Fused tricyclic compound, preparation method thereof and application of fused tricyclic compound in medicine

Abstract

The invention relates to a fused tricyclic compound, a preparation method thereof and application of the fused tricyclic compound in medicine. Specifically, the invention relates to a fused tricyclic compound as shown in a general formula (I), a preparation method of the fused tricyclic compound, a pharmaceutical composition containing the fused tricyclic compound and application of the fused tricyclic compound as a therapeutic agent, in particular to application of the fused tricyclic compound in preparation of drugs for inhibiting KRAS amplification and / or mutant activity. Wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Condensed tricyclic compound, preparation method thereof and application in medicine Technical Field

[0001] The present disclosure relates to the field of medicine and relates to a fused tricyclic compound, a method for preparing the same, and its use in medicine. In particular, the present disclosure relates to a fused tricyclic compound represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and its use in the preparation of a medicament for inhibiting KRAS amplification and / or mutant activity. Background Art

[0002] The KRAS protein, encoded by the KARS gene, is a small GTPase that belongs to the RAS superprotein family. Within cells, the KRAS protein switches between inactive and activated states. When bound to guanosine diphosphate (GDP), KRAS is inactive, and when bound to guanosine triphosphate (GTP), it becomes active, activating downstream signaling pathways. KRAS can be activated by upstream growth factors and other tyrosine kinases (such as EGFR). Following activation, KRAS activates downstream pathways such as the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways, which regulate cell proliferation and growth.

[0003] KRAS is one of the most common oncogenes in solid tumors. Approximately 19% of tumors harbor KRAS mutations, including ~90% of pancreatic cancers, ~50% of colon cancers, and ~30% of lung adenocarcinomas. KRAS mutations also occur in a certain proportion of other cancer types, such as bile duct cancer, cervical cancer, bladder cancer, liver cancer, and breast cancer. The most common sites of gene mutation are codons 12, 13, and 61, with mutations at codon 12 being the most common. KRAS mutations increase the activation of RAS in the GTP-bound state, activating downstream pathways. Furthermore, KRAS amplification / overexpression or upstream activation can occur in tumors, all of which can lead to persistent activation of the RAS downstream pathway and contribute to tumorigenesis.

[0004] Because the KRAS protein lacks traditional small molecule binding sites on its surface and has an extremely high affinity for guanylate, making it difficult to competitively inhibit with small molecules, it has long been considered an undruggable drug target. However, given the importance and prevalence of abnormal KRAS activation in cancer progression, KRAS has been and remains a highly sought-after target for drug development. Currently, only inhibitors targeting KRAS G12C and G12D have been approved or are in clinical trials. Therefore, there is still a need to develop pan-KRAS inhibitors for the treatment of multiple KRAS-mutant tumors or KRAS-dependent tumors.

[0005] The related patent applications that have been published so far include WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2022132200A1, WO2022188729A1, WO2022194245A1, WO2022199587A1, WO2022216762A1 and WO2021000885A1.

[0006] Summary of the Invention

[0007] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0008] in:

[0009] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0010] R 2 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m1 R m2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n1 R n2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0011] R 3 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m3 R m4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -W-(CR 3a R 3b ) r -Ring C, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n3 R n4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0012] W is selected from O, S and NR w ;

[0013] R 3a and R 3bare the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0014] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and is optionally substituted by one or more R 10 replace;

[0015] R 4 is selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n5 R n6 , hydroxyl, hydroxyalkyl and one or more substituents in ring B, ring B is selected from cycloalkyl, heterocyclic group, aryl and heteroaryl, and the ring B is optionally substituted by one or more R 9 replace;

[0016] Each R 1 、R 9 and R 0 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-NR m5 R MP 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, -OR P , hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0017] R P is a hydrogen atom or R PP ;

[0018] R MP is a hydrogen atom or R MPP ;

[0019] R PP and R MPP are the same or different and are each independently selected from -C(O)R P1 、-C(O)OR P3 、-C(O)NR P3 R P4 、-C(O)OCR P11 R P12 OC(O)Z, -C(O)CR P11 R P12 NR P3 R P4 、-C(O)NR P13 CR P11 R P12 C(O)OR P3 、-S(O)2R P1 、-S(O)2OR P3 and -S(O)2NR P3 R P4 ;

[0020] R P1 、R P11 、R P12 、R P3 、R P4 、R P13 and Z are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, -C(O)R P20 , cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -OC(O)R P21 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0021] R P20 and R P21 are the same or different and are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0022] Each R 10are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, =CR m9 R m10 、=NR m11 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -OC(O)NR n7 R n8 、-NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0023] R 5 、R 6 、R 7 and R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m7 R m8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n9 R n10 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0024] R w 、R m1 、R m2 、R m3 、R m4 、R m5 、R m6 、R m7 、R m8 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、Rn9 and R n10 are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0025] R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy and cyano;

[0026] or R m9 、R m10 Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0027] R m11 is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and

[0028] r is 0, 1, 2, 3, 4, or 5;

[0029] m is 0, 1, 2, 3, 4, 5 or 6.

[0030] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0031] in:

[0032] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0033] R 2 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m1 R m2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n1 R n2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0034] R 3 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m3 R m4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -W-(CR 3a R 3b ) r -Ring C, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n3 R n4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0035] W is selected from O, S and NR w ;

[0036] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0037] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and is optionally substituted by one or more R 10 replace;

[0038] R 4 is selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n5 R n6, hydroxyl, hydroxyalkyl and one or more substituents in ring B, ring B is selected from cycloalkyl, heterocyclic group, aryl and heteroaryl, and the ring B is optionally substituted by one or more R 9 replace;

[0039] Each R 1 、R 9 and R 0 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, -OR P , hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0040] R P is a hydrogen atom or R PP ;

[0041] R PP Selected from -C(O)R P1 、-C(O)OR P3 、-C(O)NR P3 R P4 、-C(O)OCR P11 R P12 OC(O)Z, -C(O)CR P11 R P12 NR P3 R P4 、-C(O)NR P13 CR P11 R P12 C(O)OR P3 、-S(O)2R P1 、-S(O)2OR P3 and -S(O)2NR P3 R P4 ;

[0042] R P1 、R P11 、R P12 、R P3、R P4 、R P13 and Z are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, -C(O)R P20 , cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -OC(O)R P21 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0043] R P20 and R P21 are the same or different and are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0044] Each R 10 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, =CR m9 R m10 、=NR m11 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -OC(O)NR n7 R n8 、-NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0045] R 5 、R 6 、R 7 and R 8are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m7 R m8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n9 R n10 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0046] R w 、R m1 、R m2 、R m3 、R m4 、R m5 、R m6 、R m7 、R m8 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n9 and R n10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0047] R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy and cyano;

[0048] or R m9 、R m10 Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0049] R m11is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and

[0050] r is 0, 1, 2, 3, 4, or 5;

[0051] m is 0, 1, 2, 3, 4, 5 or 6.

[0052] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0053] in:

[0054] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0055] R 2 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m1 R m2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n1 R n2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0056] R 3 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m3 R m4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -W-(CR 3a R 3b ) r -Ring C, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n3 R n4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0057] W is selected from O, S and NR w ;

[0058] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0059] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and is optionally substituted by one or more R 10 replace;

[0060] R 4 is selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n5 R n6 , hydroxyl, hydroxyalkyl and one or more substituents in ring B, ring B is selected from cycloalkyl, heterocyclic group, aryl and heteroaryl, and the ring B is optionally substituted by one or more R 9 replace;

[0061] Each R 1 、R 9 and R 0 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0062] Each R 10 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, =CR m9 R m10 、=NR m11 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -OC(O)NR n7 R n8 、-NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0063] R 5 、R 6 、R 7 and R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m7 R m8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n9 R n10 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0064] R w 、R m1 、R m2 、R m3 、R m4 、R m5 、R m6 、R m7 、R m8 、R n1 、R n2 、R n3 、R n4 、R n5 、 R n6 、R n7 、R n8 、R n9 and R n10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0065] R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy and cyano;

[0066] or R m9 、R m10 Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0067] R m11 is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and

[0068] r is 0, 1, 2, 3, 4, or 5;

[0069] m is 0, 1, 2, 3, 4, 5 or 6.

[0070] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0071] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0072] R 2 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m1 R m2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n1 R n2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0073] R3 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m3 R m4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -W-(CR 3a R 3b ) r -Ring C, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n3 R n4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0074] W is selected from O, S and NR w ;

[0075] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace;

[0076] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and is optionally substituted by one or more R 10 replace;

[0077] R 4 is selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n5 R n6 , hydroxyl, hydroxyalkyl and one or more substituents in ring B, ring B is selected from cycloalkyl, heterocyclic group, aryl and heteroaryl, and the ring B is optionally substituted by one or more R 9 replace;

[0078] Each R 1 、R 9 、R 10 and R 0 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NRm5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0079] R 5 、R 6 、R 7 and R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m7 R m8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n9 R n10 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0080] R w 、R m1 、R m2 、R m3 、R m4 、R m5 、R m6 、R m7 、R m8 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n9 and R n10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; and

[0081] r is 0, 1, 2, 3, 4, or 5;

[0082] m is 0, 1, 2, 3, 4, 5 or 6.

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 W-(CR 3a R 3b ) r - Ring C, W, R 3a 、R 3b , r and ring C are as defined in the general formula (I).

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3 for p is 0, 1, 2, 3, 4 or 5; W, R 3a 、R 3b 、R 10 , r and ring C are as defined in the general formula (I).

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 is an alkyl group, the alkyl group is substituted by ring B, the ring B is selected from cycloalkyl, heterocyclic group, aryl and heteroaryl, the ring B is optionally substituted by one or more R 9 Replacement, R 9 As defined in general formula (I).

[0086] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 preferably, R 6 A hydrogen atom.

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 preferably, R 7 A hydrogen atom.

[0088] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring A is a 6- to 10-membered aryl group; more preferably, ring A is selected from naphthyl, phenyl, pyridyl, benzothienyl, benzothiazolyl and benzopyrazolyl; most preferably, ring A is naphthyl.

[0089] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II') or a pharmaceutically acceptable salt thereof:

[0090] in

[0091] L 1 is optionally selected from halogen, oxo, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and an alkylene group substituted with one or more substituents in the hydroxyl group;

[0092] Ring A 1 is aryl or heteroaryl;

[0093] m is 0, 1, 2, 3, 4 or 5;

[0094] n is 0, 1, 2, 3, 4 or 5;

[0095] p is 0, 1, 2, 3, 4, or 5;

[0096] R P , Ring B, Ring C, W, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 9 、R 10 、R n5 、R n6 and r are as defined in the general formula (I).

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0098] in

[0099] L 1 is optionally selected from halogen, oxo, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and an alkylene group substituted with one or more substituents in the hydroxyl group;

[0100] Ring A 1 is aryl or heteroaryl;

[0101] m is 0, 1, 2, 3, 4 or 5;

[0102] n is 0, 1, 2, 3, 4 or 5;

[0103] p is 0, 1, 2, 3, 4, or 5;

[0104] Ring B, Ring C, W, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 9 、R 10 、R n5 、R n6 and r are as defined in the general formula (I).

[0105] In some embodiments of the present disclosure, the compound represented by the general formula (II) or (II') or a pharmaceutically acceptable salt thereof, wherein L 1 is optionally selected from halogen, C 1-6 Alkoxy, C 1-6 C substituted by one or more substituents selected from the group consisting of haloalkoxy, cyano, amino and hydroxy 1-6 Alkylene; preferably, L 1 C 1-6 Alkylene; more preferably -CH(CH3)-.

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II') or (II) or a pharmaceutically acceptable salt thereof, wherein each R 9 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 、-NR m5 R MP 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, hydroxyl and C 1-6 Hydroxyalkyl, R MP 、R m5 and R m6 As defined in Formula (I); in some embodiments, each R 9 The same or different, and each independently is -NR m5 R MP , R MP and R m5As defined in Formula (I); in some embodiments, each R 9 are the same or different and are each independently selected from amino, C 1-6 Alkylamino- and -NHR MPP , R MPP As defined in Formula (I); in some embodiments, each R 9 The same or different, and each independently is -NHC(O)OC 1-6 alkyl; in some embodiments, each R 9 The same or different, and each independently is -NHC(O)C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more amino groups; in some embodiments, each R 9 The same or different, and each independently is -NHC(O)CH(CH3)NH2; preferably, each R 9 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl; further preferably, each R 9 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and amino; more preferably, each R 9 The same or different, and each independently is an amino group.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II') or (II) or a pharmaceutically acceptable salt thereof, wherein each R 9 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, hydroxyl and C 1-6 Hydroxyalkyl, R m5 and R m6 As defined in the general formula (I); preferably, each R9 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl; further preferably, each R 9 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and amino; more preferably, each R 9 The same or different, and each independently is an amino group.

[0108] In some embodiments of the present disclosure, the compound represented by the general formula (II) or (II') or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; preferably 1.

[0109] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II') or (II) or a pharmaceutically acceptable salt thereof, wherein W is selected from CH2, NH and O; preferably, W is O.

[0110] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II') or (II) or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or a 5-membered or 6-membered heteroaryl group; preferably, ring B is a 6-membered heteroaryl group; more preferably, ring B is a pyridyl group.

[0111] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof:

[0112] in:

[0113] -Q 1 -R P’ Does not exist, or Q 1 is O or NH, R P’ R P or R MP , and -Q 1 -R P’ For-OR P or -NH-R MP ;

[0114] G 2 CR 9b or N;

[0115] G 3 CR 9c or N;

[0116] G4 CR 9d or N;

[0117] G 5 C or N;

[0118] G 6 C or N;

[0119] G 7 C or N;

[0120] R 11 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups;

[0121] R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0122] Ring A 2 Does not exist, or ring A 2 is aryl or heteroaryl;

[0123] m is 0, 1, 2, 3, 4 or 5;

[0124] p is 0, 1, 2, 3, 4, or 5;

[0125] R MP 、R P , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R m5 、R m6、R n5 、R n6 、R n7 、R n8 and r are as defined in the general formula (I).

[0126] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (V') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V'-1) or (V'-2) or a pharmaceutically acceptable salt thereof:

[0127] in,

[0128] R 11 Selected from halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups;

[0129] Q 1 、R P’ 、R m5 、R MP , G 2 to G 7 , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 , m, p and r are as defined in formula (V').

[0130] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein Ring A 2 Not present, or ring A 2 is phenyl or 5-membered or 6-membered heteroaryl; preferably, ring A 2 Does not exist, or A 2 is selected from phenyl, thienyl, thiazolyl and pyrazolyl.

[0131] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 , hydroxyl, C 1-6Hydroxyalkyl and 3 to 8 membered cycloalkyl, R m5 and R m6 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; preferably, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, C 1-6 hydroxyalkyl and 3 to 8-membered cycloalkyl; further preferably, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 haloalkyl, hydroxyl and 3 to 6-membered cycloalkyl; further preferably, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and hydroxy; most preferably, each R 1 are the same or different and are each independently selected from hydroxy, F and ethyl; in some embodiments, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, -NH2, hydroxyl, -OC(O)NH(C 1-6 alkyl) and -OC(O)N(C 1-6 Alkyl)2.

[0132] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II'), (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 、C 1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl, R m5 and R m6 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; preferably, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6hydroxyalkyl and 3 to 8-membered cycloalkyl; further preferably, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl; further preferably, each R 1 The same or different, and each independently halogen or C 1-6 Alkyl; most preferably, each R 1 are the same or different and are each independently F or ethyl; in some embodiments, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and cyano.

[0133] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3 or 4, preferably 1, 2 or 3, and more preferably 3.

[0134] In some embodiments of the present disclosure, the compounds represented by the general formula (II), (II'), (V'), (V'-1), (V'-2) or their pharmaceutically acceptable salts, wherein m is 1, 2 or 3, preferably 1 or 2, more preferably 2.

[0135] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof:

[0136] in

[0137] G 1 CR 9a or N;

[0138] G 2 CR 9b or N;

[0139] G 3 CR 9c or N;

[0140] G 4 CR 9d or N;

[0141] R 11 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups;

[0142] R 1a 、R1b 、R 1c 、R 1d 、R 9a 、R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-NR m5 R MP 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0143] q is 1, 2, 3, 4, or 5;

[0144] p is 0, 1, 2, 3, 4, or 5;

[0145] R P 、R MP , Ring C, R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R m5 、R m6 、R n5 、R n6 、R n7 、R n8 and r are as defined in the general formula (I).

[0146] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II'), (III') or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0147] in

[0148] G 1 CR 9a or N;

[0149] G 2 CR 9b or N;

[0150] G 3 CR 9c or N;

[0151] G 4 CR 9d or N;

[0152] R 11 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups;

[0153] R 1a 、R 1b 、R 1c 、R 1d 、R 9a 、R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-NR m5 R MP 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0154] q is 1, 2, 3, 4, or 5;

[0155] p is 0, 1, 2, 3, 4, or 5;

[0156] R MP , Ring C, R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R m5 、R m6、R n5 、R n6 、R n7 、R n8 and r are as defined in the general formula (I).

[0157] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof:

[0158] in

[0159] G 1 CR 9a or N;

[0160] G 2 CR 9b or N;

[0161] G 3 CR 9c or N;

[0162] G 4 CR 9d or N;

[0163] R 11 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups;

[0164] R 1a 、R 1b 、R 1c 、R 1d 、R 9a 、R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0165] q is 1, 2, 3, 4, or 5;

[0166] p is 0, 1, 2, 3, 4, or 5;

[0167] R P , Ring C, R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R m5 、R m6 、R n5 、R n6 、R n7 、R n8 and r are as defined in the general formula (I).

[0168] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II'), (III') or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0169] in

[0170] G 1 CR 9a or N;

[0171] G 2 CR 9b or N;

[0172] G 3 CR 9c or N;

[0173] G 4 CR 9d or N;

[0174] R 11 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups;

[0175] R 1a 、R 1b 、R 1c 、R 1d 、R 9a 、R 9b 、R 9c and R 9dare the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0176] q is 1, 2, 3, 4, or 5;

[0177] p is 0, 1, 2, 3, 4, or 5;

[0178] Ring C, R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R m5 、R m6 、R n5 、R n6 、R n7 、R n8 and r are as defined in the general formula (I).

[0179] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II'), (III'), (II), (III), (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom; and / or R 8 A hydrogen atom.

[0180] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II'), (III'), (II), (III), (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 preferably, R 5 A hydrogen atom.

[0181] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II'), (III'), (II), (III), (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 preferably, R 8 A hydrogen atom.

[0182] In some embodiments of the present disclosure, the compound represented by the general formula (III) or (III') or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2, preferably 1.

[0183] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II'), (III') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV') or a pharmaceutically acceptable salt thereof:

[0184] in

[0185] R P , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (III).

[0186] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II'), (III'), (IV'), (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof:

[0187] in

[0188] Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R11 , p and r are as defined in the general formula (III).

[0189] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III), (II'), (III'), (IV'), (IV) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof:

[0190] in:

[0191] R 11 Selected from halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups;

[0192] R P , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R n5 、R n6 , p and r are as defined in the general formula (IV').

[0193] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III), (II'), (III'), (IV'), (IV) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof:

[0194] in

[0195] R 11 Selected from halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups;

[0196] Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R3a 、R 3b 、R 10 、R n5 、R n6 , p and r are as defined in the general formula (IV).

[0197] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein R P is a hydrogen atom or R PP , R PP -C(O)NR P3 R P4 , R P3 and R P4 As defined in general formula (I); preferably, R P is a hydrogen atom or R PP , R PP -C(O)NR P3 R P4 , R P3 and R P4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; further preferably, R P is selected from hydrogen atom, -C(O)NHCH3 and -C(O)N(CH3)2; more preferably, R P A hydrogen atom.

[0198] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein R P’ is a hydrogen atom or R PP , R PP -C(O)NR P3 R P4 , R P3 and R P4 As defined in general formula (V'); preferably, R P’ is a hydrogen atom or R PP , R PP -C(O)NR P3 R P4 , R P3 and R P4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; further preferably, R P’ is selected from hydrogen atom, -C(O)NHCH3 and -C(O)N(CH3)2; more preferably, R P’ A hydrogen atom.

[0199] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein ring C is a 3- to 14-membered heterocyclyl or a 3- to 14-membered cycloalkyl; in some embodiments, ring C is a 3- to 8-membered heterocyclyl or a 3- to 8-membered cycloalkyl.

[0200] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein ring C is a 3- to 8-membered heterocyclic group or a 3- to 8-membered cycloalkyl group; and / or each R 10 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, -C 1-6 Alkylene-NR n7 R n8 Sum = CR m9 R m10 , R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl, R n7 and R n8 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, Ring C is a 3- to 8-membered heterocyclyl; and / or each R 10 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and =CR m9 R m10 , R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 alkyl; in some embodiments, Ring C is a 3- to 8-membered heterocyclyl; and / or each R 10 The same or different, and each independently halogen or =CR m9 R m10 , R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen and C 1-6In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein ring C is a 3- to 8-membered heterocyclic group; and / or R 10 It is a halogen.

[0201] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or their pharmaceutically acceptable salts, wherein ring C is selected from morpholinyl, Pyrrolidyl, piperidinyl,

[0202] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein ring C is selected from:

[0203] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein Selected from:

[0204] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or their pharmaceutically acceptable salts, wherein ring C is selected from cyclopropyl, azetidine, Morpholinyl, Pyrrolidinyl and piperidinyl; preferably, ring C is selected from cyclopropyl, More preferably, ring C is selected from cyclopropyl, azetidine,

[0205] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein ring C is selected from Morpholinyl, Pyrrolidinyl and piperidinyl; preferably, ring C is selected from More preferably, ring C is selected from

[0206] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein ring C is a 3- to 14-membered heterocyclic group; preferably, ring C is a 3- to 8-membered heterocyclic group; further preferably, ring C is selected from Morpholinyl, and pyrrolidinyl; more preferably, ring C is selected from More preferably, ring C is

[0207] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein Selected from R 10a Selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, =CR m9 R m10 、=NRm11 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -OC(O)NR n7 R n8 、-NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R m9a 、R m9b 、R m10a and R m10b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy and cyano; or R m9a 、R m10a and the carbon atom to which it is attached, or R m9b 、R m10b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl; R m5 、R m6 、R n7 、R n8 、R m9 、 R m10 and R m11 As defined in general formula (I); preferably selected from More preferably, More preferably selected from

[0208] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein Selected from Preferably selected from More preferably

[0209] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein Selected from R 10a Selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, and R m5 、R m6 、R n7 and R n8 As defined in general formula (I); preferably selected from More preferably, More preferably

[0210] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein Selected from Preferably selected from More preferably selected from R10a Selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, =CR m9 R m10 、=NR m11 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -OC(O)NR n7 R n8 、-NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R m9a 、R m9b 、R m10a and R m10b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy and cyano; or R m9a 、R m10a and the carbon atom to which it is attached, or R m9b 、R m10b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl; R m5 、R m6 、R n7 、R n8 、R m9 、R m10 and R m11 As defined in general formula (I).

[0211] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein Selected from Preferably selected from More preferably selected from

[0212] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein each R 10 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 、=CR m9 R m10 、=NR m11 , hydroxyl and C 1-6 Hydroxyalkyl, R m5 、R m6 、R m9 、R m10 and R m11 As defined in Formula (I); in some embodiments, each R 10 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, oxo, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 、=CR m9 R m10 、=NR m11 , hydroxyl and C 1-6 Hydroxyalkyl, R m5 and R m6 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl, R m9and R m10 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, R m11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and hydroxy; in some embodiments, each R 10 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, oxo, C 1-6 Haloalkyl, =CR m9 R m10 Sum = NR m11 , R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl, R m11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy and hydroxy; in some embodiments, each R 10 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, -C 0-6 Alkylene-NR n7 R n8 Sum = CR m9 R m10 , R m9 and R m10 are the same or different and are each independently a hydrogen atom, a halogen and a C 1-6 Alkyl, R n7 and R n8 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R 10 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and =CR m9 R m10 , R m9 and R m10 are the same or different and are each independently a hydrogen atom, a halogen and a C 1-6 alkyl; in some embodiments, each R 10 The same or different, and each independently halogen or =CR m9 R m10 , R m9 and R m10are the same or different and are each independently a hydrogen atom, a halogen and a C 1-6 alkyl; in some embodiments, each R 10 are the same or different and are each independently selected from -CH2-N(CH3)2, methyl, -CH2CHF2, F, =CH 2、 =CHF and =CF2; in some embodiments, each R 10 The same or different, and each independently selected from F, =CH 2、 =CHF and =CF2;.

[0213] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein each R 10 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, and R m5 、R m6 、R n7 and R n8 As defined in general formula (I).

[0214] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein each R 10 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6Haloalkoxy, cyano, -NR m5 R m6 , hydroxyl and C 1-6 Hydroxyalkyl, R m5 and R m6 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; preferably, each R 10 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably halogen; more preferably F.

[0215] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein p is 0, 1, 2 or 3; preferably, p is 0, 1 or 2; more preferably, p is 0 or 1; most preferably, p is 1.

[0216] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R 10a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 , hydroxyl and C 1-6 Hydroxyalkyl, R m5 and R m6 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 10a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; further preferably halogen or C 1-6 Alkyl; more preferably F or methyl.

[0217] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R m5 A hydrogen atom or C 1-6 Alkyl; preferably, R m5 is a hydrogen atom or a methyl group; more preferably, R m5 A hydrogen atom.

[0218] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R MP Selected from hydrogen atom, -C(O)C 1-6 Alkyl and -C(O)OC 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more amino groups; preferably, R MP A hydrogen atom or -C(O)OC 1-6 Alkyl; preferably, R MP is a hydrogen atom or -C(O)O(CH2)5CH3; more preferably, R MP is a hydrogen atom; in some embodiments, R MP It is -C(O)CH(CH3)NH2.

[0219] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein Q 1 is O or NH; preferably, Q 1 It is O.

[0220] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein -Q 1 -R P’ Does not exist, or -Q 1 -R P’ Selected from hydroxyl, amino, -OC(O)NH(C 1-6 alkyl) and -OC(O)N(C 1-6 alkyl) 2; preferably, -Q 1 -R P’ Does not exist, or -Q 1 -R P’is selected from hydroxy, amino, -OC(O)NH(methyl) and -OC(O)N(methyl)2; more preferably, -Q 1 -R P’ Is hydroxy or amino; most preferably, -Q 1 -R P’ It is a hydroxyl group.

[0221] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein G 5 is C or N; preferably, G 5 For C.

[0222] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein G 6 For C.

[0223] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein G 7 is C or N; in some embodiments, G 7 For C.

[0224] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein Selected from R 1 and m are as defined in Formula (V'); in some embodiments, Selected from R 1 and m are as defined in Formula (V'); in some embodiments, Selected from R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and cyano, m is 1, 2 or 3; in some embodiments, Selected from In some embodiments, Selected from In some embodiments,

[0225] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R 10a is a hydrogen atom or a halogen; preferably, R 10a is a hydrogen atom or F.

[0226] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R m9a 、R m9b 、R m10a and R m10b are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein said C 1-6 Alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; preferably, R m9a 、R m9b 、R m10a and R m10b are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; further preferably, R m9a 、R m9b 、R m10a and R m10b are the same or different and are each independently selected from hydrogen, halogen and C 1-6 an alkyl group; more preferably a hydrogen atom or a halogen; more preferably a hydrogen atom or F.

[0227] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R m9 and R m10 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein said C 1-6 Alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 is substituted by one or more substituents selected from the group consisting of haloalkoxy and cyano; preferably, R m9 and R m10 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; further preferably, R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 an alkyl group; more preferably a hydrogen atom or a halogen; more preferably a hydrogen atom or F.

[0228] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R m11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein said C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, oxo, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, hydroxy, C 1-6 substituted by one or more substituents selected from hydroxyalkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; preferably, R m11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and hydroxy; more preferably, R m11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy and hydroxyl groups.

[0229] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein -CH2- or

[0230] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R 3a and R 3b are all hydrogen atoms, or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; preferably, R 3a and R 3b are all hydrogen atoms, or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl group; further preferably, R 3a and R 3b are all hydrogen atoms, or R 3a 、R 3b Together with the same carbon atom to which they are attached, they form a cyclopropyl group; most preferably, R 3a and R 3b All are hydrogen atoms.

[0231] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-1), (IV-2), (V'), (V'-1), (V'-2) or their pharmaceutically acceptable salts, wherein r is 1 or 3.

[0232] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 for G 1 , G 2 , G 3 , G 4 and R 11 As defined in general formula (III); preferably G 1 , G 2 , G 3 , G 4 and R 11 As defined in formula (IV).

[0233] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (III') or (IV') or a pharmaceutically acceptable salt thereof, wherein R 11 A hydrogen atom or C 1-6 alkyl; and / or q is 1 or 2.

[0234] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein R 11 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; preferably, R 11 A hydrogen atom or C 1-6 Alkyl; further preferably, R 11 C 1-6 Alkyl; More preferably, R 11 It is a methyl group.

[0235] In some embodiments of the present disclosure, the compound represented by the general formula (IV-1), (IV-2), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 11 Halogen or C 1-6 Alkyl; preferably, R 11 C 1-6 Alkyl; More preferably, R 11 It is a methyl group.

[0236] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、R 9c and R 9d As defined in general formula (III).

[0237] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein G 2 N; G 3 CR 9c ; G 4 CR 9d ; R 9c and R 9d As defined in general formula (V').

[0238] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein G 1 CR 9a , R 9a As defined in general formula (III); preferably, G 1 Selected from C-NH-C(O)OC 1-6 Alkyl, C-NH2 and C-NH(C 1-6 alkyl); further preferably, G 1 is selected from C-NH-C(O)O(CH2)5CH3, C-NH2 and C-NH(methyl); more preferably, G 1 It is C-NH2.

[0239] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein G 2 is N.

[0240] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein G 3 CR 9c , R 9c As defined in general formula (III); preferably, G 3 For CH.

[0241] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein G 4 CR 9d , R 9d As defined in general formula (III); preferably, G 4 For CH.

[0242] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein R 9a 、R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, hydroxyl and C 1-6 Hydroxyalkyl, R m5 and R m6 As defined in the general formula (I); preferably, R 9a 、R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, amino, hydroxy and C 1-6 Hydroxyalkyl; further preferably, R 9a 、R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 More preferably, R 9a 、R 9b 、R 9c and R 9d are the same or different and are each independently a hydrogen atom or an amino group.

[0243] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1), (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -C(O)NR m5 R m6 、-S(O)2NR m5 R m6 、-C(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, hydroxyl and C 1-6 Hydroxyalkyl, R m5 and R m6 As defined in the general formula (I); preferably, R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, hydroxy and C 1-6 Hydroxyalkyl; further preferably, R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 More preferably, R 9b、R 9c and R 9d All are hydrogen atoms.

[0244] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 1c 、R 1d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR m5 R m6 、C 1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl, R m5 and R m6 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; preferably, R 1a 、R 1b 、R 1c 、R 1d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, R 1a 、R 1b 、R 1c 、R 1d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkyl.

[0245] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein R 1a C 1-6 Alkyl; more preferably, R 1a For ethyl.

[0246] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein R 1b is halogen; more preferably, R 1b For F.

[0247] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein R 1c A hydrogen atom.

[0248] In some embodiments of the present disclosure, the compound represented by the general formula (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein R 1d A hydrogen atom.

[0249] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (IV-1), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably a hydrogen atom or a halogen; more preferably a hydrogen atom or F; more preferably F.

[0250] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (III), (IV), (IV-1), (II'), (III'), (IV'), (IV'-1), (IV'-2), (IV-2), (V'), (V'-1), (V'-2) or pharmaceutically acceptable salts thereof, wherein R m1 、R m2 、R m3 、R m4 、R m5 、R m6 、R m7 、R m8 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、Rn8 、R n9 and R n10 The same or different, and each independently a hydrogen atom or a C 1-6 The alkyl group is preferably a hydrogen atom or a methyl group.

[0251] In some embodiments of the present disclosure, the compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof, wherein R P is a hydrogen atom or R PP , R PP -C(O)NR P3 R P4 , R P3 and R P4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; R 5 is a hydrogen atom; R 8 is a hydrogen atom; q is 1 or 2; Ring C is selected from Morpholinyl and piperidinyl; each R 10 The same or different, and each independently halogen or =CR m9 R m10 , R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; p is 0, 1 or 2; R 3a and R 3b are all hydrogen atoms, or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl group; r is 1 or 3; R 11 C 1-6 Alkyl; G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、 R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and amino; R 1a 、R 1b 、R 1c 、R 1d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 haloalkyl and 3 to 8 membered cycloalkyl; and R 2It is a halogen.

[0252] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom; R 8 is a hydrogen atom; q is 1 or 2; Ring C is selected from Morpholinyl and piperidinyl; each R 10 The same or different, and each independently halogen or =CR m9 R m10 , R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; p is 0, 1 or 2; R 3a and R 3b are all hydrogen atoms, or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl group; r is 1 or 3; R 11 C 1-6 Alkyl; G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and amino; R 1a 、R 1b 、R 1c 、R 1d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 haloalkyl and 3 to 8 membered cycloalkyl; and R 2 It is a halogen.

[0253] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom; R 8 is a hydrogen atom; q is 1 or 2; ring C is or morpholinyl; R 10 is halogen; p is 0 or 1; R 3a and R 3b are all hydrogen atoms, or R 3a 、R 3bTogether with the carbon atom to which it is attached, it forms a cyclopropyl group; r is 1 or 3; R 11 C 1-6 Alkyl; G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、R 9c and R 9d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and amino; R 1a 、R 1b 、R 1c 、R 1d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 haloalkyl and 3 to 8 membered cycloalkyl; and R 2 It is a halogen.

[0254] In some embodiments of the present disclosure, the compound represented by the general formula (IV'), (IV'-1) or (IV'-2) or a pharmaceutically acceptable salt thereof, wherein R P is a hydrogen atom or R PP , R PP -C(O)NR P3 R P4 , R P3 and R P4 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl; Selected from R 11 C 1-6 Alkyl; G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、R 9c and R 9d are the same or different and are each independently a hydrogen atom or an amino group; R 1a C 1-6 Alkyl; R 1b is halogen; R 1c is a hydrogen atom; R 1d is a hydrogen atom; and R2 It is a halogen.

[0255] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein Selected from R 11 C 1-6 Alkyl; G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、R 9c and R 9d are the same or different and are each independently a hydrogen atom or an amino group; R 1a C 1-6 Alkyl; R 1b is halogen; R 1c is a hydrogen atom; R 1d is a hydrogen atom; and R 2 It is a halogen.

[0256] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein Selected from R 11 C 1-6 Alkyl; G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、R 9c and R 9d are the same or different and are each independently a hydrogen atom or an amino group; R 1a C 1-6 Alkyl; R 1b is halogen; R 1c is a hydrogen atom; R 1d is a hydrogen atom; and R 2 It is a halogen.

[0257] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein for R 11 C 1-6 Alkyl; G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、R 9c and R 9d are the same or different and are each independently a hydrogen atom or an amino group; R 1a C 1-6 Alkyl; R 1b is halogen; R 1c is a hydrogen atom; R 1d is a hydrogen atom; and R 2 It is a halogen.

[0258] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1) or (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 11 C 1-6 Alkyl; G 2 N; G 3 CH; G 4 CH; R 2 is halogen; R 5 is a hydrogen atom; R 8 is a hydrogen atom; Selected from Selected from R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and cyano, m is 1, 2 or 3; R m5 A hydrogen atom or C 1-6 alkyl; and R MP A hydrogen atom or -C(O)OC 1-6 alkyl.

[0259] In some embodiments of the present disclosure, the compound represented by the general formula (V'), (V'-1) or (V'-2) or a pharmaceutically acceptable salt thereof, wherein R 11 C 1-6 Alkyl; G 2 N; G 3 CH; G 4 CH; R 2 is halogen; R 5 is a hydrogen atom; R8 is a hydrogen atom; Selected from Selected from Each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and cyano, m is 1, 2 or 3; R m5 A hydrogen atom or C 1-6 alkyl; and R MP A hydrogen atom or -C(O)OC 1-6 alkyl.

[0260] Table A Typical compounds of the present disclosure include, but are not limited to:

[0261] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof,

[0262] in,

[0263] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0264] Ring A 1 , Ring B, Ring C, L 1 , W, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 9 、R 10 , m, n, p and r are as defined in the general formula (II).

[0265] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof,

[0266] in,

[0267] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0268] Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , p, q and r are as defined in the general formula (III).

[0269] Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or a salt thereof,

[0270] in,

[0271] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0272] Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV).

[0273] Another aspect of the present disclosure relates to a compound represented by formula (IV-1A) or (IV-2A) or a salt thereof,

[0274] in,

[0275] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0276] Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV-1).

[0277] Another aspect of the present disclosure relates to a compound represented by general formula (V'A) or a salt thereof,

[0278] in,

[0279] R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist;

[0280] R y1 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB;

[0281] R y2 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB;

[0282] Q 1 , G 2 to G 7 , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in formula (V').

[0283] Another aspect of the present disclosure relates to a compound represented by formula (V'-1A) or (V'-2A) or a salt thereof,

[0284] in,

[0285] R yis a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist;

[0286] R y1 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB;

[0287] R y2 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB;

[0288] Q 1 , G 2 to G 7 , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-1).

[0289] Another aspect of the present disclosure relates to a compound represented by general formula (V'A) or a salt thereof,

[0290] in,

[0291] R y is a hydroxyl protecting group or an amino protecting group, wherein the hydroxyl protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc;

[0292] R y1 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB;

[0293] R y2 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB;

[0294] Q 1 , G 2 to G 7 , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in formula (V').

[0295] Another aspect of the present disclosure relates to a compound represented by formula (V'-1A) or (V'-2A) or a salt thereof,

[0296] in,

[0297] R y is a hydroxyl protecting group or an amino protecting group, wherein the hydroxyl protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc;

[0298] R y1 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB;

[0299] R y2 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB;

[0300] Q 1 , G 2 to G 7 , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in general formula (V'-1). Table B Typical intermediate compounds disclosed herein include but are not limited to:

[0301] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or (II') or a pharmaceutically acceptable salt thereof, the method comprising:

[0302] The compound of general formula (IIA) or its salt is subjected to a deprotection reaction to obtain the compound of general formula (II) or its pharmaceutically acceptable salt; and / or

[0303] The compound of general formula (II) or a pharmaceutically acceptable salt thereof and R P -R LPerforming a substitution reaction to obtain a compound of formula (II') or a pharmaceutically acceptable salt thereof;

[0304] in,

[0305] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0306] R L is a leaving group; preferably a halogen;

[0307] R P R PP ;

[0308] R PP , Ring A 1 , Ring B, Ring C, L 1 , W, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 9 、R 10 , m, n, p and r are as defined in the general formula (II').

[0309] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or (III') or a pharmaceutically acceptable salt thereof, the method comprising:

[0310] The compound of general formula (IIIA) or its salt is subjected to a deprotection reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof; and / or

[0311] The compound of formula (III) or a pharmaceutically acceptable salt thereof and R P -R L Performing a substitution reaction to obtain a compound of formula (III') or a pharmaceutically acceptable salt thereof;

[0312] in,

[0313] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0314] R L is a leaving group; preferably a halogen;

[0315] R P R PP ;

[0316] R PP , Ring C, G 1 , G2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , p, q and r are as defined in the general formula (III').

[0317] Another aspect of the present disclosure relates to a method for preparing a compound represented by formula (IV) or (IV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0318] The compound of general formula (IVA) or its salt is subjected to a deprotection reaction to obtain the compound of general formula (IV) or its pharmaceutically acceptable salt; and / or

[0319] The compound of formula (IV) or a pharmaceutically acceptable salt thereof and R P -R L Performing a substitution reaction to obtain a compound of formula (IV') or a pharmaceutically acceptable salt thereof;

[0320] in,

[0321] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0322] R L is a leaving group; preferably a halogen;

[0323] R P R PP ;

[0324] R PP , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV').

[0325] Another aspect of the present disclosure relates to a method for preparing a compound represented by formula (IV-1) or (IV'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0326] The compound of the general formula (IV-1A) or its salt is subjected to a deprotection reaction to obtain the compound of the general formula (IV-1) or its pharmaceutically acceptable salt; and / or

[0327] The compound of formula (IV-1) or a pharmaceutically acceptable salt thereof and R P -R L Performing a substitution reaction to obtain a compound of formula (IV'-1) or a pharmaceutically acceptable salt thereof;

[0328] in,

[0329] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0330] R L is a leaving group; preferably a halogen;

[0331] R P R PP ;

[0332] R PP , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV'-1).

[0333] Another aspect of the present disclosure relates to a method for preparing a compound represented by formula (IV-2) or (IV'-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0334] The compound of the general formula (IV-2A) or its salt is subjected to a deprotection reaction to obtain the compound of the general formula (IV-2) or its pharmaceutically acceptable salt; and / or

[0335] The compound of formula (IV-2) or a pharmaceutically acceptable salt thereof and R P -R LPerforming a substitution reaction to obtain a compound of formula (IV'-2) or a pharmaceutically acceptable salt thereof;

[0336] in,

[0337] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0338] R L is a leaving group; preferably a halogen;

[0339] R P R PP ;

[0340] R PP , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV'-2).

[0341] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV'-1) and (IV'-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0342] The compound of general formula (IV') or a pharmaceutically acceptable salt thereof is resolved to obtain compounds of general formula (IV'-1) and (IV'-2) or a pharmaceutically acceptable salt thereof;

[0343] in,

[0344] R P , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV'-1).

[0345] Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0346] The compound of general formula (IV) or a pharmaceutically acceptable salt thereof is resolved to obtain the compound of general formula (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof;

[0347] in,

[0348] Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV-1).

[0349] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising:

[0350] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'A) or its salt containing a hydrogen atom or an amino protecting group is subjected to a deprotection reaction to obtain R m5 、R MP and R P’ A compound of the general formula (V') wherein all of the atoms are hydrogen atoms, or a pharmaceutically acceptable salt thereof; or

[0351] R y1 R m5 And R y2 R MP The compound of the general formula (V'A) or its salt is subjected to deprotection reaction to obtain R P’ A compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0352] R P’ A compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V') or a pharmaceutically acceptable salt thereof;

[0353] in,

[0354] R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist;

[0355] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0356] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0357] R L is a leaving group; preferably a halogen;

[0358] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in formula (V').

[0359] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0360] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'-1A) or its salt containing a hydrogen atom or an amino protecting group is subjected to a deprotection reaction to obtain R m5 、R MP and R P’ A compound of the general formula (V'-1) wherein all of the atoms are hydrogen atoms or a pharmaceutically acceptable salt thereof; or

[0361] R y1 R m5 And R y2 R MP The compound of the general formula (V'-1A) or its salt is subjected to deprotection reaction to obtain R P’A compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0362] R P’ The compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof wherein R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof;

[0363] in,

[0364] R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist;

[0365] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0366] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0367] R L is a leaving group; preferably a halogen;

[0368] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-1).

[0369] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V'-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0370] R y1 is a hydrogen atom or an amino protecting group and R y2The compound of the general formula (V'-2A) or its salt wherein the compound is a hydrogen atom or an amino protecting group is subjected to a deprotection reaction to obtain R m5 、R MP and R P’ A compound of the general formula (V'-2) wherein all of the atoms are hydrogen atoms or a pharmaceutically acceptable salt thereof; or

[0371] R y1 R m5 And R y2 R MP The compound of the general formula (V'-2A) or its salt is subjected to deprotection reaction to obtain R P’ A compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0372] R P’ The compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof wherein R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof;

[0373] in,

[0374] R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist;

[0375] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0376] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0377] R L is a leaving group; preferably a halogen;

[0378] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-2).

[0379] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising:

[0380] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'A) or its salt containing a hydrogen atom or an amino protecting group is subjected to a deprotection reaction to obtain R m5 、R MP and R P’ A compound of the general formula (V') wherein all of the atoms are hydrogen atoms, or a pharmaceutically acceptable salt thereof; or

[0381] R y1 R m5 And R y2 R MP The compound of the general formula (V'A) or its salt is subjected to deprotection reaction to obtain R P’ A compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0382] R P’ A compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V') or a pharmaceutically acceptable salt thereof;

[0383] in,

[0384] R y is a hydroxyl protecting group or an amino protecting group, wherein the hydroxyl protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc;

[0385] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0386] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0387] R L is a leaving group; preferably a halogen;

[0388] Q 1 , G 2 to G7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in formula (V').

[0389] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0390] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'-1A) or its salt containing a hydrogen atom or an amino protecting group is subjected to a deprotection reaction to obtain R m5 、R MP and R P’ A compound of the general formula (V'-1) wherein all of the atoms are hydrogen atoms or a pharmaceutically acceptable salt thereof; or

[0391] R y1 R m5 And R y2 R MP The compound of the general formula (V'-1A) or its salt is subjected to deprotection reaction to obtain R P’ A compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0392] R P’ The compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof wherein R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof;

[0393] in,

[0394] R y is a hydroxyl protecting group or an amino protecting group, wherein the hydroxyl protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc;

[0395] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0396] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0397] R L is a leaving group; preferably a halogen;

[0398] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-1).

[0399] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V'-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0400] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'-2A) or its salt wherein the compound is a hydrogen atom or an amino protecting group is subjected to a deprotection reaction to obtain R m5 、R MP and R P’ A compound of the general formula (V'-2) wherein all of the atoms are hydrogen atoms or a pharmaceutically acceptable salt thereof; or

[0401] R y1 R m5 And R y2 R MP The compound of the general formula (V'-2A) or its salt is subjected to deprotection reaction to obtain R P’ A compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0402] R P’ The compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof wherein R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof;

[0403] in,

[0404] R y is a hydroxyl protecting group or an amino protecting group, wherein the hydroxyl protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc;

[0405] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0406] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0407] R L is a leaving group; preferably a halogen;

[0408] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-2).

[0409] Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (V'-1) and (V'-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0410] The compound of general formula (V') or a pharmaceutically acceptable salt thereof is resolved to obtain compounds of general formula (V'-1) and (V'-2) or a pharmaceutically acceptable salt thereof;

[0411] in,

[0412] Q 1 , G 2 to G 7 、R P’ 、R MP 、R m5 , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11, m, p and r are as defined in the general formula (V'-1).

[0413] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0414] The present disclosure further relates to the use of a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting KRAS amplification and / or KRAS mutant activity; wherein the KRAS mutant is preferably selected from one or more of KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations; and more preferably KRAS G12D and / or KRAS G12V mutations.

[0415] The present disclosure further relates to the use of a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or a pharmaceutical composition comprising the same, or a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (III'), (IV'), (IV'-1), (IV'-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a disease or condition mediated by KRAS amplification and / or KRAS mutants; the KRAS mutants are preferably selected from KRAS G12A, One or more of G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations; more preferably KRAS G12D and / or KRAS G12V mutations.

[0416] The present disclosure further relates to the use of a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing cancer; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer , lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0417] The present disclosure further relates to a method for inhibiting KRAS amplification and / or KRAS mutant activity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the KRAS mutant is preferably selected from one or more of KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations; more preferably, KRAS G12D and / or KRAS G12V mutations.

[0418] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by KRAS amplification and / or KRAS mutations, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the KRAS mutation is preferably selected from KRAS One or more of G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations; more preferably KRAS G12D and / or KRAS G12V mutations.

[0419] The present disclosure further relates to a method for treating and / or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, Preferably, the cancer is selected from the group consisting of pancreatic cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; more preferably, the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0420] The present disclosure further relates to a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0421] The present disclosure further relates to a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting KRAS amplification and / or the activity of a KRAS mutant; the KRAS mutant is preferably selected from one or more of KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations; more preferably KRAS G12D and / or KRAS G12V mutations.

[0422] The present disclosure further relates to a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing diseases or conditions mediated by KRAS amplification and / or KRAS mutants; the KRAS mutants are preferably selected from KRAS One or more of G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations; more preferably KRAS G12D and / or KRAS G12V mutations.

[0423] The present disclosure further relates to a compound of formula (I), (II), (III), (IV), (IV-1), (IV-2), (II'), (III'), (IV'), (IV'-1), (IV'-2), (V'), (V'-1), (V'-2) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing cancer; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer , liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0424] The diseases or conditions described in the present disclosure are diseases or conditions that are treated and / or prevented by inhibiting KRAS amplification and / or KRAS mutant activity; the KRAS mutant is preferably selected from one or more of KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations; more preferably KRAS G12D and / or KRAS G12V mutations.

[0425] Preferably, the disease or condition mediated by KRAS amplification and / or KRAS mutations described in the present disclosure is cancer, and the KRAS mutations are preferably selected from one or more of KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V and A146T mutations, more preferably KRAS G12D and / or KRAS G12V mutation; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0426] The colorectal cancer described in the present disclosure is preferably colon cancer or rectal cancer.

[0427] Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyomas, leiomyosarcomas, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma and synovial sarcoma; lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (such as mantle cell lymphoma, diffuse large B-cell lymphoma, follicle center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); liver cancer is preferably hepatocellular carcinoma; lung cancer (also known as bronchogenic carcinoma) is selected from Non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and squamous cell carcinoma; renal cancer is selected from renal cell carcinoma, clear cell and renal oncocytoma; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML); skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; myeloma is preferably multiple myeloma.

[0428] The active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0429] As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms may range from 0.1 to 1000 mg.

[0430] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0431] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0432] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0433] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0434] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0435] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0436] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0437] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0438] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0439] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0440] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0441] Terminology

[0442] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0443] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6 Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0444] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0445] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (ie, C 2-6 Alkenyl). Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0446] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably, the alkynyl group has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 Alkynyl), more preferably an alkynyl having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0447] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14-membered cycloalkyl), preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0448] The term " spiroalkyl " refers to 5 to 20 yuan, a polycyclic group sharing a carbon atom (claiming spiral atom) between monocycle, which can contain one or more double bonds.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example 7, 8, 9 or 10 yuan).According to the number of shared spiral atoms between ring and ring, spiroalkyl is divided into single spiroalkyl or polyspiroalkyl (for example double spiroalkyl), preferably single spiroalkyl and double spiroalkyl.More preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan single spiroalkyl.Non-limiting examples of spiroalkyl include:

[0449] Its connection point can be at any position;

[0450] wait.

[0451] Term " fused cycloalkyl " refers to 5 to 20 yuan, and each ring in the system shares the full carbon polycyclic group of a pair of carbon atoms adjacent to other rings in the system, and wherein one or more rings can contain one or more double bonds.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan).Can be divided into bicyclic or polycyclic fused cycloalkyl (such as tricyclic, tetracyclic) according to the number of composition ring, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic alkyl.The limiting examples of fused cycloalkyl includes:

[0452] Its connection point can be at any position;

[0453] wait.

[0454] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0455] Its connection point can be at any position.

[0456] The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spirocyclic, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0457] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclylthio, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0458] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0459] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl), wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms being carbon. Preferably, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (i.e., 3 to 14-membered heterocyclyl), of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms (i.e., 3 to 8-membered heterocyclyl) or 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms, of which 1-3 are heteroatoms (e.g., 1, 2 and 3); more preferably, it contains 3 to 8 ring atoms, of which 1-3 (e.g., 1, 2 and 3) are heteroatoms; and most preferably, it contains 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl), of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0460] The term "spiro heterocyclic radical" refers to a polycyclic heterocyclic group of 5 to 20 yuan, one atom (called spiral atom) shared between the monocycles, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It can contain one or more double bonds. Preferably, it is 6 to 14 yuan (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan) (i.e., 6 to 14 yuan spiral heterocyclic radical), more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan) (i.e., 7 to 10 yuan spiral heterocyclic radical). According to the number of spiral atoms shared between the rings, the spiral heterocyclic radical is divided into a single spiral heterocyclic radical or a multi-spiro heterocyclic radical (e.g., a double spiral heterocyclic radical), preferably a single spiral heterocyclic radical and a double spiral heterocyclic radical. More preferably, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

[0461] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group having 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., a 6 to 14-membered fused heterocyclyl), and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., a 7 to 10-membered fused heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0462] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein any two rings share two atoms that are not directly connected, and which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., 6 to 14-membered bridged heterocyclic groups), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0463] The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0464] wait.

[0465] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclylthio, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0466] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0467] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclylthio, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0468] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) yuan (i.e., a 5- to 10-membered heteroaryl), further preferably 8 to 10 (e.g., 8, 9, or 10) yuan, more preferably 5 or 6 yuan (i.e., a 5- or 6-membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes heteroaryls as described above fused to aryl, heterocyclyl, or cycloalkyl rings, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include: wait.

[0469] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, haloalkylthio, cycloalkylthio, heterocyclylthio, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0470] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same parent ring atom or two different ring atoms by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

[0471] The term "amino-protecting group" refers to protecting the amino group with a readily removable group to maintain its integrity during reactions elsewhere in the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, benzyl, allyl, p-methylphenylsulfonyl (Ts), and p-methoxybenzyl (PMB). These groups may optionally be substituted with one to three substituents selected from halogen, alkoxy, and nitro groups; preferably, the amino-protecting group is Boc or PMB.

[0472] The term "hydroxy protecting group" refers to a hydroxy derivative that is typically used to block or protect a hydroxy group and reacts on other functional groups of a compound. As an example, preferably, the hydroxy protecting group is, for example, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), tert-butyldiphenylsilyl (TBDPS), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl; the hydroxy protecting group is preferably MOM or TBDPS.

[0473] The term "alkynyl protecting group" refers to a readily removable group introduced onto an alkynyl group in order to maintain the active hydrogen of acetylene or a terminal alkyne while other parts of the molecule undergo reactions. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl. The alkynyl protecting group is preferably TIPS.

[0474] "Leaving group", or leaving group, is an atom or functional group that breaks away from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called a leaving group. Groups that easily accept electrons and have a strong ability to withstand negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, -OTs or -OH.

[0475] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0476] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0477] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0478] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0479] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0480] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0481] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0482] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0483] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0484] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0485] The term "hydroxy" refers to -OH.

[0486] The term "mercapto" refers to -SH.

[0487] The term "amino" refers to -NH2.

[0488] The term "alkylamino" refers to alkyl-NH-, (alkyl)2N-.

[0489] The term "cyano" refers to -CN.

[0490] The term "nitro" refers to -NO2.

[0491] The term "oxo" or "oxo" refers to "=0".

[0492] The term "carbonyl" refers to C=O.

[0493] The term "carboxy" refers to -C(O)OH.

[0494] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0495] MOM stands for methoxymethyl.

[0496] Boc refers to tert-butyloxycarbonyl.

[0497] TIPS refers to triisopropylsilyl.

[0498] TBS refers to tert-butyldimethylsilyl.

[0499] The compounds of the present disclosure may include all forms of rotational isomers and conformationally restricted states thereof. Also included are atropisomers, the term "atropisomer" being a stereoisomer resulting from hindered rotation about a single bond, where the energy difference due to steric strain or other contributing factors forms a sufficiently high rotation barrier to allow separation of individual conformers. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal proportion mixture, a mixture enriched in one atropisomer, etc.) or in the form of a purified atropisomer.

[0500] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerizations. An example of a keto-enol equilibrium is shown below:

[0501] All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

[0502] The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the compounds of the present disclosure may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, or, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereoisomers is typically accomplished by chromatography.

[0503] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0504] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S.18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0505] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0506] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0507] "Substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art will be able to determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0508] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0509] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. Salts may be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0510] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0511] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0512] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0513] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, a number is generally given for illustrative purposes only and is not limiting.

[0514] Synthesis method of the disclosed compound

[0515] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0516] Option 1

[0517] The present disclosure provides a method for preparing a compound represented by general formula (II) or (II') or a pharmaceutically acceptable salt thereof, the method comprising:

[0518] The compound of general formula (IIA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of general formula (II) or its pharmaceutically acceptable salt; and / or

[0519] The compound of general formula (II) or a pharmaceutically acceptable salt thereof and R P -R L The substitution reaction is carried out under alkaline conditions to obtain a compound of formula (II') or a pharmaceutically acceptable salt thereof; wherein,

[0520] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0521] R L is a leaving group; preferably a halogen;

[0522] RP R PP ;

[0523] R PP , Ring A 1 , Ring B, Ring C, L 1 , W, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 9 、R 10 , m, n, p and r are as defined in the general formula (II').

[0524] Option 2

[0525] The present disclosure provides a method for preparing a compound represented by general formula (III) or (III') or a pharmaceutically acceptable salt thereof, the method comprising:

[0526] The compound of general formula (IIIA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of general formula (III) or its pharmaceutically acceptable salt; and / or

[0527] The compound of formula (III) or a pharmaceutically acceptable salt thereof and R P -R L Carrying out a substitution reaction under alkaline conditions to obtain a compound of formula (III') or a pharmaceutically acceptable salt thereof;

[0528] in,

[0529] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0530] R L is a leaving group; preferably a halogen;

[0531] R P R PP ;

[0532] R PP , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 5 、R8 、R 10 、R 11 , p, q and r are as defined in the general formula (III').

[0533] Option 3

[0534] The present disclosure provides a method for preparing a compound represented by general formula (IV) or (IV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0535] The compound of general formula (IVA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of general formula (IV) or its pharmaceutically acceptable salt; and / or

[0536] The compound of formula (IV) or a pharmaceutically acceptable salt thereof and R P -R L Carrying out a substitution reaction under alkaline conditions to obtain a compound of formula (IV') or a pharmaceutically acceptable salt thereof;

[0537] in,

[0538] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0539] R L is a leaving group; preferably a halogen;

[0540] R P R PP ;

[0541] R PP , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV').

[0542] Option 4

[0543] The present disclosure provides a method for preparing a compound represented by general formula (IV-1) or (IV'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0544] The compound of the general formula (IV-1A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of the general formula (IV-1) or its pharmaceutically acceptable salt; and / or

[0545] The compound of formula (IV-1) or a pharmaceutically acceptable salt thereof and R P -R L Carrying out a substitution reaction under alkaline conditions to obtain a compound of formula (IV'-1) or a pharmaceutically acceptable salt thereof;

[0546] in,

[0547] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0548] R L is a leaving group; preferably a halogen;

[0549] R P R PP ;

[0550] R PP , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV'-1).

[0551] Plan 5

[0552] The present disclosure provides a method for preparing a compound represented by general formula (IV-2) or (IV'-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0553] The compound of general formula (IV-2A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of general formula (IV-2) or its pharmaceutically acceptable salt; and / or

[0554] The compound of formula (IV-2) or a pharmaceutically acceptable salt thereof and R P -R L Carrying out a substitution reaction under alkaline conditions to obtain a compound of formula (IV'-2) or a pharmaceutically acceptable salt thereof;

[0555] in,

[0556] R y is a hydroxyl protecting group; preferably MOM or TBDPS, more preferably MOM;

[0557] R L is a leaving group; preferably a halogen;

[0558] R P R PP ;

[0559] R PP , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV'-2).

[0560] Plan 6

[0561] The present disclosure provides a method for preparing the compounds represented by general formula (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0562] The compound of general formula (IV) or a pharmaceutically acceptable salt thereof is separated by chiral column to obtain compounds of general formula (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof;

[0563] in,

[0564] Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV-1).

[0565] Plan 7

[0566] The present disclosure provides a method for preparing the compounds represented by general formula (IV'-1) and (IV'-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0567] The compound of general formula (IV') or a pharmaceutically acceptable salt thereof is separated by chiral column to obtain compounds of general formula (IV'-1) and (IV'-2) or a pharmaceutically acceptable salt thereof;

[0568] in,

[0569] R P , Ring C, G 1 , G 2 , G 3 , G 4 、R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3a 、R 3b 、R 10 、R 11 , p and r are as defined in the general formula (IV'-1).

[0570] Plan 8

[0571] The present disclosure provides a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising:

[0572] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'A) or its salt which is a hydrogen atom or an amino protecting group is subjected to a deprotection reaction under acidic conditions to obtain R m5 、R MP and R P’ A compound of the general formula (V') wherein all of the atoms are hydrogen atoms, or a pharmaceutically acceptable salt thereof; or

[0573] R y1 R m5 And R y2 R MP The compound of general formula (V'A) or its salt is subjected to deprotection reaction under alkaline conditions to obtain R P’ A compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0574] R P’ The compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein R is a hydrogen atom is reacted with PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V') or a pharmaceutically acceptable salt thereof;

[0575] in,

[0576] R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist;

[0577] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0578] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0579] R L is a leaving group; preferably a halogen;

[0580] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in formula (V').

[0581] Plan 9

[0582] The present disclosure provides a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0583] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'-1A) or its salt, which is a hydrogen atom or an amino protecting group, is subjected to a deprotection reaction under acidic conditions to obtain R m5 、R MP and R P’ A compound of the general formula (V'-1) wherein all of the atoms are hydrogen atoms or a pharmaceutically acceptable salt thereof; or

[0584] R y1 R m5 And R y2 R MPThe compound of the general formula (V'-1A) or its salt is subjected to a deprotection reaction under alkaline conditions to obtain R P’ A compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0585] R P’ The compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof wherein R is a hydrogen atom is reacted with PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof;

[0586] in,

[0587] R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist;

[0588] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0589] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0590] R L is a leaving group; preferably a halogen;

[0591] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-1).

[0592] Plan 10

[0593] The present disclosure provides a method for preparing a compound represented by general formula (V'-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0594] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'-2A) or its salt, which is a hydrogen atom or an amino protecting group, is subjected to a deprotection reaction under acidic conditions to obtain R m5 、R MP and R P’ A compound of the general formula (V'-2) wherein all of the atoms are hydrogen atoms or a pharmaceutically acceptable salt thereof; or

[0595] R y1 R m5 And R y2 R MP The compound of the general formula (V'-2A) or its salt is subjected to a deprotection reaction under alkaline conditions to obtain R P’ A compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0596] R P’ The compound of the general formula (V'-2) or its pharmaceutically acceptable salt is a hydrogen atom under alkaline conditions with R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof;

[0597] in,

[0598] R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist;

[0599] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0600] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0601] R L is a leaving group; preferably a halogen;

[0602] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-2).

[0603] Plan 11

[0604] The present disclosure provides a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising:

[0605] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'A) or its salt which is a hydrogen atom or an amino protecting group is subjected to a deprotection reaction under acidic conditions to obtain R m5 、R MP and R P’ A compound of the general formula (V') wherein all of the atoms are hydrogen atoms, or a pharmaceutically acceptable salt thereof; or

[0606] R y1 R m5 And R y2 R MP The compound of general formula (V'A) or its salt is subjected to deprotection reaction under alkaline conditions to obtain R P’ A compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0607] R P’ The compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein R is a hydrogen atom is reacted with PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V') or a pharmaceutically acceptable salt thereof;

[0608] in,

[0609] R y is a hydroxyl protecting group or an amino protecting group, wherein the hydroxyl protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc;

[0610] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0611] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0612] R L is a leaving group; preferably a halogen;

[0613] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in formula (V').

[0614] Plan 12

[0615] The present disclosure provides a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0616] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'-1A) or its salt, which is a hydrogen atom or an amino protecting group, is subjected to a deprotection reaction under acidic conditions to obtain R m5 、R MP and R P’ A compound of the general formula (V'-1) wherein all of the atoms are hydrogen atoms or a pharmaceutically acceptable salt thereof; or

[0617] R y1 R m5 And R y2 R MP The compound of the general formula (V'-1A) or its salt is subjected to a deprotection reaction under alkaline conditions to obtain R P’ A compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0618] R P’ The compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof wherein R is a hydrogen atom is reacted with PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof;

[0619] in,

[0620] R yis a hydroxyl protecting group or an amino protecting group, wherein the hydroxyl protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc;

[0621] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0622] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0623] R L is a leaving group; preferably a halogen;

[0624] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-1).

[0625] Plan 13

[0626] The present disclosure provides a method for preparing a compound represented by general formula (V'-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0627] R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'-2A) or its salt, which is a hydrogen atom or an amino protecting group, is subjected to a deprotection reaction under acidic conditions to obtain R m5 、R MP and R P’ A compound of the general formula (V'-2) wherein all of the atoms are hydrogen atoms or a pharmaceutically acceptable salt thereof; or

[0628] R y1 R m5 And R y2 R MP The compound of the general formula (V'-2A) or its salt is subjected to a deprotection reaction under alkaline conditions to obtain R P’ A compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or

[0629] R P’ The compound of the general formula (V'-2) or its pharmaceutically acceptable salt is a hydrogen atom under alkaline conditions with R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V'-2) or a pharmaceutically acceptable salt thereof;

[0630] in,

[0631] R y is a hydroxyl protecting group or an amino protecting group, wherein the hydroxyl protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc;

[0632] R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB;

[0633] R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB;

[0634] R L is a leaving group; preferably a halogen;

[0635] Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-2).

[0636] Plan 14

[0637] The present disclosure provides a method for preparing the compounds represented by general formula (V'-1) and (V'-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0638] The compound of general formula (V') or a pharmaceutically acceptable salt thereof is separated by chiral column to obtain compounds of general formula (V'-1) and (V'-2) or a pharmaceutically acceptable salt thereof;

[0639] in,

[0640] Q1 , G 2 to G 7 、R P’ 、R m5 、R MP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in the general formula (V'-1).

[0641] The reagents providing acidic conditions in the above synthesis scheme include organic acids and inorganic acids, the organic acids include but are not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf; the inorganic acids include but are not limited to hydrogen chloride, 1,4-dioxane hydrochloric acid solution, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably 1,4-dioxane hydrochloric acid solution, trifluoroacetic acid or trifluoromethanesulfonic acid; more preferably 1,4-dioxane hydrochloric acid solution.

[0642] In the above synthesis scheme, the base providing alkaline conditions includes organic bases and inorganic bases, and the organic bases include but are not limited to tetrabutylammonium fluoride, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, anhydrous potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the base providing alkaline conditions is N,N-diisopropylethylamine or tetrabutylammonium fluoride, and more preferably N,N-diisopropylethylamine.

[0643] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, trifluoroacetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION

[0644] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0645] Example

[0646] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0647] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0648] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0649] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0650] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0651] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0652] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0653] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0654] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0655] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0656] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0657] Unless otherwise specified in the examples, the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0658] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0659] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0660] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0661] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0662] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0663] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0664] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0665] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0666] Example 1

[0667] 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 1 (mixture of diastereomers)

[0668] first step

[0669] tert-Butyl 4-((tert-Butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate 1b

[0670] 2,6-Dichloro-3-fluoropyridin-4-amine 1a (1.8 g, 9.94 mmol, prepared by the method disclosed in Preparation 14(a) on page 46 of the specification of patent application "WO2016191524A1") was dissolved in tetrahydrofuran (50 mL). A 2M solution of sodium bistrimethylsilylamide in tetrahydrofuran (20 mL) was added under ice-cooling. After stirring for 0.5 hour, di-tert-butyl dicarbonate (6.5 g, 29.7 mmol) was added and the reaction was stirred for 14 hours. The reaction solution was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (1 g, yield: 26.3%).

[0671] MS m / z (ESI): 381.1 [M+1].

[0672] Step 2

[0673] tert-Butyl 4-amino-2,6-dichloro-5-fluoronicotinate 1c

[0674] Compound 1b (1 g, 2.62 mmol) was dissolved in ethyl acetate (8 mL), and a 4 M hydrochloric acid solution in dioxane (3 mL) was added. The reaction was stirred for 2 hours. The pH was adjusted to neutral with a 4 M aqueous sodium hydroxide solution under ice-bath conditions. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 1c (500 mg, yield: 67.8%).

[0675] MS m / z (ESI): 281.1 [M+1].

[0676] Step 3

[0677] tert-Butyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate 1d

[0678] Compound 1c (500 mg, 1.77 mmol) was dissolved in tetrahydrofuran (10 mL), and trichloroacetyl isocyanate (670 mg, 3.55 mmol, Shanghai Hanhong) was added. The mixture was stirred for 30 minutes, and the reaction solution was concentrated under reduced pressure to give the crude title compound 1d (835 mg), which was used directly in the next step without purification.

[0679] MS m / z (ESI): 467.9 [M+1].

[0680] Step 4

[0681] 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol 1e

[0682] The crude compound 1d (835 mg, 1.77 mmol) was dissolved in 7 M ammonia methanol solution (10 mL) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and methyl tert-butyl ether (10 mL) was added to the residue. After stirring for 0.5 hour, the mixture was filtered and the filter cake was dried to give the crude title compound 1e (400 mg, yield: 89.9%), which was used directly in the next step without purification.

[0683] MS m / z (ESI): 249.9 [M+1].

[0684] Step 5

[0685] 2,5,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol 1f

[0686] The crude compound 1e (2 g, 8 mmol) was dissolved in phosphorus oxychloride (25 mL), and N,N-diisopropylethylamine (5.16 g, 40 mmol) was added. The mixture was stirred at 110°C for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and 20% potassium carbonate solution was added dropwise to adjust the pH to 2-3. The mixture was stirred for 2 hours and then filtered. The filter cake was washed with water and dried to obtain the crude title compound 1f (1.5 g). The product was used in the next step without purification.

[0687] MS m / z (ESI): 267.8 [M+1].

[0688] Step 6

[0689] (±)-2-((1-(2-aminopyridin-3-yl)ethyl)amino)ethan-1-ol 1h

[0690] 1-(2-Aminopyridin-3-yl)ethan-1-one 1g (3.2g, 23.5mmol, Shanghai Bidex) was dissolved in methanol (50mL), and ethanolamine (2.87g, 47mmol) and tetraisopropyl titanate (8.69g, 30.57mmol) were added, and the reaction was carried out at 70°C for 6 hours. Sodium cyanoborohydride (3.52g, 58.84mmol) was added, and the reaction was carried out at 70°C for 14 hours. After the reaction solution was cooled to room temperature, water was added to quench it, and the solution was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1h (1.8g, yield: 42%).

[0691] MS m / z (ESI): 182.2 [M+1].

[0692] Step 7

[0693] (±)-5-(2-((1-(2-aminopyridin-3-yl)ethyl)amino)ethoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol 1i

[0694] Compound 1h (100 mg, 551.7 μmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (57.8 mg, 1.50 mmol, 60% purity) was added under ice-cooling. After 30 minutes of reaction, compound 1f (135 mg, 502.86 μmol) was added and the reaction was stirred for 1 hour. The reaction solution was quenched by water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 1i (117 mg, yield: 56%).

[0695] MS m / z (ESI): 413.2 [M+1].

[0696] Step 8

[0697] 5-(2-((1-(2-aminopyridin-3-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol 1j (mixture of diastereomers)

[0698] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (42 mg, 265.4 μmol, Yao Ming) was dissolved in tetrahydrofuran (3 mL) and sodium hydride (19.28 mg, 503.34 μmol, 60% purity) was added under ice-cooling. After 30 minutes of reaction, compound 1i (104 mg, 251.67 μmol) was added and the reaction was stirred for 14 hours. The reaction solution was quenched by water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 1j (mixture of diastereomers) (60 mg, yield: 44%).

[0699] MS m / z (ESI): 536.2 [M+1].

[0700] Step 9

[0701] 3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 1k (mixture of diastereomers)

[0702] Compound 1j (60 mg, 111.94 μmol) was dissolved in chloroform (2 mL), and N,N-diisopropylethylamine (28.93 mg, 223.9 μmol) and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (37 mg, 145.5 μmol, sigma) were added. The reaction was carried out at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1k (mixture of diastereomers) (22 mg, yield: 38%).

[0703] MS m / z (ESI): 518.2 [M+1].

[0704] Step 10

[0705] 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine 1l (mixture of diastereomers)

[0706] Compound 1k (22 mg, 42.47 μmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22 mg, 61 μmol, prepared by the method disclosed in Intermediate 18 on page 104 of the specification of patent application "WO2021 / 041671") were dissolved in 1.4-dioxane (2 mL) and water (0.4 mL), and cesium carbonate (44 mg, 135.04 μmol) and tetrakistriphenylphosphine palladium (9 mg, 7.8 μmol, Shanghai Titan) were added. The reaction was carried out at 100 ° C. under a nitrogen atmosphere for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1l (mixture of diastereomers) (30 mg). The product was used directly in the next step without purification.

[0707] MS m / z (ESI): 716.2 [M+1].

[0708] Step 11

[0709] 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 1 (mixture of diastereomers)

[0710] The crude compound 11 (30 mg, 41.9 μmol) was dissolved in ethyl acetate (2 mL), and a 4 M hydrochloric acid solution in 1,4-dioxane (0.5 mL) was added under ice bath. The reaction was maintained at the temperature for 0.5 hour, and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 1 (mixture of diastereomers) (1.4 mg, yield: 5%).

[0711] MS m / z (ESI): 672.2 [M+1].

[0712] 1H NMR(500MHz,CD3OD)δ7.99(d,1H),7.79(d,1H),7.67(dd,1H),7.32-7.05(m,2H),6.84- 6.77(m,1H),6.64(d,1H),5.35(d,2H),4.50(td,1H),4.45-4.31(m,2H),3.80(td,1H), 3.63(dd,1H),3.54(dd,1H),3.47(s,1H),3.07(s,1H),2.54(dd,1H),2.47-2.24(m,3H) ,2.05(s,2H),1.95(d,1H),1.70(t,2H),1.63(s,1H),1.35-1.31(m,3H),0.90(dq,3H).

[0713] Examples 1-p1 and 1-p2

[0714] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 1-p1

[0715] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 1-p2

[0716] Compound 1 (18 mg) was separated by chiral column (Gilson 281, chromatographic column: CHIRALPAK IC, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% NH3), gradient ratio: A:B: 60:40, flow rate: 20 mL / min) to give the title compounds 1-p1 (8 mg, 44.4%) and 1-p2 (8 mg, 44.4%).

[0717] MS m / z (ESI): 672.2 [M+1].

[0718] Chiral HPLC analysis method for the isomer mixture: retention times were 6.552 min and 9.058 min, respectively (chromatographic column: CHIRALPAK IC, 250*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1.0 mL / min).

[0719] Single configuration compound (shorter retention time) 1-p2: 6.552 min (8 mg, yield: 44.4%).

[0720] MS m / z (ESI): 672.2 [M+1].

[0721] HPLC analysis: retention time 1.44 minutes, purity: 96% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0722] 1 H NMR(500MHz,CD3OD)δ7.99(dt,1H),7.82-7.77(m,1H),7.67(ddd,1H),7.30-7.05(m,2H), 6.82(ddd,1H),6.64(q,1H),5.43-5.30(m,2H),4.54-4.31(m,5H),3.84-3.76(m,1H),3.6 8-3.60(m,1H),3.55(dd,1H),3.51-3.46(m,1H),3.13-3.06(m,1H),2.54(dq,2H),2.48-2 .31(m,3H),2.31-2.24(m,1H),2.21(q,1H),2.10-2.03(m,2H),1.71(d,2H),0.89(dt,3H).

[0723] Single configuration compound (longer retention time) 1-p1: 9.058 min (8 mg, yield: 44.4%).

[0724] MS m / z (ESI): 672.2 [M+1].

[0725] HPLC analysis: retention time 1.44 minutes, purity: 96% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1×50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0726] 1H NMR(500MHz,CD3OD)δ7.99(dt,1H),7.82-7.77(m,1H),7.67(ddd,1H),7.30-7.05(m,2H) ,6.85-6.78(m,1H),6.64(q,1H),5.43-5.27(m,2H),4.56-4.30(m,5H),3.80(td,1H),3. 67-3.60(m,1H),3.58-3.51(m,1H),3.51-3.45(m,1H),3.08(dt,1H),2.54(dq,2H),2.46 -2.34(m,2H),2.30(dd,1H),2.22(q,2H),2.10-1.98(m,2H),1.70(t,2H),0.89(dt,3H).

[0727] Example 2

[0728] (±)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 2

[0729] first step

[0730] (1-(Morpholinomethyl)cyclopropyl)methanol 2b

[0731] 1-Aminomethylcyclopropanemethanol 2a (1 g, 9.89 mmol, Shanghai Shaoyuan) and bis(2-bromoethyl) ether (2.3 g, 9.91 mmol, Shanghai Bid) were dissolved in acetonitrile (60 mL), and anhydrous sodium carbonate (3.1 g, 29.52 mmol) was added. The reaction solution was refluxed for 14 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 2b (1.3 g, yield: 76.7%).

[0732] MS m / z (ESI): 172.2 [M+1].

[0733] Subsequently, the synthetic route in Example 1 was adopted to replace the raw material of the eighth step ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol with compound 2b to obtain the title compound 2 (8 mg, yield: 8.5%).

[0734] MS m / z (ESI): 684.2 [M+1].

[0735] 1H NMR(500MHz,DMSO-d6)δ7.97(dd,1H),7.77(d,1H),7.64(dd,1H),7.26-7.19(m,1H),7.04(dd,1H),6.79(dd,1H),6.63(d,1H),4.58-4.30(m,5H ),3.66(d,3H),3.61-3.47(m,2H),2.52(s,4H),2.19(t,1H),2.03(s,2H ),1.74-1.56(m,4H),0.97-0.83(m,4H),0.77-0.69(m,2H),0.51(s,2H).

[0736] Examples 2-p1 and 2-p2

[0737] (R)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 2-p1

[0738] (S)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 2-p2

[0739] Compound 2 (10 mg) was separated by chiral column (Gilson 281, chromatographic column: CHIRALPAK IC, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% NH3), gradient ratio: A:B: 50:50, flow rate: 20 mL / min) to give the title compound (3 mg, yield 30%).

[0740] MS m / z (ESI): 684.2 [M+1].

[0741] Single configuration compound (shorter retention time) (3 mg, yield 30%)

[0742] Chiral HPLC analysis method: retention time 10.288 min, purity: 99% (chromatographic column: CHIRALPAK IC, 250*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1.0 mL / min).

[0743] 1 H NMR(500MHz,CD3OD)δ7.99(dt,1H),7.79(dd,1H),7.67(ddd,1H),7.25(td,1H),7.06(dd,1H),6.82(dd,1H),6.66(q,1 H),4.68–4.17(m,5H),3.74–3.53(m,5H),2.58–2.39(m,7H),1.71(t,4H),0.93–0.85(m,4H),0.76(q,2H),0.54(s,2H).

[0744] Single configuration compound (longer retention time) (3 mg, yield 30%)

[0745] MS m / z (ESI): 672.2 [M+1].

[0746] Chiral HPLC analysis method: retention time 17.191 min, purity: 99% (chromatographic column: CHIRALPAK IC, 250*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1.0 mL / min).

[0747] 1 H NMR(500MHz,CD3OD)δ7.99(dt,1H),7.79(d,1H),7.67(dd,1H),7.25(td,1H),7.06(dd,1H),6.82(dd,1H),6.65(d,1H ),4.63–4.26(m,5H),3.73–3.53(m,5H),2.60–2.39(m,7H),1.71(t,4H),0.95–0.87(m,4H),0.77(d,2H),0.55(s,2H).

[0748] Example 3

[0749] (±)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 3

[0750] first step

[0751] 1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-1-one 3b

[0752] 3-Acetyl-2-chloropyridine 3a (50 g, 321.4 mmol, Shanghai Bid) was dissolved in N,N-dimethylformamide (500 mL), and bis(4-methoxybenzyl)amine (124 g, 481.9 mmol, Shanghai Shaoyuan) was added. The reaction was carried out at 120°C for 16 hours. The reaction solution was cooled to room temperature and filtered. Water was added to the filtrate, and the mixture was extracted with ethyl acetate (250 mL×3). The organic phases were washed with water and combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3b (60.5 g, yield: 50%).

[0753] MS m / z (ESI): 377.0 [M+1].

[0754] Step 2

[0755] (±)-2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethan-1-ol 3c

[0756] Compound 3b (60.5 g, 160.7 mmol) and ethanolamine (24.5 g, 401.1 mmol) were dissolved in methanol (250 mL), and tetraisopropyl titanate (137 g, 482 mmol, Shanghai Shaoyuan) was added. After reacting at 70°C for 3 hours, sodium cyanoborohydride (33 g, 551.7 mmol) was added and the reaction was continued for 17 hours. After the reaction solution was cooled to room temperature, water (15 mL) was added to quench it, and a large amount of solid precipitated. Dichloromethane (200 mL) was added to dilute it, and the product was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 3c (35 g, yield: 51.7%).

[0757] MS m / z (ESI): 422.2 [M+1].

[0758] Step 3

[0759] (±)-5-(2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol 3d

[0760] Compound 3c (4.8 g, 11.4 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium hydride (1.75 g, 45.5 mmol, purity 60%) was added under ice-cooling. After 30 minutes of reaction, compound 1f (3.6 g, 13.4 mmol) was added. The mixture was naturally stirred at room temperature for 16 hours. The reaction solution was quenched by water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 3d (7.4 g, yield: 99%).

[0761] MS m / z (ESI): 653.2 [M+1].

[0762] Step 4

[0763] (±)-3-(1-(2,5-dichloro-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 3e

[0764] Compound 3d (7.4 g, 11.3 mmol) was dissolved in chloroform (100 mL), and N,N-diisopropylethylamine (2.9 g, 22.6 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (4.1 g, 15.8 mmol) were added. The mixture was reacted at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 3e (2.5 g, yield: 34.7%).

[0765] MS m / z (ESI): 635.2 [M+1].

[0766] Step 5

[0767] (±)-3-(1-(5-chloro-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 3f

[0768] Compound 3e (435.9 mg, 685.9 μmol) and (2,6-dimethylidenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (170 mg, 1 mmol, prepared by the method disclosed in Example 4 on page 29 of the specification of patent application "WO2022247757") were dissolved in tetrahydrofuran (6 mL), and a 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.7 mL) was added dropwise under ice bath. The temperature was maintained and stirred for 1 hour. The reaction solution was quenched by addition of saturated aqueous ammonium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 3f (500 mg, yield: 95.3%).

[0769] MS m / z (ESI): 764.2 [M+1].

[0770] Step 6

[0771] (±)-3-(1-(2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 3g

[0772] Compound 3f (520 mg, 680.4 μmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (367 mg, 1 mmol) were dissolved in 1.4-dioxane (5 mL) and water (1 mL). Cesium carbonate (665 mg, 2 mmol) and tetrakistriphenylphosphine palladium (100 mg, 86.5 μmol) were added, and the reaction was carried out at 105° C. under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 3g (600 mg, yield: 91.6%).

[0773] MS m / z (ESI): 962.2 [M+1].

[0774] Step 7

[0775] (±)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 3

[0776] Compound 3g (600 mg, 623.6 μmol) was dissolved in trifluoroacetic acid (5 mL), and trifluoromethanesulfonic acid (0.5 mL) was added under ice bath. The reaction was maintained at the temperature for 0.5 hour and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and the pH was adjusted to 7 with saturated sodium carbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-42%, flow rate: 30 mL / min) to give the title compound 3 (8 mg, yield: 1.9%).

[0777] MS m / z (ESI): 678.1 [M+1].

[0778] 1 H NMR(500MHz,CD3OD)δ8.03–7.95(m,1H),7.79(d,1H),7.71–7.62(m,1H),7 .32–7.27(m,1H),7.06(d,1H),6.81(dd,1H),6.63(d,1H),5.07–5.03(m,4 H),4.54–4.31(m,4H),3.88–3.73(m,3H),3.67–3.40(m,3H),2.83(d,2H), 2.66–2.48(m,3H),2.39(s,1H),2.21(t,1H),1.69(t,3H),0.91(ddd,3H).

[0779] Examples 3-p1 and 3-p2

[0780] (R)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 3-p1

[0781] (S)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 3-p2

[0782] Racemate 3 (12 mg) was separated by chiral column (Gilson 281, chromatographic column: CHIRALPAK IC, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% NH3), gradient ratio: A:B: 60:40, flow rate: 20 mL / min) to give the title compounds 3-p1 (5 mg, yield: 12.7%) and 3-p2 (5 mg, yield: 12.7%).

[0783] Chiral HPLC analysis method for the isomer mixture: retention times were 7.278 min and 11.508 min, respectively (chromatographic column: CHIRALPAK IC, 250*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1.0 mL / min).

[0784] Single configuration compound (shorter retention time) 3-p2, 7.278 min (5 mg, yield: 12.7%).

[0785] MS m / z (ESI): 678.2 [M+1].

[0786] HPLC analysis: retention time 1.53 minutes, purity: 98% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0787] 1 H NMR (500MHz, CD3OD): δ8.00(d,1H),7.80(d,1H),7.68(dd,1H),7.32–7.24(m,1H),7.08–7.03(m,1H),6.87–6.80(m,1H),6.62(d,1H),5.18(d, 4H),4.55–4.10(m,5H),3.89–3.54(m,5H),2.98(t,2H),2.75(dd,2H), 2.54(t,1H),2.39(t,1H),2.21(t,1H),1.70(t,3H),0.96–0.84(m,3H).

[0788] Single configuration compound (longer retention time): 3-p1, 11.508 min (5 mg, yield: 12.7%).

[0789] MS m / z (ESI): 678.2 [M+1].

[0790] HPLC analysis: retention time 1.53 minutes, purity: 98% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0791] 1 H NMR (500MHz, CD3OD): δ8.00(dd,1H),7.80(d,1H),7.74–7.63(m,1H),7.28(dd,1H),7.06(dd,1H),6.83(ddd,1H),6.61(dd,1H),5.28–5.04(m,4H),4 .59–4.18(m,5H),3.92–3.55(m,5H),3.03(t,2H),2.80(dd,2H),2.54(p,1 H),2.43–2.32(m,1H),2.24–2.18(m,1H),1.70(t,3H),0.96–0.82(m,3H).

[0792] Example 4

[0793] 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 4 (mixture of isomers)

[0794] The synthetic route in Example 3 was adopted, and the raw material in the fifth step (2,6-dimethylidenetetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol was replaced with (2-(difluoromethylidene)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (prepared by the method disclosed in Example 11 on page 54 of the specification of patent application "WO2022247757") to obtain the title compound 4.

[0795] MS m / z (ESI): 702.2 [M+1].

[0796] Examples 4-p1, 4-p2, 4-p3, 4-p4

[0797] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 4-p1

[0798] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-2-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 4-p2

[0799] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 4-p3

[0800] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 4-p4

[0801] Compound 4 was resolved on a chiral column to give the title compound.

[0802] MS m / z (ESI): 702.2 [M+1].

[0803] Example 5

[0804] (±)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 5-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol

[0805] first step

[0806] (±)-(1-(((10-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-5-chloro-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-2-yl)oxy)methyl)cyclopropyl)methanol 5a

[0807] Compound 3e (300 mg, 472 μmol), 1,1-cyclopropane dimethanol (73 mg, 714.8 μmol, Shanghai LeYan), molecular sieves (500 mg, 944.1 μmol), and cesium carbonate (307 mg, 942.2 μmol) were mixed in dioxane (25 mL) and stirred at 110°C for 16 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5a (180 mg). The product was used directly in the next step without purification.

[0808] MS m / z (ESI): 701.0 [M+1].

[0809] Step 2

[0810] (±)-(1-(((10-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-2-yl)oxy)methyl)cyclopropyl)methanol 5b

[0811] The crude compound 5a (180 mg, 256.7 μmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (139 mg, 358.9 μmol) were dissolved in 1.4-dioxane (20 mL) and water (4 mL). Cesium carbonate (251 mg, 770.3 μmol) and tetrakistriphenylphosphine palladium (30 mg, 26 μmol, Shanghai Titan) were added, and the reaction was carried out at 100° C. under a nitrogen atmosphere for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 5b (200 mg, yield: 86.6%).

[0812] MS m / z (ESI): 899.2 [M+1].

[0813] Step 3

[0814] (±)-(1-(((10-(1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-2-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate 5c

[0815] Compound 5b (200 mg, 222.47 μmol) was dissolved in dichloromethane (10 mL). Methanesulfonyl chloride (39 mg, 340.4 μmol) and N,N-diisopropylethylamine (87 mg, 673.1 μmol) were added in an ice bath and the reaction was maintained at this temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5c (200 mg). The product was used directly in the next step without further purification.

[0816] MS m / z (ESI): 977.2 [M+1].

[0817] Step 4

[0818] (±)-3-(1-(2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 5d

[0819] Compound 5c (52 mg, 306.6 μmol), anhydrous potassium carbonate (86 mg, 622.2 μmol), sodium iodide (32 mg, 213.5 μmol), and 4-(difluoromethylidene)piperidine hydrochloride (52 mg, 306.6 μmol, prepared by the method disclosed in the literature "Bioorganic and Medicinal Chemistry, 2004, vol. 12, #7, p. 1713-1730") were mixed in acetonitrile (5 mL) and reacted at 80°C for 1 hour. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound 5d (75 mg), which was used directly in the next step without purification.

[0820] MS m / z (ESI): 1014.2 [M+1].

[0821] Step 5

[0822] (±)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 5-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol

[0823] The crude compound 5d (75 mg, 74 μmol) was dissolved in trifluoroacetic acid (2 mL), and trifluoromethanesulfonic acid (0.2 mL) was added under ice-bath. The reaction was maintained at the temperature for 0.5 hour and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and the pH was adjusted to 7 with saturated sodium carbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-42%, flow rate: 30 mL / min) to give the title compound 5 (5 mg, 16.7%).

[0824] MS m / z (ESI): 730.2 [M+1].

[0825] 1 H NMR(500MHz,CD3OD)δ8.00-7.98(m,1H),7.80-7.77(m,1H),7.68-7.66(m,1H),7.29-7.25(m,2H),7. 07-7.05(m,1H),6.82-6.80(m,1H),6.67-6.65(m,1H),5.36-5.35(m,1H),4.52-4.49(m,3H),4.47-4. 43(m,1H),3.81-3.75(m,1H),3.61-3.55(m,2H),2.56-2.53(m,5H),2.51-2.49(m,1H),2.47-2.35(m ,1H),2.23-2.21(m,4H),1.71-1.68(m,3H),0.93-0.88(m,5H),0.77-0.75(m,2H),0.52-0.50(m,2H).

[0826] Examples 5-p1 and 5-p2

[0827] (R)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 5-p1

[0828] (S)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 5-p2

[0829] Compound 5 was resolved on a chiral column to give the title compound.

[0830] MS m / z (ESI): 730.2 [M+1].

[0831] Example 6

[0832] (Z)-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 6 (mixture of isomers)

[0833] The synthetic route in Example 3 was used to replace the raw material in the fifth step (2,6-dimethylidenetetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol with (Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (prepared by the method disclosed in Example 2 on page 24 of the specification of patent application "WO2022247757") to obtain the title compound 6.

[0834] MS m / z(ESI):684.2[M+1].

[0835] Example 6-p1, 6-p2, 6-p3, 6-p4

[0836] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((S,Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 6-p1

[0837] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((S,Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 6-p2

[0838] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((R,Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 6-p3

[0839] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((R,Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 6-p4

[0840] The diastereoisomer mixture 6 was separated by chiral column to give the title compound.

[0841] MS m / z (ESI): 684.2 [M+1].

[0842] Example 7

[0843] 4-(10-(-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 7 (mixture of isomers)

[0844] The synthetic route in Example 3 was adopted, and the raw material in the fifth step (2,6-dimethylidenetetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol was replaced with (2-methylidenetetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (prepared by the method disclosed in Example 1 on page 22 of the specification of patent application "WO2022247757") to obtain the title compound 7.

[0845] MS m / z (ESI): 666.2 [M+1].

[0846] Examples 7-p1, 7-p2, 7-p3, 7-p4

[0847] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((S)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 7-p1

[0848] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((S)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 7-p2

[0849] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((R)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 7-p3

[0850] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((R)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 7-p4

[0851] The diastereoisomer mixture 7 was separated by chiral column to give the title compound.

[0852] MS m / z (ESI): 666.2 [M+1].

[0853] Example 8

[0854] (E)-4-(10-(-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 8 (mixture of isomers)

[0855] The synthetic route in Example 3 was used to replace the raw material in the fifth step (2,6-dimethylidenetetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol with (E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (prepared by the method disclosed in Example 3 on page 28 of the specification of patent application "WO2022247757") to obtain the title compound 8.

[0856] MS m / z(ESI):684.2[M+1].

[0857] Example 8-p1, 8-p2, 8-p3, 8-p4

[0858] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((S,E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 8-p1

[0859] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((S,E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 8-p2

[0860] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((R,E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 8-p3

[0861] 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((R,E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 8-p4

[0862] The diastereoisomer mixture 8 was separated by chiral column to give the title compound.

[0863] MS m / z (ESI): 684.2 [M+1].

[0864] Example 9

[0865] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ylmethylcarbamate

[0866] Compound 1-p1 (326 mg, 485.2 μmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (125 mg, 970.6 μmol) and methylaminocarbonyl chloride (52 mg, 556 μmol, Anaiji) were added. The reaction was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by high-performance liquid preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 9 (200 mg, yield: 56.5%).

[0867] MS m / z(ESI):727.0[M-1].

[0868] 1H NMR(500MHz,DMSO-d6)δ8.02–7.84(m,2H),7.78(t,1H),7.64(ddd,1H),7.50(td,1H),7.2 4(t,1H),6.68(ddd,1H),6.38(q,1H),5.78(s,1H),5.70(s,1H),5.30(d,1H),4.46(td,1H) ,4.32(ddd,1H),4.15(d,2H),3.75(ddd,1H),3.40(ddd,1H),3.15–3.00(m,3H),2.88–2.80 (m,1H),2.73–2.65(m,2H),2.41(tdd,2H),2.24–1.72(m,8H),1.59(dd,3H),0.85(dt,3H).

[0869] Example 10

[0870] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-yldimethylcarbamate

[0871] Compound 1-p1 (20 mg, 29.77 μmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (7.7 mg, 59.8 μmol) and p-nitrophenyl chloroformate (6.6 mg, 32.7 μmol) were added under ice-cooling. The temperature was maintained for 1 hour, and then dimethylamine hydrochloride (48.2 mg, 595.5 μmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 10 (6 mg, yield: 27.1%).

[0872] MS m / z (ESI): 742.9 [M+1].

[0873] 1H NMR (500MHz, CD3OD): δ8.13–7.95(m,1H),7.89(dd,1H),7.87–7.73(m,2H),7.39(t,1H) ,7.32(t,1H),6.81(td,1H),6.65(q,1H),5.33(d,1H),4.61–4.39(m,3H),4.35(s,2H),3 .79(dd,1H),3.58(ddd,2H),3.47(s,1H),3.23(s,1H),3.18(d,3H),3.03(d,3H),2.61( dd,2H),2.50–2.13(m,6H),2.03(dq,2H),1.97–1.88(m,2H),1.70(t,2H),0.92(dt,2H).

[0874] Example 11

[0875] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 11 (mixture of diastereomers)

[0876] first step

[0877] (S)-2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethan-1-ol 11a-1

[0878] (R)-2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethan-1-ol 11a-2

[0879] The racemate 3c (67 g) was separated by chiral column (Waters SFC 150, column: 250*40mm 10μm; mobile phase A: Supercritical CO2, mobile phase B: ethanol + 0.1% 7M ammonia methanol solution, gradient ratio: A:B: 82:18, flow rate: 130mL / min) to obtain the title compounds 11a-1 (25g, yield: 37.3%) and 11a-2 (29.6g, yield: 44.1%).

[0880] Single configuration compound (shorter retention time) 11a-1 (25 g, yield: 37.3%)

[0881] MS m / z (ESI): 422.2 [M+1].

[0882] Chiral HPLC analysis method: retention time 1.607min, purity: 99% (chromatographic column: 100*3mm 3μm; mobile phase A: Supercritical CO2, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 85:15, flow rate: 1.5mL / min).

[0883] Single configuration compound (longer retention time) 11a-2 (29.6 g, yield: 44.1%)

[0884] MS m / z (ESI): 422.2 [M+1].

[0885] Chiral HPLC analysis method: retention time 2.137min, purity: 99% (chromatographic column: 100*3mm 3μm; mobile phase A: Supercritical CO2, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 85:15, flow rate: 1.5mL / min).

[0886] Step 2

[0887] (R)-5-(2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol 11b

[0888] Compound 11a-2 (12.6 g, 29.9 mmol) was dissolved in tetrahydrofuran (200 mL), and sodium hydride (3.4 g, 89.6 mmol, purity 60%) was added under ice bath. After reacting for 30 minutes, compound 1f (8.8 g, 32.9 mmol) was added. The mixture was naturally returned to room temperature with stirring for 16 hours. Water was added to the reaction solution to quench the reaction and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 11b (23 g, yield: 117.7%).

[0889] MS m / z (ESI): 653.2 [M+1].

[0890] Step 3

[0891] (R)-3-(1-(2,5-dichloro-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 11c

[0892] Compound 11b (23 g, 35.2 mmol) was dissolved in chloroform (500 mL), and N,N-diisopropylethylamine (9 g, 69.6 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (11.6 g, 45.6 mmol) were added. The mixture was reacted at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 11c (5.2 g, yield: 23.2%).

[0893] MS m / z (ESI): 635.2 [M+1].

[0894] Step 4

[0895] 3-((1R)-1-(5-chloro-2-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 11d (mixture of diastereomers)

[0896] Compound 11c (200 mg, 314.7 μmol) and (2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (90 mg, 475.7 μmol, prepared by the method disclosed in Example 11 on page 54 of the specification of patent application "WO2022247757") were dissolved in tetrahydrofuran (3 mL), and a 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.35 mL) was added dropwise under an ice bath. The temperature was maintained and stirred for 1 hour. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 11d (mixture of diastereomers) (168 mg, yield: 67.7%).

[0897] MS m / z (ESI): 788.2 [M+1].

[0898] Step 5

[0899] 3-((1R)-1-(2-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalene

[0900] -10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 11e (mixture of diastereomers)

[0901] Compound 11d (168 mg, 213.1 μmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120 mg, 333.1 μmol) were dissolved in 1.4-dioxane (3.5 mL) and water (0.7 mL). Cesium carbonate (200 mg, 613.8 μmol) and tetrakistriphenylphosphine palladium (50 mg, 43.2 μmol) were added, and the mixture was reacted at 105° C. under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 11e (mixture of diastereomers) (150 mg, yield: 71.4%).

[0902] MS m / z (ESI): 986.2 [M+1].

[0903] Step 6

[0904] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 11 (mixture of diastereomers)

[0905] Compound 11e (280 mg, 284 μmol) was dissolved in trifluoroacetic acid (5 mL), and trifluoromethanesulfonic acid (0.5 mL) was added under ice bath. The reaction was maintained at the temperature for 0.5 hour, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and the pH was adjusted to 7 with saturated sodium carbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-42%, flow rate: 30 mL / min) to give the title compound 11 (mixture of diastereomers) (20 mg, yield: 28.5%).

[0906] MS m / z (ESI): 702.2 [M+1].

[0907] 1H NMR(500MHz,CD3OD)δ8.02–7.97(m,1H),7.79(d,1H),7.67(dd,1H),7.30-7.05(m,2H),6.81(dd,1H),6.65(q,1H),4.53–4.32(m,4H),3.88–3.75 (m,2H),3.66–3.49(m,3H),2.86(t,2H),2.75(d,1H),2.57(d,2H),2.39 (s,1H),2.20(q,2H),2.08–1.92(m,3H),1.70(t,2H),0.95–0.85(m,3H).

[0908] Example 12

[0909] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 4-p1

[0910] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 4-p3

[0911] The diastereoisomer mixture 11 (15 mg) was separated by chiral column (Gilson 281, chromatographic column: CHIRALPAK IC, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% NH3), gradient ratio: A:B: 60:40, flow rate: 20 mL / min) to give the title compound (3 mg, yield: 20%), (3.9 mg, yield: 26%).

[0912] Single configuration compound (shorter retention time): (3 mg, yield: 20%)

[0913] MS m / z (ESI): 702.2 [M+1].

[0914] Chiral HPLC analysis method: retention time 9.440 min, purity: 93.8% (chromatographic column: CHIRALPAK IG (IG00CD-UF003), 0.46 cm ID × 15 cm L; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 60:40, flow rate: 1 mL / min).

[0915] 1 H NMR (500MHz, CD3OD): δ7.99(dt,1H),7.79(d,1H),7.67(td,1H),7.30–7.05(m ,2H),6.81(dd,1H),6.65(q,1H),4.54–4.31(m,4H),3.87–3.74(m,2H),3.62(d d,4H),2.84(d,1H),2.77–2.70(m,1H),2.56(d,2H),2.42–2.37(m,1H),2.19(d dd,2H),2.07–2.02(m,1H),1.97-1.93(m,2H),1.70(t,2H),0.95–0.85(m,3H).

[0916] Single configuration compound (longer retention time): (3.9 mg, yield: 26%)

[0917] MS m / z (ESI): 702.2 [M+1].

[0918] Chiral HPLC analysis method: retention time 11.101 min, purity: 90.2% (chromatographic column: CHIRALPAK IG (IG00CD-UF003), 0.46 cm ID × 15 cm L; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 60:40, flow rate: 1 mL / min).

[0919] 1H NMR (500MHz, CD3OD): δ7.99(dt,1H),7.82–7.77(m,1H),7.70–7.63(m,1H),7 .29–7.05(m,2H),6.81(dd,1H),6.65(q,1H),4.56–4.32(m,4H),3.86–3.73(m ,2H),3.66–3.46(m,3H),2.86(d,1H),2.73(q,1H),2.53(dd,2H),2.44–2.33( m,1H),2.27–2.15(m,2H),2.09–1.87(m,4H),1.70(t,2H),0.95–0.85(m,3H).

[0920] Example 13

[0921] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 13 (mixture of diastereomers)

[0922] The synthetic route in Example 11 was used to replace the raw material of the fourth step (2-(difluoromethylidene)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol with (2-methylidenetetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (prepared by the method disclosed in Example 1 on page 22 of the specification of patent application "WO2022247757") to obtain the title compound 13 (a mixture of diastereomers) (1.2 mg, yield: 17%).

[0923] MS m / z (ESI): 666.2 [M+1].

[0924] 1H NMR (500MHz, CD3OD): δ7.99(s,1H),7.79(d,1H),7.67(t,1H),7.39–7.19(m,2H),7.06(t,1H) ,6.81(t,1H),6.76–6.58(m,1H),5.49(s,1H),5.36(t,1H),4.59–4.23(m,3H),3.88–3.72(m, 1H),3.67–3.49(m,1H),3.07(s,1H),2.95(d,1H),2.55(d,1H),2.39(s,1H),2.21(t,2H),2.0 5(d,1H),1.88(d,1H),1.75–1.64(m,2H),1.62(s,2H),1.45–1.18(m,7H),1.04–0.68(m,3H).

[0925] Example 14

[0926] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol (mixture of diastereomers) 14

[0927] The synthetic route in Example 11 was used to replace the raw material of the fourth step (2-(difluoromethylidene)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol with ((2-(fluoromethylidene)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (prepared using the method disclosed in Example 5 on page 32 of the specification of patent application "WO2022247757") to obtain the title compound 14 (a mixture of diastereomers) (10 mg, yield: 28.3%).

[0928] MS m / z (ESI): 684.2 [M+1].

[0929] 1H NMR (500MHz, CD3OD): δ7.99(dt,1H),7.79(d,1H),7.71–7.59(m,1H),7.40–7.15(m,2H), 7.06(t,1H),6.81(dd,1H),6.68(d,1H),6.65(d,1H),4.65–4.11(m,4H),3.88(d,1H),3.7 9(td,2H),3.68–3.59(m,1H),3.55–3.44(m,1H),3.19(s,1H),2.88(s,1H),2.75(dt,3H) ,2.55(ddd,2H),2.40(d,1H),2.19(d,1H),2.05–1.84(m,4H),1.70(t,2H),0.90(dt,3H).

[0930] Example 15

[0931] 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol (mixture of diastereomers) 15

[0932] The synthetic route in Example 3 was used to replace the raw material of the fifth step (2,6-dimethylidenetetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol with [(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]methanol (Nanjing Yaoshi) to obtain the title compound (a mixture of diastereomers) 15 (15 mg, yield: 16.4%).

[0933] MS m / z(ESI):664.2[M+1].

[0934] 1H NMR(500MHz,CD3OD)δ7.99(dq,1H),7.80(dd,1H),7.67(ddd,1H),7.32–7.03(m,2 H),6.82(ddd,1H),6.66(q,1H),4.71–4.58(m,2H),4.50(td,1H),4.38(ddd,1H),3 .79(tdd,1H),3.62(ddd,1H),3.54(ddd,1H),3.47–3.40(m,1H),3.11(tt,1H),2. 84–2.72(m,1H),2.65–2.49(m,5H),2.45–2.31(m,2H),1.70(t,3H),0.90(dt,3H).

[0935] Example 15-p1, 15-p2

[0936] 4-(10-(((S)-1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 15-p1

[0937] 4-(10-(((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 15-p2

[0938] The diastereoisomer mixture 15 (12 mg) was separated by chiral column (Gilson 281, chromatographic column: CHIRALPAK IC, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% NH3), gradient ratio: A:B: 60:40, flow rate: 20 mL / min) to obtain the title compound (5 mg, yield: 41.6%).

[0939] MS m / z (ESI): 664.2 [M+1].

[0940] Chiral HPLC analysis method for the isomer mixture: retention times were 5.708 min and 7.595 min, respectively (chromatographic column: CHIRALPAK IC, 250*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1.0 mL / min).

[0941] Single configuration compound (shorter retention time): 5.708 min (5 mg, yield: 41.6%)

[0942] MS m / z (ESI): 664.2 [M+1].

[0943] HPLC analysis: retention time 1.41 minutes, purity: 98% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0944] 1 H NMR(500MHz,CD3OD)δ7.99(dd,1H),7.80(d,1H),7.72–7.63(m,1H),7.32–7.0 4(m,2H),6.85–6.79(m,1H),6.66(q,1H),4.70–4.58(m,2H),4.50(td,1H),4.3 8(ddd,1H),3.80(td,1H),3.59(ddd,1H),3.49–3.41(m,1H),3.11(s,1H),2.83 –2.72(m,1H),2.64-2.37(m,7H),2.05(s,1H),1.70(t,3H),0.94-0.87(m,3H).

[0945] Single configuration compound (longer retention time): 7.595 min (5 mg, yield: 41.6%)

[0946] MS m / z (ESI): 664.2 [M+1].

[0947] HPLC analysis: retention time 1.41 minutes, purity: 98% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0948] 1H NMR(500MHz,CD3OD)δ7.99(dd,1H),7.80(d,1H),7.71–7.64(m,1H),7.31–7.03 (m,2H),6.82(dd,1H),6.66(q,1H),4.68(dt,1H),4.60(dd,1H),4.50(td,1H), 4.38(ddd,1H),3.79(td,1H),3.62(dd,1H),3.54(dd,1H),3.49–3.39(m,1H),3 .15–3.08(m,1H),2.77(ddd,1H),2.65-2.52(m,4H),2.44–2.30(m,2H),2.05(s, 1H),1.70(t,3H),0.98–0.84(m,3H).

[0949] Example 16

[0950] 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 16 (mixture of diastereomers)

[0951] The synthetic route in Example 3 was used to replace the raw material of the fifth step (2,6-dimethylidenetetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol with (S)-(1-(2,2-difluoroethyl)azetidine-2-yl)methanol (prepared by the method disclosed in Intermediate 12 on page 149 of the specification of the patent application "WO2022173678") to obtain the title compound 16 (a mixture of diastereomers) (3 mg, yield: 14.2%).

[0952] MS m / z(ESI):664.2[M+1].

[0953] 1H NMR(500MHz,CD3OD)δ8.01(s,1H),7.81(d,1H),7.67(t,1H),7.39–7.17(m,2H),7.06(d,1H) ),6.83(t,1H),6.67(q,1H),6.03–5.68(m,1H),4.67–4.22(m,3H),3.96–3.71(m,2H),3.72 –3.57(m,1H),3.25–3.00(m,1H),2.97–2.78(m,1H),2.58–2.51(m,1H),2.50–2.34(m,1H), 2.22(td,2H),2.05(s,1H),1.70(t,2H),1.63(s,1H),1.38–1.23(m,5H),1.04–0.77(m,3H).

[0954] Example 17

[0955] 2-Amino-4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 17

[0956] first step

[0957] 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 17a

[0958] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (6 g, 37.9 mmol) was dissolved in tetrahydrofuran (50 mL), and a 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (25.5 mL) was added under ice-bath. The temperature was maintained for 30 minutes, and then the mixture was added dropwise to a solution of compound 11c (18 g, 28.3 mol) in tetrahydrofuran (250 mL) under ice-bath. The temperature was maintained for 0.5 hours with stirring. The reaction solution was quenched by the addition of saturated aqueous ammonium chloride solution, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was slurried with isopropanol (50 mL), filtered, and the filter cake was dried to give the crude title compound 17a (16 g).

[0959] MS m / z (ESI): 758.2 [M+1].

[0960] Step 2

[0961] tert-Butyl (4-(10-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate 17c

[0962] The crude compound 17a (500 mg, 659.4 μmol) and tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate 17b (400 mg, 989.4 μmol, prepared by the method described in the Preparation Method on page 50 of the specification of the patent application "WO2021118877") were prepared. 15) was dissolved in 1.4-dioxane (10 mL), and cesium carbonate (537 mg, 1.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (97 mg, 132.5 μmol) were added. The mixture was reacted at 105°C under a nitrogen atmosphere for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 17c (748 mg, yield: 111%).

[0963] MS m / z (ESI): 1014.2 [M+1].

[0964] Step 3

[0965] 2-Amino-4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 17

[0966] Compound 17c (610 mg, 601.5 μmol) was dissolved in trifluoroacetic acid (5 mL), and trifluoromethanesulfonic acid (0.5 mL) was added. The reaction was maintained at the temperature for 1 hour, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 17 (96 mg, yield: 23.6%).

[0967] MS m / z (ESI): 674.4 [M+1].

[0968] 1 H NMR(500MHz,CD3OD)δ8.00–7.95(m,1H),7.76(d,1H),7.40(dd,1H),7.04(t,1H), 6.78(dd,1H),6.60(q,1H),5.42(t,0.5H),5.32(t,0.5H),4.48(dd,1H),4.45–4.3 3(m,3H),3.78(dd,1H),3.58(dd,1H),3.48–3.35(m,2H),3.11(td,1H),2.50–2.28 (m,2H),2.24(dd,1H),2.07(dq,2H),2.02–1.91(m,1H),1.66(d,3H),1.31(q,1H).

[0969] Example 18

[0970] 6-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 18

[0971] MS m / z (ESI): 658.4 [M+1].

[0972] Example 19

[0973] 3-((1R)-1-(5-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 19

[0974] first step

[0975] 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 19a

[0976] Compound 17a (1 g, 1.3188 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred at 50°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The pH was adjusted to pH>7 with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude title compound 19a (680 mg). The product was used directly in the next step without purification.

[0977] MS m / z (ESI): 518.2 [M+1].

[0978] Step 2

[0979] tert-Butyl (tert-butoxycarbonyl)(3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-yl)carbamate 19b

[0980] The crude compound 19a (600 mg, 1.16 mmol) was dissolved in dichloromethane (6 mL), and 4-dimethylaminopyridine (142.5 mg, 1.1569 mmol), triethylamine (1.17 g, 11.58 mmol), and di-tert-butyl dicarbonate (3.8 g, 17.3 mmol) were added. The reaction was stirred for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 19b (600 mg, yield: 72.1%).

[0981] MS m / z (ESI): 718.4 [M+1].

[0982] Step 3

[0983] tert-Butyl (3-((R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-yl)(tert-butoxycarbonyl)carbamate 19d

[0984] Compound 19b (250 mg, 348 μmol), 2-fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 19c (238 mg, 484.3 μmol, Example 27a and 27b) was dissolved in 1,4-dioxane (3 mL) and water (0.4 mL), and potassium phosphate (147.8 mg, 696 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50.9 mg, 69.6 μmol) were added. The mixture was reacted at 100°C under a nitrogen atmosphere for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 19d (250 mg, yield: 68.5%).

[0985] MS m / z (ESI): 1047.4 [M+1].

[0986] Step 4

[0987] tert-Butyl (3-((1R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-6-iodo-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-yl)(tert-butyloxycarbonyl)carbamate 19e

[0988] Compound 19d (0.5 g, 477.5 μmol) was dissolved in acetic acid (5 mL), and N-iodosuccinimide (150.4 mg, 668.5 μmol) was added under ice-cooling. The reaction was stirred at the maintained temperature for 20 minutes, and then saturated sodium sulfite solution was added to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 19e (250 mg, yield: 44.6%).

[0989] MS m / z (ESI): 1173.4 [M+1].

[0990] Step 5

[0991] tert-Butyl (3-((1R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-yl)(tert-butoxycarbonyl)carbamate 19f

[0992] Compound 19e (50 mg, 42.6 μmol) was dissolved in N,N-dimethylformamide (2 mL), and cuprous iodide (40 mg, 213 μmol) and methyl fluorosulfonyldifluoroacetate (82 mg, 426 μmol) were added. The mixture was reacted at 100°C under a nitrogen atmosphere for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 19f (47 mg). The product was used directly in the next step without purification.

[0993] MS m / z (ESI): 1115.4 [M+1].

[0994] Step 6

[0995] 3-((1R)-1-(5-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 19

[0996] The crude compound 19f (45 mg, 40.3 μmol) was dissolved in trifluoroacetic acid (0.5 mL), and trifluoromethanesulfonic acid (0.05 mL) was added. After stirring for 2 hours, the reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 19 (5 mg, yield: 18.3%).

[0997] MS m / z (ESI): 675.4 [M+1].

[0998] 1 H NMR(500MHz,CD3OD)δ8.22(d,1H),7.98(s,1H),7.12–7.00(m,1H),6.89(d,1H),6.62(dt,1H),5.61(d,1H),4.81–4.67(m,2H),4.64–4.55( m,1H),4.47(td,1H),3.92(dd,4H),3.78–3.58(m,1H),3.49(d,1H),2.70–2.56(m,1H),2.40(d,6H),2.21(t,1H),1.74(d,3H),1.62(s,1H).

[0999] Example 20

[1000] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[d]thiazol-2-amine

[1001] first step

[1002] tert-Butyl (4-(10-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate 20b

[1003] The crude compound 17a (50 mg, 65.9 μmol) and (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid 20a (20.8 mg, 98.6 μmol, prepared by the method disclosed in Preparation 25 on page 56 of the specification of the patent application "WO2021118877") were dissolved in 1.4-dioxane (10 mL) and water (2 mL), and cesium carbonate (64.5 mg, 197.9 μmol) and tetrakistriphenylphosphine palladium (15.2 mg, 13.1 μmol) were added. The reaction was carried out at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 20b (30 mg, yield: 46%).

[1004] MS m / z (ESI): 990.2 [M+1].

[1005] Step 2

[1006] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[d]thiazol-2-amine

[1007] Compound 20b (30 mg, 30.3 μmol) was dissolved in trifluoroacetic acid (0.5 mL), and trifluoromethanesulfonic acid (0.05 mL) was added under ice-bath. The reaction was maintained at the temperature for 1 hour, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 20 (5 mg, yield: 25.3%).

[1008] MS m / z (ESI): 650.4 [M+1].

[1009] 1 H NMR (500MHz, CD3OD): δ7.98(dd,1H),7.78(dd,1H),7.43(dd,1H),7.00(t,1H),6.80(dd,1H),6.63(d,1H),5.64–5.23(m,1H),4.48(dd,1H), 4.51–4.18(m,5H),3.78(dd,1H),3.56(dd,1H),3.27–3.20(m,3H),3.05(q,1H),2.68–2.12(m,5H),2.02(dt,2H),1.94(dd,1H),1.68(d,3H).

[1010] Example 21

[1011] 3-((R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 21

[1012] first step

[1013] 3-((R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 21b

[1014] The crude compound 17a (3.5 g, 4.61 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline 21a (2.1 g, 6.53 mmol, prepared by the method disclosed in Example 80 on page 257 of the specification of the patent application "WO2022148422"), tetrakis(triphenylphosphine)palladium (533.4 mg, 461.6 μmol), and cesium carbonate (4.5 g, 13.8 mmol) were mixed in 1,4-dioxane (50 mL) and water (10 mL). The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 21b (3.6 g, yield: 85%).

[1015] MS m / z (ESI): 917.2 [M+1].

[1016] Step 2

[1017] 3-((R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 21

[1018] Compound 21b (3.6 g, 3.9 mmol) was dissolved in trifluoroacetic acid (20 mL), reacted at 50°C for 5 hours, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), and 2M sodium hydroxide solution (20 mL) was added under ice bath, and the reaction was carried out at 60°C for 1 hour. The reaction solution was cooled to room temperature and diluted with water, and extracted with ethyl acetate (50 mL×2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 21 (1.6 g, yield: 61.5%).

[1019] MS m / z (ESI): 677.2 [M+1].

[1020] 1 H NMR(500MHz,CD3OD)δ7.98(dd,1H),7.77(d,1H),6.90(d,1H),6.80(dd,1H),6.62(q,1H),6.50(s,1H),5.34(d,1H),4.52–4.41(m,1H),4.4 0–4.29(m,3H),3.80–3.71(m,1H),3.56(dd,1H),3.30–3.22(m,2H),3.11–3.02(m,1H),2.32–2.13(m,3H),2.08–1.93(m,3H),1.67(d,4H).

[1021] Example 22

[1022] 3-((1R)-1-(5-(5-chloro-6-methyl-1H-indazol-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 22

[1023] first step

[1024] 3-((1R)-1-(5-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 22b

[1025] The crude compound 17a (220 mg, 290.1 ​​μmol) and 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 22a (160 mg, 290.1 ​​μmol) were prepared by the method disclosed in Int-30 on page 30 of the specification of patent application "US2019248767". The mixture was stirred for 1 h at 37°C for 24 h. The mixture was stirred for 3 hours. The mixture was stirred for 1 h. Preparation of 2-[4-(2-methyl-1-oxo-4-nitropropene)-2-nitropropene] ...

[1026] MS m / z (ESI): 972.2 [M+1].

[1027] Step 2

[1028] 3-((1R)-1-(5-(5-chloro-6-methyl-1H-indazol-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 22

[1029] Compound 22b (230 mg, 236.5 μmol) was dissolved in trifluoroacetic acid (3 mL), stirred for 1 hour, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 22 (60 mg, yield: 39.1%).

[1030] MS m / z (ESI): 648.2 [M+1].

[1031] 1 H NMR(500MHz,CD3OD)δ7.99(d,1H),7.79(d,1H),7.74(s,1H),7.64(s,1H),6.81(dd,1H),6.65(d,1H),5.29(d,1H),4.51(q,1H),4.46–4. 34(m,3H),3.82(dt,1H),3.59(s,1H),3.31–3.21(m,2H),3.05(td,1H),2.60(s,3H),2.43–2.16(m,4H),2.08–1.88(m,3H),1.69(t,3H).

[1032] Example 23

[1033] (3-((R)-1-(5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid hexyl ester 23

[1034] first step

[1035] 3-((R)-1-(5-(3-((tert-Butyldiphenylsilyl)oxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine 23a

[1036] Compound 1-p1 (100 mg, 148.9 μmol) was dissolved in dichloromethane (10 mL), and imidazole (50.7 mg, 744.3 μmol), 4-dimethylaminopyridine (18 mg, 149 μmol), and tert-butyldiphenylsilyl chloride (122.8 mg, 446.6 μmol) were added. The reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 23a (113 mg, yield: 83.4%).

[1037] MS m / z (ESI): 910.2 [M+1].

[1038] Step 2

[1039] (3-((R)-1-(5-(3-(tert-Butyldiphenylsilyl)oxy)-8-ethyl-7-fluoronaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid hexyl ester 23b

[1040] Compound 23a (100 mg, 109.9 μmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (42.6 mg, 329.6 μmol) was added. Hexyl chloroformate (21.7 mg, 131.8 μmol, Shanghai Bidex) was added dropwise. The reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 23b (37 mg, yield: 32.4%).

[1041] Step 3

[1042] (3-((R)-1-(5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamic acid hexyl ester 23

[1043] Compound 23b (150 mg, 144.5 μmol) was dissolved in tetrahydrofuran (1.5 mL), and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (723 μL) was added. The reaction was stirred for 10 minutes and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give the title compound 23 (10 mg, yield: 34.1%).

[1044] MS m / z (ESI): 799.9 [M+1].

[1045] 1 H NMR(500MHz,CD3OD)δ8.49–8.44(m,1H),8.16(t,1H),7.67(dd,1H),7.50(dt,1H),7.28–6.97(m,3H),5.34(d,1H),4.52–4.27(m,4H),3.88– 3.65(m,3H),3.08–3.01(m,1H),2.59–2.18(m,5H),2.07–2.00(m,2H), 1.80–1.65(m,8H),1.48–1.40(m,5H),1.05(t,6H),0.94–0.85(m,6H).

[1046] Example 24

[1047] 5-Ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(1-(2-(methylamino)pyridin-3-yl)ethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)naphth-2-ol 24

[1048] first step

[1049] 1-(2-(Methylamino)pyridin-3-yl)ethan-1-one 24a

[1050] Compound 3a (5 g, 32.1 mmol) and methylamine hydrochloride (4.3 g, 63.6 mmol) were mixed in N,N-dimethylformamide (50 mL), and cesium carbonate (41.8 g, 128.3 mmol) was added. The mixture was reacted at 110°C for 2 hours. The reaction solution was cooled to room temperature and filtered. Water was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were washed with water and combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 24a (2.1 g, yield: 43.5%).

[1051] MS m / z (ESI): 151.2 [M+1].

[1052] Step 2

[1053] (±)-3-(1-(2,5-dichloro-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)-N-methylpyridin-2-amine 24b

[1054] The second to fourth steps of the synthetic route in Example 3 were adopted, and the starting material compound 3b in the second step was replaced by compound 24a to obtain the title compound 24b (1 g, yield: 50%).

[1055] MS m / z (ESI): 409.2 [M+1].

[1056] Step 3

[1057] 3-(1-(5-Chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)-N-methylpyridin-2-amine 24c

[1058] Compound 24b (120 mg, 293.2 μmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (46.4 mg, 293.2 μmol) were dissolved in tetrahydrofuran (6 mL). A 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.3 mL) was added dropwise under ice-bath. The reaction was stirred at the maintained temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution for quenching. The mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with water and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure to give the crude title compound 24c (mixture of diastereomers) (200 mg).

[1059] MS m / z (ESI): 532.2 [M+1].

[1060] Step 4

[1061] 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthalen-10-yl)ethyl)-N-methylpyridin-2-amine 24d

[1062] The crude compound 24c (200 mg, 376 μmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (203 mg, 563.8 μmol), tetrakis(triphenylphosphine)palladium (86.8 mg, 75.1 μmol), and cesium carbonate (367.4 mg, 1.1 mmol) were mixed in 1,4-dioxane (10 mL) and water (2 mL). The mixture was reacted at 100° C. under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to give the title compound 24d (mixture of diastereomers) (150 mg, yield: 54.6%).

[1063] MS m / z (ESI): 730.2 [M+1].

[1064] Step 5

[1065] 5-Ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(1-(2-(methylamino)pyridin-3-yl)ethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)naphth-2-ol 24

[1066] Compound 24d (300 mg, 411.1 μmol) was dissolved in acetonitrile (3 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane was added under ice-bath. The reaction was stirred at the maintained temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL / min) to give the title compound 24 (mixture of diastereomers) (100 mg, yield: 35.4%).

[1067] MS m / z (ESI): 686.2 [M+1].

[1068] 1 H NMR (500MHz, CD3OD): δ8.07(t,1H),7.73(d,1H),7.67(dd,1H),7.35–7.19(m,2H),7.06 (dd,1H),6.74(dd,1H),6.61–6.53(m,1H),5.40(s,1H),4.50(dt,1H),4.47–4.27(m,3H ),3.81(td,2H),3.58(ddd,2H),3.31–3.18(m,3H),3.06(s,1H),2.94(d,3H),2.63–2.5 2(m,1H),2.49–2.15(m,5H),2.05(d,2H),2.00–1.89(m,1H),1.69(dd,3H),0.91(t,2H).

[1069] Examples 24-p1 and 24-p2

[1070] 5-Ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-((R)-1-(2-(methylamino)pyridin-3-yl)ethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)naphth-2-ol 24-p1

[1071] 5-Ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-((S)-1-(2-(methylamino)pyridin-3-yl)ethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)naphth-2-ol 24-p2

[1072] Compound 24 (100 mg) was separated by chiral column (Shimadzu LC-20AP, chromatographic column: CHIRALPAK IG, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% NH3), gradient ratio: A:B: 65:35, flow rate: 20 mL / min) to give the title compounds 24-p1 (40 mg, 40%) and 24-p2 (40 mg, 40%).

[1073] Single configuration compound (shorter retention time) 24-p1 (40 mg, 40%)

[1074] MS m / z (ESI): 686.2 [M+1].

[1075] Chiral HPLC analysis method: retention time 5.755 min, purity: 99% (chromatographic column: CHIRALPAK IG, 250*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 35:65, flow rate: 1.0 mL / min).

[1076] 1 H NMR(500MHz,CD3OD)δ8.07(s,1H),7.76–7.64(m,2H),7.33–7.22(m,2H),7.06(dd,1 H),6.78–6.70(m,1H),6.57(d,1H),5.38(d,1H),4.50(dt,1H),4.43–4.28(m,3H),3. 82(td,2H),3.70–3.49(m,2H),3.25(d,3H),3.07(s,1H),2.94(d,3H),2.62–2.49(m ,1H),2.43–2.16(m,5H),2.05(s,2H),2.01–1.92(m,1H),1.69(dd,3H),0.91(t,2H).

[1077] Single configuration compound (longer retention time) 24-p2 (40 mg, 40%)

[1078] MS m / z (ESI): 686.2 [M+1].

[1079] Chiral HPLC analysis method: retention time 11.873 min, purity: 99% (chromatographic column: CHIRALPAK IC, 250*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1.0 mL / min).

[1080] 1H NMR(500MHz,CD3OD)δ8.07(s,1H),7.74(s,1H),7.72–7.66(m,1H),7.34–7.22(m, 2H),7.10–7.05(m,1H),6.74(t,1H),6.57(d,1H),5.41(s,1H),4.55–4.35(m,4H) ,3.87–3.77(m,2H),3.66–3.50(m,2H),3.27(d,3H),3.07(s,1H),2.94(d,3H),2. 57(q,1H),2.43–2.13(m,5H),2.05(s,2H),1.94(d,1H),1.69(t,3H),0.91(t,2H).

[1081] Example 25

[1082] (R)-2-amino-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 25

[1083] first step

[1084] (R)-3-(1-(5-chloro-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 25a

[1085] Compound 11c (133 mg, 157 μmol) and (2,6-dimethylidenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (26 mg, 157 μmol) were dissolved in tetrahydrofuran (5 mL). A 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.3 mL) was added dropwise under ice-bath. The reaction was stirred at the maintained temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution for quenching. The mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with water and dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 25a (60 mg).

[1086] MS m / z (ESI): 764.2 [M+1].

[1087] Step 2

[1088] (R)-2-amino-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 25

[1089] The synthetic route in Example 17 was used to replace the second step raw material compound 17a with compound 25a to obtain the title compound 25 (5 mg, yield: 25%).

[1090] MS m / z (ESI): 680.2 [M+1].

[1091] 1 H NMR (500MHz, CD3OD): δ7.98(d,1H),7.78(d,1H),7.40(dd,1H),7.04(t,1H),6.80(dd,1H),6.60(q,1H),5.09–5.02(m, 4H),4.52–4.33(m,5H),3.83(d,3H),3.77(dd,1H),3.58(dd,1H),3.39(d,4H),2.85(dd,2H),2.64(d,2H),1.67(d,3H).

[1092] Example 26

[1093] (R)-3-(1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 26

[1094] first step

[1095] (R)-3-(1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 26a

[1096] Compound 25a (52 mg, 68 μmol), compound 21a (30 mg, 93.3 μmol), tetrakis(triphenylphosphine)palladium (12 mg, 10.4 μmol), and cesium carbonate (66 mg, 202 μmol) were mixed in 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 26a (30 mg, yield: 47.7%).

[1097] MS m / z (ESI): 923.2 [M+1].

[1098] Step 2

[1099] (R)-3-(1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 26

[1100] Compound 26a (30 mg, 26 μmol) was dissolved in trifluoroacetic acid (1 mL), reacted at 50° C. for 5 hours, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 26 (5 mg, yield: 28.1%).

[1101] MS m / z (ESI): 683.2 [M+1].

[1102] 1 H NMR(500MHz,CD3OD)δ7.98(dd,1H),7.77(dd,1H),6.90(d,1H),6.80(dd,1H),6.60(d,1H),6.50(s,1H),5.07(dt,4H),4.45(q,3H), 4.38–4.30(m,2H),3.86(d,2H),3.74(s,1H),3.55(d,1H),3.49–3.38(m,3H),2.86(dd,2H),2.65(d,2H),1.66(d,3H),1.33(d,2H).

[1103] Example 27

[1104] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[1105] first step

[1106] 4-(10-((R)-1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine 27b

[1107] The crude compound 17a (100 mg, 131.9 μmol) and N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine 27a (100 mg, 184.3 μmol, Example 17a on page 244 of the patent application "WO2022042630" were used. 60) was dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and cesium carbonate (107.4 mg, 329.7 μmol) and tetrakistriphenylphosphine palladium (30.4 mg, 26.3 μmol) were added. The mixture was reacted at 100° C. under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 27b (150 mg, yield: 99%).

[1108] MS m / z (ESI): 1138.2 [M+1].

[1109] Step 2

[1110] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[1111] Compound 27b (150 mg, 131.8 μmol) was dissolved in trifluoroacetic acid (2 mL), reacted at 50° C. for 5 hours, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to give the title compound 27 (50 mg, yield: 57.6%).

[1112] MS m / z (ESI): 658.2 [M+1].

[1113] 1 H NMR(500MHz,CD3OD)δ7.98(d,1H),7.77(d,1H),6.80(dd,1H),6.61(d,1H),6.35(s,1H),5.33(d,1H),4.48(dd,1H),4.41–4.30(m,3H ),3.77(dd,1H),3.55(dd,1H),3.30–3.14(m,3H),3.05(d,1H),2.63–2.48(m,3H),2.40–2.15(m,3H),2.07–1.87(m,3H),1.67(d,3H).

[1114] Example 28

[1115] 2-Amino-4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[1116] Using the synthetic route in Example 17, the first step raw material compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol was replaced with (2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol to obtain the title compound 28 (a mixture of diastereomers) (5 mg, yield: 17.8%).

[1117] MS m / z (ESI): 704.2 [M+1].

[1118] 1H NMR(500MHz,CD3OD)δ7.98(dd,1H),7.78(d,1H),7.40(dd,1H),7.04(dd,1H),6.80(dd,1H),6.62(d,1H),4.54–4.30(m,5H),3.87–3.73(m,2H), 3.58(dd,2H),3.43(s,1H),3.21–3.15(m,1H),2.86(d,1H),2.72(d,1H) ,2.57(s,1H),2.24–2.12(m,2H),2.12–1.88(m,4H),1.72–1.63(d,3H).

[1119] Example 29

[1120] 2-Amino-4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[1121] Using the synthetic route in Example 17, the first step raw material compound ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol was replaced with ((2-(fluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol to obtain the title compound 29 (a mixture of isomers) (3 mg, yield: 9%).

[1122] MS m / z (ESI): 686.2 [M+1].

[1123] 1 H NMR(500MHz,CD3OD)δ7.98(d,1H),7.78(d,1H),7.40(dd,1H),7.04(t,1H),6.80(dd,1H),6.62(d,1H),4.58–4.27(m,4H),3.92(d,1H) ),3.78(dd,2H),3.68–3.50(m,3H),2.89–2.72(m,2H),2.51(d,1H),2.29–2.16(m,1H),2.14–1.83(m,4H),1.68(d,3H),1.33(d,3H).

[1124] Example 30

[1125] (R)-2-amino-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 30

[1126] first step

[1127] tert-Butyl 4-(fluoromethylidene)piperidine-1-carboxylate 30b

[1128] 2-((Fluoromethyl)sulfonyl)pyridine (30.2 g, 79 mmol) was dissolved in tetrahydrofuran (200 mL), and a 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (75.2 mL) was added at -78°C. The temperature was maintained for 30 minutes, and then N-tert-butoxycarbonyl-4-piperidone 30a (15 g, 75.2 mmol, Shanghai Shaoyuan) was added. The temperature was maintained for 3 hours, and then the reaction was returned to room temperature for 1 hour. Saturated ammonium chloride was added to the reaction solution to quench the reaction, and the solution was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 30b (13.6 g, yield: 84.3%).

[1129] Step 2

[1130] 4-(Fluoromethylidene)piperidine hydrochloride 30c

[1131] Compound 30b (13.6 g, 63.4 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (80 mL) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude title compound 30c (9.6 g), which was used directly in the next reaction without purification.

[1132] MS m / z (ESI): 116.1 [M+1].

[1133] Step 3

[1134] Methyl 1-(4-(fluoromethylidene)piperidine-1-carbonyl)cyclopropane-1-carboxylate 30d

[1135] Dissolve 1,1-cyclopropyldicarboxylic acid monomethyl ester (22 g, 152.6 mmol, Shanghai Leyan) in dichloromethane (400 mL). Under a nitrogen atmosphere, add oxalyl chloride (77.5 g, 610.4 mmol, 52.1 mL) dropwise at 0 ° C. Add N, N-dimethylformamide (DMF) (391 mg, 5.3 mmol) and stir to react at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and the residue is dissolved in dichloromethane (80 mL) for later use.

[1136] The crude compound 30c (23.1 g, 152.6 mmol) was dissolved in dichloromethane (500 mL). Triethylamine (61.7 g, 610.4 mmol) was added at 0°C, and the above-mentioned standby solution was added dropwise. The reaction was stirred for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, and the organic phase was separated and washed with saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 30d (27.3 g, yield: 74.2%).

[1137] MS m / z (ESI): 242.2 [M+1].

[1138] Step 4

[1139] (4-(Fluoromethylidene)piperidin-1-yl)(1-(hydroxymethyl)cyclopropyl)methanone 30e

[1140] Compound 30d (14.33 g, 59.4 mmol) was dissolved in tetrahydrofuran (300 mL), and a 1 M solution of lithium aluminum hydride in tetrahydrofuran (118.8 mL) was added dropwise at 0°C. The mixture was naturally stirred at room temperature for 2 hours. 1.5 mL of water was added to the reaction solution to quench the mixture, and the mixture was diluted with 300 mL of saturated sodium tartrate solution. The mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 30e (10.8 g). The product was used directly in the next reaction without purification.

[1141] MS m / z (ESI): 214.2 [M+1].

[1142] Step 5

[1143] (R)-3-(1-(5-chloro-4-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 30f

[1144] Compound 11c (35 mg, 55 μmol) and crude compound 30e (16.4 mg, 82.6 μmol) in tetrahydrofuran (0.5 mL) were added dropwise with a 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (50 μL) under ice-bath. The reaction mixture was stirred at the maintained temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution for quenching. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with water and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure to give the crude title compound 30f (40 mg). The product was used directly in the next reaction without purification.

[1145] MS m / z (ESI): 798.4 [M+1].

[1146] Step 6

[1147] (R)-2-amino-4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 30

[1148] The synthetic route in Example 17 was used to replace the second step raw material compound 17a with compound 30f to obtain the title compound 30 (6 mg, yield: 44.3%).

[1149] MS m / z (ESI): 714.2 [M+1].

[1150] 1 H NMR(500MHz,CD3OD)δ7.98(d,1H),7.78(d,1H),7.40(dd,1H),7.04(t,1H),6.80(dd,1H),6.68–6.58(m,1H),4.53–4.45(m,3H),4.36( dd,1H),3.77(dd,1H),3.60(td,1H),2.56–2.45(m,6H),2.35(s,2H),2.10(s,2H),1.68(d,3H),1.20(t,1H),0.77(s,2H),0.52(s,2H).

[1151] Example 31

[1152] 3-((1R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)pyridin-2-amine 31

[1153] first step

[1154] (±)-(1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methanol 31b

[1155] (±)-1-(1-(Benzyloxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylmethanamine 31a (20 mg, 195.8 μmol, prepared by the method disclosed in Intermediate UU8 on page 143 of the specification of patent application "WO2022221739") was dissolved in trifluoroethanol (2 mL), and 10% palladium-carbon hydrogenation catalyst (238 mg) was added. The reaction was stirred for 20 hours, and the reaction solution was filtered and concentrated under reduced pressure to obtain the crude title compound 31b (32 mg). The product was used directly in the next step without purification.

[1156] MS m / z (ESI): 166.2 [M+1].

[1157] Step 2

[1158] 3-((1R)-1-(5-chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine 31c

[1159] Compound 11c (300 mg, 472 μmol) and crude compound 31b (78 mg, 472 μmol) were dissolved in tetrahydrofuran (10 mL). A 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (470 μL) was added dropwise under ice-bath, and the reaction was stirred at the maintained temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to obtain the title compound 31c (mixture of diastereomers) (170 mg, yield: 47.2%).

[1160] MS m / z (ESI): 764.4 [M+1].

[1161] Step 3

[1162] 3-((1R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-10-yl)ethyl)pyridin-2-amine 31

[1163] The synthetic route in Example 21 was used to replace the first step raw material compound 17a with compound 31c to obtain the title compound 31 (a mixture of diastereomers) (6 mg, yield: 44.3%).

[1164] MS m / z (ESI): 683.2 [M+1].

[1165] 1 H NMR(500MHz,CD3OD)δ7.98(d,1H),7.78(d,1H),6.90(d,1H),6.81(dd,1H),6.62(t,1H),6.50(s,1H),4.66(s,2H),4.47(s,1H),4.34(s,1H), 3.76(d,1H),3.57(s,1H),2.91(d,1H),2.72–2.54(m,1H),2.38(s,5H) ,2.29–2.01(m,1H),1.93–1.61(m,5H),1.51–1.44(m,1H),1.32(d,3H).

[1166] Examples 31-p1 and 31-p2

[1167] 3-((R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 31-p1

[1168] 3-((R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 31-p2

[1169] Compound 31 (30 mg) was separated by chiral column (Shimadzu LC-20AP, chromatographic column: Optichiral A1-10, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (1% ammonia methanol solution), gradient ratio: A:B: 75:25, flow rate: 30 mL / min) to give the title compound (8 mg, 26.6%).

[1170] Chiral HPLC analysis of the isomeric mixture: retention times were 4.979 min and 6.760 min, respectively (chromatographic column: CHIRALPAK AD-H 250*4.6 mm, 5 um; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1.0 mL / min).

[1171] Single configuration compound (shorter retention time) 4.979 min (8 mg, yield: 44.4%).

[1172] MS m / z (ESI): 683.2 [M+1].

[1173] HPLC analysis: retention time 1.53 minutes, purity: 99% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1174] 1 H NMR(500MHz,CD3OD)δ7.99(d,1H),7.79(d,1H),6.91(s,1H),6.82(d,1H),6.61(s,1H),6.50(s,1H),4.69(s,2H),4.48(s,1H),4.35 (s,1H),3.78(d,1H),3.58(d,1H),2.89–2.37(m,7H),2.27–2.01(m,1H),1.87(s,1H),1.68(d,4H),1.55–1.44(m,1H),1.31(d,3H).

[1175] Single configuration compound (longer retention time): 6.760 min (8 mg, yield: 44.4%).

[1176] MS m / z (ESI): 683.2 [M+1].

[1177] HPLC analysis: retention time 1.53 minutes, purity: 99% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1178] 1 H NMR(500MHz,CD3OD)δ7.99(d,1H),7.79(d,1H),6.91(s,1H),6.82(s,1H),6.60(d,1H),6.50(s,1H),4.72(s,2H),4.48(s,1H),4.36 (s,1H),3.77(s,1H),3.59(s,1H),2.91–2.38(d,7H),2.25–2.00(m,1H),1.89(s,1H),1.68(d,4H),1.56–1.42(m,1H),1.31(d,3H).

[1179] Example 32

[1180] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazaheptacyclo[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 32

[1181] The synthetic route in Example 11 was used to replace the raw material compound 11d in the fifth step with compound 31c to obtain the title compound 32 (a mixture of diastereomers) (25 mg, yield: 17.7%).

[1182] MS m / z (ESI): 678.3 [M+1].

[1183] 1 H NMR(500MHz,CD3OD)δ7.99(s,1H),7.80(d,1H),7.67(t,1H),7.49–7.13(m,2H),7.06(s,1H),6.82(t,1H),6.73–6.59(m,1H),4.67(d,3H),4. 59–4.27(m,3H),3.79(td,2H),3.59(dd,2H),2.91(s,1H),2.76–2.46( m,3H),2.37(s,5H),1.85–1.67(m,3H),1.39(d,2H),1.03–0.72(m,3H).

[1184] Examples 32-p1 and 32-p2

[1185] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 32-p1

[1186] 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol 32-p2

[1187] Compound 32 (21.8 mg) was separated by chiral column (Shimadzu LC-20AP, chromatographic column: CHIRALPAK AD, 5.0 cm ID×25 cm L, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 60 mL / min) to give the title compound (13.8 mg, 63.3%).

[1188] Single configuration compound (shorter retention time): (13.8 mg, 63.3%)

[1189] MS m / z (ESI): 678.3 [M+1].

[1190] Chiral HPLC analysis: retention time 5.289 minutes, purity: 99% (chromatographic column: CHIRALPAK AD-H, 0.46 cm ID × 25 cm L; mobile phase A: n-hexane, mobile phase B: ethanol (1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1 mL / min).

[1191] 1H NMR(500MHz,CD3OD)δ8.00(dt,1H),7.80(d,1H),7.68(d,1H),7.39–7.19(m,2 H),7.07(d,1H),6.90–6.77(m,1H),6.65(q,1H),4.60(s,2H),4.58–4.31(m,3H ),3.96–3.76(m,2H),3.69–3.51(m,2H),3.06–2.82(m,2H),2.74–2.52(m,3H) ,2.37(s,5H),1.91–1.57(m,3H),1.47(s,1H),1.33(d,1H),1.06–0.83(m,3H).

[1192] Single configuration compound (longer retention time): (13.8 mg, 63.3%)

[1193] MS m / z (ESI): 678.3 [M+1].

[1194] Chiral HPLC analysis: retention time 7.441 minutes, purity: 99% (chromatographic column: CHIRALPAK AD-H, 0.46 cm ID × 25 cm L; mobile phase A: n-hexane, mobile phase B: ethanol (1% diethylamine), gradient ratio: A:B: 50:50, flow rate: 1 mL / min).

[1195] 1 H NMR(500MHz,CD3OD)δ8.00(dt,1H),7.94–7.72(m,1H),7.66(d,1H),7.30–7 .20(m,2H),7.06(dd,1H),6.92–6.74(m,1H),6.64(d,1H),4.68(d,2H),4.55 –4.28(m,3H),3.78(dd,2H),3.70–3.50(m,2H),3.00(s,2H),2.70–2.50(m, 3H),2.41(s,5H),1.81–1.56(m,3H),1.46(d,1H),1.33(d,1H),0.93(d,3H).

[1196] Example 33

[1197] 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-amine 33

[1198] first step

[1199] 6-Bromo-3-fluoro-2-methyl-4-nitroaniline 33b

[1200] 3-Fluoro-2-methyl-4-nitroaniline 33a (2.2 g, 12.9 mmol, prepared by the method disclosed in EXAMPLE 7 on page 10 of the specification of patent application "US7626018") was dissolved in acetonitrile (80 mL), and N-bromosuccinimide (2.7 g, 15.5 mmol) was added. The reaction was stirred at 80°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 33b (2.9 g, yield: 90%).

[1201] MS m / z(ESI):247.0[M-1].

[1202] Step 2

[1203] 1-Bromo-4-fluoro-2-iodo-3-methyl-5-nitrobenzene 33c

[1204] Concentrated hydrochloric acid (10 mL) was added to compound 33b (1.5 g, 6.0 mmol) at 0°C. The mixture was stirred at this temperature for 10 minutes, and then a 2M aqueous sodium nitrite solution (9 mL) was added. After stirring at 0°C for 1 hour, a 2M aqueous potassium iodide solution (12 mL) was added. The mixture was stirred at this temperature for 10 minutes, and then heated to 80°C for 1 hour. The reaction solution was cooled to room temperature and quenched with saturated sodium thiosulfate. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 33c (2.1 g), which was used in the next step without purification.

[1205] Step 3

[1206] 5-Bromo-2-fluoro-4-iodo-3-methylaniline 33d

[1207] The crude compound 33c (2.1 g, 5.83 mmol) was mixed in ethanol (20 mL) and water (40 mL), and iron powder (1.3 g, 23.3 mmol) and ammonium chloride (6 g, 35 mmol) were added. The mixture was stirred at 90°C for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was extracted with dichlorohexane (50 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 33d (1.5 g, yield: 77.9%).

[1208] MS m / z(ESI):327.9[M-1].

[1209] Step 4

[1210] tert-Butyl (5-bromo-2-fluoro-4-iodo-3-methylphenyl)carbamate 33e

[1211] Compound 33d (0.8 g, 2.42 mmol) was dissolved in 1,4-dioxane (5 mL), and di-tert-butyl dicarbonate (BOC anhydride) (3.7 g, 16.9 mmol) was added. The mixture was stirred at 100°C for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 33e (1 g, yield: 95.9%).

[1212] MS m / z(ESI):427.9[M-1].

[1213] Step 5

[1214] tert-Butyl (5-bromo-2-fluoro-3-methyl-4-(trifluoromethyl)phenyl)carbamate 33f

[1215] Compound 33e (1.2 g, 2.79 mmol), cuprous iodide (1.32 g, 6.97 mmol), hexamethylphosphoric triamide (1.5 g, 8.37 mmol, Shanghai Shaoyuan), and methyl fluorosulfonyldifluoroacetate (1.6 g, 8.37 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (DMF) (10 mL). The mixture was stirred at 90°C under a nitrogen atmosphere for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate and washed with water. The organic phase was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to give the title compound 33f (500 mg, yield: 48.1%).

[1216] MS m / z(ESI):370.0[M-1].

[1217] Step 6

[1218] (5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boric acid 33g

[1219] Compound 33f (391 mg, 1.05 mmol), pinacol diboron (400.2 mg, 1.57 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (76.9 mg, 105.1 μmol), and potassium acetate (309.3 mg, 3.15 mmol) were mixed in dimethyl sulfoxide (5 mL), the nitrogen atmosphere was replaced three times, and the mixture was heated at 100°C for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 33g (100 mg, yield: 40.1%).

[1220] MS m / z (ESI): 237.9 [M+1].

[1221] Step 7

[1222] 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphthanaphthalen-10-yl)ethyl)pyridin-2-amine 33

[1223] The synthetic route in Example 22 was used to replace the first step raw material compound 22a with compound 33g to obtain the title compound 33 (5 mg, yield: 15%).

[1224] MS m / z (ESI): 675.3 [M+1].

[1225] 1 H NMR(500MHz,CD3OD)δ7.98(d,1H),7.77(d,1H),6.88(d,1H),6.80(dd,1H),5.33(d,1H),4.61(s,2H),4.48(dd,1H),4.42– 4.30(m,3H),3.77(dd,1H),3.55(dd,1H),3.24(dd,2H),3.04(td,1H),2.39–2.14(m,6H),2.07–1.89(m,3H),1.67(d,3H).

[1226] Example 34

[1227] (R)-2-amino-N-(3-((R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-yl)propanamide 34

[1228] first step

[1229] tert-Butyl ((R)-1-((3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-yl)amino)-1-oxopropan-2-yl)carbamate 34a

[1230] Compound 19a (1.4 g, 2.7 mmol) and N-tert-butoxycarbonyl-D-alanine (780 mg, 4.12 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (15 mL), and N,N-diisopropylethylamine (1.1 g, 8.27 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (1.57 g, 4.12 mmol) were added. The reaction mixture was stirred for 16 hours, and water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system A to obtain the title compound 34a (1.4 g, yield: 77.7%).

[1231] MS m / z(ESI):689.2[M+1].

[1232] Step 2

[1233] tert-Butyl ((R)-1-((3-(R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-yl)amino)-1-oxopropan-2-yl)carbamate 34b

[1234] Compound 34a (2.7 g, 3.91 mmol), compound 21a (1.5 g, 4.66 mmol), tetrakistriphenylphosphine palladium (679 mg, 587.6 μmol), and cesium carbonate (3.93 g, 11.75 mmol) were mixed in 1,4-dioxane (30 mL) and water (6 mL). The mixture was reacted at 100° C. under a nitrogen atmosphere for 2 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 34b (1.1 g, yield: 33%).

[1235] MS m / z (ESI): 848.2 [M+1].

[1236] Step 3

[1237] (R)-2-amino-N-(3-((R)-1-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazahepta[de]naphth-10-yl)ethyl)pyridin-2-yl)propanamide 34

[1238] Compound 34b (1.1 g, 1.3 mmol) was dissolved in acetonitrile (6 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added under ice-bath. The reaction was stirred at the maintained temperature for 0.5 hour and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL / min) to give the title compound 34 (210 mg, yield: 21.6%).

[1239] MS m / z (ESI): 748.2 [M+1].

[1240] 1H NMR (500MHz, CD3OD): δ8.53-8.43(m,1H),8.16(d,1H),7.50(dd,1H),6.90 (d,1H),6.82-6.72(m,1H),6.49(d,1H),5.32(dt,1H),4.53-4.31(m,3H),4 .27(d,1H),3.66(td,1H),3.51-3.37(m,1H),3.31-3.08(m,4H),3.07-2.9 9(m,1H),2.38-2.12(m,3H),2.05-1.87(m,3H),1.73(s,3H),1.11(dd,3H).

[1241] Comparative Example A

[1242] 3-((1R)-1-(9-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-8-chloro-10-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepano[5,6,7-de]quinazolin-4-yl)ethyl)pyridin-2-amine A

[1243] first step

[1244] 5-Bromo-2-fluoro-3-methylaniline A-2

[1245] 5-Bromo-2-fluoro-1-methyl-3-nitrobenzene A-1 (20 g, 85.46 mmol, Shanghai Titan) was dissolved in ethanol (200 mL) and water (40 mL), and reduced iron powder (23.8 g, 426.18 mmol) and ammonium chloride (22.9 g, 428.1 mmol) were added. The mixture was heated to 90 ° C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered through celite and the filtrate was concentrated under reduced pressure to obtain the crude title compound A-2 (16 g). The product was used directly in the next step without purification.

[1246] MS m / z (ESI): 203.9 [M+1].

[1247] Step 2

[1248] 5-Bromo-2-flu...

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m1 R m2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n1 R n2 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 3 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m3 R m4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and -W-(CR 3a R 3b ) r -Ring C, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n3 R n4 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; W is selected from O, S and NR w ; R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R 0 replace; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and is optionally substituted by one or more R 10 replace; R 4 is selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n5 R n6 , hydroxyl, hydroxyalkyl and one or more substituents in ring B, ring B is selected from cycloalkyl, heterocyclic group, aryl and heteroaryl, and the ring B is optionally substituted by one or more R 9 replace; Each R 1 、R 9 and R 0 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-NR m5 R MP 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, -OR P , hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R P is a hydrogen atom or R PP ; R MP is a hydrogen atom or R MPP ; R PP and R MPP are the same or different and are each independently selected from -C(O)R P1 、-C(O)OR P3 、-C(O)NR P3 R P4 、-C(O)OCR P11 R P12 OC(O)Z, -C(O)CR P11 R P12 NR P3 R P4 、-C(O)NR P13 CR P11 R P12 C(O)OR P3 、-S(O)2R P1 、-S(O)2OR P3 and -S(O)2NR P3 R P4 ; R P1 、R P11 、R P12 、R P3 、R P4 、R P13 and Z are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, -C(O)R P20 , cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -OC(O)R P21 , cycloalkyl, heterocyclyl, aryl and heteroaryl; R P20 and R P21 are the same or different and are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 10 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, =CR m9 R m10 、=NR m11 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -OC(O)NR n7 R n8 、-NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 5 、R 6 、R 7 and R 8 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR m7 R m8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n9 R n10 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R w 、R m1 、R m2 、R m3 、R m4 、R m5 、R m6 、R m7 、R m8 、R n1 、R n2 、R n3 、R n4 、R n5 、R n6 、R n7 、R n8 、R n9 and R n10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, a heteroarylalkyl group, a cycloalkyl group, a heterocyclyl group, an arylalkyl group and a heteroaryl group, wherein the alkyl group, the cycloalkylalkyl group, the heterocyclylalkyl group, the arylalkyl group, the heteroarylalkyl group, the cycloalkyl group, the heterocyclyl group, the arylalkyl group and the heteroaryl group are each independently selected from a halogen, an alkyl group, substituted by one or more of the same or different substituents selected from the group consisting of haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy and cyano; or R m9 、R m10 Together with the attached carbon atom, they form a cycloalkyl or heterocyclyl group, each of which is independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl; R m11 is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and r is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 W-(CR 3a R 3b ) r - Ring C, W, R 3a 、R 3b , r and ring C are as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein W is O. 4 . The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring B is phenyl or a 5-membered or 6-membered heteroaryl group.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof: in, -Q 1 -R P’ Does not exist, or Q 1 is O or NH, R P’ R P or R MP , and -Q 1 -R P’ For-OR P or -NH-R MP ; G 2 CR 9b or N; G 3 CR 9c or N; G 4 CR 9d or N; G 5 C or N; G 6 C or N; G 7 C or N; R 11 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups; R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring A 2 Does not exist, or ring A 2 is an aryl or heteroaryl group; m is 0, 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4, or 5; R P 、R MP , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R m5 、R m6 、R n5 、R n6 、R n7 、R n8 and r as defined in claim 1.

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III') or a pharmaceutically acceptable salt thereof: in, G 1 CR 9a or N; G 2 CR 9b or N; G 3 CR 9c or N; G 4 CR 9d or N; R 11 Selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyano, -NR n5 R n6 and hydroxyl groups; R 1a 、R 1b 、R 1c 、R 1d 、R 9a 、R 9b 、R 9c and R 9d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, -NR m5 R m6 、-NR m5 R MP 、-C(O)NR m5 R m6 、-S(O)2NR m5 R m6 , -C(O)alkyl, -S(O)2alkyl, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR n7 R n8 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; q is 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; R P 、R MP , Ring C, R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R m5 、R m6 、R n5 、R n6 、R n7 、R n8 and r as defined in claim 1.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom; and / or R 8 A hydrogen atom.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Ring C is a 3- to 8-membered heterocyclyl or a 3- to 8-membered cycloalkyl; and / or each R 10 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, -C 0-6 Alkylene-NR n7 R n8 Sum = CR m9 R m10 , R m9 and R m10 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl, R n7 and R n8 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b is a hydrogen atom, or R 3a 、R 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl group. 10 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein r is 1 or 3.

11. The compound according to any one of claims 6 to 10, or a pharmaceutically acceptable salt thereof, wherein R 11 A hydrogen atom or C 1-6 alkyl; and / or q is 1 or 2.

12. The compound according to any one of claims 6 to 11, or a pharmaceutically acceptable salt thereof, wherein G 2 N; G 1 CR 9a ; G 3 CR 9c ; G 4 CR 9d ; R 9a 、R 9c and R 9d As defined in claim 6.

13. A compound according to any one of claims 6 to 12, or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 1c 、R 1d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 haloalkyl and 3- to 6-membered cycloalkyl.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom or a halogen.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is the following compound:

16. A compound represented by general formula (V'A) or a salt thereof: in, R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist; R y1 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB; R y2 is a hydrogen atom or an amino protecting group, wherein the amino protecting group is preferably PMB; Q 1 , G 2 to G 7 , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in claim 5.

17. A compound or a salt thereof, which is:

18. A method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising: R y1 is a hydrogen atom or an amino protecting group and R y2 The compound of the general formula (V'A) or its salt containing a hydrogen atom or an amino protecting group is subjected to a deprotection reaction to obtain R m5 、R MP and R P’ A compound of the general formula (V') wherein all of the atoms are hydrogen atoms, or a pharmaceutically acceptable salt thereof; or R y1 R m5 And R y2 R MP The compound of the general formula (V'A) or its salt is subjected to deprotection reaction to obtain R P’ A compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein the compound is a hydrogen atom; or R P’ A compound of the general formula (V') or a pharmaceutically acceptable salt thereof wherein R PP -R L Substitution reaction to obtain R P’ R PP A compound of the general formula (V') or a pharmaceutically acceptable salt thereof; in, R y is a hydroxy protecting group or an amino protecting group, wherein the hydroxy protecting group is preferably MOM or TBDPS, and the amino protecting group is preferably Boc or PMB; or 1 -R y does not exist; R y1 is selected from hydrogen atoms, amino protecting groups and R m5 , the amino protecting group is preferably PMB; R y2 is selected from hydrogen atoms, amino protecting groups and R MP , the amino protecting group is preferably PMB; R L is a leaving group; preferably a halogen; Q 1 , G 2 to G 7 、R m5 、R MP 、R PP , Ring A 2 , Ring C, R 1 、R 2 、R 3a 、R 3b 、R 5 、R 8 、R 10 、R 11 , m, p and r are as defined in claim 5.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the preparation of a medicament for inhibiting KRAS amplification and / or KRAS mutant activity; the KRAS mutant is preferably KRAS G12D and / or KRAS G12V mutation.

21. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the preparation of a medicament for treating and / or preventing a disease or condition mediated by KRAS amplification and / or KRAS mutants; the KRAS mutants are preferably KRAS G12D and / or KRAS G12V mutations.

22. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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