HETEROARYL COMPOUNDS, METHODS OF PREPARATION OF THESE COMPOUNDS, AND PHARMACEUTICALS CONTAINING THESE COMPOUNDS

Abstract

The invention relates to a fusion heteroaryl compound, a method for preparing such a compound, and a pharmaceutical composition containing such a compound. Specifically, the invention relates to a fusion heteroaryl compound of the formula (I'), a method for preparing such a compound, and a pharmaceutical composition containing such a compound. Each group in formula (I') is as defined in the description.

Description

Condensed heteroaryl compounds, preparation methods thereof and their applications in medicine Technical Field

[0001] The present disclosure relates to the field of medicine and relates to a fused heteroaryl compound, a method for preparing the same, and its use in medicine. In particular, the present disclosure relates to a fused heteroaryl 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, WO2021000885A1 and WO2023183585A1.

[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] R A Selected from Hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally replaced by one or more R 3 replaced by;

[0010] Y is a carbon atom; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0011] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0012] G 1 CR G1 or N; G is selected from C, CR G and N;

[0013] G 8 CR 7 or N; G 9 CR 2 or N;

[0014] R B Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxyl, hydroxyalkyl, alkenyl, alkynyl, OR 14 、C(O)OR 14 、S(O) v R 14, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 6 replaced by;

[0015] R 2 、R G1 、R G and R 7 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, alkenyl, alkynyl, NR 11 R 12 、C(O)NR 11 R 12 、Alkylene NR 11 R 12 、alkylene C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、S(O) v NR 11 R 12 NR 13 S(O) v R 14 、C(=NR 13 )R 14 、C(=NR 13 )NR 11 R 12 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 , OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by;

[0016] or, G, R 7and the carbon atom to which it is attached together form ring B; Ring B is optionally substituted by one or more R 8 replaced by;

[0017] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0018] R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 11 R 12 、C(O)R 14 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by;

[0019] or, R 4 、R 5 and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 3 replaced by;

[0020] W is selected from CR 3a R 3b , O, S and NR w ;

[0021] 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;

[0022] R w is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; said alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0023] Each R 1 、R 3 、R 6 、R 01 、R 8 and R 0are the same or different and are each independently selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 11 R 12 、C(O)NR 11 R 12 、Alkylene NR 11 R 12 、alkylene C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、S(O) v NR 11 R 12 NR 13 S(O) v R 14 、C(=NR 13 )R 14 、C(=NR 13 )NR 11 R 12 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 , OR 14 、=CR 15 R 16 、=NR 13 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * replaced by;

[0024] Each R 11 、R 12 、R 13 and R 14 are the same or different and are each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyl, alkenyl, alkynyl, NR 20 R 21、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v NR 20 R 21 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * Replaced by; or R 11 、R 12 and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R * replaced by;

[0025] R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * replaced by;

[0026] Each R 20 、R 21 、R 22 and R 23 are the same or different and are each independently selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、C(O)R c, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally replaced by one or more R * or, R 20 、R 21 and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is * replaced by;

[0027] Each R * are the same or different and are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、 C(O)R c 、Alkylene NR a R b 、alkylene C(O)NR a R b , nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy and heteroaryloxy; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy and heteroaryloxy are each independently optionally selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR a R b NR a OR c NR a C(O)NR a R b NR a C(O)OR c 、C(O)NR a R b 、C(O)R c 、C(O)OR c 、Alkylene NR a R b 、alkylene C(O)NR a R b 、S(O) v R c 、S(O) v OR c 、S(O)v NR a R b , cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy and heteroaryloxy;

[0028] R a 、R b and R c are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group;

[0029] r is 0, 1, 2, 3, 4, or 5; v is 0, 1, or 2;

[0030] m is 0, 1, 2, 3, 4, 5 or 6;

[0031] p is 0, 1, 2, 3, 4, 5 or 6; and j is 0, 1, 2, 3, 4, 5 or 6.

[0032] The purpose of the present disclosure is to provide a compound represented by general formula (I'A) or a pharmaceutically acceptable salt thereof:

[0033] wherein: Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, and Ring D is optionally substituted by one or more R 0 Replaced by; R 0 , Ring A, R 1 , m, G 1 、R A and R B As defined in general formula (I').

[0034] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0035] Among them: Ring A, R 1 ,m,G,G 1 、R 2 、R 7 、R A and R B As defined in general formula (I').

[0036] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0037] in:

[0038] R A Selected from Hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR11 R 12 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally replaced by one or more R 3 replaced by;

[0039] Y is a carbon atom; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0040] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0041] G 1 CR G1 or N; G is selected from C, CR G and N;

[0042] R B Selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxyl, hydroxyalkyl, alkenyl, alkynyl, OR 14 、C(O)OR 14 、S(O) v R 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 6 replaced by;

[0043] R 2 、R G1 、R G and R 7 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, alkenyl, alkynyl, NR 11 R 12 、C(O)NR 11 R 12 、Alkylene NR 11 R 12 、alkylene C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、S(O) v R14 、S(O) v OR 14 、OS(O) v R 14 、S(O) v NR 11 R 12 NR 13 S(O) v R 14 、C(=NR 13 )R 14 、C(=NR 13 )NR 11 R 12 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 , OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by;

[0044] or, G, R 7 and the carbon atom to which it is attached together form ring B; Ring B is optionally substituted by one or more R 8 replaced by;

[0045] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0046] R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 11 R 12 、C(O)R 14 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by;

[0047] or, R 4 、R 5 and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 3 replaced by;

[0048] W is selected from CR 3a R 3b , O, S and NR w ;

[0049] 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;

[0050] R w is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; said alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace;

[0051] Each R 1 、R 3 、R 6 、R 01 、R 8 and R 0 are the same or different and are each independently selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 11 R 12 、C(O)NR 11 R 12 、Alkylene NR 11 R 12 、alkylene C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、S(O) v NR 11 R 12 NR 13 S(O) v R 14 、C(=NR13 )R 14 、C(=NR 13 )NR 11 R 12 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 , OR 14 、=CR 15 R 16 、=NR 13 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * replaced by;

[0052] Each R 11 、R 12 、R 13 and R 14 are the same or different and are each independently selected from hydrogen atom, alkyl, alkoxy, hydroxyl, alkenyl, alkynyl, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v NR 20 R 21 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * Replaced by; or R 11 、R 12 and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R * replaced by;

[0053] R 15and R 16 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * replaced by;

[0054] Each R 20 、R 21 、R 22 and R 23 are the same or different and are each independently selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、C(O)R c , cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally replaced by one or more R * or, R 20 、R 21 and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is * replaced by;

[0055] Each R * are the same or different and are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、C(O)R c 、Alkylene NR a R b 、alkylene C(O)NR a R b , nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl;

[0056] R a 、R b and R c are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group;

[0057] r is 0, 1, 2, 3, 4, or 5; v is 0, 1, or 2;

[0058] m is 0, 1, 2, 3, 4, 5 or 6;

[0059] p is 0, 1, 2, 3, 4, 5 or 6.

[0060] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A) or a pharmaceutically acceptable salt thereof, wherein R A for W.R. 3a 、R 3b , r, Y, ring C, R 3 、R 4 、R 5 , p and j are as defined in Formula (I'); in some embodiments, R A for W.R. 3a 、R 3b , r, Y, ring C, R 3 、R 4 、R 5 and p are as defined in Formula (I); in some embodiments, R A for W.R. 3a 、R 3b , r, ring C, R 3 and j are as defined in formula (I').

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A), (IM), (IN), (VI), (VII-1), (VII-2) or a pharmaceutically acceptable salt thereof, wherein R B is a 3- to 10-membered heterocyclic group, wherein the 3- to 10-membered heterocyclic group is optionally substituted by one or more R 6 Replaced by R 6 As defined in formula (I); in some embodiments, R B for R 6a 、R 6b and n are as defined in Formula (II); in some embodiments, R B for R 6a 、R 6b , u and n1 are as defined in formula (II), (III), (IV) or (V);

[0062] In some embodiments, R B Selected from hydrogen atoms, C 2-6alkenyl, 3 to 12 membered cycloalkyl and 3 to 12 membered heterocyclyl, said 3 to 12 membered cycloalkyl and 3 to 12 membered heterocyclyl are each independently optionally substituted by one or more R 6 Replaced by R 6 As defined in formula (I'); in some embodiments, R B is a hydrogen atom or a 3- to 10-membered heterocyclic group, wherein the 3- to 10-membered heterocyclic group is optionally substituted by one or more R 6 Replaced by R 6 As defined in formula (I'); in some embodiments, R B NR 11 R 12 , R 11 and R 12 As defined in formula (I');

[0063] In some embodiments, R B Selected from hydrogen atoms, R 6a is a hydrogen atom or R 6 , R 6b R 6 , u is 0, 1 or 2; n1 is 0, 1, 2 or 3; R 6 As defined in formula (I'); in some embodiments, R B is a hydrogen atom; in some embodiments, R B Selected from hydrogen atoms, In some embodiments, R B Selected from In some embodiments, R B for In some embodiments, R B A hydrogen atom or u is 1 or 2, n1 is 0, 1 or 2, R 6a and R 6b As defined in formula (II), (III), (IV) or (V); in some embodiments, R B for u is 1 or 2, R 6a As defined in formula (II), (III), (IV) or (V); in some embodiments, R B for In some embodiments, R B for

[0064] In some embodiments, R B for R 6a 、R 6band n1 are as defined in formula (III);

[0065] In some embodiments, R B Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl are each independently optionally substituted with one or more R 6 Replaced by; R 6a is a hydrogen atom or R 6 , R 6b R 6 , u is 0, 1 or 2; n1 is 0, 1, 2 or 3; R 6 As defined in formula (I');

[0066] In some embodiments, R B Selected from hydrogen atoms, methyl, vinyl, ethynyl, cyclopropyl, and cyclobutyl;

[0067] In some embodiments, R B Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 6 membered cycloalkyl and 3 to 10 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 6 membered cycloalkyl and 3 to 10 membered heterocyclic groups are each independently optionally selected from halogen, cyano, hydroxy, C 1-6 Alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R B Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl; in some embodiments, R B is selected from the group consisting of a hydrogen atom, a methyl group, a vinyl group, an ethynyl group, a cyclopropyl group, and a cyclobutyl group;

[0068] In some embodiments, R B Selected from hydrogen atoms, Cyclopropyl, In some embodiments, R B Selected from

[0069] In some embodiments, R B Selected from hydrogen atoms, Cyclopropyl, In some embodiments, R B Selected from In some embodiments, R B Selected from hydrogen atom, cyclopropyl,

[0070] In some embodiments, R B Selected from

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof,

[0072] in,

[0073] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R B , W, R 3a 、R 3b , r, R 3 and j are as defined in formula (I').

[0074] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof,

[0075] Wherein, G is C or N; q is 0, 1, 2, 3 or 4;

[0076] Ring A, Ring B, Ring C, R 1 ,m,R 8 、R 2 , G 1 、R B , W, R 3a 、R 3b , r, R 3 and j are as defined in formula (I').

[0077] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0078] Among them, R 6a is a hydrogen atom or R 6 ;

[0079] R 6b R 6 , or two R 6b and the carbon atom to which it is attached form CH(CR 6c R 6d ) u CH;

[0080] R 6c and R 6d are the same or different and are each independently a hydrogen atom or R 6 ;

[0081] n is 0, 1, 2, 3, 4, 5 or 6, u is 0, 1 or 2;

[0082] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6 , W, R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (I').

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0084] in,

[0085] R 6a is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl, wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl and heteroarylalkyl are each independently selected from halogen, alkoxy, haloalkoxy, alkenyl, alkynyl, cyano, NR 11 R 12 , hydroxyl, hydroxyalkyl, OR 14 、C(O)R 14 、C(O)NR 11 R12 、S(O) v R 14 、S(O) v NR 11 R 12 、=NR 13 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0086] R 6b R 6 , or two R 6b and the carbon atom to which it is attached form CH(CR 6c R 6d ) u CH;

[0087] R 6c and R 6d are the same or different and are each independently a hydrogen atom or R 6 ;

[0088] n is 0, 1, 2, 3, 4, 5 or 6, u is 0, 1 or 2;

[0089] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6 、R 11 to R 14 ,v,W,R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (I).

[0090] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (I'), (I'A), (IM) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0091] in,

[0092] G is CR G or N;

[0093] R 7 and R G are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl; n1 is 0, 1, 2 or 3;

[0094] Ring A, Ring C, R 1 , m, G 1 、R 2 、R 11 、R 12 、R 6a 、R 6b 、u、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (II).

[0095] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (I'), (I'A), (IN) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof:

[0096] in,

[0097] G is C or N; q is 0, 1, 2, 3 or 4;

[0098] Ring A, Ring B, Ring C, R 1 ,m,R 2 、R 8 , G 1 、R 6a 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (II).

[0099] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (I'), (I'A), (IN) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof:

[0100] in,

[0101] Q is selected from CR 8a R 8b 、O、S、C(O)、C(O)NR 8c and NR 8c ;

[0102] R 8a and R 8b are the same or different and are each independently a hydrogen atom or R 8 ;

[0103] R 8c is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group;

[0104] s is 0, 1, 2 or 3; t is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4;

[0105] Ring A, Ring C, R 1 ,m,R 2 , G 1 、R 8 、R 6a 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (II).

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A), (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IIA) or a salt thereof (in some embodiments, a pharmaceutically acceptable salt),

[0107] in,

[0108] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (II).

[0109] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A), (II), (IM), (III), (IIA) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IIIA) or a salt thereof (in some embodiments, a pharmaceutically acceptable salt),

[0110] in,

[0111] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n1、u、W、R 3a 、R3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (III).

[0112] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A), (IN), (II), (IV), (IIA) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IVA) or a salt thereof (in some embodiments, a pharmaceutically acceptable salt),

[0113] in,

[0114] Ring A, Ring B, Ring C, R 1 ,m,G,G 1 、R 2 、R 8 ,q,R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IV).

[0115] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A), (IN), (II), (IV), (V), (IIA), (IVA) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VA) or a salt thereof (in some embodiments, a pharmaceutically acceptable salt),

[0116] in,

[0117] Ring A, Ring C, R 1 ,m,Q,s,t,R 8 ,q,R 2 , G 1 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (V).

[0118] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'A), (I') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof.

[0119] wherein q is 0, 1, 2, 3 or 4; m is 1, 2, 3, 4, 5 or 6;

[0120] Ring A, Ring C, R 1 、R 8 、R 2 , G 1 、R B , W, R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (I).

[0121] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A), (VI) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VII-1) or (VII-2) or a pharmaceutically acceptable salt thereof,

[0122] in,

[0123] U is selected from NR 1a , O, S and Se; V is N or CR 1b ;

[0124] R 1a is a hydrogen atom or R 1 ; R 1b is a hydrogen atom or R 1 ; R 3c is a hydrogen atom or R 3 ;

[0125] m2 is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4;

[0126] R 1 、R 8 、R 2 , G 1 、R B 、R 3 、R 4 and R 5 As defined in general formula (I).

[0127] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (VII-2) or pharmaceutically acceptable salts thereof, wherein U is S or Se; in some embodiments, U is S; in some embodiments, U is Se.

[0128] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2) or their pharmaceutically acceptable salts, wherein V is N or CR 1b , R 1bSelected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, V is CH or N; in some embodiments, V is CH; in some embodiments, V is N.

[0129] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2) or their pharmaceutically acceptable salts, wherein U is S or Se, and / or V is CH or N; in some embodiments, U is S, and / or V is CH or N; in some embodiments, U is S, and / or V is CH; in some embodiments, U is S, and / or V is N.

[0130] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (VII-2) or pharmaceutically acceptable salts thereof, wherein m2 is 2 or 3; in some embodiments, m2 is 3.

[0131] In some embodiments of the present disclosure, in the compound represented by general formula (I'A) or a pharmaceutically acceptable salt thereof, ring D is an aryl or heteroaryl group; in some embodiments, ring D is a 5- to 10-membered heteroaryl group.

[0132] In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein G 8 CR 7 , R 7 As defined in formula (I'); in some embodiments, G 8 is N.

[0133] In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein G 9 CR 2 , R 2 As defined in formula (I'); in some embodiments, G 9 For CF.

[0134] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (I'A), (II), (IIA) or a pharmaceutically acceptable salt thereof, wherein R 7 When not forming a ring with G, R 6a Not a hydrogen atom.

[0135] In some embodiments of the present disclosure, the compound represented by the general formula (III) or (IIIA) or a pharmaceutically acceptable salt thereof, wherein R 6a Not a hydrogen atom.

[0136] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 6a A hydrogen atom or C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from halogen, OR 14 and one or more of a 3- to 6-membered heterocyclic group; R 14 As defined in formula (I); in some embodiments, R 6a A hydrogen atom or C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 alkoxy and 3 to 6 membered heterocyclic group; in some embodiments, R 6a C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 alkoxy and 3 to 6 membered heterocyclic group; in some embodiments, R 6a Selected from hydrogen atoms, hydroxyl groups and C 1-6 Hydroxyalkyl; in some embodiments, R 6a C 1-6 hydroxyalkyl;

[0137] In some embodiments, R 6a Selected from hydrogen atom, methyl, ethyl, In some embodiments, R 6a Selected from methyl, ethyl, In some embodiments, R 6a Selected from In some embodiments, R 6a for

[0138] In some embodiments, R 6a Selected from hydrogen atoms, C 1-6 Alkyl, OR 14 and C(O)R 14 , the C 1-6 Alkyl is optionally selected from halogen, OR 14 and one or more of a 3- to 6-membered heterocyclic group; R 14 As defined in formula (I'); in some embodiments, R 6a C(O)R 14, R 14 As defined in formula (I'); in some embodiments, R 6a OR 14 , R 14 As defined in formula (I');

[0139] In some embodiments, R 6a Selected from hydrogen atoms, C 1-6 Alkyl and OR 14 , the C 1-6 Alkyl is optionally selected from halogen, hydroxy, C 1-6 substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; R 14 Selected from hydrogen atoms, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 6a is a hydrogen atom or OR 14 , R 14 Selected from hydrogen atoms, C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 6a is a hydrogen atom or OH; in some embodiments, R 6a Selected from hydrogen atoms, In some embodiments, R 6a Selected from In some embodiments, R 6a Selected from hydrogen atoms, In some embodiments, R 6a for

[0140] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (V), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA), (VI), (VII-1), (VII-2) or a pharmaceutically acceptable salt thereof, wherein Selected from In some embodiments, for In some embodiments, for In some embodiments, for n1 is 0, 1, 2 or 3, R 6b R 6 , R 6 and u are as defined in formula (II); in some embodiments, for In some embodiments, for *End and R 6a connect;

[0141] In some embodiments, Selected from R 6e and R 6f are the same or different and are each independently a hydrogen atom or R 6 ; R 6b R 6 , n1 is 0, 1, 2 or 3, R 6 and u are as defined in formula (II);

[0142] In some embodiments, Selected from R 6e and R 6f are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl, each R 6b The same or different, and each independently halogen or C 1-6 Alkyl; n1 is 0, 1, 2 or 3; * end and R 6a connect.

[0143] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein u is 1 or 2; in some embodiments, u is 2.

[0144] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein each R 6b 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 11 R 12 , hydroxyl and C 1-6 Hydroxyalkyl; in some embodiments, each R 6b The same or different, and each independently halogen or C 1-6alkyl; in some embodiments, each R 6b are the same or different and are each independently halogen; in some embodiments, R 6b is F; in some embodiments, each R 6b The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R 6b It is a methyl group.

[0145] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 6e and R 6f The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R 6e and R 6f All are methyl.

[0146] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein n is 2, 3, 4, 5 or 6; in some embodiments, n is 2, 3 or 4; in some embodiments, n is 2.

[0147] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein n1 is 0, 1 or 2; in some embodiments, n1 is 0; in some embodiments, n1 is 2.

[0148] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (I'), (I'A), (IIA) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 7 Together with G, it forms ring B, which is optionally substituted by one or more R 8 substituted; in some embodiments, R 7 is a hydrogen atom, or R 7 Together with G, it forms ring B, which is optionally substituted by one or more R 8 substituted, ring B and R 8 As defined in formula (I); in some embodiments, R7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyloxy and 3 to 6 membered heterocyclyloxy; in some embodiments, R 7 is a hydrogen atom; in some embodiments, R 7 Together with G, it forms ring B, which is optionally substituted by one or more R 8 substituted, ring B and R 8 As defined in formula (I); in some embodiments, R 7 Together with G, they form ring B, which is as defined in the general formula (I).

[0149] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (I'), (I'A), (IN), (IIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- or 6-membered heteroaryl or a 4- to 7-membered heterocyclic group; in some embodiments, ring B is a 5- or 6-membered heterocyclic group or a 5-membered heteroaryl; in some embodiments, ring B is a 5- or 6-membered heterocyclic group; in some embodiments, ring B is a hydrofuranyl; in some embodiments, ring B is In some embodiments, ring B is a 5- or 6-membered heteroaryl; In some embodiments, ring B is a 5-membered heteroaryl; In some embodiments, ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, and thiazolyl; In some embodiments, ring B is pyrazolyl or imidazolyl; In some embodiments, ring B is selected from In some embodiments, Ring B is

[0150] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (V), (I'), (I'A), (IN), (IIA), (IVA), (VA), (VI), (VII-1), (VII-2) or a pharmaceutically acceptable salt thereof, wherein each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and cyano; in some embodiments, each R 8 are the same or different and are each independently selected from halogen or C 1-6 Alkyl; in some embodiments, R 8 It is a methyl group.

[0151] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (IV), (V), (I'), (I'A), (IN), (IIA), (IVA), (VA), (VI), (VII-1), (VII-2) or pharmaceutically acceptable salts thereof, wherein q is 0, 1 or 2; in some embodiments, q is 0; in some embodiments, q is 1.

[0152] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (V), (I'), (I'A), (IN), (IIA), (IVA), (VA), (VI), (VII-1), (VII-2) or a pharmaceutically acceptable salt thereof, wherein each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and cyano; and / or q is 0, 1 or 2.

[0153] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (III), (I'), (I'A), (IM), (IIA), (IIIA) or pharmaceutically acceptable salts thereof, wherein R 7 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyloxy and 3 to 6 membered heterocyclyloxy; in some embodiments, R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 7 is a hydrogen atom or a halogen; in some embodiments, R 7 A hydrogen atom.

[0154] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 4 and R 5 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, or R 4 and R 5 and the carbon atom to which it is attached together form a 3- to 6-membered cycloalkyl group;

[0155] In some embodiments, R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6Alkyl; in some embodiments, R 4 and R 5 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R 4 and R 5 are the same or different and are each independently a hydrogen atom or F; in some embodiments, R 4 is a hydrogen atom, R 5 is halogen, or R 5 is a hydrogen atom, R 4 is halogen; in some embodiments, R 4 and R 5 are the same or different and are each independently halogen; in some embodiments, R 4 and R 5 For F.

[0156] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein W is selected from CH2, NH and O; in some embodiments, W is O.

[0157] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) 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; in some embodiments, ring C is a 3- to 8-membered heterocyclyl.

[0158] In some embodiments of the present disclosure, the compound represented by the general formula (I'), (I'A), (IM), (IN) or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; in some embodiments, j is 1 or 2; in some embodiments, j is 1; in some embodiments, j is 2.

[0159] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) 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 3 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, -C 1-6 Alkylene-NR 11 R12 Sum = CR 15 R 16 , R 11 、R 12 、R 15 and R 16 As defined in formula (I); in some embodiments, ring C is a 3- to 8-membered heterocyclyl; and / or each R 3 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and =CR 15 R 16 , R 15 and R 16 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 3 The same or different, and each independently halogen or =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen.

[0160] In some embodiments of the present disclosure, the compound represented by the general formula (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or a pharmaceutically acceptable salt thereof, wherein Ring C is a 3- to 8-membered heterocyclic group or a 3- to 8-membered cycloalkyl group; and / or each R 3 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, -C 1-6 Alkylene-NR 11 R 12 Sum = CR 15 R 16 , and / or j is 0, 1, 2 or 3, R 11 、R 12 、R 15 and R 16 As defined in formula (I); in some embodiments, ring C is a 3- to 8-membered heterocyclyl; and / or each R 3 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6alkyl, and / or j is 1 or 2; in some embodiments, ring C is a 3- to 8-membered heterocyclyl; and / or each R 3 The same or different, and each independently halogen or =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen, and / or j is 1 or 2.

[0161] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein -CH2- or

[0162] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 3a and R 3b are all hydrogen atoms, or R 3a 、R 3b Together with the attached carbon atom, they form a 3- to 6-membered cycloalkyl group; in some embodiments, 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; in some embodiments, 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; in some embodiments, R 3a and R 3b All are hydrogen atoms.

[0163] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein r is 1 or 3.

[0164] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 3a and R 3b are all hydrogen atoms, or R3a 、R 3b Together with the carbon atom to which it is attached, it forms a cyclopropyl group, and / or r is 1 or 3.

[0165] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA), or pharmaceutically acceptable salts thereof, wherein W is O, and / or 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, and / or r is 1 or 3.

[0166] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein ring C is selected from cyclopropyl, azetidine, morpholinyl, Pyrrolidyl, piperidinyl,

[0167] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein ring C is selected from End and CR 3a R 3b connect.

[0168] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein Selected from End and CR 3a R 3b connect.

[0169] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein ring C is selected from cyclopropyl, azetidine, Morpholinyl, Pyrrolidinyl and piperidinyl; In some embodiments, ring C is selected from cyclopropyl, azetidine,

[0170] In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from In some embodiments, Ring C is In some embodiments, Ring C is End and CR 3a R 3b connect.

[0171] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein Selected from

[0172] In some embodiments, Selected from In some embodiments, Selected from R 3c Selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, alkyl-S-, haloalkyl, haloalkoxy, cyano, NR 11 R 12 、C(O)NR 11 R 12 、S(O)2NR 11 R 12 , -C(O)alkyl, -S(O)2alkyl, =CR 15 R 16 、=NR 13 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally replaced by one or more R * Replaced by; R 4 、R 5 、R 11 、R12 、R 13 、R 15 、R 16 and R * As defined in formula (I);

[0173] In some embodiments, Selected from In some embodiments, Selected from In some embodiments, for

[0174] In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl (in some embodiments, a hydrogen atom or a halogen), R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl (in some embodiments, a hydrogen atom or a halogen); in some embodiments, R 4 and R 5 As defined in general formula (I).

[0175] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein Selected from

[0176] In some embodiments of the present disclosure, the compound represented by the general formula (I'), (I'A), (IM), (IN) or a pharmaceutically acceptable salt thereof, wherein Selected from (In some embodiments, ), R 3c is a hydrogen atom or R 3 , R 3d Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 Haloalkyl, R 3f is a hydrogen atom or R 3 , R 3 、R 15 and R 16 As defined in formula (I');

[0177] In some embodiments, Selected from

[0178] In some embodiments, Selected from In some embodiments, Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 15 and R 16 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 a haloalkyl group and a 3- to 6-membered cycloalkyl group (a hydrogen atom or a halogen in some embodiments).

[0179] In some embodiments of the present disclosure, the compound represented by the general formula (I'), (I'A), (IM), (IN) or a pharmaceutically acceptable salt thereof, wherein Selected from

[0180] In some embodiments of the present disclosure, the compound represented by the general formula (I'), (I'A), (IM), (IN) or a pharmaceutically acceptable salt thereof, wherein Selected from

[0181] In some embodiments, Selected from In some embodiments, Selected from In some embodiments,

[0182] In some embodiments of the present disclosure, the compound represented by the general formula (VII-1) or a pharmaceutically acceptable salt thereof, wherein for In some embodiments, In some embodiments, R 3c 、R 4 and R 5 As defined in formula (V).

[0183] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-1), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein each R 3 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, -C 1-6 Alkyl NR 11 R 12 、=CR 15 R 16 、=NR 13 , hydroxyl and C 1-6 Hydroxyalkyl, R 11 、R 12 、R 13 、R 15 and R 16 As defined in Formula (I); in some embodiments, each R 3are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 alkyl; in some embodiments, each R 3 The same or different, and each independently halogen or =CR 15 R 16 , R 15 and R 16 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 3 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 3 are the same or different and are each independently selected from F, =CH2, =CHF and =CF2; in some embodiments, each R 3 are the same or different and are each independently halogen; in some embodiments, R 3 is F; in some embodiments, each R 3 The same or different, and each independently is =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 alkyl; in some embodiments, each R 3 The same or different, and each independently is =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, each R 3 are the same or different and are each independently selected from ═CH 2 , ═CHF and ═CF 2 .

[0184] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein p is 0, 1, 2 or 3; in some embodiments, p is 0, 1 or 2; in some embodiments, p is 0 or 1; in some embodiments, p is 1; in some embodiments, p is 0.

[0185] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-1), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -C 1-6 Alkyl NR 11 R 12 , hydroxyl, C 1-6 Hydroxyalkyl and =CR 15 R 16 , R 11 、R 12 、R 15 and R 16 As defined in formula (I);

[0186] In some embodiments, R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and =CR 15 R 16 In some embodiments, R 3c Selected from hydrogen atoms, halogens and =CR 15 R 16 , R 15 and R 16 As defined in formula (I); in some embodiments, R 3c is a hydrogen atom or a halogen; in some embodiments, R 3c is a hydrogen atom or F; in some embodiments, R 3c is selected from hydrogen atoms, F, ═CH 2 , ═CHF, and ═CF 2 ; in some embodiments, R 3c is selected from hydrogen atoms, =CH2, =CHF and =CF2; in some embodiments, R 3c is selected from hydrogen atom, F and =CH2.

[0187] In some embodiments of the present disclosure, R 3e Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 3e Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3eis a hydrogen atom or a halogen; in some embodiments, R 3e is halogen; in some embodiments, R 3e For F.

[0188] In some embodiments of the present disclosure, R 3d is selected from hydrogen atoms, methyl groups and difluoroethyl groups; in some embodiments, R 3d is a hydrogen atom or a methyl group; in some embodiments, R 3d It is a methyl group.

[0189] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VI), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; in some embodiments, ring A is a 6- to 10-membered aryl group; in some embodiments, ring A is selected from naphthyl, phenyl, pyridyl, benzothiophenyl, benzothiazolyl, benzopyrazolyl, pyridothiphenyl, In some embodiments, ring A is selected from naphthyl, phenyl, pyridinyl, benzothienyl, benzothiazolyl, benzopyrazolyl, pyridothiphenyl, pyridothiphenyl and pyridothiphenyl; In some embodiments, ring A is selected from phenyl, benzothienyl and pyridothiphenyl; In some embodiments, ring A is benzoselenophene or pyridoselenophene; In some embodiments, ring A is benzoselenophene; In some embodiments, ring A is selected from Phenyl, In some embodiments, Ring A is selected from Phenyl, In some embodiments, Ring A is selected from and phenyl; in some embodiments, ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is Connect to the ring where G is located.

[0190] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts 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, C2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, -NR 11 R 12 , hydroxyl, C 1-6 Hydroxyalkyl, OR 14 , 3 to 8 membered cycloalkyl and C(O)NR 11 R 12 , R 11 、R 12 and R 14 As defined in Formula (I); in some embodiments, 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, cyano, -NR 11 R 12 and a 3- to 8-membered cycloalkyl group, R 11 and R 12 As defined in Formula (I); in some embodiments, 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, cyano and -NR 11 R 12 , R 11 and R 12 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl; 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 and hydroxyl;

[0191] In some embodiments, each R 1 are the same or different and are each independently selected from halogen, C 1-6 alkyl and hydroxy; in some embodiments, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Haloalkyl, cyano and -NR 11 R 12 , R 11 and R 12 As defined in Formula (I); in some embodiments, each R 1 are the same or different and are each independently selected from halogen, cyano and -NR11 R 12 , R 11 and R 12 As defined in Formula (I); in some embodiments, each R 1 are the same or different and are each independently selected from halogen, cyano and amino; in some embodiments, each R 1 are the same or different and are each independently selected from F, Cl, CF3, cyano, OH and amino; in some embodiments, each R 1 are the same or different and are each independently selected from F, CF3, cyano and amino; in some embodiments, each R 1 are the same or different and are each independently F or cyano;

[0192] 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; in some embodiments, each R 1 are the same or different and are each independently halogen or cyano.

[0193] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein m is 1, 2, 3 or 4; in some embodiments, m is 1, 2 or 3; in some embodiments, m is 3 or 4; in some embodiments, m is 3.

[0194] In some embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein m-1 is 0, 1, 2 or 3; in some embodiments, m-1 is 1, 2 or 3; in some embodiments, m-1 is 2 or 3; in some embodiments, m-1 is 2.

[0195] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein 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, amino, and 3 to 6 membered cycloalkyl, and / or m is 1, 2, or 3; in some embodiments, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Haloalkyl, cyano and -NR11 R 12 , R 11 and R 12 As defined in general formula (I), and / or m is 1, 2 or 3.

[0196] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein for G 5 C or N, G 6 C or N, G 7 is C or N; Ring A 2 is aryl or heteroaryl (in some embodiments, phenyl or 5- or 6-membered heteroaryl), R 1 and m are as defined in Formula (I'); in some embodiments, for G 5 C or N, G 6 C or N, G 7 is C or N; Ring A 2 is a 5-membered heteroaryl group, 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, cyano and -NR 11 R 12 , R 11 and R 12 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; m is as defined in the general formula (I').

[0197] In some embodiments of the present disclosure, Ring A 2 is a 5-membered heteroaryl; in some embodiments, ring A 2 is selected from the group consisting of thienyl, furanyl, pyrazolyl, thiazolyl, imidazolyl and pyrrolyl; in some embodiments, ring A 2 is selected from thienyl, pyrazolyl and thiazolyl; in some embodiments, ring A 2 is thienyl; in some embodiments, ring A 2 It is a selenophene group.

[0198] In some embodiments of the present disclosure, G 5 N, G 6 C, G 7 is C; in some embodiments, G 5 C, G 6 C, G7 For C.

[0199] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein Selected from

[0200] In some embodiments, Selected from

[0201] In some embodiments, Selected from R 1 、R 14 and m are as defined in formula (I);

[0202] In some embodiments, Selected from R 1 and m are as defined in formula (I);

[0203] In some embodiments, Selected from In some embodiments, for In some embodiments Selected from In some embodiments Selected from R 1 and m are as defined in formula (I);

[0204] In some embodiments, Selected from

[0205] In some embodiments, Selected from In some embodiments, for R 1 and m are as defined in Formula (I'); in some embodiments, for In some embodiments, for In some embodiments, Selected from In some embodiments, for In some embodiments, for In some embodiments, Selected from In some embodiments,

[0206] In some embodiments, Selected from In some embodiments Selected from In some embodiments Selected from In some embodiments, Selected from

[0207] In some embodiments of the present disclosure, the compound represented by the general formula (VII-1) or (VII-2) or a pharmaceutically acceptable salt thereof, wherein for In some embodiments for In some embodiments for U, V, R 1 and m2 are as defined in Formula (VII-1) or (VII-2); in some embodiments Selected from In some embodiments Selected from In some embodiments Selected from

[0208] In some embodiments of the present disclosure, m-2 is 0, 1, 2 or 3; in some embodiments, m-2 is 1, 2 or 3; in some embodiments, m-2 is 3; in some embodiments, m-2 is 2.

[0209] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2) or their pharmaceutically acceptable salts, wherein R 1a Selected from hydrogen atoms, C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 1a A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 1a is a hydrogen atom or a methyl group; in some embodiments, R 1a A hydrogen atom.

[0210] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2) or their pharmaceutically acceptable salts, wherein R 1b Selected from hydrogen atoms, halogens, 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 11 R 12 , hydroxyl, C 1-6 Hydroxyalkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; R 11 and R 12 As defined in formula (I); in some embodiments, R 1b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy and cyano; in some embodiments, R 1b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 1b is a hydrogen atom or a halogen; in some embodiments, R 1b is a hydrogen atom or F; in some embodiments, R 1b A hydrogen atom.

[0211] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (III), (IM), (IN), (IIA), (IIIA) or their pharmaceutically acceptable salts, wherein G is CR G or N, R G Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, G is CR G or N, RG is a hydrogen atom or a halogen; in some embodiments, G is C-Cl or N; in some embodiments, G is N.

[0212] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein G 1 CR G1 or N, R G1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, G 1 is CH or N; in some embodiments, G 1 is N.

[0213] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IV), (IVA) or a pharmaceutically acceptable salt thereof, wherein G is C.

[0214] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V), (I'), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein G is N.

[0215] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 2 is a hydrogen atom or a halogen; in some embodiments, R 2 is halogen; in some embodiments, R 2 is F; in some embodiments, R 2 For Cl.

[0216] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein G 1 N, and / or R 2 It is a halogen.

[0217] In some embodiments of the present disclosure, the compound represented by the general formula (I), (IM), (II), (III), (IIA), (IIIA) or a pharmaceutically acceptable salt thereof, wherein G 1 N, and / or R 2 is halogen, and / or G is CR G or N, R G Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; and / or R 7 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyloxy and 3 to 6 membered heterocyclyloxy; in some embodiments, G 1 N, and / or R 2 is halogen, and / or G is CR G or N, R G is a hydrogen atom or a halogen; and / or R 7 Selected from hydrogen atoms, C 1-6 alkoxy and 3- to 6-membered cycloalkyloxy.

[0218] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein Q is NH or O; in some embodiments, Q is O.

[0219] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; in some embodiments, s is 1.

[0220] In some embodiments of the present disclosure, the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2; in some embodiments, t is 1.

[0221] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein each R 6 The same or different, and each independently selected from C 1-6 Alkyl, OR 14 NR 11 R 12 、C(O)NR 11 R 12 and C(O)R 14 , the C 1-6 Alkyl is optionally selected from halogen, OR 14 and one or more of a 3- to 6-membered heterocyclic group; R 11 、R 12and R 14 As defined in Formula (I'); in some embodiments, each R 6 The same or different, and each independently selected from C 1-6 Hydroxyalkyl, C(O)NR 11 R 12 and C(O)R 14 , R 11 、R 12 and R 14 As defined in formula (I');

[0222] In some embodiments, each R 6 The same or different, and each independently C(O)NR 11 R 12 or C(O)R 14 , R 11 、R 12 and R 14 As defined in Formula (I'); in some embodiments, each R 6 The same or different, and each independently is C 1-6 Hydroxyalkyl; in some embodiments, R 6 is hydroxypropyl; in some embodiments, R 6 OR 14 , R 14 As defined in formula (I'); in some embodiments, R 6 OR 14 , R 14 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 6 is OH; in some embodiments, R 6 Selected from OH, C(O)NH2, In some embodiments, R 6 Selected from OH, methyl, C(O)NH2, In some embodiments, R 6 for

[0223] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 11 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 11 is a hydrogen atom or a methyl group; in some embodiments, R11 is a hydrogen atom; in some embodiments, R 11 A hydrogen atom or C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; in some embodiments, R 11 Selected from ethyl,

[0224] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 12 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 12 is a hydrogen atom or a methyl group; in some embodiments, R 12 is a hydrogen atom; in some embodiments, R 12 A hydrogen atom or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a 5- or 6-membered heteroaryl group, which is optionally substituted with an NR a R b Replaced by R a and R b The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 12 A hydrogen atom or C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with a 6-membered heteroaryl group, which is replaced by NR a R b Replaced by R a and R b The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 12 A hydrogen atom or C 1-6 Alkyl, the C 1-6 The alkyl group is substituted with a pyridyl group, and the pyridyl group is substituted with NH2;

[0225] In some embodiments, R 12 Selected from G2, G 3 and G 4 The same or different, and each independently N or CR 1* , R 12a is a hydrogen atom or R * , R 1* is a hydrogen atom or R * , R * As defined in formula (I');

[0226] In some embodiments, R 12 Selected from

[0227] In some embodiments of the present disclosure, G 2 , G 3 and G 4 The same or different, and each independently N or CR 1* , R 1* Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, G 2 N, G 3 and G 4 For CH.

[0228] In some embodiments of the present disclosure, R 12a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 alkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 12a C 1-6 Alkyl; in some embodiments, R 12a It is a methyl group.

[0229] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 11 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl and 3 to 6 membered cycloalkyl C 1-6 Alkyl; and / or R 12 C 1-6 Alkyl, the C 1-6The alkyl group is substituted with a 6-membered heteroaryl group, which is replaced by NR a R b Replaced by R a and R b are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl.

[0230] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 13 A hydrogen atom or C 1-6 alkyl.

[0231] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 14 Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 alkenyl, 3- to 6-membered heterocyclic group and C(O)NR 20 R 21 , the C 1-6 The alkyl and 3 to 6 membered heterocyclic groups are each independently optionally selected from oxo, halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 is substituted by one or more hydroxyalkoxy groups, R 20 and R 21 As defined in formula (I); in some embodiments, R 14 Selected from hydrogen atoms, C 1-6 Alkyl and C(O)NR 20 R 21 , the C 1-6 Alkyl is optionally selected from halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 is substituted by one or more hydroxyalkoxy groups, R 20 and R 21 As defined in formula (I); in some embodiments, R 14 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Hydroxyalkyl and C 1-6 Alkoxy C 1-6 Alkyl; in some embodiments, R 14 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 14 is a hydrogen atom or a methyl group;

[0232] In some embodiments, R 14 Selected from hydrogen atoms, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, phenyl and 5 or 6 membered heteroaryl, said C 1-6 Alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, phenyl and 5 or 6 membered heteroaryl are each independently optionally selected from oxo, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, 3 to 6 membered cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 1-6 In some embodiments, R 14 Selected from hydrogen atoms, C 1-6 alkyl, 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl are each independently optionally selected from halogen, cyano, C 1-6 Alkyl and C 1-6 In some embodiments, R 14 Selected from C 1-6 alkyl, 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl are each independently optionally selected from halogen, cyano and C 1-6 substituted by one or more of the alkyl groups;

[0233] In some embodiments, R 14 Selected from hydrogen atoms, C 2-6 alkenyl, 3- to 6-membered heterocyclic group and C(O)NR 20 R 21 , the 3 to 6 membered heterocyclic group is optionally selected from oxo and C 1-6 One or more alkyl groups are substituted, R 20 and R 2 1 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl;

[0234] In some embodiments, R 14 Selected from hydrogen atoms, In some embodiments, R 14 Selected from hydrogen atoms, vinyl groups, In some embodiments, R 14 For vinyl.

[0235] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-1), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; in some embodiments, R 15 and R 16 are the same or different and are each independently selected from a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 is a hydrogen atom; in some embodiments, R 15 is a hydrogen atom, R 16 is halogen, or R 16 is a hydrogen atom, R 15 It is a halogen.

[0236] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-1), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 15 is a hydrogen atom or a halogen; in some embodiments, R 15 is a hydrogen atom or F; in some embodiments, R 15 A hydrogen atom.

[0237] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-1), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein R 16 is a hydrogen atom or a halogen; in some embodiments, R 16 is a hydrogen atom or F; in some embodiments, R 16 A hydrogen atom.

[0238] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (V) or a pharmaceutically acceptable salt thereof, wherein R 8c A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 8cis a hydrogen atom or a methyl group; in some embodiments, R 8c A hydrogen atom.

[0239] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (IV), (V), (VI), (VII-1), (VII-2) or a pharmaceutically acceptable salt thereof, wherein R 6c and R 6d are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; in some embodiments, R 6c and R 6d are the same or different and are each independently a hydrogen atom or a halogen.

[0240] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein each R 20 、R 21 、R 22 and R 23 are the same or different and are each independently a hydrogen atom or a C 1-6 alkyl; in some embodiments, each R 20 、R 21 、R 22 and R 23 are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, each R 20 and R 21 A hydrogen atom.

[0241] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or pharmaceutically acceptable salts thereof, wherein each R * are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R * The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R * It is a methyl group.

[0242] In the present disclosure, the general formulae (I) to (V) include the general formulae (I), (II), (III), (IV) and (V); the general formulae (I) to (VI) include the general formulae (I), (II), (III), (IV), (V) and (VI); the general formulae (I) to (VII-1) include the general formulae (I), (II), (III), (IV), (V), (VI) and (VII-1); the general formulae (I) to (VII-2) include the general formulae (I), (II), (III), (IV), (V), (VI), (VII-1) and (VII-2).

[0243] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G 1 is CH or N; G is CR G or N, R G Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7 is a hydrogen atom, or R 7 Together with G, it forms ring B, which is optionally substituted by one or more R 8 is substituted, and ring B is Each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and cyano; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 alkyl halide;

[0244] 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, 3 or 4; for u is 1 or 2, n1 is 0, R 6a C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 is substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; W is O; Selected from R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; R 3c is a hydrogen atom or a halogen; R15 is a hydrogen atom or a halogen; R 16 is a hydrogen atom or a halogen.

[0245] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein G is CR G or N; R G Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 N, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; u is 1 or 2; n1 is 0; R 6a C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; 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, 3 or 4; W is O; Selected from R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; R 3c is a hydrogen atom or a halogen; R 15 is a hydrogen atom or a halogen; R 16 is a hydrogen atom or a halogen.

[0246] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein G is CR G or N; R G Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 N, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C1-6 haloalkyl; u is 1 or 2; n1 is 0; R 6a C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 is substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; W is O; Selected from Selected from

[0247] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein Q is O; t is 1 or 2, s is 1 or 2; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; q is 0; G 1 is N; 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, 3 or 4; for u is 1 or 2, n1 is 0, R 6a C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 is substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; W is O; Selected from R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; R 3c is a hydrogen atom or a halogen; R 15 is a hydrogen atom or a halogen; R 16 is a hydrogen atom or a halogen.

[0248] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein Q is O; t is 1 or 2, s is 1 or 2; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; q is 0; G 1 is N; 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, 3 or 4; for u is 1 or 2, n1 is 0, R 6a C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 is substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; W is O; Selected from

[0249] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G 1 is CH or N; G is CR G or N, R G Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7 is a hydrogen atom; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 alkyl halide;

[0250] 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, 3 or 4; Selected from u is 1 or 2, n1 is 0, and the * end is connected to R 6a Connect, R 6a A hydrogen atom or C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 is substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; W is O; Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C1-6 Alkyl, R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl (in some embodiments, a hydrogen atom or a halogen), R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 An alkyl group (in some embodiments, a hydrogen atom or a halogen).

[0251] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein Q is O; t is 1 or 2, s is 1 or 2; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; q is 0; G 1 is N; 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, 3 or 4; Selected from u is 1 or 2, n1 is 0, and the * end is connected to R 6a Connect, R 6a A hydrogen atom or C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 is substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; W is O; Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl (in some embodiments, a hydrogen atom or a halogen), R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 An alkyl group (in some embodiments, a hydrogen atom or a halogen).

[0252] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein Q is O; t is 1 or 2, s is 1 or 2; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; q is 0; G 1 is N; 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, 3 or 4; Selected from u is 1 or 2, n1 is 0; * end and R 6a Connect, R 6a A hydrogen atom or C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 is substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; W is O; Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl (in some embodiments, a hydrogen atom or a halogen), R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 An alkyl group (in some embodiments, a hydrogen atom or a halogen).

[0253] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein Q is O; t is 1 or 2, s is 1 or 2; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; q is 0; G 1 is N; for Each R 1 are the same or different and are each independently selected from halogen, C 1-6Alkyl, C 1-6 Haloalkyl and cyano; m is 1, 2, 3 or 4; for u is 1 or 2, n1 is 0, and the * end is connected to R 6a Connect; R 6a A hydrogen atom or C 1-6 Alkyl, the C 1-6 Alkyl is optionally selected from hydroxy, C 1-6 is substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; W is O; Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl (in some embodiments, a hydrogen atom or a halogen), R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 An alkyl group (in some embodiments, a hydrogen atom or a halogen).

[0254] In some embodiments of the present disclosure, the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein Q is O; t is 1, s is 1; R 2 is halogen; q is 0; G 1 is N; for Each R 1 are the same or different and are each independently halogen or cyano; m-1 is 2; for u is 2, n1 is 0, R 6a C 1-6 Hydroxyalkyl; W is O; for R 4 and R 5 are the same or different and are each independently a hydrogen atom or a halogen.

[0255] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5- or 6-membered heterocyclic group; each R 8 are the same or different and are each independently selected from halogen, C1-6 Alkyl, C 1-6 haloalkyl and cyano; q is 0, 1 or 2; G is C or N; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 is N; 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, 3 or 4; R B is a hydrogen atom or a 3- to 10-membered heterocyclic group, wherein the 3- to 10-membered heterocyclic group is optionally substituted by one or more R 6 Replaced by each R 6 The same or different, and each independently selected from C 1-6 Hydroxyalkyl, C(O)NR 11 R 12 and C(O)R 14 , R 11 A hydrogen atom or C 1-6 Alkyl; R 12 A hydrogen atom or C 1-6 Alkyl; R 14 Selected from C 1-6 alkyl, 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 5 or 6 membered heteroaryl are each independently optionally selected from halogen, cyano and C 1-6 is substituted by one or more of the alkyl groups; W is O;

[0256] Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 15 and R 16 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 a haloalkyl group and a 3- to 6-membered cycloalkyl group (a hydrogen atom or a halogen in some embodiments).

[0257] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein ring B is a hydrogenated furanyl; each R8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and cyano; q is 0, 1 or 2; G is C; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 is N; 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, 3 or 4; R B Selected from hydrogen atoms, R 6a is a hydrogen atom or R 6 , R 6b R 6 , u is 0, 1 or 2; n1 is 0, 1, 2 or 3; each R 6 The same or different, and each independently is C 1-6 hydroxyalkyl;

[0258] W is O; Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 15 and R 16 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 a haloalkyl group and a 3- to 6-membered cycloalkyl group (a hydrogen atom or a halogen in some embodiments).

[0259] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein ring B is a hydrogenated furanyl; each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and cyano; q is 0, 1 or 2; G is C; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 is N; 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, 3 or 4; R B Selected from hydrogen atoms, R 6a is a hydrogen atom or R 6 , u is 1 or 2; n1 is 0; R 6 OR 14 , R 14 A hydrogen atom or C 1-6 alkyl;

[0260] W is O; -CH2- or Ring C is a 3- to 8-membered heterocyclic group, each R 3 The same or different, and each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, halogen and =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; j is 0, 1, 2 or 3.

[0261] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein ring B is a hydrogenated furanyl; each R 8 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and cyano; q is 0, 1 or 2; G is C; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 is N; 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, 3 or 4; R B Selected from hydrogen atoms, R 6a is a hydrogen atom or R 6 , u is 0, 1 or 2; n1 is 0; R 6 OR 14 , R14 A hydrogen atom or C 1-6 alkyl;

[0262] W is O; Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 15 and R 16 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 a haloalkyl group and a 3- to 6-membered cycloalkyl group (a hydrogen atom or a halogen in some embodiments).

[0263] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein ring B is q is 0; G is C; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 is N; 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, 3 or 4; R B Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 6 membered cycloalkyl and 3 to 10 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 6 membered cycloalkyl and 3 to 10 membered heterocyclic groups are each independently optionally selected from halogen, cyano, hydroxy, C 1-6 Alkyl, C 1-6 It is substituted by one or more of an alkoxy group and a 3- to 6-membered cycloalkyl group, and W is O; Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 15 and R 16 are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 a haloalkyl group and a 3- to 6-membered cycloalkyl group (a hydrogen atom or a halogen in some embodiments).

[0264] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein ring B is q is 0; G is C; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 is N; 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, 3 or 4; R B is selected from the group consisting of a hydrogen atom, a methyl group, a vinyl group, an ethynyl group, a cyclopropyl group, and a cyclobutyl group; W is O; Selected from

[0265] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 Together with G, it forms ring B, which is G is C; G 1 N; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R B is a hydrogen atom; 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, 3 or 4; R A for W is O; Selected from R 3c Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C1-6 haloalkyl and 3 to 6-membered cycloalkyl (in some embodiments, a hydrogen atom or a halogen), R 3d A hydrogen atom or C 1-6 Alkyl, R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl (in some embodiments, a hydrogen atom or a halogen), R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 An alkyl group (in some embodiments, a hydrogen atom or a halogen).

[0266] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 Together with G, it forms ring B, which is G is C; G 1 N; R 2 is halogen; R B is a hydrogen atom; Selected from R A for Selected from

[0267] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein ring B is q is 0; G is C; R 2 is halogen; G 1 is N; Selected from R B Selected from W is O; Selected from

[0268] In some embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein q is 0; R 2 is halogen; G 1 is N; m is 3 or 4; 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; Ring A is selected from RB Selected from hydrogen atoms, R 6a C 1-6 Hydroxyalkyl, u is 1 or 2; n1 is 0; W is O; -CH2- or Ring C is a 3- to 8-membered heterocyclic group, R 4 and R 5 are the same or different and are each independently a hydrogen atom or a halogen; each R 3 The same or different, and each independently halogen or =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen; p is 0 or 1.

[0269] In some embodiments of the present disclosure, the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof, wherein q is 0; R 2 is halogen; G 1 is N; m-1 is 2; 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; Ring A is selected from R B Selected from hydrogen atoms, W is O; Selected from

[0270] In some embodiments of the present disclosure, the compound represented by the general formula (VII-1) or (VII-2) or a pharmaceutically acceptable salt thereof, wherein q is 0; R 2 is halogen; G 1 is N; U is S or Se; V is CH or N; 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 and hydroxyl; m2 is 0, 1, 2 or 3; R 4 and R 5 are the same or different and are each independently a hydrogen atom or a halogen; R 3c Selected from hydrogen atoms, halogens and =CR 15 R 16 , R 15 is a hydrogen atom or a halogen; R 16 is a hydrogen atom or a halogen; R B Selected from hydrogen atoms, R 6a C 1-6 Hydroxyalkyl, u is 1 or 2; n1 is 0.

[0271] In some embodiments of the present disclosure, the compound represented by the general formula (VII-1) or (VII-2) or a pharmaceutically acceptable salt thereof, wherein q is 0; R 2 is halogen; G 1 N; R 4 and R 5 are the same or different and are each independently a hydrogen atom or a halogen; R 3c is selected from the group consisting of hydrogen, F, ═CH 2 , ═CHF and ═CF 2 ; Selected from R B Selected from hydrogen atoms, In some embodiments of the present disclosure, the compound represented by the general formula (VII-1) or (VII-2) or a pharmaceutically acceptable salt thereof, wherein q is 0; R 2 is halogen; G 1 is N; U is S or Se; V is CH or N; 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 and hydroxyl; m2 is 0, 1, 2 or 3; R 4 and R 5 are the same or different and are each independently a hydrogen atom or a halogen; R 3c is selected from hydrogen, F, ═CH 2 , ═CHF and ═CF 2 ; R B is a 3- to 10-membered heterocyclic group, wherein the 3- to 10-membered heterocyclic group is optionally substituted by one or more R 6 Replaced by R 6 for

[0272] In some embodiments of the present disclosure, the compound represented by the general formula (VII-1) or (VII-2) or a pharmaceutically acceptable salt thereof, wherein q is 0; R 2 is halogen; G 1 is N; U is S; V is CH or N; each R 1 are the same or different and are each independently selected from halogen, cyano and amino; m2 is 2 or 3; R 4 and R 5 are the same or different and are each independently a hydrogen atom or a halogen; R 3c Selected from hydrogen atoms, halogens and =CR 15 R 16 , R 15and R 16 are the same or different and are each independently a hydrogen atom or a halogen; R B A hydrogen atom.

[0273] Table A Typical compounds of the present disclosure include, but are not limited to:

[0274] Another aspect of the present disclosure relates to a compound represented by general formula (IIa) or a salt thereof,

[0275] Among them, R P is an amino protecting group, in some embodiments Boc;

[0276] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (II).

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

[0278] Among them, R P is an amino protecting group, in some embodiments Boc;

[0279] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n1、u、W、R 3a 、R3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (III).

[0280] Another aspect of the present disclosure relates to a compound represented by general formula (IVa) or a salt thereof,

[0281] Among them, R P is an amino protecting group, in some embodiments Boc;

[0282] Ring A, Ring B, Ring C, R 1 ,m,G,G 1 、R 2 、R 8 ,q,R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IV).

[0283] Another aspect of the present disclosure relates to a compound represented by general formula (Va) or a salt thereof,

[0284] Among them, R P is an amino protecting group, in some embodiments Boc;

[0285] Ring A, Ring C, R 1 ,m,Q,s,t,R 8 ,q,G 1 、R 2 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (V).

[0286] Another aspect of the present disclosure relates to a compound represented by general formula (VIA) or a salt thereof,

[0287] Among them, R P is an amino protecting group, in some embodiments Boc;

[0288] Ring A, Ring C, R 1 ,m,R 8 ,q,R 2 , G 1 、R B, W, R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (VI).

[0289] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0290] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0291] The compound represented by general formula (IIA) or its salt undergoes a ring-opening reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0292] Among them, R 6a for R is a hydrogen atom or an alkyl group;

[0293] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (II).

[0294] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0295] The compound represented by general formula (IIIA) or its salt undergoes a ring-opening reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

[0296] Among them, R6a for R is a hydrogen atom or an alkyl group;

[0297] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n1、u、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (III).

[0298] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0299] The compound represented by general formula (IVA) or its salt undergoes a ring-opening reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

[0300] Among them, R 6a for R is a hydrogen atom or an alkyl group;

[0301] Ring A, Ring B, Ring C, R 1 ,m,G,G 1 、R 2 、R 8 ,q,R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IV).

[0302] 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:

[0303] The compound represented by general formula (VA) or its salt undergoes a ring-opening reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (V) or its pharmaceutically acceptable salt;

[0304] Among them, R 6a for R is a hydrogen atom or an alkyl group;

[0305] Ring A, Ring C, R 1 ,m,Q,s,t,R 8,q,R 2 , G 1 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (V).

[0306] In some embodiments of the present disclosure, the method for preparing the compound represented by the general formula (II) to (V) or a pharmaceutically acceptable salt thereof, wherein R 6a for In some embodiments, R 6a for R is as defined above.

[0307] In some embodiments of the present disclosure, the preparation method of the compound represented by the general formula (II) to (V) or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom or C 1-6 Alkyl; in some embodiments, R is C 1-6 Alkyl; in some embodiments, R is methyl.

[0308] In some embodiments of the present disclosure, the method for preparing the compound represented by the general formula (II) to (V) or a pharmaceutically acceptable salt thereof, wherein for In some embodiments, R is R is as defined above.

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

[0310] At least one R 1 The compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, wherein the compound is an amino-amino protecting group or an -O-hydroxy protecting group, undergoes a deprotection reaction to obtain at least one R 1 A compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof wherein the compound is an amino group or a hydroxy group;

[0311] Wherein, in some embodiments the amino protecting group is Boc;

[0312] Ring A, Ring C, and the remaining R 1 ,m,G,G 1 、R 2 、R 7 、R B , W, R 3a 、R 3b , r, R 3 and j are as defined in Formula (IM).

[0313] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0314] At least one R 1 The compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein the compound is an -amino-amino protecting group or an -O-hydroxy protecting group, undergoes a deprotection reaction to obtain at least one R 1 A compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof wherein the compound is an amino group or a hydroxy group;

[0315] Wherein, in some embodiments the amino protecting group is Boc;

[0316] Ring A, Ring B, Ring C, and the remaining R 1 ,m,G,R 8 ,q,R 2 , G 1 、R B , W, R 3a 、R 3b , r, R 3 and j are as defined in formula (IN).

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

[0318] The compound represented by the general formula (IIa) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (IIA) or its pharmaceutically acceptable salt;

[0319] Among them, R P is an amino protecting group, in some embodiments Boc;

[0320] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IIA).

[0321] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA) or a pharmaceutically acceptable salt thereof, the method comprising:

[0322] The compound represented by general formula (IIIa) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (IIIA) or its pharmaceutically acceptable salt;

[0323] Among them, R P is an amino protecting group, in some embodiments Boc;

[0324] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n1、u、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IIIA).

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

[0326] The compound represented by the general formula (IVa) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (IVA) or its pharmaceutically acceptable salt;

[0327] Among them, R P is an amino protecting group, in some embodiments Boc;

[0328] Ring A, Ring B, Ring C, R 1 ,m,G,G 1 、R 2 、R 8 ,q,R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IVA).

[0329] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VA) or a pharmaceutically acceptable salt thereof, the method comprising:

[0330] The compound represented by the general formula (Va) or its salt undergoes a deprotection reaction to obtain the compound represented by the general formula (VA) or its pharmaceutically acceptable salt;

[0331] Among them, R P is an amino protecting group, in some embodiments Boc;

[0332] Ring A, Ring C, R 1 ,m,Q,s,t,R 8 ,q,R 2 , G 1 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (VA).

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

[0334] R 6a OR 14 The compound represented by the general formula (II) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 6a A compound represented by the general formula (II) wherein OH is OH or a pharmaceutically acceptable salt thereof;

[0335] R 14 is a hydroxy protecting group, in some embodiments benzoyl;

[0336] Among them, ring A, ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6a 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (II).

[0337] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0338] R 6a OR 14 The compound represented by the general formula (III) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 6a A compound represented by the general formula (III) wherein OH is OH or a pharmaceutically acceptable salt thereof;

[0339] R 14 is a hydroxy protecting group, in some embodiments benzoyl;

[0340] Among them, ring A, ring C, R 1,m,G,G 1 、R 2 、R 7 、R 6a 、R 6b 、n1、u、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (III).

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

[0342] R 6a OR 14 The compound represented by the general formula (IV) or its salt undergoes a deprotection reaction to obtain R 6a A compound represented by the general formula (IV) wherein OH is OH or a pharmaceutically acceptable salt thereof;

[0343] Among them, ring A, ring B, ring C, R 1 ,m,G,G 1 、R 2 、R 8 ,q,R 6a 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IV).

[0344] 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:

[0345] R 6a OR 14 The compound represented by the general formula (V) or its pharmaceutically acceptable salt undergoes a deprotection reaction to obtain R 6a A compound represented by the general formula (V) wherein OH is OH or a pharmaceutically acceptable salt thereof;

[0346] R 14 is a hydroxy protecting group, in some embodiments a benzoyl group;

[0347] Among them, ring A, ring C, R 1 ,m,R 2 ,Q,R 8 ,q,s,t,G 1 、R 6a 、R6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (V).

[0348] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:

[0349] The compound represented by general formula (VIA) or its salt undergoes a deprotection reaction to obtain the compound represented by general formula (VI) or its pharmaceutically acceptable salt;

[0350] Among them, R P is an amino protecting group, in some embodiments Boc;

[0351] Ring A, Ring C, R 1 ,m,R 8 ,q,R 2 , G 1 、R B , W, R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (VI).

[0352] Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (VII-1) and (VII-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0353] At least one R 1 The compound represented by the general formula (VII-1) or a pharmaceutically acceptable salt thereof, wherein the protecting group is -NH-amino, undergoes a deprotection reaction to obtain at least one R 1 A compound represented by the general formula (VII-1) or a pharmaceutically acceptable salt thereof, which is an amino group;

[0354] At least one R 1 The compound represented by the general formula (VII-2) or a pharmaceutically acceptable salt thereof, wherein the protecting group is -NH-amino, undergoes a deprotection reaction to obtain at least one R 1 A compound represented by the general formula (VII-2) or a pharmaceutically acceptable salt thereof, which is an amino group;

[0355] wherein m2 is 1, 2, 3 or 4; in some embodiments, the amino protecting group is Boc;

[0356] U, V, and the remaining R 1 、R8 ,q,R 2 , G 1 、R B 、R 3c 、R 4 and R 5 As defined in general formula (VII-1) or (VII-2).

[0357] 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:

[0358] The compound represented by the general formula (VA) or its salt reacts with the compound represented by the general formula (VB) or its salt to obtain the compound represented by the general formula (V) or its pharmaceutically acceptable salt;

[0359] Among them, R 6a for X is OH or halogen, in some embodiments X is halogen,, in some embodiments X is Cl;

[0360] Ring A, Ring C, R 1 ,m,Q,s,t,R 8 ,q,R 2 , G 1 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (V).

[0361] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of Formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or shown in Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0362] The present disclosure further relates to the use of a compound of Formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting KRAS amplification and / or KRAS mutant activity; in some embodiments, the KRAS mutant is 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; in some embodiments, KRAS G12D and / or KRAS G12V mutations.

[0363] The present disclosure further relates to the use of a compound of Formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or as 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 a disease or condition mediated by KRAS amplification and / or KRAS mutants; in some embodiments, the KRAS mutants are 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; in some embodiments, the KRAS G12D and / or KRAS G12V mutation.

[0364] The present disclosure further relates to the use of compounds of formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing cancer; in some embodiments, the cancer is 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; in some embodiments, selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0365] 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) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the KRAS mutant is 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; in some embodiments, it is KRAS G12D and / or KRAS G12V mutation.

[0366] 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) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the KRAS mutation is 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; in some embodiments, KRAS G12D and / or KRAS G12V mutation.

[0367] 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) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the cancer is 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; in some embodiments selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0368] The present disclosure further relates to a compound represented by Formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0369] The present disclosure further relates to a compound shown in Formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting the activity of KRAS amplification and / or KRAS mutants; in some embodiments, the KRAS mutants are 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; in some embodiments, KRAS G12D and / or KRAS G12V mutations.

[0370] The present disclosure further relates to a compound shown in Formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing a disease or condition mediated by KRAS amplification and / or KRAS mutants; in some embodiments, the KRAS mutants are 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; in some embodiments, KRAS G12D and / or KRAS G12V mutations.

[0371] The present disclosure further relates to a compound of formula (I) to (VII-2), (I'), (I'A), (IM), (IN), (IIA), (IIIA), (IVA), (VA) 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; in some embodiments, the cancer is 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 carcinoma, 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; in some embodiments selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0372] The diseases or conditions described herein are diseases or conditions that are treated and / or prevented by inhibiting KRAS amplification and / or KRAS mutant activity; in some embodiments, the KRAS mutant is 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; in some embodiments, KRAS G12D and / or KRAS G12V mutations.

[0373] The diseases or conditions mediated by KRAS amplification and / or KRAS mutations described herein are cancers. In some embodiments, the KRAS mutations are 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. In some embodiments, the KRAS G12D and / or KRAS G12V mutation; in some embodiments, the cancer is 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; in some embodiments, selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0374] The colorectal cancer described in the present disclosure is colon cancer or rectal cancer.

[0375] 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 (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicle center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); in some embodiments, liver cancer is 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 selected from renal cell carcinoma, clear cell and renal oncocytoma; leukemia 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 selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; in some embodiments, myeloma is multiple myeloma

[0376] 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.

[0377] As a general guide, the active compounds of the present disclosure are 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 can be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms can range from 0.1 to 1000 mg.

[0378] 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.

[0379] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0380] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0381] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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.

[0386] 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.

[0387] 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.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] Terminology

[0393] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0394] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, and in some embodiments, 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., C1-12 alkyl), in some embodiments 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, with the substituent being 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.

[0395] 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 In some embodiments, the alkylene group has an alkylene group of 1 to 12 carbon atoms (i.e., C 1-12 alkylene), in some embodiments 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-, and the like. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituents are 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.

[0396] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and in some embodiments 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 alkenyl), in some embodiments 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, and when substituted, the substituent is selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0397] 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. In some embodiments, an 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), in some embodiments an alkynyl group 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 selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0398] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, in some embodiments 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), in some embodiments 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), in some embodiments 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, and the like; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0399] The term " spiroalkyl " refers to 5 to 20 yuan, a polycyclic group sharing a carbon atom (claiming spiral atom) between monocycles, which can contain one or more double bonds. In some embodiments, it is 6 to 14 yuan, in some embodiments, it is 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), in some embodiments, it is single spiroalkyl and double spiroalkyl. In some embodiments, it is 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 monospiroalkyl. The non-limiting examples of spiroalkyl include:

[0400] Its connection point can be at any position;

[0401] wait.

[0402] The term " fused cycloalkyl " refers to 5 to 20 yuan, and each ring in the system shares a full carbon polycyclic group of a pair of carbon atoms adjacent to other rings in the system, wherein one or more rings can contain one or more double bonds. In some embodiments, it is 6 to 14 yuan, in some embodiments, it is 7 to 10 yuan (such as 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into bicyclic or polycyclic fused cycloalkyl (such as tricyclic, tetracyclic), in some embodiments, it is bicyclic or tricyclic, in some embodiments, it is 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 include:

[0403] Its connection point can be at any position;

[0404] wait.

[0405] 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. In some embodiments, it is 6 to 14 members, and in some embodiments, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl group, in some embodiments, it is bicyclic, tricyclic, or tetracyclic, and in some embodiments, it is bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0406] Its connection point can be at any position.

[0407] 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.; in some embodiments

[0408] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents may be selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0409] 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 may be selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0410] 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. In some embodiments, the ring comprises 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; in some embodiments, the ring comprises 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); in some embodiments, the ring comprises 3 to 8 ring atoms, of which 1-3 (e.g., 1, 2, and 3) are heteroatoms; in some embodiments, the ring comprises 5 or 6 (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.

[0411] The term "spiro heterocyclic radical" refers to a polycyclic heterocyclic group of 5 to 20 yuan, a single 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. In some embodiments, 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 radicals), in some embodiments, it is 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan) (i.e., 7 to 10 yuan spiral heterocyclic radicals). 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), in some embodiments, a single spiral heterocyclic radical and a double spiral heterocyclic radical. In some embodiments, 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:

[0412] 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 the 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., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. In some embodiments, 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 fused heterocyclyl), and in some embodiments, it is 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 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, in some embodiments bicyclic or tricyclic, in some embodiments 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:

[0413] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, any two rings sharing two atoms that are not directly connected, 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. In some embodiments, 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 bridged heterocyclic groups), in some embodiments, it is 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan) (i.e., 7 to 10 yuan 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, in some embodiments, it is bicyclic, tricyclic or tetracyclic, in some embodiments, it is bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0414] 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:

[0415] wait.

[0416] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents may be selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0417] 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, in some embodiments 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:

[0418] The aryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents may be selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0419] 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, nitrogen, and selenium (in some embodiments, the heteroatoms are selected from oxygen, sulfur, and nitrogen). In some embodiments, the heteroaryl group is 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) yuan (i.e., a 5- to 10-membered heteroaryl group), in some embodiments 8 to 10 (e.g., 8, 9, or 10) yuan, in some embodiments 5 or 6 yuan (i.e., a 5- or 6-membered heteroaryl group), such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, selenophenyl, and the like. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0420] wait.

[0421] The heteroaryl group may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, with the substituent being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0422] 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".

[0423] The term "amino-protecting group" is used to protect the amino group with a readily removable group, thereby preserving the amino group while reacting other parts of 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. In some embodiments, the amino-protecting group is Boc or PMB.

[0424] The term "hydroxy protecting group" refers to a hydroxy derivative that is typically used to block or protect the hydroxy group while reacting on other functional groups of the compound. By way of example, the hydroxy protecting group includes, but is not limited to, 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. In some embodiments, the hydroxy protecting group is benzoyl.

[0425] 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 reacting other parts of the molecule. 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, p-nitrobenzoyl, and the like. In some embodiments, the alkynyl protecting group is TIPS.

[0426] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0427] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0428] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0429] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0430] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0431] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0432] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

[0433] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0434] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0435] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0436] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0437] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0438] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0439] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; in some embodiments, -alkyl-alkoxy; including but not limited to methoxyethyl, methoxypropyl, and the like.

[0440] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0441] The term "hydroxy" refers to -OH.

[0442] The term "mercapto" refers to -SH.

[0443] The term "amino" refers to -NH2.

[0444] The term "amino-amino protecting group" refers to an -NH-amino protecting group.

[0445] The term "cyano" refers to -CN.

[0446] The term "nitro" refers to -NO2.

[0447] The term "oxo" or "oxo" refers to "=0".

[0448] The term "carbonyl" refers to C=O.

[0449] The term "carboxy" refers to -C(O)OH.

[0450] 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.

[0451] MOM stands for methoxymethyl.

[0452] Boc refers to tert-butyloxycarbonyl.

[0453] TIPS refers to triisopropylsilyl.

[0454] TBS refers to tert-butyldimethylsilyl.

[0455] 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 around 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 a purified atropisomer. Non-limiting examples include:

[0456] 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:

[0457] All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

[0458] 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.

[0459] 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; key The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0460] 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), 2c 、 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., in some embodiments, deuterium.

[0461] 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.

[0462] "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.

[0463] "Substituted" means that one or more hydrogen atoms, such as 1 to 6, and in some embodiments 1 to 3, in a group are independently replaced by a corresponding number of substituents. One skilled in the art will be able to determine (by experiment or theory) which substitutions are possible or impossible 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.

[0464] 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.

[0465] "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.

[0466] 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.

[0467] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0468] 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 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.

[0469] Synthesis method of the disclosed compound

[0470] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0471] Option 1

[0472] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0473] The compound represented by general formula (IIA) or its salt undergoes a ring-opening reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0474] Among them, R 6a for R is a hydrogen atom or an alkyl group;

[0475] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n、W、R 3a 、R 3b , r, Y, R3 、R 4 、R 5 and p are as defined in general formula (II).

[0476] Plan 1-2

[0477] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0478] R 6a OR 14 The compound represented by the general formula (II) or its pharmaceutically acceptable salt undergoes a deprotection reaction under alkaline conditions to obtain R 6a A compound represented by the general formula (II) wherein OH is OH or a pharmaceutically acceptable salt thereof;

[0479] R 14 is a hydroxy protecting group, in some embodiments a benzoyl group;

[0480] Among them, ring A, ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6a 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (II).

[0481] Option 2

[0482] The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0483] The compound represented by general formula (IIIA) or its salt undergoes a ring-opening reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

[0484] Among them, R 6a for R is a hydrogen atom or an alkyl group;

[0485] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n1、u、W、R 3a 、R 3b , r, Y, R3 、R 4 、R 5 and p are as defined in general formula (III).

[0486] Option 2-2

[0487] The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0488] R 6a OR 14 The compound represented by the general formula (III) or its pharmaceutically acceptable salt undergoes a deprotection reaction under alkaline conditions to obtain R 6a A compound represented by the general formula (III) wherein OH is OH or a pharmaceutically acceptable salt thereof;

[0489] R 14 is a hydroxy protecting group, in some embodiments a benzoyl group;

[0490] Among them, ring A, ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6a 、R 6b 、n1、u、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in general formula (III).

[0491] Option 3

[0492] The present disclosure provides a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0493] The compound represented by general formula (IVA) or its salt undergoes a ring-opening reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

[0494] Among them, R 6a for R is a hydrogen atom or an alkyl group;

[0495] Ring A, Ring B, Ring C, R 1 ,m,G,G 1 、R 2 、R 8 ,q,R 6b 、n、W、R 3a 、R 3b , r, Y, R3 、R 4 、R 5 and p are as defined in formula (IV).

[0496] Plan 3-2

[0497] The present disclosure provides a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0498] R 6a OR 14 The compound represented by the general formula (IV) or its pharmaceutically acceptable salt undergoes a deprotection reaction under alkaline conditions to obtain R 6a A compound represented by the general formula (IV) wherein OH is OH or a pharmaceutically acceptable salt thereof;

[0499] R 14 is a hydroxy protecting group, in some embodiments a benzoyl group;

[0500] Among them, ring A, ring B, ring C, R 1 ,m,G,G 1 、R 2 、R 8 ,q,R 6a 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IV).

[0501] Option 4

[0502] The present disclosure provides a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0503] The compound represented by general formula (VA) or its salt undergoes a ring-opening reaction with the compound represented by general formula (IIB) or its salt to obtain the compound represented by general formula (V) or its pharmaceutically acceptable salt;

[0504] Among them, R 6a for R is a hydrogen atom or an alkyl group;

[0505] Ring A, Ring C, R 1 ,m,Q,s,t,R 8 ,q,R 2 , G 1 、R 6b 、n、W、R 3a 、R 3b , r, Y, R3 、R 4 、R 5 and p are as defined in formula (V).

[0506] Plan 4-2

[0507] The present disclosure provides a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0508] R 6a OR 14 The compound represented by the general formula (V) or its pharmaceutically acceptable salt undergoes a deprotection reaction under alkaline conditions to obtain R 6a A compound represented by the general formula (V) wherein OH is OH or a pharmaceutically acceptable salt thereof;

[0509] R 14 is a hydroxy protecting group, in some embodiments a benzoyl group;

[0510] Among them, ring A, ring C, R 1 ,m,R 2 ,Q,R 8 ,q,s,t,G 1 、R 6a 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (V).

[0511] Plan 5

[0512] The present disclosure provides a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, the method comprising:

[0513] At least one R 1 The compound represented by the general formula (IM) or its pharmaceutically acceptable salt, wherein the compound is an amino-amino protecting group or an -O-hydroxy protecting group, undergoes a deprotection reaction under acidic conditions to obtain at least one R 1 A compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof wherein the compound is an amino group or a hydroxy group;

[0514] Wherein, in some embodiments, the amino protecting group is Boc;

[0515] Ring A, Ring C, and the remaining R 1 ,m,G,G 1 、R 2 、R 7 、R B , W, R3a 、R 3b , r, R 3 and j are as defined in Formula (IM).

[0516] Plan 6

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

[0518] At least one R 1 The compound represented by the general formula (IN) or its pharmaceutically acceptable salt, which is an -amino-amino protecting group or an -O-hydroxy protecting group, undergoes a deprotection reaction under acidic conditions to obtain at least one R 1 A compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof wherein the compound is an amino group or a hydroxy group;

[0519] Wherein, in some embodiments, the amino protecting group is Boc;

[0520] Ring A, Ring B, Ring C, and the remaining R 1 ,m,G,R 8 ,q,R 2 , G 1 、R B , W, R 3a 、R 3b , r, R 3 and j are as defined in formula (IN).

[0521] Plan 7

[0522] The present disclosure provides a method for preparing a compound represented by general formula (IIA) or a pharmaceutically acceptable salt thereof, the method comprising:

[0523] The compound represented by general formula (IIa) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (IIA) or its pharmaceutically acceptable salt;

[0524] Among them, R P is an amino protecting group, in some embodiments Boc;

[0525] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IIA).

[0526] Plan 8

[0527] The present disclosure provides a method for preparing a compound represented by general formula (IIIA) or a pharmaceutically acceptable salt thereof, the method comprising:

[0528] The compound represented by general formula (IIIa) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (IIIA) or its pharmaceutically acceptable salt;

[0529] Among them, R P is an amino protecting group, in some embodiments Boc;

[0530] Ring A, Ring C, R 1 ,m,G,G 1 、R 2 、R 7 、R 6b 、n1、u、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IIIA).

[0531] Plan 9

[0532] The present disclosure provides a method for preparing a compound represented by general formula (IVA) or a pharmaceutically acceptable salt thereof, the method comprising:

[0533] The compound represented by the general formula (IVa) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by the general formula (IVA) or its pharmaceutically acceptable salt;

[0534] Among them, R P is an amino protecting group, in some embodiments Boc;

[0535] Ring A, Ring B, Ring C, R 1 ,m,G,G 1 、R 2 、R 8 ,q,R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (IVA).

[0536] Plan 10

[0537] The present disclosure provides a method for preparing a compound represented by general formula (VA) or a pharmaceutically acceptable salt thereof, the method comprising:

[0538] The compound represented by general formula (Va) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (VA) or its pharmaceutically acceptable salt;

[0539] Among them, R P is an amino protecting group, in some embodiments Boc;

[0540] Ring A, Ring C, R 1 ,m,Q,s,t,R 8 ,q,R 2 , G 1 、R 6b 、n、W、R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (VA).

[0541] Plan 11

[0542] The present disclosure provides a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:

[0543] The compound represented by general formula (VIA) or its salt undergoes a deprotection reaction under acidic conditions to obtain the compound represented by general formula (VI) or its pharmaceutically acceptable salt;

[0544] Among them, R P is an amino protecting group, in some embodiments Boc;

[0545] Ring A, Ring C, R 1 ,m,R 8 ,q,R 2 , G 1 、R B , W, R 3a 、R 3b , r, Y, R 3 、R 4 、R 5 and p are as defined in formula (VI).

[0546] Plan 12

[0547] The present disclosure provides a method for preparing the compounds represented by general formula (VII-1) and (VII-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0548] At least one R 1 The compound represented by the general formula (VII-1) or its pharmaceutically acceptable salt having a -NH-amino protecting group undergoes a deprotection reaction under acidic conditions to obtain at least one R 1 A compound represented by the general formula (VII-1) or a pharmaceutically acceptable salt thereof, which is an amino group;

[0549] At least one R 1 The compound represented by the general formula (VII-2) or its pharmaceutically acceptable salt having a -NH-amino protecting group undergoes a deprotection reaction under acidic conditions to obtain at least one R 1 A compound represented by the general formula (VII-2) or a pharmaceutically acceptable salt thereof, which is an amino group;

[0550] wherein m2 is 1, 2, 3 or 4; in some embodiments, the amino protecting group is Boc;

[0551] U, V, and the remaining R 1 、R 8 ,q,R 2 , G 1 、R B 、R 3c 、R 4 and R 5 As defined in general formula (VII-1) or (VII-2).

[0552] Optionally, in the above schemes 1 to 4, 7 to 10, when R 1 When the group contains a protecting group, the preparation method further comprises removing R 1 The steps of removing the protecting group on the group; 1 The step of removing an amino protecting group and / or a hydroxy protecting group on the substrate.

[0553] 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 (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, hydrochloric acid 1,4-dioxane solution, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; in some embodiments, hydrochloric acid 1,4-dioxane solution, trifluoroacetic acid or trifluoromethanesulfonic acid; in some embodiments, hydrochloric acid 1,4-dioxane solution; in some embodiments, trifluoroacetic acid.

[0554] 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; in some embodiments, the base providing alkaline conditions is anhydrous potassium carbonate.

[0555] In some embodiments, the reaction in the above steps is 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 a mixture thereof. DETAILED DESCRIPTION

[0556] 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.

[0557] Example

[0558] 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 NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0559] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-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).

[0560] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0561] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0562] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0563] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0564] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0565] 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.

[0566] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0567] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0568] The known starting materials disclosed herein 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.

[0569] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0570] 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.

[0571] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0572] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0573] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0574] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0575] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0576] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0577] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: petroleum ether / 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.

[0578] Example 1

[0579] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 1

[0580] first step

[0581] tert-Butyl 4-(fluoromethylidene)piperidine-1-carboxylate 1b

[0582] (Fluoromethyl)triphenylphosphonium tetrafluoroborate (30.2 g, 79 mmol, Shanghai Bid) was dissolved in tetrahydrofuran (200 mL), and a 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (75.3 mL) was added at -70°C, and the reaction was stirred for 1 hour. N-tert-Butyloxycarbonyl-4-piperidone 1a (15 g, 75.3 mmol, Shanghai Bid) was added, and the reaction was stirred at -70°C for 1 hour, then returned to room temperature and stirred for 16 hours. Saturated ammonium chloride solution 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, dried over anhydrous sodium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1b (13.7 g, yield: 84.3%).

[0583] Step 2

[0584] 4-(Fluoromethylidene)piperidine hydrochloride 1c

[0585] Compound 1b (13.7 g, 63.5 mmol) was dissolved in 4.0 M hydrogen chloride in 1,4-dioxane (80 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give the crude title compound 1c (9.6 g). The product was directly used for the next step without purification.

[0586] MS m / z(ESI):116.1[M+1].

[0587] Step 3

[0588] Methyl 1-(4-(fluoromethylidene)piperidine-1-carbonyl)cyclopropane-1-carboxylate 1d

[0589] Dissolve 1,1-cyclopropyldicarboxylic acid monomethyl ester (22 g, 152.6 mmol, Shanghai Leyan) in dichloromethane (400 mL), replace with nitrogen three times, add oxalyl chloride (77.5 g, 610.4 mmol) and N,N-dimethylformamide (DMF) (391 mg, 5.3 mmol) dropwise at 0 ° C, return to room temperature and stir for 3 hours, concentrate the reaction solution under reduced pressure and dissolve in dichloromethane (80 mL) for later use.

[0590] The crude compound 1c (23.1 g, 152.6 mmol) was dissolved in dichloromethane (400 mL). Triethylamine (61.8 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 layers were separated. The organic phase was washed with saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 1d (27.3 g, yield: 74.2%).

[0591] MS m / z(ESI):242.1[M+1].

[0592] Step 4

[0593] (1-((4-(Fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methanol 1e

[0594] Compound 1d (14.3 g, 59.34 mmol) was dissolved in tetrahydrofuran (300 mL), and a 1.0 M solution of lithium aluminum tetrahydride in tetrahydrofuran (118.8 mL) was added dropwise at 0°C. The mixture was allowed to return to room temperature and stirred for 2 hours. Water and a saturated sodium potassium tartrate solution were added to the reaction solution in sequence, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 1e (10.8 g, yield: 91.3%).

[0595] MS m / z(ESI):200.1[M+1].

[0596] Step 5

[0597] 8-(6-bromo-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester 1g

[0598] Compound 1e (500 mg, 2.5 mmol) was dissolved in tetrahydrofuran (30 mL), and a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.5 mL) was added under ice bath. After stirring at the maintained temperature for 30 minutes, 8-(6-bromo-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester 1f (1.2 g, 2 mmol, prepared according to the method described on page 224 of the specification of patent application "WO2023183585A1") was added under ice bath. 114) in tetrahydrofuran (20 mL), the reaction mixture was stirred at the maintained temperature for 1 hour, saturated ammonium chloride solution was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain 1 g (820 mg, yield: 61%) of the title compound.

[0599] MS m / z(ESI):676.2[M+1].

[0600] Step 6

[0601] tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 1h

[0602] Compound 1g (500 mg, 740 μmol) and neopentyl glycol diboronate (250 mg, 1.11 mmol) were dissolved in 1.4-dioxane (10 mL), and potassium acetate (218 mg, 2.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (54 mg, 74 μmol) were added. The mixture was reacted at 95°C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (3 mL) and tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (242 mg, 740 μmol, using the prep method described on page 202 of the specification of patent application "WO2023183585A1") were added. aration231 disclosed method), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (64 mg, 74 μmol), potassium phosphate (233 mg, 1.1 mmol), under nitrogen atmosphere, reacted at 85 ° C for 1 hour, the reaction solution was concentrated under reduced pressure, the residue was dissolved with dichloromethane, water was added, the layers were separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were 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 give the title compound 1h (360 mg, yield: 55%).

[0603] MS m / z(ESI):889.2[M+1].

[0604] Step 7

[0605] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 1i

[0606] Compound 1h (360 mg, 405 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (2 mL) was added, and the reaction was stirred for 0.5 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The pH was adjusted to >7 with saturated sodium bicarbonate. The layers were separated, and the aqueous phase was extracted with dichloromethane (10 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 preparative high performance liquid chromatography (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%-42%, flow rate: 30 mL / min) to give the title compound 1i (71.4 mg, yield: 24.8%).

[0607] MS m / z(ESI):689.2[M+1].

[0608] 1 H NMR (500MHz, DMSO-d6): δ8.42(s,2H),7.20(s,1H),6.72-6.54(m,2H),5.47-5. 41(m,2H),5.03-5.00(m,1H),4.69-4.67(m,1H),4.35-4.07(m,4H),3.09-2.99( m,2H),2.70-2.64(m,2H),2.41-2.38(m,4H),2.36-2.27(m,2H),2.20-2.18(m,2 H),2.02-1.98(m,2H),1.88-1.71(m,4H),0.66-0.64(m,2H),0.40-0.39(m,2H).

[0609] Step 8

[0610] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 1

[0611] Compound 1i (100 mg, 145 μmol) was dissolved in methanol (5 mL), and (R)-propylene oxide (42 mg, 725 μmol, Shanghai Titan) was added. The reaction was carried out at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by high performance liquid 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 30%-42%, flow rate: 30 mL / min) to give the title compound 1 (21.6 mg, yield: 22%).

[0612] MS m / z(ESI):747.2[M+1].

[0613] 1 H NMR (500MHz, CD3OD): δ8.31(d,1H),6.51(d,1H),5.56(s,2H),5.26-5.09(m,1H),4.78(dt,1H),4.46-4.43(m,5H),4.11-3.86(m,1H), 3.03-2.85(m,2H),2.78-2.60(m,3H),2.58-2.29(m,8H),2.18-2.02(m,4H),2.00-1.86(m,2H),1.20(d,3H),0.74(s,2H),0.51(s,2H).

[0614] Example 2

[0615] 2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-1-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2

[0616] first step

[0617] Methyl 1-(4-(difluoromethylidene)piperidine-1-carbonyl)cyclopropane-1-carboxylate 2b

[0618] Dissolve 1,1-cyclopropyldicarboxylic acid monomethyl ester (3.16 g, 21.9 mmol) in dichloromethane (50 mL), replace the atmosphere with nitrogen three times, add oxalyl chloride (9.28 g, 73.1 mmol) and N,N-dimethylformamide (DMF) (1.34 g, 18.3 mmol) dropwise at 0°C, and stir the mixture to room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and dissolved in dichloromethane (80 mL) for later use.

[0619] 4-(Difluoromethylidene)piperidine hydrochloride 2a (3.1 g, 18.3 mmol, prepared by the method disclosed in "Bioorganic and Medicinal Chemistry, 2004, vol. 12, #7, p. 1713-1730") was dissolved in dichloromethane (50 mL). Triethylamine (7.39 g, 73 mmol) was added dropwise at 0°C, and the above-mentioned standby solution was stirred for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution, and the layers were separated. The organic phase was washed with saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to obtain the title compound 2b (4.4 g, yield: 92.8%).

[0620] MS m / z(ESI):260.3[M+1].

[0621] Step 2

[0622] (1-((4-(Difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methanol 2c

[0623] Compound 2b (3 g, 11.57 mmol) was dissolved in tetrahydrofuran (80 mL), and a 1.0 M solution of lithium aluminum tetrahydride in tetrahydrofuran (9.3 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred for 0.5 hours and then filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2c (2 g). The product was directly used for the next reaction without purification.

[0624] MS m / z(ESI):218.2[M+1].

[0625] Step 3

[0626] 8-(6-Bromo-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuran

[0627] tert-Butyl [3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 2d

[0628] Compound 2c (1.37 g, 6.3 mmol) was dissolved in tetrahydrofuran (50 mL), and a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (3.7 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 10 minutes. Then, a solution of compound 1f (2.4 g, 4.2 mmol) in tetrahydrofuran (15 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 2 hours. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were 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 give the title compound 2d (1.4 g, yield: 48%).

[0629] MS m / z(ESI):694.3[M+1].

[0630] Step 4

[0631] tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 2e

[0632] Compound 2d (1.4 g, 2.01 mmol) and neopentyl glycol diboronate (683 mg, 302 mmol) were dissolved in 1.4-dioxane (35 mL), and potassium acetate (692 mg, 7.05 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (144 mg, 201 μmol) were added. The mixture was reacted at 95°C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (9 mL) and tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (727 mg, 1.5 μmol) were added. mg, 2.21 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (173 mg, 201 μmol), potassium phosphate (642 mg, 3.02 mmol), reacted at 85 ° C. for 1 hour under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and water was added. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL×2). The organic phases were 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 give the title compound 2e (753 mg, yield: 41.1%).

[0633] MS m / z(ESI):907.8[M+1].

[0634] Step 5

[0635] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 20

[0636] Compound 2e (753 mg, 830 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the pH was adjusted to >7 with saturated sodium bicarbonate. The layers were separated, and the aqueous phase was extracted with dichloromethane (15 mL × 2). 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 20 (563 mg). The product was directly used for the next reaction without purification.

[0637] MS m / z(ESI):707.5[M+1].

[0638] Step 6

[0639] 2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-1-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 2

[0640] Compound 20 (563 mg, 796.6 μmol) was dissolved in ethanol (25 mL), and (R)-propylene oxide (232 mg, 4 mmol) was added. The reaction was carried out at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative high performance liquid chromatography (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%-42%, flow rate: 30 mL / min) to give the title compound 2 (154 mg, yield: 25.2%).

[0641] MS m / z(ESI):765.2[M+1].

[0642] 1H NMR (500MHz, DMSO-d6): δ8.42(s,2H),7.19(s,1H),6.65(s,1H),5.44-5.33(m,2H) ,5.04-5.02(m,1H),4.70-4.67(m,1H),4.34-4.26(m,4H),3.80-3.74(m,1H),3.45- 3.41(m,1H),3.24-3.12(m,1H),2.86-2.79(m,2H),2.42-2.21(m,7H),2.09-1.97( m,4H),1.88-1.69(m,3H),1.49-1.32(m,2H),1.11-0.99(m,3H),0.65-0.40(m,4H).

[0643] Example 3

[0644] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile

[0645] The synthetic route in Example 1 was used to replace the compound 1i in the eighth step with compound 12 to obtain the title compound 3.

[0646] MS m / z(ESI):746.2[M+1].

[0647] Example 4

[0648] (2R)-1-(8-(6-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propan-2-ol

[0649] The synthetic route in Example 1 was used to replace the compound 1i in the eighth step with compound 19 to obtain the title compound 4.

[0650] MS m / z(ESI):749.2[M+1].

[0651] Example 5

[0652] 2-Amino-7-fluoro-4-(8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrido[4,3-d]pyrimidin-7-yl)benzo[b]thiophene-3-carbonitrile 5

[0653] Using the synthetic route in Example 6, the third step 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline was replaced with tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate (prepared using the method disclosed in preparation 15 on page 50 of the specification of patent application "WO2021118877") to obtain the title compound 5 (33 mg, yield: 30%).

[0654] MS m / z(ESI):705.2[M+1].

[0655] 1 H NMR (500MHz, CDCl3): δ9.09(s,1H),7.51-7.48(m,1H),7.07-7.03(m,1H),6. 50-6.32(m,1H),5.43(s,2H),5.06(s,2H),4.44(s,2H),3.90-3.88(m,1H),3 .31-3.28(m,1H),3.03-3.02(m,1H),2.91-2.85(m,2H),2.57-2.30(m,10H), 2.03-2.02(m,6H),1.19-1.17(m,3H),0.72-0.69(m,2H),0.48-0.46(m,2H).

[0656] Example 6

[0657] (R)-1-(8-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propan-2-ol 6

[0658] first step

[0659] tert-Butyl 8-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 6b

[0660] Compound 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine 6a (550 mg, 2.17 mol, prepared by the method disclosed in Intermediate 4 on page 80 of the specification of the patent application "WO2021 / 041671") and N,N-diisopropylethylamine (2.25 g, 17.4 mmol) were dissolved in 10 mL of dichloromethane, and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (226.3 mg, 2.17 mmol, Shanghai Bid) was added at -40°C. After stirring and reacting for 1 hour at the maintained temperature, 10 mL of water was added to the reaction solution, and the reaction solution was extracted with dichloromethane (10 mLx3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6b (400 mg, yield: 41%).

[0661] MS m / z(ESI):428.2[M+1].

[0662] Step 2

[0663] tert-Butyl 8-(7-chloro-8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 6c

[0664] Compound 6b (160 mg, 361.7 μmol) was dissolved in 1,4-dioxane (2 mL), and compound 1e (108 mg, 542.6 μmol), N,N-diisopropylethylamine (140.2 mg, 1.08 mmol), and 4A molecular sieves (160 mg) were added. The mixture was stirred at 90°C 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 6c (96 mg, yield: 44.9%).

[0665] MS m / z(ESI):591.2[M+1].

[0666] Step 3

[0667] tert-Butyl 8-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 6d

[0668] Compound 6c (96 mg, 162.2 μmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (62 mg, 194.6 μmol, prepared using the method disclosed in Example 80 on page 257 of patent application WO2022148422), tetrakis(triphenylphosphine)palladium (38 mg, 33 μmol, Shanghai Titan), and anhydrous cesium carbonate (158 mg, 486 μmol) were dissolved in 3 mL of a mixture of 1,4-dioxane and water (V:V = 5:1). The reaction mixture was reacted at 100°C under a nitrogen atmosphere 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 obtain the title compound 6d (74 mg, 61% yield). MS m / z(ESI):750.2[M+1].

[0669] Step 4

[0670] 3-(4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline 6e

[0671] Compound 6d (74 mg, 99 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred for 0.5 h, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the pH was adjusted to >7 with saturated sodium bicarbonate. The layers were separated, and the aqueous phase was extracted with dichloromethane (10 mL × 2). 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 6e (64 mg). The product was used directly in the next step without purification.

[0672] MS m / z(ESI):650.2[M+1].

[0673] Step 5 (R)-1-(8-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propan-2-ol 6

[0674] Compound 6e (64 mg, 99 μmol) was dissolved in methanol (1 mL), and (R)-propylene oxide (23 mg, 400 μmol) was added. The reaction was carried out at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (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%-42%, flow rate: 30 mL / min) to give the title compound 6 (13 mg, yield: 18.9%).

[0675] MS m / z(ESI):708.2[M+1].

[0676] 1 H NMR (500MHz, CDCl3): δ8.98(s,1H),6.87(s,1H),6.49(s,1H),5.07-4.99(m,2H ),4.43(s,2H),4.18(s,2H),3.91-3.89(m,1H),3.25-3.23(m,1H),3.04-3.02(m ,1H),2.87-2.85(m,2H),2.54-2.29(m,10H),2.12-2.02(m,6H),1.80-1.78(m,2 H),1.30-1.28(m,1H),1.27-1.26(m,2H),0.70-0.68(m,2H),0.47-0.45(m,2H).

[0677] Example 7

[0678] (R)-1-(8-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-2-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)propan-2-ol 7

[0679] MS m / z(ESI):726.2[M+1].

[0680] Example 8

[0681] 2-Amino-4-(6-chloro-8-fluoro-2-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-4-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)quinazolin-7-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 8

[0682] MS m / z(ESI):739.2[M+1].

[0683] Example 9

[0684] 4-(1-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 94-((R)-1-(-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 9-p1

[0685] 4-((S)-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene))piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 9-p2

[0686] first step

[0687] tert-Butyl 8-(6-(2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 9a

[0688] Compound 1g (100 mg, 147.8 μmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (120 mg, 296.8 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22 mg, 30 μmol), and anhydrous cesium carbonate (97 mg, 297.7 μmol) were dissolved in 1,4-dioxane (15 mL). The mixture was reacted at 100°C under a nitrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 9a (131 mg), which was used directly in the next step without purification.

[0689] MS m / z(ESI):888.4[M+1].

[0690] Step 2

[0691] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 9

[0692] The crude compound 9a (131 mg, 147.5 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. After stirring for 1 hour, the reaction was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (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 9 (39.8 mg, yield: 39.3%).

[0693] MS m / z(ESI):688.3[M+1].

[0694] 1 H NMR (500MHz, DMSO-d6): δ8.09(s,2H),7.32-7.29(m,1H),7.15-7.12(m,1H),6.72-6.55(m, 2H),5.48-5.45(m,2H),4.88-4.84(m,1H),4.69-4.66(m,1H),4.34-4.28(m,2H),4.23-4.1 9(m,2H),3.10-3.03(m,2H),2.75-2.72(m,2H),2.41-2.38(m,4H),2.36-2.27(m,2H),2.21 -2.19(m,2H),2.02-1.98(m,2H),1.87-1.75(m,4H),0.66-0.64(m,2H),0.41-0.40(m,2H).

[0695] Step 3

[0696] 4-((R)-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene))piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 9-p1

[0697] 4-((S)-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene))piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 9-p2

[0698] Compound 9 (606 mg, 0.68 mmol) was separated by chiral column (chromatographic column: Daicel CHIRAL PAK IC, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% ammonia methanol solution), gradient ratio: A:B 70:30, flow rate: 20 mL / min) to give the title compound (92 mg, 19.6%), (95 mg, 20.2%).

[0699] Single configuration compound (shorter retention time, recorded as 9A, ie, 9-p1 or 9-p2): (92 mg, 19.6%).

[0700] Chiral HPLC analysis: retention time 4.973 minutes, purity: 99% (chromatographic column: CHIRAL PAK IC 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1.0 mL / min).

[0701] MS m / z(ESI):688.3[M+1].

[0702] 1 H NMR (500MHz, DMSO-d6): δ8.09(s,2H),7.32-7.26(m,1H),7.15-7.11(m,1H),6.72 -6.54(m,2H),5.44-5.36(m,2H),4.86-4.84(m,1H),4.68-4.65(m,1H),4.34-4.2 8(m,2H),4.20-4.17(m,2H),3.07-3.00(m,2H),2.70-2.64(m,2H),2.40-2.35(m, 4H),2.29-2.27(m,1H),2.19-2.08(m,3H),1.98-1.78(m,6H),0.64-0.40(m,4H).

[0703] Single configuration compound (longer retention time, recorded as 9B, ie, 9-p2 or 9-p1): (95 mg, 20.2%).

[0704] Chiral HPLC analysis: retention time 6.586 minutes, purity: 99% (chromatographic column: CHIRAL PAK IC 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1.0 mL / min).

[0705] MS m / z(ESI):688.3[M+1].

[0706] 1 H NMR (500MHz, DMSO-d6): δ8.19(s,2H),7.32-7.29(m,1H),7.15-7.11(m,1H), 6.72-6.55(m,2H),5.51-5.38(m,2H),4.86-4.84(m,1H),4.68-4.65(m,1H), 4.34-4.17(m,4H),3.13-3.00(m,2H),2.70-2.63(m,2H),2.64-2.35(m,4H), 2.29-2.19(m,2H),2.04-1.98(m,3H),1.86-1.72(m,5H),0.65-0.40(m,4H).

[0707] Example 10

[0708] 3-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-chloro-4-(trifluoromethyl)aniline 10

[0709] first step

[0710] tert-Butyl 8-(6-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 10a

[0711] Compound 1g (100 mg, 147.8 μmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (72 mg, 223.9 μmol), tetrakistriphenylphosphine palladium (35 mg, 30 μmol), and anhydrous cesium carbonate (97 mg, 297.7 μmol) were dissolved in 1,4-dioxane (15 mL) and water (2 mL). The mixture was reacted at 100°C under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 10a (116 mg), which was used directly in the next step without purification.

[0712] MS m / z(ESI):791.3[M+1].

[0713] Step 2

[0714] 3-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-chloro-4-(trifluoromethyl)aniline 10

[0715] The crude compound 10a (116 mg, 146.6 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. After stirring for 1 hour, the reaction was 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 10 (23 mg, yield: 22.7%).

[0716] MS m / z(ESI):691.3[M+1].

[0717] 1H NMR (500MHz, DMSO-d6): δ6.88-6.87(m,1H),6.72-6.54(m,2H),6.39-6.38(m,1H),6 .32(s,2H),5.47-5.44(m,2H),4.86-4.84(m,1H),4.72-4.70(m,1H),4.33-4.27(m,2 H),4.21-4.17(m,2H),3.06-2.99(m,2H),2.69-2.67(m,2H),2.39-2.36(m,4H),2.31 (s,2H),1.99-1.96(m,2H),1.85-1.77(m,4H),0.65-0.63(m,2H),0.41-0.39(m,2H).

[0718] Example 11

[0719] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 11

[0720] 4-((R)-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(difluoromethylidene))piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 11-p1

[0721] 4-((S)-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(difluoromethylidene))piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 11-p2

[0722] first step

[0723] tert-Butyl 8-(6-bromo-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 11a

[0724] Compound 2c (100 mg, 0.17 mmol) was dissolved in tetrahydrofuran (15 mL), and a 2M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.14 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 30 minutes. Then, a solution of compound 1f (1.2 g, 2 mmol) in tetrahydrofuran (5 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the solution was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 11a (100 mg, yield: 84.7%).

[0725] MS m / z(ESI):650.3[M+1].

[0726] Step 2

[0727] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 11

[0728] The synthetic route in Example 9 was used to replace the first step raw material compound 1g with compound 11a to obtain the title compound 11 (7 mg, yield: 8.8%).

[0729] MS m / z(ESI):706.3[M+1].

[0730] 1 H NMR (500MHz, DMSO-d6): δ8.09(s,2H),7.67-7.13(m,3H),5.61-5.44(m,2H),4.85-4.67(m,2H),4.30-4.20(m,4H), 3.17-3.06(m,2H),2.71-2.50(m,5H),2.28-2.09(m,5H),1.85-1.78(m,4H),1.46-1.23(m,2H),0.84-0.39(m,4H).

[0731] Step 3

[0732] 4-((R)-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(difluoromethylidene))piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 11-p1

[0733] 4-((S)-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(difluoromethylidene))piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 11-p2

[0734] Compound 11 (652 mg, 0.719 mmol) was separated by chiral column (chromatographic column: Daicel CHIRAL PAK IC, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% ammonia methanol solution), gradient ratio: A:B 75:25, flow rate: 20 mL / min) to give the title compound (98.5 mg, 19.4%), (97.6 mg, 19.2%).

[0735] Single configuration compound (shorter retention time, recorded as 11A, ie 11-p1 or 11-p2): (98.5 mg, 19.4%).

[0736] Chiral HPLC analysis: retention time 4.389 minutes, purity: 99% (chromatographic column: CHIRAL PAK IC 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 75:25, flow rate: 1.0 mL / min).

[0737] MS m / z(ESI):706.3[M+1].

[0738] 1 H NMR (500MHz, DMSO-d6): δ8.09(s,2H),7.32-7.29(m,1H),7.15-7.11(m,1H),6.69-6.64(m,1H),5.47-5.41(m,2H),4.87-4.84(m,1H),4.68-4.6 6(m,1H),4.33-4.08(m,4H),3.07-3.00(m,2H),2.70-2.64(m,2H),2.46 -2.28(m,6H),2.11-1.98(m,4H),1.86-1.72(m,4H),0.66-0.40(m,4H).

[0739] Single configuration compound (longer retention time, recorded as 11B, ie 11-p2 or 11-p1): (97.6 mg, 19.2%).

[0740] Chiral HPLC analysis: retention time 5.804 minutes, purity: 99% (chromatographic column: CHIRAL PAK IC 150*4.6 mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 75:25, flow rate: 1.0 mL / min).

[0741] MS m / z(ESI):706.3[M+1].

[0742] 1 H NMR (500MHz, DMSO-d6): δ8.09(s,2H),7.33-7.29(m,1H),7.15-7.11(m,1H),6.70-6.64(m,1H),5.48-5.45(m,2H),4.87-4.85(m,1H),4.68-4.6 6(m,1H),4.33-4.20(m,4H),3.12-3.05(m,2H),2.77-2.73(m,2H),2.46 -2.28(m,6H),2.11-1.98(m,4H),1.91-1.78(m,4H),0.66-0.41(m,4H).

[0743] Example 12

[0744] 4-(1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 12

[0745] first step

[0746] Tert-butyl 3-(6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 12c

[0747] 6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline 12b (500 mg, 1.37 mmol, prepared by the method disclosed in preparation 60 on page 189 of the specification of patent application "WO2023183585A1") was dissolved in 1,2-dichloroethane (15 mL), and N,N-diisopropylethylamine (355 mg, 2.75 mmol) and compound 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 12a (292 mg, 1.37 mmol, Shaoyuan) were added sequentially. The reaction was allowed to proceed at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 12c (715 mg, yield: 96.5%).

[0748] MS m / z(ESI):539.1[M+1].

[0749] Step 2

[0750] tert-Butyl 3-(6-bromo-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 12d

[0751] Compound 12c (715 mg, 1.32 mmol) was dissolved in dichloromethane (25 mL), and m-chloroperbenzoic acid (457 mg, 2.65 mmol) was added. The mixture was reacted at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting solid crude compound 12d was used directly in the next step without purification.

[0752] MS m / z(ESI):571.1[M+1].

[0753] Step 3

[0754] tert-Butyl 3-(6-bromo-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 12e

[0755] The crude compound 1e (84 mg, 0.42 mmol) was dissolved in tetrahydrofuran (10 mL), and a 2M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.30 mL) was added under ice-cooling. The mixture was stirred at the maintained temperature for 30 minutes. Then, a solution of compound 12d (200 mg, 0.35 mmol) in tetrahydrofuran (5 mL) was added under ice-cooling. The mixture was stirred at the maintained temperature for 1 hour. The reaction solution was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 12e (100 mg, yield: 42.3%).

[0756] MS m / z(ESI):676.2[M+1].

[0757] Step 4

[0758] 4-(1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 12

[0759] The first and second steps of the synthetic route in Example 9 were used, and the starting compound 1g in the first step was replaced by compound 12e to obtain the title compound 12 (2 mg, yield: 5.8%).

[0760] MS m / z(ESI):688.3[M+1].

[0761] 1 H NMR (500MHz, CD3OD): δ7.27(dd,1H),7.04(t,1H),6.51(d,1H),5.41(q,2H),4.86-4.73(m,3H),4.44(s,2H),4.27(d,1H),4.0 0(d,1H),3.66-3.44(m,4H),2.59-2.42(m,6H),2.36-2.30(m,2H),2.11-2.06(m,2H),1.78(s,3H),0.73(s,2H),0.50(s,2H).

[0762] Example 13

[0763] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 13

[0764] first step

[0765] tert-Butyl 8-(6-bromo-5-fluoro-3-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate 13b

[0766] (2-(Fluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol 13a (128 mg, 0.128 mmol, prepared by the method disclosed in Example 5 on page 32 of the specification of patent application "WO2022247757") was dissolved in tetrahydrofuran (10 mL), and a 2M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.53 mL) was added under ice bath. After stirring at the temperature for 30 minutes, a solution of compound 1f (357 mg, 0.624 mmol) in tetrahydrofuran (5 mL) was added under ice bath. The temperature was maintained and stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 13b (243 mg, yield: 60%).

[0767] MS m / z(ESI):604.2[M+1].

[0768] Step 2

[0769] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 13

[0770] The synthetic route in Example 9 was used to replace the second step raw material compound 1g with compound 13b to obtain the title compound 13 (4 mg, yield: 20%).

[0771] MS m / z(ESI):660.2[M+1].

[0772] 1 H NMR (500MHz, CD3OD): δ7.28(dd,1H),7.05(t,1H),6.68(d,1H),4.98–4.78(m,3H),4.55–4.29(m,4H),3.95(d,1H), 3.56(d,1H),2.94–2.75(m,4H),2.50(d,1H),2.24–2.14(m,2H),2.13–1.86(m,8H),1.67–1.57(s,1H),0.92(t,1H).

[0773] Example 14

[0774] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 14

[0775] first step

[0776] 6-Bromo-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline 14b

[0777] 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline 14a (100 mg, 0.30 mmol, prepared by the method disclosed in Preparation 301 on page 193 of the specification of patent application "WO2023183585A1") was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (124 mg, 0.61 mmol) was added. The reaction was carried out at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting compound 14b was used directly in the next step.

[0778] MS m / z(ESI):361.0[M+1].

[0779] Step 2

[0780] 6-Bromo-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazoline 14c

[0781] Compound 1e (77 mg, 0.38 mmol) was dissolved in tetrahydrofuran (5 mL), and a 2M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.19 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 30 minutes. Then, a solution of compound 14b (70 mg, 0.19 mmol) in tetrahydrofuran (5 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 14c (30 mg, yield: 33.3%).

[0782] MS m / z(ESI):466.1[M+1].

[0783] Step 3: Tert-butyl (3-cyano-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophen-2-yl)carbamate 14d

[0784] Compound 14c (30 mg, 164 μmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (52 mg, 128.6 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 13 μmol), and anhydrous cesium carbonate (52 mg, 159 μmol) were dissolved in 1,4-dioxane (5 mL). The reaction was carried out at 100°C under a nitrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 14d (43 mg), which was used directly in the next step without purification.

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

[0786] Step 4

[0787] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 14

[0788] The crude compound 14d (43 mg, 64 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.5 mL) was added. After stirring for 1 hour, the reaction was 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 14 (5 mg, yield: 19.5%).

[0789] MS m / z(ESI):578.2[M+1].

[0790] 1 H NMR (500MHz, DMSO-d6): δ9.47(s,1H),8.13(s,2H),7.36-7.33(m,1H),7.16-7.13(m,1H),6.72-6.54(m,1H),5.53(s,2H),5.01-4.98( m,1H),4.81-4.77(m,1H),4.40(s,2H),2.43-2.38(m,6H),2.20-2.18(m,2H),2.01-1.98(m,2H),0.72-0.69(m,2H),0.45-0.43(m,2H).

[0791] Example 14-p1, 14-p2

[0792] (R)-2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 14-p1

[0793] (S)-2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 14-p2

[0794] The isomer mixture 14 (450 mg) was separated by chiral column (chromatographic column: CHIRALPAK IE, 20×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B 65:35, flow rate: 20 mL / min) to give the title compounds (194 mg, yield: 43.1%) and (191 mg, yield: 42.4%).

[0795] Single configuration compound (shorter retention time, recorded as 14A, ie, 14-p1 or 14-p2): (194 mg, yield: 43.1%).

[0796] MS m / z(ESI):578.2[M+1].

[0797] Chiral HPLC analysis: retention time 4.132 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 4.6*150 mm, 5 μm; mobile phase: A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B 60:40, flow rate: 1 mL / min).

[0798] 1 H NMR (500MHz, DMSO-d6): δ9.47(s,1H),8.13(s,2H),7.36-7.33(m,1H),7.16-7.13(m,1H),6.72-6.55(m,1H),5.53(s,2H),5.01- 4.98(m,1H),4.80-4.77(m,1H),4.44-4.38(m,2H),2.43-2.33(m,6H),2.20-2.09(m,2H),2.02-1.97(m,2H),0.72-0.43(m,4H).

[0799] Single configuration compound (longer retention time, recorded as 14B, ie, 14-p2 or 14-p1): (191 mg, yield: 42.4%).

[0800] MS m / z(ESI):578.2[M+1].

[0801] Chiral HPLC analysis: retention time 6.778 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 4.6*150 mm, 5 μm; mobile phase: A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B 60:40, flow rate: 1 mL / min).

[0802] 1H NMR (500MHz, DMSO-d6): δ9.47(s,1H),8.15(s,2H),7.36-7.33(m,1H),7.16-7.13(m,1H),6.72-6.55(m,1H),5.53(s,2H),5.01- 4.98(m,1H),4.80-4.77(m,1H),4.42-4.36(m,2H),2.43-2.33(m,6H),2.20-2.08(m,2H),2.02-1.97(m,2H),0.72-0.43(m,4H).

[0803] Example 15

[0804] 2-Amino-7-fluoro-4-(5-fluoro-3-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 15

[0805] The synthetic route in Example 14 was used to replace the second-step raw material compound 1e with ((2-(fluoromethylidene)tetrahydro-1H-pyrrolizine-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 15 (3 mg, yield: 4.4%).

[0806] MS m / z(ESI):550.2[M+1].

[0807] 1 H NMR (500MHz, CD3OD): δ9.37(s,1H),7.30(dd,1H),7.06(t,1H),6.67(dd,1H),5.60(s,2H),5.06(dt,1H),4.90(d,1H),4.62–4.15(m ,2H),4.01–3.77(m,1H),3.51(d,1H),3.21(dt,1H),2.91–2.64(m,2H),2.50(d,1H),2.20(qd,1H),2.09–1.76(m,4H),1.33(d,1H).

[0808] Example 16

[0809] 2-Amino-4-(3-(((S)-4-(difluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 16

[0810] first step

[0811] 1-(tert-Butyl)2-methyl(S)-4-(difluoromethylidene)pyrrolidine-1,2-dicarboxylate 16b

[0812] 1-(tert-Butyl)-2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate 16a (500 mg, 2.1 mmol, Bid) was dissolved in N,N-dimethylformamide (6.0 mL), and (triphenylphosphinium)difluoroacetic acid inner salt (1.8 g, 5.1 mmol) was added. The reaction was carried out at 80°C for 17 hours, cooled to room temperature, and water was added. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using eluent System A to obtain the title compound 16b (500 mg, yield: 87.7%).

[0813] MS m / z(ESI):278.1[M+1].

[0814] Step 2

[0815] (S)-4-(Difluoromethylidene)pyrrolidine-2-carboxylic acid methyl ester 16c

[0816] Compound 16b (800 mg, 2.9 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated, saturated sodium bicarbonate was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 16c (420 mg, yield: 82%).

[0817] MS m / z(ESI):178.1[M+1].

[0818] Step 3

[0819] (S)-4-(difluoromethylidene)-1-methylpyrrolidine-2-carboxylic acid methyl ester 16d

[0820] Compound 16c (420 mg, 2.4 mmol) was dissolved in acetonitrile (10 mL), and iodomethane (404 mg, 2.8 mmol) and sodium bicarbonate (400 mg, 4.7 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated. The residue was purified by silica gel column chromatography using eluent System A to obtain the title compound 16d (150 mg, 33% yield).

[0821] MS m / z(ESI):192.1[M+1].

[0822] Step 4

[0823] (S)-(4-(Difluoromethylidene)-1-methylpyrrolidin-2-yl)methanol 16e

[0824] Compound 16d (150 mg, 0.78 mmol) was dissolved in tetrahydrofuran (10 mL) and a 1 M solution of lithium aluminum hydride in tetrahydrofuran (0.87 mL) was added under ice-water bath. After reacting for 1 hour, sodium sulfate decahydrate was added to quench the reaction, and the mixture was filtered and the filtrate was concentrated to afford the title compound 16e (90 mg, yield: 70%).

[0825] MS m / z(ESI):164.1[M+1].

[0826] Step 5

[0827] 2-Amino-4-(3-(((S)-4-(difluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 16

[0828] The synthetic route in Example 14 was used to replace the second step raw material compound 1e with compound 16e to obtain the title compound 16 (30 mg, yield: 50%).

[0829] MS m / z(ESI):542.1[M+1].

[0830] 1 H NMR (500MHz, CDCl3): δ9.17(s,1H),7.28-7.23(m,1H),7.07-7.03(m,1H),5.65-5.60(m,2H),5.54-5.52(m,2H),5 .06-4.96(m,2H),4.75-4.63(m,2H),3.85-3.80(m,1H),3.06-3.01(m,2H),2.85-2.81(m,1H),2.62-2.55(m,4H).

[0831] Example 17

[0832] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 17

[0833] The synthetic route in Example 13 was used to replace the first step raw material compound 13a 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 17 (5 mg, yield: 10%).

[0834] MS m / z(ESI):678.2[M+1].

[0835] 1 H NMR (500MHz, CD3OD): δ7.28(dd,1H),7.05(t,1H),5.57(s,2H),4.94–4.76(m,3H),4.57–4.23(m,5H),3 .83(d,1H),3.46(d,1H),3.34–3.17(m,3H),2.86(dd,3H),2.73(q,1H),2.53(d,1H),2.34–1.76(m,6H).

[0836] Example 18

[0837] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 18

[0838] The synthetic route in Example 13 was used, and the first step raw material compound 13a was replaced with (2,6-dimethylidenetetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (prepared using the method disclosed in Example 4 on page 29 of the specification of patent application "WO2022247757") to obtain the title compound 18 (3 mg, yield: 19.6%).

[0839] MS m / z(ESI):654.2[M+1].

[0840] 1 H NMR (500MHz, CD3OD): δ7.28(dd,1H),7.05(t,1H),5.57(s,2H),5.04(d,4H),4.46–4.29(m ,4H),3.81(d,2H),3.38–3.25(m,6H),2.95–2.77(m,4H),2.62(d,2H),2.22–1.90(m,4H).

[0841] Example 19

[0842] 3-(1-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-chloro-4-(trifluoromethyl)aniline 19

[0843] Using the synthetic route in Example 12, the fourth step raw material (tert-butyl 3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate was replaced with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to obtain the title compound 19 (3 ​​mg, yield: 11.4%).

[0844] MS m / z(ESI):691.3[M+1].

[0845] 1 H NMR (500MHz, CD3OD): δ6.90(d,1H),6.61–6.36(m,2H),5.43–5.35(m,1H),4.84–4.76(m,2H),4.44(d,2H),4.09(t,2H),3.62–3.52(m,4H),2.58 –2.45(m,4H),2.34–2.28(m,1H),2.21(t,1H),2.10–2.03(m,3H),1.92– 1.79(m,3H),1.66–1.58(m,1H),0.92(t,2H),0.73(s,2H),0.51(s,2H).

[0846] Example 20

[0847] 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 20

[0848] The sixth and seventh steps of the synthetic route in Example 1 were used, and the starting compound 1g in the sixth step was replaced by compound 11d to obtain the title compound 20 (71 mg, yield: 23.8%).

[0849] MS m / z(ESI):707.5[M+1].

[0850] 1 H NMR (500MHz, DMSO-d6): δ8.42(s,2H),7.49(s,1H),7.19-6.65(m,1H),5.44-5.32(m,2H),5.02-5.01(m,1H),4.68-4.65(m,1H),4. 31-4.18(m,4H),3.11-3.01(m,2H),2.43-2.29(m,6H),2.09-1.99(m,4H),1.86-1.74(m,4H),1.46-1.24(m,2H),0.65-0.40(m,4H).

[0851] Example 21

[0852] 2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-1-(3-hydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 21

[0853] first step

[0854] 8-(6-(2-amino-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]oct-3-ylbenzoate 21a

[0855] Under a nitrogen atmosphere, potassium hydrogen phosphate trihydrate was suspended in 2 mL of N,N-dimethylformamide, followed by the addition of dibenzoyl peroxide (24 mg, 0.099 mmol). A solution of compound 20 (44 mg, 0.062 mmol) in N,N-dimethylformamide (2 mL) was then added under an ice-water bath. The mixture was allowed to react overnight at room temperature, and water was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude title compound 21a (46 mg), which was used directly in the next step without further purification.

[0856] MS m / z(ESI):827.3[M+1].

[0857] Step 2

[0858] 2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-1-(3-hydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 21

[0859] Compound 21a was dissolved in 5 mL of methanol, followed by the addition of anhydrous potassium carbonate (15 mg, 0.11 mmol). The reaction was allowed to proceed at room temperature for 1 hour, filtered, and the filtrate was 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 obtain the title compound 21.

[0860] MS m / z(ESI):723.2[M+1].

[0861] 1 H NMR (500MHz, DMSO-d6): δ8.42(s,2H),8.12(s,1H),7.19-6.65(m,1H),5.45-5.33(m,2H),5.05-5.03(m,1H),4.70-4.68(m,1H),4.44-4.28( m,4H),3.15-3.13(m,2H),2.88-2.78(m,2H),2.42-2.27(m,5H),2.10- 1.98(m,4H),1.88-1.76(m,3H),1.46-1.35(m,2H),0.66-0.41(m,4H).

[0862] Example 22

[0863] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-(3-hydroxy-3,8-diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 22

[0864] The synthetic route of compound 21 was adopted, and the first step raw material compound 20 was replaced by compound 1i to obtain the title compound 22 (2 mg, yield: 4%).

[0865] MS m / z(ESI):705.3[M+1].

[0866] 1 H NMR (500MHz, DMSO-d6): δ8.43(s,2H),8.12(s,1H),6.63(d,1H),5.85-5.37(m ,2H),5.18-4.86(m,1H),4.70(d,1H),4.69-4.02(m,3H),3.14(dt,2H),2.83( dd,2H),2.46-2.34(m,5H),2.28(d,1H),2.20(d,2H),2.15-1.96(m,3H),1.92 -1.85(m,3H),1.84-1.74(m,1H),1.57-1.41(m,1H),0.66(s,2H),0.40(d,2H).

[0867] Example 23

[0868] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 23

[0869] first step

[0870] Tert-butyl (3-cyano-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridin-2-yl)carbamate 23a

[0871] Compound 14c (50 mg, 107 μmol) and neopentyl glycol diboronate (38 mg, 0.17 mmol) were dissolved in 1.4-dioxane (5 mL), and potassium acetate (33 mg, 0.33 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (7.65 mg, 11 μmol) were added. The mixture was reacted at 95°C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (1 mL) and tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (36 mg, 110 μmol, using the preparation method described on page 202 of the specification of patent application "WO2023183585A1") were added. 231), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (9.6 mg, 11 μmol), potassium phosphate (35 mg, 0.17 mmol), under a nitrogen atmosphere, reacted at 85°C for 1 hour, the reaction solution was concentrated under reduced pressure, the residue was dissolved with dichloromethane, water was added, the layers were separated, the aqueous phase was extracted with dichloromethane (10 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 23a (30 mg, yield: 41%).

[0872] MS m / z(ESI):679.2[M+1].

[0873] Step 2

[0874] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 23

[0875] Compound 23a (30 mg, 44 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. After stirring for 1 hour, the reaction was 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 23 (9 mg, yield: 37%).

[0876] MS m / z(ESI):579.2[M+1].

[0877] 1H NMR(500MHz,CD3OD)δ9.39(s,1H),8.33(s,1H),6.52(d,1H),5.60(s,2H),5.25(d,1H),4.55(s, 2H),2.71–2.46(m,5H),2.36(s,2H),2.21(t,1H),2.16–2.02(m,3H),0.80(s,2H),0.56(s,2H).

[0878] Example 24

[0879] 2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 24

[0880] first step

[0881] 6-Bromo-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline 24a

[0882] Compound 2c (108 mg, 0.50 mmol) was dissolved in tetrahydrofuran (3 mL), and a 2 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.25 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 30 minutes. Then, a solution of compound 14b (100 mg, 0.27 mmol) in tetrahydrofuran (3 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The solution was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 24a (20 mg, yield: 15.0%).

[0883] MS m / z(ESI):484.1[M+1].

[0884] Step 2

[0885] 2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 24

[0886] The synthetic route in Example 23 was used to replace the first step raw material compound 14c with compound 24a to obtain the title compound 24 (1 mg, yield: 11.6%).

[0887] MS m / z(ESI):597.2[M+1].

[0888] 1 H NMR(500MHz,CD3OD)9.38(s,1H),8.33(s,1H),5.59(d,2H),5.25(dt,1H),4.85–4. 78(m,1H),4.54(d,2H),2.63–2.39(m,6H),2.20(t,4H),0.78(d,2H),0.53(d,2H).

[0889] Example 25

[0890] 2-Amino-4-(3-(((S)-4-(difluoromethylidene)-1-methylpyrrolidin-2-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 25

[0891] The synthetic route in Example 24 was used to replace the first step raw material compound 2c with compound 16e to obtain the title compound 25 (28 mg, yield: 47.3%).

[0892] MS m / z(ESI):543.1[M+1].

[0893] 1 H NMR(500MHz,DMSO-d6)δ9.50(s,1H),8.48-8.47(m,2H),8.45-8.44(m,1H),5.54-5.53(m,2H),5.17-5.15(m,1H),4.83-4 .81(m,1H),4.56-4.55(m,2H),3.67-3.64(m,1H),2.94-2.87(m,2H),2.71-2.68(m,1H),2.43-2.41(m,1H),2.40(s,3H).

[0894] Example 26

[0895] 2-Amino-4-(3-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0896] The synthetic route in Example 14 was used to replace the second step raw material compound 1e with (2,6-dimethylidenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol to obtain the title compound 26 (50 mg, yield: 53.8%).

[0897] 1 H NMR(500MHz,DMSO-d6)δ9.47(s,1H),8.14-8.12(m,2H),7.36-7.33(m,1H),7.16-7.14(m,1H),5.54-5.52(m 2H),5.02-4.93(m,5H),4.80-4.78(m,1H),4.21(s,2H),3.67-3.64(m,2H),3.23-3.21(m,2H),2.70-2.66(m,2H),2.52-2.48(m,2H). MS m / z(ESI):544.2[M+1].

[0898] Example 26-p1, 26-p2

[0899] (R)-2-Amino-4-(3-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 26-p1

[0900] (S)-2-Amino-4-(3-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 26-p2

[0901] The isomer mixture 26 (50 mg) was separated by chiral column (chromatographic column: CHIRALPAK IE, 20×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B 50:50, flow rate: 15 mL / min) to give the title compounds (16 mg, yield: 32%) and (15 mg, yield: 30%).

[0902] Single configuration compound (shorter retention time, recorded as 26A, ie, 26-p1 or 26-p2): (16 mg, yield: 32%).

[0903] MS m / z(ESI):544.2[M+1].

[0904] Chiral HPLC analysis: retention time 8.894 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 4.6*150 mm, 5 μm; mobile phase: A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[0905] 1 H NMR (500MHz, CDCl3): δ9.15(s,1H),7.24-7.21(m,1H),7.06-7.02(m,1H),5.60-5.57(m,3H),5.01-4.97 (m,5H),4.38-4.37(m,2H),3.84-3.81(m,2H),3.34-3.31(m,2H),2.85-2.82(m,2H),2.60-2.56(m,2H).

[0906] Single configuration compound (longer retention time, recorded as 26B, ie, 26-p2 or 26-p1): (15 mg, yield: 30%).

[0907] MS m / z(ESI):544.2[M+1].

[0908] Chiral HPLC analysis: retention time 20.218 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 4.6*150 mm, 5 μm; mobile phase: A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[0909] 1 H NMR (500MHz, CDCl3): δ9.15(s,1H),7.24-7.22(m,1H),7.06-7.02(m,1H),5.63-5.53(m,3H),5.04-4.95 (m,5H),4.38-4.37(m,2H),3.83-3.80(m,2H),3.34-3.31(m,2H),2.84-2.82(m,2H),2.60-2.56(m,2H).

[0910] Example 27

[0911] 2-Amino-4-(3-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 27

[0912] Using the synthetic route in Example 14, the second step raw material compound 1e was replaced with (2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol to obtain the title compound 27 (33.6 mg, yield: 13.7%).

[0913] 1 H NMR (500MHz, DMSO-d6): δ9.48(s,1H),8.13(s,2H),7.36-7.33(m,1H),7.16-7.13(m,1H),5.53(s,2H),5.01-4.98(m,1H),4.81-4.77(m,1 H),4.30-4.18(m,2H),3.71-3.67(m,1H),3.04-3.01(m,1H),2.70-2.57(m,2H),2.44-2.36(m,1H),2.08-1.98(m,2H),1.91-1.80(m,3H).

[0914] MS m / z(ESI):568.1[M+1].

[0915] Example 28

[0916] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 28

[0917] The synthetic route in Example 14 was used to replace the second step raw material compound 1e with compound 2c to obtain the title compound 28 (75 mg, yield: 17.5%).

[0918] 1 H NMR(500MHz,CD3OD)δ9.35(s,1H),7.30(dd,1H),7.06(t,1H),5.59(s,2H),5.05(d,1H),4 .90(s,1H),4.53(s,2H),2.51(d,5H),2.20(s,4H),2.05(s,1H),0.77(d,2H),0.53(s,2H).

[0919] MS m / z(ESI):596.2[M+1].

[0920] Example 28-p1, 28-p2

[0921] (R)-2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluoro-benzo[b]thiophene-3-carbonitrile 28-p1

[0922] (S)-2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluoro-benzo[b]thiophene-3-carbonitrile 28-p2

[0923] The isomer mixture 28 (75 mg) was separated by chiral column (chromatographic column: CHIRALPAK IE, 20×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B 75:25, flow rate: 20 mL / min) to give the title compound (25 mg, yield: 33.3%) and (25 mg, yield: 33.3%).

[0924] Single configuration compound (shorter retention time, recorded as 28A, ie, 28-p1 or 28-p2): (25 mg, yield: 33.3%).

[0925] MS m / z(ESI):596.2[M+1].

[0926] Chiral HPLC analysis: retention time 4.744 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 4.6*150 mm, 5 μm; mobile phase: A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[0927] 1 H NMR (500MHz, CD3OD): δ9.34(s,1H),7.30(dd,1H),7.06(t,1H),5.59(s,2H),5.0 5(d,2H),4.52(s,2H),2.67-2.41(m,6H),2.21(q,4H),0.78(s,2H),0.53(d,2H).

[0928] Single configuration compound (longer retention time, recorded as 28B, ie, 28-p2 or 28-p1): (25 mg, yield: 33.3%).

[0929] MS m / z(ESI):596.2[M+1].

[0930] Chiral HPLC analysis: retention time 6.073 minutes, purity: 99% (chromatographic column: CHIRALPAK IE 4.6*150 mm, 5 μm; mobile phase: A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[0931] 1 H NMR (500MHz, CD3OD): δ9.34(s,1H),7.30(dd,1H),7.06(t,1H),5.59(s,2H),5.0 5(d,2H),4.52(s,2H),2.67-2.41(m,6H),2.21(q,4H),0.78(s,2H),0.53(d,2H).

[0932] Example 29

[0933] 2-Amino-7-fluoro-4-(5-fluoro-3-((2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 29

[0934] The synthetic route of Example 14 was used to replace the second step raw material compound 1e with (2-methylidenehexahydro-1H-pyrrolizin-7a-yl)methanol (prepared using the method disclosed in the literature "Tetrahedron, 2007, vol. 63, #22, pp. 4712-4724") to obtain the title compound 29.

[0935] MS m / z(ESI):532.2[M+1].

[0936] Example 30

[0937] 2-Amino-7-fluoro-4-(5-fluoro-3-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 30

[0938] The synthetic route in Example 24 was used to obtain the title compound 30 by replacing the first step raw material compound 2c with ((2-(fluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol.

[0939] MS m / z(ESI):551.1[M+1].

[0940] Example 31

[0941] 2-amino-4-(3-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 31

[0942] The synthetic route in Example 24 was used to obtain the title compound 31 by replacing the first step raw material compound 2c with (2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol.

[0943] MS m / z(ESI):569.1[M+1].

[0944] Example 32

[0945] 2-Amino-4-(3-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 32

[0946] The synthetic route in Example 24 was used to replace the first step raw material compound 2c with (2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol to obtain the title compound 32.

[0947] MS m / z(ESI):545.2[M+1].

[0948] Example 33

[0949] 3-Chloro-5-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-4-(trifluoromethyl)aniline 33

[0950] The synthetic route in Example 14 was used, and the second-step raw material compound 1e was replaced by compound 2c, and the third-step raw material (tert-butyl 3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate was replaced by 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to give the title compound 33 (3 mg, yield: 8%).

[0951] 1H NMR(500MHz,CD3OD)δ9.31(s,1H),6.89(d,1H),6.43–6.38(m,1H),5.55(s,2H),5.00(d,1H), 4.89(s,2H),4.54(dd,1H),4.47(dt,1H),2.48(s,5H),2.16(s,4H),0.75(d,2H),0.51(d,2H).

[0952] MS m / z(ESI):599.2[M+1].

[0953] Example 34

[0954] 4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine 34

[0955] The synthetic route in Example 14 was adopted, and the second-step raw material compound 1e was replaced by compound 2c, and the third-step raw material (tert-butyl 3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate was replaced by N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (prepared by the method disclosed in Example 60 on page 244 of the specification of patent application "WO2022042630") to obtain the title compound 34 (2.5 mg, yield: 14.1%).

[0956] 1 H NMR(500MHz,CD3OD)δ9.35(s,1H),6.29(s,1H),5.57(s,2H),5.04(d,1H),4.92(d,1H),4 .57(d,1H),4.49(d,1H),2.62–2.51(m,8H),2.24–2.15(m,5H),0.80(s,2H),0.56(s,2H).

[0957] MS m / z(ESI):580.2[M+1].

[0958] Example 35

[0959] 2-Amino-4-(1-cyclopropyl-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 35

[0960] first step

[0961] 6-Bromo-1-cyclopropyl-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline 35b

[0962] 6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline 35a (1.0 g, 2.75 mmol, prepared using the method disclosed in Preparation 60 on page 189 of patent application WO2023183585A1) was dissolved in tetrahydrofuran (30 mL). Iron triacetylacetonate (485.6 mg, 1.37 mmol) and a 1M solution of cyclopropylmagnesium bromide in tetrahydrofuran (5.5 mL, 5.5 mmol) were added sequentially. The mixture was reacted at 0°C under a nitrogen atmosphere for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System A to afford the title compound 35b (500 mg, 50% yield).

[0963] Step 2

[0964] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 35

[0965] The synthetic route in Example 12 was used to replace the second step raw material 12c with compound 35b to obtain the title compound 35.

[0966] MS m / z(ESI):618.2[M+1].

[0967] Example 36

[0968] 2-Amino-4-(1-cyclopropyl-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0969] 2-amino-4-((R)-1-cyclopropyl-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 36-p1 or

[0970] 2-Amino-4-((S)-1-cyclopropyl-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 36-p2

[0971] The synthetic route in Example 35 was used to replace the raw material compound 1e with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a-yl)methanol (Biode Pharmaceuticals) to obtain a crude title compound 36 (17 mg). The crude product 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 obtain the title compound 36-p1 or 36-p2 (3 mg, yield: 17.6%).

[0972] 1 H NMR(500MHz,CD3OD)δ7.29(dd,1H),7.06(t,1H),5.79(s,2H),5.41–5.25(m,1H),5.05(dt,1H),4.36(d,1H),4.27(d,1H),3.26–3.18( m,2H),3.09–2.99(m,1H),2.49–2.14(m,5H),2.10–1.98(m,3H),1.97–1.87(m,1H),1.69–1.58(m,1H),1.49–1.40(m,2H),0.92(t,1H).

[0973] MS m / z(ESI):578.2[M+1].

[0974] Example 37

[0975] 2-Amino-7-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 37

[0976] first step

[0977] (S)-4-(6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-6-methyl-1,4-oxazepan-6-ol 37b

[0978] Compound 35a (500 mg, 1.37 mmol) and N,N-diisopropylethylamine (445 mg, 3.44 mmol) were dissolved in dichloromethane (20 mL). (S)-6-methyl-1,4-oxazepan-6-ol hydrochloride 37a (235 mg, 1.4 mmol, Shanghai Bidex) was added at -78°C and the reaction was stirred for 17 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL×3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 37b (565 mg, yield: 89.6%).

[0979] MS m / z(ESI):458.2[M+1].

[0980] Step 2

[0981] (S)-4-(6-Bromo-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-6-methyl-1,4-oxazepan-6-ol 37c

[0982] Compound 37b (565 mg, 1.23 mmol) was dissolved in dichloromethane (25 mL), and m-chloroperbenzoic acid (503 mg, 2.47 mmol, purity 85%) was added. The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution and saturated aqueous sodium sulfite solution were added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 37c (601 mg). The product was directly used for the next reaction without purification.

[0983] MS m / z(ESI):490.2[M+1].

[0984] Step 3

[0985] (S)-4-(6-Bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-6-methyl-1,4-oxazepan-6-ol 37d

[0986] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (246 mg, 1.54 mmol) was dissolved in tetrahydrofuran (25 mL). 2M sodium bis(trimethylsilyl)amide (823.4 μL) was added under ice-cooling. After stirring for 10 minutes, a tetrahydrofuran solution (5 mL) of crude compound 37c (504 mg, 1.02 mmol) was added. The reaction was stirred at 0°C for 2 hours. Saturated aqueous ammonium chloride was added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to give the title compound 37d (363 mg, yield: 63.5%).

[0987] MS m / z(ESI):555.1[M+1].

[0988] Step 4: Tert-butyl (3-cyano-7-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzothiophen-2-yl)carbamate 37e

[0989] Compound 37d (130 mg, 234.06 μmol), tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (190 mg, 470 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (35 mg, 47.8 μmol), and cesium carbonate (153 mg, 469.6 μmol) were mixed in 1,4-dioxane (10 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 3 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 37e (163 mg, yield: 90.8%).

[0990] MS m / z(ESI):767.2[M+1].

[0991] Step 5

[0992] 2-Amino-7-fluoro-4-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-((S)-6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 37

[0993] Compound 37e (160 mg, 208.6 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred for 0.5 hour, and the reaction solution was concentrated under reduced pressure. The pH of the residue was adjusted to >7 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (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 37 (52 mg, yield: 37.3%).

[0994] 1 H NMR (500MHz, DMSO-d6): δ8.13-8.10(m,2H),7.34-7.26(m,1H),7.15-7.12(m,1H),5.76(s, 1H),5.48-5.42(m,1H),5.33-5.23(m,1H),4.94-4.83(m,1H),4.75-4.65(m,1H),4.29-4.0 2(m,3H),3.96-3.88(m,1H),3.74-3.63(m,4H),3.53-3.49(m,1H),3.41-3.38(m,1H),3.10 -3.03(m,3H),2.86-2.82(m,2H),2.17-1.99(m,3H),1.86-1.75(m,3H),1.03-1.00(m,3H).

[0995] MS m / z(ESI):667.2[M+1].

[0996] Example 38

[0997] 2-Amino-4-(3-((2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-fluoro-1-((R)-3-hydroxy-3-methylpiperidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 38

[0998] The synthetic route in Example 37 was used, and the first step raw material compound 37a was replaced by (3R)-3-methylpiperidin-3-ol hydrochloride, and the third step ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol was replaced by (2-(difluoromethylidene)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol to obtain the title compound 38 (20 mg, yield: 22.9%).

[0999] 1 H NMR(500MHz,CD3OD)δ7.28(ddd,1H),7.05(td,1H),5.56–5.46(m,2H),4.94(d,1H),4.85–4.75(m,1H),4.44–4.27(m,2H),3.88–3.63(m,2 H),3.48(tt,3H),3.18(s,2H),2.85(d,1H),2.74(d,1H),2.54(d,1H),2.27–2.11(m,2H),2.10–1.86(m,3H),1.69(dd,3H),1.21(dd,3H).

[1000] MS m / z(ESI):681.2[M+1].

[1001] Example 39

[1002] 2-Amino-4-(5-chloro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[1003] first step

[1004] 6-Bromo-5-chloro-3-(ethylsulfonyl)-7,9-dihydrofuro[3,4-f]quinazoline 39b

[1005] 6-Bromo-3-(ethylthio)-5-chloro-7,9-dihydrofuro[3,4-f]quinazoline 39a (1.94 g, 5.61 mmol, prepared by the method disclosed in preparation 300 on page 192 of the specification of patent application "WO2023183585A1") was dissolved in dichloromethane (50 mL), and m-chloroperbenzoic acid (3.42 g, 16.8 mmol, 85% purity) was added. The reaction was stirred for 2 hours, and saturated sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with dichloromethane (30 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with ethyl acetate, filtered, and the filter cake was dried to obtain the crude title compound 39b (1.76 g), which was used directly in the next reaction without purification.

[1006] MS m / z(ESI):376.9[M+1].

[1007] Step 2

[1008] 6-Bromo-5-chloro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazoline 39c

[1009] Compound 1e (222 mg, 1.11 mmol) was dissolved in tetrahydrofuran (20 mL), and a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.6 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 30 minutes. Then, a solution of crude compound 39b (300 mg, 794.4 μmol) in tetrahydrofuran (5 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The solution was extracted with ethyl acetate (15 mL × 2). The organic phases were 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 give the title compound 39c (400 mg, yield: 104.2%).

[1010] MS m / z(ESI):482.2[M+1].

[1011] Step 3: Tert-butyl (4-(5-chloro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate 39d

[1012] Compound 39c (400 mg, 828.5 μmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (670 mg, 1.65 mol, prepared according to the method described on page 50 of the patent application "WO2021118877") 15) was dissolved in 1,4-dioxane (20 mL), and cesium carbonate (540 mg, 1.65 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (121 mg, 165.3 μmol) were added. The reaction was carried out at 100°C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. Water was added, and the aqueous phase was extracted with dichloromethane (15 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 39d (370 mg, yield: 64.3%).

[1013] MS m / z(ESI):694.2[M+1].

[1014] Step 4

[1015] 2-Amino-4-(5-chloro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[1016] Compound 39d (370 mg, 533 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the pH was adjusted to >7 with saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane (10 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 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 39 (100 mg, yield: 37%).

[1017] MS m / z(ESI):594.1[M+1].

[1018] 1H NMR (500MHz, DMSO-d6): δ9.48(s,1H),8.09(s,2H),7.26-7.23(m,1H),7.15(t,1H),6.63(d,1H),5.56-5.55(m,2H),4.90-4.86(m,1H) ,4.74-4.70(m,1H),4.48-4.43(m,2H),2.43-2.33(m,6H),2.20-2.18(m,2H),2.00-1.98(m,2H),0.74-0.72(m,2H),0.46-0.44(m,2H).

[1019] Example 39-p1, 39-p2

[1020] (R)-2-Amino-4-(5-chloro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 39-p1

[1021] (S)-2-Amino-4-(5-chloro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 39-p2

[1022] The isomeric mixture 39 (100 mg) was separated by chiral column (Shimadzu LC-20A, chromatographic column: Enantiocel C9 (ColumnTek), in-house packed, SN: AS23122001, 20×250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A:B 80:20, flow rate: 20 mL / min) to give the title compounds (39 mg, yield: 39%) and (49 mg, yield: 49%).

[1023] Single configuration compound (shorter retention time, recorded as 39A, ie, 39-p1 or 39-p2): (39 mg, yield: 39%).

[1024] MS m / z(ESI):594.1[M+1].

[1025] Chiral HPLC analysis: retention time 7.263 minutes, purity: 99% (chromatographic column: CHIRALPAK IK 4.6*150 mm, 5 μm; mobile phase: A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[1026] 1 H NMR (500MHz, DMSO-d6): δ9.48(s,1H),8.09(s,2H),7.26-7.23(m,1H),7.16-7.13(m,1H),6.63(d,1H),5.56-5.55(m,2H),4.90-4.86(m,1 H),4.74-4.70(m,1H),4.49-4.44(m,2H),2.44-2.33(m,6H),2.20-2.18(m,2H),1.99-1.98(m,2H),0.74-0.72(m,2H),0.46-0.44(m,2H).

[1027] Single configuration compound (longer retention time, recorded as 39B, ie, 39-p2 or 39-p1): (49 mg, yield: 49%).

[1028] MS m / z(ESI):594.1[M+1].

[1029] Chiral HPLC analysis: retention time 8.896 minutes, purity: 97.9% (chromatographic column: CHIRALPAK IK 4.6*150 mm, 5 μm; mobile phase: A: n-hexane, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[1030] 1 H NMR (500MHz, DMSO-d6): δ9.48(s,1H),8.09(s,2H),7.25-7.23(m,1H),7.16-7.12(m,1H),6.63(d,1H),5.56-5.55(m,2H),4.90-4.86(m,1 H),4.73-4.69(m,1H),4.49-4.44(m,2H),2.44-2.33(m,6H),2.20-2.18(m,2H),1.99-1.97(m,2H),0.74-0.72(m,2H),0.46-0.44(m,2H).

[1031] Example 40

[1032] 2-Amino-5-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 40

[1033] first step

[1034] (2-((tert-Butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)boronic acid 40b

[1035] Tert-butyl (4-bromo-5-fluorobenzothiophen-2-yl)carbamate 40a (530 mg, 1.53 mmol, prepared using the method disclosed in Preparation 71 on page 189 of the specification of patent application "US2024043451"), neopentyl glycol diboron (691.6 mg, 3.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (112 mg, 153 μmol), and potassium acetate (450.7 mg, 4.6 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was reacted at 100°C under a nitrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to obtain the title compound 40b (110 mg, 23.1% yield).

[1036] MS m / z(ESI):256.0[M-55].

[1037] Step 2

[1038] tert-Butyl (5-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophen-2-yl)carbamate 40c

[1039] Compound 14c (110 mg, 235.9 μmol), compound 40b (110 mg, 353.8 μmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (16 mg, 23.6 μmol), and potassium phosphate (75 mg, 353.8 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). The mixture was reacted at 70°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent System B to obtain the title compound 40c (45 mg, 29.2% yield).

[1040] MS m / z(ESI):653.5[M+1].

[1041] Step 3: tert-Butyl (3-cyano-5-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophen-2-yl)carbamate 40d

[1042] Compound 40c (45 mg, 68.9 μmol) was dissolved in tetrahydrofuran (1 mL), and chlorosulfonyl isocyanate (48.8 mg, 344.6 μmol) was added at -45°C. The mixture was stirred and reacted for 1.5 hours, then poured into N,N-dimethylformamide (1.5 mL) and reacted at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the mixture was washed with 2 M lithium chloride solution and saturated sodium chloride solution. The organic phase was collected and concentrated under reduced pressure to give the crude title compound 40d (40 mg), which was used directly in the next step without purification.

[1043] MS m / z(ESI):678.2[M+1].

[1044] Step 4

[1045] 2-Amino-5-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 40

[1046] The crude compound 40d (40 mg, 59 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. After stirring for 1 hour, the reaction was 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 40 (3 mg, yield: 19.5%).

[1047] MS m / z(ESI):578.3[M+1].

[1048] 1 H NMR (500MHz, CD3OD): δ9.38(d,1H),7.71(dd,1H),7.08(t,1H),6.52(d,1H),5.61(d,2H),4.96(dd ,2H),4.51(s,2H),2.62(s,4H),2.38(s,2H),2.13(s,1H),1.31(d,3H),0.81(s,2H),0.57(s,2H).

[1049] Example 41

[1050] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-(1-oxa-6-azaspiro[3.5]nonan-6-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 41

[1051] first step

[1052] 6-Bromo-3-(ethylthio)-5-fluoro-1-(1-oxa-6-azaspiro[3.5]nonan-6-yl)-7,9-dihydrofuro[3,4-f]quinazoline 41b

[1053] Compound 35a (200 mg, 550 μmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (177.7 mg, 1.37 mmol) and 1-oxa-6-azaspiro[3.5]nonane (84 mg, 660 μmol, Shanghai Shaoyuan) were added sequentially. The reaction was stirred for 16 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 41b (240 mg, yield: 96.3%).

[1054] MS m / z(ESI):454.2[M+1].

[1055] Step 2

[1056] 2-Amino-7-fluoro-4-(5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-(1-oxa-6-azaspiro[3.5]nonan-6-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 41

[1057] The synthetic route in Example 12 was adopted, and the second step raw material 12c was replaced by compound 41b to obtain the title compound 41 (3 mg, yield: 2%).

[1058] MS m / z(ESI):703.3[M+1].

[1059] 1H NMR (500MHz, CD3OD): δ7.29(dd,1H),7.05(t,1H),6.52(d,1H),5.72-5.43(m,2H) ,4.64-4.32(m,4H),4.02-3.42(m,3H),2.72-2.30(m,5H),2.26-1.96(m,5H),1.95 -1.55(m,2H),1.49-1.29(m,5H),0.94(dt,2H),0.76(s,2H),0.53(s,2H).

[1060] Example 42

[1061] (R)-1-((R)-6-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)azetidine-2-carboxamide 42-p1

[1062] (R)-1-((S)-6-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)azetidine-2-carboxamide 42-p2

[1063] first step

[1064] (R)-1-(6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)azetidine-2-carboxamide 42a

[1065] Compound 35a (500 mg, 1.37 mmol) was dissolved in dichloromethane (12 mL), and N,N-diisopropylethylamine (444 mg, 3.44 mmol) and (R)-azetidine-2-carboxamide hydrochloride (188 mg, 1.37 mmol, prepared by the method disclosed in Example 184 on page 237 of the specification of patent application "WO2022156792") were added sequentially. The reaction was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 42a (500 mg, yield: 85.1%).

[1066] MS m / z(ESI):427.1[M+1].

[1067] Step 2

[1068] (R)-1-((R)-6-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)azetidine-2-carboxamide 42-p1

[1069] (R)-1-((S)-6-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)azetidine-2-carboxamide 42-p2

[1070] The synthetic route in Example 12 was adopted, and the second-step raw material 12c was replaced by compound 42a to obtain crude compound 42 (17 mg), which was purified by preparative HPLC (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 30%-42%, flow rate: 30 mL / min) to give the title compound (5 mg, yield: 29.4%).

[1071] Single configuration compound (shorter retention time, recorded as 42A, ie, 42-p1 or 42-p2): (5 mg, yield: 29.4%).

[1072] MS m / z(ESI):676.4[M+1].

[1073] HPLC analysis: retention time 1.45 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%).

[1074] 1H NMR (500MHz, CD3OD): δ7.29(dd,1H),7.05(dd,1H),6.51(d,1H),5.56(d,1H),5.47(d,1H),5.29(dd,1H),4.85(d,2H),4.70(q,1H ),4.45(d,1H),4.38(d,1H),4.25(dt,1H),2.71(qd,1H),2.64-2.46(m,5H),2.37(d,3H),2.07(d,3H),0.71(s,2H),0.48(d,2H).

[1075] Single configuration compound (longer retention time, recorded as 42B, ie, 42-p2 or 42-p1): (5 mg, yield: 29.4%).

[1076] MS m / z(ESI):676.4[M+1].

[1077] HPLC analysis: retention time 1.49 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%).

[1078] 1 H NMR (500MHz, CD3OD): δ7.24(dd,1H),7.04(dd,1H),6.51(d,1H),5.57(d,1 H),5.50(d,1H),5.39-5.28(m,2H),5.02-4.96(m,2H),4.76-4.67(m,2H),4 .49(d,1H),4.34(d,1H),4.20(q,1H),2.73(qd,2H),2.57-2.47(m,4H),2.3 5(s,1H),2.21(t,1H),2.11(s,1H),2.05(d,1H),0.72(s,2H),0.49(s,2H).

[1079] Example 43

[1080] 2-amino-7-fluoro-4-((R)-5-fluoro-3-(((R)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 43-1-p1 or

[1081] 2-amino-7-fluoro-4-((S)-5-fluoro-3-(((R)-2-methylidenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 43-1-p2 or

[1082] 2-amino-7-fluoro-4-((R)-5-fluoro-3-(((S)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 43-2-p1 or

[1083] 2-Amino-7-fluoro-4-((S)-5-fluoro-3-(((S)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 43-2-p2

[1084] first step

[1085] (R)-2-Methylidene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester 43b-1

[1086] (S)-2-Methylidene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester 43b-2

[1087] The isomeric mixture of 2-methylidene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid methyl ester 43a (5 g, prepared by the method disclosed in Intermediate A-12 on page 111 of the specification of patent application "WO2020146613") was separated by chiral column (Waters SFC 150 column: 30×250mm, 10μm; mobile phase A: Supercritical CO2, mobile phase B: ethanol (0.1% 7M NH3 in MeOH), gradient ratio: A:B: 85:15, flow rate: 120mL / min) to give the title compound (1.85g, yield: 37%), (2.22g, yield: 44.4%).

[1088] Single configuration compound (shorter retention time): (1.85 g, yield: 37%).

[1089] MS m / z (ESI): 196.2 [M+1].

[1090] Chiral HPLC analysis: retention time 0.958 minutes, purity: 99% (Waters UPCC (CA-415), column: 3*100mm, 3μm; mobile phase A: Supercritical CO2, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B: 90:10, flow rate: 1.5mL / min).

[1091] Single configuration compound (longer retention time): (2.22 g, yield: 44.4%).

[1092] Chiral HPLC analysis: retention time 1.432 minutes, purity: 99% (Waters UPCC (CA-415), column: 3×100 mm, 3 μm; mobile phase A: Supercritical CO2, mobile phase B: ethanol (0.1% diethylamine), gradient ratio: A:B: 90:10, flow rate: 1.5 mL / min).

[1093] Step 2

[1094] (R)-(2-Methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol 43c-1 or

[1095] (S)-(2-Methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol 43c-2

[1096] The compound with the longer retention time (1 g, 5.1 mmol) of compound 43b-1 or compound 43b-2 was dissolved in tetrahydrofuran (20 mL), and a 1M solution of lithium aluminum tetrahydride in tetrahydrofuran (11.5 mL) was added under ice bath. The mixture was stirred at 70°C for 1 hour. After the reaction solution was cooled to room temperature, sodium sulfate decahydrate was added and stirred for 0.5 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound 43c-1 or 43c-2 (780 mg), which was used directly in the next reaction without purification.

[1097] MS m / z(ESI):154.2[M+1].

[1098] Step 3

[1099] (R)-6-Bromo-5-fluoro-3-((2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazoline 43d-1 or

[1100] (S)-6-Bromo-5-fluoro-3-((2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazoline 43d-2

[1101] Compound 43c-1 or compound 43c-2 (630 mg, 4.11 mmol) was dissolved in tetrahydrofuran (20 mL), and a 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.5 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 30 minutes. Then, a solution of compound 14b (1 g, 2.77 mmol) in tetrahydrofuran (5 mL) was added under ice-bath. The mixture was stirred at the maintained temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 43d-1 or 43d-2 (310 mg, yield: 26.6%).

[1102] MS m / z(ESI):420.2[M+1].

[1103] Step 4

[1104] 2-amino-7-fluoro-4-((R)-5-fluoro-3-(((R)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 43-1-p1 or

[1105] 2-amino-7-fluoro-4-((S)-5-fluoro-3-(((R)-2-methylidenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 43-1-p2 or

[1106] 2-amino-7-fluoro-4-((R)-5-fluoro-3-(((S)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 43-2-p1 or

[1107] 2-Amino-7-fluoro-4-((S)-5-fluoro-3-(((S)-2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)benzo[b]thiophene-3-carbonitrile 43-2-p2

[1108] Using the synthetic route in Example 14, the third step raw material 14c was replaced with compound 43d-1 or 43d-2 to obtain compound 43-1 or 43-2 (150 mg, yield: 29.4%).

[1109] The isomeric mixture 43-1 or 43-2 (100 mg) was separated by chiral column (Gilson-281, chromatographic column: CHIRALPAK IE, 20×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% 7M NH 3 in MeOH), gradient ratio: A:B: 55:45, flow rate: 15 mL / min), and the compound with a shorter retention time, namely 43-1-p1 or 43-1-p2 or 43-2-p1 or 43-2-p2 (50 mg, yield: 50%, also recorded as 43A), was collected.

[1110] MS m / z(ESI):532.2[M+1].

[1111] 1 H NMR (500MHz, CD3OD): δ9.37(s,1H),7.30(dd,1H),7.06(t,1H),5.60(d,2H),5.08-5.03(m,1H),5.01(q,1H),4.90(d,1H),4. 48-4.35(m,2H),3.79(d,1H),3.20(dt,1H),2.86(d,1H),2.81-2.70(m,1H),2.54(d,1H),2.20(ddt,2H),2.11-1.85(m,4H).

[1112] Example 44

[1113] 2-amino-4-((R)-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 44-1-p1 or

[1114] 2-amino-4-((S)-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 44-1-p2 or

[1115] 2-amino-4-((R)-3-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 44-2-p1 or

[1116] 2-Amino-4-((S)-3-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 44-2-p2

[1117] first step

[1118] Ethyl 2-(difluoromethylidene)-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate 44b

[1119] Ethyl 2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate 44a (18.08 g, 85.60 mmol, Jiangsu Aikon) and (triphenylphosphonium)difluoroacetic acid inner salt (67.1 g, 188.3 mmol, Jiangsu Aikon) were dissolved in N,N-dimethylformamide (350 mL) and stirred at 85°C under a nitrogen atmosphere for 17 hours. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution was added and extracted with ethyl acetate (100 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 44b (4.83 g, yield: 23%).

[1120] MS m / z(ESI):246.1[M+1].

[1121] Step 2

[1122] (2-(Difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol 44c

[1123] (R)-(2-(Difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol 44c-1

[1124] (S)-(2-(Difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol 44c-2

[1125] Compound 44b (4.83 g, 19.7 mmol) was dissolved in tetrahydrofuran (250 mL). A 1M solution of diisobutylaluminum hydride in tetrahydrofuran (98.5 mL) was added under ice-cooling. After naturally returning to the temperature and stirring for 5 hours, sodium sulfate decahydrate was added and stirred for 0.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 44c (2.1 g). MS m / z (ESI): 190.1 [M+1].

[1126] The isomeric mixture 44c (1 g) was separated by chiral column (Shimadzu LC-20AP, chromatographic column: DAICELCHIRALPAK IG, 20×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.1% 7 M NH3 in MeOH), gradient ratio: A:B: 80:20, flow rate: 20 mL / min) to give the title compound (8.1 min, 450 mg, yield: 45%), (10.9 min, 450 mg, yield: 45%).

[1127] Chiral HPLC analysis of the isomer mixture 44c: retention times 3.224 min, 4.354 min (Agilent 1260 DAD, column: CHIRALPAK IG 150*4.6 mm, 5 um; mobile phase A: ethanol (0.1% diethylamine, mobile phase B: n-hexane), gradient ratio: A:B: 20:80, flow rate: 1 mL / min).

[1128] Step 3

[1129] 2-amino-4-((R)-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 44-1-p1 or

[1130] 2-amino-4-((S)-3-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 44-1-p2 or

[1131] 2-amino-4-((R)-3-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 44-2-p1 or

[1132] 2-Amino-4-((S)-3-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 44-2-p2

[1133] Using the synthetic route in Example 43, the third step raw material 43c-1 or 43c-2 was replaced by the compound 44c-1 or 44c-2 with the shorter retention time to obtain the title compound 44-1-p1 or 44-1-p2 or 44-2-p1 or 44-2-p2 (50 mg, yield: 29.4%, also denoted as 44A).

[1134] MS m / z(ESI):568.2[M+1].

[1135] 1 H NMR (500MHz, CD3OD): δ9.37(d,1H),7.30(dd,1H),7.06(dd,1H),5.60(d,2H),5.06(dt,1H),4.49(d,1H),4.39(d,1H),3.88-3.80(m,1 H),3.49-3.42(m,1H),3.18(ddd,1H),2.89-2.81(m,1H),2.77-2.70(m,1H),2.61-2.53(m,1H),2.23-2.15(m,1H),2.07-1.91(m,4H).

[1136] Example 45

[1137] 2-Amino-4-(1-((1R,5S)-3-((R)-3,3-dimethyl-4-oxooxetane-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 45

[1138] MS m / z(ESI):815.2[M+1].

[1139] Example 46

[1140] 2-Amino-4-(3-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3-((R)-3,3-dimethyl-4-oxooxetane-2-carbonyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile

[1141] MS m / z(ESI):833.2[M+1].

[1142] Example 47

[1143] 2-Amino-7-fluoro-4-(5-fluoro-3-((2-methylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7,9-dihydrofu...

Claims

1. A compound represented by general formula (I') or a pharmaceutically acceptable salt thereof: in: R A Selected from Hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 3 replaced by; Y is a carbon atom; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; G 1 CR G1 or N; G is selected from C, CR G and N; G 8 CR 7 or N; G 9 CR 2 or N; R B is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxyl, hydroxyalkyl, alkenyl, alkynyl, OR 14 、C(O)OR 14 、S(O) v R 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 6 replaced by; R 2 , R G1 , R G and R 7 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, alkenyl, alkynyl, NR 11 R 12 、C(O)NR 11 R 12 、Alkylene NR 11 R 12 、Alkylene C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、S(O) v NR 11 R 12 NR 13 S(O) v R 14 、C(=NR 13 )R 14 、C(=NR 13 )NR 11 R 12 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 , OR 14 , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by; or, G, R 7 and the carbon atom to which it is attached together form ring B; ring B is optionally substituted by one or more R 8 replaced by; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R 4 and R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 11 R 12 , C(O)R 14 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 01 replaced by; or, R 4 , R 5 and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 3 replaced by; W is selected from CR 3a R 3b , 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; R w is selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 0 replace; Each R 1 , R 3 , R 6 , R 01 , R 8 and R 0 are the same or different and are each independently selected from oxo, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, NR 11 R 12 、C(O)NR 11 R 12 、Alkylene NR 11 R 12 、Alkylene C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、S(O) v NR 11 R 12 NR 13 S(O) v R 14 、C(=NR 13 )R 14 、C(=NR 13 )NR 11 R 12 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * replaced by; Each R 11 , R 12 , R 13 and R 14 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an alkenyl group, an alkynyl group, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、Alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v NR 20 R 21 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * or R 11 , R 12 and the nitrogen atom to which it is attached form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R * replaced by; R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * replaced by; Each R 20 , R 21 , R 22 and R 23 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a NR a R b 、C(O)NR a R b 、C(O)R c , cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally replaced by one or more R * or, R 20 , R 21 and the nitrogen atom to which it is attached form a heterocyclic group, wherein the heterocyclic group is * replaced by; Each R * are the same or different and are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、C(O)R c 、Alkylene NR a R b 、Alkylene C(O)NR a R b , nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy and heteroaryloxy; the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy and heteroaryloxy are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR a R b NR a OR c NR a C(O)NR a R b NR a C(O)OR c 、C(O)NR a R b 、C(O)R c 、C(O)OR c 、Alkylene NR a R b 、Alkylene C(O)NR a R b 、S(O) v R c 、S(O) v OR c 、S(O) v NR a R b , cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryloxy and heteroaryloxy; R a , R b and R c are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group; r is 0, 1, 2, 3, 4 or 5; v is 0, 1 or 2; m is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3, 4, 5 or 6; and j is 0, 1, 2, 3, 4, 5 or 6.

2. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof: in, R A Selected from Hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, NR 11 R 12 , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 3 Replaced by; each R * are the same or different and are each independently selected from oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR a R b 、C(O)NR a R b 、C(O)R c 、Alkylene NR a R b 、Alkylene C(O)NR a R b , nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl; Ring A, R 1 ,m,G,G 1 , R 2 , R 7 , R B , W, R 3a , R 3b , r, ring C, Y, R 3 , R 4 , R 5 ,p,R 11 , R 12 , R a , R b and R c As defined in claim 1; Preferably, R A for W.R. 3a , R 3b , r, Y, ring C, R 3 , R 4 , R 5 and p is as defined in claim 1.

3. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof: in, R 6a is a hydrogen atom or R 6 ; R 6b For R 6 , or two R 6b and the carbon atom to which it is attached form CH(CR 6c R 6d ) u CH; R 6c and R 6d are the same or different and are each independently a hydrogen atom or R 6 ; n is 0, 1, 2, 3, 4, 5 or 6, u is 0, 1 or 2; Ring A, Ring C, R 1 ,m,G,G 1 , R 2 , R 7 , R 6 , W, R 3a , R 3b , r, Y, R 3 , R 4 , R 5 and p is as defined in claim 1.

4. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof: in, G is C or N; q is 0, 1, 2, 3 or 4; Ring A, Ring B, Ring C, R 1 ,m,R 8 , R 2 , G 1 , R B , W, R 3a , R 3b , r, R 3 and j as defined in claim 1.

5. The compound represented by the general formula (I') according to claim 1, 2 or 4 or a pharmaceutically acceptable salt thereof, wherein: R B Selected from hydrogen atoms, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkynyl group and the 3- to 6-membered cycloalkyl group are each independently optionally substituted with one or more R 6 Replaced by; R 6a is a hydrogen atom or R 6 , R 6b For R 6 , u is 0, 1 or 2; n1 is 0, 1, 2 or 3; R 6 As defined in claim 1; preferably, R B Selected from hydrogen atoms, R 6a is a hydrogen atom or R 6 , R 6b For R 6 , u is 0, 1 or 2; n1 is 0, 1, 2 or 3; R 6 As defined in claim 1; More preferably, R B Selected from hydrogen atoms, 6. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof: in, Q is selected from CR 8a R 8b 、O、S、C(O)、C(O)NR 8c and NR 8c ; R 8a and R 8b are the same or different and are each independently a hydrogen atom or R 8 ; R 8c is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; s is 0, 1, 2 or 3; t is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4; Ring A, Ring C, R 1 ,m,R 2 , G 1 , R 8 , R 6a , R 6b ,n,W,R 3a , R 3b , r, Y, R 3 , R 4 , R 5 and p as defined in claim 3.

7. The compound represented by the general formula (I') according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VII-1) or (VII-2) or a pharmaceutically acceptable salt thereof: in, U is selected from NR 1a , O, S and Se; V is N or CR 1b ; R 1a is a hydrogen atom or R 1 ; R 1b is a hydrogen atom or R 1 ; R 3c is a hydrogen atom or R 3 ; m2 is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; R 1 , R 8 , R 2 , G 1 , R B , R 3 , R 4 and R 5 As defined in claim 1.

8. The compound represented by the general formula (I') according to claim 3, 5 or 6 or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably n1 is 0, 1, 2 or 3, R 6b For R 6 , R 6 and u as defined in claim 3; more preferably *End and R 6a connect.

9. The compound represented by the general formula (I') according to claim 3, 5, 6, 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R 6a Selected from hydrogen atoms, C 1-6 Alkyl and OR 14 , the C 1-6 The alkyl group is optionally selected from halogen, hydroxy, C 1-6 substituted by one or more of an alkoxy group and a 3- to 6-membered heterocyclic group; R 14 Selected from hydrogen atoms, C 1-6 alkyl and 3 to 6-membered cycloalkyl; preferably, R 6a A hydrogen atom or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally selected from hydroxyl, C 1-6 More preferably, R 6a C 1-6 Alkyl, the C 1-6 The alkyl group is optionally selected from hydroxyl, C 1-6 alkoxy and 3 to 6-membered heterocyclic group or more; further preferably, R 6a C 1-6 Hydroxyalkyl.

10. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 5 to 9, wherein R 4 and R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Preferably, R 4 and R 5 are the same or different and are each independently a hydrogen atom or a halogen.

11. The compound represented by general formula (I') according to any one of claims 1 to 6 or 8 to 10, or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 8-membered heterocyclic group; and / or each R 3 The same or different, and each independently is halogen or =CR 15 R 16 , R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen.

12. A compound represented by general formula (I') according to any one of claims 1 to 6 or 8 to 11, or a pharmaceutically acceptable salt thereof, wherein W is O, and / or 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, and / or r is 1 or 3.

13. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or 8 to 12, wherein ring A is a 6- to 10-membered aryl group or a 5- to 14-membered heteroaryl group; preferably, ring A is selected from naphthyl, phenyl, pyridyl, benzothiophenyl, benzothiazolyl, benzopyrazolyl, pyridothiphenyl, pyridothiazole, pyridopyrazolyl, benzoselenophene and pyridoselenophene; more preferably, ring A is selected from phenyl, benzothiophenyl and pyridothiphenyl.

14. A compound represented by general formula (I') according to any one of claims 1 to 6 or 8 to 13, or a pharmaceutically acceptable salt thereof, wherein Selected from R 1 and m as defined in claim 1; preferably, Selected from 15. The compound represented by general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein 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, C 1-6 Hydroxyalkyl, cyano, -NR 11 R 12 and a 3- to 8-membered cycloalkyl group; preferably, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl halide, cyano and -NR 11 R 12 , R 11 and R 12 As defined in claim 1, and / or m is 1, 2 or 3.

16. The compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein G 1 N, and / or R 2 It is a halogen.

17. A compound represented by general formula (I') or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, which is selected from the following compounds:

18. A compound represented by the general formula (VA) or a salt thereof: in, Ring A, Ring C, R 1 ,m,Q,s,t,R 8 ,q,R 2 , G 1 , R 6b ,n,W,R 3a , R 3b , r, Y, R 3 , R 4 , R 5 and p as defined in claim 6.

19. The compound represented by the general formula (I') according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

20. A method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (VA) or its salt undergoes a ring-opening reaction with the compound represented by the general formula (IIB) or its salt to obtain the compound represented by the general formula (V) or its pharmaceutically acceptable salt; Among them, R 6a for R is a hydrogen atom or an alkyl group; Ring A, Ring C, R 1 ,m,Q,s,t,R 8 ,q,R 2 , G 1 , R 6b ,n,W,R 3a , R 3b , r, Y, R 3 , R 4 , R 5 and p as defined in claim 6.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

22. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 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.

23. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, 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.

24. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 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 tumors, 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.