Pyrimidine fused ring compound as well as preparation method and application thereof

Abstract

The invention discloses a pyrimidine fused ring compound with an inhibiting effect on KRAS gene mutation or a pharmaceutically acceptable salt, a stereoisomer or a solvate of the pyrimidine fused ring compound. In addition, the invention further discloses a pharmaceutical composition containing the compound and application of the pharmaceutical composition in preparation of cancer drugs.

Description

Pyrimidocyclic compounds and their preparation and use Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a class of pyrimidocyclic compounds and a preparation method and use thereof. Background Art

[0002] KRAS is a 21kD member of the Ras family of GTPase proteins and is an essential component for cell signaling. The role of KRAS in malignant tumors and its mutations in various tumor types (such as G12C mutations, G12D mutations, G12V mutations, etc.) are already known to the public, so KRAS has become a very attractive target for cancer treatment in the pharmaceutical industry. Compounds that inhibit KRAS activity are highly sought after by researchers in this field and are under intense research. At present, there have been breakthroughs in this field for KRAS G12C. For example, the KRAS G12C inhibitors of AMG and MIRATI have shown sufficient safety and efficacy. However, there is still a continued interest and effort in developing KRAS inhibitors, especially inhibitors that activate KRAS mutants, especially KRAS G12D.

[0003] Summary of the Invention

[0004] The present invention provides a class of novel pyrimidocyclic compounds that will act as KRAS G12D inhibitors, with advantages such as high activity, good selectivity, and low toxicity and side effects. The present invention also provides a class of novel pyrimidocyclic compounds that will act as KRAS G12D inhibitors, with improved bioavailability and higher AUC.

[0005] The first aspect of the present invention provides a compound represented by formula (A) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

[0006] Where,

[0007] X is O, S or NR 11 ; Among them, R 11 is selected from H, C1-C6 alkyl, C1-C6 deuterated alkyl and cycloalkyl;

[0008] Y is CR 12 R 13 , CR 14 R 15 CR 16 R 17 , C(O) or C(O)CR 18 R 19 ;in,

[0009] R 12 、R13 Each is independently selected from H, halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl, heterocyclyl-O-, aryl, heteroaryl, aryl-O-, heteroaryl-O-, -C1-C4 alkyl-C1-C6 alkoxy, -C1-C4 alkyl-C1-C6 haloalkoxy, -C1-C4 alkyl-hydroxy, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121 R 122 ; or R 12 、R 13 Together with the carbon atoms to which they are attached, they form a cycloalkyl group;

[0010] R 14 and R 15 Each is independently selected from H, nitro, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl, heterocyclyl-O-, aryl, heteroaryl, aryl-O-, heteroaryl-O-, -C1-C4 alkyl-C1-C6 alkoxy, -C1-C4 alkyl-C1-C6 haloalkoxy, -C1-C4 alkyl-hydroxy, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121 R 122 ; or R 14 、R 15 Together with the carbon atoms to which they are attached, they form a cycloalkyl group;

[0011] R 16 、R 17 Each is independently selected from H, halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl, heterocyclyl-O-, aryl, heteroaryl, aryl-O-, heteroaryl-O-, -C1-C4 alkyl-C1-C6 alkoxy, -C1-C4 alkyl-C1-C6 haloalkoxy, -C1-C4 alkyl-hydroxy, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121 R 122 ;

[0012] R 18 、R 19 Each independently selected from H, C1-C3 alkyl and halogen;

[0013] R 121 、R 122 Each independently selected from H, C1-C3 alkyl; or R121 、R 122 Together with the nitrogen atom to which they are connected, they form a 3- to 6-membered nitrogen-containing heterocyclic group;

[0014] wherein the cycloalkyl group, the heterocyclic group, the aryl group, the heteroaryl group, and the 3- to 6-membered nitrogen-containing heterocyclic group are each independently optionally substituted by a group selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy;

[0015] W is N or CR 20 ; Among them, R 20 is H, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl or heterocyclyl-O-; wherein the cycloalkyl and heterocyclyl are each independently optionally substituted by halogen;

[0016] Ring A (herein, Ring A refers to ) is selected from the group consisting of aryl, heteroaryl;

[0017] R 1 is a substituent at any position on ring A; n1 is 0, 1, 2, 3, 4 or 5;

[0018] Each R 1 Each is independently selected from: C1-C6 alkyl, halogen, hydroxy, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25 、N=S(O)(C1-C6 alkyl)2、S(O)C1-C6 alkyl、S(O)2R 26 , -S-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, C1-C6 cyanoalkyl, triazolyl, -S-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -CH2C(O)NR 27 R 28 , -C2-C6 alkynyl-NR 29 R 30 , C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C6 alkyl; wherein,

[0019] R 21is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O)OC1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1-C6 haloalkyl; or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0020] R 23 、R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0021] R 25 For hydroxyl, cyano, heterocyclic, NR 251 R 252 、C(O)NR 253 R 254 or SO2C1-C6 alkyl; wherein R 251 、R 252 、R 253 、R 254 are each independently H or C1-C6 alkyl; or R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; or R 253 、R 254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0022] R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C6 alkyl; or R 261 、R 262Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0023] R 27 、R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0024] R 29 、R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0025] Z is N or CR 2 ; Among them, R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, NR 31 R 32 , C2-C4 alkynyl or CH2OR 33 ; Among them, R 31 、R 32 are each independently hydrogen or C1-C6 alkyl; or R 31 、R 32 Together with the nitrogen atom to which they are connected, they form a 3- to 6-membered nitrogen-containing heterocyclic group; R 33 is hydrogen or C1-C6 alkyl;

[0026] R 3a 、R 3b 、R 3c are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or

[0027] R 3a With R 3b Connected to form -CHR 3a1 -or-CHR 3a2 CHR 3a3 -;R 3cis hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3a1 、R 3a2 、R 3a3 are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or

[0028] R 3a With R 3c Connected to form -CHR 3a1 -or-CHR 3a2 CHR 3a3 -;R 3b is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3a1 、R 3a2 、R 3a3 Each is independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;

[0029] L3 is a bond, O or NR 34 ;

[0030] R 6 is -L-6 to 10-membered fused heterocyclyl, -L-7 to 11-membered spiroheterocyclyl, -L-spiro-substituted 6 to 10-membered fused heterocyclyl, -L-spiro-substituted 7 to 11-membered spiroheterocyclyl, -L-parallel-substituted 6 to 10-membered fused heterocyclyl, -L-parallel-substituted 7 to 11-membered spiroheterocyclyl, or -L-spiro- and parallel-substituted 6 to 10-membered fused heterocyclyl;

[0031] The spiro-substituted 6- to 10-membered fused heterocyclic group refers to a 6- to 10-membered fused heterocyclic group in which two hydrogen atoms on the same carbon atom in any one or two carbon atoms are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a spiro-substituted 6- to 10-membered fused heterocyclic group;

[0032] The spiro-substituted 7- to 11-membered spiro heterocyclic group refers to a 7- to 11-membered spiro heterocyclic group in which two hydrogen atoms on the same carbon atom of any one or two carbon atoms are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2)m8 substituted to form a spiro-substituted 7- to 11-membered spiroheterocyclyl;

[0033] The 6- to 10-membered fused heterocyclic group substituted with a ring is a 6- to 10-membered fused heterocyclic group in which one hydrogen atom on each carbon atom in any one or two pairs of adjacent carbon atoms is replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substituted to form a 6- to 10-membered fused heterocyclic group that is substituted with a ring; or the 6- to 10-membered fused heterocyclic group that is substituted with a ring refers to a 6- to 10-membered fused heterocyclic group in which the hydrogen atoms on any two non-adjacent carbon atoms of the 6- to 10-membered fused heterocyclic group are replaced with -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a 6- to 10-membered fused heterocyclic group;

[0034] The 7- to 11-membered spiro heterocyclic group substituted with a ring is a 7- to 11-membered spiro heterocyclic group in which one hydrogen atom on each carbon atom in any one or two pairs of adjacent carbon atoms is replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substituted to form a 7- to 11-membered spiro heterocyclic group that is substituted with a ring; or the 7- to 11-membered spiro heterocyclic group that is substituted with a ring refers to a 7- to 11-membered spiro heterocyclic group in which the hydrogen atoms on any two non-adjacent carbon atoms of the 7- to 11-membered spiro heterocyclic group are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a 7- to 11-membered spiroheterocyclyl group;

[0035] The 6- to 10-membered fused heterocyclic group substituted by the spiro ring and the fused heterocyclic group refers to a 6- to 10-membered fused heterocyclic group in which one hydrogen atom on each carbon atom of any pair of adjacent carbon atoms is replaced by -(CH2) at the same time. m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7NR n (CH2) m8 Substitution to form a ring substitution and the two hydrogen atoms on the other carbon atom of the 6- to 10-membered fused heterocyclic group are simultaneously replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substitution to form spiro substitution, further forming spiro and cyclosubstituted 6 to 10 membered fused heterocyclic groups;

[0036] The 6- to 10-membered fused heterocyclic group and the 7- to 11-membered spiro heterocyclic group each independently have 1, 2, 3 or 4 groups selected from N(R m ), S, S(=O), S(=O)2, O heteroatoms as ring atoms;

[0037] The spiro-substituted 6- to 10-membered fused heterocyclic group, the spiro-substituted 7- to 11-membered spiro heterocyclic group, the 6- to 10-membered fused heterocyclic group substituted with a ring, the 7- to 11-membered spiro heterocyclic group substituted with a ring, the spiro- and 6- to 10-membered fused heterocyclic group substituted with a ring each independently have 1, 2, 3, 4 or 5 groups selected from N(R m ), S, S(=O), S(=O)2, O heteroatoms as ring atoms;

[0038] R n is hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3-20 membered heterocyclyl;

[0039] R m is none, hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl, or 3-20 membered heterocyclyl;

[0040] wherein the 6- to 10-membered fused heterocyclic group and the 7- to 11-membered spiro heterocyclic group are each independently saturated or partially unsaturated; when the 6- to 10-membered fused heterocyclic group and the 7- to 11-membered spiro heterocyclic group are partially unsaturated, the ring has one or two double bonds;

[0041] The two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group (the 6- to 10-membered fused heterocyclic group refers to a -L-6- to 10-membered fused heterocyclic group, a -L-spiro-substituted 6- to 10-membered fused heterocyclic group, a -L-parallel-substituted 6- to 10-membered fused heterocyclic group, or a 6- to 10-membered fused heterocyclic group in a -L-spiro- and parallel-substituted 6- to 10-membered fused heterocyclic group) are optionally replaced by ═CR 2a R 2bSubstituted; the 6 to 10 membered fused heterocyclic group is optionally further substituted by one or more R 6a replace;

[0042] The two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 7- to 11-membered spiroheterocyclyl (the 7- to 11-membered spiroheterocyclyl refers to the 7- to 11-membered spiroheterocyclyl in -L-7- to 11-membered spiroheterocyclyl, -L-spiro-substituted 7- to 11-membered spiroheterocyclyl or -L- and cyclo-substituted 7- to 11-membered spiroheterocyclyl) are optionally replaced by ═CR 2a R 2b Substituted; the 7 to 11 membered spiro heterocyclic group is optionally further substituted by one or more R 6a replace;

[0043] Among them, R 2a 、R 2b are each independently hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C6-C10 aryl or 5-membered or 6-membered heteroaryl; the C6-C10 aryl or 5-membered or 6-membered heteroaryl is optionally substituted by 1, 2 or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; or each pair of R 2a 、R 2b Each independently forms together with the connected carbon atom a C3-C6 monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group; the C3-C6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, or a 5- or 6-membered monocyclic heteroaryl;

[0044] Each R 6a Each is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, cyano, -Q-phenyl, -Q-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R 6b )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O)-, oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 6b)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 6b )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -C1-C3 alkyl-OC(O)heterocyclyl, -OC(O)N(R 6b )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl, -OC(O)C1-C6 alkyl, -OC(O)C1-C6 haloalkyl, -C1-C3 alkyl-OC(O)C1-C6 alkyl, -C1-C3 alkyl-OC(O)C1-C6 haloalkyl, -OC(O)phenyl, -C1-C3 alkyl-OC(O)phenyl or -CH2heterocyclyl; wherein the phenyl involved in the above groups is optionally substituted by -C(O)H or OH; the heterocyclyl in the -C1-C3 alkyl-heterocyclyl is optionally substituted by oxo; Q is a bond or O; each of the above R 6b are each independently hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl; or two R 6b Each independently forms together with the nitrogen atom to which they are attached a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; the C3-C6 cycloalkyl group is optionally substituted by 1 or 2 C1-C6 alkyl groups;

[0045] Each m4 is 2, 3 or 4;

[0046] Each m5, m6, m7, and m8 are independently 0, 1, 2, or 3; m5 and m6 are not 0 at the same time; m7 and m8 are not 0 at the same time;

[0047] or

[0048] R 6 is hydrogen, -N(R 34 )2, heterocyclic group, cycloalkyl group, C1-C6 alkyl group, -L-heterocyclic group, -L-aryl group, -L-heteroaryl group, -L-cycloalkyl group, -LN(R 34 )2, -L-NHC(=NH)NH2, -LC(O)N(R 34 )2, -L-C1-C6 haloalkyl, -L-OR 34 、-L-(CH2OR 34 )(CH2) n OR 34、-L-NR 34 C(O)-aryl, -L-COOH or -LC(O)OC1-C6 alkyl; wherein the heterocyclic group, the cycloalkyl group, the -L-NR 34 The aryl group in C(O)-aryl, the heterocyclyl group in said -L-heterocyclyl, and the cycloalkyl group in said -L-cycloalkyl may each be optionally replaced by one or more R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the aryl group in the -L-aryl group and the heteroaryl group in the -L-heteroaryl group may each be optionally replaced by one or more R 36 replace;

[0049] wherein each L is independently a bond, a C1-C4 alkylene group or a heteroaryl group; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene group are optionally independently substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenylene or C2-C4 haloalkenylene; or wherein two hydrogen atoms on any same carbon atom of the C1-C4 alkylene group are optionally simultaneously substituted by -(CH2) m3 -、-(CH2) m1 -O-(CH2) m2 -、-(CH2) m1 -NR 9 -(CH2) m2 -substituted to form a cyclic substituent; m3 is 1 or 2; each m1 is independently 0, 1, 2 or 3; each m2 is independently 0, 1, 2 or 3; and m1 and m2 are not 0 at the same time;

[0050] R 9 is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkyl-hydroxy, C1-C6 alkyl-cyano, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C3-C6 monocyclic cycloalkyl, C3-C6 deuterated cycloalkyl or C3-C6 halocycloalkyl;

[0051] Each R 35Each is independently halogen, hydroxy, C1-C3 alkyl, C2-C4 alkenylene, C2-C4 haloalkenylene, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -C1-C3 alkyl-C1-C3 alkoxy, -C1-C3 alkyl-hydroxy, heterocyclyl (e.g., 3- to 6-membered heterocyclyl), cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl (e.g., -OC(O)-3 to 6 membered heterocyclyl) or -CH2heterocyclyl (e.g., - -CH2-3 to 6-membered heterocyclyl); wherein the phenyl group in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted by -C(O)H or OH; the heterocyclyl group in the -CH2 heterocyclyl is optionally substituted by oxo; the hydrogen atom on the -C1-C3 alkyl- is substituted by one or two groups selected from halogen, deuterium, C1-C3 alkyl, and C1-C3 haloalkyl;

[0052] Each R 36 Each is independently halogen, hydroxy, HC(O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl or -N(R 34 )2;

[0053] Each R 34 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0054] In one embodiment, each R 6a Each is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, cyano, -Q-phenyl, -Q-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R 6b )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O)-, oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 6b )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 6b )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -C1-C3 alkyl-OC(O)heterocyclyl, -OC(O)N(R 6b )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl, -OC(O)C1-C6 alkyl, -OC(O)C1-C6 haloalkyl, -C1-C3 alkyl-OC(O)C1-C6 alkyl, -C1-C3 alkyl-OC(O)C1-C6 haloalkyl, -OC(O)phenyl, -C1-C3 alkyl-OC(O)phenyl or -CH2heterocyclyl; wherein the phenyl involved in the above groups is optionally substituted by -C(O)H or OH; the heterocyclyl in the -C1-C3 alkyl-heterocyclyl is optionally substituted by oxo; Q is a bond or O; each of the above R 6b are each independently hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl; or two R 6bEach independently forms a 3- to 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are connected, and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; the C3-C6 cycloalkyl group is optionally substituted by 1 or 2 C1-C6 alkyl groups.

[0055] In one embodiment, each R 6a Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C2-C4 alkenyl, halo-C2-C4 alkenyl, C2-C4 alkynyl, halo-C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkyl, cyano, -Q-phenyl, -Q-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R 6b )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O)-, oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 6b )2, -CH2NHC(O)OC1-C3 alkyl, -CH2NHC(O)N(R 6b )2, -CH2NHC(O)C1-C3 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C3 alkyl, -C1-C3 alkyl-OC(O)heterocyclyl, -OC(O)N(R 6b )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl, -OC(O)C1-C3 alkyl, -OC(O)C1-C3 haloalkyl, -C1-C3 alkyl-OC(O)C1-C3 alkyl, -C1-C3 alkyl-OC(O)C1-C3 haloalkyl, -OC(O)phenyl, -C1-C3 alkyl-OC(O)phenyl or -CH2heterocyclyl; wherein the phenyl involved in the above groups is optionally substituted by -C(O)H or OH; the heterocyclyl in the -C1-C3 alkyl-heterocyclyl is optionally substituted by oxo; Q is a bond or O; each of the above R 6b are each independently hydrogen, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or two R 6bEach independently forms a 3- to 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are connected, and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; the C3-C6 cycloalkyl group is optionally substituted by 1 or 2 C1-C6 alkyl groups.

[0056] In one embodiment, each R 6a Each is independently halogen, hydroxy, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, cyano, -N(R 6b )2; wherein each of the above R 6b are each independently hydrogen, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or two R 6b Each independently forms a 3- to 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom to which they are connected, and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; the C3-C6 cycloalkyl group is optionally substituted by 1 or 2 methyl groups.

[0057] In one embodiment, each R 6a Each is independently halogen, hydroxy, methyl, ethyl, propyl, vinyl, halogenated vinyl (e.g., monofluorovinyl, difluorovinyl, etc.), ethynyl, propynyl, halogenated methyl, halogenated ethyl, cyclopropyl, cyano, -N(R 6b )2; wherein each of the above R 6b are each independently hydrogen or methyl; the cyclopropyl group is optionally substituted with 1 or 2 methyl groups.

[0058] In one embodiment, the compound is represented by formula (I):

[0059] Where,

[0060] X, Y, W, Ring A, R 1 、n1、R 2 The respective definitions are the same as before;

[0061] R 3a 、R 3b 、R 3c Each is independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;

[0062] L1 is a bond, O or NR 34 ;

[0063] L2 is C1-C4 alkylene or heteroaryl; wherein, one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene are optionally independently substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously substituted by -(CH2) m3 -、-(CH2) m1 -O-(CH2) m2 -、-(CH2) m1 -N-(CH2) m2 -substituted to form a cyclic substituent; m3 is 1 or 2; each m1 is independently 0, 1, 2 or 3; each m2 is independently 0, 1, 2 or 3; and m1 and m2 are not 0 at the same time;

[0064] Ring B is a 3- to 6-membered nitrogen-containing heterocyclic group;

[0065] Ring C is a 3- to 6-membered nitrogen-containing heterocyclic group;

[0066] R 4 is a substituent at any position on ring B; n2 is 0, 1, 2 or 3;

[0067] R 5 is a substituent at any position on ring C; n3 is 0, 1, 2 or 3;

[0068] R 4 、R 5 The definition is as follows:

[0069] (a) Each R 4 , each R 5 Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C4 alkenylene, C2-C4 haloalkenylene, cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH; the heterocyclyl in -CH2heterocyclyl is optionally substituted with oxo; or

[0070] (b) 1 R 4 is -CH2CH2- or -CH2CH2CH2- and together with the carbon atom to which it is attached constitutes a cyclopropyl or cyclobutyl group; the remaining R 4 , each R 5 Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C4 alkenylene, C2-C4 haloalkenylene, cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH; the heterocyclyl in -CH2heterocyclyl is optionally substituted with oxo; or

[0071] (c) 1 R 5 is -CH2CH2- or -CH2CH2CH2- and together with the carbon atom to which it is attached constitutes a cyclopropyl or cyclobutyl group; the remaining R 5 , each R 4 Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C4 alkenylene, C2-C4 haloalkenylene, cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH; the heterocyclyl in -CH2heterocyclyl is optionally substituted with oxo; or

[0072] (d) 1 R 4 -CH2CH2- or -CH2CH2CH2- and together with the carbon atom to which it is attached constitutes a cyclopropyl or cyclobutyl group; 1 R 5 is -CH2CH2- or -CH2CH2CH2- and together with the carbon atom to which it is attached constitutes a cyclopropyl or cyclobutyl group; the remaining R 4 、The rest R 5 Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenylene, C2-C4 haloalkenylene, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH; the heterocyclyl in the -CH2heterocyclyl is optionally substituted with oxo;

[0073] Each R 34 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0074] In one embodiment, the compound is represented by formula (II):

[0075] In the formula, X, Y, W, ring A, R 1 、n1、R 2 , L3, R 6 The respective definitions are the same as before;

[0076] R 3a With R 3b Connected to form -CHR 3a1 -or-CHR 3a2 CHR 3a3 -;R 3c is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3a1 、R 3a2 、R 3a3 are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or

[0077] R 3a With R 3c Connected to form -CHR 3a1 -or-CHR 3a2 CHR 3a3 -;R 3b is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3a1 、R 3a2 、R 3a3 Each is independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl.

[0078] In one embodiment, the compound is represented by formula (II-1) or formula (II-2):

[0079] In each formula, q is 1 or 2; R 3 is a bridge ring (in this article, R 3 The bridge ring is usually referred to as The substituents at any position on the ) are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 1 , n1, ring A, R 2 , X, Y, W, L3, R 6 The respective groups are as defined above.

[0080] In one embodiment, the compound is represented by formula (III):

[0081] In the formula, X, Y, W, ring A, R 1 、n1、L3、R 6 The respective definitions are the same as before;

[0082] R 3d 、R 3e 、R 3f are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or

[0083] R 3d With R 3e Connected to form -CHR 3d1 -or-CHR 3d2 CHR 3d3 -;R 3f is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3d1 、R 3d2 、R 3d3 are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or

[0084] R 3d With R 3f Connected to form -CHR 3f1 -or-CHR 3f2 CHR 3f3 -;R 3e is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3f1 、R 3f2 、R 3f3 Each is independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl.

[0085] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

[0086] Wherein, X is O or NR 11 ; Among them, R 11 Selected from H and C1-C6 alkyl;

[0087] Y is CR 12 R 13 , CR 14 R 15 CR 16 R 17, C(O) or C(O)CR 18 R 19 ; Among them, R 12 、R 13 、R 14 and R 15 R is independently selected from H, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; 16 、R 17 、R 18 、R 19 Each independently selected from H, C1-C3 alkyl and halogen;

[0088] W is N or CR 20 ; Among them, R 20 is H, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl or heterocyclyl-O-; wherein the cycloalkyl and heterocyclyl are each independently substituted by halogen;

[0089] Ring A is selected from the group consisting of aryl, heteroaryl;

[0090] R 1 is a substituent at any position on ring A; each R 1 Each is independently selected from: C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25 、N=S(O)(C1-C6 alkyl)2、S(O)C1-C6 alkyl、S(O)2R 26 , -S-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, C1-C6 cyanoalkyl, triazolyl, -S-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -CH2C(O)NR 27 R 28 、-C2-C6 alkynyl NR 29 R 30 , C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C6 alkyl; wherein,

[0091] R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O)OC1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1-C6 haloalkyl; or R21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0092] R 23 、R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0093] R 25 For hydroxyl, cyano, heterocyclic, NR 251 R 252 、C(O)NR 253 R 254 or SO2C1-C6 alkyl; wherein R 251 、R 252 、R 253 、R 254 Each independently represents H or C1-C6 alkyl; R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253 、R 254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0094] R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C6 alkyl; or R 261 、R 262 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0095] R 27 、R 28are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0096] R 29 、R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0097] n1 is 0, 1, 2, or 3;

[0098] R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, NR 31 R 32 , C2-C4 alkynyl or CH2OR 33 ; Among them, R 31 、R 32 、R 33 Each is independently hydrogen or C1-C6 alkyl;

[0099] R 3a 、R 3b 、R 3c Each is independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;

[0100] L1 is a bond, O or NR 34 ;

[0101] L2 is C1-C4 alkylene or heteroaryl; wherein, one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene are optionally independently substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously substituted by -(CH2) m3 -、-(CH2) m1 -O-(CH2) m2 -、-(CH2) m1 -N-(CH2) m2-substituted to form a cyclic substituent; m3 is 1 or 2; each m1 is independently 0, 1, 2 or 3; each m2 is independently 0, 1, 2 or 3; and m1 and m2 are not 0 at the same time;

[0102] Ring B is a 3- to 6-membered nitrogen-containing heterocyclic group;

[0103] Ring C is a 3- to 6-membered nitrogen-containing heterocyclic group;

[0104] R 4 is a substituent at any position on ring B; n2 is 0, 1, 2 or 3;

[0105] R 5 is a substituent at any position on ring C; n3 is 0, 1, 2 or 3;

[0106] R 4 、R 5 The definition is as follows:

[0107] (a) Each R 4 , each R 5 Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted by -C(O)H or OH; the heterocyclyl in -CH2heterocyclyl is optionally substituted by oxo; or,

[0108] (b) 1 R 4 is -CH2CH2- or -CH2CH2CH2- and together with the carbon atom to which it is attached constitutes a cyclopropyl or cyclobutyl group; the remaining R 4 , each R 5 Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH; the heterocyclyl in -CH2heterocyclyl is optionally substituted with oxo; or

[0109] (c) 1 R 5is -CH2CH2- or -CH2CH2CH2- and together with the carbon atom to which it is attached constitutes a cyclopropyl or cyclobutyl group; the remaining R 5 , each R 4 Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH; the heterocyclyl in -CH2heterocyclyl is optionally substituted with oxo; or

[0110] (d) 1 R 4 -CH2CH2- or -CH2CH2CH2- and together with the carbon atom to which it is attached constitutes a cyclopropyl or cyclobutyl group; 1 R 5 is -CH2CH2- or -CH2CH2CH2- and together with the carbon atom to which it is attached constitutes a cyclopropyl or cyclobutyl group; the remaining R 4 、The rest R 5Each is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein the phenyl in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H or OH; the heterocyclyl in the -CH2heterocyclyl is optionally substituted with oxo;

[0111] Each R 34 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0112] In one embodiment, the compound is represented by formula (I-1) or formula (I-2):

[0113] In various types, X, Y, W, R 1 、R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5, n1, n2, n3, L1, L2, Ring A, Ring B, and Ring C are each defined by the same formula (I).

[0114] In one embodiment, the present invention provides a compound of formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

[0115] Among various

[0116] q is 1 or 2;

[0117] X is O or NR 11 ; Among them, R 11 Selected from H and C1-C6 alkyl;

[0118] Y is CR 12 R 13 , CR 14 R 15 CR 16 R 17 , C(O) or C(O)CR 18 R 19 ; Among them, R 12 、R 13 、R 14 and R 15 R is independently selected from H, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; 16 、R 17 、R 18 、R 19 Each independently selected from H, C1-C3 alkyl and halogen;

[0119] W is N or CR 20 ; Among them, R 20 is H, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl or heterocyclyl-O-; wherein the cycloalkyl and heterocyclyl are each independently substituted by halogen;

[0120] Ring A is selected from the group consisting of aryl, heteroaryl;

[0121] R 1 is a substituent at any position on ring A; each R 1 Each is independently selected from: C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25、N=S(O)(C1-C6 alkyl)2、S(O)C1-C6 alkyl、S(O)2R 26 , -S-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, C1-C6 cyanoalkyl, triazolyl, -S-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -CH2C(O)NR 27 R 28 、-C2-C6 alkynyl NR 29 R 30 , C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C6 alkyl; wherein,

[0122] R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O)OC1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1-C6 haloalkyl; or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0123] R 23 、R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0124] R 25 For hydroxyl, cyano, heterocyclic, NR 251 R 252 、C(O)NR 253 R 254 or SO2C1-C6 alkyl; wherein R 251 、R 252 、R 253 、R 254 Each independently represents H or C1-C6 alkyl; R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253 、R254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0125] R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C6 alkyl; or R 261 、R 262 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0126] R 27 、R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0127] R 29 、R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0128] n1 is 0, 1, 2, or 3;

[0129] R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, NR 31 R 32 , C2-C4 alkynyl or CH2OR 33 ; Among them, R 31 、R 32 、R 33 Each is independently hydrogen or C1-C6 alkyl;

[0130] R 3is a substituent at any position on the bridge ring and is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;

[0131] L3 is a bond, O or NR 34 ;

[0132] R 6 is -L-6 to 10-membered fused heterocyclyl, -L-7 to 11-membered spiroheterocyclyl, -L-spiro-substituted 6 to 10-membered fused heterocyclyl, -L-spiro-substituted 7 to 11-membered spiroheterocyclyl, -L-parallel-substituted 6 to 10-membered fused heterocyclyl, -L-parallel-substituted 7 to 11-membered spiroheterocyclyl, or -L-spiro- and parallel-substituted 6 to 10-membered fused heterocyclyl;

[0133] The spiro-substituted 6- to 10-membered fused heterocyclic group refers to a 6- to 10-membered fused heterocyclic group in which two hydrogen atoms on the same carbon atom in any one or two carbon atoms are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a spiro-substituted 6- to 10-membered fused heterocyclic group;

[0134] The spiro-substituted 7- to 11-membered spiro heterocyclic group refers to a 7- to 11-membered spiro heterocyclic group in which two hydrogen atoms on the same carbon atom of any one or two carbon atoms are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a spiro-substituted 7- to 11-membered spiroheterocyclyl;

[0135] The 6- to 10-membered fused heterocyclic group substituted with a ring is a 6- to 10-membered fused heterocyclic group in which one hydrogen atom on each carbon atom in any one or two pairs of adjacent carbon atoms is replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substituted to form a 6- to 10-membered fused heterocyclic group that is substituted with a ring; or the 6- to 10-membered fused heterocyclic group that is substituted with a ring refers to a 6- to 10-membered fused heterocyclic group in which the hydrogen atoms on any two non-adjacent carbon atoms of the 6- to 10-membered fused heterocyclic group are replaced with -(CH2) m4 -、-(CH2) m5O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a 6- to 10-membered fused heterocyclic group;

[0136] The 7- to 11-membered spiro heterocyclic group substituted with a ring is a 7- to 11-membered spiro heterocyclic group in which one hydrogen atom on each carbon atom in any one or two pairs of adjacent carbon atoms is replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substituted to form a 7- to 11-membered spiro heterocyclic group that is substituted with a ring; or the 7- to 11-membered spiro heterocyclic group that is substituted with a ring refers to a 7- to 11-membered spiro heterocyclic group in which the hydrogen atoms on any two non-adjacent carbon atoms of the 7- to 11-membered spiro heterocyclic group are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a 7- to 11-membered spiroheterocyclyl group;

[0137] The 6- to 10-membered fused heterocyclic group substituted by the spiro ring and the fused heterocyclic group refers to a 6- to 10-membered fused heterocyclic group in which one hydrogen atom on each carbon atom of any pair of adjacent carbon atoms is replaced by -(CH2) at the same time. m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substitution to form a ring substitution and the two hydrogen atoms on the other carbon atom of the 6- to 10-membered fused heterocyclic group are simultaneously replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substitution to form spiro substitution to form spiro and cyclosubstituted 6 to 10 membered fused heterocyclic groups;

[0138] The 6- to 10-membered fused heterocyclic group or the 7- to 11-membered spiro heterocyclic group has 1, 2, 3 or 4 groups selected from N(R m ), S, S(=O), S(=O)2, O heteroatoms as ring atoms;

[0139] The spiro-substituted 6- to 10-membered fused heterocyclic group, the spiro-substituted 7- to 11-membered spiro heterocyclic group, the 6- to 10-membered fused heterocyclic group substituted with a ring combination, the 7- to 11-membered spiro heterocyclic group substituted with a ring combination, or the spiro- and 6- to 10-membered fused heterocyclic group substituted with a ring combination each independently has 1, 2, 3, 4 or 5 groups selected from N(R m ), S, S(=O), S(=O)2, O heteroatoms as ring atoms;

[0140] R n is hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3-20 membered heterocyclyl;

[0141] R m is none, hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl, or 3-20 membered heterocyclyl;

[0142] wherein the 6- to 10-membered fused heterocyclic group or the 7- to 11-membered spiro heterocyclic group is saturated or partially unsaturated; when the 6- to 10-membered fused heterocyclic group or the 7- to 11-membered spiro heterocyclic group is partially unsaturated, the ring has 1 or 2 double bonds; two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group or the 7- to 11-membered spiro heterocyclic group are optionally replaced by ═CR 2a R 2b substituted; the 6 to 10-membered fused heterocyclic group or the 7 to 11-membered spiro heterocyclic group is optionally further substituted by 1 or more (eg, 1, 2, 3, 4 or 5) R 6a replace;

[0143] Among them, R 2a 、R 2b are each independently hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C6-C10 aryl or 5-membered or 6-membered heteroaryl; the C6-C10 aryl or 5-membered or 6-membered heteroaryl is optionally substituted by 1, 2 or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; or each pair of R 2a 、R 2b Each independently forms together with the connected carbon atom a C3-C6 monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group; the C3-C6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, or a 5- or 6-membered monocyclic heteroaryl;

[0144] Each R6a Each is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -Q-phenyl, -Q-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R 6b )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O)-, oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 6b )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 6b )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -C1-C3 alkyl-OC(O)heterocyclyl, -OC(O)N(R 6b )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl, -OC(O)C1-C6 alkyl, -OC(O)C1-C6 haloalkyl, -C1-C3 alkyl-OC(O)C1-C6 alkyl, -C1-C3 alkyl-OC(O)C1-C6 haloalkyl, -OC(O)phenyl, -C1-C3 alkyl-OC(O)phenyl or -CH2heterocyclyl; wherein the phenyl involved in the above groups is optionally substituted by -C(O)H or OH; the heterocyclyl in the -C1-C3 alkyl-heterocyclyl is optionally substituted by oxo; Q is a bond or O; each of the above R 6b are each independently hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl; or two R 6b Each independently forms together with the nitrogen atom to which they are attached a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0145] Each m4 is 2, 3 or 4;

[0146] Each m5, m6, m7, and m8 are independently 0, 1, 2, or 3; m5 and m6 are not 0 at the same time; m7 and m8 are not 0 at the same time;

[0147] or

[0148] R 6 is hydrogen, -N(R 34 )2, heterocyclic group, C1-C6 alkyl group, -L-heterocyclic group, -L-aryl group, -L-heteroaryl group, -L-cycloalkyl group, -LN(R 34 )2, -L-NHC(=NH)NH2, -LC(O)N(R 34 )2, -L-C1-C6 haloalkyl, -L-OR 34 、-L-(CH2OR 34 )(CH2) n OR 34 、-L-NR 34 C(O)-aryl, -L-COOH or -LC(O)OC1-C6 alkyl; wherein the heterocyclic group, the -L-NR 34 The aryl group in C(O)-aryl, the heterocyclyl group in said -L-heterocyclyl, and the cycloalkyl group in said -L-cycloalkyl may each be optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the aryl group in the -L-aryl group and the heteroaryl group in the -L-heteroaryl group may each be optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) R 36 replace;

[0149] wherein each L is independently a bond, a C1-C4 alkylene group or a heteroaryl group; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene group are optionally independently substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or wherein two hydrogen atoms on any same carbon atom of the C1-C4 alkylene group are optionally simultaneously substituted by -(CH2) m3 -、-(CH2) m1 -O-(CH2) m2 -、-(CH2) m1 -NR 9 -(CH2) m2 -substituted to form a cyclic substituent; m3 is 1 or 2; each m1 is independently 0, 1, 2 or 3; each m2 is independently 0, 1, 2 or 3; and m1 and m2 are not 0 at the same time;

[0150] R 9is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkyl-hydroxy, C1-C6 alkyl-cyano, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C3-C6 monocyclic cycloalkyl, C3-C6 deuterated cycloalkyl or C3-C6 halocycloalkyl;

[0151] Each R 35 Each is independently halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -C1-C3 alkyl-C1-C3 alkoxy, -C1-C3 alkyl-hydroxy, heterocyclyl (e.g., 3- to 6-membered heterocyclyl), cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl (e.g., -OC(O)-3 to 6 membered heterocyclyl) or -CH2heterocyclyl (e.g., - -CH2-3 to 6-membered heterocyclyl); wherein the phenyl group in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted by -C(O)H or OH; the heterocyclyl group in the -CH2 heterocyclyl is optionally substituted by oxo; the hydrogen atom on the -C1-C3 alkyl- is substituted by one or two groups selected from halogen, deuterium, C1-C3 alkyl, and C1-C3 haloalkyl;

[0152] Each R 36 Each is independently halogen, hydroxy, HC(O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl or -N(R34 )2;

[0153] Each R 34 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0154] In one embodiment, the compound is represented by formula (II-1A), formula (II-1B), formula (II-2A), and formula (II-2B):

[0155] In various types, X, Y, W, R 1 、R 2 、R 3 、R 6 , n1, L3, q, and ring A are each defined by formula (II-1) or formula (II-2).

[0156] In one embodiment, the compound is represented by Formula (II-1A1), Formula (II-1A2), Formula (II-1B1), Formula (II-1B2), Formula (II-1C1), or Formula (II-1C2):

[0157] In various types, X, Y, W, R 1 、R 2 、R 3 、R 6 , n1, L3, and ring A are each defined by formula (II-1) or formula (II-2).

[0158] In one embodiment, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

[0159] Where,

[0160] X is O or NR 11 ; Among them, R 11 Selected from H and C1-C6 alkyl;

[0161] Y is CR 12 R 13 , CR 14 R 15 CR 16 R 17 , C(O) or C(O)CR 18 R 19 ; Among them, R 12 、R13 、R 14 and R 15 R is independently selected from H, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; 16 、R 17 、R 18 、R 19 Each independently selected from H, C1-C3 alkyl and halogen;

[0162] W is N or CR 20 ; Among them, R 20 is H, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl or heterocyclyl-O-; wherein the cycloalkyl and heterocyclyl are each independently substituted by halogen;

[0163] Ring A is selected from the group consisting of aryl, heteroaryl;

[0164] R 1 is a substituent at any position on ring A; each R 1 Each is independently selected from: C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25 、N=S(O)(C1-C6 alkyl)2、S(O)C1-C6 alkyl、S(O)2R 26 , -S-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, C1-C6 cyanoalkyl, triazolyl, -S-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -CH2C(O)NR 27 R 28 、-C2-C6 alkynyl NR 29 R 30 , C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C6 alkyl; wherein,

[0165] R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O)OC1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1-C6 haloalkyl; or R 21 、R 22Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0166] R 23 、R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0167] R 25 For hydroxyl, cyano, heterocyclic, NR 251 R 252 、C(O)NR 253 R 254 or SO2C1-C6 alkyl; wherein R 251 、R 252 、R 253 、R 254 Each independently represents H or C1-C6 alkyl; R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253 、R 254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0168] R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C6 alkyl; or R 261 、R 262 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0169] R 27 、R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0170] R 29 、R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0171] n1 is 0, 1, 2, or 3;

[0172] R 3d 、R 3e 、R 3f are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or

[0173] R 3d With R 3e Connected to form -CHR 3d1 -or-CHR 3d2 CHR 3d3 -;R 3f is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3d1 、R 3d2 、R 3d3 are each independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or

[0174] R 3d With R 3f Connected to form -CHR 3f1 -or-CHR 3f2 CHR 3f3 -;R 3e is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3f1 、R 3f2 、R 3f3 Each is independently hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;

[0175] L3 is a bond, O or NR 34 ;

[0176] R 6 is -L-6 to 10-membered fused heterocyclyl, -L-7 to 11-membered spiroheterocyclyl, -L-spiro-substituted 6 to 10-membered fused heterocyclyl, -L-spiro-substituted 7 to 11-membered spiroheterocyclyl, -L-parallel-substituted 6 to 10-membered fused heterocyclyl, -L-parallel-substituted 7 to 11-membered spiroheterocyclyl, or -L-spiro- and parallel-substituted 6 to 10-membered fused heterocyclyl;

[0177] The spiro-substituted 6- to 10-membered fused heterocyclic group refers to a 6- to 10-membered fused heterocyclic group in which two hydrogen atoms on the same carbon atom in any one or two carbon atoms are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a spiro-substituted 6- to 10-membered fused heterocyclic group;

[0178] The spiro-substituted 7- to 11-membered spiro heterocyclic group refers to a 7- to 11-membered spiro heterocyclic group in which two hydrogen atoms on the same carbon atom of any one or two carbon atoms are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a spiro-substituted 7- to 11-membered spiroheterocyclyl;

[0179] The 6- to 10-membered fused heterocyclic group substituted with a ring is a 6- to 10-membered fused heterocyclic group in which one hydrogen atom on each carbon atom in any one or two pairs of adjacent carbon atoms is replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substituted to form a 6- to 10-membered fused heterocyclic group that is substituted with a ring; or the 6- to 10-membered fused heterocyclic group that is substituted with a ring refers to a 6- to 10-membered fused heterocyclic group in which the hydrogen atoms on any two non-adjacent carbon atoms of the 6- to 10-membered fused heterocyclic group are replaced with -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a 6- to 10-membered fused heterocyclic group;

[0180] The 7- to 11-membered spiro heterocyclic group substituted with a ring is a 7- to 11-membered spiro heterocyclic group in which one hydrogen atom on each carbon atom in any one or two pairs of adjacent carbon atoms is replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substituted to form a 7- to 11-membered spiro heterocyclic group that is substituted with a ring; or the 7- to 11-membered spiro heterocyclic group that is substituted with a ring refers to a 7- to 11-membered spiro heterocyclic group in which the hydrogen atoms on any two non-adjacent carbon atoms of the 7- to 11-membered spiro heterocyclic group are replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 substituted to form a 7- to 11-membered spiroheterocyclyl group;

[0181] The 6- to 10-membered fused heterocyclic group substituted by the spiro ring and the fused heterocyclic group refers to a 6- to 10-membered fused heterocyclic group in which one hydrogen atom on each carbon atom of any pair of adjacent carbon atoms is replaced by -(CH2) at the same time. m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substitution to form a ring substitution and the two hydrogen atoms on the other carbon atom of the 6- to 10-membered fused heterocyclic group are simultaneously replaced by -(CH2) m4 -、-(CH2) m5 O(CH2) m6 -or-(CH2) m7 NR n (CH2) m8 Substitution to form spiro substitution to form spiro and cyclosubstituted 6 to 10 membered fused heterocyclic groups;

[0182] The 6- to 10-membered fused heterocyclic group or the 7- to 11-membered spiro heterocyclic group has 1, 2, 3 or 4 groups selected from N(R m ), S, S(=O), S(=O)2, O heteroatoms as ring atoms;

[0183] The spiro-substituted 6- to 10-membered fused heterocyclic group, the spiro-substituted 7- to 11-membered spiro heterocyclic group, the 6- to 10-membered fused heterocyclic group substituted with a ring combination, the 7- to 11-membered spiro heterocyclic group substituted with a ring combination, or the spiro- and 6- to 10-membered fused heterocyclic group substituted with a ring combination each independently has 1, 2, 3, 4 or 5 groups selected from N(R m ), S, S(=O), S(=O)2, O heteroatoms as ring atoms;

[0184] R n is hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3-20 membered heterocyclyl;

[0185] R m is none, hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl, or 3-20 membered heterocyclyl;

[0186] wherein the 6- to 10-membered fused heterocyclic group or the 7- to 11-membered spiro heterocyclic group is saturated or partially unsaturated; when the 6- to 10-membered fused heterocyclic group or the 7- to 11-membered spiro heterocyclic group is partially unsaturated, the ring has 1 or 2 double bonds; two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group or the 7- to 11-membered spiro heterocyclic group are optionally replaced by ═CR 2a R 2b substituted; the 6 to 10-membered fused heterocyclic group or the 7 to 11-membered spiro heterocyclic group is optionally further substituted by 1 or more (eg, 1, 2, 3, 4 or 5) R 6a replace;

[0187] Among them, R 2a 、R 2b are each independently hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C6-C10 aryl or 5-membered or 6-membered heteroaryl; the C6-C10 aryl or 5-membered or 6-membered heteroaryl is optionally substituted by 1, 2 or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; or each pair of R 2a 、R 2b Each independently forms together with the connected carbon atom a C3-C6 monocyclic cycloalkyl or a 3- to 6-membered monocyclic heterocyclic group; the C3-C6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, or a 5- or 6-membered monocyclic heteroaryl;

[0188] Each R 6aEach is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -Q-phenyl, -Q-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyloxyCH2-, -N(R 6b )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O)-, oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 6b )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 6b )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -C1-C3 alkyl-OC(O)heterocyclyl, -OC(O)N(R 6b )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl, -OC(O)C1-C6 alkyl, -OC(O)C1-C6 haloalkyl, -C1-C3 alkyl-OC(O)C1-C6 alkyl, -C1-C3 alkyl-OC(O)C1-C6 haloalkyl, -OC(O)phenyl, -C1-C3 alkyl-OC(O)phenyl or -CH2heterocyclyl; wherein the phenyl involved in the above groups is optionally substituted by -C(O)H or OH; the heterocyclyl in the -C1-C3 alkyl-heterocyclyl is optionally substituted by oxo; Q is a bond or O; each of the above R 6b are each independently hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl; or two R 6b Each independently forms together with the nitrogen atom to which they are attached a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0189] Each m4 is 2, 3 or 4;

[0190] Each m5, m6, m7, and m8 are independently 0, 1, 2, or 3; m5 and m6 are not 0 at the same time; m7 and m8 are not 0 at the same time;

[0191] or

[0192] R 6 is hydrogen, -N(R 34 )2, heterocyclic group, C1-C6 alkyl group, -L-heterocyclic group, -L-aryl group, -L-heteroaryl group, -L-cycloalkyl group, -LN(R 34 )2, -L-NHC(=NH)NH2, -LC(O)N(R 34 )2, -L-C1-C6 haloalkyl, -L-OR 34 、-L-(CH2OR 34 )(CH2) n OR 34 、-L-NR 34 C(O)-aryl, -L-COOH or -LC(O)OC1-C6 alkyl; wherein the heterocyclic group, the -L-NR 34 The aryl group in C(O)-aryl, the heterocyclyl group in said -L-heterocyclyl, and the cycloalkyl group in said -L-cycloalkyl may each be optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the aryl group in the -L-aryl group and the heteroaryl group in the -L-heteroaryl group may each be optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) R 36 replace;

[0193] wherein each L is independently a bond, a C1-C4 alkylene group or a heteroaryl group; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene group are optionally independently substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or wherein two hydrogen atoms on any same carbon atom of the C1-C4 alkylene group are optionally simultaneously substituted by -(CH2) m3 -、-(CH2) m1 -O-(CH2) m2 -、-(CH2) m1 -NR 9 -(CH2) m2 -substituted to form a cyclic substituent; m3 is 1 or 2; each m1 is independently 0, 1, 2 or 3; each m2 is independently 0, 1, 2 or 3; and m1 and m2 are not 0 at the same time;

[0194] R 9is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkyl-hydroxy, C1-C6 alkyl-cyano, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C3-C6 monocyclic cycloalkyl, C3-C6 deuterated cycloalkyl or C3-C6 halocycloalkyl;

[0195] Each R 35 Each is independently halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -C1-C3 alkyl-C1-C3 alkoxy, -C1-C3 alkyl-hydroxy, heterocyclyl (e.g., 3- to 6-membered heterocyclyl), cyano, -phenyl, -phenyl-SO2F, -O-phenyl, -O-phenyl-SO2F, -NHC(O)phenyl, -NHC(O)phenyl-SO2F, C1-C3 alkyl-substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl CH2-, -N(R 34 )2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH2OC(O)N(R 34 )2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R 34 )2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocyclyl, -OC(O)N(R 34 )2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl (e.g., -OC(O)-3 to 6 membered heterocyclyl) or -CH2heterocyclyl (e.g., - -CH2-3 to 6-membered heterocyclyl); wherein the phenyl group in -NHC(O)phenyl or -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted by -C(O)H or OH; the heterocyclyl group in the -CH2 heterocyclyl is optionally substituted by oxo; the hydrogen atom on the -C1-C3 alkyl- is substituted by one or two groups selected from halogen, deuterium, C1-C3 alkyl, and C1-C3 haloalkyl;

[0196] Each R 36 Each is independently halogen, hydroxy, HC(O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl or -N(R34 )2;

[0197] Each R 34 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0198] In one embodiment, the compound is represented by formula (III-1) or formula (III-2):

[0199] In various types, X, Y, W, R 1 、R 3d 、R 3e 、R 3f 、R 6 , n1, L3, and ring A are each defined by the same formula (III).

[0200] In one embodiment, the compound is represented by Formula (III-1a), Formula (III-1b), Formula (III-2a) or Formula (III-2b):

[0201] In each formula, q is 1 or 2; R 3 is a substituent at any position on the bridge ring and is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; X, Y, W, ring A, R 1 、n1、L3、R 6 The definition is the same as that of formula (III-1) or formula (III-2).

[0202] In one embodiment, the compound is represented by Formula (III-1a1), Formula (III-1a2), Formula (III-1b1), Formula (III-1b2), Formula (III-1c1) or Formula (III-1c2):

[0203] In various types, R 3 is a substituent at any position on the bridge ring and is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; X, Y, W, ring A, R 1 、n1、L3、R 6 The definition is the same as that of formula (III-1) or formula (III-2).

[0204] In one embodiment, R 3 For hydrogen.

[0205] In one embodiment, Y is -CH2-.

[0206] In one embodiment, the compound is represented by Formula (III-1a3), Formula (III-1a4), Formula (III-1b3) or Formula (III-1b4):

[0207] Among various

[0208] R 3 is a substituent at any position on the bridge ring and is hydrogen, halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl;

[0209] Y is CR 12 R 13 , CR 14 R 15 CR 16 R 17 , C(O) or C(O)CR 18 R 19 ;in,

[0210] R 12 、R 13 Each is independently selected from H, halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl, heterocyclyl-O-, aryl, heteroaryl, aryl-O-, heteroaryl-O-, -C1-C4 alkyl-C1-C6 alkoxy, -C1-C4 alkyl-C1-C6 haloalkoxy, -C1-C4 alkyl-hydroxy, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121 R 122 ; and R 12 、R 13 Not H at the same time; or R 12 、R 13 Together with the carbon atoms to which they are attached, they form a cycloalkyl group;

[0211] R 14 and R 15 Each is independently selected from H, nitro, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl, heterocyclyl-O-, aryl, heteroaryl, aryl-O-, heteroaryl-O-, -C1-C4 alkyl-C1-C6 alkoxy, -C1-C4 alkyl-C1-C6 haloalkoxy, -C1-C4 alkyl-hydroxy, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR121 R 122 ; and R 14 、R 15 Not H at the same time; or R 14 、R 15 Together with the carbon atoms to which they are attached, they form a cycloalkyl group;

[0212] R 16 、R 17 Each is independently selected from H, halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl, heterocyclyl-O-, aryl, heteroaryl, aryl-O-, heteroaryl-O-, -C1-C4 alkyl-C1-C6 alkoxy, -C1-C4 alkyl-C1-C6 haloalkoxy, -C1-C4 alkyl-hydroxy, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121 R 122 ; and R 16 、R 17 Not at the same time H;

[0213] R 18 、R 19 Each independently selected from H, C1-C3 alkyl and halogen;

[0214] R 121 、R 122 Each independently selected from H, C1-C3 alkyl; or R 121 、R 122 Together with the nitrogen atom to which they are connected, they form a 3- to 6-membered nitrogen-containing heterocyclic group;

[0215] wherein the cycloalkyl group, the heterocyclic group, the aryl group, the heteroaryl group, and the 3- to 6-membered nitrogen-containing heterocyclic group are each independently optionally substituted by a group selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy;

[0216] X, W, Ring A, R 1 、n1、L3、R 6 The definition is the same as that of formula (III-1) or formula (III-2).

[0217] In one embodiment, R 3 For hydrogen.

[0218] In one embodiment, Y is CR 12 R 13 ; Among them, R 12Selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl, heterocyclyl-O-, -C1-C4 alkyl-C1-C6 alkoxy, -C1-C4 alkyl-C1-C6 haloalkoxy, -C1-C4 alkyl-hydroxy, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121 R 122 ; R 13 H; R 121 、R 122 Each independently selected from H, C1-C3 alkyl; or R 121 、R 122 Together with the nitrogen atom to which they are connected, they form a 3- to 6-membered nitrogen-containing heterocyclic group; or R 12 、R 13 Together with the carbon atoms to which they are connected, they form a cycloalkyl group; wherein the cycloalkyl group, the heterocyclic group, the aryl group, the heteroaryl group, and the 3- to 6-membered nitrogen-containing heterocyclic group are each independently optionally substituted by a group selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy.

[0219] In one embodiment, in Formula (III-1a3), Formula (III-1a4), Formula (III-1b3) or Formula (III-1b4), Y is CR 12 R 13 ; Among them, R 12 R is selected from halogen, hydroxy, cyano, methyl, ethyl, n-propyl, isopropyl, trideuteromethyl, trifluoromethyl, cyclopropyl, -C1-C4 alkyl-methoxy, -C1-C4 alkyl-hydroxy, -C1-C4 alkyl-cyano; 13 H; or R 12 、R 13 Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0220] In one embodiment, in formula (III-1a3), formula (III-1a4), formula (III-1b3) or formula (III-1b4), Y is -CH(CH3)-, -CH(CH2CH3)-, -CH(CH2CH2CH3)-, -CH(CH(CH3)2)-, -CH(cyclopropyl)-, -CH(CH2OH)-, -CH(CH2CH2OH)-, -CH(CH2CN)-, -CH(CH2CH2CN)-, -CH(CH2CF3)-, -CH(CH2CF2H)-, -CH(CH2CH2F)-, -CH(CH2F)-, -CH(CF2H)-, -CH(CF3)-, -CH(CN)-, -CH(CH2OCH3)-, -C(CH3)2-, -CH(CD3)-.

[0221] In one embodiment, the cycloalkyl group is a C3-C20 cycloalkyl group. Preferably, the cycloalkyl group is a C3-C12 cycloalkyl group (more preferably a C3-C8 monocyclic cycloalkyl group), a C5-C20 spirocycloalkyl group, a C5-C20 fused cycloalkyl group or a C5-C20 bridged cycloalkyl group.

[0222] In one embodiment, the heterocyclyl is a 3- to 20-membered heterocyclyl. Preferably, the heterocyclyl is a monocyclic heterocyclyl (e.g., a 3- to 8-membered monocyclic heterocyclyl), a 5- to 20-membered spiro heterocyclyl, a 5- to 20-membered fused heterocyclyl, and a 5- to 20-membered bridged heterocyclyl.

[0223] In one embodiment, the aryl group is a C6-C14 aryl group. Preferably, the aryl group is a monocyclic aryl group, a non-fused polycyclic aryl group, or an aromatic fused polycyclic aryl group.

[0224] In one embodiment, the heteroaryl group is a 5- to 14-membered heteroaryl group. Preferably, the heteroaryl group is a monocyclic heteroaryl group (e.g., a 5- or 6-membered monocyclic heteroaryl group), a fused bicyclic heteroaryl group (e.g., an 8- to 10-membered bicyclic heteroaryl group), or a fused tricyclic heteroaryl group.

[0225] In one embodiment, W is N or CR 20 ; Among them, R 20 It is H, cyano, C1-C3 alkyl, halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 monocyclic cycloalkyl, C3-C6 monocyclic cycloalkyl-O-, 3 to 6-membered heterocyclyl or 3 to 6-membered heterocyclyl-O-; wherein the C3-C6 monocyclic cycloalkyl and the 3 to 6-membered heterocyclyl are each independently optionally substituted by halogen.

[0226] In one embodiment, W is N or CR 20 ; Among them, R 20 is hydrogen, fluorine, methyl, methoxy or cyclopropyloxy.

[0227] In one embodiment, W is N or CR 20 ; Among them, R 20 is H, fluorine, chlorine, methyl, cyclopropyl, methoxy or cyclopropyloxy.

[0228] In one embodiment, X is -N(CH3)- or -N(cyclopropyl)-.

[0229] In one embodiment, X is -N(CD3)-.

[0230] In one embodiment, X is O.

[0231] In one embodiment, Y is CR 12 R 13 or CR 14 R 15 CR 16 R 17 ; Among them, R 12 、R 13 、R 14 and R 15 each independently selected from H, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 monocyclic cycloalkyl, C3-C6 monocyclic cycloalkyl-O-, 3 to 6-membered heterocyclyl, 3 to 6-membered heterocyclyl-O-, phenyl, 5 or 6-membered heteroaryl, phenyl-O-, 5 or 6-membered heteroaryl-O-, -C1-C2 alkyl-C1-C3 alkoxy, -C1-C2 alkyl-C1-C3 haloalkoxy, -C1-C2 alkyl-hydroxy, -C1-C2 alkyl-cyano, -C1-C2 alkyl-NR 121 R 122 ; R 16 、R 17 are each independently selected from H; R 121 、R 122 Each independently selected from H, C1-C3 alkyl; or R 121 、R 122 Together with the nitrogen atom to which they are connected, they form a 3 to 6-membered nitrogen-containing heterocyclic group; wherein the C3-C6 monocyclic cycloalkyl, the 3 to 6-membered heterocyclic group, the phenyl group, the 5- or 6-membered heteroaryl group, and the 3 to 6-membered nitrogen-containing heterocyclic group are each independently optionally substituted by a group selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy.

[0232] In one embodiment, Y is -CH2-, -CH2CH2-, -CH(CH2OCH3)-, -CH(CN)-, -CH(OH)-, -CH(CH3)-, -CH(CD3)-, -C(CH3)2-, -CH(CF3)-, -CH(CHF2)-, -CH(CH2F)-, -CH(CH2CH3)-, -CH(CH2CH2F)-, -CH(CH2CF2H)-, -CH(CH2CF3)-, -CH(CH2CH2CN)-, -CH(CH2OH)-, -CH(CH2CN)-, -CH(CH2CH2OH)-, -CH(cyclopropyl)-, -CH(isopropyl)-, -CH(CH2CH2CH3)-, -CH(CH2CH2CH2CH3)-, or

[0233] In one embodiment, Y is -CH2-.

[0234] In one embodiment, Y is selected from the group consisting of:

[0235] In one embodiment, R 2 is H, cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, NR 31 R 32 , C2-C4 alkynyl or CH2OR 33 ; Among them, R 31 、R 32 Each independently represents hydrogen or a C1-C6 alkyl group; or together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; R 33 is hydrogen or C1-C6 alkyl.

[0236] In one embodiment, R 2 is fluorine, chlorine, hydroxy, methoxy or cyano.

[0237] In one embodiment, R 2 is hydrogen, fluorine, chlorine, hydroxy, methoxy or cyano.

[0238] In one embodiment, ring A is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, indazolyl or benzo[d][1,3]dioxolane.

[0239] In one embodiment, Ring A is selected from the group consisting of: And these groups may be attached to the rest of the molecule via any suitable ring atom.

[0240] In one embodiment, R 1 is a substituent at any position on ring A; n1 is 0, 1, 2 or 3; each R 1 Each is independently selected from: C1-C3 alkyl, halogen, hydroxy, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25 、N=S(O)(C1-C3 alkyl)2、S(O)C1-C3 alkyl、S(O)2R 26 , -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, -S-C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -CH2C(O)NR 27 R 28 , -C2-C4 alkynyl NR 29 R 30 , C2-C4 deuterated alkynyl, (C1-C3 alkoxy) C1-C3 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; wherein,

[0241] R 21 is H, C1-C3 alkyl, C1-C3 haloalkyl, C(O)C1-C3 alkyl or C(O)OC1-C3 alkyl; R 22 is H, C1-C3 alkyl or C1-C3 haloalkyl; or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0242] R 23 、R 24 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0243] R 25 For hydroxyl, cyano, heterocyclic, NR 251R 252 、C(O)NR 253 R 254 or SO2C1-C3 alkyl; wherein R 251 、R 252 、R 253 、R 254 Each independently represents H or C1-C3 alkyl; R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253 、R 254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0244] R 26 is C1-C3 alkyl, C1-C3 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C3 alkyl; or R 261 、R 262 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0245] R 27 、R 28 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 27 、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0246] R 29 、R 30 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0247] In one embodiment, L2 is methylene or ethylene or propylene; wherein, one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene or ethylene or propylene are optionally each independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene or ethylene or propylene are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0248] In one embodiment, R 3a 、R 3b 、R 3c Each is independently hydrogen, fluorine, methyl or methoxy.

[0249] In one embodiment, Select from the following groups:

[0250] In one embodiment, Select from the following groups:

[0251] In one embodiment, Select from the following groups:

[0252] In each formula, each R 4 、R 5 , n2, and n3 are each independently defined as in formula (I).

[0253] In one embodiment, Select from the following groups:

[0254] In one embodiment, R 3 is hydrogen, fluorine, methyl or methoxy.

[0255] In one embodiment, R 3 For hydrogen.

[0256] In one embodiment, R 3d 、R 3e 、R 3f are each independently hydrogen, fluorine, methyl or methoxy; or

[0257] R 3d With R 3e Connected to form -CHR 3d1 -or-CHR 3d2 CHR 3d3 -;R 3f is hydrogen, fluorine, methyl or methoxy; R3d1 、R 3d2 、R 3d3 are each independently hydrogen, fluorine, methyl or methoxy; or

[0258] R 3d With R 3f Connected to form -CHR 3f1 -or-CHR 3f2 CHR 3f3 -;R 3e is hydrogen, fluorine, methyl or methoxy; R 3f1 、R 3f2 、R 3f3 Each is independently hydrogen, fluorine, methyl or methoxy.

[0259] In one embodiment, L is methylene, ethylene or propylene; wherein, one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene, ethylene or propylene are optionally independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene, ethylene or propylene are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0260] In one embodiment, R 6 is hydrogen, -N(R 34 )2, 3 to 20 membered heterocyclic group, C1-C6 alkyl group, -L-3 to 20 membered heterocyclic group, -L-C6-C14 aryl group, -L-5 to 14 membered heteroaryl group, -L-C3-C20 cycloalkyl group, -LN(R 34 )2, -L-NHC(=NH)NH2, -LC(O)N(R 34 )2, -L-C1-C6 haloalkyl, -L-OR 34 、-L-(CH2OR 34 )(CH2) n OR 34 、-L-NR 34 C(O)-C6-C14 aryl, -L-COOH or -LC(O)OC1-C6 alkyl; wherein the 3 to 20-membered heterocyclic group, the -L-NR 34 The C6-C14 aryl group in the C(O)-C6-C14 aryl group and the C3-C20 cycloalkyl group may be optionally replaced by one or more (e.g., 1, 2, 3, 4, or 5) R 35or optionally two hydrogen atoms on the same carbon atom are simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the C6-C14 aryl group in the -L-C6-C14 aryl group or the 5 to 14-membered heteroaryl group in the -L-5 to 14-membered heteroaryl group may be optionally substituted by one or more (e.g., 1, 2, 3, 4 or 5) R 36 Replace; each L, each R 34 , each R 35 , each R 36 The definitions are the same as before.

[0261] In one embodiment, R 6 is hydrogen, -N(R 34 )2, 3 to 8 membered monocyclic heterocyclic group, 5 to 20 membered spiro heterocyclic group, 5 to 20 membered fused heterocyclic group, 5 to 20 membered bridged heterocyclic group, C1-C6 alkyl, -L-3 to 8 membered monocyclic heterocyclic group, -L-5 to 20 membered spiro heterocyclic group, -L-5 to 20 membered fused heterocyclic group, -L-5 to 20 membered bridged heterocyclic group, -L-phenyl, -L-naphthyl, -L-5 to 14 membered heteroaryl, -L-C3-C12 cycloalkyl, -L-C5-C20 spirocycloalkyl, C5-C20 fused cycloalkyl, -L-C5-C20 bridged cycloalkyl, -LN(R 34 )2, -L-NHC(=NH)NH2, -LC(O)N(R 34 )2, -L-C1-C6 haloalkyl, -L-OR 34 、-L- (CH2OR 34 )(CH2) n OR 34 、-L-NR 34 C(O)-phenyl, -L-NR 34 C(O)-naphthyl, -L-COOH or -LC(O)OC1-C6 alkyl; wherein the 3- to 8-membered monocyclic heterocyclic group, 5- to 20-membered spiro heterocyclic group, 5- to 20-membered fused heterocyclic group, 5- to 20-membered bridged heterocyclic group, C3-C12 cycloalkyl, C5-C20 spirocycloalkyl, C5-C20 fused cycloalkyl, C5-C20 bridged cycloalkyl, the -L-NR 34 The phenyl group in C(O)-phenyl, the -L-NR 34 The naphthyl group in C(O)-naphthyl may be optionally replaced by one or more (e.g. 1, 2, 3, 4 or 5) R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the phenyl group in -L-phenyl, the naphthyl group in -L-naphthyl, the 5 to 14 membered heteroaryl group in -L-5 to 14 membered heteroaryl group may be optionally substituted by one or more (e.g. 1, 2, 3, 4 or 5) R 36Replace; each L, each R 34 , each R 35 , each R 36 The definitions are the same as before.

[0262] In one embodiment, R 6 is hydrogen or -N(R 34 )2. Preferably, each R 34 are each independently hydrogen or C1-C3 alkyl; or 1 R 34 is hydrogen and another R 34 It is a C1-C3 alkyl group.

[0263] In one embodiment, R 34 is hydrogen, C1-C3 alkyl or C1-C3 cyanoalkyl.

[0264] In one embodiment, the C1-C6 alkyl group is methyl, ethyl, isopropyl or isobutyl.

[0265] In one embodiment, L is methylene, ethylene or propylene; wherein, one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene, ethylene or propylene are optionally independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene, ethylene or propylene are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0266] In one embodiment, each R 6 Each independently R 4 、R 5 , L2, ring B, ring C, n2, and n3 are defined the same as those of the groups in formula (I).

[0267] In one embodiment, R 6 The heterocyclic groups are each independently hexahydro-1H-pyrrolazinyl, hexahydro-3H-pyrrolazin-3-one, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, hexahydropyrrolazine 4(1H)-oxide, azetidinyl, pyrrolidinyl, pyrrolidin-2-one, oxetanyl, piperidinyl, 1-azabicyclo[2.2.1]heptyl, morpholinyl, oxa-5-azadicyclo[2.2.1]hept ... cyclo[2.2.1]hept-5-yl, thiopyranyl, 6-oxa-2-azaspiro[3.4]octyl, 7-oxa-2-azaspiro[3.5]nonyl, 2′,3′-dihydrospiro[cyclopropane-1,1′-indenyl], (2S)-1-azabicyclo[2.2.1]hept-2-yl or tetrahydrofuranyl; each of the above groups is independently optionally substituted by one or more (e.g., 1, 2, 3, 4 or 5) R 35or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; each R 35 The definitions are the same as before.

[0268] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is hexahydro-1H-pyrrolazinyl.

[0269] In one embodiment, R 6 is -L-heterocyclic; said heterocyclic is 35 Substituted hexahydro-1H-pyrrolazinyl or hexahydro-1H-pyrrolazinyl wherein two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form cyclopropyl or cyclobutyl; wherein R 35 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, phenyl, pyrazolyl or -CH2OC(O)N(R 34 )2.

[0270] In one embodiment, the halogen is fluorine.

[0271] In one embodiment, the heterocyclyl is further supported by two additional R 35 Substituted hexahydro-1H-pyrrolizinyl; the other two R 35 Each is independently a C1-C3 alkyl group.

[0272] In one embodiment, R 6 is -L-heterocyclic; said heterocyclic is 35 A substituted azetidinyl group or an azetidinyl group in which two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; said R 35 It is a C1-C3 alkyl group.

[0273] In one embodiment, R 6 is -L-heterocyclic; said heterocyclic is 35 Substituted pyrrolidinyl or pyrrolidinyl wherein two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; wherein R 35is a hydroxyalkyl group, a haloalkyl group, a C1-C3 alkyl group, an alkoxy group, an aryl C1-C3 alkyl group, a -phenyl group, an -O-phenyl group, and an -NHC(O)phenyl group; wherein the aryl group in the aryl C1-C3 alkyl group, the phenyl group, the phenyl group in the -O-phenyl group, or the phenyl group in the -NHC(O)phenyl group are each independently optionally replaced by one or more (e.g., 1, 2, 3, 4, or 5) R 36 replace.

[0274] In one embodiment, the phenyl group, -O-phenyl group or the phenyl group in -NHC(O)phenyl group is substituted with -SO2F.

[0275] In one embodiment, R 6 is -L-heterocyclic; the heterocyclic group is 35 Substituted pyrrolidinyl; wherein one R 35 is a C1-C3 alkyl group, and the other R 35 is C1-C3 alkoxy or halogen.

[0276] In one embodiment, R 6 is -L-heterocyclic; said heterocyclic is 35 Substituted pyrrolidin-2-one or pyrrolidin-2-one in which two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form cyclopropyl or cyclobutyl; wherein R 35 It is a C1-C3 alkyl group.

[0277] In one embodiment, R 6 is -L-heterocyclic; said heterocyclic is 35 A substituted piperidinyl group or a piperidinyl group in which two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; wherein R 35 It is acetyl, (C1-C3 alkoxy)C1-C3 alkoxy or -C(O)CH2Cl.

[0278] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is morpholinyl or oxa-5-azabicyclo[2.2.1]hept-5-yl.

[0279] In one embodiment, R 6 is -L-heteroaryl; said heteroaryl is optionally substituted by one or more R 36 replace.

[0280] In one embodiment, R 6is -L-heteroaryl; L is methylene or ethylene or propylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene or ethylene or propylene group are optionally independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene or ethylene or propylene group are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the heteroaryl group is pyridyl, pyrazolyl, imidazolyl, triazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, benzimidazolyl, imidazo[1,2-a]pyridyl or pyrimidinyl; each of the above groups is optionally substituted by one or more R 36 replace.

[0281] In one embodiment, R 6 is -L-heteroaryl; L is methylene, ethylene or propylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene, ethylene or propylene are optionally independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene, ethylene or propylene are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the heteroaryl is substituted by one R 36 Substituted pyridyl; wherein R 36 is halogen, C1-C4 alkyl, -N(R 5 )2 or C1-C4 alkoxy.

[0282] In one embodiment, R 6 is -L-heteroaryl; L is methylene, ethylene or propylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene, ethylene or propylene are optionally independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene, ethylene or propylene are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the heteroaryl is substituted by one R 36 Substituted pyrazolyl; wherein R 36 is C1-C4 alkyl or -N(R 34 )2.

[0283] In one embodiment, R 6is -L-heteroaryl; L is methylene, ethylene or propylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene, ethylene or propylene are optionally independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene, ethylene or propylene are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the heteroaryl is substituted by one R 36 Substituted imidazolyl; wherein R 36 It is C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 hydroxyalkyl.

[0284] In one embodiment, R 6 is -L-heteroaryl; L is methylene, ethylene or propylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene, ethylene or propylene are optionally independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene, ethylene or propylene are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the heteroaryl is substituted by one R 36 Substituted triazole; wherein R 36 It is a C1-C4 alkyl group.

[0285] In one embodiment, R 6 is -L-aryl; said aryl is optionally substituted by one or more R 36 replace.

[0286] In one embodiment, R 6 is -L-cycloalkyl; said cycloalkyl is optionally substituted by one or more R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; each R 35 The definitions are the same as before.

[0287] In one embodiment, R 6 Yes-LN(R 34 )2; wherein, L is C1-C4 alkylene; wherein, one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene are optionally and independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally and simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0288] In one embodiment, R 6Yes-LN(R 34 )2; wherein L is methylene, ethylene or propylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the methylene, ethylene or propylene group are optionally and independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the methylene, ethylene or propylene group are optionally and simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; each R 34 Independently selected from C1-C3 alkyl.

[0289] In one embodiment, R 6 It is -L-NC(=NH)-NH2; wherein L is C1-C4 alkylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene are optionally and independently substituted with deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally and simultaneously substituted with -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0290] In one embodiment, L is ethylene or propylene.

[0291] In one embodiment, R 6 It is -L-C1-C6 haloalkyl; wherein L is C1-C4 alkylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene are optionally and independently substituted with deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally and simultaneously substituted with -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0292] In one embodiment, R 6 Yes-L-OR 34 ; wherein, L is C1-C4 alkylene; wherein, one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene are optionally and independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally and simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0293] In one embodiment, R 6 Yes -L-(CH2OR 34 )(CH2) n OR 34; wherein, L is C1-C4 alkylene; wherein, one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene are optionally and independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally and simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0294] In one embodiment, R 6 Yes-L-NR 34 C(O)-aryl; wherein L is C1-C4 alkylene; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 alkylene are optionally and independently substituted with deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally and simultaneously substituted with -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0295] In one embodiment, R 6 It is -L-heterocyclyl; L is C1-C4 alkylene; wherein, two hydrogen atoms on the same carbon atom of the C1-C4 alkylene are optionally and independently substituted by deuterium or C1-C6 alkyl; or two hydrogen atoms on the same carbon atom of the C1-C4 alkylene are optionally and simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0296] In one embodiment, R 6 is -L-6 to 10-membered fused heterocyclic group; two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6 to 10-membered fused heterocyclic group are optionally replaced by =CR 2a R 2b and / or the 6 to 10 membered fused heterocyclic group is optionally further substituted by one or more R 6a Replacement; wherein, R 2a 、R 2b are each independently hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; each R 6a are each independently halogen.

[0297] In one embodiment, L is methylene, ethylene or propylene; wherein, two hydrogen atoms on the same carbon atom of the methylene, ethylene or propylene are optionally and independently substituted by deuterium or C1-C3 alkyl; or two hydrogen atoms on the same carbon atom of the methylene, ethylene or propylene are optionally and simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0298] In one embodiment, W is CR 20 ; R 20 It is cyclopropyl, cyclopropyl-O-, cyclobutyl, cyclobutyl-O-, cyclopentyl, cyclopentyl-O-, tetrahydrofuranyl, tetrahydrofuran-O-; wherein the cyclopropyl, cyclobutyl, cyclopentyl, and tetrahydrofuranyl are each independently substituted by halogen.

[0299] In one embodiment, W is CR 20 ; R 20 It is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, 3- to 6-membered heterocyclyl or 3- to 6-membered heterocyclyl-O-; wherein the C3-C6 cycloalkyl and the 3- to 6-membered heterocyclyl are each independently substituted by halogen.

[0300] In one embodiment, R 20 is halogen or C1-C3 alkyl.

[0301] In one embodiment, R 20 It's fluorine.

[0302] In one embodiment, R 20 It's methyl.

[0303] In one embodiment, L2 or L is methylene or ethylene or propylene; wherein, the two hydrogen atoms on the same carbon atom of the methylene or ethylene or propylene are optionally and independently substituted by deuterium or C1-C3 alkyl; or the two hydrogen atoms on the same carbon atom of the methylene or ethylene or propylene are optionally and simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group.

[0304] In one embodiment, Is one, two, three or four R 1 Substituted phenyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0305] In one embodiment, Is one, two, three or four R 1 Substituted naphthyl; wherein each R 1Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, cyano or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0306] In one embodiment, Is one, two or three R 1 Substituted naphthyl; wherein each R 1 are each independently halogen, hydroxy, ethynyl, methyl, ethyl, amino, cyano or difluoromethyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0307] In one embodiment, Is one or two R 1 Substituted naphthyl; wherein each R 1 are each independently halogen, ethynyl, or amino.

[0308] In one embodiment, is optionally replaced by one or more R 1 Substituted heteroaryl.

[0309] In one embodiment, Is one, two, three or four R 1 Substituted pyridyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0310] In one embodiment, is optionally replaced by one or more (e.g. 1, 2, 3, 4 or 5) R 1substituted quinolinyl, isoquinolinyl, indazolyl or benzo[d][1,3]dioxolane.

[0311] In one embodiment, Is one, two, three or four R 1 Substituted isoquinolinyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0312] In one embodiment, Is one, two or three R 1 Substituted isoquinolinyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0313] In one embodiment, Is one, two, three or four R 1 Substituted quinolinyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0314] In one embodiment, Is one, two or three R 1 Substituted indazolyl; wherein each R 1Each is independently a C1-C3 alkyl group.

[0315] In one embodiment, It is two R 1 a benzo[d][1,3]dioxolane substituted with a group; wherein each R 1 are each independently selected from halogen.

[0316] In one embodiment, Select from the following groups:

[0317] In one embodiment, Select from the following groups:

[0318] In one embodiment, the -L3-R 6 Select from the following groups:

[0319] In various types, R L1 、R L2 are each independently hydrogen, deuterium, C1-C6 alkyl or C1-C6 haloalkyl; R 61 is a heterocyclic group, an aryl group, a heteroaryl group, a cycloalkyl group, -N(R 34 )2, -NHC(=NH)NH2, -C(O)N(R 34 )2, -C1-C6 haloalkyl, -OR 34 、-(CH2OR 34 )(CH2) n OR 34 、-NR 34 C(O)-aryl, -COOH or -C(O)OC1-C6 alkyl; wherein the heterocyclic group, the -NR 34 The aryl group and the cycloalkyl group in C(O)-aryl may each be optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the aryl group and the heteroaryl group may each be optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) R 36 Replace; each R 34 , each R 35 , each R 36 Preferably, in the above formulas, NR 34 Medium R 34 For H.

[0320] In one embodiment, the -L3-R6 Select from the following groups:

[0321] In various types, R 61 is a heterocyclic group, an aryl group, a heteroaryl group, a cycloalkyl group, -N(R 34 )2, -NHC(=NH)NH2, -C(O)N(R 34 )2, -C1-C6 haloalkyl, -OR 34 、-(CH2OR 34 )(CH2) n OR 34 、-NR 34 C(O)-aryl, -COOH or -C(O)OC1-C6 alkyl; wherein the heterocyclic group must be replaced by one or more (e.g. 1, 2, 3, 4 or 5) R 35 Substitute or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form cyclopropyl or cyclobutyl; the -NR 34 The aryl group and the cycloalkyl group in C(O)-aryl may each be optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; the aryl group and the heteroaryl group may each be optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) R 36 Replace; each R 34 , each R 35 , each R 36 Preferably, in the above formulas, NR 34 Medium R 34 For H.

[0322] In one embodiment, the -L3-R 6 -NH-R 61 、-OR 61 or -R 61 ; or said -L3-R 6 Select from the following groups:

[0323] Among various types, NR 34 Medium R 34 is H; each R 61 Each independently selected from the following group:

[0324] In one embodiment, the -L3-R6 For-OR 61 、

[0325] In one embodiment, R 61 Each independently selected from the following group:

[0326] methyl

[0327] In one embodiment, the -L3-R 6 for In one embodiment, R 61 For-OR 34 、-N(R 34 )2 or heterocyclic group; wherein the heterocyclic group may be optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH2CH2- or -CH2CH2CH2- to form a cyclopropyl or cyclobutyl group; each R 34 , each R 35 Preferably, each R 35 Each is independently halogen, hydroxy, C1-C3 alkyl, C2-C4 alkenylene, C2-C4 haloalkenylene or C1-C3 haloalkyl. 34 Each is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl. 61 Each independently selected from the following group:

[0328] In one embodiment, R 61 It is hexahydro-1H-pyrrolizinyl.

[0329] In one embodiment, R 61 Is an R 35 Substituted hexahydro-1H-pyrrolizinyl; wherein R 35 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkenyl, C2-C3 haloalkenyl, phenyl, pyrazolyl or -CH2OC(O)N(R 34 )2; Each R 34 Each independently represents hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0330] In one embodiment, the 6- to 10-membered fused heterocyclic group is selected from the group consisting of:

[0331] In one embodiment, the 6- to 10-membered fused heterocyclic group is selected from the group consisting of:

[0332] The carbon atoms marked with * are the carbon atoms that are attached to other parts of the molecule.

[0333] In one embodiment, the 7- to 11-membered spiroheterocyclyl is selected from the group consisting of:

[0334] In one embodiment, the 7- to 11-membered spiroheterocyclyl is selected from the group consisting of:

[0335] The carbon atoms marked with * are the carbon atoms that are attached to other parts of the molecule.

[0336] In one embodiment, the spiro-substituted 6- to 10-membered fused heterocyclic group is selected from the group consisting of:

[0337] In one embodiment, the spiro-substituted 6- to 10-membered fused heterocyclic group is selected from the group consisting of:

[0338] The carbon atoms marked with * are the carbon atoms that are attached to other parts of the molecule.

[0339] In one embodiment, the spiro-substituted 7- to 11-membered spiroheterocyclyl is selected from the group consisting of:

[0340] In one embodiment, the 6- to 10-membered fused heterocyclic group is selected from the group consisting of:

[0341] In one embodiment, the 6- to 10-membered fused heterocyclic group is selected from the group consisting of:

[0342] The carbon atoms marked with * are the carbon atoms that are attached to other parts of the molecule.

[0343] In one embodiment, the 7- to 11-membered spiro heterocyclyl group is selected from the group consisting of:

[0344] In one embodiment, the 7- to 11-membered spiro heterocyclyl group is selected from the group consisting of:

[0345] The carbon atoms marked with * are the carbon atoms that are attached to other parts of the molecule.

[0346] In one embodiment, the spirocyclic and annular substituted 6- to 10-membered fused heterocyclic groups are selected from the group consisting of:

[0347] In one embodiment, the spirocyclic and annular substituted 6- to 10-membered fused heterocyclic groups are selected from the group consisting of:

[0348] The carbon atoms marked with * are the carbon atoms that are attached to other parts of the molecule.

[0349] In one embodiment, L3 is O; R 6 -L-hexahydro-1H-pyrrolizinyl; wherein L is C1-C4 alkylene; two hydrogen atoms on any one carbon atom of the hexahydro-1H-pyrrolizinyl are simultaneously replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl. Preferably, the hexahydro-1H-pyrrolizinyl group is optionally substituted by one or more (e.g., 1, 2, 3, 4 or 5) R 6a Substituted; wherein each R 6a Each is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or cyano.

[0350] In one embodiment, L3 is O; R 6 -L-hexahydro-1H-pyrrolizinyl; wherein L is C1-C4 alkylene; two hydrogen atoms on any one carbon atom of the hexahydro-1H-pyrrolizinyl are simultaneously replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Together with the connected carbon atoms, they form a C3-C6 monocyclic cycloalkyl or a 3-6-membered monocyclic heterocyclic group; the C3-C6 monocyclic cycloalkyl or 3-6-membered monocyclic heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, or a 5-membered or 6-membered monocyclic heteroaryl. Preferably, the hexahydro-1H-pyrrolizinyl is further optionally substituted by 1 or more (e.g., 1, 2, 3, 4, or 5) R 6a Substituted; wherein each R 6aEach is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or cyano.

[0351] In one embodiment, L3 is O; R 6 -L-hexahydro-1H-pyrrolizinyl; wherein L is C1-C4 alkylene; the two hydrogen atoms on one of the two carbon atoms on the hexahydro-1H-pyrrolizinyl are simultaneously replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl. Preferably, the hexahydro-1H-pyrrolizinyl group is optionally substituted by one or more (e.g., 1, 2, 3, 4 or 5) R 6a Substituted; wherein each R 6a Each is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or cyano.

[0352] In one embodiment, L3 is O; R 6 -L-hexahydro-1H-pyrrolizinyl; wherein L is C1-C4 alkylene; the two hydrogen atoms on one of the two carbon atoms on the hexahydro-1H-pyrrolizinyl are simultaneously replaced by ═CR 2a R 2b Replace; Among them, a pair of R 2a 、R 2b are each independently hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; another pair of R 2a 、R 2b Together with the connected carbon atoms, they form a C3-C6 monocyclic cycloalkyl or a 3-6-membered monocyclic heterocyclic group; the C3-C6 monocyclic cycloalkyl or 3-6-membered monocyclic heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, or a 5-membered or 6-membered monocyclic heteroaryl. Preferably, the hexahydro-1H-pyrrolizinyl is further optionally substituted by 1 or more (e.g., 1, 2, 3, 4, or 5) R 6a Substituted; wherein each R 6a Each is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or cyano.

[0353] In one embodiment, L3 is O; R 6 -L-hexahydro-1H-pyrrolizinyl; wherein L is C1-C4 alkylene; the two hydrogen atoms on one of the two carbon atoms on the hexahydro-1H-pyrrolizinyl are simultaneously replaced by ═CR 2a R 2b Replacement; among them, two pairs of R 2a 、R 2b Each independently forms a C3-C6 monocyclic cycloalkyl or a 3-6 membered monocyclic heterocyclic group together with the connected carbon atom; the C3-C6 monocyclic cycloalkyl or 3-6 membered monocyclic heterocyclic group is optionally substituted by 1, 2, or 3 groups selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, or a 5-membered or 6-membered monocyclic heteroaryl. Preferably, the hexahydro-1H-pyrrolizinyl is further optionally substituted by 1 or more (e.g., 1, 2, 3, 4, or 5) R 6a Substituted; wherein each R 6a Each is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or cyano.

[0354] In one embodiment, L3 is O; R 6 -L-hexahydro-1H-pyrrolizinyl; wherein L is C1-C4 alkylene; the hexahydro-1H-pyrrolizinyl is substituted by one or more (e.g., 1, 2, 3, 4 or 5) R 6a Substituted; wherein each R 6a Each is independently halogen, hydroxy, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or cyano.

[0355] In one embodiment, R 6 Select from the following groups: methyl,

[0356] In one embodiment, R 6 -L-6 to 10-membered fused heterocyclic group; the 6 to 10-membered fused heterocyclic group has 1, 2, 3 or 4 selected from N(R m ), S, S(=O), S(=O)2, O heteroatoms as ring atoms; R mis none, hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3-20 membered heterocyclic group; wherein L is a bond, C1-C4 alkylene or heteroaryl; the 6-10 membered fused heterocyclic group is saturated; two hydrogen atoms on the same carbon atom of any one or two carbon atoms in the 6-10 membered fused heterocyclic group are optionally replaced by ═CR 2a R 2b Substituted; the 6 to 10 membered fused heterocyclic group is optionally further substituted by one or more R 6a Replacement; R 2a 、R 2b 、R 6a The same as above. Preferably, R 2a 、R 2b are each independently hydrogen, halogen, C1-C4 alkyl, or C1-C4 haloalkyl; R 6a is halogen, hydroxy, or C1-C6 alkyl.

[0357] In one embodiment, R 6 -L-6 to 10-membered fused heterocyclic group; the 6 to 10-membered fused heterocyclic group is hexahydro-1H-pyrrolizinyl; wherein L is C1-C4 alkylene; two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6 to 10-membered fused heterocyclic group are optionally replaced by ═CR 2a R 2b Substituted; the 6 to 10 membered fused heterocyclic group is optionally further substituted by one or more R 6a Replacement; R 2a 、R 2b 、R 6a The same as above. Preferably, R 2a 、R 2b are each independently hydrogen, halogen, C1-C4 alkyl, or C1-C4 haloalkyl; R 6a is halogen, hydroxy, or C1-C6 alkyl.

[0358] In one embodiment, R 6 -L-6 to 10-membered fused heterocyclic group; the 6 to 10-membered fused heterocyclic group is hexahydro-1H-pyrrolizinyl; wherein L is C1-C2 alkylene; two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6 to 10-membered fused heterocyclic group are optionally replaced by =CR 2a R 2b Substituted; the 6 to 10 membered fused heterocyclic group is optionally further substituted by one or more R 6a Replacement; R 2a 、R 2b are each independently hydrogen or fluorine; R 6a is halogen, hydroxy or C1-C6 alkyl.

[0359] In one embodiment, R 6 Select from the following groups:

[0360] In each formula, each p1 is independently 1 or 2; R 2a 、R 2b The same as above. Preferably, R 2a 、R 2b are independently hydrogen, halogen or C1-C4 alkyl, C1-C4 haloalkyl. Preferably, the 1H-pyrrolizine is optionally further substituted by one or more R 6a Replacement; R 6a Same as above. Preferably, R 6a Each is independently halogen or C1-C6 alkoxy.

[0361] In one embodiment, R 6 Select from the following groups:

[0362] In one embodiment, R 6 Select from the following groups:

[0363] In various types, R 2a 、R 2b The same as above. Preferably, R 2a 、R 2b Each independently represents hydrogen, halogen or C1-C4 alkyl, C1-C4 haloalkyl. Preferably, the 1H-pyrrolizine is optionally further substituted by one or more (e.g., two or three) R 6a Replacement; R 6a Same as above. Preferably, R 6a Each is independently halogen or C1-C6 alkoxy.

[0364] In one embodiment, the compound is selected from Table (I):

[0365] Table (I)

[0366] The first aspect of the present invention also provides a compound represented by formula (Z1'), a stereoisomer thereof, a deuterated compound or a pharmaceutically acceptable salt thereof,

[0367] in,

[0368] W is N or CRz1, Rz1 is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0369] Z is N or CRz11, Rz11 is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0370] Rz2 is substituted or unsubstituted phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, benzo[d]thiazole, indole, indazole or pyridine; the substitution means that 1, 2, 3, 4 or 5 hydrogen atoms on phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, benzo[d]thiazole, indole, indazole or pyridine are independently replaced by R 1 replace;

[0371] Rz3 is hydrogen, deuterium, methyl, deuterated methyl or halomethyl or -CD2F or -CDF2;

[0372] R 1 Selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25 、N=S(O)(C1-C6 alkyl)2、S(O)C1-C6 alkyl、S(O)2R 26 , -S-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, C1-C6 cyanoalkyl, triazolyl, -S-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -CH2C(O)NR 27 R 28 , -C2-C6 alkynyl-NR 29 R 30 , C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C6 alkyl; wherein,

[0373] R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O)OC1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1-C6 haloalkyl; or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0374] R 23 、R 24are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0375] R 25 For hydroxyl, cyano, heterocyclic, NR 251 R 252 、C(O)NR 253 R 254 or SO2C1-C6 alkyl; wherein R 251 、R 252 、R 253 、R 254 are each independently H or C1-C6 alkyl; or R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; or R 253 、R 254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0376] R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C6 alkyl; or R 261 、R 262 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0377] R 27 、R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0378] R 29、R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0379] -L3-R 6 for

[0380] R 61 is a 3- to 6-membered heterocyclic group or a 6- to 10-membered fused heterocyclic group;

[0381] The 3- to 6-membered heterocyclic group is optionally substituted by one or two groups selected from deuterium, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; or two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 3- to 6-membered heterocyclic group are optionally replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0382] The 6- to 10-membered fused heterocyclic group is optionally substituted by one or two groups selected from deuterium, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; or the two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group are optionally simultaneously replaced by deuterium or ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b are independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; or each pair of R 2a 、R 2b Each independently forms together with the carbon atom to which it is attached a C3-C6 monocyclic cycloalkyl group or a 3 to 6-membered monocyclic heterocyclic group; and

[0383] The 3- to 6-membered heterocyclic group or the 6- to 10-membered fused heterocyclic group is further optionally substituted by 1 or 2 groups selected from C1-C4 alkyl, C1-C4 haloalkyl, and halogen;

[0384] The R 62 is hydroxy or halogen; R 63 is C1-C4 alkyl, C1-C4 haloalkyl or halogen.

[0385] In one embodiment, the compound represented by formula (Z1′) is a compound represented by formula (Z1), formula (Z2) or formula (Z3);

[0386] Wherein, Rz11, Rz1, Rz2, Rz3, L3, and R6 are defined the same as before.

[0387] In one embodiment, Rz3 is methyl, deuterated methyl or halomethyl.

[0388] In one embodiment, the compound represented by formula (Z1') is a compound represented by formula (Z); wherein Rz1 and Rz2 are the same as defined above;

[0389] -L3-R 6 for R 61 is a 3- to 6-membered heterocyclic group or a 6- to 10-membered fused heterocyclic group; the 3- to 6-membered heterocyclic group is optionally substituted by one or two groups selected from C1-C4 alkyl, C1-C4 haloalkyl, and halogen; two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group are optionally simultaneously replaced by deuterium or ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl.

[0390] In one embodiment, the compound represented by formula (Z1′) is a compound represented by formula (Z);

[0391] Wherein, Rz1, Rz2, and R6 are defined as above; -L3-R 6 for R 61 The compound represented by formula (Z) of the present invention may have better bioavailability and higher AUC when used as a KRAS G12D inhibitor.

[0392] In one embodiment, the compound represented by formula (Z1′) is a compound represented by formula (Z);

[0393] Where,

[0394] Rz1 is halogen or hydrogen;

[0395] Rz2 is substituted or unsubstituted phenyl, naphthyl or pyridine; the substitution means that 1, 2, 3, 4 or 5 hydrogen atoms on the phenyl, naphthyl or pyridine are independently replaced by R 1 replace;

[0396] R 1 Selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25 、N=S(O)(C1-C6 alkyl)2、S(O)C1-C6 alkyl、S(O)2R 26 , -S-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, C1-C6 cyanoalkyl, triazolyl, -S-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -CH2C(O)NR 27 R 28 , -C2-C6 alkynyl-NR 29 R 30 , C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C6 alkyl; wherein,

[0397] R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O)OC1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1-C6 haloalkyl; or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0398] R 23 、R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0399] R 25 For hydroxyl, cyano, heterocyclic, NR 251 R 252 、C(O)NR 253 R 254 or SO2C1-C6 alkyl; wherein R 251 、R 252 、R253 、R 254 are each independently H or C1-C6 alkyl; or R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; or R 253 、R 254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0400] R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C6 alkyl; or R 261 、R 262 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0401] R 27 、R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0402] R 29 、R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0403] -L3-R 6 for R 61is a 3- to 6-membered heterocyclic group or a 6- to 10-membered fused heterocyclic group; the 3- to 6-membered heterocyclic group is optionally substituted by one or two groups selected from C1-C4 alkyl, C1-C4 haloalkyl, and halogen; two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group are optionally simultaneously replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl.

[0404] In one embodiment, Rz11 is chloro or hydrogen.

[0405] In one embodiment, Rz1 is fluoro or hydrogen.

[0406] In one embodiment, R 61 is a 6- to 10-membered fused heterocyclic group; the 6- to 10-membered fused heterocyclic group is The 6- to 10-membered fused heterocyclic group is optionally substituted by one or two groups selected from deuterium, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; or two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group are optionally replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; and the 6 to 10-membered fused heterocyclic group is further optionally substituted by 1 or 2 groups selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen.

[0407] In one embodiment, R 61 is a 3- to 6-membered heterocyclic group; the 3- to 6-membered heterocyclic group is tetrahydropyrrole, piperidine, piperazine or morpholine; the 3- to 6-membered heterocyclic group is optionally substituted by one or two groups selected from C1-C4 alkyl, C1-C4 haloalkyl, and halogen; or two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 3- to 6-membered heterocyclic group are optionally simultaneously replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; and the 3 to 6-membered heterocyclic group is further optionally substituted by 1 or 2 groups selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen.

[0408] In one embodiment, the 6- to 10-membered fused heterocyclic group is selected from the group consisting of:

[0409] In one embodiment, the 6- to 10-membered fused heterocyclic group is selected from the group consisting of:

[0410] The carbon atoms marked with * are the carbon atoms that are attached to other parts of the molecule.

[0411] In one embodiment, the -L3-R 6 for

[0412] In one embodiment, R 61 Each independently selected from the following group:

[0413] In one embodiment, the -L3-R 6 for

[0414] In one embodiment, R 61 Each independently selected from the following group:

[0415] In one embodiment, the -L3-R 6 for

[0416] In one embodiment, the R 62 is hydroxy or halogen; R 63 is methyl, ethyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0417] In one embodiment, the R 62 is hydroxyl group, R 63 It is difluoromethyl.

[0418] In one embodiment, R 6 Select from the following groups:

[0419] In each formula, each p1 is independently 1 or 2; R 2a 、R 2b The same as above. Preferably, R 2a 、R 2b are independently hydrogen, halogen or C1-C4 alkyl, C1-C4 haloalkyl. Preferably, the 1H-pyrrolizine is optionally further substituted by one or more R 6a Replacement; R 6a Same as above. Preferably, R 6a Each is independently halogen or C1-C6 alkoxy.

[0420] In one embodiment, R 61 Select from the following groups:

[0421] In various types, R 2a 、R 2b are independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; or each pair of R 2a 、R 2b Each independently forms together with the connected carbon atom a C3-C6 monocyclic cycloalkyl or a 3 to 6-membered monocyclic heterocyclic group.

[0422] In one embodiment, among the above substituents, Optionally also 1 or 2 R 6a Replacement; R 6a are each independently hydrogen, deuterium or halogen.

[0423] In one embodiment, among the above substituents, Optionally also 1 or 2 R 6a Replacement; R 6a are each independently deuterium or halogen.

[0424] In one embodiment, R 61 Select from the following groups:

[0425] In one embodiment, R 1 Selected from: C1-C3 alkyl, halogen, hydroxy, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25 、N=S(O)(C1-C3 alkyl)2、S(O)C1-C3 alkyl、S(O)2R 26 , -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, -S-C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -CH2C(O)NR 27 R 28 , -C2-C4 alkynyl NR 29 R 30 , C2-C4 deuterated alkynyl, (C1-C3 alkoxy) C1-C3 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; wherein,

[0426] R 21 is H, C1-C3 alkyl, C1-C3 haloalkyl, C(O)C1-C3 alkyl or C(O)OC1-C3 alkyl; R 22is H, C1-C3 alkyl or C1-C3 haloalkyl; or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0427] R 23 、R 24 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0428] R 25 For hydroxyl, cyano, heterocyclic, NR 251 R 252 、C(O)NR 253 R 254 or SO2C1-C3 alkyl; wherein R 251 、R 252 、R 253 、R 254 Each independently represents H or C1-C3 alkyl; R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253 、R 254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0429] R 26 is C1-C3 alkyl, C1-C3 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C3 alkyl; or R 261 、R 262 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0430] R 27 、R28 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 27 、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy;

[0431] R 29 、R 30 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

[0432] In one embodiment, Rz2 is substituted or unsubstituted phenyl, naphthyl or pyridine; the substitution means that 1, 2 or 3 hydrogen atoms on the phenyl, naphthyl or pyridine are each independently replaced by R 1 Replacement; R 1 Selected from the group consisting of C1-C6 alkyl, halogen, C1-C6 haloalkyl, NR 21 R 22 ; R 21 is H, C1-C3 alkyl, C1-C3 haloalkyl, C(O)C1-C3 alkyl or C(O)OC1-C3 alkyl; R 22 is H, C1-C3 alkyl or C1-C3 haloalkyl; or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by one or two groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy. 21 H; R 22 For H.

[0433] In one embodiment, Rz2 is substituted with 1, 2, 3 or 4 R 1 Substituted phenyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1 is ethynyl, and the rest R 1Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0434] In one embodiment, Rz2 is substituted with 1, 2 or 3 R 1 Substituted phenyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl.

[0435] In one embodiment, Rz2 is substituted with 1, 2, 3 or 4 R 1 Substituted naphthyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, cyano or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0436] In one embodiment, Rz2 is substituted with 1, 2 or 3 R 1 Substituted naphthyl; wherein each R 1 are each independently halogen, hydroxy, ethynyl, methyl, ethyl, amino, cyano or difluoromethyl. Preferably, one of R 1 is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0437] In one embodiment, Rz2 is replaced by 1 or 2 R 1 Substituted naphthyl; wherein each R 1 are each independently halogen, ethynyl, or amino.

[0438] In one embodiment, Rz2 is substituted with 1, 2, 3 or 4 R 1 Substituted pyridyl; wherein each R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; the cyclopropyl is optionally substituted with halogen or methyl. Preferably, one of R 1is ethynyl, and the rest R 1 Each is independently halogen, hydroxy, ethynyl, methyl, methyl-O-, methyl-S-, trifluoromethyl, trifluoromethyl-O-, amino, isopropyl or cyclopropyl; the cyclopropyl being optionally substituted with halogen or methyl.

[0439] In one embodiment, Rz2 is selected from the group consisting of:

[0440] In one embodiment, the compound is selected from Table A.

[0441] In one embodiment, the compound is selected from the group consisting of:

[0442] The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect above or a pharmaceutically acceptable salt, stereoisomer, deuterated compound or solvate thereof; and a pharmaceutically acceptable carrier.

[0443] As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance and without toxic side effects on the host or subject. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparation is well known to those skilled in the field of cosmetics or topical medicine.

[0444] In an embodiment of the present invention, the pharmaceutical composition can be administered in any of the following ways: orally, by spray inhalation, rectally, nasally, buccally, topically, parenterally, such as by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or by means of an explanted reservoir. Among these, oral, intraperitoneal, or intravenous administration is preferred. When administered orally, the compounds of the present invention can be prepared into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are typically prepared by mixing the active ingredient with a suitable emulsifier and suspending agent. If desired, sweeteners, flavorings, or coloring agents may also be added to the above oral formulations. For topical administration, particularly for the treatment of affected areas or organs readily accessible by topical application, such as the eyes, skin, or lower intestinal neurological disorders, the compounds of the present invention can be formulated into different topical formulations depending on the affected area or organ. For topical ophthalmic administration, the compounds of the present invention can be formulated into a micronized suspension or solution in an isotonic, sterile saline solution at a specific pH, with or without a preservative such as benzyl chloride. For ophthalmic administration, the compounds can also be formulated into an ointment such as vaseline. For topical skin administration, the compounds of the present invention can be formulated into a suitable ointment, lotion, or cream formulation, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used for ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used for lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The compounds of the present invention can also be administered in the form of sterile injectable preparations, including sterile water for injection or oil suspensions or sterile injectable solutions. Useful carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils such as monoglycerides or diglycerides can also be used as solvents or suspending media.

[0445] Another aspect of the present invention provides use of the compound described in the first aspect above, or a pharmaceutically acceptable salt, stereoisomer, deuterated compound or solvate thereof, or the pharmaceutical composition described in the second aspect above, in the preparation of a medicament for preventing and / or treating a disease or condition; the disease or condition is a KRAS G12D-related disease or disorder.

[0446] As used herein, "KRAS G12D" refers to a mutant form of the mammalian KRAS protein containing an aspartic acid substituted for a glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRAS is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Vari-antp.Gly12Asp.

[0447] As used herein, "KRAS G12D inhibitor" refers to a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, deuterated compound, or solvate thereof. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRAS G12D.

[0448] As used herein, "KRAS G12D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRAS G12D mutation. A non-limiting example of a KRAS G12D-associated disease or disorder is a KRAS G12D-associated cancer.

[0449] Another aspect of the present invention provides a method for treating KRAS G12D-related cancers, comprising the steps of administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect of the present invention or a pharmaceutically acceptable salt, stereoisomer, deuterated compound or solvate thereof; or administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the second aspect of the invention.

[0450] Herein, in one embodiment, the KRAS G12D-related cancers include but are not limited to lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer and the like. In one embodiment, the KRAS G12D-related cancers include but are not limited to astrocyte cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma and the like. In one embodiment, the KRAS G12D-associated cancers include, but are not limited to, cancers of the heart, such as sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; cancers of the lung, such as bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, and mesothelioma; cancers of the gastrointestinal tract, such as esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma) and esophageal carcinoma. Cancers of the pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, carcinoid tumor), Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), genitourinary tract (e.g., kidney (adenocarcinoma, Wilms' tumor), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and prostate cancers. ), testicular (seminoma, teratoma, embryonal carcinoma, teratoma), choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer, for example, liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampullary cancer, bile duct cancer; bone cancer, for example, osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant benign giant cell tumor, chordoma, osteochondroma (osteoechondroma), benign enchondroma, benign chondroma osteoma and giant cell tumor; cancers of the nervous system, for example, of the skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas, glioblastomas multiforme, glioblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecological cancers, e.g., uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); blood cancers, e.g. For example, blood (myeloid leukemia (acute) and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); cancers of the skin, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and cancers of the adrenal gland, such as neuroblastoma; etc.;

[0451] In one embodiment, the KRAS G12D-associated cancer is lung cancer.

[0452] In one embodiment, the KRAS G12D-associated cancer is selected from the group consisting of gastric cancer, gastric adenocarcinoma, non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

[0453] Another aspect of the present invention provides a method for treating cancer in a subject in need thereof, the method comprising:

[0454] (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., a KRAS G12D-associated cancer); and

[0455] (b) administering to the subject a therapeutically effective amount of the compound of the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, deuterated compound or solvate thereof; or administering to the subject a therapeutically effective amount of the pharmaceutical composition of the second aspect of the invention.

[0456] In one embodiment, the administration is accomplished by a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intracavitary, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous, and local administration.

[0457] Another aspect of the present invention provides a method for inhibiting KRAS G12D activity in cells, comprising the steps of: contacting the cells with the compound of the first aspect of the present invention or a pharmaceutically acceptable salt, stereoisomer, deuterated compound or solvate thereof; or contacting the cells with the pharmaceutical composition of the second aspect of the present invention.

[0458] Another aspect of the present invention provides use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, deuterated compound or solvate thereof, or the pharmaceutical composition described in the second aspect, in the preparation of a KRAS G12D inhibitor.

[0459] As used herein, the term "subject" refers to an animal, particularly a mammal, preferably a human.

[0460] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or medicament that achieves the desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the amount of a given drug depends on many factors, such as specific dosing regimen, disease or condition type and severity thereof, the uniqueness (e.g., body weight) of the patient or host in need of treatment, but, according to specific surrounding circumstances, including, for example, the specific drug, route of administration, condition for treatment, and the patient or host for treatment, the dosage can be conventionally determined by methods known in the art. Typically, for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, such as about 1-1500 mg / day. The desired dose can be conveniently expressed as a single dose, or simultaneously administered (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been provided, the specific effective amount can be appropriately adjusted according to the patient's situation and in conjunction with the physician's diagnosis.

[0461] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids, such as nitric, phosphoric, and carbonic acids; organic acids, such as propionic, hexanoic, cyclopentylpropionic, glycolic, pyruvic, gluconic, stearic, and muconic acids; salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal or alkaline earth metal ion; or coordination compounds formed with an organic base, such as ethanolamine. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid or base groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of both. Generally, non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, are preferred. In addition to salt forms, the compounds provided herein also exist in prodrug form. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0462] As used herein, the terms "solvate" and "solvate" refer to compounds of the present invention in combination with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid, etc. Solvates include stoichiometric and non-stoichiometric solvents. Certain compounds of the present invention may exist in unsolvated or solvated forms. Generally, solvated forms are equivalent to unsolvated forms and are encompassed by the present invention.

[0463] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof. The atropisomers of the present invention are stereoisomers with axial or planar chirality based on restricted intramolecular rotation. And as a drug, stereoisomers with excellent activity are preferred. The compounds of the present invention have optical isomers arising from asymmetric carbon atoms, etc., and individual isomers can be resolved and obtained, if necessary, by methods known in the art, such as crystallization or chiral chromatography.

[0464] As used herein, the term "deuterated compound" refers to various deuterated forms of any compound disclosed herein. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. One of ordinary skill in the art will appreciate how to synthesize deuterated forms of compounds of any formula disclosed herein. For example, deuterated materials such as alkyl groups can be prepared by conventional techniques (see, for example, methyl-d3-amine, available from Aldrich Chemical Co., Milwaukee, WI, catalog 489,689-2).

[0465] Herein, the two hydrogen atoms on the same carbon atom are optionally replaced by =CR 2a R 2b Substitution means that the carbon atom is connected to CR through a double bond. 2a R 2b That is, the two hydrogen atoms on the same carbon atom are optionally connected to =CR 2a R 2b Substitution means that the carbon atom is replaced replaced.

[0466] As used herein, when a group such as an alkyl group is located in the middle of a structural formula, the group is a substituent. For example, an alkyl group is an alkylene group, etc.

[0467] As used herein, the term "alkyl" refers to a chain (straight or branched) saturated aliphatic hydrocarbon group. The term "alkyl" may be a straight or branched alkyl group containing 1 to 20 carbon atoms (C1-20 alkyl), preferably an alkyl group containing 1 to 12 carbon atoms (C1-12 alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms (C1-6 alkyl groups), non-limiting examples of which 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, etc. More preferred are lower alkyl groups having 1 to 3 carbon atoms (C1-3 alkyl groups), non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, etc.

[0468] As used herein, the term "C1-C6 alkyl" refers to straight and branched aliphatic groups consisting of 1 to 6 carbon atoms. Preferably, C1-C4 alkyl or C1-C3 alkyl is used. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0469] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group in which one or more hydrogen atoms are replaced by halogen. The alkyl moiety is as defined above. Preferably, a C1-C3 haloalkyl or a C1-C4 haloalkyl group is used. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and monofluoromethyl.

[0470] As used herein, the term "C1-C6 deuterated alkyl" refers to a C1-C6 alkyl group in which one or more hydrogen atoms are replaced by deuterium atoms. The alkyl portion is as defined above. Preferably, the group is a C1-C3 deuterated alkyl group or a C1-C4 deuterated alkyl group. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and monofluoromethyl.

[0471] As used herein, the term "C1-C6 alkoxy" refers to -O-C1-C6 alkyl, preferably C1-C3 alkoxy or C1-C4 alkoxy, wherein the alkyl portion is as defined above.

[0472] As used herein, the term "C1-C6 haloalkoxy" refers to -O-C1-C6 haloalkyl, preferably C1-C3 haloalkoxy or C1-C4 haloalkoxy, wherein the haloalkyl portion is as defined above.

[0473] As used herein, the term "C1-C6 deuterated alkoxy" refers to -O-C1-C6 deuterated alkyl, preferably C1-C3 deuterated alkoxy or C1-C4 deuterated alkoxy, wherein the deuterated alkyl portion is as defined above.

[0474] As used herein, the term "C1-C6 hydroxyalkyl" refers to -C1-C6 alkyl-hydroxy (OH). Preferably, C1-C3 hydroxyalkyl (i.e., -C1-C3 alkyl-hydroxy) or C1-C4 hydroxyalkyl (i.e., -C1-C4 alkyl-hydroxy) is used. The alkyl portion is as defined above.

[0475] As used herein, the term "C1-C6 cyanoalkyl" refers to -C1-C6 alkyl-cyano. Preferably, C1-C3 cyanoalkyl or C1-C4 cyanoalkyl, wherein the alkyl portion is as defined above.

[0476] As used herein, the term "C2-C6 alkynyl" refers to straight-chain and branched aliphatic groups consisting of 2-6 carbon atoms and having one or two carbon-carbon triple bonds. Preferably, the group comprises a C2-C4 alkynyl or a C2-C3 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0477] As used herein, the term "C2-C6 haloalkynyl" refers to a C2-C6 alkynyl group in which one or more hydrogen atoms are replaced by halogen. The alkynyl moiety is as defined above. Preferably, the group is a C2-C3 haloalkynyl or a C2-C4 haloalkynyl. Examples of haloalkynyl groups include, but are not limited to, monofluoroethynyl and difluoroethynyl.

[0478] As used herein, the term "C2-C6 alkenyl" refers to straight-chain and branched aliphatic groups consisting of 2-6 carbon atoms and having one or two carbon-carbon double bonds. Preferably, the group is C2-C4 alkenyl or C2-C3 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, and the like.

[0479] As used herein, the term "C2-C6 haloalkenyl" refers to a C2-C6 alkenyl group in which one or more hydrogen atoms are replaced by halogen. The alkenyl moiety is as defined above. Preferably, the alkenyl group is C2-C3 haloalkenyl or C2-C4 haloalkenyl. Examples of haloalkenyl groups include, but are not limited to, monofluorovinyl and difluorovinyl.

[0480] As used herein, the term "C2-C6 hydroxyalkynyl" refers to -C2-C6 alkynyl-OH, wherein alkynyl is as defined above. Preferably, it is C2-C4 hydroxyalkynyl or C2-C3 hydroxyalkynyl.

[0481] As used herein, the term "C2-C6 hydroxyalkenyl" refers to -C2-C6 alkenyl-OH, wherein alkenyl is as defined above. Preferably, it is C2-C4 hydroxyalkenyl or C2-C3 hydroxyalkenyl.

[0482] As used herein, the term "C1-C4 alkylene" refers to a C1-C4 alkyl group as defined above that is positioned between two other moieties of the molecule and serves to connect them. Typical alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0483] In the present invention, the above-mentioned various alkyl, alkenyl and alkynyl groups may be optionally substituted. When substituted, the substituent is preferably one or more substituent groups described in this application.

[0484] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to saturated monocyclic or polycyclic cyclic hydrocarbon groups, for example, including monocyclic cycloalkyl, spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl. The ring carbon atoms of cycloalkyl described in the present invention can optionally be replaced by 1,2 or 3 oxo groups to form a cyclic ketone structure. For example, the term "C3-C20 cycloalkyl" refers to a cycloalkyl group with 3 to 20 ring carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl. Preferably, it is C3-C12 cycloalkyl (more preferably C3-C8 monocyclic cycloalkyl), C5-C20 spirocycloalkyl, C5-C20 condensed cycloalkyl or C5-C20 bridged cycloalkyl.

[0485] The term "C3-C8 monocyclic cycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring carbon atoms. Preferably, it is a C3-C6 monocyclic cycloalkyl or a C4-C6 monocyclic cycloalkyl. More preferably, it is a C3, C4, C5 or C6 monocyclic cycloalkyl. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0486] As used herein, the terms "spiroalkyl" and "spiroalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing a carbon atom (called a spiro atom). Spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl and polyspiroalkyl groups according to the number of spiro atoms shared between the rings. The term "C5-C20 spiroalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring sharing the spiro atom is a C3-C8 monocyclic cycloalkyl ring. Preferably, it is a C6-C14 spiroalkyl group. More preferably, it is a C6-C14 monospiroalkyl group. More preferably, it is a C7-C11 spiroalkyl group. More preferably, it is a 7- to 11-membered monospiroalkyl group. Most preferably, it is C7 (C4 monocyclic cycloalkyl ring / C4 monocyclic cycloalkyl ring), C8 (C4 monocyclic cycloalkyl ring / C5 monocyclic cycloalkyl ring), C9 (C4 monocyclic cycloalkyl ring / C6 monocyclic cycloalkyl ring, C5 monocyclic cycloalkyl ring / C5 monocyclic cycloalkyl ring), C10 (C5 monocyclic cycloalkyl ring / C6 monocyclic cycloalkyl ring) or C11 (C6 monocyclic cycloalkyl ring / C6 monocyclic cycloalkyl ring) monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to:

[0487] These spirocycloalkyl groups may be attached to the rest of the molecule via any of the ring atoms.

[0488] As used herein, the terms "fused cycloalkyl" and "fused cycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing a pair of adjacent carbon atoms. Depending on the number of rings formed, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. The term "C5-C20 fused cycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring sharing an adjacent pair of carbon atoms is a C3-C8 monocyclic cycloalkyl ring. Preferably, the group is a C6-C14 fused cycloalkyl group. More preferably, the group is a C6-C14 bifused cycloalkyl group. More preferably, the group is a C7-C10 bifused cycloalkyl group. More preferably, the group is a C7-C10 bifused cycloalkyl group. Most preferably, the group is a C8 (a C5 monocyclic cycloalkyl ring fused to a C5 monocyclic cycloalkyl ring), a C9 (a C5 monocyclic cycloalkyl ring fused to a C6 monocyclic cycloalkyl ring), or a C10 (a C6 monocyclic cycloalkyl ring fused to a C6 monocyclic cycloalkyl ring) bifused cycloalkyl group. Specific examples of fused cycloalkyl groups include, but are not limited to:

[0489] These fused cycloalkyl groups may be attached to the rest of the molecule via any one of the ring atoms.

[0490] As used herein, the terms "bridged cycloalkyl" and "bridged cycloalkyl ring" refer to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing two carbon atoms that are not directly connected. Depending on the number of rings formed, the bridged cycloalkyl group can be classified as bicyclic, tricyclic, tetracyclic or polycyclic. The term "C5-C20 bridged cycloalkyl" refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein any two rings share two carbon atoms that are not directly connected. Preferably, it is a C6-C14 bridged cycloalkyl group. More preferably, it is a C7-C10 bridged cycloalkyl group. Specific examples of bridged cycloalkyl groups include, but are not limited to:

[0491] These bridged cycloalkyl groups can be attached to the rest of the molecule via any ring atom.

[0492] For example, examples of cycloalkyl groups herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and bicyclo[1.1.1]pentyl.

[0493] As used herein, the term "cycloalkoxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as previously described.

[0494] In the present invention, the above-mentioned various cycloalkyl groups may be optionally substituted. When substituted, the substituent is preferably one or more substituent groups described in the present application.

[0495] As used herein, the terms "heterocyclyl" and "heterocyclyl ring" are used interchangeably to refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclyls, spiro heterocyclyls, fused heterocyclyls, and bridged heterocyclyls. The ring carbon atoms of the heterocyclyl groups described in the present invention may be optionally substituted with 1, 2, or 3 oxo groups to form cyclic ketones, cyclic lactones, or cyclic lactams. For example, the term "3 to 20 membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group having 3 to 20 ring atoms, wherein one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(=O). m ' (wherein m' is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Wherein, when the ring atom is a nitrogen atom, it may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents as defined herein). The 3 to 20 membered heterocyclyl of the present invention includes monocyclic heterocyclyl (e.g., 3 to 8 membered monocyclic heterocyclyl), 5 to 20 membered spiro heterocyclyl, 5 to 20 membered fused heterocyclyl and 5 to 20 membered bridged heterocyclyl.

[0496] As used herein, the term "3- to 20-membered nitrogen-containing heterocyclic group" refers to a saturated or partially unsaturated monocyclic hydrocarbon group having 3 to 20 ring atoms and containing at least one nitrogen atom; wherein the group is attached to the rest of the molecule via the nitrogen atom; and the group optionally contains one or two additional nitrogen, oxygen or S(=O) atoms. m The 3- to 20-membered nitrogen-containing heterocyclic group of the present invention includes a monocyclic heterocyclic group (e.g., a 3- to 8-membered monocyclic nitrogen-containing heterocyclic group), a 5- to 20-membered nitrogen-containing spiro heterocyclic group, a 5- to 20-membered nitrogen-containing fused heterocyclic group, and a 5- to 20-membered nitrogen-containing bridged heterocyclic group.

[0497] As used herein, the terms "3 to 8 membered monocyclic heterocyclyl" and "3 to 8 membered monocyclic heterocyclyl ring" refer to a group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(=O). m ' (wherein m' is an integer from 0 to 2) is a saturated or partially unsaturated monocyclic hydrocarbon group containing a heteroatom. Preferably, it is a 3- to 6-membered monocyclic heterocyclic group having 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferably, it is a 4- to 6-membered monocyclic heterocyclic group having 4 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferably, it is a 5- or 6-membered monocyclic heterocyclic group having 5 or 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents as defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (i.e., S(=O) m', m' is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocyclic group may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Specific examples of monocyclic heterocyclic groups include, but are not limited to, aziridine, oxirane, azetidine, azetidine-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidine-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidine-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2 -ketone, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholine-3-one, morpholine-2-one, thiomorpholine-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4- Dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydropyridin-2(1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrol-2-one, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3- Dioxol-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazole-2-one, furan-2,5-dione, 3,6-dihydropyridine-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc.

[0498] As used herein, the term "3- to 6-membered nitrogen-containing heterocyclic group" refers to a saturated or partially unsaturated monocyclic hydrocarbon group having 3 to 6 ring atoms and containing at least one nitrogen atom as a ring atom; wherein the group can be linked to the other parts of the molecule through the nitrogen atom or through other ring atoms of the group; and the group may optionally contain one or two additional nitrogen, oxygen or S(=O) atoms. m m' (wherein m' is an integer from 0 to 2) is a heteroatom as a ring atom. Specific examples can be selected from 3- to 8-membered monocyclic heterocyclic groups, including but not limited to tetrahydropyrrolyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl and the like.

[0499] As used herein, the terms "spiroheterocyclyl" and "spiroheterocyclyl ring" refer to a polycyclic heterocyclic group formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (called a spiro atom), wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(=O). m ' (wherein m' is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom can be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents defined herein). Each monocycle can contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are divided into monospiro heterocyclic groups, dispiro heterocyclic groups or polyspiro heterocyclic groups according to the number of shared spiro atoms between the rings. The term "5 to 20 yuan spiro heterocyclic group" refers to a spiro heterocyclic group with 5 to 20 ring atoms, wherein one monocycle in the monocycle sharing the spiro atom is a 3 to 8 yuan monocyclic heterocyclic ring, and the other monocycle is a 3 to 8 yuan monocyclic heterocyclic ring or a 3 to 8 yuan monocyclic cycloalkyl ring. Preferably, there are 6 to 14 ring atoms, wherein 1 or 2 ring atoms are 6 to 14 yuan spiro heterocyclic groups with heteroatoms. More preferably, it is a 7 to 11-membered spiro heterocyclic radical having 7 to 11 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. Most preferably, it is a 7-membered (4-membered monocyclic heterocyclic radical ring / 4-membered monocyclic heterocyclic radical ring or 4-membered monocyclic heterocyclic radical ring / 4-membered monocyclic cycloalkyl or 4-membered monocyclic cycloalkyl ring / 4-membered monocyclic heterocyclic radical ring), an 8-membered (4-membered monocyclic heterocyclic radical ring / 5-membered monocyclic heterocyclic radical ring), a 9-membered (4-membered monocyclic heterocyclic radical ring / 6-membered monocyclic heterocyclic radical ring, a 5-membered monocyclic heterocyclic radical ring / 5-membered monocyclic heterocyclic radical ring), a 10-membered (5-membered monocyclic heterocyclic radical ring / 6-membered monocyclic heterocyclic radical ring) or an 11-membered (6-membered monocyclic heterocyclic radical ring / 6-membered monocyclic heterocyclic radical ring) monospiro heterocyclic radical. Specific examples of spiro heterocyclic radicals include, but are not limited to:

[0500] These spiro heterocyclyl groups may be attached to the rest of the molecule via any suitable ring atom.

[0501] As used herein, the term "5- to 20-membered nitrogen-containing spiro heterocyclic group" refers to a spiro heterocyclic group having 5 to 20 ring atoms and containing at least one nitrogen atom; wherein the group is attached to the rest of the molecule via the nitrogen atom; and the group optionally contains one or two or three additional atoms selected from nitrogen, oxygen or S(=O) m ' (wherein m' is an integer from 0 to 2) of heteroatoms as ring atoms.

[0502] As used herein, the terms "fused heterocyclyl" and "fused heterocyclyl ring" refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing a pair of adjacent ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(=O). m ' (wherein m' is an integer from 0 to 2) heteroatom, and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents defined herein). Each monocyclic ring may contain one or more double bonds, but no ring has a completely conjugated π electron system. The shared adjacent ring atom pairs may be CC or NC. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups. The term "5 to 20 membered fused heterocyclic group" refers to a fused heterocyclic group having 5 to 20 ring atoms, wherein the monocyclic ring sharing adjacent ring atom pairs is a 3 to 8 membered monocyclic heterocyclic ring. Preferably, it is a 6 to 14 membered fused heterocyclic group having 6 to 14 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferably, it is a 6-10-membered, 6-9-membered or 6-8-membered fused heterocyclic group having 6 to 10, 6 to 9 or 6 to 8 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferably, it is an 8-10-membered fused heterocyclic group having 8 to 10 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. Most preferably, it is an 8-membered (5-membered monocyclic heterocyclic ring fused to a 5-membered monocyclic heterocyclic ring), a 9-membered (5-membered monocyclic heterocyclic ring fused to a 6-membered monocyclic heterocyclic ring) or a 10-membered (6-membered monocyclic heterocyclic ring fused to a 6-membered monocyclic heterocyclic ring) bicyclic fused heterocyclic group. Specific examples of fused heterocyclic groups include, but are not limited to:

[0503] These fused heterocyclic groups may be attached to the rest of the molecule through any suitable ring atom.

[0504] As used herein, the term "5- to 20-membered nitrogen-containing fused heterocyclic group" refers to a fused heterocyclic group having 5 to 20 ring atoms and containing at least one nitrogen atom; wherein the group is attached to the rest of the molecule via the nitrogen atom; and the group optionally contains one or two or three additional atoms selected from nitrogen, oxygen or S(=O) m ' (wherein m' is an integer from 0 to 2) of heteroatoms as ring atoms.

[0505] As used herein, the terms "bridged heterocyclyl" and "bridged heterocyclyl ring" refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing two ring atoms that are not directly connected, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(=O). m ' (wherein m' is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. The term "5 to 20 membered bridged heterocyclic group" refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms, wherein any two rings share two ring atoms that are not directly connected, each monocyclic ring may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably it is a 6 to 14 membered bridged heterocyclic group. More preferably it is a 7 to 10 membered bridged heterocyclic group. Specific examples of bridged heterocyclic groups include, but are not limited to:

[0506] These bridged heterocyclic groups may be attached to the rest of the molecule via any suitable ring atom.

[0507] As used herein, the term "5- to 20-membered nitrogen-containing bridged heterocyclic group" refers to a bridged heterocyclic group having 5 to 20 ring atoms and containing at least one nitrogen atom; wherein the group is linked to the rest of the molecule through the nitrogen atom; and the group optionally contains another 1, 2, or 3 atoms selected from nitrogen, oxygen, or S(=O). m ' (wherein m' is an integer from 0 to 2) of heteroatoms as ring atoms.

[0508] In the present invention, the various heterocyclic groups mentioned above may be optionally substituted. When substituted, the substituents are preferably one or more substituent groups described in this application.

[0509] Specifically, specific examples of the heterocyclic group of the present invention include, but are not limited to, epoxy, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolyl, imidazopyridinyl, thiazolyl, oxazolidinyl, oxazolidinyl, decahydroquinolinyl, piperidinonyl, morpholinyl, azabicyclohexyl, azabicycloheptyl, azabicyclooctyl, azabicyclononyl, azabicyclodecyl, azaspiroheptyl, azaspiro Cyclooctyl, azaspirononyl, azaspirodecanyl, tetrahydrospiro[cyclopropane-1,2'-pyrrolazinyl]yl, hexahydro-1H-pyrrolazinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaspiroheptyl, oxaspirooctyl, oxaspirononyl, oxaspirodecyl, diazaspirononyl, oxabicyclohexyl, oxabicycloheptyl, oxabicyclooctyl, hexahydrooxazinyl 4(1H)-oxide.

[0510] As used herein, the term "aryl" refers to an all-carbon monocyclic, all-carbon non-fused polycyclic (rings are covalently bonded and non-fused) or all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, wherein at least one ring in the group is aromatic, i.e., has a conjugated π electron system. For example, the term "C6-C14 aryl" refers to an aryl group having 6 to 14 ring atoms. Preferably, it is a C6-C10 aryl group. In the present invention, C6-C14 aryl includes monocyclic aryl, non-fused polycyclic aryl, and aromatic fused polycyclic. Examples of monocyclic aryl include phenyl, and examples of non-fused polycyclic aryl include biphenyl.

[0511] In the present invention, when the C6-C14 aromatic group is an aromatic condensed polycyclic ring, the aromatic condensed polycyclic ring may be a polycyclic group formed by condensing a single aromatic ring with one or more single aromatic rings, and its non-limiting examples include naphthyl, anthracenyl, and the like.

[0512] In some embodiments of the present invention, when the C6-C14 aryl group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring may also be a polycyclic group formed by the fusion of a single aromatic ring (such as a phenyl group) and one or more non-aromatic rings, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring. The non-aromatic ring includes but is not limited to a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, the ring carbon atoms of which may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the ring carbon atoms of which may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure). The polycyclic group in which the above-mentioned single aromatic ring is fused to one or more non-aromatic rings may be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a single aromatic ring or a non-aromatic ring.

[0513] In the present invention, the above-mentioned various aryl groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more substituent groups described in this application.

[0514] As used herein, the term "aryl" refers to a C6-C14 aromatic group consisting of 1 to 3 aromatic rings. It may be optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) R 6 or one or more (e.g. 1, 2, 3, 4 or 5) R 7 Substitution. In one embodiment, the aryl group is a C6-C10 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to a bicyclic or tricyclic ring system, wherein one or both rings in the aryl group may be saturated or partially saturated, respectively. If the aryl group contains two saturated rings, the two saturated rings may be a fused ring system or a spirocyclic ring system. Examples of aryl groups containing two saturated rings (and being spirocyclic ring systems) include the following:

[0515] As used herein, the term "aryl C1-C6 alkyl" or "aralkyl" refers to a group comprising an aryl group covalently linked to an alkyl group. The aryl group is as defined above, the alkyl group is as defined above, and either or both of the aryl and alkyl groups may be independently optionally substituted or unsubstituted. An example of an aralkyl group is (C6-C10)aryl(C1-C6)alkyl-. Specific examples include, but are not limited to, benzyl, phenethyl, and naphthylmethyl. An example of a substituted aryl C1-C6 alkyl group is one in which the alkyl group is substituted with a hydroxyalkyl group.

[0516] As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic (i.e., sharing adjacent pairs of ring atoms, where the shared adjacent pairs of ring atoms may be CC or NC) group whose ring atoms are substituted by at least one heteroatom independently selected from nitrogen, oxygen or sulfur, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atom may be optionally quaternized. The heteroaryl group has 6, 10 or 14 shared π electrons, and at least one ring in the group is aromatic. For example, the term "5- to 14-membered heteroaryl" refers to a group having 5 to 14 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from nitrogen, oxygen or S(=O). m The heteroaryl group is preferably a 5- to 10-membered heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. The 5- to 14-membered heteroaryl group of the present invention may be a monocyclic heteroaryl group (e.g., a 5- or 6-membered monocyclic heteroaryl group), a fused bicyclic heteroaryl group (e.g., an 8- to 10-membered bicyclic heteroaryl group), or a fused tricyclic heteroaryl group.

[0517] As used herein, the term "5- or 6-membered monocyclic heteroaryl" refers to a group having 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(=O). m m' (wherein m' is an integer from 0 to 2). Specific examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

[0518] As used herein, the term "8- to 10-membered bicyclic heteroaryl" refers to a group having 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from nitrogen, oxygen or S(=O). mThe fused bicyclic heteroaryl group may be a bicyclic group (preferably a 9- or 10-membered bicyclic heteroaryl ring) formed by the fusion of a monocyclic heteroaryl ring (such as a phenyl group) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), or a bicyclic group (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).

[0519] Any two connected ring atoms on the monocyclic heteroaryl ring, including CC, NC, and NN, can be fused with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, such as a monocyclic cycloalkyl ring, a monocyclic heterocyclyl ring, a monoaryl ring, a 5- or 6-membered monocyclic heteroaryl ring, to form a fused polycyclic ring. The two connected ring atoms on the monocyclic heteroaryl ring forming a fused ring with another ring are preferably CC, including, but not limited to, the following forms:

[0520] In the above groups The labeled ring atoms are attached to the rest of the molecule.

[0521] Non-limiting examples of 8- to 10-membered bicyclic heteroaryls include benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, and the like.

[0522] Specific examples of bicyclic heteroaryl groups include, but are not limited to: These groups may be attached to the rest of the molecule via any suitable ring atom. The ring attached to the parent structure may be a monocyclic heteroaryl ring or a benzene ring.

[0523] In some embodiments of the present invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl can be a polycyclic group formed by the fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and one or more non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. The non-aromatic ring includes but is not limited to a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the ring carbon atoms of the monocyclic cycloalkyl ring may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure), etc. The polycyclic group formed by the fusion of the above-mentioned monocyclic heteroaryl ring and one or more non-aromatic rings can be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.

[0524] In the present invention, the various heteroaryl groups mentioned above may be substituted or unsubstituted. When substituted, the substituents are preferably one or more substituent groups described in this application.

[0525] As used herein, the term "acetyl" refers to -C(O)CH3.

[0526] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0527] Unless otherwise indicated, structures described herein are also intended to include compounds in which only one or more isotopically enriched atoms are present. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. BRIEF DESCRIPTION OF THE DRAWINGS

[0528] Figure 1 is a single crystal diffraction molecular stereostructure diagram of compound B. DETAILED DESCRIPTION

[0529] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. The synthetic methods of the intermediates or starting compounds herein are partially presented as preparation examples, partially presented in a particular example, and the preparation of the compound will not be repeated in the remaining examples if the same intermediates or starting compounds are used.

[0530] The present invention is described in detail below by way of examples, but this is not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof are disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Where specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or the conditions recommended by the manufacturer. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially.

[0531] For example, the compound of formula (A-4) can be produced in the following manner.

[0532] First, the compound of formula (A-1) is used as a raw material, and Reaction to form a compound of formula (A-2); then reacting the compound of formula (A-2) with The compound of formula (A-3) is reacted to form a compound of formula (A-4); the compound of formula (A-3) is subjected to a de-Boc reaction to form a compound of formula (A-4); R L1 、R L2 、R L3 、R L4 Each is independently a leaving group (e.g., a halogen, a boronic acid group (e.g., ), borate groups (e.g. ), -S(=O)CH3, -S(=O)2CH3, -OH, -SnBu3, benzotriazolyl-O- (e.g. )); X, Y, Z, W, R 1 、n1、L3、R 6 The definitions are the same as before.

[0533] For another example, the compound of formula (A-4) can be prepared in the following manner.

[0534] First, the compound of formula (A-1) is used as a raw material, and Reaction to form a compound of formula (A-2-1); then reacting the compound of formula (A-2-1) with The compound of formula (A-3-1) is reacted to form a compound of formula (A-3-1); the compound of formula (A-3-1) is then subjected to a de-Boc reaction to form a compound of formula (A-4); R L1 、R L2 、R L3 、R L4 Each is independently a leaving group (e.g., a halogen, a boronic acid group (e.g., ), borate groups (e.g. ), -S(=O)CH3, -S(=O)2CH3, -OH, -SnBu3, benzotriazolyl-O- (e.g. )); X, Y, Z, W, R 1 、n1、L3、R 6 The same definitions as above; R 1a refers to R protected by a protecting group 1 (For example, when R 1 When an acetylene group exists in the 1 When an amino group exists in the present invention, the amino group may be protected by Boc).

[0535] For another example, the compound of formula (A-4) can be prepared in the following manner.

[0536] First, the compound of formula (A-1) is used as a raw material, and Reaction to form a compound of formula (A-5); then reacting the compound of formula (A-5) with The compound of formula (A-3) is reacted to form a compound of formula (A-3); the compound of formula (A-3) is then subjected to a de-Boc reaction to form a compound of formula (A-4); X, Y, Z, W, R 1 、n1、L3、R 6 The definitions are the same as before.

[0537] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).

[0538] NMR measurements were performed using a Bruker Avance NEO 400 or Bruker Avance NEO 500 nuclear magnetic resonance spectrometer. Chemical shifts (δ) were expressed in parts per million (ppm). The measurement solvents were as indicated in the examples, and the internal standard was tetramethylsilane (TMS).

[0539] MS was determined using an Agilent 1100 liquid chromatograph.

[0540] High performance liquid chromatography (HPLC) analysis was performed using a Waters 2695 high performance liquid chromatograph.

[0541] High performance liquid chromatography (HPLC) was performed using a Waters 2767 HPLC.

[0542] Chiral HPLC analysis was performed using a Waters 2695 high performance liquid chromatograph or a Waters Investigator SFC system.

[0543] Chiral preparations were performed using a Gilson GX-281 chromatograph or a Waters SFC-80 chromatograph.

[0544] The thin layer chromatography silica gel plates used are Qingdao GF254 or Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used for thin layer chromatography (TLC) are 0.15mm-0.2mm in size. The size used for thin layer chromatography separation and purification of products is 0.4mm-0.5mm in size.

[0545] Column chromatography generally uses an ISCO CombiFlash NextGen 300 column chromatography system using Agela Flash Column Silica-Cs series silica gel columns.

[0546] The preparative HPLC used in the following examples, unless otherwise specified, can adopt the following conditions:

[0547] Preparative HPLC (formic acid method 1): Column type: Waters XBridge C18, 19*250 mm, 5 μm; Mobile phase system: A: 0.1% formic acid in water; B: preparative-grade acetonitrile; Flow rate: 15 mL / min; B% = 20%-100%; Column temperature: room temperature.

[0548] Preparative HPLC (formic acid method 2): chromatographic column: Welch Xtimate C18, 21.2*150 mm, 5 μm; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; flow rate: 15 mL / min; column temperature: room temperature.

[0549] Preparative HPLC (ammonium bicarbonate method 1): Column type: Waters XBridge C18, 19*250 mm, 5 μm; Mobile phase system: A: 5 mmol / L ammonium bicarbonate aqueous solution; B: preparative-grade acetonitrile; Flow rate: 15 mL / min; B% = 20%-100%; Column temperature: room temperature.

[0550] Preparative HPLC (ammonium bicarbonate method 2): chromatographic column: WelchXtimate C18, 21.2*150 mm, 5 μm; mobile phase A: 5 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 15 mL / min; column temperature: room temperature.

[0551] Preparative HPLC (ammonia method): chromatographic column: Waters Xbridge C18, 19*150 mm, 5 μm; mobile phase A: 0.1% ammonia solution, mobile phase B: acetonitrile; flow rate: 15 mL / min; column temperature: room temperature.

[0552] Preparative HPLC (trifluoroacetic acid method): chromatographic column: WelchXtimate C18, 21.2*150 mm, 5 μm; mobile phase A: 0.1% trifluoroacetic acid-water, mobile phase B: acetonitrile; flow rate: 15 mL / min; column temperature: room temperature.

[0553] Preparation Example 1 Synthesis of tert-butyl (1R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (A1)

[0554] Step 1: Add (S)-5-oxopyrrolidine-2-carboxylic acid methyl ester (200g, 1397mmol) and dimethyl sulfate (134mL) to a 1L single-necked flask. After the addition is complete, the system is reacted at 56°C for 18 hours. The reaction is complete when monitored by TLC. Cool to room temperature, add triethylamine (292mL) dropwise, and stir for 30 minutes. Add 400mL of water and extract with ethyl acetate (400mL x 3). The organic phase is washed with saturated brine (400mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is dried to obtain (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester (150g, yield: 68.4%) as a yellow oil. ES-API: [M+1] + =158.1.

[0555] Step 2: Add (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester (150 g, 954.3 mmol) and methyl nitroacetate (123.8 g, 1040.2 mmol) to a 1 L single-necked flask. After addition, the system was reacted at 60°C for 40 hours. The reaction was monitored for completion by NMR. Column chromatography (dichloromethane / ethyl acetate = 50 / 1) was used to obtain (S,Z)-5-(2-methoxy-1-nitro-2-oxyethylidene)pyrrolidine-2-carboxylic acid methyl ester (80.0 g, yield: 34.2%) as a yellow solid. ES-API: [M+1] + =245.1.

[0556] Step 3: In a 1L single-necked flask, add (S,Z)-5-(2-methoxy-1-nitro-2-oxyethylidene)pyrrolidine-2-carboxylic acid methyl ester (20.0g, 81.9mmol), palladium carbon (2.0g), and methanol (600mL). After the addition is complete, replace the gas with hydrogen three times. The system is reacted at 60°C for 5 days. The reaction is monitored by LC-MS. Repeat the addition for 4 batches. Filter and concentrate the filtrate to obtain (1R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (A11, 60g, crude product). ES-API: [M+1] + =185.1

[0557] Step 4: To a 1 L single-necked flask, add methyl (1R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (A1, 60.0 g, 325 mmol), triethylamine (65.9 g, 651.5 mmol), and dichloromethane (600 mL). Cool to 0°C and add di-tert-butyl dicarbonate (106.6 g, 488.6 mmol). After addition, allow the system to react overnight at room temperature. LC-MS monitors the reaction for completion. Add water (1 L) and extract with dichloromethane (1 L). The organic phase was dried by rotary evaporation, and the crude product was purified by column chromatography (dichlorohexane / methanol = 20:1) to afford 8-(tert-butyl)-2-methyl(1R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (A12, 70.0 g, yield: 75.8%) as a yellow solid. ES-API: [M-Boc+1] + =285.1.

[0558] Step 5: Add 8-(tert-butyl)-2-methyl(1R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (A12, 20.0 g, 70.3 mmol) and tetrahydrofuran (300 mL) to a 500 mL three-necked flask. Cool to 0°C and add lithium aluminum tetrahydride (5.87 g, 154.7 mmol) in portions (keeping the temperature below 5°C). Once the addition is complete, allow the system to react overnight at room temperature. Completion of the reaction is monitored by LC-MS. Cool to 0°C, quench the reaction with water, stir for 1 hour, filter, and rinse the filter cake with dichloromethane / methanol (10:1). Concentrate the filtrate to obtain the crude product. The crude product was subjected to preparative HPLC (ammonium bicarbonate method 1) on reverse phase to give tert-butyl (1R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (A1, 5.8 g, yield: 32.2%) as a yellow solid. ES-API: [M-Boc+1] + =243.2.

[0559] Preparation Example 2 Synthesis of Isomer (A2-1)

[0560] Step 1: Dissolve (R)-5-oxopyrrolidine-2-carboxylic acid methyl ester (395.3 g, 2.762 mmol) in 3500 mL of dichloromethane. Add trimethyloxonium tetrafluoroborate (612.697 g, 4.142 mol, 1.5 eq) in portions at 5°C. React at 25°C for 24 hours. Monitor the reaction for completion by TLC. Pour the reaction solution slowly into 5000 mL of saturated sodium carbonate aqueous solution at a pH of 8-9. Separate the layers and extract the aqueous phase with 1500 mL of dichloromethane. Combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, and filter to dryness to obtain (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester (406.7 g, 2.588 mol, yield: 93.702%) as a light yellow oily liquid. ES-API: [M+1] + =158.1.

[0561] Step 2: Add (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester (406.7 g, 2.588 mol) to nitroacetic acid methyl ester (308.133 g, 2.588 mol, 1 eq). React at 60°C for 48 hours, and monitor the reaction for completion under nuclear magnetic resonance. Column chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) yields 250.0 g of crude yellow oily liquid. Purify by beating, filter, and dry to obtain (R)-5-(2-methoxy-1-nitro-2-oxyethylene)pyrrolidine-2-carboxylic acid methyl ester (146.2 g, 598.687 mmol, yield: 23.136%) as a light yellow solid. ES-API: [M+1] + =245.1.

[0562] Step 3: In a 5L autoclave, (R)-5-(2-methoxy-1-nitro-2-oxyethylidene)pyrrolidine-2-carboxylic acid methyl ester (146.2 g, 598.687 mmol) was dissolved in methanol (1500 mL) and tetrahydrofuran (1500 mL). Pd(OH)2 / C (15.00 g, 20% purity) was added and the mixture was replaced with hydrogen three times. The reaction temperature was 0.4 MPa and the reaction temperature was 40°C for 72 hours. Hydrogen was added several times during the reaction. The mixture was cooled to room temperature and then removed from the autoclave. The reaction mixture was filtered and dried to obtain (1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (A21, 110.3 g, crude product) as a yellow oily liquid. ES-API: [M+1] + =185.1.

[0563] Step 4: Dissolve crude (1S,5R)-methyl 4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate (A21, 10.00 g, 54.291 mmol) in water (50 mL) and tetrahydrofuran (50 mL). Add NaCO (5.754 g, 54.291 mmol). Add (Boc)O (11.849 g, 54.291 mmol) dropwise at 10°C. Incubate at 20°C for 12 hours. Monitor reaction completion by TLC. The reaction mixture was filtered, and the filter cake was washed with 50 mL of ethyl acetate. The aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phases were combined and dried by column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to obtain 8-(tert-butyl)-2-methyl(1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (A22, 3.61 g, 12.698 mmol, yield: 23.388%) as a white solid. ES-API: [M-Boc+1] + =285.1.

[0564] Step 5: Dissolve 8-(tert-Butyl)-2-methyl(1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (A22, 2.00 g, 7.035 mmol) in tetrahydrofuran (20 mL). Add lithium aluminum tetrahydride (400.489 mg, 10.552 mmol, 1.5 eq) portionwise at 0°C. After addition, react at 20°C for 12 hours. TLC monitors the reaction for completion. At 0°C, add 0.4 mL of water, 0.4 mL of 15% sodium hydroxide solution, and 1.2 mL of water dropwise. After addition, add anhydrous magnesium sulfate, stir for 10 minutes, and filter and concentrate to obtain the crude product. The crude product was purified by reverse phase reaction to give tert-butyl (1S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (A2, 0.65 g, yield: 38%) as a pale yellow solid. ES-API: [M-Boc+1] + =243.2.

[0565] Step 6: (1S, 5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (A2, 100 mg) was prepared and separated by chiral SFC [column type: CHIRALPAK-IG, 30*250 mm, 10 um, mobile phase: carbon dioxide: methanol (0.1% ammonia water) = 80:20 (v / v), flow rate: 150 mL / min, column temperature = 35 ° C, detection wavelength 210 nm] to obtain an isomer compound with the structure of (1S, 2S, 5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (A2-1, 58 mg, peak 2, retention time 10.391 min, the structure was inferred by the single crystal data of Example 14). Isomers were detected by chiral HPLC (column type: CHIRALPAK-AY, 4.6*250mm, 5um, mobile phase: hexane:ethanol (0.1% diethylamine) = 95:5 (v / v), flow rate: 1mL / min, column temperature = 37°C, detection wavelength 210nm). 1 HNMR (400MHz, DMSO-d6): δ4.57(t,J=5.2Hz,1H),4.01-3.87(m,2H),3.23-3.13(m,2H) ,2.78-2.66(m,2H),2.59-2.52(m,1H),1.84-1.47(m,4H),1.40(s,9H).ES-API:[M+1] + =243.2.

[0566] Preparation Example 3 Synthesis of (R)-(1-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[0567] Step 1: A mixture of ethyl N-Boc-3-oxopyrrolidine-2-carboxylate (20.0 g, 77.73 mmol), tert-butyl(3-iodopropoxy)dimethylsilane (70.0 g, 233.106 mmol), potassium carbonate (53.70 g, 388.51 mmol), and N,N-dimethylformamide (150.0 mL) was stirred overnight at room temperature under nitrogen. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL x 2). The product was washed with saturated brine (400 mL x 3), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified using a flash silica gel column (ethyl acetate / petroleum ether: 0-10%) to obtain 1-(tert-butyl)-2-ethyl-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-oxopyrrolidine-1,2-dicarboxylate (14.2 g, 33.08 mmol, 43.0% yield) as a colorless, transparent oily liquid. ES-API: [M-Boc+H]+ =330.3.

[0568] Step 2: Methyltriphenylphosphonium bromide (59.0 g, 165.260 mmol) was added to tetrahydrofuran (150.0 mL) and cooled to 0°C. Under a nitrogen atmosphere, a solution of potassium tert-butoxide in tetrahydrofuran (132.0 mL, 132.0 mmol, 1 M) was added to the above mixture at 0°C. After the addition was complete, the reaction was warmed to room temperature and stirred for 0.5 hours. 1-(tert-Butyl)-2-ethyl 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-oxopyrrolidine-1,2-dicarboxylate (14.20 g, 33.052 mmol) was dissolved in tetrahydrofuran (50 mL) and slowly added to the above reaction mixture under a nitrogen atmosphere. After the addition was complete, stirring was continued at 60°C for 5 hours. Saturated ammonium chloride (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL x 3). The organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified using a flash silica gel column (ethyl acetate / petroleum ether: 0%-8%) to afford 1-(tert-butyl)-2-ethyl-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methylenepyrrolidine-1,2-dicarboxylate (9.0 g, 21.045 mmol, 63.67% yield) as a colorless, transparent liquid. ES-API: [M-Boc+H] + =328.3.

[0569] Step 3: Separate 1-(tert-butyl)-2-ethyl-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methylenepyrrolidine-1,2-dicarboxylic acid (9.0 g, 21.045 mmol) according to the following conditions: (Chromatographic column: Daicel IB 250*30mm, 10μm; mobile phase A: n-hexane; mobile phase B: ethanol; detection wavelength: 254nm / 214nm; flow rate: 25mL / min; isocratic elution program: mobile phase A: mobile phase B = 99:1 (v / v); column temperature: room temperature) yielded two isomers. One of the structures was arbitrarily designated as 1-(tert-butyl)-2-ethyl(S)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methylenepyrrolidine-1,2-dicarboxylic acid (4.20g, peak 1, retention time 4.21min, yield: 46.0%), a pale yellow oily liquid. ES-API: [M-Boc+H] +=328.3. Another structure was arbitrarily designated as 1-(tert-butyl)2-ethyl (R)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methylenepyrrolidine-1,2-dicarboxylate (4.60 g, peak 2, retention time 4.725 min, yield: 46.0%), a light yellow oily liquid. ES-API: [M-Boc+H] + =328.3.

[0570] Step 4: To a solution of 1-(tert-butyl)-2-ethyl (R)-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methylenepyrrolidine-1,2-dicarboxylate (3.50 g, 8.184 mmol) in dichloromethane (20.0 mL) was added thionyl chloride (8.0 mL, 110 mmol) under ice-water bath and reacted at 40°C for 12 h. The solvent was evaporated under reduced pressure, and 40 mL of acetonitrile and potassium carbonate (1000 mg, 7.24 mmol) were added to the system and reacted at 70°C for 1 h. After cooling to room temperature, the mixture was filtered. The filtrate was evaporated under reduced pressure and purified by column chromatography [DCM:MeOH = 100:0 to 90:10, (v / v)] to obtain (R)-1-methylenetetrahydro-1H-pyrrolidine-7a(5H)-carboxylic acid ethyl ester (830 mg, 4.251 mmol, yield 51.94%).

[0571] Step 5: (R)-1-methylenetetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (830 mg, 4.251 mmol) was dissolved in tetrahydrofuran (20.0 mL) and cooled to 0°C. Under a nitrogen atmosphere, lithium aluminum tetrahydride solution (8.50 mL, 8.50 mmol, 1 Min THF) was added to the above solution. The reaction was stirred at 0°C for 1 hour. Water (0.3 mL) was added to quench the reaction, and 15% aqueous sodium hydroxide solution (0.3 mL) and water (0.9 mL) were added. Tetrahydrofuran (10 mL) was added and filtered. The filtrate was concentrated to give (R)-(1-methylenetetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (300.0 mg, 1.958 mmol, yield 46.06%) as a colorless transparent liquid. ES-API: [M+H] + =154.1. 1 H NMR(400MHz,CD3OD)δ5.04-5.01(m,1H),4.91-4.89(m,1H),3.35-3.43(m,2H),3.12-3.04(m,1H) ,3.01-2.95(m,1H),2.77-2.69(m,1H),2.68-2.46(m,3H),2.00-1.90(m,1H),1.88-1.72(m,3H).

[0572] Example 1 Synthesis of 5-ethyl-4-((6R,9S)-12-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7B,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (Z1)

[0573] Step 1: To a solution of triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (500 mg, 1.012 mmol) in N,N-dimethylformamide (5.0 mL) was added cesium fluoride (3.0 g, 20.24 mmol) and reacted at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (100 mL x 2). The ethyl acetate phase was combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and dried to give 2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (558 mg, crude). ES-API: [M+H] + =339.3.

[0574] Step 2: To a solution of 2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (558 mg, crude product) in methanol (10.0 mL) was added 10% palladium on carbon (60 mg). The mixture was replaced with hydrogen four times and allowed to react at room temperature for 2 hours under hydrogen protection. After the reaction was complete, the mixture was filtered and the solvent was evaporated under reduced pressure to obtain 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (284 mg, total yield over 2 steps: 82%). ES-API: [M+1] + =343.3.

[0575] Step 3: Dissolve 2,4,6-trichloronicotinic acid (5.0 g, 22.22 mmol) in dichloromethane (40.0 mL) at 0°C. Add oxalyl chloride (6.0 mL) dropwise to the above system, and add 8 drops of N,N-dimethylformamide. Stir the reaction system at room temperature for 1 hour. After 1 hour, the solvent was evaporated under reduced pressure, and a solution of dry tetrahydrofuran (30.0 mL) was added. The mixture was cooled to 0-5°C and added dropwise to a mixed solution of ammonia (30.0 mL) and tetrahydrofuran (30.0 mL). Stir at room temperature for 1 hour. Extract with ethyl acetate (100 mL x 2). The ethyl acetate phase was combined and washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and dried to obtain 2,4,6-trichloronicotinamide (6.0 g, crude product). ES-API: [M+H] + =224.9 / 226.9.

[0576] Step 4: In a 500 mL three-necked round-bottom flask, dissolve (2,4-dimethoxyphenyl)methanamine (4.45 g, 26.66 mmol) in dry dioxane (90.0 mL). Cool to 0-5°C in an ice-water bath. Add N,N-diisopropylethylamine (8.61 g, 66.66 mmol) under nitrogen and allow to react at this temperature for approximately 10-15 minutes. Dissolve 2,4,6-trichloronicotinamide (6.0 g, crude) in dry dioxane (20 mL) and add dropwise to the above solution. Continue the reaction at 50°C for 5 hours. After completion of the reaction, the reaction mixture was poured into ice water (400 mL), extracted with ethyl acetate (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The crude product was purified by column chromatography [petroleum ether:ethyl acetate = 100:0 to 50:50, (v / v)] to obtain 2,6-dichloro-4-((2,4-dimethoxybenzyl)amino)nicotinamide (4.16 g, total yield over two steps: 52%). ES-API: [M+H] + =356.1 / 358.1.

[0577] Step 5: Add 2,6-dichloro-4-((2,4-dimethoxybenzyl)amino)nicotinamide (3.723 g, 10.47 mmol) and dry tetrahydrofuran (60 mL) to a 500 mL three-necked round-bottom flask at room temperature. Cool to 0-5°C in an ice-water bath. Add sodium hydride (838 mg, 20.95 mmol) in portions and react at this temperature for 20 minutes. Add N,N'-carbonyldiimidazole (5.09 g, 31.41 mmol) to dry tetrahydrofuran (30 mL) and add dropwise to the above solution. After addition, react at this temperature for 0.5-1 hour. After the reaction was complete, the reaction solution was poured into ice water (300 mL) and the pH was adjusted to 7-8 with 6 M aqueous hydrochloric acid in an ice-water bath. The product was filtered to obtain 5,7-dichloro-1-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (3.7 g, yield: 92.7%). ES-API: [M+H] + =382.0 / 384.0.

[0578] Step 6: Add dry tetrahydrofuran (100 mL) to a 250 mL single-necked flask at room temperature, followed by tert-butyl (1R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (358.0 mg, 1.480 mmol). Cool to 0-5°C in an ice-water bath, and add sodium hydride (1.20 mg, 2.960 mmol). React under nitrogen for 10-20 minutes, then add 5,7-dichloro-1-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (565.0 mg, 1.480 mmol) in portions. Continue the reaction at 0-5°C for 20-30 minutes. After completion of the reaction, the reaction solution was poured into ice water (300 mL) and adjusted to pH 7-8 with 6 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL x 2). The ethyl acetate phases were combined and washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and dried to give (1R,5S)-2-(((7-chloro-1-(2,4-dimethoxybenzyl)-2,4-dioxa-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (850 mg, yield: 97%). ES-API: [M+H] + =588.3.

[0579] Step 7: To a 250 mL single-necked flask at room temperature, add dry N,N-dimethylformamide (20 mL) and (1R,5S)-tert-butyl 2-(((7-chloro-1-(2,4-dimethoxybenzyl)-2,4-dioxa-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (850 mg, 1.448 mmol). Add 1-propylphosphonic anhydride (5.0 g, 7.856 mmol), react at room temperature for 5 minutes, and then add 1,8-diazabicyclo[5.4.0]undec-7-ene (1.14 g, 7.488 mmol) dropwise. React at room temperature for 1-2 hours. After the reaction was complete, the above solution was slowly added dropwise to 100 mL of ice water to precipitate a large amount of solid, which was filtered and dried under reduced pressure to obtain the target compound (6R,9S)-2-chloro-13-(3,4-dimethoxybenzyl)-12-oxo-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (620 mg, yield: 75.2%). ES-API: [M+H] + =570.3.

[0580] Step 8: To trifluoroacetic acid (5 mL) was added (6R,9S)-2-chloro-13-(3,4-dimethoxybenzyl)-12-oxo-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (420 mg, 0.7380 mmol) and stirred at 55° C. for 1 hour. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain (6R,9S)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methoxynaphtho[1,8-ab]heptene-12(13H)-one (500 mg, crude). ES-API:[M+H] + =320.1.

[0581] Step 9: To a mixed solution of (6R,9S)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-12(13H)-one (350 mg, 1.094 mmol) in tetrahydrofuran (5.0 mL) and water (5.0 mL) was added sodium carbonate (350 mg, 3.282 mmol), cooled in an ice-water bath, and added benzoyloxycarbonyl succinimide (354 mg, 1.422 mmol), and the mixture was reacted at room temperature for 3 hours. After the reaction was complete, dichloromethane (80 mL) was added to the reaction solution, and the mixture was washed with saturated sodium bicarbonate aqueous solution (100 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to obtain (6R,9S)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (460 mg, yield 93%). ES-API: [M+H] + =454.1.

[0582] Step 10: To a solution of (6R,9S)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (460 mg, 1.013 mmol) in toluene (3.0 mL) were added phosphorus oxychloride (465 mg, 3.039 mmol) and N,N-diisopropylethylamine (392.0 mg, 3.039 mmol) in sequence at 0°C, and the reaction was carried out at 125°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain (6R,9S)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (520 mg, crude product). ES-API: [M+H] + =472.2.

[0583] Step 11: To a solution of (6R,9S)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (200 mg, 0.4246 mmol) in N,N-dimethylformamide (3.0 mL) was added potassium fluoride (500 mg, 8.492 mmol) and the mixture was reacted at 120°C under nitrogen for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (50 mL x 2). The ethyl acetate phases were combined and washed with saturated brine (50 mL x 4), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain (6R,9S)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (130 mg, yield: 67.4%). ES-API: [M+H] + =456.1.

[0584] Step 12: Dissolve (6R,9S)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (140 mg, 0.3076 mmol) in tetrahydrofuran / water (2 mL / 0.5 mL), add 2-(8-ethyl-3-(methoxymethoxy)-1,4-diol)-1,4-diol; The mixture was stirred for 2 hours under a microwave-assisted oven dry condition. The mixture was stirred for 3 hours. The mixture was stirred for 1 hour. The mixture was stirred for 2 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (80 mL) and water (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-70%) to obtain the product (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (144 mg, yield: 73%). ES-API: [M / 2+1] + =636.3.

[0585] Step 13: To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (43.0 mg, 0.2714 mmol) in tetrahydrofuran (5.0 mL) in an ice-water bath, sodium hydride (22 mg, 0.5428 mmol) was added and the mixture was allowed to react at room temperature for 0.5 h. Benzyl (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylene[1,8-ab]heptene-14-carboxylate (145 mg, 0.1357 mmol) was added to the reaction mixture and the mixture was allowed to react at room temperature for 1-2 h. After the reaction was complete, ice water (50 mL) was added to the system, and the mixture was extracted with dichloromethane (50 mL x 2). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash silica gel column chromatography (methanol / dichloromethane: 0-10%) to obtain (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (170 mg, crude product). ES-API: [M / 2+1] + =775.3.

[0586] Step 14: To a solution of (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (170 mg, crude) in methanol (10.0 mL) was added a 5% by weight 10% palladium on carbon (500 mg) was replaced with hydrogen four times, and the mixture was reacted at room temperature under a hydrogen atmosphere for 2 hours to give (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene (162 mg, crude product). ES-API: [M / 2+1] + =7641.3.

[0587] Step 15: (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene (162 mg, crude) was dissolved in acetonitrile (6.0 mL). 4M hydrochloric acid / dioxane solution (2.0 mL, 8.0 mmol) was added under ice-cooling and the mixture was reacted under ice-cooling for 0.5 h. After completion of the reaction, the reaction solution was concentrated to dryness, dichloromethane (20 mL) was added, and triethylamine (3.0 mL) was added under ice-water cooling. The mixture was stirred for 10 minutes, and extracted with dichloromethane (100 mL x 1) and water (50 mL x 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure. The crude product was subjected to preparative HPLC (formic acid method 1) to obtain 5-ethyl-4-((6R,9S)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-2-yl)naphthalen-2-ol (5-ethyl-4-((6R,9S)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-2-yl)naphthalen-2-ol. R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol) (Z1, 4.69 mg, 3-step total yield: 5%, formate salt). ES-API: [M+1] + =597.3. 1 HNMR(500MHz,CD3OD)δ8.48(s,1H),7.58(d,J=8.0Hz,1H),7.34(t,J=8.0Hz,1H),7.25-6.91(m,4H),5.50-5.31(m,1H),5.11-4.97(m,1H ),4.70-4.30(m,4H),4.20-4.10(m,1H),3.85-3.73(m,2H),3.65-3.40(m,3H),3.29-3.14(m,2H),2.56-1.75(m,12H),1.00-0.85(m,3H).

[0588] Example 2 Synthesis of 5-ethyl-4-((5aS,6S,9R)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (Z2)

[0589] Step 1: Add dry tetrahydrofuran (100 mL) to a 250 mL single-necked flask at room temperature, followed by tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (358.0 mg, 1.480 mmol). Cool to 0-5°C in an ice-water bath, then add sodium hydride (1.20 mg, 2.960 mmol). After reacting for 10-20 minutes under nitrogen, add 5,7-dichloro-1-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (565.0 mg, 1.480 mmol) in portions and continue to react at 0-5°C for another 20-30 minutes. Upon completion of the reaction, the reaction mixture was poured into ice water (300 mL) and adjusted to pH 7-8 with 6 M aqueous hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (100 mL x 2). The combined ethyl acetate phases were washed with saturated brine (100 mL x 1). The mixture was dried over anhydrous sodium sulfate, filtered, and dried to give tert-butyl (1S,2S,5R)-2-(((7-chloro-1-(2,4-dimethoxybenzyl)-2,4-dioxa-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (850 mg, yield: 97%). ES-API: [M+H] + =588.3.

[0590] Step 2: To a 250 mL single-necked flask at room temperature, add dry N,N-dimethylformamide (20 mL) and tert-butyl (1S,2S,5R)-2-(((7-chloro-1-(2,4-dimethoxybenzyl)-2,4-dioxa-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (850 mg, 1.448 mmol). Finally, add 1-propylphosphonic anhydride (5.0 g, 7.856 mmol). After reacting at room temperature for 5 minutes, add 1,8-diazobispiro[5.4.0]undec-7-ene (1.14 g, 7.488 mmol) dropwise. React at room temperature for 1-2 hours. After the reaction was completed, the above solution was slowly added dropwise to ice water (100 mL) to precipitate a large amount of solid. The solid was filtered and the filter cake was dried under reduced pressure to obtain tert-butyl (5aS,6S,9R)-2-chloro-13-(3,4-dimethoxybenzyl)-12-oxo-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (620 mg, yield: 73%). ES-API: [M+H] + =570.3.

[0591] Step 3: To trifluoroacetic acid (5.0 mL) was added tert-butyl (5aS,6S,9R)-2-chloro-13-(2,4-dimethoxybenzyl)-12-oxo-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (420 mg, 0.7380 mmol) and stirred at 55 °C for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain (5aS,6S,9R)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-12(13H)-one (500 mg, crude product). ES-API: [M+H] + =320.1.

[0592] Step 4: To a mixed solution of (5aS,6S,9R)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-12(13H)-one (350 mg, 1.094 mmol) in tetrahydrofuran (5.0 mL) and water (5.0 mL) was added sodium carbonate (350 mg, 3.282 mmol), the system was cooled in an ice-water bath, and benzoyloxycarbonyl succinimide (354 mg, 1.422 mmol) was added and the reaction was carried out at room temperature for 3 hours. After the reaction was complete, dichloromethane (80 mL) was added to the reaction solution, which was then washed with saturated aqueous sodium bicarbonate (100 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to obtain (5aS,6S,9R)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (460 mg, yield: 93%). ES-API: [M+H] + =454.1.

[0593] Step 5: To a solution of benzyl (5aS,6S,9R)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (460 mg, 1.013 mmol) in toluene (3.0 mL) were added phosphorus oxychloride (465 mg, 3.039 mmol) and N,N-diisopropylethylamine (392.0 mg, 3.039 mmol) in sequence at 0°C and the reaction was carried out at 125°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain (5aS,6S,9R)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (520 mg, crude product). ES-API: [M+H] + =472.2.

[0594] Step 6: To a solution of (5aSs,6S,9R)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (200 mg, 0.4246 mmol) in N,N-dimethylformamide (3.0 mL) was added potassium fluoride (500 mg, 8.492 mmol) and reacted at 120°C under nitrogen for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (50 mL x 2). The ethyl acetate phases were combined and washed with saturated brine (50 mL x 4). The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and dried to give (5aS,6S,9R)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (130 mg, yield: 62%). ES-API: [M+H] + =456.1

[0595] Step 7: Dissolve (5aS,6S,9R)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (140 mg, 0.3076 mmol) in tetrahydrofuran / water (2 mL / 0.5 mL), add 2-(8-ethyl-3-(methoxy)-1,4-diol)-1,4-diol; The mixture was stirred for 2 hours. The mixture was stirred for 2 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 1 hour. After nitrogen was replaced 4 times, the mixture was microwaved at 80°C for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (80 mL) and water (60 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-70%) to obtain (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (144 mg, yield: 73%). ES-API: [M / 2+1] + =636.3.

[0596] Step 8: To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (43.0 mg, 0.2714 mmol) in tetrahydrofuran (5.0 mL) in an ice-water bath, sodium hydride (22 mg, 0.5428 mmol) was added and allowed to react at room temperature for 0.5 hour. After 0.5 hour, benzyl (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (145 mg, 0.1357 mmol) was added to the reaction system and allowed to react at room temperature for 1-2 hours. After the reaction was complete, ice water (50 mL) was added to the system, and the mixture was extracted with dichloromethane (50 mL x 2). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified on a flash silica gel column (methanol / dichloromethane: 0-10%) to obtain (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (170 mg, crude). ES-API: [M / 2+1] + =775.3.

[0597] Step 9: To a solution of (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (170 mg, crude) in methanol (10.0 mL) was added a 1% (mass fraction) of 1% (m / z)- ... 0% palladium on carbon (500 mg) was replaced with hydrogen four times, and the mixture was reacted at room temperature for 2 hours under a hydrogen atmosphere to obtain (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene (162 mg, crude product). ES-API: [M / 2+1] + =7641.3.

[0598] Step 10: (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene (162 mg, crude) was dissolved in acetonitrile (6.0 mL). 4M hydrochloric acid / dioxane solution (2.0 mL, 8.0 mmol) was added under ice-cooling and the mixture was reacted under ice-cooling for 0.5 h. After completion of the reaction, the reaction solution was concentrated to dryness and dichloromethane (20 mL) was added. Triethylamine (3.0 mL) was added under ice-water bath conditions. After stirring for 10 minutes, dichloromethane (100 mL x 1) and water (50 mL x 1) were added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The crude product was subjected to preparative HPLC (ammonium bicarbonate method 1) to obtain 5-ethyl-4-((5aS,6S,9R)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (5-ethyl-4-((5aS,6S,9R)- 12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3, 10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol) (Z2, 4.65 mg, 3-step yield: 2.73%). ES-API:[M+1] + =597.3. 1HNMR(500MHz,CD3OD)δ7.57(d,J=8.2Hz,1H),7.32(t,J=7.5Hz,1H),7.27-7.09(m,3H),7.06-6.90(m,1H) ,5.43-5.18(m,1H),5.01(dd,J=31.4,13.5Hz,1H),4.58(d,J=11.5Hz,1H),4.53-4.38(m,1H),4.25(d,J=1 0.4Hz,1H),4.19(d,J=10.4Hz,1H),4.16-4.04(m,1H),3.71(s,1H),3.63(s,1H),3.27-3.17(m,4H),3.01( td,J=9.6,5.5Hz,1H),2.55-2.08(m,5H),2.05-1.71(m,7H),0.97(t,J=7.5Hz,1H),0.90(t,J=7.4Hz,2H).

[0599] Example 3 Synthesis of 4-((6R,9S)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)-5-ethylnaphthol-2-ol (Z175-1)

[0600] Step 1: Dissolve (6R,9S)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methoxynaphtho[1,8-ab]heptene-14-carboxylate (380.0 mg, 0.8351 mmol) in tetrahydrofuran / water (12.0 mL / 2.0 mL), add triisopropyl ((6-(methoxymethoxy)-8-( The mixture was stirred for 1 h at 80°C for 2 h after nitrogen was replaced 4 times with the mixture of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (825.0 mg, 1.670 mmol), potassium phosphate (800 mg, 3.773 mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl)palladium(II) (80.0 mg, 0.110 mmol). The mixture was stirred for 1 h in a microwave oven at 80°C after nitrogen was replaced 4 times. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-70%) to obtain (6R,9S)-12-fluoro-2-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (500 mg, yield: 76%). ES-API: [M+1] + =788.3.

[0601] Step 2: To a solution of benzyl (6R,9S)-12-fluoro-2-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (500 mg, 0.6345 mmol) in N,N-dimethylformamide (20.0 mL) was added cesium fluoride (1.93 g, 12.69 mmol) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was extracted with ethyl acetate (150 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-70%) to obtain (6R,9S)-2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (370 mg, yield: 92%). ES-API: [M+1] + =631.3.

[0602] Step 3: To a solution of (6R,9S)-2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (370 mg, 0.5863 mmol) in methanol (20.0 mL) was added the following: The mixture was stirred for 2 hours at room temperature with 10% palladium carbon (500 mg), the hydrogen atmosphere was replaced 4 times, and the mixture was reacted under a hydrogen atmosphere for 2 hours to obtain (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene (200 mg, yield: 68%). ES-API: [M+1] + =502.3.

[0603] Step 4: To a solution of (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene (200 mg, 0.3984 mmol) in dichloromethane (20.0 mL) were added triethylamine (2.0 mL, 14.41 mmol) and di-tert-butyl dicarbonate (175 mg, 0.7968 mmol) in sequence and stirred at room temperature for 2 hours. After the reaction, the reaction solution was extracted with ethyl acetate (150 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-70%) to obtain tert-butyl (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (150 mg, yield: 62%). ES-API: [M+1] + =602.3.

[0604] Step 5: To a solution of (2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (28.0 mg, 0.1661 mmol) in tetrahydrofuran (5.0 mL) was added sodium hydride (13.28 mg, 0.3322 mmol) under ice-water bath conditions and allowed to react at room temperature for 0.5 hour. After 0.5 hour, tert-butyl (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (50 mg, 0.0830 mmol) was added to the reaction system and allowed to react at room temperature for 1-2 hours. After the reaction was complete, ice water (50 mL) was added to the system, and the mixture was extracted with dichloromethane (50 mL x 2). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified using a flash silica gel column (methanol / dichloromethane: 0-10%) to obtain tert-butyl (6R,9S)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (110 mg, crude). ES-API: [M+1] +=747.3.

[0605] Step 6: Dissolve tert-butyl (6R,9S)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (110 mg, crude) in acetonitrile (6.0 mL). Add 4M hydrochloric acid / dioxane solution (2.0 mL, 8.0 mmol) under ice-cooling and react under ice-cooling for 0.5 h. After completion of the reaction, the reaction solution was concentrated to dryness and dichloromethane (20 mL) was added. Triethylamine (3.0 mL) was then added under ice-water cooling. After stirring for 10 minutes, dichloromethane (100 mL x 1) and water (50 mL x 1) were added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate and filtered. The filtrate was dried under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (ammonium bicarbonate method 1) to obtain 4-((6R,9S)-12-((2,6-dimethyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-2-yl)-5-ethylnaphthol-2-ol (4-((6R,9S)-12-((2,6-dimethyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-2-yl)-5-ethylnaphthol-2-ol. hylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-p entaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethylnaphthalen-2-ol) (Z175-1, 7.47 mg, 2-step yield: 14.9%). ES-API:[M+1] + =603.3.

[0606] Example 4 Synthesis of 4-((6R,9S)-12-(3-(dimethylamino)azetidin-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)-5-ethylnaphthol-2-ol (Z308)

[0607] Step 1: To a solution of N,N-dimethylazetidin-3-amine hydrochloride (45.0 mg, 0.332 mmol) in dioxane (5.0 mL) was added N,N-diisopropylethylamine (430 mg, 3.322 mmol) and finally tert-butyl (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methoxynaphtho[1,8-ab]heptene-14-carboxylate (100 mg, 0.1660 mmol) under ice-water bath conditions. The mixture was reacted at 110°C for 2 hours. After 2 hours, ice water (50 mL) was added to the system, and the mixture was extracted with dichloromethane (50 mL x 2). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. It was purified on a flash silica gel column (methanol / dichloromethane: 0-10%) to give tert-butyl (6R,9S)-12-(3-(dimethylamino)azetidin-1-yl)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (110 mg, yield: 97%). ES-API: [M+1] + =682.3.

[0608] Step 2: Dissolve tert-butyl (6R,9S)-12-(3-(dimethylamino)azetidin-1-yl)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (110 mg, 0.1612 mmol) in acetonitrile (6.0 mL). Add 4M hydrochloric acid / dioxane solution (2.0 mL, 8.0 mmol) under ice-cooling and react under ice-cooling for 0.5 h. After completion of the reaction, concentrate the reaction solution to dryness, add dichloromethane (20 mL), and then add triethylamine (3.0 mL) under ice-water cooling. After stirring for 10 minutes, dichloromethane (100 mL) and water (50 mL) were added and extracted once. The dichloromethane phase was dried over anhydrous sodium sulfate and filtered. The filtrate was dried under reduced pressure to give a crude product. The crude product was prepared by HPLC (ammonium bicarbonate method 1) to give 4-((6R,9S)-12-(3-(dimethylamino)azetidin-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-2-yl)-5-ethylnaphthol-2-ol (4-((6R,9S)-12-(3- (dimethylamino)azetidin-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza- 6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethylnaphthalen-2-ol) (Z308, 14.92 mg, yield: 16.8%). ES-API:[M+1] + =538.3.

[0609] Example 5 Synthesis of trans-2-(((5S,5aS,6S,9R)-2-(3-amino-8-ethynylnaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hept-12-yl)oxy)cyclopentan-1-ol (Z718)

[0610] Step 1: trans-cyclopentane-1,2-diol (46 mg, 0.45 mmol) was dissolved in tetrahydrofuran (5 mL), and 60% sodium hydride (11 mg, 0.27 mmol) was added at 0°C. The reaction was stirred at this temperature for 30 minutes, and then a solution of (5S,5as,6S,9R)-2-(3-((tert-butyloxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-1-fluoro-5-methyl-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (80 mg, 0.092 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction was stirred at this temperature for 30 minutes. The reaction mixture was added with ethyl acetate (40 mL), and washed with water (10 mL) and saturated brine (15 mL) in that order. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (tetrahydrofuran / petroleum ether: 0-30%) to give the target product, (5S,5aS,6S,9R)-2-(3-((tert-butoxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-1-fluoro-12-(((trans-2-hydroxycyclopentyl)oxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (50 mg, 59.9% yield) as a pale yellow solid. ES-API: [M+H] + =923.3.

[0611] Step 2: (5S,5aS,6S,9R)-2-(3-((tert-butoxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-1-fluoro-12-(((trans-2-hydroxycyclopentyl)oxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (20 mg, 0.054 mmol) was dissolved in N,N-dimethylformamide (3 mL) and cesium fluoride (82 mg, 0.54 mmol) was added at room temperature. The reaction was stirred at room temperature for 30 minutes. Ethyl acetate (30 mL) was added to the reaction solution. The reaction mixture was stirred for 2 h (10 min), washed sequentially with water (5 mL), diluted brine (10 mL x 3), and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the target product, (5S,5aS,6S,9R)-2-(3-((tert-butoxycarbonyl)amino)-8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((trans-2-hydroxycyclopentyl)oxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylene[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (40 mg, yield 96.3%), as a light brown solid. ES-API: [M+H] + =767.2.

[0612] Step 3: Tert-butyl (5S,5aS,6S,9R)-2-(3-((tert-butoxycarbonyl)amino)-8-ethynylnaphthalen-1-yl)-1-fluoro-12-((trans-2-hydroxycyclopentyl)oxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (40 mg, 0.018 mmol) was dissolved in ethyl acetate (1 mL). 4 M hydrogen chloride in 1,4-dioxane (1.5 mL) was added at 0°C and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (ammonia method) to give the target product trans-2-(((5S,5aS,6S,9R)-2-(3-amino-8-ethynylnaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hept-12-yl)oxy)cyclopentan-1-ol ((1R,2R)-2-(((5S,5aS,6S,9R)-2-(3-amino- 8-ethynylnaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)cyclopentan-1-ol) (Z718, 6 mg, yield 20.4%, white solid). ES-API: [M+H] + =567.2.

[0613] Example 6 Synthesis of 5-ethyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aSs)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (Z140-1)

[0614] Step 1: To a solution of 2,6-dichloro-5-fluoronicotinic acid (8.0 g, 38.095 mmol) in dry tetrahydrofuran (150 mL) was added dropwise methyllithium (47.6 mL, 76.19 mmol, 1.6 M) at -78°C. After the addition was complete, the mixture was stirred at -20°C for 2 hours. The temperature was lowered to -78°C again, and a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (12.405 g, 38.095 mmol) in tetrahydrofuran (30 mL) was added dropwise over 30 minutes. After the addition was complete, the mixture was reacted at 0°C for 1.5 hours. After the reaction was complete, the reaction solution was poured into ice water (500 mL) and washed with chloroform (100 mL x 1). The aqueous phase was adjusted to pH 3 with hydrochloric acid (3 M). The aqueous phase was evaporated to dryness under reduced pressure. The crude product was purified by column chromatography [dichloromethane:methanol = 100:0 to 90:10, (v / v)] to obtain 4-bromo-2,6-dichloro-5-fluoronicotinic acid (7.6 g, yield: 88%). ES-API: [M+H] + =287.9.

[0615] Step 2: Dissolve 4-bromo-2,6-dichloro-5-fluoronicotinic acid (6.0 g, 20.90 mmol) in thionyl chloride (40.0 mL) at room temperature. Add 16 drops of N,N-dimethylformamide and stir at 100°C for 1 hour. The solvent is evaporated under reduced pressure. The crude product is added to a mixture of tetrahydrofuran (100 mL) and saturated sodium bicarbonate (100 mL) at 0°C. Finally, add methylaminothiomethyl ester (12.91 g, 68.607 mmol) and stir at this temperature for 30 minutes. The reaction mixture is then extracted with ethyl acetate (200 mL). The organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl)aminothiomethyl ester (2.23 g, yield: 29.8%). ES-API:[M+1] + =359.5.

[0616] Step 3: Under nitrogen protection, methyl (4-bromo-2,6-dichloro-5-fluoronicotinoyl) aminomethylimidothioate (880 mg, 2.45 mmol) and N, N-diisopropylethylamine (1.4 mL, 8.37 mmol) were sealed in dioxane (12 mL) and heated at 100 ° C for 16 hours. The reaction was concentrated until the volume was ~5 mL. Water (15 mL) and 2M aqueous hydrochloric acid solution (3 mL) were added to the residue. After the precipitate was formed, it was filtered and the filter cake was washed with water (10 mL). The filter cake was dried under reduced pressure to give 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (350 mg, yield: 51%) as a yellow solid. ES-API: [M+H]+ =280.0.

[0617] Step 4: To a suspension of sodium hydride (427.29 mg, 10.682 mmol) in tetrahydrofuran (20 mL) was added tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (813.53 mg, 3.357 mmol) at 0°C and stirred for 10 minutes. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (854 mg, 3.052 mmol) was added and the mixture was heated and stirred at 60°C for 1 hour. Upon completion of the reaction, the mixture was quenched with water and extracted with dichloromethane / methanol (10:1, 25 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1451 mg, 2.992 mmol, yield: 98.02%) as a yellow solid. ES-API: [M+H] + =486.1.

[0618] Step 5: To a solution of tert-butyl (1S, 2S, 5R) -2- (((7-chloro-8-fluoro-4-hydroxy-2- (methylthio) pyrido [4, 3-d] pyrimidin-5-yl) oxy) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1451 mg, 2.992 mmol) and N, N-diisopropylethylamine (4.957 mL, 29.916 mmol) in dichloromethane (20 mL) was added propylphosphonic anhydride (50% in ethyl acetate) (11422.33 mg, 17.949 mmol) and stirred at room temperature for 3 hours. Quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting solid was suspended in acetonitrile and stirred at room temperature for 10 minutes. Filtration and collection of the filter cake afforded tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (623 mg, yield: 45.0%) as a white solid. ES-API: [M+H] + =468.1.

[0619] Step 6: To a solution of tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (540 mg, 1.153 mmol) in dichloromethane (15 mL) was added m-chloroperbenzoic acid (322.61 mg, 1.589 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated sodium sulfite and extracted with dichloromethane (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by flash silica gel column chromatography (0-10% methanol / dichloromethane) to give tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (452 ​​mg, yield: 81.0%) as a white solid. ES-API: [M+H] + =484.1.

[0620] Step 7: To a solution of sodium hydride (45.07 mg, 1.878 mmol) in tetrahydrofuran was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (239.16 mg, 1.502 mmol) at 0°C. The reaction was stirred at room temperature for 10 minutes. The mixture was cooled to 0°C and a solution of (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (363.5 mg, 0.751 mmol) in tetrahydrofuran (5 mL) was added. The reaction was stirred at 0°C for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (0-5% methanol / dichloromethane) to afford tert-butyl (5aR,6S,9R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (134 mg, 30.85% yield) as a yellow solid. ES-API: [M+H] + =579.2.

[0621] Step 8: To tert-butyl (5aR,6S,9R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (134.0 mg, 0.233 mmol) and triisopropyl ((6-(methoxymethoxy)-8-(4, To a solution of (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), ... The crude product was purified by flash silica gel column chromatography (0-4% methanol / dichloromethane) to afford tert-butyl (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (164 mg, yield: 77.33%) as a yellow solid. ES-API: [M+H] + =911.5.

[0622] Step 9: To a solution of tert-butyl (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (165 mg, 0.181 mmol) in N,N-dimethylformamide (3.0 mL) was added cesium fluoride (127.55 mg, 0.840 mmol) and the mixture was stirred at room temperature for 0.5 hour. The reaction was complete. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield tert-butyl (5aS,6S,9R)-2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (150 mg, crude) as a yellow oil. ES-API: [M+H] + =755.3.

[0623] Step 10: To a solution of tert-butyl (5aS,6S,9R)-2-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (100 mg, 0.1324 mmol) in methanol (5.0 mL) was added palladium on carbon (75.0 mg, 0.061 mmol), the hydrogen atmosphere was replaced, and the mixture was reacted at room temperature under a hydrogen atmosphere for 1 hour. The mixture was filtered and concentrated. The crude product was purified by flash silica gel column chromatography (0-3% methanol / dichloromethane) to give tert-butyl (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (70 mg, yield: 70%) as a yellow solid. ES-API: [M+H] + =759.4.

[0624] Step 11: A reaction mixture of tert-butyl (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (80 mg, 0.105 mmol), acetonitrile (2.0 mL) and 4 M hydrochloric acid / dioxane solution (0.500 mL, 2.000 mmol) was reacted at 0°C for 1 hour. The crude product was concentrated and subjected to preparative HPLC (ammonium bicarbonate method 1) to give 5-ethyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (5-ethyl-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol. ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11, 13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol) (Z140-1, 9.65 mg, yield: 14.9%), yellow solid. ES-API:[M+1] + =615.3.

[0625] Example 7 Synthesis of (5aS,6S,9R)-2-(8-ethynylnaphth-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene (Z350)

[0626] Step 1: To tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150.0 mg, 0.321 mmol) and triisopropyl ((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydropyridin-3,4-dihydropyridin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150.0 mg, 0.321 mmol) To a solution of (1,2-naphthalene-1-yl)ethynyl)silane (220.0 mg, 0.506 mmol) in dioxane (6 mL) and water (1.5 mL) were added potassium phosphate (300 mg, 1.415 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (100 mg, 0.137 mmol). The mixture was purged with nitrogen and microwaved at 80°C for 40 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate (30 mL x 2) and saturated brine (30 mL). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography (methanol / dichloromethane = 0-4%) to give tert-butyl (5aS,6S,9R)-1-fluoro-12-(methylthio)-2-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (272 mg, crude) as a yellow solid. ES-API: [M+H] + =800.4.

[0627] Step 2: To a solution of tert-butyl (5aS,6S,9R)-1-fluoro-12-(methylthio)-2-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (272 mg, crude) in dichloromethane (15 mL) was added m-chloroperbenzoic acid (67.12 mg, 0.389 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated sodium sulfite and extracted with dichloromethane (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give tert-butyl (5aS,6S,9R)-1-fluoro-12-(methylsulfinyl)-2-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (230 mg, total yield over 2 steps: 93.8%) as a white solid. ES-API: [M+H] + =756.3.

[0628] Step 3: To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (100.0 mg, 0.628 mmol) in tetrahydrofuran (10.0 mL) was added sodium hydride (50.0 mg, 1.25 mmol) at 0°C. After stirring at the same temperature for 10 minutes, tert-butyl (5aS,6S,9R)-1-fluoro-1H-pyrrolazin-7a(5H)-yl)methanol was added. A solution of 2-(methylsulfinyl)-2-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (230.0 mg, 0.304 mmol) in tetrahydrofuran (5 mL) was stirred at 0°C for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to give tert-butyl (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (260 mg, crude) as a yellow solid. ES-API: [M+H] + =851.5.

[0629] Step 4: To a solution of (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (260 mg, crude) in N,N-dimethylformamide (5.0 mL) was added cesium fluoride (1000 mg, 6.583 mmol). The reaction was stirred at room temperature for 0.5 hours. The reaction was complete. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield tert-butyl (5aS,6S,9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (120 mg, 57% yield over two steps) as a yellow oil. ES-API: [M+H] + =695.3.

[0630] Step 5: A reaction mixture of (5aS,6S,9R)-2-(8-ethynylnaphth-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (120 mg, 0.173 mmol) and acetonitrile (5.0 mL) and 4 M hydrochloric acid / dioxane solution (2.0 mL, 8.000 mmol) was reacted at 0°C for 1 hour. The crude product was concentrated and subjected to preparative HPLC (ammonium bicarbonate method 1) to give (5aS,6S,9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene ((5aS,6S,9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene) l)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahy dro-5H-4-oxa-3,10a,11,13,14-pen-taaza-6,9-methanonaphtho[1,8-ab]heptalene) (Z350, 34 mg, yield: 33%), yellow solid. ES-API:[M+1] + =595.3. 1HNMR(500MHz,CD3OD)δ8.07(d,J=8.2Hz,1H),8.03(dd,J=7.8,3.6Hz,1H),7.73(ddd,J=13 .6,7.2,1.2Hz,1H),7.67-7.47(m,3H),5.30(d,J=54.1Hz,1H),5.05(ddd,J=13.5,6.6,2.2 Hz,1H),4.59(ddd,J=13.2,8.9,2.0Hz,1H),4.44(ddd,J=13.2,7.4,5.9Hz,1H),4.28(t,J =10.1Hz,1H),4.21(dd,J=10.5,5.4Hz,1H),4.12(d,J=6.2Hz,1H),3.72(s,1H),3.63(d,J= 5.2Hz,1H),3.27-3.16(m,4H),3.02(td,J=9.8,5.9Hz,1H),2.29-2.21(m ,1H),2.16-2.10(m,1H),1.99(dq,J=13.5,6.7Hz,2H),1.95-1.75(m,5H).

[0631] Example 8 Synthesis of 4-((5aS,6S,9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hept-2-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (Z380)

[0632] Step 1: To tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.214 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- To a solution of triisopropylsilane (200.0 mg, 0.390 mmol) in tetrahydrofuran (6 mL) and water (1.5 mL) were added potassium phosphate (200 mg, 0.943 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (50 mg, 0.069 mmol). The mixture was purged with nitrogen and microwaved at 80°C for 40 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate (30 mL x 2) and saturated brine (30 mL). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0-4%) to give tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (210 mg, crude) as a yellow solid. ES-API: [M+H] + =818.3.

[0633] Step 2: To a solution of tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (210 mg, crude) in dichloromethane (15 mL) was added m-chloroperbenzoic acid (55 mg, 0.320 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated sodium sulfite and extracted with dichloromethane (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (210 mg, crude) as a white solid. ES-API: [M+H] + =834.4.

[0634] Step 3: To a solution of (2,6-dimethyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (65.0 mg, 0.393 mmol) in tetrahydrofuran (10.0 mL) was added sodium hydride (50.0 mg, 1.25 mmol) at 0°C. After stirring at the same temperature for 10 minutes, tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methyl)- A solution of 1,2-dimethyl-1,4-dihydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (160.0 mg, 0.192 mmol) in tetrahydrofuran (5 mL) was added. The reaction was stirred at 0°C for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-5% methanol / dichloromethane) to give tert-butyl (5aS,6S,9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (211 mg, crude) as a yellow solid. ES-API: [M+H] + =935.5.

[0635] Step 4: To a solution of (5aS,6S,9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (211 mg, crude) in N,N-dimethylformamide (5.0 mL) was added cesium fluoride (1000 mg, 6.583 mmol). The reaction was stirred at room temperature for 0.5 hours. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield tert-butyl (5aS,6S,9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (200 mg, crude) as a yellow oil. ES-API: [M+H] + =773.3.

[0636] Step 5: (5aS,6S,9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (200 mg, crude product) and acetonitrile (5.0 mL) and 4M hydrochloric acid / dioxane solution (2.0 mL, 8.000 mmol) were reacted at 0°C for 1 hour. The crude product was concentrated and subjected to preparative HPLC (ammonium bicarbonate method 1) to give 4-((5aS,6S,9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptane-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (4-((5aS,6S,9R)-12-((2,6- dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pen-taaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol) (Z380, 8.95 mg, 5-step total yield: 5.23%), yellow solid. ES-API: [M+1] + =635.3. 1 H NMR(500MHz,CD3OD)δ7.86-7.78(m,1H),7.37-7.27(m,2H),7.19(dd,J=35.4,2.5Hz,1H),5.23-4.95(m,5H),4.69-4.01(m,5H ),3.86-3.46(m,5H),3.35(s,2H),3.21(t,J=12.9Hz,1H),2.78(d,J=16.5Hz,2H),2.58(d,J=16.4Hz,2H),2.08-1.65(m,5H).

[0637] Example 9 Synthesis of 4-((5aS,6S,9R)-3-chloro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepin[2′,1′:3,4][1,4]oxazepin[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol (Z381)

[0638] Step 1: To a suspension of sodium hydroxide (60% dispersion in oil) (32 mg, 0.81 mmol) in tetrahydrofuran (10 mL) at 0°C was added tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (131 mg, 0.54 mmol) and stirred at this temperature for 10 minutes. 7-Bromo-2,6-dichloro-5-fluoroquinazolin-4(3H)-one (170 mg, 0.54 mmol) was added and the mixture was heated and stirred at 60°C for 1 hour. Upon completion of the reaction, the reaction was quenched with water and extracted with dichloromethane / methanol (10:1, 25 mL x 3). The organic layer was dried over anhydrous sodium sulfate and spun down to give tert-butyl (1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)methyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (150 mg, yield: 51.0%). ES-API: [M+H] + =533.2.

[0639] Step 2: To a solution of tert-butyl (1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)methyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (110 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 mg, 0.62 mmol) in ultra-dry dichloromethane (10 mL) was added 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (86 mg, 0.42 mmol) and stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with dichloromethane (25 mL x 3), washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase preparative HPLC (trifluoroacetic acid method) to give tert-butyl (5aS,6S,9R)-2-bromo-3,13-dichloro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepine[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-15-carboxylate (64 mg, yield: 60.3%). ES-API: [M+H] + =515.1.

[0640] Step 3: To a solution of tert-butyl (5aS,6S,9R)-2-bromo-3,13-dichloro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepin[2',1':3,4][1,4]oxazepin[5,6,7-de]quinazoline-15-carboxylate (45 mg, 0.09 mmol) in ultra-dry N,N-dimethylformamide (10 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (29 mg, 0.18 mmol), potassium fluoride (51 mg, 0.9 mmol), and 4A molecular sieves. Stir at 120°C under nitrogen for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane (25 mL x 3). The mixture was then washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (trifluoroacetic acid method) to give tert-butyl (5aS,6S,9R)-2-bromo-3-chloro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepine[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-15-carboxylate (22 mg, yield: 38.4%). ES-API: [M+H] + =638.2.

[0641] Step 4: tert-Butyl (5aS,6S,9R)-2-bromo-3-chloro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepine[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-15-carboxylate (22 mg, 0.03 mmol) and 2-(8-ethyl- To a solution of 3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17 mg, 0.05 mmol) in tetrahydrofuran (6 mL) and water (1.0 mL) were added potassium phosphate (21 mg, 0.1 mmol) and [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (15 mg). The mixture was reacted at 60°C under nitrogen for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (30 mL x 2) and saturated brine (10 mL). The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (methanol / dichloromethane = 1:15) to give tert-butyl (5aS,6S,9R)-3-chloro-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepin[2',1':3,4][1,4]oxazepin[5,6,7-de]quinazoline-15-carboxylate (10 mg, yield: 43%). ES-API: [M+H] + =774.1.

[0642] Step 5: tert-Butyl (5aS,6S,9R)-3-chloro-2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepine[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-15-carboxylate (10 mM) g, 0.013 mmol) and acetonitrile (2.0 mL) and 4M hydrochloric acid / dioxane solution (0.5 mL, 2.000 mmol) were reacted at 0°C for 1 hour. The reaction solution was concentrated and the resulting crude product was subjected to preparative HPLC (formic acid method 1) to give 4-((5aS,6S,9R)-3-chloro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-5a,6,7,8,9, 10-Hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol (4-((5aS,6S,9R)-3-chloro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoaze-pino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-2-yl)-5-ethylnaphthalen-2-ol) (Z381, 5.0 mg, yield: 61.1%, formate salt), yellow solid. ES-API: [M+1] + =630.3. 1 H NMR (400MHz, CD3OD) δ8.51 (s, 2H), 7.59 (d, J = 8.1Hz, 1H), 7.37-7.27 (m, 1H), 7.24-7.07(m,2H),6.97(d,J=2.7Hz,1H),6.79(dd,J=12.2,2.6Hz,1H),5.4 4(d,J=52.4Hz,1H),5.09(dd,J=29.8,11.5Hz,3H),4.66-4.44(m,1H),4.24 -4.08(m,1H),3.92-3.57(m,5H),3.29-3.22(m,2H),2.63-2.31(m,5H),2.2 7-2.13(m,2H),1.99(dd,J=30.6,18.8Hz,5H),0.91(dt,J=14.5,7.4Hz,3H).

[0643] Example 10 Synthesis of 5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]hepten-2-yl)naphthalen-2-ol (Z131-1)

[0644] Step 1: To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (100.0 mg, 0.628 mmol) in tetrahydrofuran (10.0 mL) was added sodium hydride (50.0 mg, 1.25 mmol) at 0°C. After stirring at the same temperature for 10 minutes, tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3- A solution of (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (210.0 mg, 0.252 mmol) in tetrahydrofuran (5 mL) was stirred at 0°C for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-5% methanol / dichloromethane) to give tert-butyl (5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,1...

Claims

1. A compound represented by formula (Z1') or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, in, W is N or CRz1, Rz1 is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy; Z is N or CRz11, Rz11 is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy; Rz2 is substituted or unsubstituted phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, benzo[d]thiazole, indole, indazole or pyridine; the substitution means that 1, 2, 3, 4 or 5 hydrogen atoms on phenyl, naphthyl, quinoline, isoquinoline, benzo[b]thiophene, benzo[d]thiazole, indole, indazole or pyridine are independently replaced by R 1 replace; Rz3 is hydrogen, deuterium, methyl, deuterated methyl or halomethyl or -CD2F or -CDF2; R 1 Selected from the group consisting of C1-C6 alkyl, halogen, hydroxy, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, NR 21 R 22 、C(O)NR 23 R 24 、CH2R 25 、N=S(O)(C1-C6 alkyl)2、S(O)C1-C6 alkyl、S(O)2R 26 , -S-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, C1-C6 cyanoalkyl, triazolyl, -S-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -CH2C(O)NR 27 R 28 , -C2-C6 alkynyl-NR 29 R 30 , C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein the cycloalkyl is optionally substituted with halogen or C1-C6 alkyl; wherein, R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O)OC1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1-C6 haloalkyl; or R 21 、R 22 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 23 、R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 、R 24 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 25 For hydroxyl, cyano, heterocyclic, NR 251 R 252 、C(O)NR 253 R 254 or SO2C1-C6 alkyl; wherein R 251 、R 252 、R 253 、R 254 are each independently H or C1-C6 alkyl; or R 251 、R 252 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; or R 253 、R 254 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261 R 262 ; Among them, R 261 、R 262 are each independently H or C1-C6 alkyl; or R 261 、R 262 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 27 、R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 、R 28 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 29 、R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 、R 30 Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group, wherein the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; -L3-R 6 for R 61 is a 3- to 6-membered heterocyclic group or a 6- to 10-membered fused heterocyclic group; The 3- to 6-membered heterocyclic group is optionally substituted by one or two groups selected from deuterium, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; or two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 3- to 6-membered heterocyclic group are optionally replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; The 6- to 10-membered fused heterocyclic group is optionally substituted by one or two groups selected from deuterium, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; or two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group are optionally replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b are independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; or each pair of R 2a 、R 2b Each independently forms together with the carbon atom to which it is attached a C3-C6 monocyclic cycloalkyl group or a 3 to 6-membered monocyclic heterocyclic group; and The 3- to 6-membered heterocyclic group or the 6- to 10-membered fused heterocyclic group is further optionally substituted by 1 or 2 groups selected from C1-C4 alkyl, C1-C4 haloalkyl, and halogen; The R 62 is hydroxy or halogen; R 63 is C1-C4 alkyl, C1-C4 haloalkyl or halogen.

2. The compound according to claim 1, or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (Z1') is a compound represented by formula (Z1), formula (Z2) or formula (Z3); Wherein, Rz11, Rz1, Rz2, Rz3, L3, and R6 are respectively defined as in claim 1.

3. The compound according to claim 1 or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein: The compound represented by formula (Z1') is a compound represented by formula (Z); wherein Rz1 and Rz2 are each defined as in claim 1; -L3-R 6 for R 61 is a 3- to 6-membered heterocyclic group or a 6- to 10-membered fused heterocyclic group; the 3- to 6-membered heterocyclic group is optionally substituted by one or two groups selected from C1-C4 alkyl, C1-C4 haloalkyl, and halogen; two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group are optionally simultaneously replaced by deuterium or ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl.

4. The compound according to claim 1 or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein: The compound represented by formula (Z1') is a compound represented by formula (Z); Wherein, Rz1, Rz2, and R6 are defined in claim 1; -L3-R 6 for R 61 Same definition as claim 1.

5. The compound according to claim 1 or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein: Rz1 is fluorine or hydrogen.

6. The compound according to claim 1 or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein: R 61 Select from the following groups: In various types, R 2a 、R 2b are independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; or each pair of R 2a 、R 2b Each independently forms together with the connected carbon atom a C3-C6 monocyclic cycloalkyl or a 3 to 6-membered monocyclic heterocyclic group.

7. The compound according to claim 6, or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein: Among the substituents, Optionally also 1 or 2 R 6a Replacement; R 6a are each independently hydrogen, deuterium or halogen.

8. The compound according to claim 1 or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein: R 61 is a 6- to 10-membered fused heterocyclic group; the 6- to 10-membered fused heterocyclic group is The 6- to 10-membered fused heterocyclic group is optionally substituted by one or two groups selected from deuterium, C1-C4 alkyl, C1-C4 haloalkyl, and halogen; or two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 6- to 10-membered fused heterocyclic group are optionally replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; and the 6 to 10-membered fused heterocyclic group is further optionally substituted by 1 or 2 groups selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen.

9. The compound according to claim 1 or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein: R 61 is a 3- to 6-membered heterocyclic group; the 3- to 6-membered heterocyclic group is tetrahydropyrrole, piperidine, piperazine or morpholine; the 3- to 6-membered heterocyclic group is optionally substituted by one or two groups selected from C1-C4 alkyl, C1-C4 haloalkyl, and halogen; or two hydrogen atoms on the same carbon atom in any one or two carbon atoms of the 3- to 6-membered heterocyclic group are optionally simultaneously replaced by ═CR 2a R 2b Replacement; wherein, R 2a 、R 2b Each is independently hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl; and the 3 to 6-membered heterocyclic group is further optionally substituted by 1 or 2 groups selected from C1-C4 alkyl, C1-C4 haloalkyl, halogen.

10. The compound according to claim 1 or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein: R 61 Select from the following groups:

11. The compound according to claim 1 or its stereoisomer, deuterated compound or pharmaceutically acceptable salt, wherein: Rz2 is selected from the group consisting of:

12. A compound or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from Table A or selected from the following group:

13. The compound according to claim 1 or 12, or a stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein: The compounds are in free base form or in pharmaceutically acceptable salt form.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 12 or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

15. Use of the compound according to any one of claims 1 to 12, or its stereoisomer, deuterated compound, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for preventing and / or treating a disease or condition; the disease or condition is a KRAS G12D-related disease or disorder.

16. The use according to claim 15, wherein The KRAS G12D-associated disease or disorder is cancer.

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