Fused tetracyclic compounds, their preparation method and their medical applications

Abstract

The present disclosure relates to a fused tetracyclic compound, its preparation method and its pharmaceutical application.Specifically, the present disclosure relates to a fused tetracyclic compound represented by general formula (I), its preparation method and pharmaceutical composition comprising such compound, and its use as a therapeutic agent, particularly in the preparation of a drug for inhibiting KRAS G12D.Wherein, each group in general formula (I) is as defined in the specification. TIFF2024522766000297.tif3664

Description

[Technical field]

[0001] The present disclosure belongs to the pharmaceutical field, and relates to a fused tetracyclic compound, its preparation method and its pharmaceutical application.In particular, the present disclosure relates to a fused tetracyclic compound represented by general formula (I), its preparation method and pharmaceutical composition comprising such compound, and its use in preparing a drug for inhibiting KRAS G12D. [Background technology]

[0002] RAS is one of the oncogenic genes with the highest mutation rate in tumors, and approximately 30% of human malignant tumors are associated with RAS gene mutations. The RAS family includes KRAS, NRAS, and HRAS, among which KRAS mutations are the most common, accounting for approximately 85% of cases. KRAS mutations are common in solid tumors, and are frequently present in the three major lethal cancers in humans: lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Among KRAS gene mutations, 97% are mutations in the 12th or 13th amino acid residue, of which G12D is the key mutation. Data analysis of Western populations showed that G12D mutations accounted for 36%, 12%, and 4% of patients in pancreatic cancer, colorectal cancer, and non-small cell lung cancer, respectively.

[0003] After KRAS is activated, various functions such as cell proliferation, survival, migration and metabolism are regulated by many downstream signaling pathways, including RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. When the KRAS gene is mutated, the protein is continuously activated, which continuously activates downstream signaling pathways and promotes tumor development.

[0004] KRAS protein has long been considered an undruggable drug target, since it lacks traditional small molecule binding sites on its surface and is extremely difficult to inhibit due to its ultra-high affinity for guanylate. However, the importance and ubiquity of KRAS aberrant activation in cancer progression has made KRAS a highly attractive target for drug development. Currently, most patients with KRAS mutations are still without a drug, since in addition to KRAS G12C inhibitors, effective KRAS inhibitors for other mutations are still lacking. G12D is a mutant that is widely and highly expressed in various tumors, and the development of inhibitors against it has important clinical significance.

[0005] Currently disclosed related patent applications include WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, and WO2021000885A1. Summary of the Invention

[0006] The present disclosure aims to provide compounds of general formula (I) or medicamentable salts thereof: [ka] Among them, G 0 are O, S, S(O), S(O)2, and CR. G0a R G0b and N.R. G0c Selected from G 1 is CR G1a R G1b , C.R. G1a R G1b CR G1c R G1d , C=O and C(O)CR G1a R G1b Selected from G 2 is NR d and T is a chemical bond or CR a R b , N.R. Tand O; Q is N or CR 2a and Ring A is an aryl group or a heteroaryl group; Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; L is a single bond, O and NR e Selected from R a , R b , R G0a , R G0b , R G1a , R G1b , R G1c and R G1d are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group; or R G1a , R G1b forms a cycloalkyl group together with the carbon atom to which it is attached, or R G1c , R G1d forms a cycloalkyl group together with the carbon atom to which it is attached; Each R 1 are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) u -NR f R g , a hydroxy group, and a hydroxyalkyl group; R 2a and R 4a are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) v -NR h R i , a hydroxy group, a hydroxyalkyl group, and a cycloalkyl group; Each R 3 and R 6are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) w -NR j R k , -(CH2) w1 -(O) z1 -C(O)NR j1 R k1 , -(CH2) w2 -(O) z2 -C(O)OR j2 , a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 5a and R 5b are identical or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxyl group, and a hydroxyalkyl group; or R 5a , R 5b together with the carbon atom to which it is linked form a cycloalkyl or heterocyclyl group, each of which is independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl groups; R G0c , R T , R d , R e , R f , R g , R h , R i , R j , R k , R j1 , R k1 and R j2 are identical or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; u, v, w, w1 and w2 are identical or different and are each independently selected from 0, 1, 2 and 3; z1 is 0 or 1, z2 is 0 or 1; r is 0, 1, 2 or 3; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4 or 5, and t is 0, 1, 2, 3, 4, or 5.

[0007] The present disclosure provides compounds represented by the general formula (I) or a medicamentable salt thereof: [ka] Among them, G 0 are O, S, S(O), S(O)2, and CR. G0a R G0b and N.R. G0c Selected from G 1 is CR G1a R G1b , C.R. G1a R G1b CR G1c R G1d , C=O and C(O)CR G1a R G1b Selected from G 2 is NR d and T is a chemical bond or CR a R b , N.R. T and O; Q is N or CR 2a and Ring A is an aryl group or a heteroaryl group; Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; L is a single bond, O and NR e Selected from R a , R b , R G0a , R G0b , RG1a , R G1b , R G1c and R G1d are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group; or R G1a , R G1b forms a cycloalkyl group together with the carbon atom to which it is attached, or R G1c , R G1d forms a cycloalkyl group together with the carbon atom to which it is attached; Each R 1 are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) u -NR f R g , a hydroxy group, and a hydroxyalkyl group; R 2a and R 4a are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) v -NR h R i , a hydroxy group, a hydroxyalkyl group, and a cycloalkyl group; Each R 3 and R 6 are identical or different and each independently represent a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) w -NR j R k , a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 5a and R 5bare identical or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxy group, and a hydroxyalkyl group; R G0c , R T , R d , R e , R f , R g , R h , R i , R j , R k and R j are identical or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; u, v and w are the same or different and are each independently selected from 0, 1, 2 and 3; r is 0, 1 or 2; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4 or 5, and t is 0, 1, 2, 3, 4, or 5.

[0008] 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 (I') or a medicamentable salt thereof: [ka] Among them, y is 0, 1, 2, 3 or 4; Ring A, Ring B, G 0 , G 1 , T., G. 2 , Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, r and t are as defined in general formula (I).

[0009] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or (I') or a medicamentable salt thereof, wherein: [ka] teeth, [ka] and preferably [ka] and more preferably [ka] It is.

[0010] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or (I′) or a medicamentable salt thereof, wherein: 0 is O, CR G0a R G0b and N.R. G0c Selected from R G0a and R G0b are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group and C 1-6 haloalkyl groups, R G0c is a hydrogen atom or C 1-6 is an alkyl group, preferably G 0 is selected from O, CH2 and NH, more preferably, G 0 is O.

[0011] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or (I′) or a medicamentable salt thereof, wherein: 1 is CR G1a R G1b , C.R. G1a R G1b CR G1c R G1d or C=O, R G1a , R G1b , RG1c and R G1d are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group and C 1-6 haloalkyl groups, preferably G 1 is CH2 or C=O, more preferably, G 1 is CH2.

[0012] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or (I′) or a medicamentable salt thereof, wherein -G 0 -G 1 - is selected from -O-CH2-, -NH-C(O)-, -NH-CH2-, -CH2-CH2- and -O-CH2-CH2-, preferably -O-CH2- or -NH-C(O)-, more preferably -O-CH2-.

[0013] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or (I') or a medicamentable salt thereof, wherein T is a chemical bond.

[0014] 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, Ring A, Ring B, G 2 , Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, q, r and t are as defined in general formula (I).

[0015] 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 preferably [ka] and more preferably [ka] It is.

[0016] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein Q is N or CH, preferably N.

[0017] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein R 2a is a hydrogen atom, halogen, C 1-6 Alkyl group and C 1-6 haloalkyl groups, preferably R 2a is a hydrogen atom or C 1-6 More preferably, R 2a is a hydrogen atom.

[0018] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, preferably ring A is a phenyl group or a naphthyl group, more preferably a naphthyl group.

[0019] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3 is as defined in general formula (I), preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 More preferably, each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 haloalkyl, hydroxy and cyclopropyl groups, and even more preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 It is selected from an alkyl group and a hydroxy group.

[0020] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3 is as defined in general formula (I), preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 More preferably, each R 3 are the same or different, and are each independently selected from a hydrogen atom, F, an ethyl group, an ethynyl group, and a hydroxy group.

[0021] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3A , R 3B and R 3C are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 haloalkyl groups and hydroxy groups, preferably R 3A is halogen, C 1-6 Alkyl group and C 2-6 alkynyl groups, R 3B is a hydrogen atom or a halogen atom, and R 3C is a hydroxy group, and more preferably, R 3A is selected from F, an ethyl group, and an ethynyl group; R 3B is a hydrogen atom or F, and R 3C is a hydroxy group.

[0022] 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 and R 3B are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl groups and C 1-6 haloalkyl groups, preferably R 3A is halogen, C1-6 Alkyl group and C 2-6 alkynyl groups, R 3B is a hydrogen atom or a halogen atom, and more preferably, R 3A is selected from F, an ethyl group, and an ethynyl group; R 3B is selected from a hydrogen atom or F.

[0023] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3 is as defined in general formula (I), preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 More preferably, each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 haloalkyl, hydroxy and cyclopropyl groups, and even more preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 It is selected from an alkyl group and a hydroxy group.

[0024] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3 is as defined in general formula (I), preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 More preferably, each R 3 are the same or different, and are each independently selected from a hydrogen atom, F, an ethyl group, an ethynyl group, and a hydroxy group.

[0025] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3 is as defined in general formula (I), preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 More preferably, each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 haloalkyl, hydroxy and cyclopropyl groups, and even more preferably each R 3 are the same or different and are each independently selected from a hydrogen atom, a halogen, a cyclopropyl group, and a hydroxy group.

[0026] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3 is as defined in general formula (I), preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 More preferably, each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 More preferably, each R is selected from haloalkyl groups, hydroxyl groups, and 3- to 8-membered cycloalkyl groups. 3 are the same or different, and each is independently selected from Cl, a hydroxy group, CF3, and a cyclopropyl group.

[0027] In some embodiments of the present disclosure, the present invention provides a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 3D , R 3E and R 3F are the same or different, and each independently represents a halogen, C 1-6 is selected from a haloalkyl group, a hydroxyl group, and a 3- to 8-membered cycloalkyl group, preferably R 3D is C 1-6haloalkyl group or 3-8 membered cycloalkyl group, R 3E is a halogen, and R 3F is a hydroxy group, and more preferably, R 3D is CF3 or a cyclopropyl group, R 3E is Cl, and R 3F is a hydroxy group.

[0028] 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 3D and R 3E are the same or different, and each independently represents a halogen, C 1-6 is selected from haloalkyl groups and 3- to 8-membered cycloalkyl groups, preferably R 3D is C 1-6 haloalkyl group or 3-8 membered cycloalkyl group, R 3E is halogen, more preferably R 3D is CF3 or a cyclopropyl group, R 3E is Cl.

[0029] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein ring B is a 7-10 membered fused heterocyclyl group, and R 6 can be substituted at any position of the ring B, and preferably, the ring B is [ka] and R 6 can be substituted at any position of ring B.

[0030] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein ring B is a 3-8 membered heterocyclyl group.

[0031] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and R 6 is as defined in general formula (I), preferably [ka] teeth [ka] and R 6 is a halogen, more preferably [ka] teeth [ka] and R 6 is a halogen, and R 6 More preferably, is F.

[0032] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] and preferably [ka] It is.

[0033] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein: [ka] teeth [ka] Selected from R 6 is as defined in general formula (I), preferably [ka] teeth [ka] More preferably, [ka] teeth [ka] Selected from.

[0034] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein R 4a is a hydrogen atom, halogen, C 1-6 Alkyl group and C 1-6 It is selected from haloalkyl groups, preferably a hydrogen atom or a halogen, more preferably a hydrogen atom or F.

[0035] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein R d is a hydrogen atom or C 1-6is an alkyl group, preferably R d is a hydrogen atom.

[0036] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein: 2 is NH.

[0037] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein L is selected from CH2, NH and O, and is preferably O.

[0038] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein R e is a hydrogen atom or C 1-6 is an alkyl group, preferably R e is a hydrogen atom.

[0039] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein each R 1 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, cyano group, amino group, -(CH2) u -NR f R g , hydroxy group and C 1-6 hydroxyalkyl groups, R f and R g are identical or different, and each independently represents a hydrogen atom or C 1-6 is an alkyl group, u is 0 or 1, and preferably each R 1 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group and C 1-6 More preferably, R is selected from haloalkyl groups. 1 is a hydrogen atom.

[0040] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, cyano group, amino group, -(CH2) w -NR j R k , hydroxy group and C 1-6 hydroxyalkyl groups, R j and R k are identical or different, and each independently represents a hydrogen atom or C 1-6 is an alkyl group, w is 0 or 1, and preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 More preferably, each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 haloalkyl, hydroxy and cyclopropyl groups, and even more preferably each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 It is selected from an alkyl group and a hydroxy group.

[0041] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein each R 3are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 More preferably, each R 3 are the same or different, and each independently selected from a hydrogen atom, F, an ethyl group, an ethynyl group, and a hydroxy group, or selected from Cl, a hydroxy group, CF3, and a cyclopropyl group.

[0042] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein R 5a and R 5b are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl groups, hydroxy groups and C 1-6 hydroxyalkyl groups, preferably R 5a and R 5b are identical or different, and each independently represents a hydrogen atom, C 1-6 Alkyl groups, hydroxyl groups and C 1-6 More preferably, R 5a and R 5b is a hydrogen atom.

[0043] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein R 5a and R 5b is a hydrogen atom, or R 5a , R 5b forms a 3- to 6-membered cycloalkyl group together with the carbon atom to which it is linked, and preferably, R 5a and R 5b is a hydrogen atom, or R 5a , R 5b together with the carbon atom to which it is linked form a cyclopropyl group.

[0044] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein each R 6 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, cyano group, amino group, -(CH2) w -NR j R k , hydroxy group and C 1-6 hydroxyalkyl groups, R j and R k are identical or different, and each independently represents a hydrogen atom or C 1-6 is an alkyl group, w is 0 or 1, and preferably each R 6 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group and C 1-6 It is selected from haloalkyl groups, more preferably hydrogen or halogen, and even more preferably F.

[0045] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein each R 6 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Hydroxyalkyl groups and -CH2-OC(O)NR j1 R k1 Selected from R j1 and R k1 are identical or different, and each independently represents a hydrogen atom or C 1-6 is an alkyl group, and preferably each R 6 are identical or different, and are each independently selected from a hydrogen atom, F, a hydroxymethyl group, and -CH2-OC(O)N(CH3)2.

[0046] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein R j1 is C 1-6 It is an alkyl group, preferably a methyl group.

[0047] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I′) or (II) or a medicamentable salt thereof, wherein R k1 is C 1-6 It is an alkyl group, preferably a methyl group.

[0048] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein r is 0 or 1, preferably 1.

[0049] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein r is 1 or 3.

[0050] In some embodiments of the present disclosure, the compound represented by the above general formula (I), (I') or (II) or a medicament salt thereof, wherein p is 0 or 1, preferably 1. In some embodiments of the present disclosure, the compound represented by the above general formula (I), (I') or (II) or a medicament salt thereof, wherein (R 1 ) p does not exist.

[0051] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I) or (II) or a medicamentable salt thereof, wherein q is 2 or 3, preferably 2.

[0052] 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 y is 1 or 2, preferably 1.

[0053] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein t is 1 or 2, preferably 1.

[0054] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein u is 0 or 1.

[0055] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein v is 0 or 1.

[0056] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein w is 0 or 1.

[0057] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein w1 is 0 or 1.

[0058] In some embodiments of the present disclosure, the compound is represented by the above general formula (I), (I') or (II) or a medicamentable salt thereof, wherein w2 is 0 or 1.

[0059] 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 ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, ring B is a 7- to 10-membered fused heterocyclyl group, and R 6 can be substituted at any position of the ring B; 2 is NH, Q is N or CH, L is O, p is 1, R 1 is a hydrogen atom, halogen, C 1-6 Alkyl group and C 1-6haloalkyl, q is 2 or 3, and each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 R is selected from the group consisting of hydroxyalkyl groups and 3- to 8-membered cycloalkyl groups; 4a is a hydrogen atom, halogen, C 1-6 Alkyl group and C 1-6 haloalkyl groups, r is 0 or 1, R 5a and R 5b are identical or different, and each independently represents a hydrogen atom, C 1-6 Alkyl groups, hydroxyl groups and C 1-6 hydroxyalkyl groups, t is 1, and R 6 is a hydrogen atom, halogen, C 1-6 Alkyl group and C 1-6 It is selected from haloalkyl groups.

[0060] 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 ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, ring B is a 3- to 8-membered heterocyclyl group, and G 2 is NH, Q is N or CH, L is O, (R 1 ) p is absent, q is 2 or 3, and each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, hydroxy group, C 1-6 R is selected from the group consisting of hydroxyalkyl groups and 3- to 8-membered cycloalkyl groups; 4a is a hydrogen atom or a halogen atom, r is 1 or 3, R 5a and R 5b is a hydrogen atom, or R 5a , R 5b forms a cyclopropyl group together with the carbon atom to which it is linked, t is 1, and R6 is a hydrogen atom, halogen, C 1-6 Hydroxyalkyl groups and -CH2-OC(O)NR j1 R k1 Selected from R j1 and R k1 are identical or different, and each independently represents a hydrogen atom or C 1-6 It is an alkyl group.

[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: [ka] teeth [ka] And each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 selected from a haloalkyl group, a hydroxyl group, and a 3- to 8-membered cycloalkyl group; [ka] teeth [ka] and R 6 is a halogen, and G 2 is NH, Q is N or CH, L is O, (R 1 ) p does not exist, and R 4a is a hydrogen atom or a halogen atom, r is 0 or 1, R 5a and R 5b is a hydrogen atom.

[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: [ka] teeth [ka] and [ka] teeth [ka] And each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 2-6 Alkynyl group, C 1-6 selected from a haloalkyl group, a hydroxyl group, and a 3- to 8-membered cycloalkyl group; [ka] teeth [ka] and R 6 is a halogen, and G 2 is NH, Q is N or CH, L is O, (R 1 ) p does not exist, and R 4a is a hydrogen atom or a halogen atom, r is 0 or 1, R 5a and R 5b is a hydrogen atom.

[0063] 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 each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6selected from a haloalkyl group, a hydroxyl group, and a 3- to 8-membered cycloalkyl group; [ka] teeth [ka] and R 6 is a halogen, and G 2 is NH, Q is N or CH, L is O, (R 1 ) p does not exist, and R 4a is a hydrogen atom or a halogen atom, r is 0 or 1, R 5a and R 5b is a hydrogen atom.

[0064] 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 [ka] teeth [ka] And each R 3 are identical or different and each independently represents a hydrogen atom, a halogen, or C 1-6 Alkyl group, C 1-6 selected from a haloalkyl group, a hydroxyl group, and a 3- to 8-membered cycloalkyl group; [ka] teeth [ka] and R 6is a halogen, and G 2 is NH, Q is N or CH, L is O, (R 1 ) p does not exist, and R 4a is a hydrogen atom or a halogen atom, r is 0 or 1, R 5a and R 5b is a hydrogen atom.

[0065] [Table 1-1]

[0066] [Table 1-2]

[0067] [Table 1-3]

[0068] [Table 1-4]

[0069] [Table 1-5]

[0070] [Table 1-6]

[0071] [Table 1-7]

[0072] [Table 1-8]

[0073] [Table 1-9]

[0074]

Table 1-10

[0075]

Table 1-11

[0076]

Table 1-12

[0077]

Table 1-13

[0078]

Table 1-14

[0079]

Table 1-15

[0080]

Table 1-16

[0081]

Table 1-17

[0082]

Table 1-18

[0083]

Table 1-19

[0084]

Table 1-20

[0085]

Table 1-21

[0086]

Table 1-22

[0087]

Table 1-23

[0088]

Table 1-24

[0089]

Table 1-25

[0090]

Table 1-26

[0091]

Table 1-27

[0092]

Table 1-28

[0093]

Table 1-29

[0094]

Table 1-30

[0095]

Table 1-31

[0096]

Table 1-32

[0097]

Table 1-33

[0098]

Table 1-34

[0099]

Table 1-35

[0100]

Table 1-36

[0101]

Table 1-37

[0102]

Table 1-38

[0103]

Table 1-39

[0104]

Table 1-40

[0105]

Table 1-41

[0106]

Table 1-42

[0107]

Table 1-43

[0108]

Table 1-44

[0109]

Table 1-45

[0110]

Table 1-46

[0111]

Table 1-47

[0112]

Table 1-48

[0113]

Table 1-49

[0114]

Table 1-50

[0115]

Table 1-51

[0116]

Table 1-52

[0117]

Table 1-53

[0118]

Table 1-54

[0119]

Table 1-55

[0120]

Table 1-56

[0121]

Table 1-57

[0122]

Table 1-58

[0123]

Table 1-59

[0124]

Table 1-60

[0125]

Table 1-61

[0126]

Table 1-62

[0127]

Table 1-63

[0128]

Table 1-64

[0129]

Table 1-65

[0130]

Table 1-66

[0131]

Table 2-1

[0132]

Table 2-2

[0133]

Table 2-3

[0134]

Table 2-4

[0135]

Table 2-5

[0136]

Table 2-6

[0137]

Table 2-7

[0138]

Table 2-8

[0139]

Table 2-9

[0140]

Table 2-10

[0141]

Table 2-11

[0142]

Table 2-12

[0143]

Table 2-13

[0144]

Table 2-14

[0145] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof: [ka] Among them, R is an amino protecting group, preferably Boc; G 0 , G 1 , T, ring A, ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, q, r and t are as defined in general formula (I).

[0146] Another aspect of the present disclosure relates to a compound represented by general formula (I'A) or a salt thereof: [ka] Among them, R is an amino protecting group, preferably Boc; R y is a hydroxy protecting group, preferably MOM; y is 0, 1, 2, 3 or 4; G 0 , G 1 , T, ring A, ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, r and t are as defined in general formula (I').

[0147] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof: [ka] Among them, R is an amino protecting group, preferably Boc; Ring A, Ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, q, r and t are as defined in general formula (II).

[0148] [Table 3-1]

[0149] [Table 3-2]

[0150] [Table 3-3]

[0151] [Table 3-4]

[0152] [Table 3-5]

[0153] [Table 3-6]

[0154] [Table 3-7]

[0155] [Table 3-8]

[0156] [Table 3-9]

[0157]

Table 3-10

[0158]

Table 3-11

[0159]

Table 3-12

[0160]

Table 3-13

[0161]

Table 3-14

[0162]

Table 3-15

[0163]

Table 3-16

[0164]

Table 3-17

[0165]

Table 3-18

[0166]

Table 3-19

[0167]

Table 3-20

[0168]

Table 3-21

[0169]

Table 3-22

[0170]

Table 3-23

[0171]

Table 3-24

[0172]

Table 3-25

[0173]

Table 3-26

[0174]

Table 3-27

[0175]

Table 3-28

[0176]

Table 3-29

[0177]

Table 3-30

[0178]

Table 3-31

[0179]

Table 3-32

[0180]

Table 3-33

[0181]

Table 3-34

[0182]

Table 3-35

[0183]

Table 3-36

[0184]

Table 3-37

[0185]

Table 3-38

[0186]

Table 3-39

[0187]

Table 3-40

[0188]

Table 3-41

[0189]

Table 3-42

[0190]

Table 3-43

[0191]

Table 3-44

[0192]

Table 3-45

[0193]

Table 3-46

[0194]

Table 3-47

[0195]

Table 3-48

[0196]

Table 3-49

[0197] [Table 3-50]

[0198] [Table 3-51]

[0199] [Table 3-52]

[0200] [Table 3-53]

[0201] [Table 3-54]

[0202] [Table 3-55]

[0203] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I) or a medicamentable salt thereof, the method comprising: [ka] Deprotecting the compound of general formula (IA) or a salt thereof to obtain a compound of general formula (I) or a medicamentable salt thereof, optionally comprising R 3 and / or R 6 When the group contains a protecting group, R 3 and / or R 6 removing a protecting group on the group, Among them, R is an amino protecting group, preferably Boc; G 2 is NH, G 0, G 1 , T, ring A, ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, q, r and t are as defined in general formula (I).

[0204] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I') or a medicamentable salt thereof, the method comprising: [ka] Deprotecting the compound of general formula (I'A) or a salt thereof to obtain a compound of general formula (I') or a medicamentable salt thereof, optionally comprising: 3 and / or R 6 When the group contains a protecting group, R 3 and / or R 6 removing a protecting group on the group, Among them, R is an amino protecting group, preferably Boc; R y is a hydroxy protecting group, preferably MOM; y is 0, 1, 2, 3 or 4; G 2 is NH, G 0 , G 1 , T, ring A, ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, r and t are as defined in general formula (I').

[0205] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (II) or a medicamentable salt thereof, the method comprising: [ka] Deprotecting the compound of general formula (IIA) or a salt thereof to obtain a compound of general formula (II) or a medicamentable salt thereof, optionally comprising: 3 and / or R 6 When the group contains a protecting group, R 3 and / or R 6 removing a protecting group on the group, wherein R is an amino protecting group, preferably Boc; G 2 is NH, Ring A, Ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, q, r and t are as defined in general formula (II).

[0206] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of general formula (I), (I'), (II), Table A or Table B according to the present disclosure or a medicament salt thereof, and one or more pharma- ceutically acceptable vectors, diluents or excipients.

[0207] The present disclosure further relates to the use of a compound as shown in general formula (I), (I'), (II), Table A or Table B, or a medicament salt thereof, or a pharmaceutical composition comprising same, in the preparation of a medicament for inhibiting KRAS G12D.

[0208] The present disclosure further relates to the use of a compound of general formula (I), (I'), (II), Table A or Table B, or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is cancer, and the disease or condition is selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, and the like. cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and spongioblastoma, and more preferably pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0209] The present disclosure further relates to a method for inhibiting KRAS G12D, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as set forth in general formula (I), (I'), (II), Table A or Table B, or a medicamentable salt thereof, or a pharmaceutical composition comprising same.

[0210] The present disclosure further relates to a method for treating and / or preventing a disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as set forth in general formula (I), (I'), (II), Table A or Table B, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, wherein said disease or condition is cancer, and said disease or condition includes brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, or the like. cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and spongioblastoma, and more preferably pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0211] The present disclosure further relates to a compound of general formula (I), (I'), (II), Table A or Table B, or a medicamentable salt thereof, or a pharmaceutical composition containing same, for use as a medicament.

[0212] The present disclosure further relates to a compound as shown in general formula (I), (I'), (II), Table A or Table B, or a medicamentable salt thereof, or a pharmaceutical composition comprising same, for use as an agent for inhibiting KRAS G12D.

[0213] The present disclosure further relates to a compound as shown in general formula (I), (I'), (II), Table A or Table B, or a medicamentable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is cancer, and the disease or condition is selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, and the like. cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and spongioblastoma, and more preferably pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0214] The diseases or conditions described in this disclosure are those that are treated and / or prevented by inhibiting KRAS G12D.

[0215] The colorectal cancer described in this disclosure is preferably colon cancer or rectal cancer.

[0216] Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma, the soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma and synovial sarcoma, the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma), and the liver cancer is preferably hepatocellular carcinoma; The lung cancer (also called bronchiolo- carcinoma) is selected from non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and squamous cell carcinoma, the renal cancer is selected from renal cell carcinoma, clear cell and renal eosinophilic tumor, the leukemia is selected from chronic lymphocytic leukemia (CLL), chronic granulocytic leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), the skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma, and the myeloma is preferably multiple myeloma.

[0217] The active compound can be prepared in a suitable form for administration by any suitable route, and the composition of the present disclosure can be prepared by one or more pharma- ceutically acceptable vectors in a conventional manner. Thus, the active compound of the present disclosure can be prepared in a dosage form for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous administration), inhalation, or insufflation. The compound of the present disclosure can be prepared in a dosage form such as, for example, tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, tablets for external application, or syrups.

[0218] However, as a general guideline, it is preferred that the active compounds of the present disclosure be in a unit dose form or in a form that the patient can self-administer 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 liquid, drug powder, granule, topical tablet, suppository, reconstituted powder or liquid formulation. A suitable unit dose may be 0.1 to 1000 mg.

[0219] 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, excipients, etc. The composition may contain 0.1 to 99% by weight of the active compound, depending on the method of administration.

[0220] The tablets contain the active ingredient and non-toxic medicamentous excipients suitable for mixing in the preparation of tablets. These excipients may be inert diluents, granulating agents, disintegrating agents, binding agents and lubricants. The 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, thus providing a sustained release effect over an extended period of time.

[0221] 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.

[0222] 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.

[0223] Oily suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil.Oily suspensions can contain thickening agents.In order to provide a palatable preparation, the above-mentioned sweeteners and flavorings can be added.These compositions can be preserved by adding antioxidants.

[0224] 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 or 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.

[0225] 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. To maintain such a constant concentration, a continuous intravenous administration device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

[0226] 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 according to known techniques using the above-mentioned suitable dispersing or wetting agents and suspending agents. 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.

[0227] 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.

[0228] The compounds of the present disclosure can be administered by adding water to prepare dispersible powders and granules in an aqueous suspension. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives.

[0229] 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 severity of the disease, 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, etc., and the optimal treatment method, such as the treatment mode, the daily dosage of the compound or the type of medicinal salt, etc., can be verified according to conventional treatment plans.

[0230] Explanation of terms Unless specifically stated to the contrary, terms used in the specification and claims have the following meanings.

[0231] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples are 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 such groups 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.

[0232] The term "alkylene group" refers to a saturated, straight or branched chain aliphatic hydrocarbon group, the residue derived by removing two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkane, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH)-, 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCHCH-), 1,4-butylene (-CHCHCHCHCH-), and the like. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available linkage site, and said substituents are preferably one or more selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0233] The term "alkenyl group" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where alkyl is as defined above, and preferably has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkenyl group), more preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6alkenyl groups). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more selected from 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.

[0234] The term "alkynyl group" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where alkyl is as defined above. Preferably, the alkyl group has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkynyl groups), more preferably alkynyl groups having 2 to 6 carbon atoms (i.e., C 2-6 alkynyl groups). Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more selected from 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.

[0235] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3-14 membered cycloalkyl group), preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3-8 membered cycloalkyl group), more preferably 3 to 6 carbon atoms (i.e., 3-6 membered cycloalkyl group). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl groups, and the like, and polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.

[0236] The term "spirocycloalkyl group" refers to a polycyclic group having 5 to 20 members, in which the monocyclic rings share one carbon atom (called a spiro atom), and may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups or polyspirocycloalkyl groups (e.g., bisspirocycloalkyl groups), and are preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, it is a 3 / 4 member, 3 / 5 member, 3 / 6 member, 4 / 4 member, 4 / 5 member, 4 / 6 member, 5 / 3 member, 5 / 4 member, 5 / 5 member, 5 / 6 member, 5 / 7 member, 6 / 3 member, 6 / 4 member, 6 / 5 member, 6 / 6 member, 6 / 7 member, 7 / 5 member or 7 / 6 member monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0237] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares a pair of adjacent carbon atoms with another ring in the system, and in which one or more rings may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings that constitute it, it can be divided into bicyclic or polycyclic fused cycloalkyl groups (e.g., tricyclic, tetracyclic), and is preferably a bicyclic or tricyclic, 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 ...7-membered / 5-membered or 7-membered / 6-membered bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes.

[0238] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Depending on the number of rings that constitute it, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups are: [ka]

[0239] The cycloalkyl rings include the above cycloalkyl groups (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which are: [ka] Including, [ka] is preferred.

[0240] A cycloalkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available attachment point, and said substituents are preferably one or more selected from halogen, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxo groups, heterocyclyloxo groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

[0241] The term "alkoxy group" refers to -O-(alkyl group), where alkyl group is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy and butoxy groups. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably 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.

[0242] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 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), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, 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- ring moieties, and the remaining ring atoms are carbon. Preferably, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms (i.e., a 3- to 14-membered heterocyclyl group), of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms, more preferably it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., a 3- to 8-membered heterocyclyl group) or 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14) of which 1 to 3 are heteroatoms (e.g., 1, 2, and 3), more preferably it contains 3 to 8 ring atoms, of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms, and most preferably it contains 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclyl group), of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups, and bridged heterocyclyl groups.

[0243] The term "spiroheterocyclyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (called a spiro atom), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., a 6-14 membered spiroheterocyclyl group), and more preferably 7-10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., a 7-10 membered spiroheterocyclyl group). Spiroheterocyclyl groups are divided into monospiroheterocyclyl groups or polyspiroheterocyclyl groups (e.g., bisspiroheterocyclyl groups) according to the number of spiro atoms shared between the rings, and are preferably monospiroheterocyclyl groups and bisspiroheterocyclyl groups. More preferably, they are 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 of spiroheterocyclyl groups are: [ka] Includes.

[0244] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more of the rings optionally containing one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., 6- to 14-membered fused heterocyclyl group), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 7- to 10-membered fused heterocyclyl group). Depending on the number of rings, the heterocyclyl groups can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclyl groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0245] The term "bridged heterocyclyl group" refers to a 5-20 membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally substituted with an oxo group (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It is preferably 6-14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., a 6-14 membered bridged heterocyclyl group), more preferably 7-10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., a 7-10 membered bridged heterocyclyl group). Depending on the number of rings that they consist of, they can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0246] The heterocyclyl rings include heterocyclyl groups as described above (including monocyclic, spiro, fused and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, where the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka] etc.

[0247] The heterocyclyl group may be substituted or unsubstituted and, when substituted, it may be substituted at any available point of attachment, and said substituents are preferably one or more selected from halogen, 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.

[0248] The term "aryl group" refers to a 6-14 membered all carbon monocyclic or fused polycyclic (fused polycyclic rings are rings that share adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6-10 membered, such as phenyl and naphthyl groups. The aryl rings include those fused to a heteroaryl, heterocyclyl or cycloalkyl ring, as described above, where the ring connected to the parent structure is an aryl ring, non-limiting examples of which are: [ka] Includes.

[0249] The aryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and said substituents are preferably one or more selected from halogen, 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.

[0250] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members (e.g., 5, 6, 7, 8, 9, or 10 members) (i.e., a 5-10 membered heteroaryl group), more preferably 8 to 10 members (e.g., 8, 9, or 10 members), and even more preferably 5 or 6 members (i.e., a 5- or 6-membered heteroaryl group), such as a furanyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, and the like. The heteroaryl rings include heteroaryl groups as defined above fused to an aryl group, a heterocyclyl group, or a cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes.

[0251] The heteroaryl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and said substituents are preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

[0252] The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom or two hydrogen atoms from the same parent ring atom or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene" groups.

[0253] The term "amino protecting group" refers to a group that protects an amino group with an easily removable group so that the amino group is not changed when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl group (SEM), tetrahydropyranyl group, tert-butoxycarbonyl group (Boc), acetyl group, benzyl group, allyl group, p-toluenesulfonyl group (Ts), and p-methoxybenzyl group. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy group, and nitro group, and the amino protecting group is preferably Boc.

[0254] The term "hydroxy protecting group" generally refers to a hydroxy derivative that is used to block or protect a hydroxy group and react with other functional groups of a compound. For example, the hydroxy protecting group is preferably, for example, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl and p-nitrobenzoyl, and the hydroxy protecting group is preferably MOM.

[0255] The term "alkynyl protecting group" refers to a group that is easily removable that is introduced into an alkynyl group so that the active hydrogen in the acetylene or terminal alkyne is not altered when other parts of the molecule react. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like, with the preferred alkynyl protecting group being TIPS.

[0256] The term "cycloalkyloxy" refers to a cycloalkyl-O- group, where the cycloalkyl group is as defined above.

[0257] The term "heterocyclyloxy group" refers to a heterocyclyl-O- group, where the heterocyclyl group is as defined above.

[0258] The term "aryloxy group" refers to an aryl-O- group, where the aryl group is as defined above.

[0259] The term "heteroaryloxy group" refers to a heteroaryl-O- group, where the heteroaryl group is as defined above.

[0260] The term "alkylthio group" refers to an alkyl-S- group, in which the alkyl group is as defined above.

[0261] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

[0262] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0263] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.

[0264] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, where the alkyl group is as defined above.

[0265] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0266] The term "hydroxy group" refers to --OH.

[0267] The term "mercapto" refers to -SH.

[0268] The term "amino group" refers to -NH2.

[0269] The term "cyano" refers to -CN.

[0270] The term "nitro group" refers to --NO.sub.2.

[0271] The term "oxo group" or "oxo" refers to "=O".

[0272] The term "carbonyl group" refers to C=O.

[0273] The term "carboxy" refers to -C(O)OH.

[0274] The term "carboxylic acid ester group" refers to a -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where the alkyl and cycloalkyl groups are defined above.

[0275] MOM refers to a methoxymethyl group.

[0276] Boc refers to a tert-butoxycarbonyl group.

[0277] TIPS refers to the triisopropylsilyl group.

[0278] TBS refers to the tert-butyldimethylsilyl group.

[0279] The compounds of the present disclosure may include all of their rotamers and conformationally restricted states. Atropisomers are further included, the term "atropisomer" being a stereoisomer produced by inhibiting rotation around a single bond axis, where the energy difference due to steric strain or other facilitating factors creates a rotation barrier high enough so that the individual conformers are separated. For example, some compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal ratio mixture, a mixture enriched in one atropisomer, etc.) or in the form of purified atropisomers. Non-limiting examples are: [ka] Includes.

[0280] The compounds and intermediates 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 structural isomers of different energies that are interconvertible by a low energy barrier. For example, proton tautomers (also called protolytic tautomers) include, for example, keto-enol and imine-enamine, lactam-lactim isomerizations, and other protolytic interconversions. An illustrative example of a keto-enol equilibrium is as follows: [ka]

[0281] All tautomeric forms are within the scope of this disclosure. The naming of a compound does not exclude any tautomeric form.

[0282] 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, conformational isomers, 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. Both Z and E configurations are included for any carbon-carbon double bond, even if only one configuration is named. 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 derivatization with chiral auxiliaries, or, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional 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 pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0283] 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] The above two types of arrangements may be included at the same time.

[0284] 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.

[0285] 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 linked to a carbon atom may be independently replaced with a deuterium atom, where deuterium replacement may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced with at least one deuterium.

[0286] "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 a halogen or cyano group" 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.

[0287] "Substituted" refers to one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group being independently replaced with a corresponding number of substituents. 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 having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0288] "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.

[0289] "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. The salts 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.

[0290] The term "therapeutically effective amount" of a drug or pharmacologically active agent refers to a dose of the drug or agent sufficient to produce or at least partially produce 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.

[0291] As used herein, the term "pharmacologically acceptable" means that these compounds, materials, compositions and / or dosage forms are, within the scope of reasonable medical judgment, applicable to contact with the tissues of a patient without undue toxicity, irritation, allergic response or other problem or complication, and are effective for the desired use, with a reasonable benefit / risk ratio.

[0292] As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly indicates otherwise.

[0293] The term "about" when used with parameters such as pH, concentration, temperature, etc., indicates that the parameter 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 the numbers are given merely for illustration, not limitation.

[0294] 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: Technical proposal 1

[0295] The present disclosure provides a process for preparing a compound of general formula (I) or a medicamentable salt thereof, the process comprising: [ka] The method comprises the steps of: subjecting a compound of general formula (IA) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (I) or a medicamentable salt thereof; and optionally, 3 and / or R6 When the R group contains a protecting group, the R 3 and / or R 6 removing a protecting group on the group, wherein R is an amino protecting group, preferably Boc; G 2 is NH, G 0 , G 1 , T, ring A, ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, q, r and t are as defined in general formula (I). Technical proposal 2

[0296] The present disclosure provides a method for preparing a compound of general formula (I') or a medicamentable salt thereof, the method comprising: [ka] The method comprises the step of subjecting a compound of general formula (I'A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (I') or a medicamentable salt thereof, and optionally comprising the step of: 3 and / or R 6 When the R group contains a protecting group, the R 3 and / or R 6 removing a protecting group on the group, wherein R is an amino protecting group, preferably Boc; R y is a hydroxy protecting group, preferably MOM; y is 0, 1, 2, 3 or 4; G 2 is NH, G 0 , G 1 , T, ring A, ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R5b , R 6 , p, r and t are as defined in general formula (I'). Technical proposal 3

[0297] The present disclosure provides a process for preparing a compound of general formula (II) or a medicamentable salt thereof, the process comprising: [ka] The compound of general formula (IIA) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound of general formula (II) or a medicamentable salt thereof, and optionally R 3 and / or R 6 When the R group contains a protecting group, the R 3 and / or R 6 removing a protecting group on the group, wherein R is an amino protecting group, preferably Boc; G 2 is NH, Ring A, Ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, q, r and t are as defined in general formula (II).

[0298] In the above synthesis scheme, the reagent providing the acidic condition includes an organic acid or an inorganic acid, the organic acid includes, but is not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me3SiCl, and TMSOTf, and the inorganic acid includes, but is not limited to, hydrogen chloride, hydrochloric acid in dioxane, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, preferably hydrochloric acid in dioxane.

[0299] In the above synthesis scheme, the reagent providing the basic condition includes organic bases or inorganic bases, the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, a solution of tetrabutylammonium fluoride in tetrahydrofuran, or 1,8-diazabicycloundec-7-ene, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide.

[0300] In the above synthesis scheme, R 3 and / or R 6 When a terminal alkynyl group is included in the aryl group, the terminal alkynyl group can be protected with TIPS, and the reagent for removing TIPS is preferably a solution of tetrabutylammonium fluoride in tetrahydrofuran or cesium fluoride.

[0301] The reaction of the above steps is preferably carried out in a solvent, and the solvents used include, but are not limited to, pyridine, 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, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0302] 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. Working Example

[0303] 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 -6 The unit is ppm. NMR measurements were performed using a Bruker AVANCE-400 or Bruker AVANCE NEO500M 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.

[0304] For the MS measurements, a liquid chromatograph mass spectrometer Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS) was used.

[0305] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector).

[0306] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive).

[0307] For high performance liquid chromatography (HPLC) analysis, high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 were used.

[0308] For chiral HPLC analysis, a high performance liquid chromatograph Agilent 1260 DAD was used.

[0309] For preparative high performance liquid chromatography, preparative chromatographs Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 were used.

[0310] For chiral separation, a preparative chromatograph Shimadzu LC-20AP was used.

[0311] Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0312] 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.

[0313] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the vector.

[0314] Kinase mean inhibition rate and IC 50 The values ​​were measured using a plate reader NovoStar (BMG, Germany).

[0315] The known starting materials according to the present invention may be synthesized by or according to 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 Chemicals, etc.

[0316] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0317] An argon or nitrogen atmosphere refers to an argon or nitrogen balloon of approximately 1 L volume connected to the reaction flask.

[0318] Hydrogen atmosphere refers to a hydrogen balloon of approximately 1 L volume attached to the reaction flask.

[0319] 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.

[0320] The hydrogenation reaction was generally carried out by repeating the process of evacuating and refilling with hydrogen three times.

[0321] A CEM Discover-S 908860 microwave reactor was used for microwave reactions.

[0322] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0323] In the examples, unless otherwise specified, the reaction temperature is room temperature, 20°C to 30°C.

[0324] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing solvent system of thin layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate, and the volume ratio of the solvents may be adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of basic or acidic reagent such as triethylamine and acetic acid.

[0325] Where the compounds in the Examples contain two or more chiral centers, the relative stereochemistry of these compounds has been identified by NMR studies and / or X-ray diffraction. In such cases, the prefix "rel" is used and these compounds are identified with the R / S nomenclature, where R / S does not denote absolute stereochemistry but provides only relative stereochemical information. For example, [ka] teeth, [ka] It refers to a 1:1 mixture, i.e., a racemic mixture.

[0326] Example 1 5-Fluoro-4-((5aS,6S,9R)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1-p1 and 1:1 mixture of diastereomers of 5-fluoro-4-((5aR,6R,9S)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1-p2 [ka] [ka]

[0327] Step 1 (±)-5-Methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate methyl 1b (±)-2-Pyrrolidone-5-methyl formate 1a (100g, 698.61mmol, Shanghai Bide) and dimethyl sulfate (110g, 872.10mmol) were mixed and reacted at 60°C for 16 hours. The reaction solution was cooled to room temperature and poured into a solution of triethylamine (100g) and methyl tert-butyl ether (150mL) in an ice bath. The solution was extracted with methyl tert-butyl ether (300mL x 6) and then concentrated under reduced pressure to obtain the crude product title compound 1b (90g, yield: 81.9%). The product was used in the next reaction without purification. MS m / z (ESI): 158.1[M+1].

[0328] Step 2 (±)-Methyl 5-(2-methoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate 1c Crude compound 1b (90 g, 572.64 mmol) and methyl nitroacetate (68.18 g, 572.63 mmol) were mixed and heated to 60° C. for 30 hours while stirring. The reaction solution was cooled to room temperature, and then ethyl acetate (300 mL) was added. After stirring for 0.5 hours, the solution was filtered. The filter cake was dried to obtain the title compound 1c (70 g, yield: 50%). The product was used in the next reaction without purification. MS m / z (ESI): 245.1[M+1].

[0329] Step 3 Methyl 4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (mixture of diastereomers) 1d Crude compound 1c (14 g, 57.3 mmol) was dissolved in 600 mL of methanol, 10% palladium carbon catalyst (wet) (14 g) was added, and the mixture was replaced with hydrogen gas three times and reacted with stirring for 48 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product, title compound 1d (10 g, yield: 94.6%), which was used in the next reaction without purification. MS m / z (ESI): 185.2[M+1].

[0330] Step 4 8-(tert-Butyl) 2-methyl(±)-rel-(1R,2R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 1e Crude compound 1d (10 g, 54.2 mmol) was dissolved in 300 mL of dichloromethane, and triethylamine (16 g, 158.12 mmol) and di-tert-butyl dicarbonate (11 g, 50.4 mmol, Shanghai Shaoyuan) were added under ice bath, and the mixture was reacted with stirring for 14 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 1e (3.3 g, yield: 21.3%). MS m / z (ESI): 285.2 [M+1]. HPLC analysis: retention time 1.02 min, purity: 98.5% (column: ACQUITY UPLC® BEH, C18, 1.7 μm, 2.1×50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: 10% to 95% acetonitrile).

[0331] Step 5 8-(tert-Butyl) 2-methyl(±)-rel-(1R,2R,5S)-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 1f Compound 1e (400 mg, 1.4 mmol) was dissolved in 2 mL of tetrahydrofuran, and 3.5 mL of 2 M borane dimethyl sulfide complex tetrahydrofuran solution was added. The mixture was reacted for 14 hours with stirring, and the reaction mixture was quenched by adding methanol. The mixture was then reacted at 50° C. for 14 hours. The reaction mixture 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 (176 mg, yield: 46.2%). MS m / z (ESI): 271.2[M+1].

[0332] Step 6 (±)-rel-(1R,2R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 1g Compound 1f (1 g, 3.69 μmol) was dissolved in 15 mL of tetrahydrofuran, and 4.4 mL of 1 M lithium aluminum hydride in tetrahydrofuran was added. The mixture was allowed to react at 0° C. for 1 hour while stirring. 0.2 mL of water, 0.2 mL of 15% aqueous sodium hydroxide solution, and 0.4 mL of water were added to the reaction solution in that order, and then anhydrous sodium sulfate was added and stirred for 10 minutes. The mixture was filtered, and the filtrate was concentrated to obtain the title compound 1g (430 mg, yield: 47.9%). The product was used in the next reaction without purification. MS m / z (ESI): 243.1[M+1].

[0333] Step 7 4-((tert-butoxycarbonyl)amino)-2,6-dichloronicotinic acid tert-butyl ester 1i 4-Amino-2,6-dichloropyridine 1h (1g, 6.13mmol, Shanghai Bide) was dissolved in 1,4-dioxane (15mL), and 15mL of 2M sodium bis(trimethylsilyl)amide tetrahydrofuran solution was added under ice bath, and the mixture was reacted with stirring for 0.5 hours. Then, di-tert-butyl dicarbonate (3.3g, 15.1mmol) was added, and the mixture was reacted with stirring for 14 hours. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (30mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure to obtain the title compound 1i (500mg, yield: 22.5%). The product was used directly in the next reaction without purification. MS m / z (ESI): 363.1[M+1].

[0334] Step 8 4-Amino-2,6-dichloronicotinic acid tert-butyl ester 1j Compound 1i (300 mg, 825.9 μmol) was dissolved in acetonitrile (8 mL), 0.35 mL of 4 M hydrochloric acid in dioxane was added, and the mixture was reacted with stirring for 2 hours. The pH was adjusted to neutral with 4 M aqueous sodium hydroxide solution in an ice bath, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure to obtain the crude product, title compound 1j (62 mg, yield: 28.5%). The product was used in the next reaction without purification. MS m / z (ESI): 363.1[M+1].

[0335] Step 9 2,6-dichloro-4-(3-(2,2,2-trichloroacetyl)ureido) nicotinic acid tert-butyl ester 1K Crude compound 1j (240 mg, 912.13 μmol) was dissolved in tetrahydrofuran (10 mL), trichloroacetyl isocyanate (260 mg, 1.38 mmol) was added, and the mixture was reacted with stirring for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 1k (411 mg, yield: 99.7%), which was used in the next reaction without purification. MS m / z (ESI): 449.9[M+1].

[0336] Step 10 5,7-Dichloropyrido[4,3-d]pyrimidine-2,4-diol 1l Crude compound 1k (410 mg, 913 μmol) was dissolved in 7M ammonia methanol solution (10 mL) and reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, methyl tert-butyl ether (10 mL) was added to the residue, stirred for 0.5 hours, filtered, and the filter cake was dried to obtain the crude product title compound 1l (200 mg, yield: 94.3%). The product was used in the next reaction without purification. MS m / z (ESI): 232.1[M+1].

[0337] Step 11 2,4,5,7-Tetrachloropyrido[4,3-d]pyrimidine 1m Crude compound 1l (150 mg, 646.4 μmol) was dissolved in phosphorus oxychloride (3 mL), N,N-diisopropylethylamine (420 mg, 3.2 mmol) was added, and the mixture was reacted at 110° C. for 3 hours with stirring. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to obtain the crude product, title compound 1m (170 mg, yield: 97.7%), which could be used in the next step without purification. MS m / z (ESI): 267.8[M+1].

[0338] Step 12 (±)-rel-(5aR,6R,9S)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 1n Compound 1m (104 mg, 386.7 μmol) and N,N-diisopropylethylamine (750 mg, 5.8 mmol) were dissolved in 7 mL of dichloromethane, and 1g (45 mg, 185.7 mmol) was added at -40°C. The mixture was reacted with stirring for 2 hours while maintaining the temperature. The reaction solution was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1n (30 mg, yield: 39.3%). MS m / z (ESI): 474.2[M+1].

[0339] Step 13 (5aS,6S,9R)-2-Chloro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 1o-1 and Diastereomeric mixture of (5aR,6R,9S)-2-chloro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 1o-2 Compound 1n (30 mg, 68.4 μmol) was dissolved in 1,4-dioxane (2 mL), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (22 mg, 138.1 μmol, Yakumei), 0.1 mL of 2M sodium bis(trimethylsilyl)amide tetrahydrofuran solution, and 4A molecular sieves (300 mg) were added, and the reaction was carried out at 90 ° C. for 14 hours with stirring. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain a 1:1 mixture of diastereomers of the title compounds 1o-1 and 1o-2 (14 mg, yield: 36.4%). MS m / z (ESI): 561.2[M+1].

[0340] Step 14 (5aS,6S,9R)-2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 1p-1 and Diastereomeric mixture of (5aR,6R,9S)-2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 1p-2 A 1:1 mixture of diastereomers of compounds 1o-1 and 1o-2 (20 mg, 35.6 μmol), 2-(8-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24 mg, 72.2 μmol, obtained by preparation according to the method disclosed in Example 282 on page 522 of the specification in patent application "WO2021 / 041671"), tetrakis(triphenylphosphine)palladium (6 mg, 5.19 μmol, adamas), and cesium carbonate (58 mg, 178 μmol) were dissolved in a mixed solution of 3 mL of 1,4-dioxane and water (V:V = 5:1). The reaction was carried out at 100° C. for 14 hours under a nitrogen atmosphere, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain a 1:1 mixture of diastereomers of the title compounds 1p-1 and 1p-2 (5 mg, yield: 19.2%). MS m / z (ESI): 731.2[M+1].

[0341] Step 15 5-Fluoro-4-((5aS,6S,9R)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1-p1 and Diastereomeric mixture of 5-fluoro-4-((5aR,6R,9S)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1-p2 A 1:1 mixture of diastereomers of compounds 1p-1 and 1p-2 (5 mg, 6.8 μmol) was dissolved in ethyl acetate (1 mL), 0.5 mL of 4 M hydrochloric acid dioxane solution was added, and the mixture was reacted at 0 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and then purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain a 1:1 mixture of diastereomers of the title compounds 1-p1 and 1-p2 (1 mg, yield: 25%). MS m / z (ESI): 587.2[M+1]. HPLC analysis: retention time 1.12 min, purity: 96.3% (column: ACQUITY UPLC® BEH, C18, 1.7 μm, 2.1×50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: 10% to 95% acetonitrile). 1 H NMR (500 MHz, CD3OD): δ 7.57 (dd, 1H), 7.39 (tt, 1H), 7.29-7.25 (m, 1H), 7.16 (d, 1H), 7.11 (d, 1H), 6.92 (ddd, 1H), 5.38 (dd, 1H), 4.51-4.44 (m, 1H), 4.31 (t, 1H), 4.23 (t, 1H), 4.14 (s, 1H), 3.75 (s, 1H), 3.67 (d, 1H), 3.49-3.45 (m, 1H), 3.26-3.18 (m, 2H), 3.06 (s, 1H), 2.36-1.84 (m, 12H), 1.62 (s, 1H).

[0342] Example 2 5-Ethyl-4-((5aS,6S,9R)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 2-p1 and 1:1 mixture of diastereomers of 5-ethyl-4-((5aR,6R,9S)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 2-p2 [ka] According to the synthetic route in Example 1, the raw material of step 14, 2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, was replaced with 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (obtained by preparing it according to the method disclosed in intermediate 21 on page 111 of the specification in patent application "WO2021 / 041671"), and a 1:1 mixture of diastereomers of the title compound 2-p1 and 2-p2 (0.81 mg, yield: 7.18%) was obtained. MS m / z (ESI): 597.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.60 (d, 1H), 7.36 (d, 1H), 7.26-7.19 (m, 2H), 7.17 (d, 1H), 7.05 (s, 1H), 5.36 (t, 1H), 4.47 (d, 2H), 4.33-4.10 (m, 5H), 3.76-3.68 (m, 4H), 3.68 (s, 2H), 3.19 (t, 2H), 2.80 (t, 1H), 2.56-2.24 (m, 4H), 1.99-1.79 (m, 5H), 1.63 (t, 3H).

[0343] Example 3 5-Fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 3-p1 5-Fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 3-p2 [ka] [ka]

[0344] Step 1 2,6-Dichloro-3-fluoropyridin-4-amine 3a Compound 1h (5 g, 30.6 mmol) was dissolved in 20 mL of N,N-dimethylformamide and 20 mL of acetonitrile, and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (13 g, 36.8 mmol) was added and reacted at 80°C for 0.5 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 3a (2.2 g, yield: 39.6%). MS m / z (ESI): 180.9[M+1].

[0345] Step 2 5-Fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 3-p1 5-Fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 3-p2

[0346] Following the synthesis route in Example 1, the starting compound 1h in step 7 was replaced with compound 3a to give a 1:1 mixture of diastereomers of the title compounds 3-p1 and 3-p2 (20 mg, yield: 32.1%). MS m / z (ESI): 605.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.57 (dd, 1H), 7.41-7.34 (m, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 7.08 (d, 1H), 5.38 (s, 1H), 5.27 (s, 1H), , 4.59 (d, 4H), 4.15 (d, 1H), 3.73 (s, 1H), 3.64 (d, 1H), 3.46 (q, 1H), 3.05 (br, 1H), 2.37 (d, 1H), 2.28 (s, 1H), 2.20 (dd, 2H), 2.05-2.00 (m, 2H), 1.95-1.83 (m, 3H), 1.60 (s, 1H), 1.15-1.10 (m, 3H).

[0347] The diastereomeric mixture of compounds 3-p1 and 3-p2 was separated using a chiral column (Shimadzu LC-20AP, column: DAICEL CHIRALPAK® IC, 25×250 mm, 10 μm, mobile phase A: n-hexane, mobile phase B: ethanol), gradient ratio: A:B: 30:70, flow rate: 30 mL / min) to give the title compounds 3-p1 (6 mg, yield: 9.6%) and 3-p2 (5 mg, yield: 8.0%). Single configuration compound (relatively short retention time) 3-p2: (5 mg, yield: 8.0%). MS m / z (ESI): 605.2[M+1].

[0348] Chiral HPLC analysis: retention time 8.52 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1H NMR (500 MHz, CD3OD): δ 7.57 (dd, 1H), 7.41-7.34 (m, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 7.08 (d, 1H), 5.38 (s, 1H), 5.27 (s, 1H), , 4.59 (d, 4H), 4.15 (d, 1H), 3.73 (s, 1H), 3.64 (d, 1H), 3.46 (q, 1H), 3.05 (br, 1H), 2.37 (d, 1H), 2.28 (s, 1H), 2.20 (dd, 2H), 2.05-2.00 (m, 2H), 1.95-1.83 (m, 3H), 1.60 (s, 1H), 1.15-1.10 (m, 3H). Single configuration compound (relatively long retention time) 3-p1: (6 mg, yield: 9.6%). MS m / z (ESI): 605.2[M+1].

[0349] Chiral HPLC analysis: retention time 11.45 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1 H NMR (500 MHz, CD3OD): δ 7.56 (dd, 1H), 7.41-7.34 (m, 1H), 7.30 (d, 1H), 7.18-7.08 (d, 1H), 6.99-6.87 (m, 1H), 5.38 (s, 1H), 5.27 (s, 1H), 4.59 (d, 4H), 4.15 (d, 1H), 3.73 (s, 1H), 3.64 (d, 1H), 3.46 (q, 1H), 3.05 (br, 1H), 2.37 (d, 1H), 2.28 (s, 1H), 2.20 (dd, 2H), 2.05-2.00 (m, 2H), 1.95-1.83 (m, 3H), 1.60 (s, 1H), 1.15-1.10 (m, 3H).

[0350] Example 4 5-Ethyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 4-p1 5-Ethyl-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 4-p2 [ka] [ka]

[0351] Step 1 (±)-rel-(1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 4a Compound 1g (8.8g, 36.3mmol), tert-butyldimethylchlorosilane (16g, 106.1558mmol), 4-dimethylaminopyridine (4g, 32.4739mmol) were dissolved in 200mL of dichloromethane, triethylamine (15g, 148.23mmol, 21.4286mL) 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 4a (8g, yield: 61.7%). MS m / z (ESI): 357.1[M+1].

[0352] Step 2 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester 4b Compound 3a (1.8g, 9.94mmol) was dissolved in tetrahydrofuran (50mL), 20mL of 2M sodium bis(trimethylsilyl)amide tetrahydrofuran solution was added under ice bath, and the mixture was reacted with stirring for 0.5 hours. Then, di-tert-butyl dicarbonate (6.5g, 29.7mmol) was added, and the mixture was reacted with stirring for 14 hours. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (50mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, and the residue was purified with eluent system B to obtain the title compound 4b (1g, yield: 26.3%). The product was used in the next reaction without purification. MS m / z (ESI): 381.1[M+1].

[0353] Step 3 4-Amino-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester 4c Compound 4b (1 g, 2.62 mmol) was dissolved in ethyl acetate (8 mL), 3 mL of 4 M hydrochloric acid in dioxane was added, and the mixture was reacted with stirring for 2 hours. The pH was adjusted to neutral with 4 M aqueous sodium hydroxide solution in an ice bath, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, and the residue was purified with eluent system B to obtain the crude product title compound 4c (500 mg, yield: 67.8%). MS m / z (ESI): 281.1[M+1].

[0354] Step 4 2,6-Dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido) tert-butyl nicotinate 4d Crude compound 4c (500 mg, 1.77 mmol) was dissolved in tetrahydrofuran (10 mL), trichloroacetyl isocyanate (670 mg, 3.55 mmol) was added, and the mixture was reacted with stirring for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 4d (835 mg, yield: 99.7%), which was used in the next reaction without purification. MS m / z (ESI): 467.9[M+1].

[0355] Step 5 5,7-Dichloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol 4e Crude compound 4d (835 mg, 1.77 mmol) was dissolved in 7M ammonia methanol solution (10 mL) and reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, methyl tert-butyl ether (10 mL) was added to the residue, stirred for 0.5 hours, filtered, and the filter cake was dried to obtain the crude product title compound 4e (400 mg, yield: 89.9%). The product was used in the next reaction without purification. MS m / z (ESI): 249.9[M+1].

[0356] Step 6 2,4,5,7-Tetrachloro-8-fluoro-pyrido[4,3-d]pyrimidine 4f Crude compound 4e (300 mg, 1.19 mmol) was dissolved in phosphorus oxychloride (6 mL), N,N-diisopropylethylamine (800 mg, 6.19 mmol) was added, and the mixture was reacted at 110° C. for 3 hours with stirring. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to obtain the crude product, title compound 4f (344 mg, yield: 97.7%), which was used in the next step without purification. MS m / z (ESI): 285.8[M+1].

[0357] Step 7 (±)-rel-(1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 4g Compound 4f (1.0 g, 3.48 mmol) and N,N-diisopropylethylamine (0.9 g, 6.9 mmol) were dissolved in 15 mL of dichloromethane, and 4a (1.25 g, 3.5 mmol) was added at -78°C. The mixture was reacted with stirring for 1 hour at the same temperature, and then the mixture was allowed to react for 16 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system B to obtain the title compound 4g (1.56 g, yield: 73.7%) as a crude product. MS m / z (ESI): 606.2[M+1].

[0358] Step 8 (1S,2S,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 4h-1 and Diastereomeric mixture of (1R,2R,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 4h-2 Compound 4g (1.4 g, 2.3 mmol) was dissolved in 1,4-dioxane (20 mL), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (650 mg, 4.08 mmol, Pharmacopoeia), N,N-diisopropylethylamine (1.5 g, 11.6 mmol), 4A molecular sieves (1.4 g) were added, and the mixture was stirred at 105 ° C for 6 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the crude product, a diastereomeric mixture of the title compounds 4h-1 and 4h-2 (1.68 g, yield: 99.8%). The product was used in the next step without purification. MS m / z (ESI): 729.2[M+1]

[0359] Step 9 (5aS,6S,9R)-2-Chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 4i-1 and Diastereomeric mixture of (5aR,6R,9S)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 4i-2 The diastereomeric mixture of crude compounds 4h-1 and 4h-2 (1.68 g, 2.3 mmol) was added to tetrabutylammonium fluoride (2.59 g, 11.51 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified with eluent system B to give the diastereomeric mixture of title compounds 4i-1 and 4i-2 (1.0 g, yield: 75.0%). MS m / z (ESI): 579.2[M+1].

[0360] Step 10 (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 4j-1 and 1:1 mixture of diastereomers of (5aR,6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 4j-2 A diastereomeric mixture of compounds 4i-1 and 4i-2 (1.9 g, 3.28 mmol), 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 4.38 mmol, obtained by preparation according to the method disclosed in intermediate 21 on page 111 of the specification in patent application "WO2021 / 041671"), tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol, adamas), and cesium carbonate (4.7 g, 14.4 mmol) were dissolved in a mixed solution of 36 mL of 1,4-dioxane and water (V:V = 5:1). The reaction was carried out at 100° C. for 6 hours under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure to give a crude product, a 1:1 mixture of diastereomers of the title compounds 4j-1 and 4j-2 (2.5 g, yield: 100%). MS m / z (ESI): 759.2[M+1].

[0361] Step 11 5-Ethyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 4-p1 5-Ethyl-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 4-p2 The crude compound 4j-1 and the diastereomeric mixture of 4j-2 (2.4 g, 3.16 mol) were dissolved in ethyl acetate (40 mL), 17 mL of 4 M hydrochloric acid dioxane solution was added, and the mixture was reacted at 0 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain the title compound 4-p1 and 4-p2 diastereomeric 1: 1 mixture (620 mg, yield: 32.6%). MS m / z (ESI): 615.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.63 (d, 1H), 7.37 (q, 1H), 7.29 (q, 1H), 7.18 (dd, 1H), 7.08 (t, 1H), 5.48-5.29 (m, 2H), 4.55-4.28 (m, 4H), 4.17 (dd, 1H), 3.84-3.75 (m, 1H), 3.70 (t, 1H), 3.47 (q, 1H), 3.31-3.07 (m, 3H), 2.57-2.17 (m, 5H), 2.15-1.79 (m, 7H), 1.63 (t, 1H), 1.08-0.87 (m, 3H).

[0362] The diastereomeric mixture of compounds 4-p1 and 4-p2 was separated on a chiral column (Shimadzu LC-20AP, column: DAICEL CHIRALPAK® IC, 25×250 mm, 10 μm, mobile phase A: n-hexane, mobile phase B: ethanol (0.1% of 7M NH3 in MeOH)), gradient ratio: A:B: 30:70, flow rate: 30 mL / min) to give the title compounds 4-p1 (50 mg, yield: 35.7%) and 4-p2 (50 mg, yield: 35.7%). Single configuration compound (relatively short retention time) 4-p2: (50 mg, yield: 35.7%). MS m / z (ESI): 615.2[M+1].

[0363] Chiral HPLC analysis: retention time 9.85 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1H NMR (500 MHz, CD3OD): δ 7.61-7.59 (m, 1H), 7.36-7.32 (m, 1H), 7.26-7.25 (m, 1H), 7.18-7.13 (m 1H), 7.05-6.95 (m, 1H), 5.37-5.22 (m, 2H), 5.09-5.00 (m, 1H), 4.61-4.56 (m, 1H), 4.49-4.41 (m, 1H), 4.30 (dd, 1H), 4.24-4.18 (m, 1H), 4.16-4.09 (m, 1H), 3.72 (dd, 1H), 3.62 (dd, 1H), 3.27-3.17 (m, 3H), 3.01 (td, 1H), 2.48 (dt, 1H), 2.40 - 2.10 (m, 5H), 1.99 (td, 2H), 1.94-1.75 (m, 4H), 0.99-0.88 m, 3H). Single configuration compound (relatively long retention time) 4-p1: (50 mg, yield: 35.7%). MS m / z (ESI): 615.2[M+1].

[0364] Chiral HPLC analysis: retention time 16.0 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1H NMR (500 MHz, CD3OD): δ 7.61-7.59 (m, 1H), 7.36-7.32 (m, 1H), 7.26-7.25 (m, 1H), 7.18-7.13 (m 1H), 7.05-6.94 (m, 1H), 5.36-5.33 (m, 2H), 5.10-5.01 (m, 1H), 4.61-4.56 (m, 1H), 4.49-4.41 (m, 1H), 4.30 (dd, 1H), 4.24-4.22 (m, 1H), 4.16-4.10 (m, 1H), 3.73-3.72 (m, 1H), 3.64-3.61 (m, 1H), 3.26-3.20 (m, 3H), 3.04-2.99 (m, 1H), 2.48 (dt, 1H), 2.38-2.17 (m, 5H), 2.03-1.96 (m, 2H), 1.93-1.78 (m, 4H), 0.99-0.88 m, 3H).

[0365] Example 5 5-Ethyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 5-p1 and 1:1 mixture of diastereomers of 5-ethyl-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 5-p2 [ka] In steps 8 to 11 of the synthetic route in Example 4, the raw material in step 8, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, was replaced with ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (obtained by the method disclosed in intermediate B-21 on page 132 of the specification in patent application "WO2020 / 146613") to obtain a 1:1 mixture of diastereomers of the title compounds 5-p1 and 5-p2. MS m / z (ESI): 615.2[M+1].

[0366] Example 6 3-Chloro-4-cyclopropyl-5-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)phenol 6-p1 3-Chloro-4-cyclopropyl-5-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)phenol 6-p2 [ka] [ka]

[0367] Step 1 (5aS,6S,9R)-2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl 6a-1 and Diastereomeric mixture of (5aR,6R,9S)-2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 6a-2 A 1:1 mixture of diastereomers of compounds 4i-1 and 4i-2 (190 mg, 328 μmol), 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (144.4 mg, 426 μmol, obtained by preparation according to the method disclosed in Example 283 on page 526 of the specification in patent application "WO2021 / 041671"), tetrakis(triphenylphosphine)palladium (75.8 mg, 65.6 μmol, adamas), and cesium carbonate (320.7 mg, 984 μmol) were dissolved in a mixed solution of 10 mL of 1,4-dioxane and water (V:V = 5:1). The mixture was reacted at 100° C. for 6 hours under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure to give a crude product, a 1:1 mixture of diastereomers of the title compounds 6a-1 and 6a-2 (240 mg, yield: 97.1%). MS m / z (ESI): 755.2[M+1].

[0368] Step 2 3-Chloro-4-cyclopropyl-5-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)phenol 6-p1 3-Chloro-4-cyclopropyl-5-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)phenol 6-p2 The crude compound 6a-1 and 6a-2 diastereomeric 1:1 mixture (240 mg, 327 μmol) was dissolved in acetonitrile (5 mL), 2 mL of 4 M hydrochloric acid dioxane solution was added, and the mixture was reacted with stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain the title compound 6-p1 and 6-p2 diastereomeric 1:1 mixture (75 mg, yield: 37.6%). MS m / z (ESI): 611.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 6.96 (dd, 1H), 6.77 (d, 1H), 5.38 (s, 1H), 5.28 (s, 1H), 5.06 (d, 1H), 4.61 (d, 1H), 4.45 (dd, 1H), 4.31 (dd, 1H), 4.24 (dd, 1H), 4.14 (d, 1H), 3.74 (d, 1H), 3.65 (s, 1H), 3.24 (dd, 5H), 3.08-3.01 (m, 1H), 2.41-2.32 (m, 1H), 2.32-2.19 (m, 2H), 2.16 (d, 1H), 2.02 (m, 3H), 1.92 (dd, 4H), 1.86-1.82 (m, 2H).

[0369] The diastereomeric mixture of compounds 6-p1 and 6-p2 was separated on a chiral column (Shimadzu LC-20AP, column: DAICEL CHIRALPAK® IC, 25×250 mm, 10 μm, mobile phase A: n-hexane, mobile phase B: ethanol (0.1% of 7M NH3 in MeOH)), gradient ratio: A:B: 30:70, flow rate: 30 mL / min) to give the title compounds 6-p1 (26 mg, yield: 13%) and 6-p2 (32 mg, yield: 16%). Single configuration compound (relatively short retention time) 6-p2: (32 mg, yield: 16%). MS m / z (ESI): 611.2[M+1].

[0370] Chiral HPLC analysis: retention time 5.74 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1H NMR (500 MHz, CD3OD): δ 6.96 (d, 1H), 6.77 (d, 1H), 5.39 (d, 1H), 5.28 (s, 1H), 5.06 (dd, 1H), 4.61 (dd, 1H), 4.45 (dd, 1H), 4.32 (d, 1H), 4.23 (d, 1H), 4.14 (d, 1H), 3.74 (dd, 1H), 3.68-3.63 (m, 1H), 3.25 (tq, 5H), 3.05 (td, 1H), 2.40-2.11 (m, 4H), 2.07-1.74 (m, 9H). Single configuration compound (relatively long retention time) 6-p1: (26 mg, yield: 13%). MS m / z (ESI): 611.2[M+1].

[0371] Chiral HPLC analysis: retention time 9.9 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1 H NMR (500 MHz, CD3OD): δ 6.96 (d, 1H), 6.77 (d, 1H), 5.39 (s, 1H), 5.28 (s, 1H), 5.07 (dd, 1H), 4.63-4.59 (m, 1H), 4.45 (dd, 1H), 4.31 (d, 1H), 4.25 (d, 1H), 4.15 (dd, 1H), 3.74 (d, 1H), 3.66 (dd, 1H), 3.32-3.17 (m, 5H), 3.05 (dt, 1H), 2.40-2.12 (m, 4H), 2.08-1.76 (m, 9H).

[0372] Example 7 5-Ethyl-4-((5aS,6S,9R)-1-fluoro-12-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 7-p1 and 1:1 mixture of diastereomers of 5-ethyl-4-((5aR,6R,9S)-1-fluoro-12-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 7-p2 [ka] In steps 8 to 11 of the synthetic route in Example 4, the raw material in step 8, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, was replaced with (hexahydro-1H-pyrrolidin-7a-yl)methanol (Amino) to obtain a diastereomeric mixture of the title compounds 7-p1 and 7-p2. MS m / z (ESI): 597.2[M+1].

[0373] Example 8 5,6-Difluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 8-p1 5,6-Difluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 8-p2 [ka] In steps 10 to 11 of the synthetic route in Example 4, the raw material in step 10, 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, was replaced with 2-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (obtained by preparing it according to the method disclosed in Example 246 on page 437 of the specification in patent application "WO2021 / 041671"), and a diastereomeric 1:1 mixture of the title compounds 8-p1 and 8-p2 (40 mg, yield: 37.9%) was obtained. MS m / z (ESI): 623.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.56 (dd, 1H), 7.41-7.34 (m, 1H), 7.30 (d, 1H), 7.18 -7.08 (d, 1H), 5.38 (s, 1H), 5.27 (s, 1H), , 4.59 (d, 4H), 4.15 (d, 1H), 3.73 (s, 1H), 3.64 (d, 1H), 3.46 (q, 1H), 3.05 (br, 1H), 2.37 (d, 1H), 2.28 (s, 1H), 2.20 (dd, 2H), 2.05 - 2.00 (m, 2H), 1.95-1.83 (m, 3H), 1.60 (s, 1H), 1.15-1.10 (m, 3H).

[0374] The diastereomeric mixture of compounds 8-p1 and 8-p2 was separated on a chiral column (Shimadzu LC-20AP, column: DAICEL CHIRALPAK® IC, 25×250 mm, 10 μm, mobile phase A: n-hexane, mobile phase B: ethanol (0.1% of 7M NH3 in MeOH)), gradient ratio: A:B: 40:60, flow rate: 30 mL / min) to give the title compounds 8-p1 (16 mg, yield: 15.1%) and 8-p2 (19 mg, yield: 17.9%). Single configuration compound (relatively short retention time) 8-p2: (19 mg, yield: 17.9%). MS m / z (ESI): 623.2[M+1].

[0375] Chiral HPLC analysis: retention time 6.95 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1 H NMR (500 MHz, CD3OD): δ 7.56 (dd, 1H), 7.41-7.34 (m, 1H), 7.30 (d, 1H), 7.18 -7.08 (d, 1H), 5.38 (s, 1H), 5.27 (s, 1H), , 4.59 (d, 4H), 4.15 (d, 1H), 3.73 (s, 1H), 3.64 (d, 1H), 3.46 (q, 1H), 3.05 (br, 1H), 2.37 (d, 1H), 2.28 (s, 1H), 2.20 (dd, 2H), 2.05-2.00 (m, 2H), 1.95-1.83 (m, 3H), 1.60 (s, 1H), 1.15-1.10 (m, 3H). Single configuration compound (relatively long retention time) 8-p1: (16 mg, yield: 17.9%). MS m / z (ESI): 623.2[M+1].

[0376] Chiral HPLC analysis: retention time 9.86 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1 H NMR (500 MHz, CD3OD): δ 7.58 (dd, 1H), 7.41-7.34 (m, 1H), 7.30 (d, 1H), 7.18 -7.08 (d, 1H), 5.39 (s, 1H), 5.27 (s, 1H), , 4.59 (d, 4H), 4.15 (d, 1H), 3.73 (s, 1H), 3.64 (d, 1H), 3.46 (q, 1H), 3.05 (br, 1H), 2.37 (d, 1H), 2.28 (s, 1H), 2.20 (dd, 2H), 2.05-2.00 (m, 2H), 1.95-1.83 (m, 3H), 1.60 (s, 1H), 1.15-1.10 (m, 3H).

[0377] Example 9 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 9-p1 5-Ethyl-6-fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 9-p2 [ka] [ka]

[0378] Step 1 (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl 9a-1 and 1:1 mixture of diastereomers of (5aR,6R,9S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate 9a-2 A diastereomeric mixture of compounds 4i-1 and 4i-2 (300 mg, 518.1 μmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (280 mg, 777.2 μmol, obtained by preparation according to the method disclosed in intermediate 18 on page 104 of the specification in patent application "WO2021 / 041671"), tetrakis(triphenylphosphine)palladium (120 mg, 103.8 μmol), and cesium carbonate (506 mg, 1.55 mmol) were dissolved in a mixed solution of 6 mL of 1,4-dioxane and water (V:V = 5:1). The reaction was carried out at 100° C. for 6 hours under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure to obtain a crude product, a 1:1 mixture of diastereomers of the title compounds 9a-1 and 9a-2 (400 mg). The product was used in the next step without purification. MS m / z (ESI): 777.2[M+1].

[0379] Step 2 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 9-p1 5-Ethyl-6-fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 9-p2 The crude compound 9a-1 and 9a-2 diastereomeric mixture (160 mg, 205.9 μmol) was dissolved in ethyl acetate (5 mL), 1 mL of 4 M hydrochloric acid dioxane solution was added, and the mixture was reacted at 0 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain the title compound 9-p1 and 9-p2 diastereomeric 1: 1 mixture (10 mg, yield: 7.2%). MS m / z (ESI): 633.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.67 (ddd, 1H), 7.32-7.21 (m, 2H), 7.11-7.01 (m, 1H), 5.38-5.35 (m, 2H), 5.11-5.03 (m, 1H), 4.64-4.59 (m, 1H), 4.52-4.46 (m, 1H), 4.34-4.29 (m, 1H), 4.25 (dd, 1H), 4.18-4.12 (m, 1H), 3.74 (br, 1H), 3.65 (br, 1H), 3.26-3.23 (m, 3H), 3.05-3.01 (m, 1H), 2.61-1.81 (m, 12H), 0.94-0.82 (m, 3H).

[0380] The diastereomeric mixture of compounds 9-p1 and 9-p2 was separated on a chiral column (Shimadzu LC-20AP, column: DAICEL CHIRALPAK® IC, 25×250 mm, 10 μm, mobile phase A: n-hexane, mobile phase B: ethanol (0.1% of 7M NH3 in MeOH)), gradient ratio: A:B: 40:60, flow rate: 30 mL / min) to give the title compounds 9-p1 (26 mg, yield: 43.3%) and 9-p2 (26 mg, yield: 43.3%). Single configuration compound (relatively short retention time) 9-p2: (26 mg, yield: 43.3%). MS m / z (ESI): 633.2[M+1].

[0381] Chiral HPLC analysis: retention time 7.89 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1H NMR (500 MHz, CD3OD): δ 7.67 (ddd, 1H), 7.32-7.21 (m, 2H), 7.11-7.01 (m, 1H), 5.38-5.27 (m, 2H), 5.11-5.03 (m, 1H), 4.64-4.59 (m, 1H), 4.52-4.44 (m, 1H), 4.33 (d, 1H), 4.24 (dd, 1H), 4.18-4.12 (m, 1H), 3.75 (br, 1H), 3.66 (br, 1H), 3.27-3.18 (m, 3H), 3.05-3.03 (m, 1H), 2.60-1.81 (m, 12H), 0.93-0.82 (m, 3H).

[0382] Single configuration compound (relatively long retention time) 9-p1: (26 mg, yield: 43.3%). MS m / z (ESI): 633.2[M+1].

[0383] Chiral HPLC analysis: retention time 13.8 min, purity: 99% (column: DAICEL CHIRALPAK® IC, 250×4.6 mm, 5 μm, mobile phase: n-hexane and ethanol (containing 0.2% diethylamine), flow rate: 1.0 mL / min). 1 H NMR (500 MHz, CD3OD): δ 7.67 (ddd, 1H), 7.32-7.21 (m, 2H), 7.11-7.01 (m, 1H), 5.38-5.35 (m, 2H), 5.11-5.03 (m, 1H), 4.64-4.59 (m, 1H), 4.52-4.46 (m, 1H), 4.34-4.29 (m, 1H), 4.25 (dd, 1H), 4.18-4.12 (m, 1H), 3.74 (br, 1H), 3.65 (br, 1H), 3.26-3.23 (m, 3H), 3.05-3.01 (m, 1H), 2.61-1.81 (m, 12H), 0.94-0.82 m, 3H).

[0384] Example 10 5-Ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 10-p1 and 1:1 mixture of diastereomers of 5-ethynyl-6-fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 10-p2 [ka] In steps 10 to 11 of the synthetic route in Example 4, the raw material in step 10, 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, was replaced with ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (obtained by preparing it according to the method disclosed in intermediate 15 on page 96 of the specification in patent application "WO2021 / 041671"), and a 1:1 mixture of diastereomers of the title compounds 10-p1 and 10-p2 (2 mg, yield: 3.5%) was obtained. MS m / z (ESI): 629.2[M+1]. 1H NMR (500 MHz, DMSO-d6): δ 7.93 (dd, 1H), 7.86 (s, 1H), 7.41 (t, 1H), 7.27 (s, 1H), 5.40-5.22 (m, 2H), 4.78 (d, 1H), 4.42 (dd, 1H), 4.14 (dd, 1H), 4.06-3.99 (m, 2H), 3.62-3.53 (m, 2H), 3.20-3.03 (m, 4H), 2.89-2.81 (m, 1H), 2.20-1.96 (m, 4H), 1.90-1.52 (m, 9H), 0.94 (t, 3H).

[0385] Example 11 5-Ethyl-4-((5aS,6S,9R)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-iminoazepano[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-2-yl)naphthalen-2-ol 11-p1 and 1:1 mixture of diastereomers of 5-ethyl-4-((5aR,6R,9S)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-iminoazepano[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-2-yl)naphthalen-2-ol 11-p2 [ka] [ka]

[0386] Step 1 Methyl 2-amino-4-bromo-3,6-difluorobenzoate 11b 2-Amino-4-bromo-3,6-difluorobenzoic acid 11a (9 g, 35.71 mmol, prepared according to the method disclosed on page 110 of the specification of patent application "WO2018206539 A1") was dissolved in dichloromethane (100 mL) and methanol (10 mL), and 35.71 mL of a 2M n-hexane solution of trimethylsilyldiazomethane was added dropwise under an ice bath. After the addition was completed, the mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified with eluent system B to obtain the title compound 11b (6.8 g, yield: 71.5%). MS m / z (ESI): 265.9[M+1].

[0387] Step 2 Methyl 4-bromo-3,6-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate 11c Compound 11b (2 g, 7.51 mmol) was dissolved in tetrahydrofuran (30 mL) as a solvent, and trichloroacetyl isocyanate (1.42 g, 7.5373 mmol, Jiangsu Aikang) was added in several portions. The mixture was allowed to react with stirring for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 11c (3.4 g, yield: 99%). The product could be used in the next reaction without purification. MS m / z (ESI): 452.9[M+1].

[0388] Step 3 7-Bromo-5,8-difluoroquinazoline-2,4-diol 11d Crude compound 11c (3.4 g, 7.48 mmol) was dissolved in 30 mL of 7 M ammonia in methanol, reacted with stirring for 2 h, concentrated under reduced pressure to remove most of the solvent, and then slurried with 20 mL of methyl tert-butyl ether, filtered, and the filter cake was washed with methyl tert-butyl ether and dried to obtain the crude product title compound 11d (2 g, yield: 96.4%), which could be used in the next step without purification. MS m / z (ESI): 276.9[M+1].

[0389] Step 4 7-Bromo-2,4-dichloro-5,8-difluoroquinazoline 11e Compound 11d (500 mg, 1.80 mmol) was dissolved in a solvent, phosphorus oxychloride (5 mL), and reacted at 100° C. for 3 hours with stirring. The reaction solution was concentrated under reduced pressure to obtain the crude product, title compound 11e (500 mg, yield: 88.2%), which could be used in the next step without purification. MS m / z (ESI): 312.9[M+1].

[0390] Step 5 5-Ethyl-4-((5aS,6S,9R)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-iminoazepano[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-2-yl)naphthalen-2-ol 11-p1 and Diastereomeric mixture of 5-ethyl-4-((5aR,6R,9S)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-iminoazepano[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-2-yl)naphthalen-2-ol 11-p2 Following steps 7 to 11 of the synthetic route in Example 4, the starting compound 4f in step 7 was replaced with compound 11e to give a 1:1 mixture of diastereomers of the title compounds 11-p1 and 11-p2 (5 mg, yield: 15.4%). MS m / z (ESI): 614.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.64-7.59 (m, 1H), 7.35 (td, 1H), 7.24 (dt, 1H), 7.15 (dd, 1H), 6.97-6.88 (m, 1H), 6.84-6.80 (m, 1H), 5.45 -5.35 (m, 2H), 5.18-5.09 (m, 1H), 4.58- 4.49 (m, 1H), 4.45-4.40 (m, 1H), 4.38 -4.29 (m, 2H), 4.19-4.10 (m, 1H), 3.76 (s, 1H), 3.65-3.60 (m, 1H), 3.52-3.40 (m, 2H), 3.29-3.15 (m, 2H), 2.56-1.79 (m, 12H), 0.97 -0.86 (m, 3H).

[0391] Example 12 5-Ethyl-4-((5aR,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 12-p1 5-Ethyl-4-((5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 12-p2 [ka] [ka]

[0392] Step 1 8-(tert-Butyl) 2-methyl(±)-rel-(1R,2S,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 12a Crude compound 1d (10 g, 54.2 mmol) was dissolved in 300 mL of dichloromethane, and triethylamine (16 g, 158.12 mmol) and di-tert-butyl dicarbonate (11 g, 50.4 mmol, Shanghai Shaoyuan) were added under ice bath, and the mixture was reacted with stirring for 14 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 12a (1.6 g, yield: 10.3%). MS m / z (ESI): 285.2 [M+1]. HPLC analysis: retention time 0.94 min, purity: 98.5% (column: ACQUITY UPLC® BEH, C18, 1.7 μm, 2.1×50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: 10% to 95% acetonitrile).

[0393] Step 2 (±)-rel-(1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 12b Compound 12a (3.15 g, 11.09 mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (1.05 g, 31 mmol) was added under ice bath, and the reaction was carried out with stirring for 2 hours. The reaction was quenched by adding 1.7 mL of water and 1.7 mL of 15% aqueous sodium hydroxide solution, followed by addition of anhydrous sodium sulfate, filtration to remove the drying agent, and concentration of the filtrate under reduced pressure to obtain the crude product, title compound 12b (2.6 g, yield: 96.6%), which could be used in the next reaction without purification. MS m / z (ESI): 243.2 [M+1].

[0394] Step 3 5-Ethyl-4-((5aR,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 12-p1 5-Ethyl-4-((5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 12-p2 Following steps 1 to 11 of the synthetic route in Example 4, the starting compound 1g in step 1 was replaced with compound 12b to obtain the title compounds 12-p1 and 12-p2 (3 mg, 3 mg, yields: 37%, 37%). Single configuration compound (relatively short retention time): (3 mg, yield: 37%). MS m / z (ESI): 615.2[M+1].

[0395] HPLC analysis: retention time 1.24 min, purity: 90% (column: ACQUITY UPLC® BEH, C18, 1.7 μm, 2.1×50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10% to 95%) 1H NMR (500 MHz, CD3OD): δ 7.63 (d, 1H), 7.40-7.35 (m, 1H), 7.30-7.28 (m, 1H), 7.21-7.16 (m, 1H), 7.12-6.95 (m, 1H), 5.47 (d, 1H), 5.36 (t, 1H), 5.15-5.07 (m, 1H), 4.69 - 4.44 (m, 3H), 4.23 (d, 1H), 3.92-3.76 (m, 2H), 3.62 (br, 2H),2.62-2.27 (m, 7H), 2.24-1.85 (m, 8H), 0.95-0.88 (m, 3H).

[0396] Compound with single stereo configuration (relatively long retention time): (3 mg, yield: 37%). MS m / z (ESI): 615.2[M+1].

[0397] HPLC analysis: retention time: 1.28 minutes, purity: 90% (Kurarum: ACQUITY UPLC (registered trademark) BEH, C18, 1.7μm, 2.1×50mm, mobile phase: water (10m Mのhydrogen carbonate (アンモニウム), アセトニトリル, blending ratio: アセトニトリル10%~95%) 1 H NMR (500 MHz, CD3OD): δ 7.63 (d, 1H), 7.38 (td, 1H), 7.29 (t, 1H), 7.19 (t, 1H), 7.12-6.95 (m, 1H), 5.52 (d, 1H), 5.36 (t, 1H), 4.67-4.53 (m, 4H), 4.44 (t, 1H), 3.98-3.67 (m, 6H), 2.55-2.42 (m, 2H), 2.40-2.34 (m, 1H), 2.30-2.28 (m, 2H), 2.21-2.03 (m, 2H), 2.02-18.4 (m, 3H),1.05-0.89 (m, 6H).

[0398] Example 13 5-Ethynyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 13-p1 and 1:1 mixture of diastereomers of 5-ethynyl-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 13-p2 [ka] In steps 10 to 11 of the synthetic route in Example 4, the raw material in step 10, 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, was replaced with triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalene-1-yl)ethynyl)silane (obtained by preparing it according to the method disclosed in intermediate 17 on page 103 of the specification in patent application "WO2021 / 041671"), and a diastereomeric 1:1 mixture of the title compounds 13-p1 and 13-p2 (8 mg, yield: 14.1%) was obtained. MS m / z (ESI): 611.2[M+1]. 1H NMR (500 MHz, DMSO-d6): δ 7.63 (d, 1H), 7.37 (q, 1H), 7.29 (q, 1H), 7.18 (dd, 1H), 7.08 (t, 1H), 5.40-5.22 (m, 2H), 4.78 (d, 1H), 4.42 (dd, 1H), 4.14 (dd, 1H), 4.06-3.99 (m, 2H), 3.62-3.53 (m, 2H), 3.20-3.03 (m, 4H), 2.89-2.81 (m, 1H), 2.20-1.96 (m, 4H), 1.90-1.52 (m, 6H), 0.94 (t, 3H).

[0399] Example 14 3-Chloro-5-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)phenol 14-p1 [ka] [ka]

[0400] Step 1 (5aS,6S,9R)-2-Chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 4i-1 The diastereomeric mixture of compounds 4i-1 and 4i-2 (29.6 g, 51.1 mmol) was separated by chiral column (Waters SFC 150, column: DAICEL CHIRALPAK (registered trademark) IC, 25 × 250 mm, 10 μm, mobile phase A: Supercritical CO2, mobile phase B: ethanol, gradient blend ratio: A:B: 45:55, flow rate: 110 mL / min) to obtain the title compound 4i-1 (7.8 g, yield: 26.3%). Chiral HPLC analysis: retention time 3.199 min, purity: 99% (column: DAICEL CHIRALPAK® OZ, 100×3 mm, 3 μm, mobile phase: Supercritical CO2 and ethanol (containing 0.1% diethylamine), flow rate: 2.0 mL / min).

[0401] Step 2 (5aS,6S,9R)-2-(3-chloro-5-(methoxymethoxy)-2-(trifluoromethyl)phenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 14a-1 Compound 4i-1 (60 mg, 103.6 μmol), 2-(3-chloro-2-trifluoromethyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75 mg, 204.6 μmol, obtained by preparation according to the method disclosed in Example 284 on page 530 of the specification in patent application "WO2021 / 041671"), tetrakis(triphenylphosphine)palladium (24 mg, 10.7 μmol, adamas), and cesium carbonate (101 mg, 309.9 μmol) were dissolved in a mixed solution of 3 mL of 1,4-dioxane and water (V:V = 5:1). The mixture was reacted at 100 ° C. for 6 hours under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure to obtain the crude product, the title compound 14a-1 (81 mg, yield: 99%). MS m / z (ESI): 783.2[M+1].

[0402] Step 3 3-Chloro-5-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)phenol 14-p1 The crude compound 14a-1 (80 mg, 102.1 μmol), which is the product of step 2 above, was dissolved in acetonitrile (1 mL), and 0.5 mL of 4 M hydrochloric acid in dioxane was added. The mixture was reacted with stirring for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain the title compound 14-p1 (26 mg, yield: 39.8%). MS m / z (ESI): 639.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.11 (d, 1H), 6.73 (d, 1H), 5.44-5.26 (m, 1H), 5.06 (d, 1H), 4.61 (d, 1H), 4.45 (s, 1H), 4.33 (d, 1H), 4.27 (d, 1H), 4.14 (s, 1H), 3.74 (d, 1H), 3.66 (d, 1H), 3.22 (d, 1H), 3.07 (d, 1H), 2.44-2.12 (m, 4H), 2.04 (dq, 3H), 1.89 (ddd, 6H).

[0403] Example 15 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 15 [ka] [ka]

[0404] Step 1 (R)-5-Methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate methyl 15b (R)-2-Pyrrolidone-5-methyl formate 15a (20 g, 139.7 mmol, Shanghai Bide) and dimethyl sulfate (22.1 g, 175.2 mmol) were mixed and reacted at 60° C. for 22 hours. The reaction solution was cooled to room temperature and poured into a solution of triethylamine (20 g) and methyl tert-butyl ether (30 mL) in an ice bath. The mixture was extracted with methyl tert-butyl ether (60 mL×6) and then concentrated under reduced pressure to obtain the crude product title compound 15b (16.3 g, yield: 74.2%). The product was used in the next reaction without purification. MS m / z (ESI): 158.1[M+1].

[0405] Step 2 (R)-Methyl 5-(2-methoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate 15c Crude compound 15b (16.3 g, 103.7 mmol) and methyl nitroacetate (13.6 g, 114.2 mmol, Shanghai Shaoyuan) were mixed and heated to 60° C. for 24 hours under stirring. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain title compound 15c (8.37 g, yield: 33%). MS m / z (ESI): 245.1[M+1].

[0406] Step 3 (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate methyl ester 15d Compound 15c (7.5 g, 30.7 mmol) was dissolved in 150 mL of methanol, 10% palladium carbon catalyst (wet) (1.5 g) was added, the mixture was purged with hydrogen gas three times, and the mixture was heated to 50° C. and reacted with stirring for 24 hours. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 15d (5.6 g). The product was used in the next step without purification. MS m / z (ESI): 185.2[M+1].

[0407] Step 4 8-(tert-Butyl) 2-methyl(1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 15e Crude compound 15d (5.65 g, 30.4 mmol) was dissolved in 60 mL of dichloromethane, and triethylamine (6.2 g, 61.27 mmol) and di-tert-butyl dicarbonate (6.6 g, 30.24 mmol) were added under ice bath, and the mixture was reacted with stirring for 14 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 15e (3 g, yield: 34.7%). MS m / z (ESI): 285.2 [M+1].

[0408] Step 5 (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 15f Compound 15e (3 g, 10.55 mmol) was dissolved in 30 mL of tetrahydrofuran, and 32 mL of 1M lithium aluminum hydride tetrahydrofuran solution was added dropwise under ice bath, and the mixture was allowed to react for 4 hours while stirring at room temperature. 1.05 mL of water, 1.05 mL of 15% sodium hydroxide solution, and 3.15 mL of water were added in turn under ice bath, and the mixture was allowed to stir at room temperature for 15 minutes. Anhydrous magnesium sulfate (1 g) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, the title compound 15f (2.4 g). The product was used in the next step without purification. MS m / z (ESI): 243.2[M+1].

[0409] Step 6 (1S,2S,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester 15g Crude compound 15f (2.4 g, 9.9 mmol) was dissolved in 25 mL of dichloromethane, tert-butyldimethylchlorosilane (4.48 g, 29.7 mmol), 4-dimethylaminopyridine (122 mg, 990 μmol) were added, triethylamine (4 g, 39.5 mmol) was added dropwise, and the mixture was reacted with stirring for 16 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined and washed with saturated sodium chloride solution, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 15g (1.95 g, yield: 55.2%). MS m / z (ESI): 357.1[M+1].

[0410] Step 7 (1S,2S,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 15H Compound 4f (50 g, 174 mmol) and N,N-diisopropylethylamine (65 g, 503 mmol) were dissolved in 75 mL of dichloromethane, and a solution of 15 g (60 g, 168.3 mmol) in dichloromethane (250 mL) was added dropwise at −78° C., and the mixture was allowed to warm to room temperature and react for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system B to obtain the title compound 15h (86 g, yield: 84%). MS m / z (ESI): 606.2[M+1].

[0411] Step 8 (1S,2S,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5,7-dichloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl 15i Compound 15h (5 g, 8.23 ​​mmol) was dissolved in 1,4-dioxane (80 mL), and 1,1-bis(hydroxymethyl)cyclopropane (1.3 g, 12.7 mmol, Shanghai Shaoyuan), cesium carbonate (5.4 g, 16.6 mmol), and 4A molecular sieves (5 g) were added. The mixture was stirred at 110° C. for 14 hours, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the crude product, title compound 15i (5.5 g). The product was used in the next step without purification. MS m / z (ESI): 672.2[M+1].

[0412] Step 9 (5aS,6S,9R)-2-Chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 15j Crude compound 15i (5.5g, 8.2mmol) was dissolved in tetrahydrofuran (80mL), tetrabutylammonium fluoride (5.57g, 24.7mmol) and N,N-diisopropylethylamine (5.33g, 41.2mmol) were added, and the mixture was stirred for 1 hour, then heated to 60°C and reacted with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with water (80mL), extracted with ethyl acetate (50mL x 2), the organic phase was combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain title compound 15j (3g, yield: 69.7%). MS m / z (ESI): 522.2[M+1].

[0413] Step 10 (5aS,6S,9R-2-chloro-1-fluoro-12-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 15k Compound 15j (200 mg, 344.8 μmol), N,N-diisopropylethylamine (112 mg, 866.5 μmol) was dissolved in dichloromethane (10 mL), methanesulfonyl chloride (60 mg, 523.7 μmol) was added under ice bath, and the temperature was kept as it was while stirring for 1 hour. The reaction solution was quenched by adding saturated ammonium chloride solution, extracted with dichloromethane (5 mL × 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the crude product, the title compound 15k (206 mg). The product was used in the next step without purification. MS m / z (ESI): 600.2[M+1].

[0414] Step 11 (5aS,6S,9R)-2-chloro-1-fluoro-12-((1-(((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 15l Crude compound 15k (206 mg, 343.3 μmol) was dissolved in acetonitrile (10 mL), L-prolinol (53 mg, 524 μmol, Shanghai Shaoyuan), anhydrous potassium carbonate (143 mg, 1.03 mmol), sodium iodide (103 mg, 687 μmol) were added, and the mixture was heated to 80 ° C. and reacted with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2), and the organic phase was combined and concentrated under reduced pressure to obtain the crude product title compound 15l (200 mg). The product was used directly in the next step without purification. MS m / z (ESI): 605.2[M+1].

[0415] Step 12 (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(1-(((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl ester 15m Compound 15l (100mg, 165μmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (84mg, 233μmol), tetrakis(triphenylphosphine)palladium (39mg, 33.7μmol), and cesium carbonate (108mg, 331μmol) were dissolved in 11mL of a mixed solution of 1,4-dioxane and water (V:V=10:1). The mixture was reacted at 100°C for 4 hours under a nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure. The residue was purified by thin layer chromatography using developing solvent system A to obtain the title compound 15m (50mg, yield: 37.6%). MS m / z (ESI): 803.2[M+1].

[0416] Step 13 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 15 Compound 15m (50 mg, 62.2 μmol) was dissolved in ethyl acetate (2 mL), 0.5 mL of 4 M hydrochloric acid dioxane solution was added under ice bath, and the temperature was kept unchanged for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min) to obtain the title compound 15 (10 mg, yield: 24.3%). MS m / z (ESI): 659.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.67 (ddd, 1H), 7.30 (d, 1H), 7.27-7.21 (m, 1H), 7.06 (dd, 1H), 5.36 (t, 1H), 5.06 (dd, 1H), 4.78 (s, 1H), 4.65-4.60 (m, 1H), 4.48 (ddd, 1H), 4.15 (dd, 2H), 3.71 (d, 2H), 3.57-3.38 (m, 4H), 3.24 (t, 1H), 2.51-2.34 (m, 2H), 2.22 (q, 2H), 2.03-1.76 (m, 7H), 1.71 (s, 1H), 1.62 (s, 1H), 0.96-0.82 (m, 4H), 0.67 (s, 1H), 0.55 (s, 1H).

[0417] Example 16 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((R)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 16 [ka] [ka]

[0418] Step 1 (R)-tert-butyl 2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate 16b 1-(tert-Butyl) 2-methyl (R)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate 16a (543 mg, 2.39 mmol, Yakuhin Kotoku) was dissolved in tetrahydrofuran (10 mL), and 1M lithium aluminum hydride in tetrahydrofuran (24 mL) was added under ice bath. After reacting for 2 hours, sodium sulfate decahydrate was added to quench the reaction, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product title compound 16b (421 mg, yield: 88.4%). The product was used in the next step without purification. MS m / z (ESI): 144.2[M-55].

[0419] Step 2 (R)-(2,5-Dihydro-1H-pyrrol-2-yl)methanol 2,2,2-trifluoroacetate 16c Crude compound 16b (421 mg, 2.1 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.68 g, 1.1 mL) was added in an ice bath, and the mixture was reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 16c (500 mg), which was used in the next step without purification. MS m / z (ESI): 100.2[M+1].

[0420] Step 3 (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dihydro-1H-pyrrole 16d Crude compound 16c (450 mg, 2.1 mmol) was dissolved in 10 mL of dichloromethane, tert-butyldimethylchlorosilane (226 mg, 2.74 mmol) was added, triethylamine (1.1 g, 10.8 mmol) was added dropwise, and the mixture was reacted with stirring for 16 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined and washed with saturated sodium chloride solution, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain title compound 16d (110 mg, yield: 24.4%). MS m / z (ESI): 214.1[M+1].

[0421] Step 4 (5aS,6S,9R)-12-((1-(((R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl 16e In steps 11-12 of the synthetic route in Example 15, L-prolinol, the raw material in step 11, was replaced with compound 16d to obtain the crude product title compound 16e (40 mg), which was used in the next step without purification. MS m / z (ESI): 915.2[M+1].

[0422] Step 5 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((R)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 16 Crude compound 16e (40 mg, 43.7 μmol) was dissolved in ethyl acetate (2 mL), 0.5 mL of 4 M hydrochloric acid dioxane solution was added under ice bath, and the temperature was kept unchanged for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min) to obtain the title compound 16 (8 mg, yield: 27.8%). MS m / z (ESI): 657.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (ddd, 1H), 7.34-7.21 (m, 2H), 7.06 (dd, 1H), 5.95-5.86 (m, 1H), 5.79 (d, 1H), 5.08 (dd, 1H), 4.81 (s, 1H), 4.62 (dd, 1H), 4.49 (ddd, 1H), 4.17 (dd, 1H), 4.11 (d, 2H), 3.86-3.66 (m, 2H), 3.59 (dd, 1H), 3.48 (d, 2H), 3.27 (d, 1H), 2.58 (dt, 1H), 2.48 (p, 1H), 2.22 (dt, 1H), 2.05 (d, 1H), 2.01-1.79 (m, 4H), 1.62 (t, 1H), 0.96-0.82 (m, 3H), 0.75 (s, 2H), 0.68 (d, 1H), 0.56 (d, 1H).

[0423] Example 17 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((S)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 17 [ka] Following the synthesis route in Example 15, the raw material L-prolinol in step 11 was replaced with D-prolinol to obtain the title compound 17 (10 mg, yield: 24.3%). MS m / z (ESI): 659.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ7.67-7.65 (m, 1H), 7.30-7.24 (m, 2H), 7.11 (s, 1H),7.02 (s, 1H), 5.05-5.01 (m, 1H), 4.75-4.73 (m, 1H), 4.63-4.59 (m, 1H), 4.48-4.46 (m, 1H), 4.17-4.13 (m, 2H), 3.76-3.74 (m, 1H), 3.65-3.64 (m, 1H), 3.57-3.54 (m, 1H), 3.47-3.39 (m, 3H), 3.36-3.23 (m, 1H), 2.70-2.68 (m, 1H), 2.60-2.47 (m, 2H), 2.45-2.10 (m, 2H), 2.05-1.78 (m, 7H), 1.74-1.69 (m, 1H), 0.94-0.91 (m, 1H), 0.86-0.84 (m, 2H), 0.74-0.71 (m, 2H), 0.63-0.65 (m, 1H), 0.56-0.53 (m, 1H).

[0424] Example 18 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((S)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 18 [ka] [ka]

[0425] Step 1 (S)-2-(Hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate tert-butyl ester 18a 1-(tert-Butyl) 2-methyl (R)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate 18a (520 mg, 2.28 mmol, Yakuhin Kotoku) was dissolved in tetrahydrofuran (5 mL), and 1 M lithium aluminum hydride in tetrahydrofuran (24 mL) was added under ice bath. After reacting for 2 hours, sodium sulfate decahydrate was added to quench the reaction, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product, the title compound 18b (421 mg). The product was used in the next step without purification. MS m / z (ESI): 144.2[M-55].

[0426] Step 2 (S)-(2,5-Dihydro-1H-pyrrol-2-yl)methanol 2,2,2-trifluoroacetate 18c Crude compound 18b (162 mg, 813 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 g, 8.77 mmol) was added under ice bath, and the mixture was reacted with stirring for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude product, title compound 18c (260 mg). The product was used in the next step without purification. MS m / z (ESI): 100.2[M+1].

[0427] Step 3 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((S)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 18 Following the synthesis route in Example 15, the starting material L-prolinol in step 11 was replaced with compound 18c to give the title compound 18 (2 mg, yield: 12.1%). MS m / z (ESI): 657.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.70-7.63 (m, 1H), 7.31-7.21 (m, 2H), 7.11-7.01 (m, 1H), 5.90-5.84 (m, 1H), 5.77 (d, 1H), 5.11-5.04 (m, 1H), 4.83-4.79 (m, 1H), 4.61 (d, 1H), 4.48 (td, 1H), 4.15 (dd, 1H), 4.09 (d, 1H), 4.00 (d, 1H), 3.76 (s, 1H), 3.66 (s, 1H), 3.64-3.54 (m, 2H), 3.45 (d, 1H), 3.25 (d, 1H), 2.49 (dd, 2H), 2.21 (t, 2H), 2.05 (s, 1H), 1.87 (d, 4H), 1.63 (d, 1H), 0.92-085 (m, 3H), 0.71 (s, 1H), 0.63 (d, 1H), 0.51 (d, 1H).

[0428] Example 19 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((1S,2R,5R)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 19 [ka] [ka]

[0429] Step 1 (1S,2R,5R)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 19b (1S,2R,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 19a (100mg, 440μmol, Nanjing medicinal stone) was dissolved in tetrahydrofuran (2mL), and borane tetrahydrofuran complex (0.55mL, 1M in THF) was added under ice bath, and the mixture was reacted with stirring for 14 hours. Then, borane dimethylsulfide complex (0.2mL, 10M in THF) was added, and the mixture was heated to 60℃ and reacted for 1 hour. The reaction solution was cooled to room temperature, quenched by adding methanol, and concentrated under reduced pressure to obtain the crude product, the title compound 19b (94mg). The product was used in the next step without purification.

[0430] Step 2 ((1S,2R,5R)-3-Azabicyclo[3.1.0]hexan-2-yl)methanol 19c Crude compound 19b (94 mg, 440 μmol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added in an ice bath, and the mixture was allowed to react with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol, anhydrous potassium carbonate was added, and the mixture was stirred for 10 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, title compound 19c (30 mg). The product was used in the next step without purification. MS m / z (ESI): 114.2[M+1].

[0431] Step 3 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((1S,2R,5R)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 19 Following the synthesis route in Example 15, the starting material L-prolinol in step 11 was replaced with compound 19c to give the title compound 19 (10 mg, yield: 20%). MS m / z (ESI): 671.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (dd, 1H), 7.32-7.20 (m, 2H), 7.06 (dd, 1H), 5.15 -4.94 (m, 2H), 4.69-4.61 (m, 1H), 4.48 (td, 1H), 4.16 (dd, 1H), 3.90-3.73 (m, 2H), 3.71-3.59 (m, 2H), 3.46 (dd, 1H), 3.30-3.13 (m, 2H), 2.68 (s, 1H), 2.58 (s, 1H), 2.49 (dd, 1H), 2.39 (s, 1H), 2.22 (q, 1H), 2.01-.71 (m, 4H), 1.59 (s, 3H), 1.43 (d, 1H), 0.89 (dt, 4H), 0.56 (q, 2H), 0.39 (d, 1H), 0.27 (t, 1H).

[0432] Example 20 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((1S,2S,5R)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 20 [ka] Using the synthetic route in Example 19, the raw material compound 19a in step 1 was replaced with (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Chinese medicine stone) to obtain the title compound 19 (2 mg, yield: 12.1%). MS m / z (ESI): 671.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (ddd, 1H), 7.32-7.21 (m, 2H), 7.06 (dd, 1H), 5.13-5.01 (m, 1H), 4.66-4.58 (m, 2H), 4.54-4.43 (m, 2H), 4.30 (t, 1H), 4.16 (d, 1H), 3.65 m, 4H), 3.53-3.43 (m, 2H), 3.26 (d, 2H), 2.93 (m, 3H), 2.53 (m, 2H), 2.27-2.18 (m, 2H), 1.89 (m, 3H), 1.63 (s, 1H), 1.50-1.42 (m, 1H), 0.99-0.81 (m, 3H), 0.67 (s, 1H), 0.51 (s, 1H), 0.39 (s, 1H).

[0433] Example 21 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((1R,2R,5S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 21 [ka] Using the synthetic route in Example 19, the raw material compound 19a in step 1 was replaced with (1R,2R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Chinese medicine crystal) to obtain the title compound 21 (2 mg, yield: 11%). MS m / z (ESI): 671.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.67 (td, 1H), 7.32-7.20 (m, 2H), 7.06 (dd, 1H), 5.07 (dd, 2H), 4.66-4.56 (m, 2H), 4.54-4.41 (m, 2H), 4.41-4.34 (m, 1H), 4.16 (dd, 1H), 3.78 (s, 1H), 3.68 (s, 1H), 3.61 (s, 1H), 3.47 (s, 1H), 3.27 (d, 1H), 2.97-2.85 (m, 2H), 2.58 (dd, 1H), 2.48 (d, 1H), 2.23 (dt, 2H), 2.05 (s, 1H), 1.99-1.83 (m, 3H), 1.62 (s, 1H), 1.46 (s, 2H), 0.89 (dt, 3H), 0.67 (s, 2H), 0.51 (s, 1H), 0.38 (s, 1H).

[0434] Example 22 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(((1R,2S,5S)-2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 22 [ka] Using the synthetic route in Example 19, the raw material compound 19a in step 1 was replaced with (1R,2S,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Chinese medicine) to obtain the title compound 22 (10 mg, yield: 24.2%). MS m / z (ESI): 671.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.67 (ddd, 1H), 7.33-7.20 (m, 2H), 7.06 (dd, 1H), 5.07 (dd, 2H), 4.80 (d, 1H), 4.49 (td, 1H), 4.16 (dd, 1H), 3.93 (s, 1H), 3.79 (s, 1H), 3.72-3.58 (m, 2H), 3.47 (d, 1H), 3.30-3.16 (m, 2H), 2.69 (d, 1H), 2.58 (dd, 1H), 2.48 (h, 2H), 2.23 (dt, 1H), 2.05 (d, 1H), 2.00-1.71 (m, 4H), 1.69-1.55 (m, 2H), 1.45 (s, 1H), 0.89 (dt, 4H), 0.57 (d, 2H), 0.40 (d, 1H), 0.29 (s, 1H).

[0435] Example 23 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-((1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol (diastereomeric mixture) 23 [ka] [ka]

[0436] Step 1 (±)-(3-Azabicyclo[3.1.0]hexan-1-yl)methanol 23b (±)-3-Azabicyclo[3.1.0]hexane-1-carboxylic acid hydrochloride 23a (100 mg, 611.2 μmol, Shanghai Shaoyuan) was dissolved in tetrahydrofuran (5 mL), and borane tetrahydrofuran complex (3 mL, 1M in THF) was added under ice bath, and the mixture was reacted with stirring for 14 hours. The mixture was then heated to 60° C. and reacted for 1 hour. The reaction solution was cooled to room temperature, quenched by adding methanol, and concentrated under reduced pressure to obtain the crude product, the title compound 23b (70 mg). The product was used in the next step without purification. MS m / z (ESI): 114.2[M+1].

[0437] Step 2 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-((1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol (diastereomeric mixture) 23 Following the synthesis route in Example 15, the starting material L-prolinol in step 11 was replaced with compound 23b to give the title compound 23 (10 mg, yield: 24.2%). MS m / z (ESI): 671.2[M+1]. 1H NMR (500 MHz, CD3OD): δ7.68-7.66 (m, 1H), 7.30-7.26 (m, 2H), 7.11 (s, 1H),7.02 (s, 1H),5.07-5.01 (m, 1H),4.61-4.59 (m, 1H), 4.48-4.35(m, 3H), 4.18-4.16 (m, 1H), 3.77-3.76 (m, 1H), 3.67-3.65 (m, 2H), 3.57-3.54 (m, 1H), 3.27-3.17 (m, 3H), 2.57-2.46(m, 5H), 2.26-2.24 (m, 1H),1.93-1.85 (m, 4H), 1.35-1.26 (m, 3H), 0.94-0.92 (m, 2H), 0.86-0.83 (m, 2H), 0.68-0.65 (m, 1H), 0.51-0.48(m, 2H).

[0438] Example 24 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((3-(hydroxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol (diastereomeric mixture) 24 [ka] [ka]

[0439] Step 1 (1S,2S,5R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2-((3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl (diastereomeric mixture) 24b Compound 15h (300 mg, 494.2 μmol) was dissolved in tetrahydrofuran (5 mL), and (3-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (diastereomeric mixture) 24a (142 mg, 497.3 μmol, obtained by preparation according to the method disclosed in intermediate B-3 on page 115 of the specification in patent application "WO2020 / 146613") was added, and 0.3 mL of 2M sodium bis(trimethylsilyl)amide tetrahydrofuran solution was added under ice bath, and the reaction was carried out with stirring for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, the title compound 24b (420 mg). The product was used in the next step without purification. MS m / z (ESI): 855.2[M+1].

[0440] Step 2 (5aS,6S,9R)-2-Chloro-1-fluoro-12-((3-(hydroxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl (diastereomeric mixture) 24c Crude compound 24b (423 mg, 494.1 μmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (556 mg, 2.46 mmol) was added, and the mixture was heated to 60° C. and reacted with stirring for 1 hour. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL×2), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain title compound 24c (106 mg, yield: 36.2%). MS m / z (ESI): 591.2[M+1].

[0441] Step 3 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((3-(hydroxymethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol (diastereomeric mixture) 24 Following steps 12 and 13 of the synthetic route in Example 15, starting compound 15l in step 12 was replaced with compound 24c to obtain the title compound 24 (30 mg, yield: 34.6%). MS m / z (ESI): 645.2[M+1]. 1H NMR (500 MHz, CD3OD): δ 7.70-7.64 (m, 1H), 7.30 (d, 1H), 7.25 (td, 1H), 7.06 (m, 1H), 5.08 (dd, 1H), 4.62 (dd, 1H), 4.48 (td, 1H), 4.42 (s, 1H), 4.37-4.30 (m, 1H), 4.16 (dd, 1H), 3.86 (dd, 1H), 3.78 (d, 1H), 3.75 (s, 1H), 3.66 (s, 1H), 3.50-3.45 (m, 2H), 3.30-3.18 (m, 1H), 3.11 (s, 1H), 2.97 (s, 1H), 2.58 (dd, 1H), 2.49 (dd, 1H), 2.22 (dd, 2H), 2.07 (s, 1H), 1.95-1.78 (m, 7H), 1.63 (m, 1H), 0.88 (m, 3H).

[0442] Example 25 ((S)-1-((1-((((5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidin-2-yl)methyl dimethylcarbamate 25 [ka] [ka]

[0443] Step 1 (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(1-(((S)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl 25a According to the synthetic route in Example 15, L-prolinol, which is the raw material in step 11, was replaced with D-prolinol, and the title compound 25a (184 mg, yield: 52.2%) was obtained by the methods of steps 11 and 12. MS m / z (ESI): 803.2[M+1].

[0444] Step 2 (5aS,6S,9R)-12-((1-(((S)-2-(((dimethylaminocarbonyl)oxy)methyl)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate tert-butyl 25b Compound 25a (120 mg, 149.5 μmol) and triethylamine (90 mg, 889.4 μmol) were dissolved in 5 mL of tetrahydrofuran, 4-nitrophenyl chloroformate (90 mg, 446.5 μmol) was added, and the mixture was stirred for 5 hours. Dimethylamine hydrochloride (242 mg, 3 mmol) was then added, and the mixture was stirred for 15 minutes. The reaction solution was diluted with 10 mL of ethyl acetate, washed with water and saturated sodium chloride solution in order, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 25b (100 mg, yield: 76.5%). MS m / z (ESI): 874.2[M+1].

[0445] Step 3 ((S)-1-((1-((((5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)pyrrolidin-2-yl)methyl dimethylcarbamate 25 Compound 25b (100 mg, 114.4 μmol) was dissolved in ethyl acetate (2 mL), 0.5 mL of 4 M hydrochloric acid dioxane solution was added under ice bath, and the temperature was maintained for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30 × 150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient blending ratio: acetonitrile 30% to 45%, flow rate: 30 mL / min) to obtain the title compound 25 (25 mg, yield: 29.9%). MS m / z (ESI): 730.2[M+1]. 1 H NMR (500 MHz, CD3OD):δ 7.67 (t, 1H), 7.29 (q, 1H), 7.27-7.22 (m, 1H), 7.07 (dd, 1H), 5.14-5.04 (m, 1H), 4.61 (dd, 1H), 4.51 (td, 1H), 4.16 (dd, 1H), 4.05-3.92 (m, 2H), 3.80 (d, 2H), 3.65 (s, 1H), 3.50 (t, 2H), 3.29-3.18 (m, 1H), 2.88 (s, 3H), 2.78 (s, 3H), 2.61-2.42 (m, 2H), 2.37-2.18 (m, 2H), 1.92 (s, 5H), 1.79 (s, 3H), 1.66-1.53 ​​(m, 2H), 0.88 (m, 3H), 0.69 (s, 2H), 0.60 (d, 1H), 0.47 (d, 1H).

[0446] Biological evaluation Test Example 1: Biological evaluation of AGS cell ERK phosphorylation inhibition experiment (HTRF method) 1. Purpose of the test This experiment was carried out to detect the inhibitory effect of compounds on cellular ERK phosphorylation, and to assess IC 50 The inhibitory effect of the compounds according to the present disclosure on the KRAS target was evaluated by the magnitude of

[0447] II. Experimental Method AGS cells (Nanjing Kebai, CBP60476) were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, AGS cells were seeded in a 96-well plate at a density of 40,000 cells / well in complete medium, with 190 μL of cell suspension per well, and cultured overnight in a cell incubator at 37°C and 5% CO2.

[0448] The next day, 10 μL of the compound to be measured, which was prepared in complete medium and diluted in a gradient, was added to each well, and the final concentration of the compound was 10 μM with 9 concentration points diluted in a 5-fold gradient. A blank control containing 0.5% DMSO was placed, and the well plate was placed in a cell incubator at 37°C and 5% CO2 for 1 hour. After incubation, the 96-well cell culture plate was removed, the medium was aspirated, and each well was washed once with 200 μL of PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320). The PBS was aspirated, and 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking solution (blocking reagent, Cisbio, 64KB1AAC) was added to each well, and the well plate was placed on a shaker and dissolved by shaking at room temperature for 40 minutes. After dissolution, the mixture was mixed uniformly by pipetting, and 16 μL of the dissolution solution from each well was transferred to two HTRF 96-well detection plates (Cisbio, 66PL96100), respectively, and then 4 μL of premixed phosphorylated ERK1 / 2 antibody solution (Cisbio, 64AERPEG) or 4 μL of premixed total ERK1 / 2 antibody solution (Cisbio, 64NRKPEG) was added to the two plates, respectively. The microplates were sealed with plate sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark.

[0449] On the third day, fluorescence values ​​were read at 665 nm and 620 nm emission wavelengths with excitation at 337 nm using an ENVISION multifunction plate reader (PerkinElmer, ENVISION).

[0450] 3. Data Analysis The IC of the compound inhibitory activity was calculated by the compound concentration and the ratio of phosphorylated ERK / total ERK using the software Graphpad Prism. 50 The values ​​were calculated and the results are shown in Table 1 below.

[0451] [Table 4]

[0452] Conclusion: The compounds disclosed herein have good inhibitory effects on AGS cell ERK phosphorylation.

[0453] Test Example 2: Biological evaluation of GP2d and AGS cell 3D proliferation inhibition experiments 1. Purpose of the test The inhibitory effect of the compounds of the present disclosure on the KRAS target was evaluated by testing their inhibitory effect on the 3D proliferation of GP2d and AGS cells.

[0454] II. Experimental Method GP2d cells (Nanjing Kebai, CBP60010) were cultured in complete medium, i.e., DMEM / high glucose medium (Hyclone, SH30243.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, GP2d cells were seeded in a 96-well low-attachment plate (Corning, CLS7007-24EA) at a density of 1000 cells / well in complete medium, with 90 μL of cell suspension per well, centrifuged at 2000 rpm at room temperature for 5 minutes, and then cultured overnight in a cell incubator at 37°C and 5% CO2.

[0455] AGS cells (Nanjing Kebai, CBP60476) were cultured in complete medium, i.e., RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, AGS cells were seeded in a 96-well low-attachment plate (Corning, CLS7007-24EA) at a density of 1000 cells / well in complete medium, with 90 μL of cell suspension per well, centrifuged at 2000 rpm at room temperature for 5 minutes, and then cultured overnight in a cell incubator at 37°C and 5% CO2.

[0456] The next day, 10 μL of the compound to be measured, which was prepared in complete medium and diluted with gradient, was added to each well, and the final concentration of the compound in GP2d cells was 1 μM to 9 concentration points diluted with 3-fold gradient, and the final concentration of the compound in AGS cells was 10 μM to 9 concentration points diluted with 3-fold gradient, and a blank control containing 0.5% DMSO was set up. The well plate was placed in a cell incubator at 37°C and 5% CO2 and incubated for 120 hours. On the 7th day, the 96-well cell culture plate was removed, 50 μL of CellTiter-Glo® 3D reagent (Promega, G9682) was added to each well, shaken at room temperature for 25 minutes, and then blown and mixed uniformly, and 50 μL was removed and transferred to a white opaque 96-well plate (PE, 6005290), and the luminescence signal value was read by a multifunction microplate reader (PerkinElmer, ENVISION).

[0457] 3. Data Analysis The IC of the inhibitory activity of the compound was calculated using the software Graphpad Prism. 50 The values ​​were calculated and the results are shown in Table 2 below.

[0458] [Table 5]

[0459] Conclusion: The compounds disclosed herein have good inhibitory effects on the 3D proliferation of AGS and GP2d cells.

[0460] Test Example 3: Detection of affinity of compounds according to the present disclosure for KRAS protein isoform G12D or WT by SPR method First, biotinylated Avi-KRAS-WT or Avi-KRAS-G12D was diluted to 20 μg / mL with 1×HBS-P+ (Cat.#BR1006-71) buffer containing 100 mM MgCl2, and then passed through SA (Cat.#BR1005-31) biosensor chip channel 2 for 420 s, obtaining a coupling level of approximately 5000 to 7000 RU. Furthermore, low molecular weight compound samples were injected in ascending order for 120 s and then dissociated for 720 s. The test employed a single cycle kinetics model. The reaction signal was detected in real time by a Biacore 8K instrument to obtain a binding dissociation curve. After the test was completed, data analysis was performed using the Biacore 8K evaluation software, and the data was fitted with a 1:1 model to obtain affinity data.

[0461] [Table 6]

[0462] Conclusion: The compounds according to the present disclosure have good affinity for KRAS protein isoforms G12D or WT.

Claims

1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 wherein, G ０ is selected from O, S, S(O), S(O) ２ , CR Ｇ０ａ R Ｇ０ｂ and NR Ｇ０ｃ and is selected from G １ is CR Ｇ１ａ R Ｇ１ｂ 、CR Ｇ１ａ R Ｇ１ｂ CR Ｇ１ｃ R Ｇ１ｄ 、C=O and C(O)CR Ｇ１ａ R Ｇ１ｂ selected from, G ２ is NR ｄ and T is a chemical bond or is selected from CR ａ R ｂ , NR Ｔ and O, Q is N or CR ２ａ and ring A is an aryl group or a heteroaryl group, ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, L is a single bond, O, or NR ｅ selected from, R ａ 、 R ｂ 、 R Ｇ０ａ 、 R Ｇ０ｂ 、 R Ｇ１ａ 、 R Ｇ１ｂ 、 R Ｇ１ｃ and R Ｇ１ｄ are the same or different and each independently is selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, or R Ｇ１ａ 、 R Ｇ１ｂ forms a cycloalkyl group together with the carbon atom to which it is attached, or R Ｇ１ｃ 、 R Ｇ１ｄ forms a cycloalkyl group together with the carbon atom to which it is attached, Each R １ is the same or different and each independently is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, -(CH ２ ) ｕ -NR ｆ R ｇ , a hydroxy group or a hydroxyalkyl group, R ２ａ and R ４ａ are the same or different and each independently is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, -(CH ２ ) ｖ -NR ｈ R ｉ , hydroxy group, hydroxyalkyl group and cycloalkyl group, Each R ３ and R ６ are the same or different and each independently is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, -(CH ２ ｗ ｊ R ｋ ２ ｗ１ ｚ１ ｊ１ R ｋ１ ２ ｗ２ ｚ２ ｊ２ -C(O)OR, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, and is selected from​​​​​​​​​​ R ５ａ and R ５ｂ are the same or different and each independently is selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxy group, and a hydroxyalkyl group, or R ５ａ and R ５ｂ together with the connecting carbon atoms form a cycloalkyl group or a heterocyclyl group, and the cycloalkyl group or the heterocyclyl group is each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cyano group, amino group, hydroxy group and hydroxyalkyl group, R Ｇ０ｃ 、R Ｔ 、R ｄ 、R ｅ 、R ｆ 、R ｇ 、R ｈ 、R ｉ 、R ｊ 、R ｋ 、R ｊ１ 、R ｋ１ and R ｊ２ are the same or different and each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, u, v, w, w1 and w2 are the same or different and each is independently selected from 0, 1, 2 and 3, z1 is 0 or 1, z2 is 0 or 1, r is 0, 1, 2 or 3, p is 0, 1, 2, 3, 4 or 5, q is 0, 1, 2, 3, 4 or 5 and t is 0, 1, 2, 3, 4 or 5, a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

2. G １ is CH ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. G ０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein G is O.

4. A compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, that is, 【Chemical 2】 Among them, ring A, ring B, G ２ , Q, L, R １ , R ３ , R ４ａ , R ５ａ , R ５ｂ , R ６ , p, q, r and t are as defined in claim 1, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is N.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a naphthyl group.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered heterocyclyl group.

8. R ４ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom or a halogen.

9. G ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein G is NH.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is O.

11. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom.

12. Each R ３ is the same or different and each independently is a hydrogen atom, halogen, C １－６ alkyl group, C ２－６ alkynyl group, C １－６ haloalkyl group, hydroxy group, C １－６ hydroxyalkyl group, and a 3- to 8-membered cycloalkyl group, selected from The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R ５ａ and R ５ｂ is a hydrogen atom, or R ５ａ , R ５ｂ forms a 3- to 6-membered cycloalkyl group together with the carbon atoms to which they are attached, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. Each R ６ is the same or different and each independently is a hydrogen atom, a halogen, C １－６ hydroxyalkyl group and -CH ２ -O-C(O)NR ｊ１ R ｋ１ selected from, R ｊ１ and R ｋ１ is the same or different and each independently is a hydrogen atom or C １－６ alkyl group, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. 【Chemical Formula 3】 【Chemical Formula 4】 [Chemical 5] ​ 【Chemical Formula 7】 【Chemical Formula 8】 【Chemical Formula 9】 【Chemical 10】 【Chemical 11】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is such a compound.

16. A compound represented by the general formula (I'A) or a salt thereof, 【Chemical Formula 12】 wherein, R is an amino protecting group, preferably Boc, R ｙ is a hydroxy protecting group, preferably MOM, y is 0, 1, 2, 3 or 4, G ０ 、G １ 、T, ring A, ring B, Q, L, R １ 、R ３ 、R ４ａ 、R ５ａ 、R ５ｂ 、R ６ 、p, r and t are as defined in claim 1, a compound or a salt thereof.

17. 【Fig. 13】 【Chemical Formula 14】 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 【Chemical 18】 【Chemical 19】 【Chemical 20】 a compound or a salt thereof selected from such compounds.

18. A method for preparing a compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, 【Chemical 21】 A step of subjecting a compound of general formula (I'A) or a salt thereof to a deprotection reaction to obtain a compound of general formula (I') or a pharmaceutically acceptable salt thereof, and optionally, R ３ and / or R ６ When the R group contains a protecting group, before, simultaneously with or after the deprotection reaction, the step of removing the protecting group on the R ３ and / or R ６ group is further included, wherein, R is an amino protecting group, preferably Boc, R ｙ is a hydroxy protecting group, preferably MOM, y is 0, 1, 2, 3 or 4, G ２ is NH, G ０ 、G １ 、T, ring A, ring B, Q, L, R １ 、R ３ 、R ４ａ 、R ５ａ 、R ５ｂ 、R ６ 、p, r, and t are as defined in claim 1. a method.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable vectors, diluents or excipients.

20. A medicament for inhibiting KRAS G12D, comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

21. A medicament for treating and / or preventing a disease or medical condition, comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein the disease or medical condition is cancer.

22. A medicament for treating and / or preventing a disease or medical condition, comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein the disease or medical condition is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and spongioblastoma, preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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