; L1 is a bond, NH or -NHCH2-; R1, R2 and R3 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl; R5 is a C3-C8 cycloalkyl group, a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. Alternatively, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S; R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; m can be 0, 1, 2, 3, or 4; x is 1, 2, 3, or 4; and y is 1, 2 or 3.

14. The compound according to any one of claims 1 to 10, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (VI): ， in, Ring A is a C3-C8 cycloalkyl group, containing one or two heteroatoms selected from N or O, and is a 5- to 8-membered heterocyclic group, C6-C 10 The aryl group, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O, is optionally substituted with one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and C2-C6 cyanoalkyl; L1 is a bond, NH or -NHCH2-; R2, R3, R7 and R8 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl; R5 is a C3-C8 cycloalkyl group, a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O, or S, or a 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N or O; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. Alternatively, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S; R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; m can be 0, 1, 2, 3, or 4; x is 1, 2, 3 or 4; y is 1, 2 or 3, and z is 1, 2, or 3; Or it may have a structure selected from formula (VII): ， in, Ring B is phenyl, C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S; L1 is -NR a (CR a R b ) n -; L3 is a key or -(CR) a R b ) n -; R a and R b Independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxyl, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; Or, R a and R b Together with the atoms to which they are attached, they form a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O, or S, optionally substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; L3 is a bond, -CH2- or ; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl. Alternatively, R1 and R2, together with the atoms they are attached to, form C7-C. 10 The cycloalkyl or 7- to 10-membered heterocyclic group containing 1, 2 or 3 N, O or S heteroatoms, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, deuterated alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl or heterocyclic group. R5 is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; x is 1, 2, 3 or 4; y is 1, 2 or 3, and n is 0 or 1.

15. The compound according to any one of claims 1 to 10, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (VIII): ， in, Ring B is phenyl, C5-C7 cycloalkyl, a 5- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S, or a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O or S; L1 is -NR a (CR a R b ) n -; L3 is a key or -(CR) a R b ) n -; R a and R b Independently selected from hydrogen, deuterium, halogen, amino, cyano, oxo, hydroxyl, alkyl, alkoxy, haloalkyl, and hydroxyalkyl; Or, R a and R b Together with the atoms to which they are attached, they form a 5- to 10-membered heteroaryl group containing one or two heteroatoms selected from N, O, or S, optionally substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; L3 is a bond, -CH2- or ; K is selected from C(O) or S(O)2; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl. Alternatively, R1 and R2, together with the atoms they are attached to, form C7-C. 10 The cycloalkyl or 7- to 10-membered heterocyclic group containing 1, 2 or 3 N, O or S heteroatoms, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, deuterated alkyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl or heterocyclic group. R5 is a C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing one or two heteroatoms selected from N, O or S; optionally, R5 is substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. R6 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; x is 1, 2, 3 or 4; y is 1, 2 or 3, and n is 0 or 1.

16. The compound according to any one of claims 1 to 15, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (IX), (X), or (IX-A): ， ， ， in, A1, A2, and A4 are each independently selected from C, CH, N, NH, S, and O; A3 is selected from C, CH, N, NH, S, O, and bonds; B1 is selected from C, CH, and N; B2 is selected from C, CH, N, and bonds; B3 is selected from CH, N, S, and O; E1 and E2 are each independently selected from CH, CH2, N, NH, S, O, and C. 1-3 Alkyl group, -*N(CH3)C 1-3 Alkylene#, -*NH-C 1-3 Alkylene-#, wherein * can be oriented toward the D1 side or toward the B1 side, and correspondingly, # can be oriented toward the B1 side or the D1 side; D1 is selected from C and CR. d1 N, S and O; D2 is selected from CR d1 C(R) d1 )2, N, NR d1 It may not exist; if D2 does not exist, the key connected to D2 also does not exist. D3 is selected from C and CR. d1 C(R) d1 2. N; Each R d1 Independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, and amino groups. X1 is selected from C, CR d1 C(R) d1 )2, N, NR d1 ; X2 is selected from CR d1 C(R) d1 )2, N, NR d1 The key may not exist; X3 is selected from CR d1 C(R) d1 )2, N, NR d1 The key may not exist; X4 is selected from CR d1 C(R) d1 )2, N, NR d1 The key may not exist; When X1, X2, or X3 does not exist, the keys they are connected to also do not exist; Double or single bonds can be represented as needed to meet valence requirements; R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; R2, R 34 Independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, deuterated alkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, -NR 2a R 2b , cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents selected from alkyl, alkoxy, and halogen. Alternatively, the two atoms in R2 together with the two adjacent atoms they are attached to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R 2a and R 2b Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl, and is optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, ynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. L2 is selected from bond, *C(O), *CR 3a R 3b *C=R 3d *C=NR 3e 、*O、*S、NR 3f ; R 3a and R 3b Each is independently selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, amino, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, aryl, and heteroaryl; Or R 3a and R 3b Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which may optionally be substituted by one or more substituents selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino. R 3d Selected from C1-C3 alkyl groups; R 3e Selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino; R 3f Selected from C1-C3 alkyl groups; L4 is selected from *C(O) and *CH2; J is selected from *CH2, *CH, and *C(O); L5 is selected from *CH2 and *C(O); * Indicates a connection point with the parent structure; R4 can be hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, or amino. R5 is selected from (i) hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl; and (ii) cycloalkyl, heterocyclic, aryl, heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; m can be 0, 1, 2, 3, or 4; t is 0, 1, or 2.

17. The compound according to claim 16, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formulas (IX) and (X), wherein, A1, A2, and A4 are each independently selected from C, CH, N, NH, S, and O; A3 is selected from C, CH, N, NH, S, O, and bonds; B1 is selected from C, CH, and N; B2 is selected from C, CH, N, and bonds; B3 is selected from CH, N, S, and O; E1 and E2 are each independently selected from CH, CH2, N, NH, S, O, and C. 1-3 Alkoxy group, -N(CH3)C 1-3 Alkylene; D1 is selected from C and CR. d1 N, S and O; D2 is selected from CH, CH2, N or does not exist. When D2 does not exist, the bond that D2 is connected to also does not exist. D3 is selected from CH, CH2, N, and NH; R d1 Selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, and amino groups. X1 is selected from C, CH, CH2, N, and NH; X2 is selected from CH, CH2, CH3, N, NH, NH2, or may not exist; X3 is selected from CH, CH2, N, NH, bonds, or does not exist; X4 is selected from CH, CH2, CH3, N, NH, NH2, bonds, or does not exist; When X1, X2, or X3 does not exist, the keys they are connected to also do not exist; Double or single bonds can be represented as needed to meet valence requirements; R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkynyl, alkylthio, haloalkyl, hydroxyalkyl, -NR 2a R 2b , cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents selected from alkyl, alkoxy, and halogen. Alternatively, the two atoms in R2 together with the two adjacent atoms they are attached to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R 2a and R 2b Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl; Ring A is selected from cycloalkyl, heterocyclic, aryl, heteroaryl, and optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, ynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclic, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. L2 is selected from bond, *C(O), *CR 3a R 3b *C=R 3d *C=NR 3e 、*O、*S、NR 3f ; R 3a and R 3b Each is independently selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, amino, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, aryl, and heteroaryl; Or R 3a and R 3b Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which may optionally be substituted by one or more substituents selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino. R 3d Selected from C1-C3 alkyl groups; R 3e Selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino; R 3f Selected from C1-C3 alkyl groups; L4 is selected from *C(O) and *CH2; J is selected from *CH2, *CH, and *C(O); L5 is selected from *CH2 and *C(O); * Indicates a connection point with the parent structure; R4 can be hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, or amino. R5 is selected from (i) hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl; and (ii) cycloalkyl, heterocyclic, aryl, heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; m can be 0, 1, 2, 3, or 4; t is 0, 1, or 2.

18. The compound of claim 17 or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein... (i) Ring A is C6-C 10 The aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, or 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O, optionally, ring A is substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; Preferably, ring A is phenyl, C3-C8 cycloalkyl, or a 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O. Optionally, ring A is substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. More preferably, ring A is Preferred More preferably * indicates the position connected to N; More preferably, ring A is , , , , , , , , , , , or ; Or (ii) Selected from phenyl or 5- to 6-membered heteroaryl groups containing no more than 2 heteroatoms selected from N, O or S.

19. The compound according to any one of claims 17 to 18, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, Selected from phenyl or 5- to 6-membered heteroaryl groups containing no more than 2 heteroatoms selected from N, O or S.

20. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 19, wherein, R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkoxy, C1-C6 halo-alkylthio; (ii) -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl, C3-C8 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl; Preferably, R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkoxy, C1-C3 halo-alkylthio; (ii) -O-C3-C6 cycloalkyl, -S-C3-C6 cycloalkyl, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 cyanoalkyl, C1-C3 alkyl; x is 0, 1, 2 or 3.

21. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 20, wherein, Selected from , , , , ; Selected from Preferred ; in, R 11 R 12 and R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C2-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. R 13 The group is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 halo-alkylthio, C1-C6 haloalkoxy, (ii) -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl, 3 to 6-membered cycloalkyl, 5 to 8-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl; Preferably, R 11 R 12 and R 14 Each is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C4 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. Preferably, R 13 The group is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 halo-alkylthio, C1-C3 haloalkoxy, (ii) -O-C3-C6 cycloalkyl, -S-C3-C6 cycloalkyl, 3 to 6-membered cycloalkyl, 5 to 8-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl.

22. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 21, wherein, Selected from , , , , , , , , , , , ; Selected from .

23. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 22, wherein, Selected from , , , , , , , , , , , , ,in R 21 R 22 and R 23 Each is independently selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -NR 2a R 2b (ii) 3- to 8-membered cycloalkyl groups, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, C6-C 10 aryl, C5-C containing one or two heteroatoms selected from N, O and S 10 The heteroaryl group is optionally substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, amino, cyano, hydroxyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl. Or, R 22 and R 23 Together with the atoms they are attached, they form 3- to 8-membered cycloalkyl groups, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, C6-C 10 Aryl, 5 to 8-membered heteroaryl containing one or two heteroatoms selected from N, O and S; R 2a and R 2b Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, amino, 3- to 6-membered cycloalkyl, 5- to 8-membered heterocyclic, C6-C 10 Aryl, 5 to 8-membered heteroaryl.

24. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 23, wherein, Selected from , , , , , , , , , , , , , , , , ,in, R 21 R 22 and R 23 Each is independently selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 cyanoalkyl, C1-C3 alkyl, C1-C6 deuterated alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -NR 2a R 2b (ii) C3-C6 cycloalkyl, 3- to 6-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N, O and S, optionally substituted by one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl; Or, R 22 and R 23 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups containing one or two heteroatoms selected from N, O, and S, C6-C8 aryl, and 5- to 8-membered heteroaryl groups containing one or two heteroatoms selected from N, O, and S; optionally substituted by one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. R 2a R 2b Each is independently selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, (ii) C3-C8 cycloalkyl, C3-C6 heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, C5-C8 heteroaryl, optionally substituted by one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl.

25. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 24, wherein, R 21 R 22 and R 23 Each is independently selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 cyanoalkyl, C1-C3 alkyl, C1-C3 deuterated alkyl, -NR 2a R 2b (ii) , , , , , , , , Optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxy, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; or, R 22 and R 23 Together with the atoms they are attached to, they form , , Optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxy, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; R 2a and R 2b Each is independently selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, and (ii) , , , , , , , , Optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl.

26. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 25, wherein, Selected from , , , , , , ,in, D1 is selected from C and CR. d1 N, S and O; D2 is selected from CH, CH2, and N; D3 is selected from CH, CH2, N, and NH; R d1 Selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, and amino; X1 is selected from CH, CH2, N, and NH; X2 is selected from CH, CH2, CH3, N, NH, and NH2; X3 is selected from CH, CH2, N, and NH; X4 is selected from CH, CH2, N, NH, and NH2.

27. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 26, wherein, Selected from , , , , , , , .

28. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 27, wherein, Cycle A is selected from phenyl, C3-C8 cycloalkyl, 5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N or O, or 5- to 8-membered heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 alkylamino, C1-C3 alkylcyano, and C1-C3 hydroxyalkyl, wherein the cycloalkyl and heterocyclic group are saturated or partially unsaturated.

29. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 28, wherein, Ring A is selected from , , , , , , , , , , Optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 alkylamino, C1-C3 alkylcyano, and C1-C3 hydroxyalkyl.

30. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 29, wherein, Ring A is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , .

31. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 30, wherein, L2 is selected from bonds, *C=O, *CF2, *C-OH, *C(F)CH3, *C(OH)CH3, *C=CH2, *C=NH, *C=N-OH, *CO-CH3, *O, *S. , , *NCH3; L4 is selected from *C(O) and *CH2; J is selected from *CH2, *CH, and *C(O); L5 is selected from *CH2 and *C(O).

32. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 31, wherein, (i) R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl. R5 is selected from branched or straight-chain C1-C3 alkyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic groups containing one or two heteroatoms selected from N, O or S, or 5- to 8-membered heteroaryl groups containing one or two heteroatoms selected from N or O, optionally substituted by one or more substituents selected from deuterium, halogen, amino, cyano, hydroxyl, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, wherein the cycloalkyl or heterocyclic group is saturated or partially unsaturated; Alternatively, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S; m is 0, 1, or 2; or (ii) R5 is selected from , , , , , , , , , , , , , , Each R 28 R 281 R 282 Independently absent or selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, HC(O)-, alkyl-C(O)-, alkoxy, alkoxyalkyl, deuterated alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, alkylcarbonyl, cycloalkyl, heterocyclic, cycloalkyloxy, aryl, heteroaryl, methylidene (=CH2), wherein the alkyl, hydroxyl, alkenyl, alkynyl, amino, HC(O)-, alkyl-C(O)-, alkoxy, alkoxyalkyl, deuterated alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, alkylcarbonyl, cycloalkyl, heterocyclic, cycloalkyloxy, aryl, heteroaryl, methylidene (=CH2) is optionally surrounded by 1, 2, 3, 4 or 5 R 29 replace; Each R 29 Independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, alkyl, deuterated alkyl, alkenyl, alkoxy, deuterated alkoxy, alkoxyalkyl, deuterated alkoxyalkyl, alkylthio, haloalkyl, cyano, oxo (=O), cycloalkyl, cycloalkyloxy, heterocyclic, aryl, heteroaryl, and hydroxyalkyl; preferably selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; Or R4 and R 5a Together with the atoms they are attached to, they form 3- to 6-membered heterocyclic groups, which are selected from... , , Preferred , , n5 is 0, 1, 2, 3, or 4.

33. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 17 to 32, wherein, R4 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 haloalkyl and C1-C3 hydroxyalkyl; R5 is selected from -C(CH3)2. , , , , , , , , , , , These groups are optionally substituted by 1, 2, 3, 4 or 5 substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, and oxo. Alternatively, R4 and R5 together with the atoms they are attached to form , , , .

34. The compound according to any one of claims 1 to 33, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (XI), ， in, R4 and R5, together with the atoms they are attached to, form 5- to 7-membered heterocyclic groups containing one or two heteroatoms selected from N, O, or S. R4 and R5 together with the atoms they are attached to form , .

35. The compound according to any one of claims 1 to 34, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (XII), ， in, R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkoxy, C1-C6 halo-alkylthio, -NR 2a R 2b (ii) -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl, C3-C8 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl; R 2a R 2b Each of the following is independently selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, (ii) C3-C8 cycloalkyl, C3-C6 heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, C5-C8 heteroaryl, and optionally substituted by one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, and C1-C3 hydroxyalkyl; D1 is selected from C, CH, CH2, and N; D2 is selected from CH, CH2, NH, and N. D3 is selected from C, CH, and N; R d1 Selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, -NH-C1-C3 alkyl, -CONH3 and -NHCO-N-C1-C3 alkyl. X1 is selected from C, CH, CH2, N, and NH; X2 is selected from CH, CH2, N, NH and bonds; X3 is selected from CH, CH2, N, and NH; X4 is selected from CH, CH2, N, and NH; R 15 The group is selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, and (ii) C1-C3 alkyl-C3-C8 cycloalkyl, C1-C3 alkyl-5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl; R 16 Selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, and amino. x is 2, 3 or 4.

36. The compound according to any one of claims 1 to 35, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (XIII), ， in, R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkoxy, C1-C6 halo-alkylthio, -NR 2a R 2b (ii) -O-C3-C8 cycloalkyl, -S-C3-C8 cycloalkyl, C3-C8 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 cyanoalkyl, C1-C6 alkyl; Cycle D is selected from C3-C8 cycloalkyl groups, 5- to 12-membered fused heterocyclic groups containing one or two heteroatoms selected from N, O and S, wherein the cycloalkyl group and the 5- to 10-membered fused heterocyclic group are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, C1-C6 cyanoalkyl, and C1-C6 alkyl. R 15 The group is selected from (i) hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, amino, and (ii) C1-C3 alkyl-C3-C8 cycloalkyl, C1-C3 alkyl-5- to 8-membered heterocyclic group containing one or two heteroatoms selected from N, O and S, C6-C8 aryl, 5- to 8-membered heteroaryl group containing one or two heteroatoms selected from N, O and S, optionally substituted with one or more substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, cyano, hydroxyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl; R 16 Selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, and amino. x is 2, 3 or 4.

37. The compound or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug according to any one of claims 1 to 36, wherein... Ring D is selected from , Optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, oxo, C1-C6 cyanoalkyl, and C1-C6 alkyl.

38. The compound according to any one of claims 1 to 37, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (XIV) or (XV), 、 ， in, R 17 R 18 and R 19 The group is independently selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; and (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic groups are optionally substituted by 1, 2, 3, 4, or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, and alkyl. E1 is selected from CH, CH2, N, NH, S, and O; E2 is selected from N, NH, S, and O; R 20 and R 20 a is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; R 21 and R 22 It is independently selected from hydrogen, deuterium, F, Cl, Br, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano and C1-C6 hydroxyalkyl; R 23 Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl. r can be 0, 1, 2 or 3.

39. The compound according to claim 38, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure selected from formula (XIV) or (XV), in, R 17 R 18 and R 19 It is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; E1 is selected from CH, CH2, N, NH, S, and O; E2 is selected from N, NH, S, and O; R 20 and R 20 a is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; R 21 and R 22 It is independently selected from hydrogen, deuterium, F, Cl, Br, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano and C1-C6 hydroxyalkyl; R 23 Selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C1-C6 alkoxyalkyl, C1-C6 deuterated alkoxyalkyl, C1-C6 alkylthio, C1-C6 haloalkyl, cyano, and C1-C6 hydroxyalkyl; r can be 0, 1, 2, or 3; Preferably, the C1-C6 deuterated alkyl group is selected from -CD3, -CHD2, -CH2D, -CD2CH3, and -CH2CD3.

40. The compound according to claim 1, or a tautomer, cis or trans isomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, The compound is: 。 41. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claims 1 to 40 or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

42. A method for treating a disease mediated by a KRAS mutation, comprising administering to a subject in need an effective amount of any one of claims 1 to 40, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutical composition of claim 41.

43. The method according to claim 42, wherein, The KRAS mutations include KRAS G12C, KRAS G12V, or KRAS G13D mutations.

44. A method for treating cancer, comprising administering to a subject in need an effective amount of any one of claims 1 to 40, or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the pharmaceutical composition of claim 41.

45. The method according to claims 42 to 44, wherein, The cancers mentioned are selected from: cardiac sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: Bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet tumor, glucagonoma, gastrinoma, carcinoid tumor, vasodilator intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital tract Kidneys (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenocarcinoma-like tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromycinoma, osteoid osteoma and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granulomatous tumor, xanthoma, osteitis deformans), Meninges (meningioma, meningeal sarcoma, glioma), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecology: Uterus (endometrial cancer (serous) Cystoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell-sheath cell tumor, Sertoli-stromal cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); blood: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

46. ​​A compound of formula (XVI) or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, ， A1, A2, and A4 are each independently selected from C, CH, N, NH, S, and O; A3 is selected from C, CH, N, NH, S, O, and bonds; B1 is selected from C, CH, and N; B2 is selected from C, CH, N, and bonds; B3 is selected from C, CH, N, S, and O; E1 and E2 are each independently selected from CH, CH2, N, NH, S, O, and C. 1-3 Alkyl group, -*N(CH3)C 1-3 Alkylene#, -*NH-C 1-3 Alkylene-#, wherein * can be oriented toward the D1 side or toward the B1 side, and correspondingly, # can be oriented toward the B1 side or the D1 side; D1 is selected from C and CR. d1 N, S and O; D2 is selected from C and CR. d1 CH2, N, or none of them exist. When D2 does not exist, the bond connected to D2 also does not exist. D3 is selected from C and CR. d1 CH2, N and NH; Each R d1 Independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, and amino groups. X1 is selected from C, CR d1 CH2, N, NH; X2 is selected from C and CR. d1 CH2, CH3, N, NH, NH2, bonds may or may not exist; X3 is selected from C, CR d1 CH2, N, NH bonds may or may not exist; X4 is selected from C, CR d1 CH2, CH3, N, NH, NH2, bonds may or may not exist; When X1, X2, or X3 does not exist, the keys they are connected to also do not exist; Double or single bonds can be represented as needed to meet valence requirements; R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, deuterated alkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, -NR 2a R 2b , cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents selected from alkyl, alkoxy, and halogen. Alternatively, the two atoms in R2 together with the two adjacent atoms they are attached to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R 2a and R 2b Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl, and is optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, ynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. L2 is selected from bond, *C(O), *CR 3a R 3b *C=R 3d *C=NR 3e 、*O、*S、NR 3f ; R 3a and R 3b Each is independently selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, amino, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, aryl, and heteroaryl; Or R 3a and R 3b Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which may optionally be substituted by one or more substituents selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino. R 3d Selected from C1-C3 alkyl groups; R 3e Selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino; R 3f Selected from C1-C3 alkyl groups; R 30 R 31 Independently selected from: (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkylthio, alkoxyalkyl, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio; (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the amino, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkylthio, alkoxyalkyl, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; or (iii) a nitrogen protecting group, preferably Boc; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; t is 0, 1, or 2.

47. A method for preparing a compound of formula (X) or a tautomer, cis or trans isomer, meso compound, racemic compound, enantiomer, diastereomer, deuterated derivative or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, comprising: A ， A1, A2, and A4 are each independently selected from C, CH, N, NH, S, and O; A3 is selected from C, CH, N, NH, S, O, and bonds; B1 is selected from C, CH, and N; B2 is selected from C, CH, N, and bonds; B3 is selected from C, CH, N, S, and O; E1 and E2 are each independently selected from CH, CH2, N, NH, S, O, and C. 1-3 Alkyl group, -*N(CH3)C 1-3 Alkylene#, -*NH-C 1-3 Alkylene-#, wherein * can be oriented toward the D1 side or toward the B1 side, and correspondingly, # can be oriented toward the B1 side or the D1 side; D1 is selected from C and CR. d1 N, S and O; D2 is selected from C and CR. d1 CH2, N, or none of them exist. When D2 does not exist, the bond connected to D2 also does not exist. D3 is selected from C and CR. d1 CH2, N and NH; Each R d1 Independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, and amino groups. X1 is selected from C, CR d1 CH2, N, NH; X2 is selected from C and CR. d1 CH2, CH3, N, NH, NH2, bonds may or may not exist; X3 is selected from C, CR d1 CH2, N, NH bonds may or may not exist; X4 is selected from C, CR d1 CH2, CH3, N, NH, NH2, bonds may or may not exist; When X1, X2, or X3 does not exist, the keys they are connected to also do not exist; Double or single bonds can be represented as needed to meet valence requirements; R1 is selected from (i) hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio, haloalkyl, hydroxyalkyl, haloalkoxy, halo-alkylthio, (ii) -O-cycloalkyl, -S-cycloalkyl, cycloalkyl, heterocyclic, wherein the cycloalkyl and heterocyclic are optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, alkyl; R2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, cyanoalkyl, deuterated alkyl, alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, -NR 2a R 2b , cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl are optionally substituted by one or more substituents selected from alkyl, alkoxy, and halogen. Alternatively, the two atoms in R2 together with the two adjacent atoms they are attached to form cycloalkyl, heterocyclic, aryl, or heteroaryl groups; R 2a and R 2b Each is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, cyano, amino, cycloalkyl, heterocyclic, aryl, and heteroaryl; Ring A is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl, and is optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, ynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. L2 is selected from bond, *C(O), *CR 3a R 3b *C=R 3d *C=NR 3e 、*O、*S、NR 3f ; R 3a and R 3b Each is independently selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, amino, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, aryl, and heteroaryl; Or R 3a and R 3b Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which may optionally be substituted by one or more substituents selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino. R 3d Selected from C1-C3 alkyl groups; R 3e Selected from hydrogen, deuterium, C1-C3 alkyl, halogen, hydroxyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, and amino; R 3f Selected from C1-C3 alkyl groups; L4 is selected from *C(O) and *CH2; J is selected from *CH2, *CH, and *C(O); L5 is selected from *CH2 and *C(O); * Indicates a connection point with the parent structure; R4 can be hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, or amino. R5 is selected from (i) hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl; and (ii) cycloalkyl, heterocyclic, aryl, heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, alkenyl, alkynyl, cyano, amino, alkylthio, haloalkyl, hydroxyalkyl, aminoalkyl, cyanoalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein the cycloalkyl and heterocyclic groups are saturated or partially unsaturated. R 34 Halogens are preferred as leaving groups; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; m can be 0, 1, 2, 3, or 4; t is 0, 1, or 2.

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