Condensed ring compound as well as preparation method and medical application thereof

Abstract

The invention relates to a fused ring compound, a preparation method thereof and application of the fused ring compound in medicine. Specifically, the invention relates to a fused ring compound as shown in a general formula (IN), a preparation method thereof, a pharmaceutical composition containing the compound and application of the fused ring compound as a therapeutic agent, in particular to application of the fused ring compound in preparation of drugs for inhibiting KRAS G12D. Wherein each group in the general formula (IN) is as defined in the specification. # imgabs0 #

Description

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

[0001] The present disclosure relates to the field of medicine and relates to a fused ring compound, a method for preparing the same, and its application in medicine. In particular, the present disclosure relates to a fused ring compound represented by the general formula (IN), a method for preparing the same, a pharmaceutical composition containing the same, and its use in the preparation of a medicament for inhibiting KRAS G12D. Background Art

[0002] RAS is one of the most frequently mutated oncogenes in tumors, with approximately 30% of human malignancies linked to RAS gene mutations. The RAS family includes KRAS, NRAS, and HRAS, with KRAS mutations being the most common, accounting for approximately 85%. KRAS mutations are common in solid tumors, with high frequency in the three most lethal human cancers: lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Of the KRAS gene mutations, 97% involve mutations at amino acid residues 12 or 13, with G12D being a key mutation. Analysis of data from European and American populations shows that G12D mutations occur in 36%, 12%, and 4% of patients with pancreatic cancer, colorectal cancer, and non-small cell lung cancer, respectively.

[0003] Once activated, KRAS regulates multiple aspects of cell function, including proliferation, survival, migration, and metabolism, through numerous downstream signaling pathways, including RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. Following KRAS gene mutation, the protein remains continuously activated, leading to persistent activation of downstream signaling pathways and promoting tumorigenesis.

[0004] Because the KRAS protein lacks traditional small molecule binding sites on its surface and has an extremely high affinity for guanylate, making it extremely difficult to inhibit, it has long been considered an undruggable drug target. However, given the importance and prevalence of abnormal KRAS activation in cancer progression, KRAS has been and remains a target of great interest in drug development. Currently, with the exception of KRAS G12C inhibitors, there is still a lack of KRAS inhibitors that are effective against other mutations, leaving most patients with KRAS mutations without treatment. G12D, as a mutant that is widely and highly expressed in various tumors, has important clinical significance for the development of inhibitors against it.

[0005] The related patent applications that have been published so far include WO2023030385A1, WO2023274383A1, WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1 and WO2021000885A1.

[0006] Summary of the Invention

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

[0008] in:

[0009] Ring C is a heterocyclic group;

[0010] R x1 is a hydrogen atom or R x Preferably, R x1 R x ;

[0011] R x Selected from =NOR 61 、=CR 62 R 63 Sum = NR 64 ;

[0012] G 0 Selected from O, S, S(O), S(O)2, CR G0a R G0b and NR G0c ;

[0013] G 1 Selected from CR G1a R G1b , CR G1a R G1b CR G1c R G1d , C=O and C(O)CR G1a R G1b ;

[0014] G 2 NR d ;

[0015] T is a chemical bond or selected from CR a R b NR T and O;

[0016] Q is N or CR 2a ;

[0017] Ring A is an aryl group or a heteroaryl group;

[0018] L is selected from a single bond, O and NR e ;

[0019] R a 、R b 、R G0a 、R G0b 、R G1a 、R G1b 、R G1c and R G1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; or, R G1a 、R G1b Together with the attached carbon atom, they form a cycloalkyl group; or, R G1c 、R G1d Together with the attached carbon atom, it forms a cycloalkyl group;

[0020] Each R 1 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) u -NR f R g , hydroxyl and hydroxyalkyl;

[0021] R 2a and R 4a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) v -NR h R i , hydroxy, hydroxyalkyl and cycloalkyl;

[0022] Each R 3 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) w -NR j R k 、-(CH2) w1 -(O) x1 -C(O)NR j1 R k1 、-(CH2) w2 -(O) x2 -C(O)OR j2 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0023] Each R 6are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) y -NR m R n 、-(CH2) y1 -(O) z1 -C(O)NR m1 R n1 、-(CH2) y2 -(O) z2 -C(O)OR m2 、=NOR 61 、=CR 62 R 63 、=NR 64 , nitro, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0024] R 61 、R 62 、R 63 and R 64 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;

[0025] R 5a and R 5b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl; or

[0026] R 5a 、R 5b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl;

[0027] R G0c 、R T 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R k 、R j1 、R k1 、R j2 、R m 、R n 、R m1 、R n1 and R m2are the same 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 heterocyclic group, an aryl group, and a heteroaryl group;

[0028] u, v, w, w1, w2, y, y1 and y2 are the same or different and are each independently selected from 0, 1, 2 and 3;

[0029] x1, x2, z1 and z2 are the same or different and are each independently selected from 0 or 1;

[0030] r is 0, 1, 2, or 3;

[0031] p is 0, 1, 2, 3, 4, or 5;

[0032] q is 0, 1, 2, 3, 4, or 5; and

[0033] t1 is 0, 1, 2, 3, 4, or 5.

[0034] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IN') or a pharmaceutically acceptable salt thereof:

[0035] in

[0036] a is 0, 1, 2, 3, or 4;

[0037] G 0 , G 1 , G 2 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, t1 and r are as defined in the general formula (IN).

[0038] The present disclosure provides a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof:

[0039] in:

[0040] Ring B is a heterocyclic group;

[0041] G 0 Selected from O, S, S(O), S(O)2, CR G0a R G0b and NR G0c ;

[0042] G 1 Selected from CR G1a RG1b , CR G1a R G1b CR G1c R G1d , C=O and C(O)CR G1a R G1b ;

[0043] G 2 NR d ;

[0044] T is a chemical bond or selected from CR a R b NR T and O;

[0045] Q is N or CR 2a ;

[0046] Ring A is an aryl group or a heteroaryl group;

[0047] L is selected from a single bond, O and NR e ;

[0048] R a 、R b 、R G0a 、R G0b 、R G1a 、R G1b 、R G1c and R G1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; or, R G1a 、R G1b Together with the attached carbon atom, they form a cycloalkyl group; or, R G1c 、R G1d Together with the attached carbon atom, it forms a cycloalkyl group;

[0049] Each R 1 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) u -NR f R g , hydroxyl and hydroxyalkyl;

[0050] R 2a and R 4a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) v -NR h R i , hydroxy, hydroxyalkyl and cycloalkyl;

[0051] Each R 3 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) w -NR j R k 、-(CH2) w1 -(O) x1 -C(O)NR j1 R k1 、-(CH2) w2 -(O) x2 -C(O)OR j2 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0052] Each R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) y -NR m R n 、-(CH2) y1 -(O) z1 -C(O)NR m1 R n1 、-(CH2) y2 -(O) z2 -C(O)OR m2 、=NOR 61 、=CR 62 R 63 、=NR 64 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0053] R 61 、R 62 、R 63 and R 64 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;

[0054] R 5a and R 5b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl; or

[0055] R 5a 、R 5bTogether with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl;

[0056] R G0c 、R T 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R k 、R j1 、R k1 、R j2 、R m 、R n 、R m1 、R n1 and R m2 are the same 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 heterocyclic group, an aryl group, and a heteroaryl group;

[0057] u, v, w, w1, w2, y, y1 and y2 are the same or different and are each independently selected from 0, 1, 2 and 3;

[0058] x1, x2, z1 and z2 are the same or different and are each independently selected from 0 or 1;

[0059] r is 0, 1, 2, or 3;

[0060] p is 0, 1, 2, 3, 4 or 5; and

[0061] q is 0, 1, 2, 3, 4, or 5; and

[0062] t is 0, 1, 2, 3, 4, or 5.

[0063] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IM') or a pharmaceutically acceptable salt thereof:

[0064] in

[0065] a is 0, 1, 2, 3, or 4;

[0066] G 0 , G 1 , G 2 , T, Ring A, Ring B, Q, L, R 1 、R3 、R 4a 、R 5a 、R 5b 、R 6 , p, t and r are as defined in Formula (IM).

[0067] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or (IM) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

[0068] in:

[0069] G 0 Selected from O, S, S(O), S(O)2, CR G0a R G0b and NR G0c ;

[0070] G 1 Selected from CR G1a R G1b , CR G1a R G1b CR G1c R G1d , C=O and C(O)CR G1a R G1b ;

[0071] G 2 NR d ;

[0072] T is a chemical bond or selected from CR a R b NR T and O;

[0073] Q is N or CR 2a ;

[0074] Ring A is an aryl group or a heteroaryl group;

[0075] L is selected from a single bond, O and NR e ;

[0076] R a 、R b 、R G0a 、R G0b 、R G1a 、R G1b 、R G1c and R G1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; or, R G1a 、R G1bTogether with the attached carbon atom, they form a cycloalkyl group; or, R G1c 、R G1d Together with the attached carbon atom, it forms a cycloalkyl group;

[0077] Each R 1 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) u -NR f R g , hydroxyl and hydroxyalkyl;

[0078] R 2a and R 4a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) v -NR h R i , hydroxy, hydroxyalkyl and cycloalkyl;

[0079] Each R 3 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) w -NR j R k 、-(CH2) w1 -(O) x1 -C(O)NR j1 R k1 、-(CH2) w2 -(O) x2 -C(O)OR j2 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0080] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) y -NR m R n 、-(CH2) y1 -(O) z1 -C(O)NR m1 R n1 、-(CH2) y2-(O) z2 -C(O)OR m2 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or

[0081] R 6a and R 6e and the carbon atom to which it is connected, R 6a and R 6g and the carbon atom to which it is connected, R 6c and R 6e and the carbon atom or R 6c and R 6g Together with the carbon atoms to which it is attached, it forms a bridge, said bridge having 1, 2, 3 or 4 CH2, any one of which may be optionally replaced by O, S or NH, said bridge being optionally substituted by one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; or

[0082] R 6a and R 6b and the carbon atom to which it is connected, R 6c and R 6d and the carbon atom to which it is connected, R 6e and R 6f The carbon atom or R 6g and R 6h Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl;

[0083] R 5a and R 5b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl; or

[0084] R 5a 、R 5b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl;

[0085] R G0c 、R T 、R d 、R e 、R f 、R g 、R h 、R i 、R j、R k 、R j1 、R k1 、R j2 、R m 、R n 、R m1 、R n1 and R m2 are the same 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 heterocyclic group, an aryl group, and a heteroaryl group;

[0086] u, v, w, w1, w2, y, y1 and y2 are the same or different and are each independently selected from 0, 1, 2 and 3;

[0087] x1, x2, z1 and z2 are the same or different and are each independently selected from 0 or 1;

[0088] r is 0, 1, 2, or 3;

[0089] p is 0, 1, 2, 3, 4 or 5; and

[0090] q is 0, 1, 2, 3, 4 or 5.

[0091] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof:

[0092] in

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

[0094] G 0 , G 1 , G 2 , T, Ring A, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and r are as defined in the general formula (I).

[0095] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably More preferably G 0 , G 1 , G 2 、R 1 and p are as defined in general formula (I).

[0096] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein G 0 Selected from O, CR G0a R G0b and NR G0c , R G0a and R G0b are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 Haloalkyl, R G0c A hydrogen atom or C 1-6 Alkyl; preferably, G 0 is selected from O, CH2 and NH; further preferably, G 0 It is O.

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein G 1 CR G1a R G1b , CR G1a R G1b CR G1c R G1d Or C=O, R G1a 、R G1b 、R G1c and R G1d are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 preferably, G 1 is CH2 or C=O; further preferably, G 1 For CH2.

[0098] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein G 1 CR G1a H, R G1a As defined in general formula (IN); preferably, G1 CR G1a H, R G1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; further preferably, G 1 CR G1a H, R G1a A hydrogen atom or C 1-6 Alkyl; more preferably, G 1 CR G1a H, R G1a C 1-6 Alkyl; more preferably, G 1 CR G1a H, R G1a It is a methyl group.

[0099] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable 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)-; further preferably -O-CH2-; in some embodiments, -G 0 -G 1 - is -O-CH(CH3)-.

[0100] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein T is a chemical bond.

[0101] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxyl and C 1-6 Hydroxyalkyl, or R 5a 、R 5b Together with the carbon atom to which it is attached, it forms a 3- to 8-membered cycloalkyl group; preferably, R 5a and R 5b is a hydrogen atom, or R 5a 、R 5b Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; more preferably, R 5a and R5b is a hydrogen atom, or R 5a 、R 5b Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0102] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein r is 1 or 3.

[0103] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein -CH2- or Preferably

[0104] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IM), (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II') or a pharmaceutically acceptable salt thereof:

[0105] in

[0106] Ring A, G 2 , Q, L, R G1a 、R 1 、R 3 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and q are as defined in formula (I); preferably, R G1a C 1-6 alkyl.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IM), (I) or (II') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0108] in

[0109] Ring A, G 2 , Q, L, R 1 、R 3 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d、R 6e 、R 6f 、R 6g 、R 6h , p and q are as defined in the general formula (I).

[0110] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (IVV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof:

[0111] in

[0112] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0113] G 2 , Q, L, R G1a 、R 1 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in general formula (I); preferably, R G1a C 1-6 alkyl.

[0114] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (IVV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0115] in

[0116] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0117] G 2 , Q, L, R 1 、R 4a 、R6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in general formula (I).

[0118] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or (IN') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IVV') or a pharmaceutically acceptable salt thereof:

[0119] in

[0120] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0121] Ring C, G 2 , Q, L, R G1a 、R 1 、R 4a 、R 6 、R x1 , t1 and p are as defined in the general formula (IN); preferably, R G1a C 1-6 alkyl.

[0122] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (IVV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV') or (VV') or a pharmaceutically acceptable salt thereof:

[0123] in

[0124] R x Selected from =NOR 61 、=CR 62 R 63 Sum = NR 64 ;

[0125] R 61 、R 62 、R 63 and R 64 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;

[0126] t is 0, 1, 2, 3, or 4;

[0127] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0128] Ring B is a heterocyclic group;

[0129] R x1 , t1, ring C, G 2 , Q, L, R G1a 、R 1 、R 4a 、R 6 and p are as defined in formula (IN); preferably, R G1a C 1-6 alkyl.

[0130] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (IVV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV') or a pharmaceutically acceptable salt thereof:

[0131] in

[0132] R x Selected from =NOR 61 、=CR 62 R 63 Sum = NR 64 ;

[0133] R 61 、R 62 、R 63 and R 64 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;

[0134] t is 0, 1, 2, 3, or 4;

[0135] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0136] Ring B, G 2 , Q, L, R G1a 、R 1 、R 4a 、R 6 and p are as defined in formula (IM); preferably, R G1a C1-6 alkyl.

[0137] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or (IN') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VV') or a pharmaceutically acceptable salt thereof:

[0138] in

[0139] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0140] Ring C, G 2 , Q, L, R G1a 、R 1 、R 4a 、R 6 、R x1 , t1 and p are as defined in the general formula (IN); preferably, R G1a C 1-6 alkyl.

[0141] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (VV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof:

[0142] in

[0143] R x Selected from =NOR 61 、=CR 62 R 63 Sum = NR 64 ;

[0144] R 61 、R 62 、R 63 and R 64 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;

[0145] t is 0, 1, 2, 3, or 4;

[0146] R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

[0147] Ring B, G 2 , Q, L, R G1a 、R 1 、R 4a 、R 6 and p are as defined in formula (IM); preferably, R G1a C 1-6 alkyl.

[0148] In some embodiments of the present disclosure, the compound represented by the general formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably More preferably G 2 、R 1 and p are as defined in general formula (I).

[0149] In some embodiments of the present disclosure, the compound represented by the general formula (II'), (III'), (IV'), (V'), (IVV'), (VV') or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably selected from More preferably In this paragraph, R G1a is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups, G 2 、R 1 and p are as defined in general formula (I).

[0150] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (III'), (IV'), (IVV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III'-1) or a pharmaceutically acceptable salt thereof:

[0151] in:

[0152] R G1a is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; preferably, R G1a C 1-6 alkyl;

[0153] G 2 , Q, L, R 1 、R3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in formula (III').

[0154] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (IV'), (IVV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV'-1) or a pharmaceutically acceptable salt thereof:

[0155] in

[0156] R G1a is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; preferably, R G1a C 1-6 alkyl;

[0157] Ring B, G 2 , Q, L, R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (IV').

[0158] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (VV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VV'-1) or a pharmaceutically acceptable salt thereof:

[0159] in

[0160] R G1a is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; preferably, R G1a C 1-6 alkyl;

[0161] Ring C, G 2 , Q, L, R 1 、R 3a 、R 3b 、R 4a 、R 6 、Rx1 , t1 and p are as defined in formula (VV').

[0162] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (V'), (VV') or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V'-1) or a pharmaceutically acceptable salt thereof:

[0163] in

[0164] R G1a is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; preferably, R G1a C 1-6 alkyl;

[0165] G 2 , Q, L, R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (V').

[0166] In some embodiments of the present disclosure, the compound represented by the general formula (IM), (IM'), (IV'), (IV'-1), (V'), (V'-1) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered heterocyclic group; preferably, ring B is selected from morpholinyl, Tetrahydropyrrolyl, piperidinyl, More preferably, ring B is selected from piperidinyl, tetrahydropyrrolyl, More preferably, ring B is selected from piperidinyl, tetrahydropyrrolyl,

[0167] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein ring C is a 3- to 8-membered heterocyclic group; preferably, ring C is selected from azetidinyl, morpholinyl, Tetrahydropyrrolyl, piperidinyl,

[0168] In some embodiments of the present disclosure, the compound represented by the general formula (IM), (IM') or a pharmaceutically acceptable salt thereof, wherein Selected from R 61 、R 62 、R 63 and R 64 As defined in formula (IV'); preferably selected from

[0169] In some embodiments of the present disclosure, the compound represented by the general formula (IM), (IM') or a pharmaceutically acceptable salt thereof, wherein Selected from R 61 、R 62 、R 63 and R 64 As defined in formula (IV'); preferably selected from More preferably selected from

[0170] In some embodiments of the present disclosure, the compound represented by the general formula (IM), (IM') or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably, Selected from More preferably, for

[0171] In some embodiments of the present disclosure, the compound represented by the general formula (IM), (IM') or a pharmaceutically acceptable salt thereof, wherein for R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, for R 62 and R 63 are halogens; in some embodiments, for R 62 is halogen, R 63 A hydrogen atom.

[0172] In some embodiments of the present disclosure, the compound represented by the general formula (IV'), (IV'-1), (V'), (V'-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 61 、R 62 、R 63 and R 64 As defined in formula (IV'); preferably selected from R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 Alkyl; more preferably selected from

[0173] In some embodiments of the present disclosure, the compound represented by the general formula (IV'), (IV'-1), (V'), (V'-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 61 、R 62 、R 63 and R 64 As defined in formula (IV'); preferably selected from R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 Alkyl; more preferably selected from More preferably,

[0174] In some embodiments of the present disclosure, the compound represented by the general formula (IV'), (IV'-1), (V'), (V'-1) or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably selected from More preferably, for

[0175] In some embodiments of the present disclosure, the compound represented by the general formula (IV'), (IV'-1), (V'), (V'-1) or a pharmaceutically acceptable salt thereof, wherein for R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, for R 62 and R 63 are halogens; in some embodiments, for R 62 is halogen, R 63 A hydrogen atom.

[0176] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein Selected from R 61 、R 62 、R 63 and R 64 As defined in general formula (IN); preferably selected from R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 Alkyl; further preferably selected from More preferably selected from

[0177] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IVV') or a pharmaceutically acceptable salt thereof, wherein Selected from R 61 、R 62 、R 63 and R 64 As defined in general formula (IN); preferably selected from R61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 Alkyl; further preferably selected from More preferably selected from More preferably selected from More preferably, for

[0178] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IVV') or a pharmaceutically acceptable salt thereof, wherein for R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, for R 62 and R 63 are halogens; in some embodiments, for R 62 is halogen, R 63 A hydrogen atom.

[0179] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein for R 62 and R 63 As defined in general formula (IN); preferably R 62 and R 63 The same or different, and each independently a hydrogen atom or a halogen; more preferably selected from

[0180] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein t1 is 0 or 1; preferably, t1 is 0.

[0181] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, each R 6 The same or different, and each independently selected from =NOR 61 、=CR 62 R 63 、=NR 64 and oxo, R 61 、R 62 、R 63 and R 64 As defined in general formula (IN); preferably, each R 6 The same or different, and each independently selected from =NOR 61 、=CR 62 R 63 、=NR 64 and oxo, R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 alkyl; more preferably, each R 6 The same or different, and each independently is =CR 62 R 63 or oxo, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen.

[0182] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R 61 A hydrogen atom or C 1-6 Alkyl; preferably, R 61 C 1-6 Alkyl; More preferably, R 61 It is a methyl group.

[0183] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen; preferably, R 62 and R63 are the same or different and are each independently a hydrogen atom or F.

[0184] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R 64 A hydrogen atom or C 1-6 Alkyl; preferably, R 64 is a hydrogen atom or a methyl group.

[0185] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably selected from

[0186] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein Selected from Preferably selected from More preferably

[0187] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (III'), (IV'), (V'), (IVV'), (VV') or a pharmaceutically acceptable salt thereof, wherein R G1a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 preferably, R G1a A hydrogen atom or C 1-6 Alkyl; further preferably, R G1a C 1-6 Alkyl; More preferably, R G1a It is a methyl group.

[0188] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (III'), (III'-1), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein R G1a Selected from halogen, C 1-6 Alkyl and C 1-6 preferably, R G1a C 1-6 Alkyl; More preferably, R G1a It is a methyl group.

[0189] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6c and R 6g Together with the carbon atoms to which they are connected, they form a bridge, wherein the bridge has 1, 2, 3 or 4 CH2 groups in addition to the bridgehead carbon atoms; preferably, R 6c and R 6g Together with the connected carbon atoms, it forms a bridge, and the bridge has 1 CH2 in addition to the bridgehead carbon atom.

[0190] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b are all hydrogen atoms, or R 6a and R 6b Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; preferably, R 6a and R 6b are all hydrogen atoms, or R 6a and R 6b Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0191] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6c and R 6d are all hydrogen atoms, or R 6c and R 6d Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group; preferably, R 6c and R 6d are all hydrogen atoms, or R 6c and R6d Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0192] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6e and R 6f All are hydrogen atoms.

[0193] In some embodiments of the present disclosure, the compound represented by the general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6g and R 6h All are hydrogen atoms.

[0194] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein Q is N or CH; preferably N.

[0195] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein R 2a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 preferably, R 2a A hydrogen atom or C 1-6 Alkyl; More preferably, R 2a A hydrogen atom.

[0196] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II') or (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring A is selected from naphthyl, phenyl, pyridyl, benzothienyl, benzothiazolyl and benzopyrazolyl; more preferably, ring A is selected from naphthyl, phenyl and benzothienyl; further preferably, ring A is phenyl or naphthyl; more preferably, it is naphthyl.

[0197] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IM), (I), (II'), (II) or a pharmaceutically acceptable salt thereof, wherein Selected from q1 is 0, 1, 2, 3, or 4, R 3 As defined in formula (IN); preferably, Selected from q1 is 2 or 3, R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and cyano; further preferably, Selected from q1 is 2 or 3, R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl and cyano; in some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from In some embodiments, Selected from

[0198] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein R 4a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 A haloalkyl group; preferably a hydrogen atom or a halogen; more preferably a halogen; more preferably F.

[0199] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein R d A hydrogen atom or C 1-6 Alkyl; preferably, R d A hydrogen atom.

[0200] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein G 2 For NH.

[0201] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein L is selected from CH2, NH and O; preferably O.

[0202] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein R e A hydrogen atom or C 1-6 Alkyl; preferably, R e A hydrogen atom.

[0203] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein each R 1are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, amino, -(CH2) u -NR f R g , hydroxyl and C 1-6 Hydroxyalkyl, R f and R g The same or different, and each independently a hydrogen atom or a C 1-6 alkyl, u is 0 or 1; preferably, each R 1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0204] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or pharmaceutically acceptable salts thereof, wherein p is 0 or 1, preferably 0.

[0205] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II') or (II) or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, cyano, amino, -(CH2) w -NR j R k , hydroxyl and C 1-6 Hydroxyalkyl, R j and R k The same or different, and each independently a hydrogen atom or a C 1-6 alkyl, w is 0 or 1; preferably, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, -OC(O)NHC 1-6 Alkyl, amino, cyano, C 1-6 Hydroxyalkyl and 3 to 8-membered cycloalkyl; more preferably, R3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, C 1-6 hydroxyalkyl and 3 to 8-membered cycloalkyl; further preferably, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 haloalkyl, hydroxyl and cyclopropyl; further preferably, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and hydroxy; most preferably, each R 3 are the same or different and are each independently selected from F, ethyl and hydroxy; in some embodiments, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, -OC(O)NHC 1-6 alkyl, amino, and cyano; in some embodiments, each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and cyano.

[0206] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IM), (I), (II') or (II) or a pharmaceutically acceptable salt thereof, wherein q is 2, 3 or 4, preferably q is 2 or 3, more preferably 3.

[0207] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (IM), (I), (II'), (II) or a pharmaceutically acceptable salt thereof, wherein q1 is 2 or 3, preferably 2.

[0208] In some embodiments of the present disclosure, the compound represented by the general formula (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'-1), or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, R 3a Selected from hydrogen atoms, halogens and C 1-6 Alkyl; further preferably, R 3ais halogen; more preferably, R 3a For F.

[0209] In some embodiments of the present disclosure, the compound represented by the general formula (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'-1), or a pharmaceutically acceptable salt thereof, wherein R 3b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, R 3b Selected from hydrogen atoms, halogens and C 1-6 Alkyl; further preferably, R 3b C 1-6 Alkyl; More preferably, R 3b For ethyl.

[0210] In some embodiments of the present disclosure, the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a C 1-6 Alkyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; Selected from q1 is 2 or 3, R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 alkyl halides and cyano groups; Selected from and for

[0211] In some embodiments of the present disclosure, the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a C 1-6 Alkyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; for p is 0; Selected from and Selected from

[0212] In some embodiments of the present disclosure, the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a is methyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; for p is 0; Selected from and for

[0213] In some embodiments of the present disclosure, the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a is methyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; for p is 0; Selected from and Selected from

[0214] In some embodiments of the present disclosure, the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a is methyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; for p is 0; Selected from and for

[0215] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a C 1-6 Alkyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; for p is 0; Selected from and Selected from

[0216] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a is methyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; for p is 0; Selected from and for

[0217] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a is methyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; for p is 0; Selected from and Selected from

[0218] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0 O; G 1 CR G1a H, R G1a is methyl; T is a single bond; Q is N; R 4a is halogen; G 2 is NH; L is O; for p is 0; Selected from and for

[0219] In some embodiments of the present disclosure, the compound represented by the general formula (II') or a pharmaceutically acceptable salt thereof, wherein R G1a C 1-6 alkyl; Selected from Q is N; Ring A is phenyl or naphthyl; R 4a is halogen; G 2 is NH; L is O; p is 0; q is 2 or 3; and each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and hydroxyl groups.

[0220] In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein Selected from Q is N; Ring A is phenyl or naphthyl; R 4a is halogen; G 2 is NH; L is O; p is 0; q is 2 or 3; and each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and hydroxyl groups.

[0221] In some embodiments of the present disclosure, the compound represented by the general formula (III') or a pharmaceutically acceptable salt thereof, wherein R G1a is methyl; Selected from Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0222] In some embodiments of the present disclosure, the compound represented by the general formula (III'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is methyl; Selected from Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0223] In some embodiments of the present disclosure, the compound represented by the general formula (III'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is methyl; for Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0224] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0225] In some embodiments of the present disclosure, the compound represented by the general formula (IV') or a pharmaceutically acceptable salt thereof, wherein R G1a is methyl; Selected from R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 Alkyl; Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0226] In some embodiments of the present disclosure, the compound represented by the general formula (IV'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is methyl; Selected from Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0227] In some embodiments of the present disclosure, the compound represented by the general formula (IV'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is methyl; Selected from Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0228] In some embodiments of the present disclosure, the compound represented by the general formula (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein R G1a is methyl; Selected from R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 Alkyl; Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0229] In some embodiments of the present disclosure, the compound represented by the general formula (IV'-1) or (V'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is methyl; Selected from Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R3a is halogen; and R 3b C 1-6 alkyl.

[0230] In some embodiments of the present disclosure, the compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein Q is N; G 0 O; G 1 CR G1a H; R G1a A hydrogen atom or C 1-6 Alkyl; G 2 is NH; T is a chemical bond; R 4a is halogen; L is O; Ring A is naphthyl; each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and hydroxyl; q is 2 or 3; R 5a and R 5b is a hydrogen atom, or R 5a 、R 5b Together with the carbon atom to which it is attached, it forms a cyclopropyl group; r is 1 or 3; Ring C is a 3- to 8-membered heterocyclic group; R 6 =CR 62 R 63 or oxo, R x1 Selected from =NOR 61 、=CR 62 R 63 Sum = NR 64 , R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 alkyl; t1 is 0 or 1; and p is 0.

[0231] In some embodiments of the present disclosure, the compound represented by the general formula (IVV'), (VV') or a pharmaceutically acceptable salt thereof, wherein R G1a A hydrogen atom or C 1-6 alkyl; Selected from R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 Alkyl; Q is N; R 4a is halogen; G 2is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0232] In some embodiments of the present disclosure, the compound represented by the general formula (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a C 1-6 alkyl; Selected from R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 Alkyl; Q is N; R 4a is halogen; G 2 is NH; L is O; p is 0; R 3a is halogen; and R 3b C 1-6 alkyl.

[0233] Table A Typical compounds of the present disclosure include, but are not limited to:

[0234] Another aspect of the present disclosure relates to a compound represented by the general formula (INA) or a salt thereof,

[0235] in,

[0236] R is an amino protecting group; preferably Boc;

[0237] G 0 , G 1 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, q, t1 and r are as defined in the general formula (IN).

[0238] Another aspect of the present disclosure relates to a compound represented by general formula (IN'A) or a salt thereof,

[0239] in,

[0240] R is an amino protecting group; preferably Boc;

[0241] R y is a hydroxyl protecting group; preferably MOM;

[0242] a is 0, 1, 2, 3, or 4;

[0243] G 0 , G 1 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, t1 and r are as defined in the general formula (IN').

[0244] Another aspect of the present disclosure relates to a compound represented by the general formula (IMA) or a salt thereof,

[0245] in,

[0246] R is an amino protecting group; preferably Boc;

[0247] 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, t and r are as defined in Formula (IM).

[0248] Another aspect of the present disclosure relates to a compound represented by the general formula (IM'A) or a salt thereof,

[0249] in,

[0250] R is an amino protecting group; preferably Boc;

[0251] R y is a hydroxyl protecting group; preferably MOM;

[0252] a is 0, 1, 2, 3, or 4;

[0253] G 0 , G 1 , T, Ring A, Ring B, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 , p, t and r are as defined in the general formula (IM').

[0254] Another aspect of the present disclosure relates to a compound represented by formula (IA) or a salt thereof,

[0255] in,

[0256] R is an amino protecting group; preferably Boc;

[0257] G 0 , G 1 , T, Ring A, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p, q and r are as defined in the general formula (I).

[0258] Another aspect of the present disclosure relates to a compound represented by general formula (I'A) or a salt thereof,

[0259] in,

[0260] R is an amino protecting group; preferably Boc;

[0261] R y is a hydroxyl protecting group; preferably MOM;

[0262] a is 0, 1, 2, 3, or 4;

[0263] G 0 , G 1 , T, Ring A, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and r are as defined in the general formula (I').

[0264] Another aspect of the present disclosure relates to a compound represented by general formula (II'A) or a salt thereof,

[0265] in,

[0266] R is an amino protecting group; preferably Boc;

[0267] Rings A, Q, L, R G1a 、R 1 、R 3 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and q are as defined in the general formula (II').

[0268] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof,

[0269] in,

[0270] R is an amino protecting group; preferably Boc;

[0271] Rings A, Q, L, R 1 、R 3 、R 4a、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and q are as defined in the general formula (II).

[0272] Another aspect of the present disclosure relates to a compound represented by general formula (III'A) or a salt thereof,

[0273] in,

[0274] R is an amino protecting group; preferably Boc;

[0275] R y is a hydroxyl protecting group; preferably MOM;

[0276] Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in formula (III').

[0277] Another aspect of the present disclosure relates to a compound represented by general formula (III'-1A) or a salt thereof,

[0278] in,

[0279] R is an amino protecting group; preferably Boc;

[0280] R y is a hydroxyl protecting group; preferably MOM;

[0281] Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6hand p are as defined in the general formula (III'-1).

[0282] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof,

[0283] in,

[0284] R is an amino protecting group; preferably Boc;

[0285] R y is a hydroxyl protecting group; preferably MOM;

[0286] Q, L, R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in formula (III).

[0287] Another aspect of the present disclosure relates to a compound represented by general formula (IVV'A) or a salt thereof,

[0288] in,

[0289] R is an amino protecting group; preferably Boc;

[0290] R y is a hydroxyl protecting group; preferably MOM;

[0291] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in Formula (IVV').

[0292] Another aspect of the present disclosure relates to a compound represented by general formula (IV'A) or a salt thereof,

[0293] in,

[0294] R is an amino protecting group; preferably Boc;

[0295] R y is a hydroxyl protecting group; preferably MOM;

[0296] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (IV').

[0297] Another aspect of the present disclosure relates to a compound represented by general formula (IV'-1A) or a salt thereof,

[0298] in,

[0299] R is an amino protecting group; preferably Boc;

[0300] R y is a hydroxyl protecting group; preferably MOM;

[0301] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (IV'-1).

[0302] Another aspect of the present disclosure relates to a compound represented by general formula (VV'A) or a salt thereof,

[0303] in,

[0304] R is an amino protecting group; preferably Boc;

[0305] R y is a hydroxyl protecting group; preferably MOM;

[0306] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in formula (VV').

[0307] Another aspect of the present disclosure relates to a compound represented by general formula (VV'-1A) or a salt thereof,

[0308] in,

[0309] R is an amino protecting group; preferably Boc;

[0310] Ry is a hydroxyl protecting group; preferably MOM;

[0311] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in the general formula (VV'-1).

[0312] Another aspect of the present disclosure relates to a compound represented by general formula (V'A) or a salt thereof,

[0313] in,

[0314] R is an amino protecting group; preferably Boc;

[0315] R y is a hydroxyl protecting group; preferably MOM;

[0316] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (V').

[0317] Another aspect of the present disclosure relates to a compound represented by general formula (V'-1A) or a salt thereof,

[0318] in,

[0319] R is an amino protecting group; preferably Boc;

[0320] R y is a hydroxyl protecting group; preferably MOM;

[0321] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (V'-1).

[0322] In some embodiments of the present disclosure, the compound represented by the general formula (IN), (INA), (IN'), (IN'A), (IVV'), (IVV'A), (VV'), (VV'A), (VV'-1), (VV'-1A) or a pharmaceutically acceptable salt thereof, wherein R x1 R x , R x As defined in general formula (IN); preferably, R x1 Selected from =NOR 61 、=CR 62 R 63 Sum = NR 64 , R 61 C 1-6 Alkyl, R 62 and R 63 are the same or different and are each independently a hydrogen atom or a halogen, R 64 A hydrogen atom or C 1-6 alkyl.

[0323] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0324] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0325] The compound of general formula (INA) or its salt is subjected to deprotection reaction to obtain the compound of general formula (IN) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0326] in,

[0327] R is an amino protecting group; preferably Boc;

[0328] G 2 for NH;

[0329] G 0 , G1 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, q, t1 and r are as defined in the general formula (IN).

[0330] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IN') or a pharmaceutically acceptable salt thereof, the method comprising:

[0331] The compound of general formula (IN'A) or its salt is subjected to deprotection reaction to obtain the compound of general formula (IN') or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0332] in,

[0333] R is an amino protecting group; preferably Boc;

[0334] R y is a hydroxyl protecting group; preferably MOM;

[0335] a is 0, 1, 2, 3, or 4;

[0336] G 2 for NH;

[0337] G 0 , G 1 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, t1 and r are as defined in the general formula (IN').

[0338] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, the method comprising:

[0339] The compound of general formula (IMA) or its salt is subjected to deprotection reaction to obtain the compound of general formula (IM) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0340] in,

[0341] R is an amino protecting group; preferably Boc;

[0342] G 2 for NH;

[0343] 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, t and r are as defined in Formula (IM).

[0344] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM') or a pharmaceutically acceptable salt thereof, the method comprising:

[0345] The compound of general formula (IM'A) or its salt is subjected to deprotection reaction to obtain the compound of general formula (IM') or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0346] in,

[0347] R is an amino protecting group; preferably Boc;

[0348] R y is a hydroxyl protecting group; preferably MOM;

[0349] a is 0, 1, 2, 3, or 4;

[0350] G 2 for NH;

[0351] G 0 , G 1 , T, Ring A, Ring B, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 , p, t and r are as defined in the general formula (IM').

[0352] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0353] The compound of formula (IA) or its salt is subjected to deprotection reaction to obtain the compound of formula (I) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0354] in,

[0355] R is an amino protecting group; preferably Boc;

[0356] G 2 for NH;

[0357] G 0 , G 1 , T, Ring A, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p, q and r are as defined in the general formula (I).

[0358] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I') or a pharmaceutically acceptable salt thereof, the method comprising:

[0359] The compound of general formula (I'A) or its salt is subjected to deprotection reaction to obtain the compound of general formula (I') or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0360] in,

[0361] R is an amino protecting group; preferably Boc;

[0362] R y is a hydroxyl protecting group; preferably MOM;

[0363] a is 0, 1, 2, 3, or 4;

[0364] G 2 for NH;

[0365] G 0 , G 1, T, Ring A, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and r are as defined in the general formula (I').

[0366] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II') or a pharmaceutically acceptable salt thereof, the method comprising:

[0367] The compound of general formula (II'A) or its salt is subjected to deprotection reaction to obtain the compound of general formula (II') or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0368] Wherein R is an amino protecting group; preferably Boc;

[0369] G 2 for NH;

[0370] Rings A, Q, L, R G1a 、R 1 、R 3 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and q are as defined in the general formula (II').

[0371] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0372] The compound of general formula (IIA) or its salt is subjected to deprotection reaction to obtain the compound of general formula (II) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0373] Wherein R is an amino protecting group; preferably Boc;

[0374] G 2 for NH;

[0375] Rings A, Q, L, R 1 、R 3 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and q are as defined in the general formula (II).

[0376] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III') or a pharmaceutically acceptable salt thereof, the method comprising:

[0377] The compound of general formula (III'A) or its salt is subjected to a deprotection reaction to obtain a compound of general formula (III') or a pharmaceutically acceptable salt thereof;

[0378] in,

[0379] R is an amino protecting group; preferably Boc;

[0380] R y is a hydroxyl protecting group; preferably MOM;

[0381] G 2 for NH;

[0382] Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in formula (III').

[0383] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0384] The compound of the general formula (III'-1A) or its salt is subjected to a deprotection reaction to obtain the compound of the general formula (III'-1) or its pharmaceutically acceptable salt;

[0385] in,

[0386] R is an amino protecting group; preferably Boc;

[0387] R y is a hydroxyl protecting group; preferably MOM;

[0388] G 2 for NH;

[0389] Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in the general formula (III'-1).

[0390] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0391] The compound of general formula (IIIA) or its salt is subjected to a deprotection reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof;

[0392] in,

[0393] R is an amino protecting group; preferably Boc;

[0394] R y is a hydroxyl protecting group; preferably MOM;

[0395] G 2 for NH;

[0396] Q, L, R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6hand p are as defined in general formula (III).

[0397] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IVV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0398] The compound of the general formula (IVV'A) or a salt thereof is subjected to a deprotection reaction to obtain a compound of the general formula (IVV') or a pharmaceutically acceptable salt thereof;

[0399] in,

[0400] R is an amino protecting group; preferably Boc;

[0401] R y is a hydroxyl protecting group; preferably MOM;

[0402] G 2 for NH;

[0403] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in Formula (IVV').

[0404] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0405] The compound of the general formula (IV'A) or its salt is subjected to a deprotection reaction to obtain the compound of the general formula (IV') or its pharmaceutically acceptable salt;

[0406] in,

[0407] R is an amino protecting group; preferably Boc;

[0408] R y is a hydroxyl protecting group; preferably MOM;

[0409] G 2 for NH;

[0410] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (IV').

[0411] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0412] The compound of the general formula (IV'-1A) or its salt is subjected to a deprotection reaction to obtain the compound of the general formula (IV'-1) or its pharmaceutically acceptable salt;

[0413] in,

[0414] R is an amino protecting group; preferably Boc;

[0415] R y is a hydroxyl protecting group; preferably MOM;

[0416] G 2 for NH;

[0417] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (IV'-1).

[0418] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0419] The compound of the general formula (VV'A) or a salt thereof is subjected to a deprotection reaction to obtain a compound of the general formula (VV') or a pharmaceutically acceptable salt thereof;

[0420] in,

[0421] R is an amino protecting group; preferably Boc;

[0422] R y is a hydroxyl protecting group; preferably MOM;

[0423] G 2 for NH;

[0424] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in formula (VV').

[0425] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VV'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0426] The compound of the general formula (VV'-1A) or a salt thereof is subjected to a deprotection reaction to obtain a compound of the general formula (VV'-1) or a pharmaceutically acceptable salt thereof;

[0427] in,

[0428] R is an amino protecting group; preferably Boc;

[0429] R y is a hydroxyl protecting group; preferably MOM;

[0430] G 2 for NH;

[0431] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in the general formula (VV'-1).

[0432] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising:

[0433] The compound of the general formula (V'A) or its salt is subjected to a deprotection reaction to obtain the compound of the general formula (V') or its pharmaceutically acceptable salt;

[0434] in,

[0435] R is an amino protecting group; preferably Boc;

[0436] R y is a hydroxyl protecting group; preferably MOM;

[0437] G 2 for NH;

[0438] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (V').

[0439] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0440] The compound of the general formula (V'-1A) or a salt thereof is subjected to a deprotection reaction to obtain a compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof;

[0441] in,

[0442] R is an amino protecting group; preferably Boc;

[0443] R y is a hydroxyl protecting group; preferably MOM;

[0444] G 2 for NH;

[0445] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (V'-1).

[0446] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure having the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or as shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0447] The present disclosure further relates to the use of a compound of Formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting KRAS G12D.

[0448] The present disclosure further relates to the use of a compound of Formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a disease or condition mediated by KRAS G12D.

[0449] The present disclosure further relates to the use of a compound of formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutical composition comprising the same or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a tumor; the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer , salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0450] 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 of Formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0451] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by KRAS G12D, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0452] The present disclosure further relates to a method for treating and / or preventing tumors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, , oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0453] The present disclosure further relates to a compound of Formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0454] The present disclosure further relates to a compound of the general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting KRAS G12D.

[0455] The present disclosure further relates to a compound of Formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a disease or condition mediated by KRAS G12D.

[0456] The present disclosure further relates to a compound of formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing tumors; the tumors are preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer Preferably, the cancer is selected from the group consisting of pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; more preferably, the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0457] The diseases or conditions described herein are diseases or conditions that are treated and / or prevented by inhibiting KRAS G12D.

[0458] Preferably, the disease or condition mediated by KRAS G12D described in the present disclosure is a tumor; the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0459] The colorectal cancer described in the present disclosure is preferably colon cancer or rectal cancer.

[0460] Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyomas, leiomyosarcomas, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma and synovial sarcoma; lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (such as mantle cell lymphoma, diffuse large B-cell lymphoma, follicle center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); liver cancer is preferably hepatocellular carcinoma; lung cancer (also known as bronchogenic carcinoma) is selected from Non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and squamous cell carcinoma; renal cancer is selected from renal cell carcinoma, clear cell and renal oncocytoma; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML); skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; myeloma is preferably multiple myeloma.

[0461] The active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0462] As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms may range from 0.1 to 1000 mg.

[0463] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0464] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. Tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0465] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0466] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0467] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0468] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0469] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0470] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0471] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0472] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0473] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0474] Terminology

[0475] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0476] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 1-12alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6 Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point. The substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0477] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (ie, C 2-6 Alkenyl). Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0478] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably, the alkynyl group has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C 2-12 Alkynyl), more preferably an alkynyl having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0479] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14-membered cycloalkyl), preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0480] The term " spiroalkyl " refers to 5 to 20 yuan, a polycyclic group sharing a carbon atom (claiming spiral atom) between monocycle, which can contain one or more double bonds.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example 7, 8, 9 or 10 yuan).According to the number of shared spiral atoms between ring and ring, spiroalkyl is divided into single spiroalkyl or polyspiroalkyl (for example double spiroalkyl), preferably single spiroalkyl and double spiroalkyl.More preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan single spiroalkyl.Non-limiting examples of spiroalkyl include:

[0481] Term " fused cycloalkyl " refers to 5 to 20 yuan, and each ring in the system shares the full carbon polycyclic group of a pair of carbon atoms adjacent to other rings in the system, and wherein one or more rings can contain one or more double bonds.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan).Can be divided into bicyclic or polycyclic fused cycloalkyl (such as tricyclic, tetracyclic) according to the number of composition ring, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic alkyl.Non-limiting examples of fused cycloalkyl include:

[0482] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0483] The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spirocyclic, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0484] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0485] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0486] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl), wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms being carbon. Preferably, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (i.e., 3 to 14-membered heterocyclyl), of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms (i.e., 3 to 8-membered heterocyclyl) or 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms, of which 1-3 are heteroatoms (e.g., 1, 2 and 3); more preferably, it contains 3 to 8 ring atoms, of which 1-3 (e.g., 1, 2 and 3) are heteroatoms; and most preferably, it contains 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl), of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls, and bridged heterocyclyls.

[0487] The term "spiro heterocyclic radical" refers to a polycyclic heterocyclic group of 5 to 20 yuan, one atom (called spiral atom) shared between the monocycles, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It can contain one or more double bonds. Preferably, it is 6 to 14 yuan (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 yuan) (i.e., 6 to 14 yuan spiral heterocyclic radical), more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan) (i.e., 7 to 10 yuan spiral heterocyclic radical). According to the number of spiral atoms shared between the rings, the spiral heterocyclic radical is divided into a single spiral heterocyclic radical or a multi-spiro heterocyclic radical (e.g., a double spiral heterocyclic radical), preferably a single spiral heterocyclic radical and a double spiral heterocyclic radical. More preferably, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

[0488] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group having 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., a 6 to 14-membered fused heterocyclyl), and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., a 7 to 10-membered fused heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0489] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein any two rings share two atoms that are not directly connected, and which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., 6 to 14-membered bridged heterocyclic groups), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0490] The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0491] wait.

[0492] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0493] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0494] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0495] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) yuan (i.e., a 5- to 10-membered heteroaryl), further preferably 8 to 10 (e.g., 8, 9, or 10) yuan, more preferably 5 or 6 yuan (i.e., a 5- or 6-membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes heteroaryls as described above fused to aryl, heterocyclyl, or cycloalkyl rings, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0496] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0497] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same parent ring atom or two different ring atoms by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

[0498] The term "amino-protecting group" is used to protect the amino group with a readily removable group, thereby preserving the amino group while reacting other parts of the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, benzyl, allyl, p-toluenesulfonyl (Ts), and p-methoxybenzyl. These groups may optionally be substituted with one to three substituents selected from halogen, alkoxy, and nitro groups; the amino-protecting group is preferably Boc.

[0499] The term "hydroxy protecting group" refers to a hydroxy derivative that is typically used to block or protect a hydroxy group and react on other functional groups of a compound. As an example, preferably, the hydroxy protecting group is, for example, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl; the hydroxy protecting group is preferably MOM.

[0500] The term "alkynyl protecting group" refers to a readily removable group introduced onto an alkynyl group in order to maintain the active hydrogen of acetylene or a terminal alkyne while other parts of the molecule undergo reactions. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl. The alkynyl protecting group is preferably TIPS.

[0501] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0502] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0503] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0504] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0505] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0506] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0507] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0508] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0509] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0510] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0511] The term "hydroxy" refers to -OH.

[0512] The term "mercapto" refers to -SH.

[0513] The term "amino" refers to -NH2.

[0514] The term "cyano" refers to -CN.

[0515] The term "nitro" refers to -NO2.

[0516] The term "oxo" or "oxo" refers to "=0".

[0517] The term "carbonyl" refers to C=O.

[0518] The term "carboxy" refers to -C(O)OH.

[0519] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0520] MOM stands for methoxymethyl.

[0521] Boc refers to tert-butyloxycarbonyl.

[0522] TIPS refers to triisopropylsilyl.

[0523] TBS refers to tert-butyldimethylsilyl.

[0524] The compounds of the present disclosure may include all forms of rotational isomers and conformationally restricted states. Also included are atropisomers, the term "atropisomer" being a conformational stereoisomer resulting from hindered or greatly slowed rotation around a single bond in the molecule (this is due to spatial interactions with other parts of the molecule and the asymmetric substituents at both ends of the single bond), and its interconversion is slow enough to allow separation and separation under predetermined conditions. For example, some of the disclosed compounds may exist in the form of a mixture of atropisomers (such as an equiproportional mixture, a mixture enriched in a single atropisomer, etc.) or a purified atropisomer. The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerizations. An example of a keto-enol equilibrium is shown below:

[0525] All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

[0526] The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the compounds of the present disclosure may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, or, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereoisomers is typically accomplished by chromatography.

[0527] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0528] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0529] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0530] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0531] "Substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. Those skilled in the art will be able to determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0532] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0533] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. Salts may be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0534] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0535] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0536] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0537] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, a number is generally given for illustrative purposes only and is not limiting.

[0538] Synthesis method of the disclosed compound

[0539] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0540] Plan 1-1

[0541] The present disclosure provides a method for preparing a compound represented by general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0542] The compound of general formula (INA) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (IN) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction may further include removing R under acidic or alkaline conditions before, simultaneously with or after the deprotection reaction. 3 Steps for adding protective groups to groups;

[0543] Wherein R is an amino protecting group; preferably Boc;

[0544] G 2 for NH;

[0545] G 0 , G 1 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, q, t1 and r are as defined in the general formula (IN).

[0546] Plan 1-2

[0547] The present disclosure provides a method for preparing a compound represented by general formula (IN') or a pharmaceutically acceptable salt thereof, the method comprising:

[0548] The compound of general formula (IN'A) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (IN') or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups;

[0549] in,

[0550] R is an amino protecting group; preferably Boc;

[0551] R y is a hydroxyl protecting group; preferably MOM;

[0552] a is 0, 1, 2, 3, or 4;

[0553] G 2 for NH;

[0554] G 0 , G 1 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, t1 and r are as defined in the general formula (IN').

[0555] Plan 1-3

[0556] The present disclosure provides a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, the method comprising:

[0557] The compound of general formula (IMA) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (IM) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction may further include removing R under acidic or alkaline conditions before, simultaneously with or after the deprotection reaction. 3 Steps for adding protective groups to groups;

[0558] Wherein R is an amino protecting group; preferably Boc;

[0559] G 2 for NH;

[0560] 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, t and r are as defined in Formula (IM).

[0561] Plan 1-4

[0562] The present disclosure provides a method for preparing a compound represented by general formula (IM') or a pharmaceutically acceptable salt thereof, the method comprising:

[0563] The compound of general formula (IM'A) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (IM') or its pharmaceutically acceptable salt; optionally, when R 3When the group contains a protecting group, the deprotection reaction may further include removing R under acidic or alkaline conditions before, simultaneously with or after the deprotection reaction. 3 Steps for adding protective groups to groups;

[0564] in

[0565] R is an amino protecting group; preferably Boc;

[0566] R y is a hydroxyl protecting group; preferably MOM;

[0567] a is 0, 1, 2, 3, or 4;

[0568] G 2 for NH;

[0569] G 0 , G 1 , T, Ring A, Ring B, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 , p, t and r are as defined in the general formula (IM').

[0570] Option 2-1

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

[0572] The compound of general formula (IA) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (I) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction may further include removing R under acidic or alkaline conditions before, simultaneously with or after the deprotection reaction. 3 Steps for adding protective groups to groups;

[0573] Wherein R is an amino protecting group; preferably Boc;

[0574] G 2 for NH;

[0575] G 0 , G 1 , T, Ring A, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6a 、R 6b 、R 6c 、R 6d 、R6e 、R 6f 、R 6g 、R 6h , p, q and r are as defined in the general formula (I).

[0576] Option 2-2

[0577] The present disclosure provides a method for preparing a compound represented by general formula (I') or a pharmaceutically acceptable salt thereof, the method comprising:

[0578] The compound of general formula (I'A) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (I') or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction may further include removing R under acidic or alkaline conditions before, simultaneously with or after the deprotection reaction. 3 Steps for adding protective groups to groups;

[0579] in

[0580] R is an amino protecting group; preferably Boc;

[0581] R y is a hydroxyl protecting group; preferably MOM;

[0582] a is 0, 1, 2, 3, or 4;

[0583] G 2 for NH;

[0584] G 0 , G 1 , T, Ring A, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and r are as defined in the general formula (I').

[0585] Plan 3-1

[0586] The present disclosure provides a method for preparing a compound represented by general formula (II') or a pharmaceutically acceptable salt thereof, the method comprising:

[0587] The compound of general formula (II'A) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (II') or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction may further include removing R under acidic or alkaline conditions before, simultaneously with or after the deprotection reaction. 3 Steps for adding protective groups to groups;

[0588] Wherein R is an amino protecting group; preferably Boc;

[0589] G 2 for NH;

[0590] Rings A, Q, L, R G1a 、R 1 、R 3 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , p and q are as defined in the general formula (II').

[0591] Plan 3-2

[0592] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0593] The compound of general formula (IIA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain a compound of general formula (II) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction may further include removing R under acidic or alkaline conditions before, simultaneously with or after the deprotection reaction. 3 Steps for adding protective groups to groups;

[0594] Wherein R is an amino protecting group; preferably Boc;

[0595] G 2 for NH;

[0596] Rings A, Q, L, R 1 、R 3 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h, p and q are as defined in the general formula (II).

[0597] Plan 4-1

[0598] The present disclosure provides a method for preparing a compound represented by general formula (III') or a pharmaceutically acceptable salt thereof, the method comprising:

[0599] The compound of general formula (III'A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of general formula (III') or its pharmaceutically acceptable salt;

[0600] in

[0601] R is an amino protecting group; preferably Boc;

[0602] R y is a hydroxyl protecting group; preferably MOM;

[0603] G 2 for NH;

[0604] Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in formula (III').

[0605] Plan 4-2

[0606] The present disclosure provides a method for preparing a compound represented by general formula (III'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0607] The compound of the general formula (III'-1A) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound of the general formula (III'-1) or a pharmaceutically acceptable salt thereof;

[0608] in

[0609] R is an amino protecting group; preferably Boc;

[0610] R y is a hydroxyl protecting group; preferably MOM;

[0611] G 2 for NH;

[0612] Q, L, RG1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in the general formula (III'-1).

[0613] Plan 4-3

[0614] The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0615] The compound of general formula (IIIA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof;

[0616] in

[0617] R is an amino protecting group; preferably Boc;

[0618] R y is a hydroxyl protecting group; preferably MOM;

[0619] G 2 for NH;

[0620] Q, L, R 1 、R 3a 、R 3b 、R 4a 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h and p are as defined in formula (III).

[0621] Plan 5-1

[0622] The present disclosure provides a method for preparing a compound represented by general formula (IVV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0623] The compound of general formula (IVV'A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of general formula (IVV') or its pharmaceutically acceptable salt;

[0624] in

[0625] R is an amino protecting group; preferably Boc;

[0626] R y is a hydroxyl protecting group; preferably MOM;

[0627] G 2 for NH;

[0628] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in Formula (IVV').

[0629] Plan 5-2

[0630] The present disclosure provides a method for preparing a compound represented by general formula (IV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0631] The compound of general formula (IV'A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of general formula (IV') or its pharmaceutically acceptable salt;

[0632] in

[0633] R is an amino protecting group; preferably Boc;

[0634] R y is a hydroxyl protecting group; preferably MOM;

[0635] G 2 for NH;

[0636] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (IV').

[0637] Plan 5-3

[0638] The present disclosure provides a method for preparing a compound represented by general formula (IV'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0639] The compound of the general formula (IV'-1A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of the general formula (IV'-1) or its pharmaceutically acceptable salt;

[0640] in

[0641] R is an amino protecting group; preferably Boc;

[0642] R y is a hydroxyl protecting group; preferably MOM;

[0643] G 2 for NH;

[0644] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (IV'-1).

[0645] Plan 6-1

[0646] The present disclosure provides a method for preparing a compound represented by general formula (VV') or a pharmaceutically acceptable salt thereof, the method comprising:

[0647] The compound of the general formula (VV'A) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound of the general formula (VV') or a pharmaceutically acceptable salt thereof;

[0648] in

[0649] R is an amino protecting group; preferably Boc;

[0650] R y is a hydroxyl protecting group; preferably MOM;

[0651] G 2 for NH;

[0652] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in formula (VV').

[0653] Plan 6-2

[0654] The present disclosure provides a method for preparing a compound represented by general formula (VV'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0655] The compound of the general formula (VV'-1A) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound of the general formula (VV'-1) or a pharmaceutically acceptable salt thereof;

[0656] in

[0657] R is an amino protecting group; preferably Boc;

[0658] R y is a hydroxyl protecting group; preferably MOM;

[0659] G 2 for NH;

[0660] Ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 , t1 and p are as defined in the general formula (VV'-1).

[0661] Plan 6-3

[0662] The present disclosure provides a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising:

[0663] The compound of the general formula (V'A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of the general formula (V') or its pharmaceutically acceptable salt;

[0664] in

[0665] R is an amino protecting group; preferably Boc;

[0666] R y is a hydroxyl protecting group; preferably MOM;

[0667] G 2 for NH;

[0668] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (V').

[0669] Plan 6-4

[0670] The present disclosure provides a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0671] The compound of the general formula (V'-1A) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound of the general formula (V'-1) or a pharmaceutically acceptable salt thereof;

[0672] in

[0673] R is an amino protecting group; preferably Boc;

[0674] R y is a hydroxyl protecting group; preferably MOM;

[0675] G 2 for NH;

[0676] Ring B, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x , t and p are as defined in the general formula (V'-1).

[0677] The reagents providing acidic conditions in the above synthesis scheme include organic acids and inorganic acids, the organic acids include but are not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf; the inorganic acids include but are not limited to hydrogen chloride, hydrochloric acid dioxane solution, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably hydrochloric acid dioxane solution.

[0678] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and 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, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7-ene, 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.

[0679] In the above synthesis scheme, when R 3 When the terminal alkyne is contained, the terminal alkyne may be protected by TIPS, and the reagent for removing TIPS is preferably a tetrabutylammonium fluoride tetrahydrofuran solution or cesium fluoride.

[0680] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, 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

[0681] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0682] Example

[0683] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0684] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0685] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0686] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0687] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0688] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0689] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0690] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0691] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0692] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0693] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0694] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0695] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0696] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0697] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0698] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0699] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0700] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0701] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0702] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0703] Example 1

[0704] 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptacyclo-2-yl)naphthalen-2-ol 1

[0705] first step

[0706] tert-Butyl 4-((tert-Butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate 1b

[0707] The crude product 2,6-dichloro-3-fluoropyridin-4-amine 1a (1.8 g, 9.94 mmol, prepared by the method disclosed in Preparation 14(a) on page 46 of the specification of patent application "WO2016191524A1") was dissolved in tetrahydrofuran (50 mL), and 2M sodium bistrimethylsilylamide tetrahydrofuran solution (20 mL) was added under ice bath. After stirring for 0.5 hour, di-tert-butyl dicarbonate (6.5 g, 29.7 mmol) was added and the reaction was stirred for 14 hours. Saturated aqueous ammonium chloride was added to the reaction solution to quench the reaction, and the solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system B to obtain the title compound 1b (1 g, yield: 26.3%).

[0708] MS m / z(ESI):381.1[M+1].

[0709] Step 2

[0710] tert-Butyl 4-amino-2,6-dichloro-5-fluoronicotinate 1c

[0711] Compound 1b (1 g, 2.62 mmol) was dissolved in ethyl acetate (8 mL), and a 4 M hydrochloric acid solution in dioxane (3 mL) was added. The reaction was stirred for 2 hours. The pH was adjusted to neutral with a 4 M aqueous sodium hydroxide solution under ice bath. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system A to give the title compound 1c (500 mg, yield: 67.8%).

[0712] MS m / z(ESI):281.1[M+1].

[0713] Step 3

[0714] tert-Butyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate 1d

[0715] Compound 1c (500 mg, 1.77 mmol) was dissolved in tetrahydrofuran (10 mL), and trichloroacetyl isocyanate (670 mg, 3.55 mmol, Shanghai Hanhong) was added. The mixture was stirred for 30 minutes, and the reaction solution was concentrated under reduced pressure to give the crude title compound 1d (835 mg), which was used directly in the next step without purification.

[0716] MS m / z(ESI):467.9[M+1].

[0717] Step 4

[0718] 5,7-Dichloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol 1e

[0719] The crude compound 1d (835 mg, 1.77 mmol) was dissolved in 7 M ammonia methanol solution (10 mL) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and methyl tert-butyl ether (10 mL) was added to the residue. After stirring for 0.5 hour, the mixture was filtered and the filter cake was dried to give the crude title compound 1e (400 mg, yield: 89.9%). The product was used directly in the next step without purification.

[0720] MS m / z(ESI):249.9[M+1].

[0721] Step 5

[0722] 2,4,5,7-Tetrachloro-8-fluoro-pyrido[4,3-d]pyrimidine 1f

[0723] The crude compound 1e (875 mg, 3.5 mmol) was dissolved in phosphorus oxychloride (25 mL), and N,N-diisopropylethylamine (2.3 g, 17.5 mmol) was added. The mixture was stirred at 110°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude title compound 1f (1.14 g). The product was used directly in the next step without purification.

[0724] MS m / z(ESI):285.8[M+1].

[0725] Step 6

[0726] (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester 1h

[0727] Mix 1 g (20 g, 139.7 mmol, Shanghai Bidex) of (R)-2-pyrrolidone-5-carboxylic acid methyl ester and dimethyl sulfate (22.1 g, 175.2 mmol), react at 60°C for 22 hours, cool the reaction solution to room temperature, pour into a solution of triethylamine (20 g) and water (100 mL) under an ice bath, extract with methyl tert-butyl ether (60 mL × 6), and concentrate under reduced pressure to obtain the crude title compound 1h (16.3 g, yield: 74.2%). The crude product was used directly in the next step without purification.

[0728] MS m / z(ESI):158.1[M+1].

[0729] Step 7

[0730] (R)-5-(2-methoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylic acid methyl ester 1i

[0731] The crude compound 1h (16.3 g, 103.7 mmol) and methyl nitroacetate (13.6 g, 114.2 mmol, Shanghai Shaoyuan) were mixed, heated to 60°C with stirring for 24 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1i (8.37 g, yield: 33%).

[0732] MS m / z(ESI):245.1[M+1].

[0733] Step 8

[0734] (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester 1j

[0735] Compound 1i (7.5 g, 30.7 mmol) was dissolved in 150 mL of methanol, 10% palladium carbon catalyst (wet) (1.5 g) was added, and hydrogen was replaced three times. The mixture was heated to 50°C and stirred for 24 hours. The reaction solution was cooled to room temperature and filtered through celite. The filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1j (5.6 g). The product was used directly in the next step without purification.

[0736] MS m / z(ESI):185.2[M+1].

[0737] Step 9

[0738] 8-(tert-Butyl) 2-methyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 1k

[0739] The crude compound 1j (5.65 g, 30.4 mmol) was dissolved in 60 mL of dichloromethane. Triethylamine (6.2 g, 61.27 mmol) and di-tert-butyl dicarbonate (6.6 g, 30.24 mmol) were added under ice-cooling. The reaction mixture was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 1k (3 g, yield: 34.7%).

[0740] MS m / z(ESI):285.2[M+1].

[0741] Step 10

[0742] tert-Butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0743] Compound 1k (3 g, 10.55 mmol) was dissolved in 30 mL of tetrahydrofuran, and 32 mL of 1 M lithium aluminum hydride solution in tetrahydrofuran was added dropwise under ice-bath. The mixture was stirred at room temperature for 4 hours. 1.05 mL of water, 1.05 mL of 15% sodium hydroxide solution, and 3.15 mL of water were added in sequence under ice-bath. The mixture was stirred 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 give the crude title compound 1l (2.4 g), which was used in the next step without purification.

[0744] MS m / z(ESI):243.2[M+1].

[0745] Step 11

[0746] tert-Butyl (1S,2S,5R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0747] The crude compound 1l (2.4 g, 9.9 mmol) was dissolved in 25 mL of dichloromethane, and tert-butyldimethylsilyl chloride (4.48 g, 29.7 mmol) and 4-dimethylaminopyridine (122 mg, 990 μmol) were added. Triethylamine (4 g, 39.5 mmol) was added dropwise, and the reaction was stirred 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, washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1m (1.95 g, yield: 55.2%).

[0748] MS m / z(ESI):357.1[M+1].

[0749] Step 12

[0750] tert-Butyl (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

[0751] Compound 1f (50 g, 174 mmol) and N,N-diisopropylethylamine (65 g, 503 mmol) were dissolved in 75 mL of dichloromethane. A solution of compound 1m (60 g, 168.3 mmol) in dichloromethane (250 mL) was added dropwise at -78°C. The mixture was allowed to naturally return 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 1n (86 g, yield: 84%).

[0752] MS m / z(ESI):606.2[M+1].

[0753] Step 13

[0754] tert-Butyl (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

[0755] Compound 1n (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), The mixture was stirred at 110 °C for 14 h, and the reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the crude title compound 1o (5.5 g). The product was used in the next step without purification.

[0756] MS m / z(ESI):672.2[M+1].

[0757] Step 14

[0758] tert-Butyl (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-methanaphtho[1,8-ab]heptyl-14-carboxylate 1p

[0759] The crude compound 1o (5.5 g, 8.2 mmol) was dissolved in tetrahydrofuran (80 mL), and tetrabutylammonium fluoride (5.57 g, 24.7 mmol) and N,N-diisopropylethylamine (5.33 g, 41.2 mmol) were added. After stirring for 1 hour, the mixture was heated to 60°C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (50 mL×2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 1p (3 g, yield: 69.7%).

[0760] MS m / z(ESI):522.2[M+1].

[0761] Step 15

[0762] Tert-butyl (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-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-methano[1,8-ab]heptan-14-carboxylate 1q

[0763] Compound 1p (2 g, 3.83 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 5.8 mmol), tetrakis(triphenylphosphine)palladium (889 mg, 769 μmol), and cesium carbonate (3.8 g, 11.66 mmol) were dissolved in 36 mL of a mixture of 1,4-dioxane and water (V:V = 10:1). The reaction was carried out at 100°C under a nitrogen atmosphere for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to provide the title compound 1q (1 g, 36.2% yield).

[0764] MS m / z(ESI):720.2[M+1].

[0765] Step 16

[0766] (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-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-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 1r

[0767] Compound 1q (150 mg, 145.8 μmol) and N,N-diisopropylethylamine (55.6 mg, 437.6 μmol) were dissolved in dichloromethane (5 mL). Methanesulfonyl chloride (25 mg, 218.8 μmol) was added under ice bath, and the reaction was stirred at the maintained temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution for quenching, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude title compound 1r (130 mg). The product was used directly in the next step without purification.

[0768] MS m / z(ESI):798.2[M+1].

[0769] Step 17

[0770] (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 1s

[0771] The crude compound 1r (130 mg, 162.9 μmol) was dissolved in acetonitrile (3 mL), and morpholine (28.4 mg, 325.8 μmol), anhydrous potassium carbonate (67.6 mg, 488.8 μmol), and sodium iodide (24.4 mg, 162.9 μmol) were added. The mixture was heated to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL×2). The organic phases were combined and concentrated under reduced pressure to give the crude title compound 1s (128 mg). The product was used directly in the next step without purification.

[0772] MS m / z(ESI):789.2[M+1].

[0773] Step 18

[0774] 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptacyclo-2-yl)naphthalen-2-ol 1

[0775] The crude compound 1s (128 mg, 162.2 μmol) was dissolved in ethyl acetate (3 mL), and 2 mL of a 4 M hydrochloric acid-dioxane solution was added under ice-bath conditions. The reaction was maintained at this temperature for 4 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 ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 1 (35 mg, 33.4% yield).

[0776] MS m / z(ESI):645.2[M+1].

[0777] 1 H NMR (500MHz, CD3OD): δ7.67(t,1H),7.31-7.21(m,2H),7.06(d,1H),5.07(dd,2H),4.62(dd,1H),4.45(tt,3H),4.15(dd,1H),3.77( s,1H),3.66(d,4H),3.25(s,1H),2.57-2.43(m,6H),2.22(d,1H),1.90(dt,4H),0.93(t,2H),0.84(t,2H),0.73(s,2H),0.52(s,2H).

[0778] Example 2

[0779] 4-((5aS,6S,9R)-12-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]hept-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0780] first step

[0781] (5aS,6S,9R)-12-(1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]hept-14-carboxylic acid tert-butyl ester 2a

[0782] The crude compound 1r (150 mg, 131.6 μmol) was dissolved in acetonitrile (3 mL), and (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (35.7 mg, 263.2 μmol, Shanghai Leyan), anhydrous potassium carbonate (72.7 mg, 526.4 μmol), and sodium iodide (19.7 mg, 263.2 μmol) were added. The mixture was heated to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL×2). The organic phases were combined and concentrated under reduced pressure to give the crude title compound 2a (105 mg). The product was used directly in the next step without purification.

[0783] MS m / z(ESI):801.2[M+1].

[0784] Step 2

[0785] 4-((5aS,6S,9R)-12-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]hept-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0786] The crude compound 2a (100 mg, 188 μmol) was dissolved in ethyl acetate (3 mL), and 2 mL of 4 M hydrochloric acid-dioxane solution was added under ice-bath. The reaction temperature was maintained for 4 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 ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 2 (35 mg, 33.4% yield).

[0787] MS m / z(ESI):657.2[M+1].

[0788] 1 H NMR (500MHz, CD3OD): δ7.67(s,1H),7.27(d,2H),7.06(d,1H),5.36(s,1H),5.06(dd,1H),4 .61(s,1H),4.49(d,2H),4.40(s,1H),4.15(d,1H),3.99(s,1H),3.75(s,1H),3.65(s,1H),3 .22(d,2H),2.98(s,1H),2.83(s,1H),2.66(d,2H),2.48(s,1H),2.22(s,1H),2.05(s,1H), 1.89(d,4H),1.72(s,1H),1.62(s,1H),0.92(s,2H),0.84(d,1H),0.71(s,2H),0.57(d,2H).

[0789] Example 3

[0790] 4-((5aS,6S,9R)-12-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]hept-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 3

[0791] first step

[0792] tert-Butyl (5aS,6S,9R)-12-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-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-methano[1,8-ab]hept-14-carboxylate 3a

[0793] The crude compound 1r (150 mg, 188 μmol) was dissolved in acetonitrile (3 mL), and (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (51 mg, 376.1 μmol, Shanghai Leyan), anhydrous potassium carbonate (100 mg, 723.5 μmol), and sodium iodide (28 mg, 187 μmol) were added. The mixture was heated to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL × 2). The organic phases were combined and concentrated under reduced pressure to give the crude title compound 3a (150 mg). The product was used directly in the next step without purification.

[0794] MS m / z(ESI):801.2[M+1].

[0795] Step 2

[0796] 4-((5aS,6S,9R)-12-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]hept-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 3

[0797] The crude compound 3a (100 mg, 124.8 μmol) was dissolved in ethyl acetate (3 mL), and 2 mL of 4 M hydrochloric acid-dioxane solution was added under ice-bath. The reaction was maintained at the temperature for 4 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 ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 3 (10 mg, yield: 12.2%).

[0798] MS m / z(ESI):657.2[M+1].

[0799] 1 H NMR (500MHz, CD3OD): δ7.67(d,1H),7.29(d,1H),7.28-7.23(m,1H),7.11(s,1H) ),5.12-5.00(m,2H),4.61(d,1H),4.47(dd,3H),4.15(d,1H),4.04(s,1H),3.73 (d,2H),3.25(s,1H),3.02(d,1H),2.80(s,3H),2.58(d,1H),2.47(s,1H),2.25 -2.17(m,1H),2.05(s,1H),2.00-1.71(m,6H),0.88(dq,3H),0.79-0.52(m,4H).

[0800] Example 4

[0801] 4-((5aS,6S,9R)-12-((1-((4-oxa-7-azaspiro[2.5]octan-7-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza[6,9]methanaphtho[1,8-ab]heptyl)-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0802] first step

[0803] tert-Butyl (5aS,6S,9R)-12-((1-((4-oxa-7-azaspiro[2.5]octan-7-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]methano[1,8-ab]heptyl-14-carboxylate 4a

[0804] The crude compound 1r (100 mg, 125 μmol) was dissolved in acetonitrile (3 mL), and 4-oxa-7-azaspiro[2.5]octane hydrochloride (40 mg, 267 μmol, Shanghai Bidex), anhydrous potassium carbonate (70 mg, 506 μmol), and sodium iodide (20 mg, 133 μmol) were added. The mixture was heated to 80°C and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL×2). The organic phases were combined and concentrated under reduced pressure to give the crude title compound 4a (102 mg). The product was used directly in the next step without purification.

[0805] MS m / z(ESI):815.2[M+1].

[0806] Step 2

[0807] 4-((5aS,6S,9R)-12-((1-((4-oxa-7-azaspiro[2.5]octan-7-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza[6,9]methanaphtho[1,8-ab]heptyl)-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0808] The crude compound 4a (100 mg, 122 μmol) was dissolved in ethyl acetate (3 mL), and 2 mL of 4 M hydrochloric acid-dioxane solution was added under ice bath. The temperature was maintained for 4 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 ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 4 (15 mg, yield: 18.2%).

[0809] MS m / z(ESI):671.2[M+1].

[0810] 1H NMR (500MHz, CD3OD): δ7.67(ddd,1H),7.31-7.22(m,2H),7.06(dd,1H),5.08(d dd,2H),4.68-4.56(m,2H),4.53-4.40(m,3H),4.16(dd,1H),3.82-3.72(m,3H) ,3.67(d,1H),3.27(d,1H),2.70-2.43(m,6H),2.29-2.19(m,1H),2.05(d,1H), 2.01-1.79(m,4H),0.92(td,2H),0.84(t,1H),0.78-0.67(m,3H),0.56(d,3H).

[0811] Example 5

[0812] 5-ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-5-methyl-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptacyclo-2-yl)naphthalen-2-ol

[0813] first step

[0814] (1-(Morpholinomethyl)cyclopropyl)methanol 5b

[0815] 1-Aminomethylcyclopropanemethanol 5a (1 g, 9.89 mmol, Shanghai Shaoyuan) and bis(2-bromoethyl) ether (2.3 g, 9.91 mmol, Shanghai Bid) were dissolved in acetonitrile (60 mL), and anhydrous sodium carbonate (3.1 g, 29.52 mmol) was added. The reaction solution was refluxed for 14 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified with eluent system A to give the title compound 5b (1.3 g, yield: 76.7%).

[0816] MS m / z(ESI):172.2[M+1].

[0817] Step 2

[0818] 2,5,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol 5c

[0819] The crude compound 1e (2 g, 8 mmol) was dissolved in phosphorus oxychloride (25 mL), and N,N-diisopropylethylamine (5.16 g, 40 mmol) was added. The mixture was stirred at 110°C for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and 20% potassium carbonate solution was added dropwise to adjust the pH to 2-3. The mixture was stirred for 2 hours and filtered. The filter cake was washed with water and dried to obtain the crude title compound 5c (1.5 g). The product was used in the next step without purification.

[0820] MS m / z(ESI):267.8[M+1].

[0821] Step 3

[0822] tert-Butyl (1S,2S,5R)-2-((S)-1-((2,7-dichloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 5e

[0823] Tert-butyl (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 5d (370 mg, 1.44 mmol, prepared by the method disclosed in Intermediate 29 on page 164 of the specification of patent application "WO2022173678A1") was dissolved in tetrahydrofuran (10 mL), and sodium hydride (201 mg, 5.2 mmol, 60% purity) was added under ice bath. After reacting for 30 minutes, compound 5c (353 mg, 1.31 mmol) was added and stirred for 2 hours. The reaction solution was quenched by adding water and concentrated under reduced pressure to obtain the crude title compound 5e (600 mg). The product was used directly in the next step without purification.

[0824] MS m / z(ESI):488.2[M+1].

[0825] Step 4

[0826] (5S,5aS,6S,9R)-2,12-Dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 5f

[0827] Compound 5e (78 mg, 159.7 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (61.9 mg, 478.9 μmol) and phosphorus oxychloride (122.4 mg, 798.2 μmol) were added under ice-cooling and stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 5f (75 mg). The product was used directly in the next step without purification.

[0828] MS m / z(ESI):470.2[M+1].

[0829] Step 5

[0830] (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 5g

[0831] Compound 5b (123.8 mg, 722.9 μmol) and crude compound 5f (170 mg, 361 μmol) were dissolved in dimethyl sulfoxide (4 mL), and potassium fluoride (105 mg, 1.8 mmol) was added. The mixture was reacted at 100°C for 14 hours. After the reaction solution was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to obtain 5 g (200 mg, yield: 91.4%) of the title compound.

[0832] MS m / z(ESI):605.2[M+1].

[0833] Step 6

[0834] tert-Butyl (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-12-((1-(morpholinylmethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate

[0835] Compound 5g (218 mg, 360 μmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (195 mg, 540 μmol, prepared by the method disclosed in Intermediate 18 on page 104 of the specification of patent application "WO2021 / 041671") were dissolved in 1.4-dioxane (4 mL) and water (0.5 mL), and cesium carbonate (352 mg, 1.08 mmol) and tetrakistriphenylphosphine palladium (83.26 mg, 72 μmol) were added. The reaction was carried out at 110°C under a nitrogen atmosphere for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 5h (200 mg, yield: 69%).

[0836] MS m / z(ESI):803.2[M+1].

[0837] Step 7

[0838] 5-ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-5-methyl-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptacyclo-2-yl)naphthalen-2-ol

[0839] Compound 5h (200 mg, 249 μmol) was dissolved in ethyl acetate (5 mL), and a 4 M hydrogen chloride solution in 1,4-dioxane (2 mL) was added under ice bath. The reaction was maintained at the temperature for 0.5 hour, and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 5 (90 mg, yield: 54.8%).

[0840] MS m / z(ESI):659.2[M+1].

[0841] 1 H NMR (500MHz, CD3OD): δ7.67(dt,1H),7.29(t,1H),7.24(t,1H),7.05(dd,1H),5.4 0(ddd,1H),4.57(dt,1H),4.51-4.36(m,2H),4.11(t,1H),3.74(d,1H),3.70-3.6 0(m,5H),3.21(t,1H),2.60-2.39(m,7H),2.21(ddt,1H),2.10(dq,1H),1.94-1.7 5(m,3H),1.58(dd,3H),0.99(d,1H),0.81(t,2H),0.74(d,2H),0.59-0.48(m,2H).

[0842] Example 6

[0843] 4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0844] first step

[0845] Tert-butyl (5S,5aS,6S,9R)-12-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-chloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-14-carboxylate 6b

[0846] (1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol 6a (1.4 g, 6.4 mmol) was dissolved in tetrahydrofuran (15 mL). A 2 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of crude compound 5f (2.3 g, 4.9 mmol) in tetrahydrofuran (20 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the solution was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 6b (2 g, yield: 62.8%).

[0847] MS m / z(ESI):650.2[M+1].

[0848] Step 2

[0849] tert-Butyl (5S,5aS,6S,9R)-12-((1-((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 6c

[0850] Compound 6b (2 g, 3.07 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.66 g, 4.6 mmol) were dissolved in 1.4-dioxane (40 mL) and water (8 mL), and cesium carbonate (3 g, 9.2 mmol) and tetrakistriphenylphosphine palladium (710 mg, 615 μmol) were added. The reaction was carried out at 105° C. under a nitrogen atmosphere for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 6c (2.5 g, yield: 95.8%).

[0851] MS m / z(ESI):848.2[M+1].

[0852] Step 3

[0853] tert-Butyl (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 6d

[0854] Compound 6c (500 mg, 589.58 μmol) was dissolved in tetrahydrofuran (6 mL), and tetrabutylammonium fluoride (160 mg, 710.5 μmol) was added. After stirring for 1 hour, the reaction solution was diluted with ethyl acetate (20 mL) and washed with water and saturated sodium chloride solution in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 6d (435 mg). The product was used directly in the next step without purification.

[0855] MS m / z(ESI):734.2[M+1].

[0856] Step 4

[0857] tert-Butyl (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-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-methano[1,8-ab]heptyl-14-carboxylate 6e

[0858] The crude compound 6d (435 mg, 592.8 μmol) was dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (229 mg, 1.77 mmol) and methanesulfonyl chloride (95 mg, 829.3 μmol) were added in an ice bath. The reaction mixture was stirred and maintained at the temperature for 30 minutes. Saturated ammonium chloride solution was added to the reaction solution for quenching. The mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 6e (480 mg). The product was used directly in the next step without purification.

[0859] MS m / z(ESI):812.2[M+1].

[0860] Step 5

[0861] (5S,5aS,6S,9R)-tert-Butyl 12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptane-14-carboxylate

[0862] Crude compound 6e (235 mg, 289.4 μmol) and 4-(difluoromethylidene)piperidine hydrochloride (74 mg, 436.32 μmol, prepared by the method disclosed in "Bioorganic and Medicinal Chemistry, 2004, vol. 12, #7, p. 1713-1730") were dissolved in acetonitrile (5 mL). Anhydrous potassium carbonate (120 mg, 868.27 μmol) and sodium iodide (44 mg, 293.54 μmol) were added, and the mixture was stirred at 80°C for 1 hour. The reaction solution was cooled to room temperature and filtered. Water was added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 6f (245 mg). The product was used in the next step without purification.

[0863] MS m / z(ESI):849.2[M+1].

[0864] Step 6

[0865] 4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0866] The crude compound 6f (250 mg, 294.5 μmol) was dissolved in ethyl acetate (5 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was added under ice bath. The reaction was maintained at the temperature for 0.5 hour, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 6 (140 mg, yield: 67.4%).

[0867] MS m / z(ESI):705.3[M+1].

[0868] 1 H NMR (500MHz, CD3OD): δ7.67(dt,1H),7.32–7.22(m,2H),7.12-6.98(m,1H), 5.40(ddt,1H),4.57(td,1H),4.53–4.36(m,2H),4.10(t,1H),3.72(d,1H),3 .62(s,1H),3.20(t,1H),2.63–2.39(m,7H),2.29–2.01(m,6H),1.94–1.86( m,1H),1.81(dt,2H),1.58(dd,3H),0.89(dt,3H),0.75(d,2H),0.52(s,2H).

[0869] Example 7

[0870] 4-((5S,5aS,6S,9R)-12-((1-((3-(difluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 7

[0871] Step 1: tert-Butyl 3-(difluoromethylidene)pyrrolidine-1-carboxylate 7c

[0872] Potassium tert-butoxide (912 mg, 8.1 mmol) was dissolved in N,N-dimethylacetamide (3 mL), and 1-tert-butoxycarbonyl-3-pyrrolidone 7a (1 g, 5.4 mmol) and 2-((difluoromethyl)sulfonyl)pyridine 7b (872 mg, 4.5 mmol, Shanghai Bidex) were added at -40°C. The temperature was maintained for 15 minutes. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. 3N hydrochloric acid (10 mL) was added and the solution was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 7c (167 mg, yield: 16.8%).

[0873] MS m / z(ESI):164[M-55].

[0874] Step 2

[0875] 3-(Difluoromethylidene)pyrrolidine hydrochloride 7d

[0876] Compound 7c (167 mg, 761.7 μmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (2 mL) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude title compound 7d (118 mg), which was used directly in the next step without purification.

[0877] MS m / z(ESI):120.2[M+1].

[0878] Step 3

[0879] 4-((5S,5aS,6S,9R)-12-((1-((3-(difluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 7

[0880] The synthetic route in Example 6 was used to replace the fifth step raw material compound 4-(difluoromethylidene)piperidine hydrochloride with compound 7d to obtain the title compound 7 (3 mg, yield: 12%).

[0881] MS m / z(ESI):691.3[M+1].

[0882] 1H NMR (500MHz, CD3OD): δ7.68-7.63(m,1H),7.29-7.23(m,2H),7.12-7.01(m,1H),5.41-5.39(m,1H),4.59-4.42(m,3H),4.11-4.08(m,1H) ),3.70-3.61(m,3H),3.17-2.70(m,3H),2.70-2.44(m,7H),2.21-1.79(m,7H),1.59-1.57(m,3H),0.99-0.92(m,2H),0.75-0.73(m,2H).

[0883] Example 8

[0884] 1-((1-((((5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-12-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-one O-methyloxime 8

[0885] The synthetic route of Example 6 was used to replace the raw material in the fifth step, 4-(difluoromethylidene)piperidine hydrochloride, with piperidin-4-one O-methyloxime (prepared using the method disclosed in the literature "Molecules, 2016, vol. 21, #12, art. no. 1674") to obtain the title compound 8 (5 mg, yield: 20%).

[0886] MS m / z(ESI):700.3[M+1].

[0887] 1 H NMR (500MHz, CD3OD): δ7.67(dt,1H),7.32–7.21(m,2H),7.12-6.98(m,1H),5.42(ddd,1H),4 .65–4.41(m,4H),4.12(t,1H),3.78(d,4H),3.66(s,1H),3.27–3.18(m,1H),2.68-2.67(m,2 H),2.60-2.54(m,4H),2.52-2.44(m,2H),2.30(q,2H),2.24–2.17(m,1H),2.15–2.07(m,1H) ,1.91(d,1H),1.88–1.78(m,2H),1.59(dd,3H),0.99-0.95(m,3H),0.76(t,2H),0.54(s,2H).

[0888] Example 9

[0889] 4-((1-((((5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-12-yl)oxy)methyl)cyclopropyl)methyl)-1-(methylamino)-1λ 6 -Thiomorpholine 1-oxide 9

[0890] The synthetic route in Example 6 was adopted, and the raw material 4-(difluoromethylidene)piperidine hydrochloride in the fifth step was replaced by 1-(methylaminoylidene)-1λ 6 -Thiomorpholine-1-oxide (prepared using the method disclosed in Intermediate S on page 239 of the specification of patent application "WO2022 / 23772,2022,A1") gave the title compound 9 (5 mg, yield: 6%).

[0891] MS m / z(ESI):720.3[M+1].

[0892] 1 H NMR (500MHz, CD3OD): δ7.68-7.64(m,1H),7.29-7.22(m,2H),7.13-7.01(m,1H),5.40-5.37(m,1H),4.61-4.39(m,3H),4.13-4.10(m,1H),3.77-3 .66(m,2H),3.25-2.85(m,9H),2.82-2.46(m,6H),2.23-1.80(m,6H),1.5 8-1.57(m,3H),1.00-0.97(m,1H),0.83-0.77(m,3H),0.56-0.54(s,2H).

[0893] Example 10

[0894] 4-((1-((((5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-12-yl)oxy)methyl)cyclopropyl)methyl)-1-aminoylidene-1λ 6 -Thiomorpholine 1-oxide 10

[0895] Using the synthetic route in Example 6, the fifth step raw material 4-(difluoromethylidene)piperidine hydrochloride was replaced by compound 1-aminoylidene-1λ 6 -Thiomorpholine-1-oxide (prepared by the method disclosed in the document "Tetrahedron, 2014, vol. 70, #37, p. 6613-6622") gave the title compound 10 (5 mg, yield: 6%).

[0896] MS m / z(ESI):706.3[M+1].

[0897] 1 H NMR (500MHz, CD3OD): δ7.69-7.65(m,1H),7.30-7.22(m,2H),7.12-7.01(m,1H),5.44-5.42(m,1H),4.61-4.39(m,3H),4.14-4.12(m,1H) ),3.85-3.72(m,2H),3.27-2.90(m,9H),2.70-2.64(m,4H),2.25-1.74(m,7H),1.59-1.57(m,3H),1.00-0.97(m,1H),0.84-0.71(m,3H).

[0898] Example 11

[0899] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((E)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphthol-2-ol

[0900] first step

[0901] (E)-tert-Butyl 3-(fluoromethylidene)pyrrolidine-1-carboxylate 11a-1

[0902] (Z)-3-(Fluoromethylidene)pyrrolidine-1-carboxylic acid tert-butyl ester 11a-2

[0903] 2-((Fluoromethyl)sulfonyl)pyridine (4.7 g, 26.8 mmol, Shanghai Shaoyuan) was dissolved in tetrahydrofuran (100 mL). A 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (33 mL) was added at -78°C. The temperature was maintained for 30 minutes, followed by the addition of 1-tert-butoxycarbonyl-3-pyrrolidone 7a (5 g, 27 mmol). The temperature was maintained for 3 hours, then the mixture was returned to room temperature for 1 hour. The reaction solution was quenched by the addition of saturated ammonium chloride solution, 3N hydrochloric acid (50 mL) was added, and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compounds 11a-1 (800 mg, yield: 14.7%) and 11a-2 (800 mg, yield: 14.7%).

[0904] MS m / z(ESI):146.2[M-55].

[0905] 11a-1: 1 H NMR (500MHz, CDCl3): δ6.70(s,0.5H),6.54(s,0.5H),3.93(s,2H),3.48(t,2H),2.66(t,2H),1.48(s,9H).

[0906] 11a-2: 1 H NMR (500MHz, CDCl3): δ6.61 (s, 0.5H), 6.45 (s, 0.5H), 4.07 (s, 2H), 3.49 (t, 2H), 2.49 (t, 2H), 1.48 (s, 9H).

[0907] Step 2

[0908] (E)-3-(Fluoromethylidene)pyrrolidine hydrochloride 11b

[0909] Compound 11a-1 (700 mg, 3.5 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (10 mL) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude title compound 11b (480 mg), which was used directly in the next step without purification.

[0910] MS m / z(ESI):101.2[M+1].

[0911] Step 3

[0912] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((E)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphthol-2-ol

[0913] Using the synthetic route in Example 6, the fifth step raw material compound 4-(difluoromethylidene)piperidine hydrochloride was replaced by compound 11b to obtain the title compound 11 (5 mg, yield: 12.1%).

[0914] MS m / z(ESI):673.3[M+1].

[0915] 1 H NMR (500MHz, CD3OD): δ7.67(dt,1H),7.33–7.20(m,2H),7.11(d,1H),6.70(d,1H), 5.40(ddd,1H),4.58(dd,1H),4.50–4.36(m,2H),4.10(t,1H),3.71(d,1H),3.62(s, 1H),3.22–3.17(m,4H),2.75(s,2H),2.62–2.51(m,5H),2.25–2.06(m,2H),1.85–1. 76(m,3H),1.58(dd,3H),1.31(s,2H),0.98(t,1H),0.81(t,2H),0.74-0.58(m,3H).

[0916] Example 12

[0917] 2-((1-((((5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-12-yl)oxy)methyl)cyclopropyl)methyl)hexahydrocyclopenta[c]pyrrol-5(1H)-one O-methyloxime 12

[0918] MS m / z(ESI):726.3[M+1].

[0919] Example 13

[0920] 1-((1-((((5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-12-yl)oxy)methyl)cyclopropyl)methyl)azepan-4-one O-methyloxime 13 (mixture of cis and trans isomers)

[0921] The synthetic route in Example 6 was used to replace the raw material in the fifth step, 4-(difluoromethylidene)piperidine hydrochloride, with azacycloheptan-4-one O-methyloxime trifluoroacetate (prepared using the method disclosed in the document "RSC Advances, 2017, vol. 7, #3, p. 1480-1483") to obtain the title compound 13.

[0922] MS m / z(ESI):714.3[M+1].

[0923] Example 14

[0924] 4-((5S,5aS,6S,9R)-12-(1-((5-(difluoromethylidene)hexahydrocyclopenta[c]pyrrol-2(1H)yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0925] The synthetic route in Example 7 was used to replace the first step raw material compound 7a with N-tert-butyloxycarbonyl-hexahydro-5-oxocyclopenta[c]pyrrole (Shanghai Bidex) to obtain the title compound 14 (10 mg, yield: 39.9%).

[0926] MS m / z(ESI):731.3[M+1].

[0927] 1H NMR (500MHz, CD3OD): δ7.68-7.66(m,1H),7.29-7.26(m,2H),7.12-7.01(m,1H),5.41-5.39(m,1H),4.58-4.39(m,3H),4.1 1-4.10(m,1H),3.71-3.47(m,3H),3.19-3.18(m,3H),2.73-2.08(m,12H),1.82-1.79(m,3H),1.59-1.57(m,3H),0.99-0.92 (m,2H),0.72-0.54(m,5H).

[0928] Example 15

[0929] 4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)azepan-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 15

[0930] The synthetic route in Example 7 was used to replace the first step raw material compound 7a with compound 4-oxoazepane-1-carboxylic acid tert-butyl ester (Shanghai Bidex) to obtain the title compound 15 (5 mg, yield: 19.3%).

[0931] MS m / z(ESI):719.3[M+1].

[0932] 1H NMR (500MHz, CD3OD): δ7.68-7.65(m,1H),7.29-7.24(m,1H),7.12-7.11(m,1H),6.98-6.95(m,1H),5.39-5.36 (m,1H),4.59-4.57(m,1H),4.46-4.42(m,2H),4.14-4.10(m,1H),3.76-3.74(m,1H),3.68-3.63(m,1H),3.25-3 .20(m,1H),2.98-2.81(m,6H),2.56-2.42(m,4H),2.33-2.30(m,2H),2.23-2.20(m,1H),2.18-2.06(m,2H),1.9 2-1.81(m,4H),1.62-1.59(m,3H),0.99-0.95(m,1H),0.93-0.91(m,1H),0.80-0.79(m,2H),0.62-0.60(m,2H).

[0933] Example 16

[0934] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)naphthalen-2-ol 16 (diastereoisomer mixture)

[0935] Example 16-p1, 16-p2

[0936] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((S,Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptylcyclo-2-yl)naphthalen-2-ol 16-p1

[0937] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((R,Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)naphthalen-2-ol 16-p2

[0938] Example 17

[0939] 4-((5S,5aS,6S,9R)-12-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptylcyclo-2-yl)-5-ethyl-6-fluoronaphthalene-2-ol 17

[0940] The synthetic route in Example 5 was adopted, and the raw material compound 5b in the fifth step was replaced by (2,6-dimethylidenetetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (prepared by the method disclosed in Example 4 on page 30 of the specification of patent application "WO2022247757") to obtain the title compound 17 (20 mg, yield: 24.4%).

[0941] MS m / z(ESI):653.3[M+1].

[0942] 1 H NMR (500MHz, CD3OD): δ7.72-7.56(m,1H),7.37-7.18(m,2H),7.12-6.91(m,1H),5.43-5.27 (m,1H),5.11-4.95(m,2H),4.62-4.49(m,1H),4.44-4.21(m,2H),4.13-4.01(m,1H),3.85-3 .54(m,4H),3.50-3.37(m,4H),3.23-3.08(m,2H),2.87-2.72(m,2H),2.70-2.39(m,3H),2.2 7-1.97(m,2H),1.97-1.66(m,3H),1.60-1.46(m,2H),1.02-0.90(m,1H),0.84-0.64(m,2H).

[0943] Example 18

[0944] 4-((5S,5aS,6S,9R)-12-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 18 (diastereoisomer mixture)

[0945] The synthetic route in Example 5 was used, and the raw material compound 5b in the fifth step was replaced with (2-(difluoromethylidene)tetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (prepared by the method disclosed in Example 11 on page 54 of the specification of patent application "WO2022247757") to obtain the title compound 18 (50 mg, yield: 24.2%) (diastereoisomer mixture).

[0946] MS m / z(ESI):677.3[M+1].

[0947] 1 H NMR (500MHz, CD3OD): δ7.67(dt,1H),7.32–7.21(m,2H),7.12-6.99(m,1H),5.39(ddd,1H),4 .59(p,1H),4.37(dd,1H),4.29(d,1H),4.15–4.08(m,1H),3.81(dt,1H),3.71(d,1H),3.62( d,1H),3.48–3.40(m,1H),3.26–3.12(m,2H),2.88–2.77(m,1H),2.73(q,1H),2.64–2.45(m, 2H),2.24–2.11(m,2H),2.04(dddd,2H),1.97–1.76(m,5H),1.58(dd,3H),0.99-0.79(m,3H).

[0948] Example 18-p1, 18-p2

[0949] 4-((5S,5aS,6S,9R)-12-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 18-p1

[0950] 4-((5S,5aS,6S,9R)-12-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 18-p1

[0951] The isomeric mixture 18 (30 mg, 44.3 μmol) was separated by chiral column (Gilson 281, chromatographic column: CHIRALPAK IG, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% NH3 in MeOH), gradient ratio: A:B: 75:25, flow rate: 20 mL / min) to obtain 10 mg, 10 mg of the title compound, yield: 33%, 33%.

[0952] Chiral HPLC analysis of the isomeric mixture: retention times were 10.274 min and 14.616 min, respectively (Chromatographic column: CHIRALPAK IG, 150 x 4.6 mm, 5 μm; Mobile phase A: 90% ethanol (containing 0.1% diethylamine) + 10% dichloromethane, Mobile phase B: n-hexane, gradient ratio: A:B: 30:70, flow rate: 1.0 mL / min). Single-configuration compound (shorter retention time): 10.274 min (10 mg, yield: 33%).

[0953] MS m / z(ESI):677.3[M+1].

[0954] HPLC analysis: retention time 1.45 minutes, purity: 90% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0955] 1H NMR (500MHz, CD3OD): δ7.71–7.64(m,1H),7.33–7.22(m,2H),7.12-6.98(m, 1H),5.54–5.47(m,1H),4.68(ddd,1H),4.56–4.49(m,1H),4.44(d,1H),4.24 (t,1H),4.03(s,1H),3.93(s,1H),3.69(d,1H),3.36(s,2H),2.92(d,2H),2. 67(d,1H),2.59–2.43(m,2H),2.32–1.87(m,9H),1.60(d,3H),0.89(dt,3H).

[0956] Single configuration compound (longer retention time): 14.616 min (10 mg, yield: 33%).

[0957] MS m / z(ESI):677.3[M+1].

[0958] HPLC analysis: retention time 1.45 minutes, purity: 90% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0959] 1 H NMR (500MHz, CD3OD): δ7.68(dt,1H),7.33–7.22(m,2H),7.12-6.89(m,1H),5.53–5.46(m,1H),4.68(td,1H),4.54(d,1H),4.45(d,1H),4.24( t,1H),3.99(d,3H),3.70(d,1H),3.37(s,1H),3.01–2.88(m,2H),2.67 (d,1H),2.52(ddt,2H),2.32–1.87(m,9H),1.61(dd,3H),0.89(dt,3H).

[0960] Example 19

[0961] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)naphthalen-2-ol 19 (diastereoisomer mixture)

[0962] Example 19-p1, 19-p2

[0963] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((S,E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptylcyclo[2-yl]naphthol-2-ol 19-p1

[0964] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((R,E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptylcyclo[2-yl]naphtho[1,8-ab] ...

[0965] Example 20

[0966] 4-((5aS,6S,9R)-12-((2,6-dimethylidenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptylcyclo-2-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0967] The first to fifteenth and eighteenth steps of the synthetic route in Example 1 were used, and the starting compound 1,1-bis(hydroxymethyl)cyclopropane in the thirteenth step was replaced by 2,6-dimethylidenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol to obtain the title compound 20 (7 mg, yield: 8.5%).

[0968] MS m / z(ESI):639.2[M+1].

[0969] 1H NMR (500MHz, CD3OD): δ7.69(ddd,1H),7.34–7.24(m,2H),7.08(dd,1H),5.11–5.02(m, 4H),4.67–4.61(m,1H),4.51(ddd,1H),4.40-4.34(m,2H),4.17(dd,1H),3.82(d,2H),3 .78–3.74(m,1H),3.70–3.66(m,1H),3.50–3.39(m,1H),3.32–3.19(m,3H),2.84(d,2H ),2.63(d,2H),2.54–2.44(m,1H),2.29–2.20(m,1H),2.01–1.79(m,4H),0.90(dt,3H).

[0970] Example 21

[0971] 4-((5aS,6S,9R)-12-((2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 21 (diastereoisomer mixture)

[0972] The first to fifteenth and eighteenth steps of the synthetic route in Example 1 were used, and the raw material compound 1,1-bis(hydroxymethyl)cyclopropane in the thirteenth step was replaced by (2-(difluoromethylidene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (prepared by the method disclosed in Example 11 on page 54 of the specification of patent application "WO2022247757") to obtain the title compound 21 (diastereoisomer mixture).

[0973] MS m / z(ESI):663.2[M+1].

[0974] Example 21-p1, 21-p2

[0975] 4-((5aS,6S,9R)-12-(((S)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 21-p1

[0976] 4-((5aS,6S,9R)-12-(((R)-2-(difluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)-2-yl)-5-ethyl-6-fluoronaphthalene-2-ol 21-p2

[0977] Compound 21 was resolved on a chiral column to give the title compound.

[0978] MS m / z(ESI):663.2[M+1].

[0979] Example 22

[0980] 4-((5S,5aS,6S,9R)-12-((1-((3-(difluoromethylidene)azetidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 22

[0981] The synthetic route in Example 7 was used to replace the first step raw material compound 7a with compound 3-oxoazetidine-1-carboxylic acid tert-butyl ester (Shanghai Bidex) to obtain the title compound 22 (5 mg, yield: 19.3%).

[0982] MS m / z(ESI):677.2[M+1].

[0983] 1 H NMR (500MHz, CD3OD): δ7.67(dt,1H),7.33–7.21(m,2H),7.11(d,1H),5.40(ddd,1H),4.59(dd,1H),4.41–4.29(m,2H), 4.11(t,1H),3.99–3.95(m,3H),3.73(d,1H),3.63(s,1H),3.31(t,1H),2.79–2.67(m,2H),2.52(dt,2H),2.15(d,2H), 1.97–1.78(m,3H),1.58(dd,3H),1.31(s,3H),0.98(t,1H),0.81(t,2H),0.72-0.59(m,3H).

[0984] Example 23

[0985] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphthol-2-ol

[0986] first step

[0987] tert-Butyl 4-(fluoromethylidene)piperidine-1-carboxylate 23b

[0988] 2-((Fluoromethyl)sulfonyl)pyridine (4.2 g, 23.97 mmol) was dissolved in tetrahydrofuran (50 mL), and a 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (30 mL) was added at -78°C. The temperature was maintained for 30 minutes, and then N-tert-butoxycarbonyl-4-piperidone 23a (5 g, 25.09 mmol, Shanghai Shaoyuan) was added. The temperature was maintained for 3 hours, and then the mixture was returned to room temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution for quenching, and 3N hydrochloric acid (100 mL) was added. After stirring for 1 hour, the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 23b (2 g, yield: 37%).

[0989] Step 2

[0990] 4-(Fluoromethylidene)piperidine hydrochloride 23c

[0991] Compound 23b (1 g, 4.64 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (20 mL) and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude title compound 23c (700 mg), which was used directly in the next step without purification.

[0992] MS m / z(ESI):116.1[M+1].

[0993] Step 3

[0994] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphthol-2-ol

[0995] The synthetic route in Example 6 was used to replace the raw material compound 4-(difluoromethylidene)piperidine hydrochloride in the fifth step with the crude compound 23c to obtain the title compound 23 (15 mg, yield: 18.1%).

[0996] MS m / z(ESI):687.2[M+1].

[0997] 1 H NMR (500MHz, CD3OD): δ7.67(dt,1H),7.32–7.21(m,2H),7.05(dd,1H),6.52(d,1H),5 .45–5.38(m,1H),4.62–4.39(m,5H),4.11(t,2H),3.73(d,1H),3.63(s,1H),3.50–3.4 4(m,1H),3.28–3.17(m,3H),2.66–2.43(m,5H),2.35(s,2H),2.25–2.15(m,1H),2.10( s,2H),1.94–1.72(m,3H),1.58(dd,3H),0.98(t,1H),0.84–0.71(m,2H),0.54(s,1H).

[0998] Example 24

[0999] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)-2-naphthol 24 (isomer mixture)

[1000] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)-2-naphthol 16 (diastereoisomer mixture)

[1001] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)-2-naphthol 19 (diastereoisomer mixture)

[1002] The synthetic route in Example 5 was adopted, and the raw material compound 5b in the fifth step was replaced with (2-(fluoromethylidene)tetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (prepared by the method disclosed in Example 5 on page 33 of the specification of patent application "WO2022247757") to give the crude title compound 24 (240 mg), which was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to give compounds 16 and 19 (10 mg, 10 mg, yield: 15%, 15%).

[1003] Diastereoisomer mixture (shorter retention time): (10 mg, yield: 15%).

[1004] MS m / z(ESI):659.2[M+1].

[1005] HPLC analysis: retention time 1.40 minutes, purity: 92% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1006] 1H NMR (500MHz, CD3OD): δ7.65(dt,1H),7.30–7.18(m,2H),7.03(dd,1H), 6.73(d,1H),5.44–5.28(m,1H),4.57(t,1H),4.35(d,1H),4.28(dd,1H),4.09(t,1H),3.71(dd,2H),3.60(s,1H),3.40( d,1H),3.22–3.11(m,2H),2.85(d,1H),2.70(q,1H),2.62–2.41(m,2H),2.21–1.77(m,9H),1.56(dd,3H),0.85(dt,3H).

[1007] Diastereoisomer mixture (longer retention time): (10 mg, yield: 15%).

[1008] MS m / z(ESI):659.2[M+1].

[1009] HPLC analysis: retention time 1.41 minutes, purity: 96% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[1010] 1 H NMR (500MHz, CD3OD): δ7.66(dt,1H),7.31–7.20(m,2H),7.04(dd,1H),6.75(d,1H),5.43(d,1H),4.67–4.56(m,1H),4.55–4.39(m,2H),4.15(d d,2H),3.77(s,2H),3.45(s,1H),3.30–3.13(m,2H),3.04–2.80(m,2H) ,2.65–2.38(m,2H),2.32–1.81(m,9H),1.58(d,3H),0.96–0.74(m,3H).

[1011] Example 25

[1012] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((Z)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphthol-2-ol

[1013] The synthetic route in Example 11 was used to replace the second step raw material compound 11a-1 with compound 11a-2 to obtain the title compound 25 (6 mg, yield: 14.5%).

[1014] MS m / z(ESI):673.3[M+1].

[1015] 1 H NMR (500MHz, CD3OD): δ7.67(dt,1H),7.42–7.17(m,2H),7.05(dd,1H),6.56(dq,1H),5.4 0(ddd,1H),4.57(ddd,1H),4.48–4.32(m,2H),4.10(t,1H),3.86–3.60(m,2H),3.35(d,3H ),3.29–3.07(m,1H),2.78–2.71(m,2H),2.70–2.45(m,4H),2.42(s,2H),2.26–2.05(m,2 H),1.99–1.76(m,3H),1.58(dd,3H),0.98(t,1H),0.81(t,2H),0.74(d,2H),0.58(d,2H).

[1016] Example 26

[1017] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((E)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphthalen-2-amine

[1018] MS m / z(ESI):672.3[M+1].

[1019] Example 27

[1020] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((Z)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphthalen-2-amine

[1021] MS m / z(ESI):672.3[M+1].

[1022] Example 28

[1023] (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoronaphth-1-yl)-1-fluoro-12-((1-(((Z)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptacyclo

[28]

[1024] The synthetic route in Example 6 was used, and the second-step raw material compound 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared by the method disclosed in Intermediate L on page 93 of the specification of patent application "WO2022232331"), and the fifth-step raw material compound 4-(difluoromethylidene)piperidine hydrochloride was replaced with compound 11a-2 to obtain the title compound.

[1025] MS m / z(ESI):657.2[M+1].

[1026] Example 29

[1027] (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-((1-(((E)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl]cyclo

[29]

[1028] The synthetic route in Example 6 was used, and the second-step raw material compound 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared by the method disclosed in Intermediate L on page 93 of the specification of patent application "WO2022232331"), and the fifth-step raw material compound 4-(difluoromethylidene)piperidine hydrochloride was replaced with compound 11a-1 to obtain the title compound.

[1029] MS m / z(ESI):657.2[M+1].

[1030] Example 30

[1031] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((Z)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptylcyclo-2-yl)naphth-2-ylmethylcarbamate 30

[1032] MS m / z(ESI):730.2[M+1].

[1033] Example 31

[1034] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((E)-3-(fluoromethylidene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptylcyclo-2-yl)naphth-2-ylmethylcarbamate 31

[1035] MS m / z(ESI):730.2[M+1].

[1036] Example 32

[1037] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphthalen-2-amine 32

[1038] MS m / z(ESI):686.2[M+1].

[1039] Example 33

[1040] (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoronaphth-1-yl)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptacyclo

[33]

[1041] The synthetic route in Example 6 was used, and the second-step raw material compound 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared by the method disclosed in Intermediate L on page 93 of the specification of patent application "WO2022232331"), and the fifth-step raw material compound 4-(difluoromethylidene)piperidine hydrochloride was replaced with compound 23c to obtain the title compound.

[1042] MS m / z(ESI):671.2[M+1].

[1043] Example 34

[1044] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphth-2-ylmethylcarbamate 34

[1045] MS m / z(ESI):744.2[M+1].

[1046] Example 35

[1047] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((5-(fluoromethylidene)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)naphth-2-ol 35

[1048] first step

[1049] tert-Butyl (3aR,6aS)-5-(fluoromethylidene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 35b

[1050] 2-((Fluoromethyl)sulfonyl)pyridine (1.8 g, 4.7 mmol, Shanghai Shaoyuan) was dissolved in tetrahydrofuran (15 mL), and a 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (5.4 mL) was added at -78°C. The temperature was maintained for 30 minutes, and a solution of cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 35a (1 g, 4.4 mmol, Nanjing Yaoshi) in tetrahydrofuran (3 mL) was added. The temperature was maintained for 1 hour, and then the reaction was returned to room temperature for 16 hours. Saturated ammonium chloride solution was added to the reaction solution for quenching, and the solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 35b (760 mg, yield: 70.9%).

[1051] Step 2

[1052] (3aR,6aS)5-(Fluoromethylidene)octahydrocyclopenta[c]pyrrole hydrochloride 35c

[1053] Compound 35b (760 mg, 3.1 mmol) was dissolved in acetonitrile (1.5 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (6 mL) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to give the crude title compound 35c (560 mg). The product was used directly in the next reaction without purification.

[1054] MS m / z(ESI):142.3[M+1].

[1055] Step 3

[1056] 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((5-(fluoromethylidene)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptacyclo-2-yl)naphthol-2-ol 35

[1057] The synthetic route in Example 6 was used to replace the fifth step raw material compound 4-(difluoromethylidene)piperidine hydrochloride with compound 35c to obtain the title compound 35 (5 mg, yield: 10.3%).

[1058] MS m / z(ESI):713.3[M+1].

[1059] 1 H NMR (500MHz, CD3OD): δ7.67-7.63(m,1H),7.28-7.21(m,2H),7.04(d,1H),6.50(d,1H) ,5.39-5.34(m,1H),4.58-4.53(m,1H),4.41(t,2H),4.08(t,1H),3.70(d,1H),3.60(s, 1H),3.18(t,1H),2.98(s,2H),2.71-2.37(m,8H),2.29-2.16(m,3H),2.06-2.00(m,2H ),1.91-1.76(m,3H),1.57(d,3H),0.96(t,1H),0.79(t,2H),0.72(s,2H),0.55(s,2H).

[1060] Example 36

[1061] 3-Chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline

[1062] first step

[1063] tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-4-carboxylate 36a

[1064] Compound 6b (100 mg, 153.8 μmol) was dissolved in tetrahydrofuran (4 mL), and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (187 μL) was added. The mixture was stirred for 2 hours, and saturated aqueous ammonium chloride was added to the reaction solution for quenching. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the crude title compound 36a (82 mg), which was used directly in the next step without purification.

[1065] MS m / z(ESI):536.2[M+1].

[1066] Step 2

[1067] tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-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-methanaphtho[1,8-ab]heptyl-14-carboxylate 36b

[1068] The crude compound 36a (83 mg, 154.9 μmol) and N,N-diisopropylethylamine (60 mg, 464.2 μmol) were dissolved in dichloromethane (3 mL). Methanesulfonyl chloride (25 mg, 218.2 μmol) was added under ice-cooling and the reaction was allowed to return to room temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction solution for quenching. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give the crude title compound 36b (95 mg), which was used directly in the next step without purification.

[1069] MS m / z(ESI):614.2[M+1].

[1070] Step 3

[1071] tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 36c

[1072] The crude compound 36b (95 mg, 154.7 μmol) and compound 23c (35.5 mg, 234.5 μmol) were dissolved in acetonitrile (4 mL), and anhydrous potassium carbonate (64 mg, 463 μmol) and sodium iodide (70 mg, 467 μmol) were added. The mixture was stirred at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 36c (80 mg, yield: 81.6%).

[1073] MS m / z(ESI):633.2[M+1].

[1074] Step 4

[1075] (5S,5aS,6S,9R)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-12-((1-(4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 36e

[1076] Compound 36c (20 mg, 31.6 μmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline 36d (15 mg, 46.6 μmol, prepared by the method disclosed in Example 80 on page 257 of the specification of patent application "WO2022148422"), tetrakis(triphenylphosphine)palladium (7 mg, 6.1 μmol), and cesium carbonate (31 mg, 95.1 μmol) were mixed in 1,4-dioxane (1 mL) and water (0.2 mL) and reacted at 100°C under a nitrogen atmosphere for 1 hour. The reaction solution was cooled to room temperature and diluted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 36e (20 mg). The product was used directly in the next step without purification.

[1077] MS m / z(ESI):792.2[M+1].

[1078] Step 5

[1079] 3-Chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline

[1080] The crude compound 36e (15 mg, 18.9 μmol) was dissolved in dichloromethane (1 mL), and a 4 M hydrochloric acid solution in 1,4-dioxane (0.5 mL) was added under ice-bath. The reaction was maintained at the temperature for 0.5 hour, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 36 (4 mg, yield: 30.5%).

[1081] MS m / z(ESI):690.3[M-1].

[1082] 1 H NMR (500MHz, CD3OD): δ6.90(s,1H),6.58(d,1H),6.42(s,1H),5.37(dd,1H),4.58–4.39(m,3H),4.07(t,1H),3.70(d,1H),3.60(d ,1H),3.20–3.14(m,1H),2.61–2.42(m,6H),2.33(s,2H),2.08(s,3H),1.92–1.74(m,3H),1.58(d,3H),0.74(s,2H),0.52(s,2H).

[1083] Example 37

[1084] 2-Amino-7-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)benzo[b]thiophene-3-carbonitrile 37

[1085] The synthetic route in Example 36 was used to replace the raw material compound 36d in the fourth step with the compound (tert-butyl 3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate (prepared by the method disclosed in preparation 15 on page 50 of the specification of the patent application "WO2021118877") to obtain the title compound 37 (4 mg, yield: 34.4%).

[1086] MS m / z(ESI):687.3[M-1].

[1087] 1H NMR (500MHz, CD3OD): δ7.39(dd,1H),7.04(t,1H),6.51(d,1H),5.41(dd,1H),4.53–4.46(m,2H),4.40(d,1H),4.10(d,1H),3.7 0(d,1H),3.60(d,1H),3.19(s,1H),2.62–2.31(m,8H),2.09(d,3H),1.92–1.75(m,3H),1.61(d,3H),0.75(s,2H),0.52(s,2H).

[1088] Example 38

[1089] 2-Fluoro-3-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-5-methyl-4-(trifluoromethyl)aniline

[1090] first step

[1091] tert-Butyl (5S,5aS,6S,9R)-2-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methylphenyl)-12-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 38b

[1092] Compound 6b (200 mg, 307.6 μmol), 2-fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 38a (200 mg, 407 μmol, using Example 27a and 27b), tetrakistriphenylphosphine palladium (55 mg, 47.6 μmol), cesium carbonate (300 mg, 920.7 μmol) were mixed in 1,4-dioxane (5 mL) and water (1 mL) and reacted at 100 ° C for 1 hour under nitrogen atmosphere. The reaction solution was cooled to room temperature and diluted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 38b (280 mg), which was used in the next step without purification.

[1093] MS m / z(ESI):979.2[M+1].

[1094] Step 2

[1095] (5S,5aS,6S,9R)-2-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-6-iodo-5-methylphenyl)-12-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 38c

[1096] The crude compound 38b (280 mg, 285.91 μmol) was dissolved in N,N-dimethylformamide (DMF) (4 mL), and silver acetate (120 mg, 718.9 μmol) and iodine (145 mg, 571.3 μmol) were added sequentially. The mixture was reacted at 15°C for 1 hour. Water was added to the reaction solution, which was then extracted with ethyl acetate (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 38c (180 mg, yield: 57%).

[1097] MS m / z(ESI):1105.2[M+1].

[1098] Step 3

[1099] tert-Butyl (5S,5aS,6S,9R)-2-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-12-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 38d

[1100] Compound 38c (150 mg, 135.7 μmol) was dissolved in N,N-dimethylformamide (DMF) (1 mL), and cuprous iodide (125 mg, 656.3 μmol) and methyl fluorosulfonyldifluoroacetate (260 mg, 1.4 mmol, Shanghai Bidex) were added sequentially. The reaction was carried out at 100°C for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 38d (80 mg, yield: 57.6%).

[1101] MS m / z(ESI):1047.2[M+1].

[1102] Step 4

[1103] (5S,5aS,6S,9R)-2-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-1-fluoro-12-(1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 38e

[1104] The first to third steps of the synthetic route in Example 36 were used, and the raw material compound 6b in the first step was replaced by compound 38d to obtain the crude title compound 38e (40 mg).

[1105] MS m / z(ESI):1030.2[M+1].

[1106] Step 5

[1107] 2-Fluoro-3-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-5-methyl-4-(trifluoromethyl)aniline

[1108] The crude compound 38e (40 mg, 38.8 μmol) was dissolved in trifluoroacetic acid (1 mL), and trifluoromethanesulfonic acid (0.1 mL) was added under ice bath. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to about 7 with a small amount of saturated sodium bicarbonate solution. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 38 (10 mg, yield: 37.3%).

[1109] MS m / z(ESI):690.2[M+1].

[1110] 1 H NMR (500MHz, CD3OD): δ6.87(d,1H),6.51(d,1H),5.41–5.34(m,1H),4.61–4. 39(m,3H),4.08(t,1H),3.70(d,1H),3.60(s,1H),3.47(q,1H),3.18(d,1H), 2.61–2.29(m,7H),2.21(t,1H),2.07(s,2H),1.83(dd,3H),1.59(dd,3H),1.36(s,3H),0.74(s,2H),0.52(s,2H).

[1111] Example 39

[1112] 3-Chloro-5-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline

[1113] first step

[1114] tert-Butyl (5S,5aS,6S,9R)-2-chloro-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 39a

[1115] The crude compound 36c (50 mg, 81.4 μmol) and 4-(difluoromethylidene)piperidine hydrochloride (54.2 mg, 319 μmol) were dissolved in acetonitrile (5 mL), and anhydrous potassium carbonate (56.3 mg, 407 μmol) and sodium iodide (36.6 mg, 244 μmol) were added. The mixture was stirred at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to give the title compound 39a (50 mg, yield: 94.3%).

[1116] MS m / z(ESI):651.2[M+1].

[1117] Step 2

[1118] (5S,5aS,6S,9R)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-12-((1-(4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 39b

[1119] Compound 39a (50 mg, 76.8 μmol), compound 36d (37 mg, 115 μmol), tetrakistriphenylphosphine palladium (17.7 mg, 15.3 μmol), and cesium carbonate (75 mg, 230 μmol) were mixed in 1,4-dioxane (3 mL) and water (0.5 mL), replaced with nitrogen, and reacted at 100°C for 16 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 39b (60 mg). The product was used directly in the next step without purification.

[1120] MS m / z(ESI):810.2[M+1].

[1121] Step 3

[1122] 3-Chloro-5-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-4-(trifluoromethyl)aniline

[1123] The crude compound 39b (50 mg, 61.7 μmol) was dissolved in dichloromethane (3 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added under ice-bath. The reaction was allowed to return to room temperature for 1 hour, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 39 (4 mg, yield: 9%).

[1124] MS m / z(ESI):710.2[M+1]

[1125] 1 H NMR (500MHz, CD3OD): δ6.90(d,1H),6.56(s,1H),6.42(s,1H),5.38(d,1H),4.44(s,3H),4.10(s,2H),3.71(d,2H) ),3.20(d,1H),2.63(s,5H),2.26–2.05(m,3H),1.82(s,2H),1.59(d,2H),1.31(s,3H),0.77(s,2H),0.56(s,2H).

[1126] Example 40

[1127] 3-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline 40

[1128] first step

[1129] (5S,5aS,6S,9R)-2-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 40a

[1130] The third to fifth steps of the synthetic route in Example 6 were used, and the raw material compound 6c in the third step was replaced by compound 38d to obtain the crude title compound 40a (31 mg).

[1131] MS m / z(ESI):1048.2[M+1].

[1132] Step 2

[1133] 3-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline 40

[1134] The crude compound 40a (31 mg, 19.7 μmol) was dissolved in trifluoroacetic acid (1 mL), and trifluoromethanesulfonic acid (0.1 mL) was added under ice bath. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to about 7 with a small amount of saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 40 (5 mg, yield: 24.6%).

[1135] MS m / z(ESI):708.2[M+1].

[1136] 1 H NMR (500MHz, CD3OD): δ6.87(d,1H),5.38–5.36(m,1H),4.61–4.39(m,3H),4.08(t,1H),3.70(d,1H),3.60(s,1H),3.47(q,1H), 3.18(d,1H),2.61–2.29(m,7H),2.21(t,1H),2.07(s,2H),1.83(dd,3H),1.59(dd,3H),1.35(s,3H),0.74(s,2H),0.52(s,2H).

[1137] Example 41

[1138] 2-Amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 41

[1139] first step

[1140] tert-Butyl (5S,5aS,6S,9R)-2-chloro-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 41a

[1141] The crude compound 36b (30 mg, 48.8 μmol) and 4-(difluoromethylidene)piperidine hydrochloride (12.4 mg, 73.2 μmol) were dissolved in acetonitrile (4 mL), and anhydrous potassium carbonate (20.2 mg, 146.5 μmol) and sodium iodide (22 mg, 146.5 μmol) were added. The mixture was stirred at 80°C for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the crude title compound 41a (31 mg), which was used in the next step without purification.

[1142] MS m / z(ESI):651.2[M+1].

[1143] Step 2

[1144] tert-Butyl (5S,5aS,6S,9R)-2-(2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-12-(1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptane-14-carboxylate 41b

[1145] The crude compound 41a (31 mg, 47.6 μmol), tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (26.9 mg, 66.6 μmol), tetrakis(triphenylphosphine)palladium (11 mg, 9.5 μmol), and cesium carbonate (46.5 mg, 142.8 μmol) were mixed in N,N-dimethylformamide (1 mL) and reacted at 100°C under a nitrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 41b (43 mg), which was used directly in the next step without purification.

[1146] MS m / z (ESI): 907.2 [M+1].

[1147] Step 3

[1148] 2-Amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 41

[1149] Crude compound 41b (40 mg, 44.1 μmol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added. After stirring for 1 hour, the reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to obtain the title compound 41 (2 mg, yield: 6.4%). MS m / z (ESI): 707.2 [M+1]. 1 H NMR (500MHz, CD3OD): δ7.39(dd,1H),7.04(t,1H),5.41(dd,1H),4.91(s,3H),4.54(d,1H),4.48(d,1H),4.39(d,1H),4.10(d,1H),3.71(d,1H), 3.61(s,1H),3.19(d,1H),2.70–2.41(m,5H),2.22(s,3H),2.10(q,2H), 2.01–1.83(m,2H),1.79(d,2H),1.61(d,3H),0.75(s,2H),0.52(s,2H).

[1150] Example 42

[1151] 4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine 42

[1152] first step

[1153] (5S,5aS,6S,9R)-2-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-1-fluoro-12-(1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptane-4-carboxylic acid tert-butyl ester 42b

[1154] Compound 36c (100 mg, 157.9 μmol), N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine 42a (111.4 mg, 205.3 μmol, prepared by the method disclosed in Example 60 on page 244 of the specification of patent application "WO2022042630"), tetrakis(triphenylphosphine)palladium (36.5 mg, 31.6 μmol), cesium carbonate (128.7 mg, 394.8 μmol) and 1,2-dextrin were added. mol) was mixed with 1,4-dioxane (2 mL) and water (0.4 mL), and the mixture was reacted at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System A to give the title compound 42b (160 mg, yield: 99.9%).

[1155] MS m / z (ESI): 1014.1 [M+1].

[1156] Step 2

[1157] 4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine 42

[1158] Compound 42b (15 mg, 157.9 μmol) was dissolved in trifluoroacetic acid (2 mL), reacted at 100° C. for 5 hours, and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was separated and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 42 (30 mg, yield: 28.2%).

[1159] MS m / z(ESI):673.2[M+1].

[1160] 1 H NMR (500MHz, CD3OD): δ6.49(d,1H),5.35(d,1H),4.51(d,1H),4.41(q,2H),4.06(d,1H),3.69(d,1H),3.59(s,1H),3.15(d,1H),2 .57–2.42(m,8H),2.31(s,2H),2.19(d,1H),2.06(s,3H),1.77(d,2H),1.67–1.51(m,4H),0.89(d,1H),0.72(s,2H),0.50(s,2H).

[1161] Example 43

[1162] 2-Fluoro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-3-methyl-4-(trifluoromethyl)aniline

[1163] first step

[1164] 6-Bromo-3-fluoro-2-methyl-4-nitroaniline 43b

[1165] 3-Fluoro-2-methyl-4-nitroaniline 43a (2.2 g, 12.9 mmol, prepared by the method disclosed in EXAMPLE 7 on page 10 of US Patent Application No. 7,626,018) was dissolved in acetonitrile (80 mL). N-bromosuccinimide (2.7 g, 15.5 mmol) was added and stirred at 80°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System B to afford the title compound 43b (2.9 g, 90% yield). MS m / z (ESI): 247.0 [M-1].

[1166] Step 2

[1167] 1-Bromo-4-fluoro-2-iodo-3-methyl-5-nitrobenzene 43c

[1168] Concentrated hydrochloric acid (10 mL) was added to compound 43b (1.5 g, 6.0 mmol) at 0°C, and the temperature was maintained with stirring for 10 minutes. Then, a 2M aqueous sodium nitrite solution (9 mL) was added, and the reaction mixture was stirred at 0°C for 1 hour. Then, a 2M aqueous potassium iodide solution (12 mL) was added, and the temperature was maintained with stirring for 10 minutes. The reaction mixture was heated to 80°C for 1 hour. The reaction solution was cooled to room temperature and quenched with saturated sodium thiosulfate. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the crude title compound 43c (2.1 g), which was used in the next step without purification.

[1169] Step 3

[1170] 5-Bromo-2-fluoro-4-iodo-3-methylaniline 43d

[1171] Compound 43c (2.1 g, 5.83 mmol) was mixed in ethanol (20 mL) and water (40 mL), and iron powder (1.3 g, 23.3 mmol) and ammonium chloride (6 g, 35 mmol) were added. The mixture was stirred at 90°C for 3 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was extracted with dichlorohexane (50 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered out and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 43d (1.5 g, yield: 77.9%).

[1172] MS m / z(ESI):327.9[M-1].

[1173] Step 4

[1174] tert-Butyl (5-bromo-2-fluoro-4-iodo-3-methylphenyl)carbamate 43e

[1175] Compound 43d (0.8 g, 2.42 mmol) was dissolved in 1,4-dioxane (5 mL), and di-tert-butyl dicarbonate (BOC anhydride) (3.7 g, 16.9 mmol) was added. The mixture was stirred at 100°C for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System B to obtain the title compound 43e (1 g, yield: 95.9%). MS m / z (ESI): 427.9 [M-1].

[1176] Step 5

[1177] tert-Butyl (5-bromo-2-fluoro-3-methyl-4-(trifluoromethyl)phenyl)carbamate 43f

[1178] Compound 43e (1.2 g, 2.79 mmol), cuprous iodide (1.32 g, 6.97 mmol), hexamethylphosphoric triamide (1.5 g, 8.37 mmol, Shanghai Shaoyuan), and methyl fluorosulfonyldifluoroacetate (1.6 g, 8.37 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (DMF) (10 mL), replaced with nitrogen, and stirred at 90°C for 2 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was diluted with ethyl acetate and washed with water. The organic phase was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 43f (500 mg, yield: 48.1%).

[1179] MS m / z(ESI):370.0[M-1].

[1180] Step 6

[1181] (5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boric acid 43g

[1182] Compound 43f (391 mg, 1.05 mmol), pinacol diboron (400.2 mg, 1.57 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (76.9 mg, 105.1 μmol), and potassium acetate (309.3 mg, 3.15 mmol) were mixed in dimethyl sulfoxide (5 mL), and the nitrogen atmosphere was replaced three times. The mixture was heated at 100°C for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (10 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 43g (100 mg, yield: 40.1%).

[1183] MS m / z(ESI):237.9[M+1].

[1184] Step 7

[1185] (5S,5aS,6S,9R)-2-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylic acid tert-butyl ester 43h

[1186] Compound 36c (70 mg, 110.5 μmol), compound 43g (26.2 mg, 110.5 μmol), tetrakis(triphenylphosphine)palladium (25.5 mg, 25.2 μmol), and cesium carbonate (108 mg, 331.6 μmol) were mixed in 1,4-dioxane (1 mL) and water (0.2 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to give the title compound 43h (40 mg, 45.8% yield). MS m / z (ESI): 790.2 [M+1].

[1187] Step 8

[1188] 2-Fluoro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-3-methyl-4-(trifluoromethyl)aniline

[1189] Compound 43h (97.7 mg, 123.7 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compound 43 (5 mg, yield: 5.8%).

[1190] MS m / z(ESI):690.2[M+1].

[1191] 1H NMR (500MHz, CD3OD): δ6.87(d,1H),6.52(d,1H),5.38(d,1H),4.57(d,2H),4.53–4.31(m,2H),4.09(d,1H),3.71(s,1H),3.61(s,1H),3 .47(s,1H),3.17(d,2H),2.55(s,5H),2.36(t,4H),2.10(s,3H),1.90–1.76(m,3H),1.60(d,3H),1.33(d,2H),0.75(d,2H),0.53(d,2H).

[1192] Example 44

[1193] 5-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline

[1194] The synthetic route in Example 43 was adopted, and the raw material compound 36c in the seventh step was replaced by compound 41a to obtain the title compound 44 (3 mg, yield: 3.4%).

[1195] MS m / z(ESI):708.2[M+1].

[1196] 1 H NMR (500MHz, CD3OD): δ6.87(d,1H),5.38(d,1H),4.73–4.52(m,2H),4.49–4.35(m,2H),4.08(d,1H),3.71(s,1H),3.61(s,1H),3.17 (d,2H),2.75–2.42(m,5H),2.36(s,3H),2.21(s,3H),2.08(s,1H),1.79(d,4H),1.60(d,3H),1.33(d,2H),0.74(d,2H),0.52(d,2H).

[1197] Example 45

[1198] 4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[1199] The synthetic route in Example 42 was adopted, and the first step raw material compound 36c was replaced by compound 41a to obtain the title compound 45 (20 mg, yield: 25%).

[1200] MS m / z(ESI):691.2[M+1].

[1201] 1 H NMR (500MHz, CD3OD): δ6.36(s,1H),5.37(dd,1H),4.60(s,1H),4.53(dt,1H),4.43(s,2H),4.08(d,1H),3.71(d,1H),3.65– 3.58(m,1H),3.18(d,1H),2.55(d,7H),2.20(d,4H),2.07(d,2H),1.95–1.74(m,3H),1.59(d,3H),0.74(s,2H),0.53(s,2H).

[1202] Biological evaluation

[1203] Test Example 1: Biological Evaluation of ERK Phosphorylation Inhibition Experiment in AGS Cells (HTRF Method)

[1204] 1. Test Purpose

[1205] This experiment detects the inhibitory effect of compounds on cell ERK phosphorylation according to IC 50 The inhibitory effect of the disclosed compounds on KRAS targets was evaluated.

[1206] 2. Experimental Methods

[1207] AGS cells were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium supplemented with 10% fetal bovine serum. On the first day of the experiment, AGS cells were seeded at a density of 40,000 cells / well in a 96-well plate using complete medium, with 190 μL of cell suspension per well. The cells were incubated overnight at 37°C in a 5% CO2 incubator.

[1208] On the second day, 10 μL of a serial dilution of the test compound prepared in complete medium was added to each well. The final concentration of the compound was a five-fold serial dilution starting from 10 μM, with nine concentration points. A blank control containing 0.5% DMSO was set up. The plate was incubated in a cell culture 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 200 μL of PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well for washing. The PBS was aspirated, and 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well. The plate was shaken on a shaker at room temperature for 40 minutes to allow for lysis. After lysis, pipette to mix thoroughly. Transfer 16 μL of lysate per well to two HTRF 96-well assay plates (Cisbio, 66PL96100). Then, add 4 μL of premixed phosphorylated ERK1 / 2 antibody solution (Cisbio, 64AERPEG) or 4 μL of premixed total ERK1 / 2 antibody solution (Cisbio, 64NRKPEG) to each well of each plate. Seal the microplate with sealing film, centrifuge in a microplate centrifuge for 1 minute, and incubate overnight at room temperature in the dark.

[1209] On the third day, a multifunctional microplate reader (PerkinElmer, EnVision) was used to read the fluorescence values ​​at 337 nm excitation wavelength and 665 nm and 620 nm emission wavelengths.

[1210] 3. Data Analysis

[1211] The ratio of the fluorescence signals at 665 nm and 620 nm of phosphorylated ERK1 / 2 and total ERK1 / 2 at each concentration of the compound was calculated, and the IC value of the inhibitory activity of the compound was calculated using Graphpad Prism software based on the phosphorylated ERK1 / 2 ratio corrected by the compound concentration and the total ERK1 / 2 ratio. 50 The results are shown in Table 1 below.

[1212] Table 1 Data on ERK phosphorylation inhibitory activity in AGS cells

[1213] Conclusion: The disclosed compounds have a good inhibitory effect on ERK phosphorylation in AGS cells.

[1214] Test Example 2: Biological Evaluation of GP2d and AGS Cell 3D Proliferation Inhibition Experiment

[1215] 1. Test Purpose

[1216] The inhibitory effect of the disclosed compounds on the KRAS target was evaluated by testing the 3D proliferation inhibitory effect of the disclosed compounds on GP2d and AGS cells.

[1217] 2. Experimental Methods

[1218] GP2d cells were cultured in complete medium (DMEM / high glucose medium (Hyclone, SH30243.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, GP2d cells were seeded at a density of 1000 cells / well in a 96-well low attachment plate (Corning, CLS7007-24EA) using complete medium. 90 μL of cell suspension was added to each well, centrifuged at 2000 rpm for 5 minutes at room temperature, and then incubated overnight at 37°C in a 5% CO2 incubator.

[1219] AGS cells were cultured in complete medium (RPMI1640 medium (Hyclone, SH30809.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, AGS cells were seeded at a density of 1000 cells / well in a 96-well low attachment plate (Corning, CLS7007-24EA) using complete medium. 90 μL of cell suspension was added to each well. The cells were centrifuged at 2000 rpm for 5 minutes at room temperature and then incubated overnight at 37°C in a 5% CO2 incubator.

[1220] On the second day, 10 μL of a serial dilution of the test compound prepared in complete culture medium was added to each well. The final concentration of the compound for GP2d cells was 9 concentration points of a 5-fold serial dilution starting from 1 μM, and the final concentration of the compound for AGS cells was 9 concentration points of a 5-fold serial dilution starting from 10 μM. A blank control containing 0.5% DMSO was set up for both. The well plate was placed in a cell culture incubator at 37°C and 5% CO2 for 5 days. On the seventh day, the 96-well cell culture plate was removed and 50 μL of the test compound was added to each well. 3D Cell Viability Assay reagent (Promega, G9682) was shaken at room temperature in the dark for 25 minutes, then pipetted to mix thoroughly and 100 μL was transferred from each well to a white opaque 96-well plate (PerkinElmer, 6005290). The luminescence signal was read using a multi-function microplate reader (PerkinElmer, EnVision2105).

[1221] 3. Data Analysis

[1222] The IC of the inhibitory activity of the compounds was calculated using Graphpad Prism software 50 The results are shown in Table 2 below.

[1223] Table 2 3D proliferation inhibitory activity data of AGS and GP2d cells

[1224] Conclusion: The disclosed compounds have a good inhibitory effect on the 3D proliferation of AGS and GP2d cells.

[1225] Test Example 3: Biological Evaluation of AsPC-1 Cell 3D Proliferation Inhibition Experiment

[1226] On the first day of the experiment, well-grown AsPC-1 cells reaching 70%-80% confluence were digested and resuspended in RPMI 1640 (Hyclone, SH30809.01) supplemented with 10% FBS. The cell density was adjusted to the desired level. 90 μL of the cell suspension was added to each well of a U-shaped low-adhesion 96-well plate (Corning, CLS7007-24EA) for a cell density of 1500 cells / well. The plate was centrifuged at 2500 rpm for 5 minutes and incubated overnight in a 37°C, 5% CO2 incubator. On the second day, a 20 mM DMSO-dissolved test compound was diluted with DMSO to a starting concentration of 2 mM. This was then serially diluted 5-fold to a total of nine concentration points, with DMSO as a control. The serially diluted compound was then further diluted 20-fold with culture medium. 10 μL of the test compound diluted with culture medium was added to each well of the plate for a final concentration of 10 μM starting at the 10-fold concentration and then serially diluted to nine concentration points. The cell wells containing 0.5% DMSO were set as the solvent control wells, and the wells containing only culture medium and 0.5% DMSO were set as blank control wells. Each concentration of compound and control wells were set up in duplicate, and the final DMSO concentration in each well was 0.5%. After centrifugation at 2500 rpm for 3 minutes, the cell plate was placed in a 37°C, 5% CO2 incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed and 50 μL of luminescent cell activity detection reagent was added to each well. 3D Cell Viability Assay (Promega, G9683) was shaken in the dark at room temperature for 25 minutes. After mixing by pipetting up and down, 100 μL was transferred to each well of the white opaque OptiPlate. TM -96-well plate (PerkinElmer, 6005290), and the luminescence signal value was read using a multi-function microplate reader (PerkinElmer, EnVision2105).

[1227] The inhibition rate was calculated using the following formula: Inhibition rate = (luminescence value 溶媒对照孔 - Luminous value 受试化合物 ) / (luminous value 溶 媒对照孔 - Luminous value 空白对照孔) × 100%. GraphPad Prism software was used to draw a curve based on the concentration of the compound and the corresponding inhibition rate, and the IC of the compound was calculated. 50 value.

[1228] Table 3. AsPC-1 cell 3D proliferation inhibitory activity data

[1229] Conclusion: The disclosed compounds have a good inhibitory effect on the 3D proliferation of AsPC-1 cells.

[1230] Test Example 4: Pharmacokinetic Evaluation

[1231] 1. Abstract

[1232] Balb / c nude mice were used as test animals. The plasma drug concentrations of the example compounds at different time points after gavage (ig) were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compounds in balb / c nude mice was studied and their pharmacokinetic characteristics were evaluated.

[1233] 2. Experimental plan

[1234] 2.1. Investigational Drugs

[1235] Compounds 37 and 39.

[1236] 2.2 Experimental Animals

[1237] Eighteen female BALB / c nude mice were divided equally into two groups and provided by Weitonglihua Laboratory Animal Technology Co., Ltd. with production license SCXK (Zhejiang) 2019-0001.

[1238] 2.3 Drug preparation

[1239] A certain amount of the test compound was weighed and added with 5% DMF + 45% PG + 50% (10% HS15-pH7.4 buffer) + 400 mpk SNAC to prepare a 4 mg / mL colorless clear solution.

[1240] 2.4 Drug Administration

[1241] The dosage was 40.0 mg / kg, and the administration volume was 10 mL / kg.

[1242] 3. Operation

[1243] Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, collect 0.1 mL of blood from the eye socket and place it in an EDTA-K2 anticoagulant tube. Centrifuge at 10,000 rpm for 1 minute (4°C). Separate the plasma within 1 hour and store at -20°C until testing. The entire process from blood collection to centrifugation should be performed in an ice bath.

[1244] Determination of the test compound content in balb / c nude mouse plasma after administration of various drug concentrations: 25 μL of balb / c nude mouse plasma samples were collected at various times after administration, mixed with 200 μL of acetonitrile containing an internal standard (compound 37: internal standard verapamil 100 ng / mL; compound 39: internal standard diclofenac 100 ng / mL). The mixture was vortexed for 5 minutes and centrifuged at 3700 rpm for 20 minutes. The supernatant was mixed with water (1:1 ratio). 0.5-2 μL of the supernatant was then aliquoted for LC / MS / MS analysis.

[1245] 4. Pharmacokinetic parameter results

[1246] Table 4. Pharmacokinetic parameters of the disclosed compounds in balb / c nude mice

[1247] Conclusion: The disclosed compounds have good pharmacokinetic advantages in balb / c nude mice.

Claims

1. A compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof: in: Ring C is a heterocyclic group; R x1 is a hydrogen atom or R x ; R x Selected from =NOR 61 、=CR 62 R 63 Sum = NR 64 ; G 0 Selected from O, S, S(O), S(O)2, CR G0a R G0b and NR G0c ; G 1 selected from CR G1a R G1b 、CR G1a R G1b CR G1c R G1d 、C=O and C(O)CR G1a R G1b ; G 2 NR d ; T is a chemical bond or selected from CR a R b NR T and O; Q is N or CR 2a ; Ring A is an aryl group or a heteroaryl group; L is selected from a single bond, O and NR e ; R a 、R b 、R G0a 、R G0b 、R G1a 、R G1b 、R G1c and R G1d are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; or, R G1a 、R G1b Together with the attached carbon atom, they form a cycloalkyl group; or, R G1c 、R G1d Together with the attached carbon atom, it forms a cycloalkyl group; Each R 1 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) u -NR f R g , hydroxyl and hydroxyalkyl; R 2a and R 4a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) v -NR h R i , hydroxy, hydroxyalkyl and cycloalkyl; Each R 3 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) w -NR j R k 、-(CH2) w1 -(O) x1 -C(O)NR j1 R k1 、-(CH2) w2 -(O) x2 -C(O)OR j2 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; Each R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) y -NR m R n 、-(CH2) y1 -(O) z1 -C(O)NR m1 R n1 、-(CH2) y2 -(O) z2 -C(O)OR m2 、=NOR 61 、=CR 62 R 63 、=NR 64 、 nitro, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 61 、R 62 、R 63 and R 64 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl; R 5a and R 5b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl; or R 5a 、R 5b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted with one or more substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl; R G0c 、R T 、R d 、R e 、R f 、R g 、R h 、R i 、R j 、R k 、R j1 、R k1 、R j2 、R m 、R n 、R m1 、R n1 and R m2 are the same 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 heterocyclic group, an aryl group, and a heteroaryl group; u, v, w, w1, w2, y, y1 and y2 are the same or different and are each independently selected from 0, 1, 2 and 3; x1, x2, z1 and z2 are the same or different and are each independently selected from 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 t1 is 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein G 1 CR G1a H, R G1a As defined in claim 1; preferably, G 1 CR G1a H, R G1a It is a methyl group.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G 0 It is O.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Selected from R 61 、R 62 、R 63 and R 64 As defined in claim 1.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II') or a pharmaceutically acceptable salt thereof: in, R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH2) y -NR m R n 、-(CH2) y1 -(O) z1 -C(O)NR m1 R n1 、-(CH2) y2 -(O) z2 -C(O)OR m2 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R 6a and R 6e and the carbon atom to which it is connected, R 6a and R 6g and the carbon atom to which it is connected, R 6c and R 6e and the carbon atom or R 6c and R 6g Together with the carbon atoms to which it is attached, it forms a bridge, said bridge having 1, 2, 3 or 4 CH2, any one of which may be optionally replaced by O, S or NH, said bridge being optionally substituted by one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; or R 6a and R 6b and the carbon atom to which it is connected, R 6c and R 6d and the carbon atom to which it is connected, R 6e and R 6f and the carbon atom or R 6g and R 6h Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl; Ring A, G 2 , Q, L, R G1a 、R 1 、R 3 、R 4a 、R m 、R n 、R m1 、R n1 、R m2 , y, y1, y2, z1, z2, p and q are as defined in claim 1; preferably, R G1a C 1-6 alkyl. 6 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is N.

7. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV') or (VV') or a pharmaceutically acceptable salt thereof: in, R x Selected from =NOR 61 、=CR 62 R 63 Sum = NR 64 ; R 61 、R 62 、R 63 and R 64 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl; t is 0, 1, 2, 3, or 4; R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; Ring B is a heterocyclic group; R x1 , t1, ring C, G 2 , Q, L, R G1a 、R 1 、R 4a 、R 6 and p as defined in claim 1; preferably, R G1a C 1-6 alkyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring A is selected from naphthyl, phenyl, pyridyl, benzothienyl, benzothiazolyl and benzopyrazolyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 4a is a hydrogen atom or a halogen.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein G 2 For NH.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein L is O. 12 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 0.

13. A compound according to any one of claims 1 to 6, 8 to 12, or a pharmaceutically acceptable salt thereof, wherein each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, -OC(O)NHC 1-6 Alkyl, amino, cyano, C 1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, -OC(O)NHC 1-6 Alkyl, amino and cyano groups.

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, which is the following compound:

15. A compound represented by the general formula (IN'A) or a salt thereof: in, R is an amino protecting group; preferably Boc; R y is a hydroxyl protecting group; preferably MOM; a is 0, 1, 2, 3, or 4; G 0 , G 1 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, t1 and r are as defined in claim 1.

16. A compound or a salt thereof, which is:

17. A method for preparing a compound represented by general formula (IN') or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IN'A) or its salt is subjected to deprotection reaction to obtain the compound of general formula (IN') or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for adding protective groups to groups; in, R is an amino protecting group; preferably Boc; R y is a hydroxyl protecting group; preferably MOM; a is 0, 1, 2, 3, or 4; G 2 for NH; G 0 , G 1 , T, Ring A, Ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 , p, t1 and r are as defined in claim 1.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

19. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for inhibiting KRAS G12D.

20. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a medicament for treating and / or preventing a disease or condition mediated by KRAS G12D.

21. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a medicament for treating and / or preventing a tumor; wherein the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial 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 glioblastoma; more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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