Nitrogen-containing heterocyclic compounds, their preparation method and medicinal use

Abstract

The present disclosure relates to nitrogen-containing heterocyclic compounds, their preparation methods and their pharmaceutical uses. In particular, the present disclosure relates to nitrogen-containing heterocyclic compounds represented by general formula (I), their preparation methods and pharmaceutical compositions comprising such compounds, as well as their use as therapeutic agents, in particular as HER2 inhibitors and in the preparation of medicaments for treating and / or preventing diseases or conditions by inhibiting HER2. TIFF2025509995000189.tif3764

Description

[Technical field]

[0001] The present disclosure belongs to the pharmaceutical field and relates to nitrogen-containing heterocyclic compounds, their preparation methods and their pharmaceutical uses.Specifically, the present disclosure relates to nitrogen-containing heterocyclic compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, and their use as therapeutic agents, particularly as HER2 inhibitors and in the preparation of medicaments for treating and / or preventing diseases or conditions by inhibiting HER2. [Background technology]

[0002] Human epidermal growth factor receptor 2 (HER2; Neu, ERBB2) is a member of the type I receptor tyrosine kinase family, which further includes EGFR (ERBB1), HER3 (ERBB3) and HER4 (ERBB4). Up to now, no ligand that can directly bind to HER2 has been found in the human body, and HER2 must form a homodimer or heterodimer with other members of the family (e.g., HER3). When HER2 is dimerized, its conformation is changed, tyrosine kinase activity in the cell is activated, and downstream pathways (MAPK signaling pathway and PI3K / AKT signaling pathway) are activated, which exerts corresponding physiological effects.

[0003] Aberrant HER2 signaling has been observed in various human malignancies, and oncogenic mutations occur in the extracellular, juxtamembrane and intracellular domains of HER2. In essence, these mutations confer persistent activity to HER2, promoting cancer initiation, tumor maintenance and growth. They are the basis of tumor transformation and tumor maintenance in a variety of tumor types, including breast, gastric and lung cancers. Overexpression of HER2 increases HER2 signaling, and HER2 amplification is associated with poorer survival outcomes, especially in breast cancer. HER2 mutations account for 6-7% of all human cancers. Therefore, disrupting HER2 oncogenic signaling can effectively treat tumors with HER2 oncogenic mutations or HER2 wild-type amplification. Currently, a variety of drugs directed against HER2 have been approved by the FDA for the treatment of breast cancer, including anti-HER2 antibodies (trastuzumab and pertuzumab), HER2-directed antibody-drug conjugates (trastuzumab-DM1 (T-DM1, ado-trastuzumabemtansine)), and small molecules that inhibit the HER2 kinase domain (afatinib, neratinib, lapatinib, tucatinib, and pyrotinib).

[0004] These drugs can inhibit HER2 wild type, e.g., tucatinib, but these inhibitors are ineffective against HER2 with exon 20 mutation. HER2 gene exon 20 mutation enhances kinase activity (Wang et al., Cancer Cell, 2006, 10(1):25-38). Such enhanced HER2 kinase activity stimulates tumor transformation by entering into downstream signal cascades and promoting cell growth, proliferation and survival. Genetic studies in mouse models have revealed that non-small cell lung cancer is the most common HER2 exon 20 mutation, an insertion of four amino acids YVMA (p.A775_G776insYVMA), which can induce oncogenic growth. Tumors can be reduced by reducing HER2-YVMA expression, indicating that such oncogenic variants of HER2 are necessary for tumor maintenance. In addition, afatinib, a broad-spectrum ERBB inhibitor, can effectively inhibit HER2-YVMA oncogenic signaling in vivo.

[0005] Statistically, approximately 2-4% of lung cancer patients have activating mutations in HER2 exon 20. Current clinically approved ERBB-targeting tyrosine kinase inhibitors are largely ineffective in these patients, mainly due to dose-limiting toxicity mediated by wild-type EGFR. Alectinib, ibrutinib, neratinib, poziotinib and pyrotinib are broad-spectrum ERBB inhibitors of known mutated HER2 exon 20. However, clinically, afatinib and other broad-spectrum ERBB inhibitors have shown limited therapeutic efficacy in NSCLC patients with HER2 exon 20 mutations, due to being limited by the effective dose.

[0006] Therefore, there is an urgent medical need to develop a molecule that specifically inhibits HER2 exon 20 mutant proteins but is ineffective against EGFR wild type, thereby overcoming the drawback of dose-limiting toxicity mediated by EGFR wild type.The present invention aims to provide a new inhibitor of mutant HER2 exon 20 that is selective for EGFR wild type.

[0007] Currently, a series of patent applications for HER2 inhibitors have been disclosed, including WO2007059257A1, WO2017148391A1, WO2021213800A1 and WO2021156178A1. Summary of the Invention

[0008] The present disclosure aims to provide a compound represented by general formula (I) or a medicamentable salt thereof: [ka] Among them, Ring A is an aryl group or a heteroaryl group; Ring B is a 7- to 10-membered fused heterocyclyl group or a 7- to 10-membered bridged heterocyclyl group; G is N or C(R A ) and R A is selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, a hydroxy group, and an amino group; V 1 is C(R a ) or N, V 2 and V 3 are the same or different and each independently C(R a ) or N, or V 2 is C(R bb ), V 3 is C(R cc ) and R bb and R cc together with the carbon atom to which each is attached form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, the cycloalkyl group, the heterocyclyl group, the aryl group or the heteroaryl group being optionally substituted with one or more substituents selected from halogen, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cyano group, hydroxy group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group; L 1 , O, NR b1 , C(O), S, S(O) and S(O)2; L 2 , O, NR b2 , C(O), (CR c R d ) u , (CR c R d ) u O, O(CR c R d ) u , (CR c R d ) u NR b2 , N.R. b2 (CR c R d ) u , C(O)NR b2 and N.R. b2 C(O), E is a 9-10 membered heteroaryl group, which may optionally be one or more R 16 is replaced by R 16 is a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, -OR 4 , -NR 5 R 6 , -C(O)R 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)NR 5 R 6 , -S(O) p R 4 , -S(O) p NR 5 R 6 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, each of which is independently optionally selected from an oxo group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 4a , -NR 5a R 6a, substituted with one or more substituents selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R a is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a haloalkyl group, a hydroxyalkyl group, -OR e , -(CH2) s -NR f R g , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R b1 and R b2 are the same or different and each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group; R c and R d are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a hydroxyl group, and a hydroxyalkyl group; R 1 is selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, Each R 2 are the same or different and each independently represent a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a haloalkyl group, a hydroxyalkyl group, -OR 7 , -(CH2) v -NR 8 R 9 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; Each R 3 are the same or different and each independently represent an oxo group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, -OR 10 , -NR 11 R 12 , -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -C(O)NR 11 R 12 , -NR 13 C(O)R 10 , -NR13 C(O)OR 10 , -NR 13 C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , -NR 13 S(O) p R 10 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, and the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 10a , -NR 11a R 12a , substituted with one or more substituents selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 10 are the same or different in each occurrence and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and each of the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group may each independently and optionally be selected from one or more R B is replaced by R B is an oxo group, halogen, alkyl group, alkenyl group, alkynyl group, cyano group, -OR 10b , -NR 11b R 12b , -C(O)R 10b , -C(O)NR 11b R 12b, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, each of which is independently optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a hydroxyl group, a cyano group and an amino group; R e , R 4 , R 4a , R 7 , R 10a and R 10b each occurrence is the same or different and each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and each of the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a hydroxy group, an alkoxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R f , R g , R 5 , R 6 , R 8 , R 9 , R 11 and R 12 each occurrence is the same or different and each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a hydroxy group, an alkoxy group, a haloalkoxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; Or, R f , R g together with the nitrogen atom to which it is linked form a heterocyclyl group, or R 5 , R 6 together with the nitrogen atom to which it is linked form a heterocyclyl group, or R 8 , R 9 together with the nitrogen atom to which it is linked form a heterocyclyl group, or R 11 , R 12 together with the nitrogen atom to which it is linked form a heterocyclyl group, which is optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cyano, hydroxy, alkoxy, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 13 each occurrence is the same or different and is independently selected from a hydrogen atom, an alkyl group, and a cycloalkyl group; R 5a , R 6a , R 11a , R 12a , R 11b and R 12b each occurrence is the same or different and is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group; s is 0, 1 or 2; v is 0, 1 or 2; u is 1, 2, 3 or 4; p is 0, 1 or 2; n is 0, 1, 2, 3 or 4, and m is an integer from 0 to 10.

[0009] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is Among them, Ring A is an aryl group or a heteroaryl group; Ring B is a 7- to 10-membered fused heterocyclyl group or a 7- to 10-membered bridged heterocyclyl group; G is N or C(R A ) and R A is selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, a hydroxy group, and an amino group; V 1 , V 2 and V 3 are the same or different and each independently C(R a ) or N, L 1 , O, NR b1 , C(O), S, S(O) and S(O)2; L 2 , O, NR b2 , C(O), (CR c R d ) u , (CR c R d ) u O, O(CR c R d ) u , (CR c R d ) u NR b2 , N.R. b2 (CR c R d ) u , C(O)NR b2 and N.R. b2 C(O), E is a 9-10 membered heteroaryl group, which may optionally be one or more R 16 is replaced by R 16 is a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, -OR 4 , -NR 5 R 6 , -C(O)R 4 , -C(O)OR4 , -OC(O)R 4 , -C(O)NR 5 R 6 , -S(O) p R 4 , -S(O) p NR 5 R 6 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, each of which is independently optionally selected from an oxo group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 4a , -NR 5a R 6a , substituted with one or more substituents selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R a is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a haloalkyl group, a hydroxyalkyl group, -OR e , -(CH2) s -NR f R g , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R b1 and R b2 are the same or different and each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group; R c and R d are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a hydroxyl group, and a hydroxyalkyl group; R 1 is selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, Each R 2 are the same or different and each independently represent a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, a haloalkyl group, a hydroxyalkyl group, -OR 7 , -(CH2)v -NR 8 R 9 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; Each R 3 are the same or different and each independently represent an oxo group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, -OR 10 , -NR 11 R 12 , -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -C(O)NR 11 R 12 , -NR 13 C(O)R 10 , -NR 13 C(O)OR 10 , -NR 13 C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , -NR 13 S(O) p R 10 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, and the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 10a , -NR 11a R 12a , substituted with one or more substituents selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 10are the same or different in each occurrence and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and each of the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group may each independently and optionally be selected from one or more R B is replaced by R B is an oxo group, halogen, alkyl group, alkenyl group, alkynyl group, cyano group, -OR 10b , -NR 11b R 12b , -C(O)R 10b , -C(O)NR 11b R 12b , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, each of which is independently optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a hydroxyl group, a cyano group and an amino group; R e , R 4 , R 4a , R 7 , R 10a and R 10b each occurrence is the same or different and each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and each of the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a hydroxy group, an alkoxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R f , R g , R 5, R 6 , R 8 , R 9 , R 11 and R 12 each occurrence is the same or different and each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a hydroxy group, an alkoxy group, a haloalkoxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; Or, R f , R g together with the nitrogen atom to which it is linked form a heterocyclyl group, or R 5 , R 6 together with the nitrogen atom to which it is linked form a heterocyclyl group, or R 8 , R 9 together with the nitrogen atom to which it is linked form a heterocyclyl group, or R 11 , R 12 together with the nitrogen atom to which it is linked form a heterocyclyl group, which is optionally substituted with one or more substituents selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cyano, hydroxy, alkoxy, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 13 each occurrence is the same or different and is independently selected from a hydrogen atom, an alkyl group, and a cycloalkyl group; R 5a , R 6a , R 11a , R 12a , R 11b and R 12beach occurrence is the same or different and is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group; s is 0, 1 or 2; v is 0, 1 or 2; u is 1, 2, 3 or 4; p is 0, 1 or 2; n is 0, 1, 2, 3 or 4, and A compound represented by the general formula (I) or a medicamentable salt thereof, wherein m is an integer of 0 to 10.

[0010] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or a medicamentable salt thereof, wherein L 1 is O.

[0011] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or a medicamentable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, and preferably ring A is a phenyl group.

[0012] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or a medicamentable salt thereof, wherein R A is a hydrogen atom, halogen, C 1-6 R is selected from the group consisting of an alkyl group and a cyano group. A is a cyano group.

[0013] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or a medicamentable salt thereof, wherein G is N or C-CN, and preferably G is N.

[0014] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or a medicamentable salt thereof, wherein R 1 is a hydrogen atom.

[0015] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or a medicamentable salt thereof, wherein R c and R d are both hydrogen atoms.

[0016] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or a medicamentable salt thereof, wherein u is 1 or 2, and preferably u is 1.

[0017] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or a medicamentable salt thereof, wherein L 2 is O or (CR c R d ) u O and R c , R d and u are as defined in general formula (I), preferably L 2 is O or CHO, more preferably, L 2 is O.

[0018] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by the general formula (II) or a medicamentable salt thereof: [ka] Among them, r is 0 or 1; Ring B, E, R 2 , R 3 , V 1 , V 2 , V 3 , m and n are as defined in formula (I), or a medicamentable salt thereof.

[0019] In some embodiments of the present disclosure, the compound is represented by the above general formula (II) or a medicamentable salt thereof, wherein V 1 , V 2 and V3 are the same or different and each independently C(R a ) or N, R a is as defined in general formula (I).

[0020] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein ring B is an 8-membered fused heterocyclyl group or a 7-8 membered bridged heterocyclyl group, and preferably ring B is [ka] and R 3 can be substituted at any substitutable position of ring B.

[0021] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof is [ka] teeth [ka] Selected from R 3 can be substituted at any substitutable position of the ring B, and preferably [ka] teeth [ka] Selected from R 3 can be substituted at any substitutable position of the ring B, and more preferably [ka] teeth [ka] A compound represented by general formula (I) or general formula (II) or a medicamentable salt thereof.

[0022] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof is [ka] teeth [ka] Selected from R 3a is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, and the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 10a , -NR 11a R 12a , cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; R 3b is a hydrogen atom, oxo group, halogen, alkyl group, alkenyl group, alkynyl group, cyano group, nitro group, -OR 10 , -NR 11 R 12 , -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -C(O)NR 11 R 12 , -NR 13 C(O)R 10 , -NR 13 C(O)OR 10 , -NR13 C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , -NR 13 S(O) p R 10 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, and the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 10a , -NR 11a R 12a , cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; R 10 , R 11 , R 12 , R 10a , R 11a , R 12a and p are as defined in general formula (I), Preferably, [ka] teeth [ka] Selected from R 3a is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, and the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 10a , -NR 11a R 12a , cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; R 3b is a halogen, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, -OR 10 , -NR 11 R 12 , -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -C(O)NR 11 R 12 , -NR 13 C(O)R 10 , -NR 13 C(O)OR 10 , -NR 13 C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , -NR 13 S(O) p R 10 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, and the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are each independently optionally selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 10a , -NR 11a R 12a , cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; R10 , R 11 , R 12 , R 10a , R 11a , R 12a and p are as defined in general formula (I), a compound represented by general formula (I), general formula (II) or a medicamentable salt thereof.

[0023] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein each R 3 are the same or different and each independently represent a halogen, C 1-6 Alkyl group, -OR 10 and -C(O)R 10 and C above. 1-6 The alkyl group may optionally be a halogen, a cyano group, -OR 10a , -NR 11a R 12a , 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group, and R 10 , R 10a , R 11a and R 12a is as defined in general formula (I), preferably R 3 is halogen or -C(O)R 10 and R 10 is as defined in general formula (I), more preferably R 3 HA-C(O)R 10 and R 10 is as defined in general formula (I).

[0024] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein R 3a is C 1-6 Alkyl group or -C(O)R 10 And the above C 1-6 The alkyl group may optionally be a halogen, a cyano group, -OR 10a , -NR 11a R 12a, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group, and R 10 , R 10a , R 11a and R 12a is as defined in general formula (I), preferably R 3a HA-C(O)R 10 and R 10 is as defined in general formula (I).

[0025] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein R 3b is halogen, C 1-6 Alkyl group, -OR 10 and -C(O)R 10 and C above. 1-6 The alkyl group may optionally be a halogen, a cyano group, -OR 10a , -NR 11a R 12a , 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group, and R 10 , R 10a , R 11a and R 12a is as defined in general formula (I), preferably R 3b is halogen, more preferably R 3b is fluorine.

[0026] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3a HA-C(O)R 10 and R 10is as defined in general formula (I), R 3b is a halogen, Preferably, [ka] teeth [ka] Selected from R 3a HA-C(O)R 10 and R 10 is as defined in general formula (I), R 3b is a halogen, More preferably, [ka] teeth [ka] Selected from R 3a HA-C(O)R 10 and R 10 is as defined in general formula (I), R 3b is a halogen, more preferably [ka] teeth [ka] and R 3a HA-C(O)R 10 and R 10 is C 2-6 An alkenyl group (preferably a vinyl group), most preferably [ka] teeth [ka] The compound represented by the general formula (I) or a medicamentable salt thereof:

[0027] In some embodiments of the present disclosure, the compound is represented by the above general formula (II) or a medicamentable salt thereof, wherein r is 0.

[0028] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3a HA-C(O)R 10 and R 10 is as defined in general formula (I), R 3b is a halogen, Preferably, [ka] teeth [ka] Selected from R 3a HA-C(O)R 10 and R 10 is as defined in general formula (I), R 3b is a halogen, More preferably, [ka] teeth [ka] Selected from R 3a HA-C(O)R 10 and R 10 is as defined in general formula (I), R 3b is a halogen, more preferably [ka] teeth [ka] and R 3a HA-C(O)R 10 and R 10 is C 2-6 An alkenyl group (preferably a vinyl group), most preferably [ka] teeth [ka] A compound represented by the general formula (II) or a medicamentable salt thereof:

[0029] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein R 10 each occurrence is the same or different and independently represents a hydrogen atom, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 alkynyl group, 3- to 8-membered cycloalkyl group, and 3- to 8-membered heterocyclyl group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 The alkynyl group, the 3- to 8-membered cycloalkyl group, and the 3- to 8-membered heterocyclyl group each independently and optionally include one or more R B is replaced by R B is an oxo group, halogen, C 1-6 Alkyl group, -OR 10b , -NR 11b R 12b , -C(O)R 10b , -C(O)NR 11b R 12b , a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group, 1-6 The alkyl group, the 3- to 8-membered cycloalkyl group, and the 3- to 8-membered heterocyclyl group are each independently optionally selected from oxo group, halogen, C 1-6 Alkyl group, C 1-6Haloalkyl group, C 1-6 Hydroxyalkyl group, C 1-6 substituted with one or more substituents selected from an alkoxy group, a hydroxy group, a cyano group, and an amino group; R 10b , R 11b and R 12b is as defined in general formula (I), Preferably, R 10 is C 2-6 alkenyl group, 2-6 The alkenyl group may optionally be one or more R B is replaced by R B is halogen, C 1-6 an alkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group; 1-6 The alkyl group, the 3- to 8-membered cycloalkyl group, and the 3- to 8-membered heterocyclyl group are each independently optionally selected from oxo group, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 substituted with one or more substituents selected from an alkoxy group, a hydroxy group, a cyano group, and an amino group; More preferably, R 10 is C 2-6 alkenyl group, 2-6 The alkenyl group is optionally halogen or C 1-6 substituted with one or more substituents selected from alkyl groups; More preferably, R 10 is C 2-6 is an alkenyl group, Most preferably, R 10 A compound represented by general formula (I) or general formula (II), or a medicinal salt thereof, wherein:

[0030] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein R 10a and R 10b each occurrence is the same or different and independently represents a hydrogen atom or C 1-6 It is an alkyl group.

[0031] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein R 11a , R 12a , R 11b and R 12b each occurrence is the same or different and independently represents a hydrogen atom or C 1-6 It is an alkyl group.

[0032] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein m is 0, 1 or 2, and preferably m is 1.

[0033] In some embodiments of the present disclosure, the compound is represented by the above general formula (I) or general formula (II) or a medicamentable salt thereof, wherein R 3 teeth [ka] and R 12c , R 12d and R 12e are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 an alkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group; 1-6 The alkyl group, the 3- to 8-membered cycloalkyl group, and the 3- to 8-membered heterocyclyl group are each independently optionally selected from oxo group, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 It is substituted with one or more substituents selected from an alkoxy group, a hydroxy group, a cyano group, and an amino group.

[0034] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or a medicamentable salt thereof is a compound represented by the general formula (III) or a medicamentable salt thereof: [ka] Among them, Ring B is a 7- to 10-membered nitrogen-containing fused heterocyclyl group or a 7- to 10-membered nitrogen-containing bridged heterocyclyl group; R 12c , R 12d and R 12e are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 an alkyl group, a 3- to 8-membered cycloalkyl group, and a 3- to 8-membered heterocyclyl group; 1-6 The alkyl group, the 3- to 8-membered cycloalkyl group, and the 3- to 8-membered heterocyclyl group are each independently optionally selected from oxo group, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Substituted with one or more substituents selected from an alkoxy group, a hydroxy group, a cyano group, and an amino group; and E, R 2 , L 2 , V 1 , V 2 , V 3 and n are as defined in general formula (I), or a medicament salt thereof. In some embodiments of the present disclosure, the compound is represented by the above general formula (III), or a medicament salt thereof, wherein V 1 , V 2 and V 3 are the same or different and each independently C(R a ) or N, R a is as defined in general formula (I).

[0035] In some embodiments of the present disclosure, the compound is represented by the above general formula (III) or a medicamentable salt thereof, wherein L 2 is O.

[0036] In some embodiments of the present disclosure, the compound represented by the above general formula (III) or a medicamentous salt thereof, wherein ring B is an 8-membered nitrogen-containing fused heterocyclyl group or a 7-8-membered nitrogen-containing bridged heterocyclyl group, preferably ring B is a 7-8-membered nitrogen-containing bridged heterocyclyl group, more preferably ring B is [ka] and R 3 can be substituted at any substitutable position of ring B.

[0037] In some embodiments of the present disclosure, the compound is represented by the above general formula (III) or a medicamentous salt thereof, wherein: [ka] teeth [ka] and preferably [ka] teeth [ka] It is.

[0038] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II), general formula (III) or a medicamentable salt thereof, wherein E is [ka] X is selected from N or CR 16a and X 1 , X 2 and X 3 are each independently N or CR 16b and X 4 and X 5 are the same or different and each independently represent N or CR 16c and X 6 is O, S and NR 16d Selected from X 7 , X 8 , X 9 and X 10 are the same or different and each independently represent N or CR 16e and X 7 , X 8 , X9 and X 10 At least one of the is N and R 16a , R 16b , R 16c and R 16e are the same or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, -OR 4 , -NR 5 R 6 , -C(O)R 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)NR 5 R 6 , -S(O) p R 4 , -S(O) p NR 5 R 6 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, each of which is independently optionally selected from an oxo group, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, -OR 4a , -NR 5a R 6a , cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; R 16d is selected from a hydrogen atom, an alkyl group, and a cycloalkyl group, and the alkyl group and the cycloalkyl group are each independently optionally selected from an oxo group, a halogen, an alkyl group, a cyano group, -OR 4a and -NR 5a R 6a q is 0, 1, 2 or 3; and R 4 , R 4a , R 5 , R 6 , R 5a , R 6a , R 16 and p is as defined in formula (I), a compound represented by formula (I), formula (II), formula (III) or a medicamentable salt thereof.

[0039] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R 16 is halogen, C 1-6 Alkyl group, cyano group, -OR 4 and 3-8 membered cycloalkyl groups, 1-6 The alkyl group is optionally substituted with one or more halogens, and R 4 is as defined in general formula (I), preferably R 16 is halogen or C 1-6 More preferably, R 16 is C 1-6 is an alkyl group, most preferably R 16 is a methyl group.

[0040] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R 4 is a hydrogen atom or C 1-6 It is an alkyl group.

[0041] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R 4a is a hydrogen atom or C 1-6 It is an alkyl group.

[0042] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R 5 and R 6 each occurrence is the same or different and independently represents a hydrogen atom or C 1-6 It is an alkyl group.

[0043] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R5a and R 6a each occurrence is the same or different and independently represents a hydrogen atom or C 1-6 It is an alkyl group.

[0044] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R 16a , R 16b , R 16c and R 16e are the same or different and each independently represent a hydrogen atom, a halogen atom, or C 1-6 alkyl group, preferably R 16a , R 16b , R 16c and R 16e are each independently a hydrogen atom.

[0045] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R 16d is a hydrogen atom, C 1-6 R is selected from alkyl groups and 3- to 8-membered cycloalkyl groups. 16d is C 1-6 More preferably, R 16d is a methyl group.

[0046] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein E is [ka] and preferably [ka] and X is N or CR 16a and R 16a , R 16b and R 16c are the same or different and each independently represent a hydrogen atom, a halogen atom, or C 1-6alkyl groups, R 16d is a hydrogen atom, C 1-6 R is selected from alkyl groups and 3- to 8-membered cycloalkyl groups; 16 is halogen or C 1-6 is an alkyl group, and q is 0, 1, 2, or 3.

[0047] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein q is 0 or 1, and preferably q is 0.

[0048] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein E is [ka] Selected from.

[0049] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein each R 2 are the same or different and each independently C 1-6 is an alkyl group or a halogen, preferably R 2 is C 1-6 More preferably, R 2 is a methyl group.

[0050] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein each R 2 are the same or different and each independently represents a methyl group or fluorine.

[0051] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein n is 0, 1, or 2, preferably, n is 1 or 2, and more preferably, n is 1.

[0052] In some embodiments of the present disclosure, the compound is represented by the above general formula (II) or general formula (III) or a medicamentous salt thereof, among which: [ka] teeth [ka] and R 2a is a hydrogen atom or a halogen, and E and R 2 is as defined in general formula (I), preferably [ka] teeth [ka] and E and R 2 is as defined in general formula (I), more preferably [ka] teeth [ka] and E is as defined in general formula (I).

[0053] In some embodiments of the present disclosure, the compound is represented by the above general formula (II) or general formula (III) or a medicamentous salt thereof, among which: [ka] teeth [ka] and R 2a is a hydrogen atom or a halogen atom, and R 2 is C 1-6 is an alkyl group, E is as defined in general formula (I), [ka] is preferred, where E is as defined in general formula (I), more preferably [ka] and E is as defined in general formula (I).

[0054] In some embodiments of the present disclosure, the compound is represented by the above general formula (II) or general formula (III) or a medicamentous salt thereof, among which: [ka] teeth [ka] and preferably [ka] It is.

[0055] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R e is a hydrogen atom or C 1-6 It is an alkyl group.

[0056] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein R a is a hydrogen atom, halogen, C 1-6 Alkyl group, cyano group and -OR e Selected from R e is as defined in general formula (I), preferably R a is a hydrogen atom or C 1-6 R is preferably an alkoxy group. a is selected from a hydrogen atom, a methoxy group, and an ethoxy group, and more preferably, R a is a hydrogen atom or a methoxy group.

[0057] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, among which V 1 is C(R a ) or N, V 2 and V 3 are the same or different and each independently C(R a ) or N, or V 2 is C(R bb ) and V 3 is C(R cc ) and R bb and R cc each together with the carbon atom to which it is linked forms a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group; R a is a hydrogen atom or C 1-6 is an alkoxy group, preferably V 1 , V 2 and V 3 are the same or different and each independently C(R a ) or N, R a is a hydrogen atom or C 1-6 is an alkoxy group, more preferably V 1 is N or CH, V 2 is C(R a ) or N, R a is a hydrogen atom or C 1-6 is an alkoxy group, V 3 is CH.

[0058] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, wherein V 1 , V 2 and V 3 are each independently C(R a ) and R a is as defined in general formula (I), or V 1 and V 2 are both N, and V 3 is C(R a ) and Ra is as defined in general formula (I), Preferably, V 1 , V 2 and V 3 are each independently C(R a ) and R a is a hydrogen atom or C 1-6 an alkoxy group, or V 1 and V 2 are both N, and V 3 is C(R a ) and R a is a hydrogen atom or C 1-6 is an alkoxy group, More preferably, V 1 , V 2 and V 3 are both CH, or V 1 and V 3 are both CH, and V 2 CC 1-6 an alkoxy group, or V 1 and V 2 are both N, and V 3 is CH, Most preferably, V 1 , V 2 and V 3 A compound represented by general formula (I), general formula (II), or general formula (III), or a medicamentable salt thereof, wherein each of

[0059] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), general formula (II), or general formula (III) or a medicamentable salt thereof, among which V 1 is C(R a ) and V 2 and V 3 are the same or different and each independently C(R a ) or N, R a is as defined in general formula (I), preferably V 1 , V 2 and V 3 are the same or different and each independently C(R a ) and R ais as defined in general formula (I), more preferably V 1 , V 2 and V 3 Both are CH.

[0060] In some embodiments of the present disclosure, the compound is represented by the above general formula (III) or a medicamentable salt thereof, wherein R 12c , R 12d and R 12e are the same or different and each independently represent a hydrogen atom, a halogen atom, or C 1-6 alkyl group, preferably R 12c , R 12d and R 12e are both hydrogen atoms.

[0061] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II) or a medicamentable salt thereof, wherein B is an 8-membered fused heterocyclyl group or a 7-8 membered bridged heterocyclyl group, and R 2 is C 1-6 alkyl group or halogen, n is 1 or 2, R 3 is halogen or -C(O)R 10 and R 10 is C 2-6 alkenyl group, 2-6 The alkenyl group is optionally halogen or C 1-6 is substituted with one or more substituents selected from alkyl groups, m is 1, and E is [ka] r is 0 or 1; V 1 is C(R a ) or N, V 2 and V 3 are the same or different and each independently C(R a ) or N, or V 2 is C(R bb ) and V 3 is C(R cc ) and R bb and R cceach together with the carbon atom to which it is linked forms a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group; R a is a hydrogen atom or C 1-6 It is an alkoxy group.

[0062] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (II) or a medicamentable salt thereof, wherein B is an 8-membered fused heterocyclyl group or a 7-8 membered bridged heterocyclyl group, and R 2 is C 1-6 is an alkyl group or a halogen, n is 1, and R 3 is halogen or -C(O)R 10 and R 10 is C 2-6 alkenyl group, 2-6 The alkenyl group is optionally halogen or C 1-6 is substituted with one or more substituents selected from alkyl groups, m is 1, and E is [ka] r is 0 or 1; V 1 , V 2 and V 3 are each independently C(R a ) and R a is a hydrogen atom or C 1-6 an alkoxy group, or V 1 and V 2 are both N, and V 3 is C(R a ) and R a is a hydrogen atom or C 1-6 It is an alkoxy group.

[0063] In some embodiments of the present disclosure, the compound is represented by the above general formula (II) or a medicamentable salt thereof, wherein B is a 7-8 membered bridged heterocyclyl group, and R 2 is C 1-6 is an alkyl group or a halogen, n is 1 or 2, R 3 HA-C(O)R 10 and R 10 is C 2-6alkenyl group, m is 1, and E is [ka] r is 0; V 1 , V 2 and V 3 Both are CH.

[0064] In some embodiments of the present disclosure, the compound is represented by the above general formula (III) or a medicamentous salt thereof, wherein: [ka] teeth [ka] and R 2 is C 1-6 is an alkyl group or a halogen, n is 1 or 2, R 12c , R 12d and R 12e are both hydrogen atoms, and E is [ka] Selected from V 1 , V 2 and V 3 are the same or different and each independently C(R a ) or N, R a is a hydrogen atom or C 1-6 It is an alkoxy group.

[0065] In some embodiments of the present disclosure, the compound is represented by the above general formula (III) or a medicamentous salt thereof, wherein: [ka] teeth [ka] and R 2 is C 1-6 is an alkyl group or a halogen, n is 1, and R12c , R 12d and R 12e are the same or different and each independently represent a hydrogen atom, a halogen atom, or C 1-6 E is selected from alkyl groups; [ka] Selected from V 1 , V 2 and V 3 are each independently C(R a ) and R a is a hydrogen atom or C 1-6 an alkoxy group, or V 1 and V 2 are both N, and V 3 is C(R a ) and R a is a hydrogen atom or C 1-6 It is an alkoxy group.

[0066] In some embodiments of the present disclosure, the compound is represented by the above general formula (III) or a medicamentous salt thereof, wherein: [ka] teeth [ka] and R 2 is C 1-6 is an alkyl group or a halogen, n is 1 or 2, R 12c , R 12d and R 12e are both hydrogen atoms, and E is [ka] Selected from V 1 , V 2 and V 3 Both are CH.

[0067] [Table 1-1]

[0068]

Table 1-2

[0069]

Table 1-3

[0070]

Table 1-4

[0071]

Table 1-5

[0072]

Table 1-6

[0073]

Table 1-7

[0074]

Table 1-8

[0075]

Table 1-9

[0076]

Table 1-10

[0077]

Table 1-11

[0078] [Table 1-12]

[0079] [Table 1-13]

[0080] Another aspect of the present disclosure relates to a compound represented by general formula (IIIa) or a salt thereof: [ka] Among them, E, ring B, R 2 , L 2 , V 1 , V 2 , V 3 and n are as defined in general formula (III).

[0081] In some embodiments of the present disclosure, the compound is represented by the above general formula (IIIa) or a salt thereof, wherein V 1 , V 2 and V 3 are the same or different and each independently C(R a ) or N, R a is as defined in general formula (I).

[0082] [Table 2-1]

[0083] [Table 2-2]

[0084] [Table 2-3]

[0085] [Table 2-4]

[0086]

Table 2-5

[0087]

Table 2-6

[0088]

Table 2-7

[0089]

Table 2-8

[0090]

Table 2-9

[0091]

Table 2-10

[0092]

Table 2-11

[0093]

Table 2-12

[0094]

Table 2-13

[0095]

Table 2-14

[0096] [Table 2-15]

[0097] [Table 2-16]

[0098] [Table 2-17]

[0099] [Table 2-18]

[0100] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (II) or a medicamentable salt thereof, comprising: [ka] The method includes a step of subjecting a compound represented by general formula (IIa) or a salt thereof to a nucleophilic substitution reaction with a compound represented by general formula (IIb) or a salt thereof to obtain a compound represented by general formula (II) or a medicamentable salt thereof, Among them, R is C 1-6 is an alkyl group, preferably R is a methyl group; E, ring B, R 2 , R 3 , V 1 , V 2 , V 3 , r, m and n are as defined in general formula (II).

[0101] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III) or a medicamentable salt thereof, comprising: [ka] The method includes a step of subjecting a compound represented by general formula (IIIa) or a salt thereof to a condensation reaction with a compound represented by general formula (IIIb) or a salt thereof to obtain a compound represented by general formula (III) or a medicamentable salt thereof, Among them, X L is a halogen, preferably X L is chlorine, E, ring B, R 2 , L 2 , V 1 , V 2 , V 3 , R 12c , R 12d , R 12e and n are as defined in general formula (III).

[0102] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by general formula (I), general formula (II), general formula (III) and Table A or a medicamentable salt thereof, and one or more pharma- ceutically acceptable vectors, diluents or excipients.

[0103] The present disclosure further relates to the use of a compound represented by general formula (I), general formula (II), general formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition containing same, in the preparation of a type I receptor tyrosine kinase inhibitor.

[0104] The present disclosure further relates to the use of a compound represented by general formula (I), general formula (II), general formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, in the preparation of a HER2 inhibitor.

[0105] The present disclosure further relates to the use of a compound represented by general formula (I), general formula (II), general formula (III) and Table A, or a medicament salt thereof, or a pharmaceutical composition containing same, in the preparation of a medicament for inhibiting HER2.

[0106] The present disclosure further relates to the use of a compound of general formula (I), general formula (II), general formula (III) and Table A, or a medicament salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for treating and / or preventing a HER2-mediated disease or condition.

[0107] The present disclosure further relates to the use of a compound of general formula (I), general formula (II), general formula (III) and Table A, or a medicament salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for treating and / or preventing a disease or condition by inhibiting HER2.

[0108] The present disclosure further relates to the use of a compound of general formula (I), general formula (II), general formula (III) or as set forth in Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing cancer, including brain cancer, breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, cervical cancer, fallopian tube cancer, endometrial cancer, prostate cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, esophageal cancer, liver cancer, skin cancer, mesothelioma, bladder cancer, and the like. Preferably, the cancer is selected from bladder cancer, renal cell carcinoma, renal pelvis cancer, ureter cancer, small intestine cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, vaginal cancer, vulvar cancer, leukemia, adrenal cancer, urethral cancer, penile cancer, testicular cancer, bone cancer, osteosarcoma, myeloma, soft tissue sarcoma, pituitary adenoma, brain stem glioma, spinal tumor and lymphoma, more preferably, the cancer is selected from breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer and ovarian cancer, and even more preferably, the lung cancer is non-small cell lung cancer.

[0109] The present disclosure further relates to a method of inhibiting HER2, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same.

[0110] The present disclosure further relates to a method for treating and / or preventing a disease or condition by inhibiting HER2, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same.

[0111] The present disclosure further relates to a method for treating and / or preventing a HER2-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same.

[0112] 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 represented by general formula (I), general formula (II), general formula (III) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising same, wherein the cancer is brain cancer, breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, cervical cancer, fallopian tube cancer, endometrial cancer, prostate cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, esophageal cancer, liver cancer, Preferably, the cancer is selected from skin cancer, mesothelioma, bladder cancer, renal cell cancer, renal pelvis cancer, ureter cancer, small intestine cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, vaginal cancer, vulvar cancer, leukemia, adrenal cancer, urethral cancer, penile cancer, testicular cancer, bone cancer, osteosarcoma, myeloma, soft tissue sarcoma, pituitary adenoma, brain stem glioma, spinal tumor and lymphoma, more preferably, the cancer is selected from breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer and ovarian cancer, and even more preferably, the lung cancer is non-small cell lung cancer.

[0113] The present disclosure further relates to a compound of formula (I), formula (II), formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, for use as a medicament.

[0114] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition containing same, for use as a HER2 inhibitor.

[0115] The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, for inhibiting HER2.

[0116] The present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) and Table A, or medicamentable salts thereof, or pharmaceutical compositions comprising same, for treating and / or preventing a disease or condition by inhibiting HER2.

[0117] The present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III) and Table A, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, for treating and / or preventing a HER2-mediated disease or condition.

[0118] The present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III) and Table A or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing cancer, including brain cancer, breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, cervical cancer, fallopian tube cancer, endometrial cancer, prostate cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, esophageal cancer, liver cancer, skin cancer, mesothelioma, bladder cancer, renal cell carcinoma, bladder cancer, and ovarian cancer. Preferably, the cancer is selected from cancer of the renal pelvis, cancer of the ureter, cancer of the small intestine, cancer of the pancreas, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the vagina, cancer of the vulva, leukemia, cancer of the adrenal gland, cancer of the urethra, cancer of the penis, cancer of the testis, cancer of the testis, bone cancer, osteosarcoma, myeloma, soft tissue sarcoma, pituitary adenoma, brain stem glioma, spinal tumor and lymphoma, more preferably, the cancer is selected from cancer of the breast, stomach, lung, colorectal, pancreatic, prostate, bladder and ovarian, and even more preferably, the lung cancer is non-small cell lung cancer.

[0119] The diseases or conditions described in this disclosure are those diseases or conditions that are treated and / or prevented by inhibiting HER2.

[0120] In some embodiments of the disclosure, the disease or condition is cancer, and the cancer is selected from the group consisting of brain cancer, breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, cervical cancer, fallopian tube cancer, endometrial cancer, prostate cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, esophageal cancer, liver cancer, skin cancer, mesothelioma, bladder cancer, renal cell carcinoma, renal pelvis cancer, ureter cancer, small intestine cancer, pancreatic cancer, thyroid cancer, Preferably, the cancer is selected from parathyroid cancer, vaginal cancer, vulvar cancer, leukemia, adrenal cancer, urethral cancer, penile cancer, testicular cancer, bone cancer, osteosarcoma, myeloma, soft tissue sarcoma, pituitary adenoma, brain stem glioma, spinal tumor and lymphoma, more preferably, the cancer is selected from breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer and ovarian cancer, even more preferably, the lung cancer is non-small cell lung cancer.

[0121] In some embodiments of the present disclosure, the HER2 is a mutant HER2, preferably a HER2 with a mutation in exon 20. Of these, the mutation in exon 20 is preferably an insertion mutation of four amino acids YVMA (p.A775_G776insYVMA).

[0122] As a general guideline, the active compounds of the present disclosure are preferably in unit dose form or in a form that can be self-administered by the patient as a single agent. The unit dose of the compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled drug solution, drug powder, granule, topical tablet, suppository, reconstituted powder or liquid formulation. A suitable unit dose may be 0.1 to 1000 mg.

[0123] The pharmaceutical composition according to the present disclosure may contain one or more additives in addition to the active compound, and the additives are selected from components such as fillers (diluents), binders, wetting agents, disintegrants, or excipients. The composition may contain 0.1 to 99% by weight of the active compound, depending on the method of administration.

[0124] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, tablets for external application, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavorings, coloring agents, and preservatives, so as to provide a visually and palatably pleasing pharmaceutical preparation. Tablets contain the active ingredient and non-toxic medicament-acceptable excipients suitable for mixing in the preparation of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a long period of time.

[0125] Oral formulations may be provided by soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or with a water-soluble vector or oil-based solvent.

[0126] Aqueous suspensions contain the active substances and mixing excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending, dispersing 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.

[0127] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil.Oil suspensions can also contain thickening agents.To provide a palatable preparation, the above-mentioned sweeteners and flavorings can also be added.These compositions can be preserved by adding antioxidants.

[0128] The pharmaceutical compositions according to the present disclosure may 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 contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0129] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injectable solution or microemulsion can be injected into the patient's bloodstream by local injection of large amounts. Alternatively, it is preferable to administer the solutions and microemulsions in a manner that allows a constant cyclic concentration of the compounds of the present disclosure to be maintained. A continuous intravenous administration device can be used to maintain such a constant concentration. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

[0130] The pharmaceutical composition according to the present disclosure may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be prepared using a suitable dispersing or wetting agent and suspending agent according to known techniques. The sterile injectable preparation may be a sterile injectable solution or suspension prepared in a non-toxic diluent or solvent that is parenterally acceptable. Sterile fixed oils may also be conveniently used as a solvent or suspension medium. Any fixed oil for formulation may be used for this purpose. Fatty acids may also be used to prepare an injectable.

[0131] The compounds of the present disclosure may 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 room temperature but liquid in the rectum, and therefore melts in the rectum to release the drug.

[0132] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the activity of the specific compound used, the patient's age, the patient's weight, the patient's physical condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the composition of the drug, the severity of the disease, etc., and the optimal treatment method, such as the treatment mode, the daily dosage of the compound or the type of medicinal salt, can be verified according to conventional treatment plans.

[0133] Explanation of terms Unless specifically stated to the contrary, terms used in the specification and claims have the following meanings.

[0134] The term “alkyl group” refers to a saturated, straight or branched chain aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl group) is preferred, and alkyl groups having 1 to 6 carbon atoms (i.e., C 1-6Non-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, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43-methylhexyl, 44-methylhexyl, 45-methylhex Examples of the branched chain isomers include 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 and, when substituted, it may be substituted at any available attachment point, and the substituents are preferably one or more selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0135] The term "alkenyl group" refers to an alkyl group, the molecule of which contains at least one carbon-carbon double bond, where alkyl is as defined above, and has from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 The alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl groups are preferred. Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available point of attachment, and the substituents are preferably one or more selected from D atoms, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0136] The term "alkynyl group" refers to an alkyl group, the molecule of which contains at least one carbon-carbon triple bond, where alkyl is as defined above, and has from 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 The alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl groups are preferred. Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. The alkynyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available point of attachment, and the substituents are preferably one or more selected from D atoms, alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0137] The term "alkoxy group" refers to -O-(alkyl group), where alkyl group is defined above. Non-limiting examples include methoxy, ethoxy, propoxy and butoxy groups. The alkoxy group may be substituted or unsubstituted, and if substituted, it may be substituted at any available attachment point, and the substituent is preferably one or more selected from D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group.

[0138] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic all-carbocyclic ring (i.e., a monocyclic cycloalkyl group) or polycyclic ring system (i.e., a polycyclic cycloalkyl group) having 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 cycloalkyl group). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group), and most preferably a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered cycloalkyl group).

[0139] The monocyclic cycloalkyl groups include, by way of non-limiting example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups.

[0140] The polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups.

[0141] The term "spirocycloalkyl group" refers to a polycyclic ring system in which the rings share one carbon atom (referred to as a spiro atom), which may contain one or more double bonds within the ring, or which may contain one or more heteroatoms within the ring selected from nitrogen, oxygen and sulfur (which may optionally be oxidized, i.e., to form nitrogen oxides, and which may optionally be substituted with an oxo group, i.e., to form sulfoxides or sulfones, but which do not include -OO-, -OS- or -SS-), provided that at least one all-carbocyclic ring is included and the point of attachment is at the all-carbocyclic ring, which has from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered spirocycloalkyl group). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spirocycloalkyl group), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7- to 10-membered spirocycloalkyl group). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (e.g., a bisspirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bisspirocycloalkyl group, more preferably 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 monospirocycloalkyl group. Non-limiting examples are: The connection point may be located anywhere. [ka] [ka] etc.

[0142] The term "fused cycloalkyl group" refers to a polycyclic ring system in which the rings share two adjacent carbon atoms, such as a monocyclic cycloalkyl group fused to one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused to one or more heterocyclyl groups, aryl groups, or heteroaryl groups, in which the point of attachment is on the monocyclic cycloalkyl group, which may contain one or more double bonds in the ring, and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20 membered fused cycloalkyl group). The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., a 6-14 membered fused cycloalkyl group), and more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e., a 7-10 membered fused cycloalkyl group). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (e.g., tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples are: The connection point may be located anywhere. [ka] [ka] etc.

[0143] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic ring system in which the rings share two carbon atoms that are not directly connected to each other, and may contain one or more double bonds in the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., a 5-20 membered bridged cycloalkyl group). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6-14 membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7-10 membered bridged cycloalkyl group). The bridged cycloalkyl group includes a bicyclic bridged cycloalkyl group and a polycyclic bridged cycloalkyl group (e.g., a tricyclic bridged cycloalkyl group, a tetracyclic bridged cycloalkyl group, etc.), and is preferably a bicyclic bridged cycloalkyl group or a tricyclic bridged cycloalkyl group. Non-limiting examples are: The connection point may be located anywhere. [ka] Includes.

[0144] The cycloalkyl group may be substituted or unsubstituted and, when substituted, it may be substituted at any available attachment point, and the substituents are preferably one or more selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0145] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl group) or polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl group) containing at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur within the ring (wherein the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS- or -SS-) and having 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 group). The heterocyclyl group is preferably a heterocyclyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclyl group), for example, a 4- to 12-membered heterocyclyl group containing at least one nitrogen atom, more preferably a heterocyclyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclyl group), even more preferably a heterocyclyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclyl group), and most preferably a heterocyclyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclyl group).

[0146] The monocyclic heterocyclyl groups include, by way of non-limiting example, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl groups.

[0147] The polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups and bridged heterocyclyl groups.

[0148] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclic ring system in which the rings share one atom (referred to as a spiro atom), optionally containing one or more double bonds within the ring, and containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur within the ring (wherein the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS- or -SS-), provided that at least one monocyclic heterocyclyl group is included and the point of attachment is at the monocyclic heterocyclyl group having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered spiroheterocyclyl group). The above spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (ie, a 6- to 14-membered spiroheterocyclyl group), and more preferably a spiroheterocyclyl group having 7 to 11 ring atoms (ie, a 7- to 11-membered spiroheterocyclyl group). The spiroheterocyclyl group includes monospiroheterocyclyl groups and polyspiroheterocyclyl groups (such as bisspiroheterocyclyl groups), preferably monospiroheterocyclyl groups or bisspiroheterocyclyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiroheterocyclyl groups. Non-limiting examples are: [ka] etc.

[0149] The term "fused heterocyclyl group" refers to a polycyclic heterocyclic ring system in which the rings share two adjacent atoms, optionally containing one or more double bonds within the ring, and containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur within the ring, wherein the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group, i.e., to form a sulfoxide or sulfone, but not limited to -OO-, -OS- or -SS-. which are monocyclic heterocyclyl groups fused to one or more monocyclic heterocyclyl groups, or monocyclic heterocyclyl groups fused to one or more cycloalkyl groups, aryl groups, or heteroaryl groups, where the point of attachment is on the monocyclic heterocyclyl group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5-20 membered fused heterocyclyl group). The above-mentioned fused heterocyclyl group is preferably a fused heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclyl group), more preferably a fused heterocyclyl group having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused heterocyclyl group), and even more preferably a fused heterocyclyl group having 8 ring atoms (i.e., an 8-membered fused heterocyclyl group). The fused heterocyclyl groups include bicyclic and polycyclic fused heterocyclyl groups (e.g., tricyclic fused heterocyclyl groups, tetracyclic fused heterocyclyl groups, etc.), preferably bicyclic fused heterocyclyl groups or tricyclic fused heterocyclyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples are: [ka] etc.

[0150] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclic ring system in which the rings share two atoms that are not directly linked, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur within the ring (which nitrogen may optionally be oxidized, i.e., to form a nitrogen oxide, and which sulfur may optionally be substituted with an oxo group, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS- or -SS-) and which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered bridged heterocyclyl group). The bridged heterocyclyl group is preferably a bridged heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl group), more preferably a bridged heterocyclyl group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclyl group), and even more preferably a bridged heterocyclyl group having 7 to 8 ring atoms (i.e., a 7- to 8-membered bridged heterocyclyl group). Depending on the number of rings constituting the heterocyclyl group, it can be divided into a bicyclic bridged heterocyclyl group and a polycyclic bridged heterocyclyl group (e.g., a tricyclic bridged heterocyclyl group, a tetracyclic bridged heterocyclyl group, etc.), and is preferably a bicyclic bridged heterocyclyl group or a tricyclic bridged heterocyclyl group. Non-limiting examples are: [ka] etc.

[0151] The heterocyclyl group may be substituted or unsubstituted and, when substituted, it may be substituted at any available attachment point, and the substituents are preferably one or more selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0152] The term "aryl group" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl group) or a polycyclic aromatic ring system (i.e., a polycyclic aryl group) having a conjugated π-electron system and having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 6-14-membered aryl group). The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6-10-membered aryl group). The monocyclic aryl group is, for example, a phenyl group. The polycyclic aryl group includes, as non-limiting examples, a naphthyl group, an anthryl group, a phenanthryl group, and the like. The polycyclic aryl groups further include those in which a phenyl group is fused to one or more of a heterocyclyl group or a cycloalkyl group, or a naphthyl group is fused to one or more of a heterocyclyl group or a cycloalkyl group, where the point of attachment is at the phenyl or naphthyl group, and in this case the number of ring atoms still refers to the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include: [ka] etc.

[0153] The aryl group may be substituted or unsubstituted and, when substituted, it may be substituted at any available attachment point, and the substituents are preferably one or more selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, oxo groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0154] The term "heteroaryl group" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl group) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl group) having a conjugated π-electron system and containing at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur within the ring (which nitrogen may optionally be oxidized, i.e., to form a nitrogen oxide, and which sulfur may optionally be substituted with an oxo group, i.e., to form a sulfoxide or sulfone, but does not include -OO-, -OS-, or -SS-) and which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5-14 membered heteroaryl group). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), more preferably a monocyclic heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered monocyclic heteroaryl group) or a bicyclic heteroaryl group having 9 to 10 ring atoms (i.e., a 9- to 10-membered bicyclic heteroaryl group), and most preferably a 5- or 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring or a 9- to 10-membered bicyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur in the ring.

[0155] Examples of the monocyclic heteroaryl group include, but are not limited to, a furanyl group, a thienyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiadiazolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a furazanyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridonyl group, an N-alkylpyridone (e.g., [ka] etc.), pyrazinyl group, pyridazinyl group, etc.

[0156] The polycyclic heteroaryl groups include, as non-limiting examples, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl groups further include monocyclic heteroaryl groups fused with one or more aryl groups, where the connection point is on the aromatic ring, and in this case the number of ring atoms still indicates the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl groups further include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclyl groups, where the connection point is on the monocyclic heteroaromatic ring, and in this case the number of ring atoms still indicates the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples are: [ka] etc.

[0157] The heteroaryl group may be substituted or unsubstituted and, when substituted, it may be substituted at any available point of attachment, and the substituents are preferably one or more selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0158] The term "amino-protecting group" refers to a group that is easily removed and introduced to an amino group so that the amino group is not altered when other parts of the molecule are reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, and the like.

[0159] The term "hydroxy protecting group" refers to a labile group that is introduced into a hydroxy group to react with another functional group of a compound in order to block or protect the hydroxy group. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

[0160] The term "cycloalkyloxy" refers to a cycloalkyl-O- group, in which the cycloalkyl group is as defined above.

[0161] The term "heterocyclyloxy" refers to a heterocyclyl-O- group, in which the heterocyclyl group is as defined above.

[0162] The term "aryloxy group" refers to an aryl-O- group, in which the aryl group is defined above.

[0163] The term "heteroaryloxy group" refers to a heteroaryl-O- group, in which the heteroaryl group is as defined above.

[0164] The term "alkylthio group" refers to an alkyl-S- group, in which the alkyl group is as defined above.

[0165] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0166] The term "aminoalkyl group" refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is as defined above.

[0167] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0168] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above.

[0169] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0170] The term "hydroxy group" refers to --OH.

[0171] The term "mercapto" refers to -SH.

[0172] The term "amino group" refers to -NH2.

[0173] The term "cyano" refers to -CN.

[0174] The term "nitro group" refers to --NO.sub.2.

[0175] The term "oxo" or "oxo group" refers to "=O".

[0176] The term "carbonyl group" refers to C=O.

[0177] The term "carboxy" refers to -C(O)OH.

[0178] The compounds of the present disclosure may have specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but differ in the spatial arrangement of atoms. 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 (e.g., racemates, mixtures of diastereomers). Substituents in the compounds of the present disclosure may have other asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of the present disclosure. 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. Single isomers of certain compounds of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxy group), by forming a diastereomeric salt with an appropriate optically active acid or base, and then performing diastereomeric resolution by conventional methods known in the art to obtain the pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0179] In the chemical structures of the compounds described in this disclosure, [ka] indicates that the configuration is not specified, i.e., if chiral isomers are present in the chemical structure, [ka] The bond [ka] or [ka] Any carbon-carbon double bond may have both the Z and E configurations, even if only one configuration is named.

[0180] The compounds of the present disclosure may 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 a structural isomer that exists in equilibrium and that isomeric form is easily converted from one to the other. It includes all possible tautomers, i.e., exists in the form of a single isomer or in the form of a mixture of the above tautomers in any ratio. Non-limiting examples include keto-enol, imine-enamine, lactam-lactim, etc. An example of lactam-lactim equilibrium is as follows: [ka]

[0181] For example, reference to a pyrazolyl group should be understood to include any one or a mixture of the two tautomers of the following two structures: [ka]

[0182] All tautomeric forms are within the scope of the disclosure, and the naming of a compound does not exclude any tautomeric form.

[0183] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, with deuterium being preferred.

[0184] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxicity and side effects, increasing drug stability, improving therapeutic efficacy, and extending the biological half-life of drugs.All isotopic variations of the compounds according to the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.Each available hydrogen atom connected to a carbon atom may be independently replaced with a deuterium atom, of which the deuterium replacement may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced with at least one deuterium.

[0185] When a position of a compound according to the present disclosure is specifically designated as "deuterium" or "D," it should be understood that the position has an abundance of deuterium at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium is incorporated), hi some embodiments, each designated deuterium atom has an abundance of deuterium at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium is incorporated).In some embodiments, each designated deuterium atom has an abundance of deuterium at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium is incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium is incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium is incorporated). In some embodiments, each designated deuterium atom has an abundance of deuterium at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium is incorporated).

[0186] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "C optionally substituted with halogen or cyano groups" 1-6 By "alkyl group" is meant that a halogen or cyano group may or may not be present, and this description includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0187] "Substituted" or "substituted" refers to the replacement of one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group, with a corresponding number of substituents, independently of one another. A person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0188] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their medicament salts with other chemical components, and other components such as pharmaceutical acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredient to further exert biological activity.

[0189] "Pharmaceutical salt" refers to a salt of a compound according to the present disclosure, which may be selected from inorganic salts or organic salts. Such salts have the desired biological activity while being safe and effective when used in a mammalian body. They may be prepared separately during the final isolation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. In general, bases for forming pharmaceutical acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. In general, acids for forming pharmaceutical acceptable salts include inorganic acids and organic acids.

[0190] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a dose of the drug or agent sufficient to obtain or at least partially obtain a desired effect. The therapeutically effective amount is determined by the person concerned and depends on the age and general condition of the recipient, and also on the specific active agent, but the appropriate therapeutically effective amount for an individual can be determined by one skilled in the art through routine testing.

[0191] As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly indicates otherwise.

[0192] The term "about" when applied to parameters such as pH, concentration, temperature, etc., indicates that the parameter in question may be varied within ±10%, and in some cases more preferably ±5%. As will be appreciated by those skilled in the art, when a parameter is not critical, generally numbers are given merely for illustration, not limitation.

[0193] Methods for synthesizing compounds according to the present disclosure In order to achieve the objectives of the present disclosure, the present disclosure adopts the following technical solutions:

[0194] Technical proposal 1 A method for preparing a compound of general formula (II) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method comprises the steps of: subjecting a compound represented by general formula (IIa) or a salt thereof to a nucleophilic substitution reaction with a compound represented by general formula (IIb) or a salt thereof under basic conditions to obtain a compound represented by general formula (II) or a medicamentable salt thereof; Among them, R is C 1-6 is an alkyl group, preferably R is a methyl group; E, ring B, R 2 , R 3 , V 1 , V 2 , V 3 , r, m and n are as defined in general formula (II).

[0195] Technical proposal 2 A process for preparing a compound of general formula (III) or a medicamentable salt thereof according to the present disclosure, comprising the steps of: [ka] The method includes a step of subjecting a compound represented by general formula (IIIa) or a salt thereof and a compound represented by general formula (IIIb) or a salt thereof to a condensation reaction under basic conditions to obtain a compound represented by general formula (III) or a medicamentable salt thereof, Among them, X L is a halogen, preferably X L is chlorine, E, ring B, R 2 , L 2 , V 1 , V 2 , V 3 , R 12c , R 12d , R 12e and n are as defined in general formula (III).

[0196] In the above synthesis scheme, the base includes organic base and inorganic base, the organic base includes but is not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, the inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, anhydrous potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide, preferably, the base described in Technical Scheme 1 is potassium tert-butoxide, and the base described in Technical Scheme 2 is N,N-diisopropylethylamine.

[0197] The above synthesis scheme is preferably carried out in a solvent, and the solvents used include, but are not limited to, ethylene glycol dimethyl ether, acetic 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, glacial acetic acid, and mixtures thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0198] The present disclosure will be further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure. EXAMPLES

[0199] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are within the range of 10 -6The units are shown in ppm. NMR measurements were performed using a Bruker AVANCE-400 or Bruker AVANCE NEO 500M nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0200] For MS measurements, liquid chromatograph mass spectrometers Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used.

[0201] For high performance liquid chromatography (HPLC) analysis, high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 were used.

[0202] For chiral HPLC analysis, a high performance liquid chromatograph Agilent 1260 DAD was used.

[0203] For high-performance liquid preparative chromatography, preparative chromatographs Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 were used.

[0204] For chiral separation, a preparative chromatograph Shimadzu LC-20AP was used.

[0205] Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0206] As the silica gel plate for thin layer chromatography, Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate is used, the specification of the silica gel plate used for thin layer chromatography (TLC) is 0.15-0.2 mm, and the specification for separating and purifying the product by thin layer chromatography is 0.4-0.5 mm.

[0207] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the vector.

[0208] Kinase mean inhibition rate and IC 50 The values ​​were measured using a plate reader NovoStar (BMG, Germany).

[0209] Known starting materials according to the present disclosure may be synthesized by or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), Darui Chemical, and Yaoming Kangde.

[0210] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0211] An argon or nitrogen atmosphere refers to an argon or nitrogen balloon of approximately 1 L volume connected to the reaction flask.

[0212] Hydrogen atmosphere refers to a hydrogen balloon of approximately 1 L volume connected to the reaction flask.

[0213] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenation apparatus were used.

[0214] The hydrogenation reaction was generally carried out by repeating the process of evacuating and refilling with hydrogen three times.

[0215] A CEM Discover-S 908860 microwave reactor was used for microwave reactions.

[0216] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0217] In the examples, unless otherwise specified, the reaction temperature is room temperature, 20 to 30°C.

[0218] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvents used in the reaction, the eluent system of column chromatography used in purifying the compounds, and the developing solvent system of thin layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system, and the volume ratio of the solvents was adjusted according to the polarity of the compounds, and may be adjusted by adding a small amount of basic or acidic reagent such as triethylamine and acetic acid.

[0219] Example 1 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 1 [ka] [ka]

[0220] Step 1 Exo-3-(p-toluenesulfonyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 1b Tert-butyl exo-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate 1a (1g, 4.4mmol, Shanghai Shaoyuan), p-toluenesulfonyl chloride (1g, 5.24mmol), 4-dimethylaminopyridine (542mg, 4.4mmol) were dissolved in 20mL of dichloromethane, N,N-diisopropylethylamine (853mg, 6.6mmol) was added, and the reaction was carried out with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1b (1g, yield: 59.5%).

[0221] Step 2 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl acetate 1e 4-Chloroquinazoline-6-acetic acid ester 1c (200 mg, 898 μmol, prepared according to the method disclosed in the literature "Bioorganic & Medicinal Chemistry Letters, 2009, 19 (19): 5531-5538") was dissolved in isopropanol (5 mL), and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline 1d (216 mg, 898 μmol, prepared according to the method disclosed in the specification of the patent application "WO2021156180A1" on page 33, method 1) was added, and the mixture was reacted at 80 ° C. for 2 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 1e (200 mg, yield: 52.2%). MS m / z (ESI): 427.2 [M+1].

[0222] Step 3 endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 1f Compound 1e (200 mg, 469 μmol) was dissolved in N,N-dimethylformamide (15 mL), and compound 1b (197 mg, 516 μmol) and cesium carbonate (229 mg, 703 μmol) were added and reacted at 80° C. for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 1f (150 mg, yield: 53.8%). MS m / z (ESI): 594.2 [M+1].

[0223] Step 4 6-((endo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazolin-4-amine 2,2,2-trifluoroacetate 1g Compound 1f (100 mg, 168 μmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added at 0° C., and the mixture was reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, the title compound 1g (100 mg). The product was used in the next reaction without purification. MS m / z (ESI): 494.2 [M+1].

[0224] Step 5 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 1 The crude product, compound 1g (100mg, 168μmol), was dissolved in 5mL of dichloromethane, N,N-diisopropylethylamine (42mg, 329μmol) was added, and acryloyl chloride (18mg, 197μmol) was added in an ice bath, and the mixture was reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150mm, 5μm, mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 30%-45%, flow rate: 30mL / min), and the title compound 1 (15mg, yield: 16.6%) was obtained. MS m / z (ESI): 548.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 8.61 (s, 1H), 8.52 (d, 1H), 8.24 (s, 1H), 7.90 (d, 1H), 7.70 (s, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.44 (d, 1H), 7.08 (d, 1H), 6.93 (d, 1H), 6.83 (s, 1H), 6.58-6.53 (m, 1H), 6.41-6.37 (m, 1H), 5.74 (d, 1H), 4.90-4.88 (m, 1H), 4.83-4.81 (m, 1H), 4.44-4.42 (m, 1H), 2.42-2.40 (m, 1H), 2.37-2.31 (m, 3H), 2.29 (s, 3H), 2.28-2.26 (m, 2H), 2.09-2.02 (m, 2H).

[0225] Example 2 1-(endo-3-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 2 [ka] Using the synthetic route in Example 1, the raw material compound 1d in step 2 was replaced with 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (obtained by the method disclosed in Method 1 on page 34 of the specification of patent application "WO2021156178A1") to obtain the title compound 2 (10 mg, 11%). MS m / z (ESI): 561.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 8.68 (s, 1H), 8.00 (s, 1H), 7.90-7.87 (m, 2H), 7.54 (s, 1H), 7.42-7.35 (m, 5H), 7.11 (d, 1H), 6.89 (d, 1H), 6.56-6.51 (m, 1H), 6.42-6.39 (m, 1H), 5.74 (d, 1H), 4.83-4.78 (m, 2H), 4.39 (s, 1H), 3.87 (s, 3H), 2.38-2.36 (m, 1H), 2.34 (s, 3H), 2.30-2.27 (m, 3H), 2.24-2.08 (m, 4H).

[0226] Example 3 6-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidin-4-amine 3 [ka] [ka]

[0227] Step 1 N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6-(methylsulfonyl)pyrimido[5,4-d]pyrimidin-4-amine 3b N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidin-4-amine 3a (1 g, 3.32 mmol, obtained by preparation according to the method disclosed in compound J on page 40 of the specification in patent application "WO2021156178A1") was dissolved in dichloromethane (25 mL), metachloroperbenzoic acid (482 mg, 2.8 mmol) was added, and the reaction was allowed to proceed with stirring for 0.5 hours. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain the crude product title compound 3b (650 mg). The product was used directly in the next reaction without purification. MS m / z (ESI): 462.1 [M+1].

[0228] Step 2 6-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidin-4-amine 3 The crude product, compound 3b (35 mg, 75.8 μmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (15 mg, 94 μmol, Yakuhin Kotoku) was dissolved in dichloromethane (2 mL), potassium tert-butoxide (16 mg, 142 μmol) was added, and the mixture was reacted at 60° C. for 1 hour with stirring. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure. The residue was purified by high-performance liquid preparative 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 blend ratio: acetonitrile 30%-45%, flow rate: 30 mL / min), title compound 3 (5.3 mg, yield: 10.4%) was obtained. MS m / z (ESI): 541.1 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 9.28 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.69 (d, 1H), 7.38-7.34 (m, 2H), 7.10 (d, 1H), 6.95 (d, 1H), 5.42-5.35 (m, 1H), 4.37 (d, 1H), 4.27 (d, 1H), 3.88 (s, 3H), 3.37-3.22 (m, 3H), 3.05 (s, 1H), 2.39 (s, 3H), 2.26-2.19 (m, 2H), 2.08-2.00 (m, 3H), 1.95 (s, 1H).

[0229] Example 4 1-(endo-3-((7-methoxy-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 4 [ka] [ka]

[0230] Step 1 tert-Butyl endo-3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 4b 4-Chloro-7-methoxyquinazolin-6-ol 4a (140 mg, 664 μmol, Jiangsu Aikang), compound 1a (181 mg, 797 μmol), triphenylphosphine (262 mg, 997 μmol) were dissolved in tetrahydrofuran (5 mL), diisopropyl azodicarboxylate (269 mg, 1.33 mmol, Shanghai Shaoyuan) was added dropwise in an ice bath, and the mixture was allowed to warm to room temperature and react for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to obtain the title compound 4b (270 mg, yield: 96%). MS m / z (ESI): 420.2 [M+1].

[0231] Step 2 6-((endo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-7-methoxy-N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)quinazolin-4-amine hydrochloride 4c Compound 4b (60 mg, 142 μmol) and 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (36.2 mg, 142 μmol) were dissolved in isopropanol (5 mL), and 2 drops of 4 M hydrogen chloride in isopropanol were added. The mixture was reacted at 80° C. for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 4c (90 mg). This was used in the next reaction without purification. MS m / z (ESI): 537.2 [M+1].

[0232] Step 3 1-(endo-3-((7-methoxy-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 4 The crude product, compound 4c (76 mg, 140 μmol), was dissolved in 5 mL of dichloromethane, N,N-diisopropylethylamine (55 mg, 424 μmol) was added, and acryloyl chloride (15 mg, 169 μmol) was added in an ice bath, and the mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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 blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min), and the title compound 4 (10 mg, yield: 11.9%) was obtained. MS m / z (ESI): 591.2 [M+1]. 1 H NMR (500 MHz, CDCl3):δ 8.64 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.50 (s, 1H), 7.41-7.31 (m, 4H), 7.09 (dd, 1H), 6.87 (d, 1H), 6.53 (dd, 1H), 6.39 (d, 1H), 5.74-5.68 (m, 1H), 4.82 (d, 1H), 4.78 (d, 1H), 4.38 (d, 1H),4.01 (s, 3H), 3.87 (s, 3H), 2.45 (d, 1H), 2.41-2.32 (m, 1H), 2.29 (s, 3H), 2.27-2.20 (m, 2H), 2.16 (d, 1H), 2.12 (d, 1H), 2.07-2.01 (m, 3H).

[0233] Example 5 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one5 [ka] Following the synthesis route in Example 4, the starting compound in Step 2, 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline, was replaced with compound 1d to obtain the title compound 5 (20 mg, 18.3%). MS m / z (ESI): 578.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H), 8.51 (d, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.68 (s, 1H), 7.65 (d, 1H), 7.44 (s, 1H), 7.30 (s, 1H), 7.08 (d, 1H), 6.95-6.89 (m, 1H), 6.86 (s, 1H), 6.56 (dd, 1H), 6.39 (d, 1H), 5.72 (d, 1H), 4.89 (s, 1H), 4.80 (d, 1H), 4.42 (s, 1H), 4.03 (s, 3H), 2.49 (d, 1H), 2.39 (t, 1H), 2.30 (d, 1H), 2.25 (d, 1H), 2.23 (s, 3H), 2.21-2.11 (m, 1H), 2.06 (d, 3H).

[0234] Example 6 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 6 [ka] [ka]

[0235] Step 1 exo-3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 6b Compound 4a (100mg, 474μmol, Jiangsu Aikang), endo-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl 6a (130mg, 570μmol, Shanghai Bide), triphenylphosphine (186mg, 712μmol) were dissolved in tetrahydrofuran (5mL), diisopropyl azodicarboxylate (192mg, 949μmol) was added dropwise in an ice bath, and the temperature was allowed to return to room temperature and react for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to obtain the title compound 6b (180mg, yield: 90.3%). MS m / z (ESI): 420.2 [M+1].

[0236] Step 2 6-((exo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-7-methoxyquinazolin-4-amine hydrochloride 6c Compound 6b (180 mg, 428 μmol) and compound 1d (103 mg, 428 μmol) were dissolved in isopropanol (3 mL), 0.1 mL of a 4 M hydrogen chloride solution in isopropanol was added, and the mixture was reacted at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 6c (220 mg), which was used in the next reaction without purification. MS m / z (ESI): 524.2 [M+1].

[0237] Step 3 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 6 The crude product, compound 6c (220 mg, 393 μmol), was dissolved in 5 mL of dichloromethane, N,N-diisopropylethylamine (152 mg, 1.2 mmol) was added, and acryloyl chloride (45.6 mg, 504 μmol) was added in an ice bath, and the mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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 blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min), and the title compound 6 (100 mg, yield: 41.2%) was obtained. MS m / z (ESI): 578.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 8.70 (s, 1H), 8.52 (d, 1H), 8.25 (s, 1H), 7.85 (s, 1H), 7.67 (d, 1H), 7.64-7.58 (m, 1H), 7.51 (s, 1H), 7.29 (s, 1H), 7.09 (d, 1H), 6.93 (dd, 1H), 6.82 (d, 1H), 6.55 (dd, 1H), 6.47-6.40 (m, 1H), 5.79-5.73 (m, 1H), 4.86 (d, 1H), 4.80 (dt, 1H), 4.47 (d, 1H), 4.00 (s, 3H), 2.31 (dd, 1H), 2.23 (s, 4H), 2.12 (dd, 1H), 2.02 (td, 2H), 1.91-1.78 (m, 2H), 1.72 (td, 1H).

[0238] Example 7 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 7 [ka] [ka]

[0239] Step 1 tert-Butyl endo-3-((4-chloroquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 7b 4-Chloroquinazolin-6-ol 7a (20 mg, 110 μmol, prepared by the method disclosed in the literature "European Journal of Medicinal Chemistry, 2018, vol. 147, p. 130-149"), compound 1a (30 mg, 133 μmol), and triphenylphosphine (58 mg, 221 μmol) were dissolved in tetrahydrofuran (5 mL), diisopropyl azodicarboxylate (34 mg, 166 μmol) was added dropwise in an ice bath, and the mixture was allowed to naturally return to room temperature and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to obtain the title compound 7b (40 mg, yield: 92.6%). MS m / z (ESI): 390.2 [M+1].

[0240] Step 2 tert-Butyl endo-3-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 7c Compound 7b (40 mg, 102 μmol) was dissolved in isopropanol (2 mL), and 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline (25 mg, 102 μmol, prepared by the method disclosed in example 1 on page 95 of the specification of patent application "WO2020057511A1") was added thereto, and the reaction was carried out at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, the title compound 7c (60 mg). The product was used in the next reaction as it was without purification. MS m / z (ESI): 595.2 [M+1].

[0241] Step 3 6-((endo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)quinazolin-4-amine 2,2,2-trifluoroacetate 7d The crude product, compound 7c (60 mg, 101 μmol), was dissolved in 1 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added at 0° C. The mixture was reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 7d (62 mg). The product was used in the next reaction without purification. MS m / z (ESI): 495.2 [M+1].

[0242] Step 4 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 7 The crude product, compound 7d (62 mg, 101 μmol), was dissolved in 2 mL of dichloromethane, N,N-diisopropylethylamine (39 mg, 303 μmol) was added, and acryloyl chloride (14 mg, 152 μmol) was added in an ice bath, and the mixture was reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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 blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min), and the title compound 7 was obtained. MS m / z (ESI): 549.2 [M+1].

[0243] Example 8 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 8 [ka] Following the synthesis route in Example 7, the starting compound 1a in step 1 was replaced with compound 6a to give the title compound 8 (30 mg, yield: 27%). MS m / z (ESI): 549.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 9.22 (s, 1H), 8.73 (s, 1H), 8.35 (s, 1H), 7.91 (d, 1H), 7.74 (s, 1H), 7.69 (d, 1H), 7.62 (s, 1H), 7.49 (d, 1H), 7.37 (s, 1H), 7.16 (d, 1H), 6.92 (s, 1H), 6.56 (dd, 1H), 6.46 (d, 1H), 5.78 (d, 1H), 4.93-4.86 (m, 2H), 4.50 (d, 1H), 2.35-2.31 (m, 1H), 2.28 (s, 3H), 2.26-2.23 (m, 1H), 2.19 (m, 1H), 2.09-2.04 (m, 1H), 2.01-1.90 (m, 2H), 1.85-1.77 (m, 2H).

[0244] Example 9 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 9 [ka] Following the synthesis route in Example 1, the starting compound 1a in step 1 was replaced with compound 6a to give the title compound 9 (100 mg, yield: 44%). MS m / z (ESI): 548.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 8.52 (d, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 7.89 (d, 1H), 7.65 (d, 1H), 7.59 (dd, 2H), 7.46 (dd, 1H), 7.07 (d, 1H), 6.93 (dd, 1H), 6.78 (d, 1H), 6.55 (dd, 1H), 6.47-6.40 (m, 1H), 5.79-5.73 (m, 1H), 4.89 (dt, 2H), 4.47 (d, 1H), 2.36-2.28 (m, 1H), 2.21 (s, 4H), 2.14 (q, 1H), 2.05-1.92 (m, 2H), 1.91-1.83 (m, 1H), 1.82-1.75 (m, 2H).

[0245] Example 10 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 10 [ka] [ka]

[0246] Step 1 tert-Butyl endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 10a Compound 7b (1.2 g, 3 mmol) was dissolved in isopropanol (5 mL), and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline (845 mg, 3.27 mmol, obtained by the method disclosed in Example 95 on page 143 of the specification of patent application "WO2022003575A1") was added and reacted at 80 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 10a (1.05 g, yield: 55.7%). MS m / z (ESI): 612.2 [M+1].

[0247] Step 2 6-((endo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)quinazolin-4-amine hydrochloride 10b Compound 10a (1.05 g, 1.7 mmol) was dissolved in methanol (10 mL), and 0.1 mL of 4 M hydrogen chloride in 1,4-dioxane was added. The mixture was reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 10b (940 mg). The crude product was used in the next reaction without purification. MS m / z (ESI): 512.2 [M+1].

[0248] Step 3 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 10 The crude product, compound 10b (250 mg, 488.7 μmol), was dissolved in 5 mL of dichloromethane, N,N-diisopropylethylamine (126 mg, 974 μmol) was added, and acryloyl chloride (50 mg, 552.4 μmol) was added in an ice bath, and the mixture was reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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 blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min), and the title compound 10 (110 mg, yield: 39.7%) was obtained. MS m / z (ESI): 566.2 [M+1]. 1 H NMR (500 MHz, MeOD): δ 8.80-8.78 (d, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.84-7.82 (m, 1H), 7.77 (s, 1H), 7.60-7.56 (m, 2H), 7.14-7.10 (m, 2H), 7.02-7.01 (m, 1H), 6.79-6.74 (m, 1H), 6.35 (dd, 1H), 5.81 (dd, 1H), 4.97-4.93 (m, 1H), 4.76-4.73 (m, 1H), 4.61-4.59 (m, 1H), 2.44-2.17 (m, 10H), 2.06-2.02 (m, 1H).

[0249] Example 11 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 11 [ka] Using the synthesis route in Example 4, the raw material in step 2, 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline, was replaced with 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline to obtain the title compound 11 (6 mg, yield: 15.5%). MS m / z (ESI): 579.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 9.22 (s, 1H), 8.69 (s, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.68 (d, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.12 (d, 1H), 6.89 (s, 1H), 6.56 (dd, 1H), 6.46-6.34 (m, 1H), 5.73 (d, 1H), 4.86 (s, 1H), 4.84-4.77 (m, 1H), 4.42 (s, 2H), 4.03 (s, 3H), 2.52-2.47 (m, 1H), 2.40-2.35 (m, 1H), 2.31-2.26 (m, 1H), 2.25 (s, 3H), 2.23-2.12 (m, 2H), 2.08-2.03 (m, 2H).

[0250] Example 12 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 12 [ka] [ka]

[0251] Step 1 tert-Butyl exo-3-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 12a Compound 6b (30 mg, 71 μmol) and 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline (20 mg, 83 μmol) were dissolved in isopropanol (4 mL) and reacted at 80° C. for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 12a (44 mg). The crude product was used in the next reaction without purification. MS m / z (ESI): 625.2 [M+1].

[0252] Step 2 6-(exo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-7-methoxyquinazolin-4-amine 2,2,2-trifluoroacetate 12b The crude product, Compound 12a (40 mg, 64 μmol), was dissolved in 1 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added in an ice bath. The mixture was allowed to naturally return to room temperature and reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, title Compound 12b (40 mg), which was used in the next reaction without purification. MS m / z (ESI): 525.2 [M+1].

[0253] Step 3 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 12 The crude product, compound 12b (40 mg, 62 μmol), was dissolved in 2 mL of dichloromethane, N,N-diisopropylethylamine (22 mg, 170 μmol) was added, and acryloyl chloride (5.6 mg, 62 μmol) was added in an ice bath, and the mixture was reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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 blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min), and the title compound 12 (10 mg, yield: 30%) was obtained. MS m / z (ESI): 579.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 9.22 (d, 1H), 8.70 (s, 1H), 8.35 (s, 1H), 7.71 (d, 1H), 7.66 (dd, 1H), 7.49 (d, 1H), 7.37 (s, 1H), 7.16 (d, 1H), 6.92 (d, 1H), 6.56 (dd, 1H), 6.44 (dd, 1H), 5.77 (dd, 1H), 4.88 (d, 1H), 4.80 (tt, 1H), 4.56-4.42 (m, 1H), 4.02 (s, 3H), 2.32-2.29 (m, 1H), 2.28 (s, 3H), 2.27-2.10 (m, 2H), 2.04 (t, 3H), 1.86 (q, 3H).

[0254] Example 13 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 13 [ka] Using the synthesis route in Example 12, the raw material in step 1, 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline, was replaced with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline to obtain the title compound 13 (15 mg, 36%). MS m / z (ESI): 596.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 8.73 (d, 1H), 8.54 (dd, 1H), 8.49 (d, 1H), 8.26 (d, 1H), 7.45 (s, 1H), 7.32 (d, 1H), 7.01 (d, 1H), 6.93 (dt, 1H), 6.88 (d, 1H), 6.62-6.34 (m, 2H), 5.77 (dt, 1H), 4.98-4.79 (m, 2H), 4.50 (s, 1H), 4.03 (d, 3H), 2.36 (d, 1H), 2.25 (s, 1H), 2.17 (s, 3H), 2.05 (d, 3H), 1.91 (s, 2H), 1.79 (t, 2H).

[0255] Example 14 1-(exo-3-((7-methoxy-4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 14 [ka] Using the synthesis route in Example 12, the raw material in step 1, 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline, was replaced with 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline to obtain the title compound 14 (12 mg, yield: 29%). MS m / z (ESI): 591.2 [M+1]. 1H NMR (500 MHz, CDCl3): δ 8.63 (d, 1H), 8.37 (s, 1H), 7.83 (d, 1H), 7.69-7.64 (m, 1H), 7.45 (s, 1H), 7.37-7.33 (m, 1H), 7.31 (s, 1H), 7.24 (d, 1H), 7.18 (s, 1H), 7.13-7.07 (m, 1H), 6.84 (dt, 1H), 6.50 (dq, 1H), 6.40 (d, 1H), 5.76-5.70 (m, 1H), 4.77 (dd, 2H), 4.40 (s, 1H), 3.96 (d, 3H), 3.85 (d, 3H), 2.25 (d, 4H), 2.17 (dd, 2H), 2.07-1.97 (m, 2H), 1.80 (s, 1H), 1.72 (s, 1H), 1.61 (s, 1H).

[0256] Example 15 1-(exo-3-((4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 15 [ka] According to the synthesis route in Example 12, the raw material in Step 1, 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline, was replaced with 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (obtained by the method disclosed in Example G of the intermediate on page 75 of the specification of the patent application "WO2022003575A1") to obtain the title compound 15 (20 mg, yield: 45%). MS m / z (ESI): 609.2 [M+1]. 1H NMR (500 MHz, MeOD): δ 8.33 (t, 1H), 8.16 (d, 1H), 7.80 (d, 1H), 7.60 (t, 1H), 7.33 (s, 1H), 7.27 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 6.82-6.70 (m, 2H), 6.36 (d, 1H), 5.81 (d, 1H), 5.08 (s, 2H), 4.65 (s, 1H), 4.07-3.90 (m, 6H), 2.42 (s, 1H), 2.34 (s, 1H), 2.30 (s, 3H), 2.06 (d, 4H), 1.89 (d, 1H), 1.76 (s, 1H).

[0257] Example 16 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 16 [ka] [ka]

[0258] Step 1 tert-Butyl endo-3-((4-(methoxycarbonyl)-5-nitropyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 16b Compound 6a (1g, 4.6mmol) was dissolved in N,N-dimethylformamide (20mL), sodium hydride (212mg, 5.54mmol, 60% purity) was added in an ice bath, and the temperature was maintained for 20 minutes. Then, 2-chloro-5-nitroisonicotinic acid methyl ester 16a (1.26g, 5.54mmol, Shanghai Bide) was added, and the mixture was reacted at 35℃ for 30 minutes. The mixture was then stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (30mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to obtain the title compound 16b (600mg, yield: 31.8%). MS m / z (ESI): 408.2 [M+1].

[0259] Step 2 tert-Butyl endo-3-((5-amino-4-(methoxycarbonyl)pyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 16c Compound 16b (500 mg, 1.2 mmol) was dissolved in methanol (20 mL), and 10% palladium carbon catalyst (wet) (50 mg) was added. The mixture was reacted under a hydrogen atmosphere for 14 hours with stirring. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 16c (360 mg). The product was used in the next reaction without purification. MS m / z (ESI): 378.2 [M+1].

[0260] Step 3 tert-Butyl endo-3-((4-hydroxypyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 16d The crude product, compound 16c (200 mg, 529.9 μmol), was dissolved in ethanol (20 mL), and formamidine acetate (276 mg, 2.6 mmol, Shanghai Shaoyuan) was added. The mixture was stirred at 80 ° C for 14 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to obtain the crude product, title compound 16d (160 mg). The product was used in the next reaction without purification. MS m / z (ESI): 373.2 [M+1].

[0261] Step 4 tert-Butyl endo-3-((4-chloropyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 16e The crude product, compound 16d (160 mg, 429.66 μmol), was dissolved in toluene (10 mL), phosphorus oxychloride (329.4 mg, 2.15 mmol), N,N-diisopropylethylamine (55.42 mg, 429.6 μmol) were added, and the mixture was stirred at 80 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and then poured into ice water. Extraction was performed with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to obtain the crude product, title compound 16e (100 mg). The product was used in the next reaction without purification. MS m / z (ESI): 391.1 [M+1].

[0262] Step 5 tert-Butyl endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 16f The crude product, compound 16e (100 mg, 255.8 μmol), was dissolved in isopropanol (10 mL), and compound 1d (61.5 mg, 255.8 μmol) was added. The mixture was reacted at 80° C. for 1 hour with stirring. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 16f (150 mg). The product was used in the next reaction without purification. MS m / z (ESI): 595.2 [M+1].

[0263] Step 6 6-((endo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)pyrido[3,4-d]pyrimidin-4-amine hydrochloride 16g The crude product, compound 16f (150 mg, 252.2 μmol), was dissolved in dichloromethane (3 mL), and 4 M hydrogen chloride in 1,4-dioxane (1 mL) was added. The mixture was reacted with stirring for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 16g (130 mg). The crude product was used in the next reaction without purification. MS m / z (ESI): 495.2 [M+1].

[0264] Step 7 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 16 The crude product, compound 16g (130mg, 245μmol), was dissolved in 5mL of dichloromethane, N,N-diisopropylethylamine (63mg, 490mmol) was added, and acryloyl chloride (24.4mg, 269μmol) was added in an ice bath, and the mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150mm, 5μm, mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain the title compound 16 (110mg, yield: 39.7%). MS m / z (ESI): 549.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 9.97 (s, 1H), 8.97-8.91 (m, 2H), 8.58 (s, 1H), 8.39 (s, 1H), 7.92 (s, 2H), 7.90 (d, 1H), 7.25 (d, 1H), 7.04 (dd, 1H), 6.82 (d, 1H), 6.75 (dd, 2H), 6.20 (dd, 1H), 5.71 (dd, 1H), 5.45 (s, 1H), 4.60-4.55 (m, 2H), 2.32-2.24 (m, 2H), 2.22 (s, 3H), 2.18 (d, 2H), 2.04-1.91 (m, 3H).

[0265] Example 17 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 17 [ka] [ka]

[0266] Step 1 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)-7-ethoxyquinazolin-6-ol 17b 4-Chloro-7-ethoxyquinazolin-6-ol 17a (140 mg, 623 μmol, obtained by preparation according to the method disclosed in Example 3 on page 54 of the specification of patent application "WO2021231400A1") was dissolved in isopropanol (2 mL), 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline (160 mg, 623 μmol) was added, and the reaction was carried out with stirring at 110 ° C. for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 17b (92 mg, yield: 33%). MS m / z (ESI): 447.2 [M+1].

[0267] Step 2 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 17 Following steps 3 to 5 of the synthetic route in Example 1, the starting compound 1e in step 3 was replaced with compound 17b to obtain the title compound 17 (1.6 mg, yield: 1.4%). MS m / z (ESI): 610.2 [M+1]. 1H NMR (500 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.98 (d, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.81 (s, 1H), 7.49 (t, 1H), 7.21 (s, 1H), 7.12-7.08 (m, 1H), 6.95 (d, 1H), 6.79-6.74 (m, 1H), 6.66 (s, 1H), 6.19 (dd, 1H), 5.70 (dd, 1H), 4.89 (t, 1H), 4.55 (dd, 2H), 4.21 (q, 2H), 2.16 (d, 3H), 2.14-1.96 (m, 7H), 1.88 (t, 1H), 1.43 (t, 3H).

[0268] Example 18 1-(endo-3-((4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 18 [ka] Following the synthesis route in Example 1, the starting compound 1d in step 2 was replaced with 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline to obtain the title compound 18 (15 mg, yield: 25%). MS m / z (ESI): 579.2 [M+1]. 1H NMR (500 MHz, CDCl3): δ 8.70 (s, 1H), 8.09 (t, 1H), 7.96-7.79 (m, 2H), 7.49 (s, 1H), 7.44 (dd, 1H), 7.40-7.33 (m, 2H), 7.16 (d, 1H), 7.10 (dd, 1H), 6.73 (dd, 1H), 6.55 (dd, 1H), 6.44 (dd, 1H), 5.75 (dd, 1H), 4.86-4.81 (m, 2H), 4.41 (d, 1H), 3.88 (s, 3H), 2.39-2.34 (m, 2H), 2.30 (s, 3H), 2.29-2.21 (m, 2H), 2.19-2.14 (m, 2H), 2.10-1.99 (m, 2H).

[0269] Example 19 1-(exo-3-((4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 19 [ka] [ka]

[0270] Step 1 1-(exo-3-((4-chloroquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 19a Compound 7a (27 mg, 149 μmol), compound 6a (34 mg, 149 μmol), and triphenylphosphine (80 mg, 305 μmol) were dissolved in tetrahydrofuran (5 mL), and diisopropyl azodicarboxylate (60 mg, 296 μmol) was added dropwise in an ice bath. The temperature was allowed to return to room temperature and the reaction was carried out for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to obtain the title compound 19a (34 mg, yield: 58.3%). MS m / z (ESI): 390.2 [M+1].

[0271] Step 2 6-((exo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)quinazolin-4-amine hydrochloride 19b Compound 19a (34 mg, 87.2 μmol) and 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (25 mg, 92.1 μmol) were dissolved in isopropanol (3 mL), 0.1 mL of 4 M hydrochloric acid in isopropanol was added, and the mixture was reacted at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 19b (45 mg). The crude product was used in the next reaction without purification. MS m / z (ESI): 525.2 [M+1].

[0272] Step 3 1-(exo-3-((4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 19 The crude product, compound 19b (45 mg, 80.3 μmol), was dissolved in 3 mL of dichloromethane, N,N-diisopropylethylamine (33 mg, 255.3 mmol) was added, and acryloyl chloride (10 mg, 110 μmol) was added in an ice bath, and the mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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 blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min), to obtain the title compound 19 (15 mg, yield: 30%). MS m / z (ESI): 579.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 8.70 (s, 1H), 8.17 (t, 1H), 7.96-7.77 (m, 2H), 7.54-7.44 (m, 2H), 7.41-7.33 (m, 2H), 7.10 (dd, 1H), 6.74 (dd, 1H), 6.55 (dd, 1H), 6.45 (dd, 1H), 5.77 (dd, 1H), 4.92 (tq, 2H), 4.65-4.36 (m, 1H), 3.88 (s, 3H), 2.42-2.32 (m, 1H), 2.31 (s, 3H), 2.30-2.14 (m, 3H), 2.13-2.06 (m, 1H), 2.05-1.88 (m, 2H), 1.88-1.76 (m, 2H).

[0273] Example 20 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 20 [ka] According to the synthesis route in Example 16, the starting compound 1d in step 5 was replaced with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline to obtain the title compound 20 (10 mg, yield: 6.4%). MS m / z (ESI): 567.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 8.70 (s, 1H), 8.09 (t, 1H), 7.96-7.79 (m, 2H), 7.49 (s, 1H), 7.44 (dd, 1H), 7.40-7.33 (m, 2H), 7.16 (d, 1H), 7.10 (dd, 1H), 6.73 (dd, 1H), 6.55 (dd, 1H), 6.44 (dd, 1H), 5.75 (dd, 1H), 4.83 (dt, 2H), 4.41 (d, 1H), 2.39-2.34 (td, 2H), 2.30 (s, 3H), 2.28-2.23 (m, 1H), 2.19-2.14 (m, 2H), 2.08-2.02 (m, 2H).

[0274] Example 21 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 21 [ka] [ka]

[0275] Step 1 Exo-3-((4-chloropyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 21a Following steps 1 to 4 of the synthetic route in Example 16, the starting compound 6a in step 1 was replaced with compound 1a to obtain the title compound 21a (200 mg, yield: 21.2%). MS m / z (ESI): 391.2 [M+1].

[0276] Step 2 tert-Butyl exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 21b Compound 21a (15 mg, 38.3 μmol) was dissolved in isopropanol (2 mL), 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline (10 mg, 38.7 μmol) was added, and the mixture was reacted at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 21b (23 mg). The product was used in the next reaction without purification. MS m / z (ESI): 613.2 [M+1].

[0277] Step 3 6-((exo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)pyrido[3,4-d]pyrimidin-4-amine 2,2,2-trifluoroacetate 21c Compound 21b (23 mg, 37.5 μmol) was dissolved in dichloromethane (3 mL), 0.5 mL of trifluoroacetic acid (1 mL) was added, and the mixture was reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 21c (24 mg). The crude product was used in the next reaction without purification. MS m / z (ESI): 513.2 [M+1].

[0278] Step 4 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 21 The crude product, compound 21c (24 mg, 37 μmol), was dissolved in 2 mL of dichloromethane, N,N-diisopropylethylamine (48 mg, 371 μmol) was added, and acryloyl chloride (3.5 mg, 38 μmol) was added in an ice bath, and the mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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 blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min), and the title compound 21 (15 mg, yield: 71%) was obtained. MS m / z (ESI): 567.2 [M+1]. 1 H NMR (500 MHz, CDCl3): δ 9.04 (s, 1H), 8.74 (s, 1H), 8.55 (dd, 2H), 8.26 (s, 1H), 7.69 (s, 1H), 7.06 (s, 1H), 7.02 (dd, 1H), 6.95-6.89 (m, 2H), 6.57 (dd, 1H), 6.44 (dd, 1H), 5.79-5.71 (m, 2H), 4.91 (d, 1H), 4.49 (s, 1H), 2.42 (s, 1H), 2.27 (s, 1H), 2.22 (d, 3H), 2.21-2.14 (m, 1H), 1.99 (h, 4H), 1.77 (t, 1H).

[0279] Example 22 1-(endo-3-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 22 [ka] [ka]

[0280] Step 1 tert-Butyl endo-3-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 22b Compound 6a (78.8 mg, 346 μmol) was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (18.5 mg, 462 μmol, 60% purity) was added in an ice bath, and the temperature was kept as it was for 20 minutes. After reacting, N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-amine 22a (100 mg, 231 μmol, patent The compound K was prepared by the method disclosed in "Synthesis of Compound K" on page 38 of the specification of the application "WO2021156180A1" and reacted at 60°C for 1 hour, then cooled to room temperature. The reaction solution was quenched by adding water, extracted with ethyl acetate (10mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to obtain the title compound 22b (80mg, yield: 58%). MS m / z (ESI): 596.2 [M+1].

[0281] Step 2 1-(endo-3-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 22 Following steps 4-5 of the synthetic route in Example 1, starting compound 1f in step 4 was replaced with compound 22b to obtain the title compound 22 (15 mg, yield: 20%). MS m / z (ESI): 550.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.36 (s, 1H), 8.95 (d, 1H), 8.65 (s, 1H), 8.39 (s, 1H), 7.98-7.91 (m, 2H), 7.26 (d, 1H), 7.04 (dd, 1H), 6.82-6.73 (m, 2H), 6.21 (dd, 1H), 5.80 (d, 1H), 5.72 (dd, 1H), 4.57 (d, 2H), 2.22 (s, 5H), 2.13-1.96 (m, 6H).

[0282] Example 23 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-8,9-dihydrofuro[2,3-h]quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 23 [ka] [ka]

[0283] Step 1 tert-Butyl endo-3-(p-toluenesulfonyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 23a Compound 6a (4g, 17.6mmol), p-toluenesulfonyl chloride (4g, 21.1mmol), 4-dimethylaminopyridine (2.17g, 17.6mmol) were dissolved in 50mL of dichloromethane, N,N-diisopropylethylamine (2.27mg, 17.6mmol) was added, and the mixture was reacted with stirring for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 23a (4.5g, yield: 67%).

[0284] Step 2 6-Iodo-8,9-dihydrofuro[2,3-h]quinazolin-4-ol 23c Methyl 4-amino-7-iodo-2,3-dihydrobenzofuran-5-carboxylate 23b (1 g, 3.13 mmol, prepared according to the method disclosed in Example 11 on page 93 of the specification of the patent application "WO2021249475A1") was dissolved in ethanol (50 mL), and formamidine acetate (1.6 g, 15.3 mmol, Shanghai Shaoyuan) was added. The mixture was stirred under reflux for 14 hours. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure to remove most of the solvent. Water was added to the residue, stirred for 0.5 hours, filtered, and the filter cake was washed with water and dried to obtain the crude product title compound 23c (1 g). The product was used directly in the next reaction without purification. MS m / z (ESI): 315.2 [M+1].

[0285] Step 3 4-Chloro-6-iodo-8,9-dihydrofuro[2,3-h]quinazoline 23d The crude product, compound 23c (500 mg, 1.59 mmol), was dissolved in phosphorus oxychloride (20 mL), N,N-diisopropylethylamine (41 mg, 317 μmol) was added, and the mixture was reacted at 100° C. for 2 hours with stirring. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, poured into ice water, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to obtain the crude product, title compound 23d (529 mg). The product was used directly in the next reaction without purification. MS m / z (ESI): 333.1 [M+1].

[0286] Step 4 N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-iodo-8,9-dihydrofuro[2,3-h]quinazolin-4-amine 23e The crude product, compound 23d (300 mg, 902 μmol), was dissolved in isopropanol (20 mL), compound 1d (216 mg, 898 μmol) was added, and the mixture was reacted at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 23e (380 mg, yield: 78%). MS m / z (ESI): 537.2 [M+1].

[0287] Step 5 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-8,9-dihydrofuro[2,3-h]quinazolin-6-ol 23f Compound 23e (300mg, 559.3μmol) was dissolved in dimethylsulfoxide (3mL) and water (1mL), potassium hydroxide (94mg, 1.67mmol), copper acetylacetonate (15mg, 57.3μmol, J&K), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxamide (18.4mg, 56μmol, Shanghai Bide) was added, and the mixture was purged with nitrogen gas and reacted at 95℃ for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 23f (60mg, yield: 25%). MS m / z (ESI): 427.2 [M+1].

[0288] Step 6 23g exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-8,9-dihydrofuro[2,3-h]quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester Compound 23f (60 mg, 140 μmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 23b (86 mg, 281 μmol) and cesium carbonate (82 mg, 281 μmol) were added and reacted at 80° C. for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 23g (75 mg, yield: 83%). MS m / z (ESI): 636.2 [M+1].

[0289] Step 7 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-8,9-dihydrofuro[2,3-h]quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 23 Following steps 2-3 of the synthetic route in Example 12, the starting compound 12a in step 2 was replaced with compound 23g to give the title compound 23 (40 mg, yield: 60%). MS m / z (ESI): 590.2 [M+1]. 1 H NMR (500 MHz, MeOD): δ 8.76 (t, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 7.80 (d, 1H), 7.71 (s, 1H), 7.68-7.62 (m, 1H), 7.21 (d, 1H), 7.10 (dd, 1H), 6.86 (s, 1H), 6.76 (dq, 1H), 6.36 (d, 1H), 5.82 (d, 1H), 5.15 (s, 1H), 4.90 (s, 2H), 4.78 (s, 1H), 4.65 (d, 1H), 3.56 (m, 2H), 2.39 (s, 1H), 2.33 (d, 1H), 2.26 (d, 3H), 2.17 (s, 1H), 2.09-1.96 (m, 3H), 1.85 (t, 1H), 1.74 (t, 1H).

[0290] Example 24 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 24 [ka] [ka]

[0291] Step 1 6-Chloro-3-nitropyridine formamide 24b 6-Chloro-2-cyano-3-nitropyridine 24a (5 g, 27.2 mmol, Shanghai Rakuken) was added to 90% sulfuric acid (50 mL) in several portions and reacted at 70° C. for 3 hours with stirring. The reaction solution was cooled to room temperature and poured into ice water to precipitate a solid. The solid was filtered, and the filter cake was washed with water and dried to obtain the crude product title compound 24b (3 g). The product was used in the next reaction without purification. MS m / z (ESI): 202.2 [M+1].

[0292] Step 2 tert-Butyl endo-3-((6-formamido-5-nitropyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 24c Compound 6a (676.6 mg, 3 mmol) was dissolved in dimethyl sulfoxide (10 mL), potassium tert-butoxide (835 mg, 7.4 mmol) was added in an ice bath, and the mixture was allowed to naturally return to room temperature and reacted with stirring for 30 minutes. Compound 24b (500 mg, 2.5 mmol) in dimethyl sulfoxide (5 mL) was then added and reacted with stirring for 2 hours. The reaction solution was quenched by adding water, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to obtain the title compound 24c (500 mg, yield: 51.3%). MS m / z (ESI): 393.2 [M+1].

[0293] Step 3 tert-Butyl endo-3-((5-amino-6-formamidopyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 24d Compound 24c (500 mg, 1.27 mmol) was dissolved in methanol (10 mL), Raney nickel (150 mg) was added, and the mixture was reacted under a hydrogen atmosphere with stirring for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 24d (320 mg). The product was used in the next reaction without purification. MS m / z (ESI): 363.2 [M+1].

[0294] Step 4 tert-Butyl endo-3-((4-hydroxypyrido[3,2-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 24e The crude product, compound 24d (320 mg, 882.9 μmol), was mixed with diethoxymethyl acetate (5 mL, J&K) and stirred at 100° C. for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to obtain the title compound 24e (110 mg, yield: 33%). MS m / z (ESI): 373.2 [M+1].

[0295] Step 5 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 24 Following steps 4 to 7 of the synthetic route in Example 16, the starting compound 16d in step 4 was replaced with compound 24e to give the title compound 24 (5 mg, yield: 10.8%). MS m / z (ESI): 549.2 [M+1]. 1H NMR (500 MHz, MeOD): δ 8.76 (d, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.11 (d, 1H), 7.95-7.88 (m, 2H), 7.40 (d, 1H), 7.21 (d, 1H), 7.09 (dd, 1H), 6.83-6.73 (m, 2H), 6.35 (dd, 1H), 5.91 (t, 1H), 5.81 (dd, 1H), 5.36 (dd, 1H), 4.79-4.73 (m, 1H), 4.63-4.58 (m, 1H), 2.46-2.33 (m, 3H), 2.27 (s, 3H), 2.26-2.15 (m, 3H), 2.05 (q, 2H).

[0296] Example 25 1-(endo-3-((8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 25 [ka] According to the synthetic route in Example 22, the raw material compound 22a in step 1 was replaced with N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-amine (obtained by the method disclosed in compound K on page 41 of the specification of patent application "WO2021156178A1") to obtain the title compound 25 (15 mg, yield: 20%). MS m / z (ESI): 563.2 [M+1]. 1H NMR (500 MHz, MeOD): δ 9.25 (t, 1H), 8.58 (d, 1H), 8.14 (d, 1H), 7.83 (s, 1H), 7.73 (d, 1H), 7.60-7.54 (m, 1H), 7.15 (s, 1H), 7.12-7.08 (m, 1H), 6.92 (t, 1H), 6.77 (t, 1H), 6.35 (d, 1H), 5.84-5.75 (m, 2H), 4.75 (m, 1H), 4.60 (m, 1H), 3.93 (t, 3H), 2.44 (t, 3H), 2.33 (m, 3H), 2.28 (s, 1H), 2.24-2.16 (m, 3H), 2.05 (m, 1H).

[0297] Example 26 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 26 [ka] [ka]

[0298] Step 1 tert-Butyl exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 26a The crude product, compound 21a (1.7 g, 4.86 mmol), was dissolved in isopropanol (50 mL), compound 1d (1.17 g, 4.87 mmol) was added, and the mixture was reacted at 80° C. for 5 hours with stirring. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 26a (2.8 g), which was used in the next reaction without purification. MS m / z (ESI): 595.2 [M+1].

[0299] Step 2 6-((exo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)pyrido[3,4-d]pyrimidin-4-amine hydrochloride 26b The crude product, Compound 26a (2.8 g, 4.7 mmol), was dissolved in dichloromethane (20 mL), and 20 mL of 4 M hydrogen chloride in 1,4-dioxane (20 mL) was added. The mixture was reacted with stirring for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude product, title Compound 26b (2.5 g). The product was used in the next reaction without purification. MS m / z (ESI): 495.2 [M+1].

[0300] Step 3 1-(exo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 26 The crude product, compound 26b (2.5 g, 4.7 mmol), was dissolved in 20 mL of dichloromethane, N,N-diisopropylethylamine (1.8 g, 14 mmol) was added, and acryloyl chloride (469 mg, 5.18 mmol) was added in an ice bath, and the mixture was reacted for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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 blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min), and the title compound 26 (1.5 g, yield: 58%) was obtained. MS m / z (ESI): 549.2 [M+1]. 1H NMR (500 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.94 (d, 2H), 8.58 (s, 1H), 8.39 (s, 1H), 7.95 (d, 1H), 7.93-7.85 (m, 2H), 7.23 (d, 1H), 7.03 (dd, 1H), 6.83-6.79 (m, 1H), 6.78-6.73 (m, 1H), 6.22 (dd, 1H), 5.72 (dd, 1H), 5.61 (tt, 1H), 4.64 (dt, 2H), 2.38-2.35 (m, 1H), 2.27 (dd, 1H), 2.20 (s, 3H), 2.09-2.01 (m, 1H), 1.97-1.84 (m, 3H), 1.69 (t, 1H), 1.55 (t, 1H).

[0301] Example 27 1-(exo-3-((4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 27 [ka] According to the synthesis route in Example 26, the raw material compound 1d in step 1 was replaced with 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline to obtain the title compound 27 (50 mg, yield: 45.3%). MS m / z (ESI): 580.2 [M+1]. 1H NMR (500 MHz, CDCl3): δ 9.00 (s, 1H), 8.68 (s, 1H), 8.20 (t, 1H), 7.89 (s, 1H), 7.57 (d, 1H), 7.40-7.35 (m, 2H), 7.09 (dd, 1H), 7.04 (s, 1H), 6.73 (dd, 1H), 6.57 (dd, 1H), 6.44 (dd, 1H), 5.78-5.68 (m, 2H), 4.93-4.88 (m, 1H), 4.48 (d, 1H), 3.88 (s, 3H), 2.41 (dd, 1H), 2.31 (d, 4H), 2.17 (dt, 1H), 2.05 (q, 2H), 1.96-1.91 (m, 1H), 1.76 (t, 1H).

[0302] Example 28 1-(exo-3-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 28 [ka] Following the synthesis route in Example 26, the starting compound 1d in step 1 was replaced with 3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline to give the title compound 28 (50 mg, yield: 47%). MS m / z (ESI): 562.2 [M+1]. 1H NMR (500 MHz, CDCl3): δ 8.96 (s, 1H), 8.67 (s, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.67 (d, 1H), 7.51 (dd, 1H), 7.38-7.31 (m, 2H), 7.09 (dd, 1H), 6.89 (d, 1H), 6.58 (dd, 1H), 6.43 (dd, 1H), 5.79-5.70 (m, 2H), 4.89 (d, 1H), 4.48 (d, 1H), 3.87 (s, 3H), 2.45 (dd, 1H), 2.35 (s, 3H), 2.25-2.15 (m, 2H), 2.05 (q, 3H), 1.93 (s, 1H), 1.72 (t, 1H).

[0303] Biological evaluation The present disclosure will be further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

[0304] Test Example 1: Ba / F3 cell proliferation experiment Logarithmically grown EGFR wild-type Ba / F3 cells (Cobioer, product number: CBP73110) were used as a 2.5 × 10 3 Seed 5 × 10 HER2 wild-type Ba / F3 cells (Cobioer, Cat. No.: CBP73110) or HER2 A775_G776insYVMA mutant Ba / F3 (Cobioer, Cat. No.: CBP73184) in logarithmic growth phase at 10 × 10 cells / 100 μL of growth medium in a 96-well plate. 3 Cells / 100μL of growth medium were seeded into 96-well plates and placed in a 37℃ cell incubator overnight. The next day, 100μL / well of compounds serially diluted 3-fold in medium were added, all treatments were performed in triplicate, and culture was continued for 72 hours in a 37℃ cell incubator. Celltiter-Glo Luminescent cell activity assay was performed.

[0305] The corresponding cell proliferation rate of each well was calculated by the following formula: Proliferation % = (average of compound wells G3-G0 to be measured) / (average of DMSO control wells G3-G0) x 100. According to the corresponding proliferation rate of each gradient concentration well and its concentration, the gradient curve of cell proliferation was fitted with Prism Graphpad software, and the GI of the compound was calculated. 50 was calculated (GI 50 was defined as the concentration of the corresponding compound at which cell growth inhibition rate was 50%.

[0306] The structure of tucatinib (synthesized with reference to Example 11 in patent WO2007059257A2), a selective HER2 inhibitor, is as follows: [ka]

[0307] [Table 3]

[0308] Conclusion: The compounds disclosed herein have potent inhibitory effects on the proliferation of HER2 exon 20 YVMA insertion mutation- and HER2 wild-type-dependent Ba / F3 cells, and are highly selective for EGFR wild-type-dependent Ba / F3 cells. Furthermore, the compounds disclosed herein have significantly superior proliferation inhibitory activity against HER2 exon 20 YVMA insertion mutation-Ba / F3 cells to tucatinib.

[0309] Test Example 2: Pharmacokinetic evaluation TPGS: D-α-vitamin E polyethylene glycol succinate HPMC: Hydroxypropyl methylcellulose PEG400: Polyethylene glycol 400

[0310] 1. SD rat test 1. Summary Using SD rats as test animals, the plasma drug concentrations of the compounds of the examples were measured at different times after intragastric administration (ig) in SD rats by LC / MS / MS.The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied, and their pharmacokinetic characteristics were evaluated.

[0311] 2. Test plan 2.1 Study Drugs This is the compound of Example 10. 2.2 Test animals The four SD rats, half male and half female, were provided by Weitong Lihua Experimental Animal Technology Co., Ltd. After fasting overnight, they were intragastrically administered with the drug. 2.3 Drug Preparation A certain amount of each of the compounds of the examples was weighed out, and 5% DMSO+20% PEG400+70% (10% TPGS)+5% (1% HPMC K100LV) was added to prepare a 5 mg / mL colorless, transparent solution. 2.4 Administration The dose is 50 mg / kg and the administration volume is 10.0 mL / kg.

[0312] 3, operation Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulant test tube, and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored on dry ice for measurement. The process from blood collection to centrifugation was carried out under ice bath conditions. The animals were fed for 2 hours after administration. The contents of the compounds to be measured in the plasma of SD rats after various concentrations of drugs were administered were measured: 50 μL of SD rat plasma samples at each time point after administration, 25 μL of camptothecin (1 μg / mL) and 450 μL of acetonitrile were taken, mixed by vortex and centrifuged at 3700 rpm for 10 minutes. 0.1 μL of the supernatant was taken for LC / MS / MS analysis.

[0313] 4. Pharmacokinetic parameters [Table 4]

[0314] Conclusion: The compounds according to the present disclosure have high exposure in SD rats and have obvious pharmacokinetic advantages.

[0315] II. C57 Mouse Test 1. Summary Using C57 mice as test animals, the plasma drug concentrations of the compounds of the examples were measured at different times after intragastric administration (ig) in C57 mice by LC / MS / MS. The pharmacokinetic behavior of the compounds of the present disclosure in C57 mice was studied, and their pharmacokinetic characteristics were evaluated.

[0316] 2. Test plan 2.1 Study Drugs The compound of Example 10, the compound of Example 18 and the compound of Example 26. 2.2 Test animals 27 male C57 mice provided by Beijing Huafukang Biotechnology Co., Ltd. were divided into three groups and administered intragastrically. 2.3 Drug Preparation A certain amount of each of the example compounds was weighed out, and 5% DMSO+20% PEG400+70% (10% TPGS)+5% (1% HPMC K100LV) was added to prepare a 2.5 mg / mL colorless, transparent solution. 2.4 Administration The dose was 50 mg / kg and the administration volume was 20.0 mL / kg.

[0317] 3, operation Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10,000 rpm for 2 minutes (4°C), and plasma was separated within 1 hour and stored at -20°C for measurement. The process from blood collection to centrifugation was carried out under ice bath conditions. The animals were fed for 2 hours after administration.

[0318] The contents of the compounds to be measured in the plasma of C57 mice after administration of various concentrations of drugs were measured: 50 μL of C57 mouse plasma samples, 25 μL of labetalol (1 μg / mL) and 450 μL of acetonitrile were taken at each time point after administration, mixed by vortex and centrifuged at 3700 rpm for 10 minutes. 0.1 μL of the supernatant was taken for LC / MS / MS analysis.

[0319] 4. Pharmacokinetic parameters [Table 5]

[0320] Conclusion: The compounds disclosed herein have high exposure in C57 mice and have obvious pharmacokinetic advantages.

Claims

1. General formula (I): 【Chemistry 1】 [In the formula, Ring A is an aryl group or a heteroaryl group, Ring B is a 7-10 membered condensed heterocyclyl group or a 7-10 membered cross-linked heterocyclyl group. G is N or C (R Ａ ) and R Ａ This is selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups, and amino groups. V １ is C(R ａ ) or N, V ２ and V ３ are the same or different and each independently is C(R ａ ), or N, or V ２ is C(R ｂｂ ), V ３ is C(R ｃｃ ), and R ｂｂ and R ｃｃ together with the carbon atoms to which they are attached form a cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, and the cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally substituted with one or more substituents selected from halogen, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cyano group, hydroxy group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group L １ O, NR ｂ１ , C(O), S, S(O) and S(O) ２ Selected from, L ２ O, NR ｂ２ , C(O), (CR ｃ R ｄ ) ｕ , (CR ｃ R ｄ ) ｕ O, O (CR ｃ R ｄ ) ｕ , (CR ｃ R ｄ ) ｕ NR ｂ２ , NR ｂ２ (CR ｃ R ｄ ) ｕ C(O)NR ｂ２ and NR ｂ２ Selected from C(O), E is a 9-10 member heteroaryl group, and the 9-10 member heteroaryl group can optionally have one or more R １６ Replaced by, R １６ This includes halogens, alkyl groups, alkenyl groups, alkynyl groups, cyano groups, nitro groups, and -OR groups. ４ , -NR ５ R ６ , -C(O)R ４ , -C(O)OR ４ , -OC(O)R ４ , -C(O)NR ５ R ６ , -S(O) ｐ R ４ , -S(O) ｐ NR ５ R ６ Selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups are each independently and optionally selected from oxo groups, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, cyano groups, -OR ４ａ , -NR ５ａ R ６ａ , substituted with one or more substituents selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, R ａ This includes hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, cyano groups, nitro groups, haloalkyl groups, hydroxyalkyl groups, and -OR ｅ ,-(CH ２ ) ｓ -NR ｆ R ｇ Selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, R ｂ１ and R ｂ２ They are identical or different, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group and heterocyclyl group. R ｃ and R ｄ They are identical or different, and each is independently selected from a hydrogen atom, halogen, alkyl group, hydroxyl group, and hydroxyalkyl group. R １ It is selected from hydrogen atoms, alkyl groups, and cycloalkyl groups. Each R ２ They are the same or different, and each is independently a halogen, alkyl group, alkenyl group, alkynyl group, cyano group, nitro group, haloalkyl group, hydroxyalkyl group, -OR ７ ,-(CH ２ ) ｖ -NR ８ R ９ Selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, Each R ３ is the same or different and each independently is an oxo group, halogen, alkyl group, alkenyl group, alkynyl group, cyano group, nitro group, -OR １０ , -NR １１ R １２ , -C(O)R １０ , -C(O)OR １０ , -OC(O)R １０ , -C(O)NR １１ R １２ , -NR １３ C(O)R １０ , -NR １３ C(O)OR １０ , -NR １３ C(O)NR １１ R １２ , -S(O) ｐ R １０ , -S(O) ｐ , -S(O)NR １１ R １２ , -NR １３ S(O) ｐ R １０ is selected from a cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, and the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently optionally substituted with one or more substituents selected from an oxo group, halogen, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, aminoalkyl group, cyano group, -OR １０ａ , -NR １１ａ R １２ａ , a cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, R １０ Each instance of R is either the same or different, and each is independently selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, and each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently and optionally selected as one or more R Ｂ Replaced by, R Ｂ This includes oxo groups, halogens, alkyl groups, alkenyl groups, alkynyl groups, cyano groups, and -OR groups. １０ｂ , -NR １１ｂ R １２ｂ , -C(O)R １０ｂ , -C(O)NR １１ｂ R １２ｂ , selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently and optionally substituted with one or more substituents selected from oxo groups, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, hydroxyl groups, cyano groups and amino groups. R ｅ , R ４ , R ４ａ , R ７ , R １０ａ and R １０ｂ Each instance of these groups is either identical or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and each of these alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a hydroxyl group, an alkoxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. R ｆ , R ｇ , R ５ , R ６ , R ８ , R ９ , R １１ and R １２ Each instance of these groups is either identical or different, and each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and each alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently and optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. Or, R ｆ , R ｇ It forms a heterocycline group together with the linked nitrogen atom, or R ５ , R ６ It forms a heterocycline group together with the linked nitrogen atom, or R ８ , R ９ It forms a heterocycline group together with the linked nitrogen atom, or R １１ , R １２ The carbon atom forms a heterocyclyl group with the linked nitrogen atom, and the heterocyclyl group is optionally substituted with one or more substituents selected from oxo groups, halogens, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, cyano groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, amino groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R １３ Each instance is either identical or different, and each is independently selected from a hydrogen atom, an alkyl group, and a cycloalkyl group. R ５ａ , R ６ａ , R １１ａ , R １２ａ , R １１ｂ and R １２ｂ Each instance is either identical or different, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, aminoalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, arylalkyl group, and heteroarylalkyl group. s is 0, 1, or 2. v is 0, 1, or 2. u is 1, 2, 3 or 4, p is 0, 1, or 2. n is 0, 1, 2, 3 or 4, and m is an integer between 0 and 10. The compound indicated by or a medicinal salt thereof.

2. General formula (I): 【Chemistry 2】 [In the formula, Ring A is an aryl group or a heteroaryl group, Ring B is a 7-10 membered condensed heterocyclyl group or a 7-10 membered cross-linked heterocyclyl group. G is N or C (R Ａ ) and R Ａ This is selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups, and amino groups. V １ , V ２ and V ３ They are identical or different, and each is independently C(R) ａ ) or N, L １ O, NR ｂ１ , C(O), S, S(O) and S(O) ２ Selected from, L ２ O, NR ｂ２ , C(O), (CR ｃ R ｄ ) ｕ , (CR ｃ R ｄ ) ｕ O, O (CR ｃ R ｄ ) ｕ , (CR ｃ R ｄ ) ｕ NR ｂ２ , NR ｂ２ (CR ｃ R ｄ ) ｕ C(O)NR ｂ２ and NR ｂ２ Selected from C(O), E is a 9-10 member heteroaryl group, and the 9-10 member heteroaryl group can optionally have one or more R １６ Replaced by, R １６ This includes halogens, alkyl groups, alkenyl groups, alkynyl groups, cyano groups, nitro groups, and -OR groups. ４ , -NR ５ R ６ , -C(O)R ４ , -C(O)OR ４ , -OC(O)R ４ , -C(O)NR ５ R ６ , -S(O) ｐ R ４ , -S(O) ｐ NR ５ R ６ Selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups are each independently and optionally selected from oxo groups, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, cyano groups, -OR ４ａ , -NR ５ａ R ６ａ , substituted with one or more substituents selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, R ａ This includes hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, cyano groups, nitro groups, haloalkyl groups, hydroxyalkyl groups, and -OR ｅ ,-(CH ２ ) ｓ -NR ｆ R ｇ Selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, R ｂ１ and R ｂ２ They are identical or different, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group and heterocyclyl group. R ｃ and R ｄ They are identical or different, and each is independently selected from a hydrogen atom, halogen, alkyl group, hydroxyl group, and hydroxyalkyl group. R １ It is selected from hydrogen atoms, alkyl groups, and cycloalkyl groups. Each R ２ They are the same or different, and each is independently a halogen, alkyl group, alkenyl group, alkynyl group, cyano group, nitro group, haloalkyl group, hydroxyalkyl group, -OR ７ ,-(CH ２ ) ｖ -NR ８ R ９ Selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, Each R ３ They are identical or different, and each is independently an oxo group, halogen, alkyl group, alkenyl group, alkynyl group, cyano group, nitro group, -OR １０ , -NR １１ R １２ , -C(O)R １０ , -C(O)OR １０ , -OC(O)R １０ , -C(O)NR １１ R １２ , -NR １３ C(O)R １０ , -NR １３ C(O)OR １０ , -NR １３ C(O)NR １１ R １２ , -S(O) ｐ R １０ , -S(O) ｐ NR １１ R １２ , -NR １３ S(O) ｐ R １０ Selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, the alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups are each independently and optionally selected from oxo groups, halogens, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, cyano groups, -OR １０ａ , -NR １１ａ R １２ａ , substituted with one or more substituents selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, R １０ Each instance of R is either the same or different, and each is independently selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, and each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently and optionally selected as one or more R Ｂ Replaced by, R Ｂ This includes oxo groups, halogens, alkyl groups, alkenyl groups, alkynyl groups, cyano groups, and -OR groups. １０ｂ , -NR １１ｂ R １２ｂ , -C(O)R １０ｂ , -C(O)NR １１ｂ R １２ｂ , selected from cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently and optionally substituted with one or more substituents selected from oxo groups, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, hydroxyl groups, cyano groups and amino groups. R ｅ , R ４ , R ４ａ , R ７ , R １０ａ and R １０ｂ Each instance of these groups is either identical or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and each of these alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently and optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a hydroxyl group, an alkoxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. R ｆ , R ｇ , R ５ , R ６ , R ８ , R ９ , R １１ and R １２ Each instance of these groups is either identical or different, and each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and each alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently and optionally substituted with one or more substituents selected from an oxo group, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. Or, R ｆ , R ｇ It forms a heterocycline group together with the linked nitrogen atom, or R ５ , R ６ It forms a heterocycline group together with the linked nitrogen atom, or R ８ , R ９ It forms a heterocycline group together with the linked nitrogen atom, or R １１ , R １２ The carbon atom forms a heterocyclyl group with the linked nitrogen atom, and the heterocyclyl group is optionally substituted with one or more substituents selected from oxo groups, halogens, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, cyano groups, hydroxyl groups, alkoxy groups, haloalkoxy groups, amino groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups. R １３ Each instance is either identical or different, and each is independently selected from a hydrogen atom, an alkyl group, and a cycloalkyl group. R ５ａ , R ６ａ , R １１ａ , R １２ａ , R １１ｂ and R １２ｂ Each instance is either identical or different, and each is independently selected from a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, aminoalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, arylalkyl group, and heteroarylalkyl group. s is 0, 1, or 2. v is 0, 1, or 2. u is 1, 2, 3 or 4, p is 0, 1, or 2. n is 0, 1, 2, 3 or 4, and m is an integer between 0 and 10. The compound indicated by or a medicinal salt thereof.

3. L1 is O, and / or Ring A is a 6-10 membered aryl group or a 5-10 membered heteroaryl group, preferably a phenyl group, and / or G is N, and / or R1 is a hydrogen atom, and / or L2 is O or (CR c R d)u O, where R c, R d and u are as defined in claim 1, preferably L2 is O or CH2O. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

4. General formula (II): 【Chemistry 2】 [In the formula, r is 0 or 1, Ring B, E, R ２ , R ３ , V １ , V ２ , V ３ , m and n are as defined in claim 1. The compound shown or a medicinal salt thereof, A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

5. General formula (II): 【Transformation 3】 [In the formula, r is 0 or 1, Rings B, E, R2, R3, V1, V2, V3, m, and n are as defined in claim 2. The compound shown or a medicinal salt thereof, A compound represented by general formula (I) as described in claim 2, or a medicinal salt thereof.

6. Ring B is an 8-membered condensed heterocyclyl group or a 7-8 membered cross-linked heterocyclyl group, preferably ring B is 【Chemistry 4】 And, R ３ It is replaceable at any replaceable position of ring B. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

7. Each R ３ They are the same or different, and each is independently a halogen, C １－６ Alkyl alkyl group, -OR １０ and -C(O)R １０ Selected from, the above C １－６ Alkyl groups can be optionally halogens, cyano groups, or -OR groups. １０ａ , -NR １１ａ R １２ａ , substituted with one or more substituents selected from 3-8 membered cycloalkyl groups, 3-8 membered heterocyclyl groups, 6-10 membered aryl groups, and 5-10 membered heteroaryl groups, and R １０ , R １０ａ , R １１ａ and R １２ａ is as defined in claim 1, preferably R ３ is halogen or -C(O)R １０ And R １０ This is as defined in claim 1, A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

8. General formula (III): 【Transformation 5】 [In the formula, Ring B is a 7-10 member nitrogen-containing condensed heterocyclyl group or a 7-10 member nitrogen-containing bridged heterocyclyl group. R １２ｃ , R １２ｄ and R １２ｅ They are identical or different, and each is independently a hydrogen atom, halogen, and C １－６ Selected from alkyl groups, 3-8 membered cycloalkyl groups, and 3-8 membered heterocyclyl groups, the C １－６ Alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 8-membered heterocyclyl groups can each be independently and optionally selected as an oxo group, halogen, or C. １－６ alkyl group, C １－６ Haloalkyl group, C １－６ It is substituted with one or more substituents selected from alkoxy groups, hydroxyl groups, cyano groups, and amino groups, preferably R １２ｃ , R １２ｄ and R １２ｅ They are the same or different, and each is independently a hydrogen atom, halogen, and C １－６ Selected from alkyl groups, more preferably R １２ｃ , R １２ｄ and R １２ｅ Both are hydrogen atoms, and E, R ２ , L ２ , V １ , V ２ , V ３ and n are as defined in claim 1. The compound shown or a medicinal salt thereof, A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

9. General formula (III): 【Transformation 6】 [In the formula, Ring B is a 7-10 member nitrogen-containing condensed heterocyclyl group or a 7-10 member nitrogen-containing bridged heterocyclyl group. R12c, R12d, and R12e are the same or different and each is independently selected from a hydrogen atom, a halogen, a C1-6 alkyl group, a 3-8 membered cycloalkyl group, and a 3-8 membered heterocyclyl group, and each of the C1-6 alkyl group, 3-8 membered cycloalkyl group, and 3-8 membered heterocyclyl group is independently and optionally substituted with one or more substituents selected from an oxo group, a halogen, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a hydroxyl group, a cyano group, and an amino group, preferably R12c, R12d, and R12e are the same or different and each is independently selected from a hydrogen atom, a halogen, and a C1-6 alkyl group, more preferably R12c, R12d, and R12e are all hydrogen atoms, and E, R2, L2, V1, V2, V3, and n are as defined in claim 2. The compound shown or a medicinal salt thereof, A compound represented by general formula (I) as described in claim 2, or a medicinal salt thereof.

10. E is 【Transformation 7】 Selected from, X is N or CR １６ａ And R １６ａ , R １６ｂ and R １６ｃ They are the same or different, and each is independently a hydrogen atom, halogen, and C １－６ Selected from alkyl groups, R １６ｄ C is a hydrogen atom. １－６ Selected from alkyl groups and 3- to 8-membered cycloalkyl groups, R １６ is halogen or C １－６ It is an alkyl group, and q is 0, 1, 2, or 3. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

11. Each R ２ They are identical or different, and each is independently C １－６ It is an alkyl group or halogen. A compound represented by general formula (I) as described in claim 1 or 2, or a medicinal salt thereof.

12. V １ is C(R ａ ) or N, V ２ and V ３ They are identical or different, and each is independently C(R) ａ ) or N, or V ２ is C(R ｂｂ ) and V ３ is C(R ｃｃ ) and R ｂｂ and R ｃｃ Each of these groups forms a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocycline group together with the carbon atoms to which it is linked, R ａ is a hydrogen atom or C １－６ It is an alkoxy group, A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

13. V1 is N or CH, V 2 is C(Ra) or N, Ra is a hydrogen atom or a C1-6 alkoxy group. V 3 is CH. A compound represented by general formula (I) as described in claim 2, or a medicinal salt thereof. 【Request Item 14】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 Selected from the following compounds: A compound represented by general formula (I) as described in claim 1, or a medicinal salt thereof.

15. General formula (IIIa): 【Chemistry 13】 [In the formula, E, ring B, R ２ , L ２ , V １ , V ２ , V ３ And n is as defined in claim 8. The compound or salt thereof indicated by [the symbol].

16. General formula (IIIa): 【Chemistry 14】 [In the formula, E, ring B, R2, L2, V1, V2, V3, and n are as defined in claim 9. The compound or salt thereof indicated by [the symbol]. 【Request Item 17】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 A compound or a salt thereof selected from the following compounds.

18. A method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, 【Chemistry 22】 The process includes the step of reacting a compound represented by general formula (IIa) or a salt thereof with a compound represented by general formula (IIb) or a salt thereof in a nucleophilic substitution reaction to obtain a compound represented by general formula (II) or a pharmaceutically usable salt thereof, Here, R is C １－６ It is an alkyl group, preferably R is a methyl group. E, ring B, R ２ , R ３ , V １ , V ２ , V ３ ,r,m and n are as defined in claim 4, method.

19. A method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, 【Chemistry 23】 The process includes the step of condensing a compound represented by general formula (IIIa) or a salt thereof with a compound represented by general formula (IIIb) or a salt thereof to obtain a compound represented by general formula (III) or a medicinal salt thereof, Here, X Ｌ is a halogen, preferably X Ｌ It is chlorine, E, ring B, R ２ , L ２ , V １ , V ２ , V ３ , R １２ｃ , R １２ｄ , R １２ｅ and n are as defined in claim 8, method.

20. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, comprising one or more pharmaceutically acceptable vectors, diluents, or excipients, Pharmaceutical composition.

21. A pharmaceutical composition according to claim 20 for inhibiting HER2.

22. A pharmaceutical composition according to claim 20 for treating and / or preventing a disease or condition by inhibiting HER2, wherein the disease or condition is preferably cancer.

23. A pharmaceutical composition according to claim 20 for treating and / or preventing cancer, wherein the cancer is preferably selected from brain cancer, breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, cervical cancer, fallopian tube cancer, endometrial cancer, prostate cancer, stomach cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, esophageal cancer, liver cancer, skin cancer, mesothelioma, bladder cancer, renal cell carcinoma, renal pelvis cancer, ureteral cancer, small intestine cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, vaginal cancer, vulvar cancer, leukemia, adrenal cancer, urethral cancer, penile cancer, testicular cancer, bone cancer, osteosarcoma, myeloma, soft tissue sarcoma, pituitary adenoma, brainstem glioma, spinal tumor, and lymphoma, and more preferably, the cancer is selected from breast cancer, stomach cancer, lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer, and ovarian cancer.

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