Pyrimidine cyclic compounds, their preparation and uses

Abstract

This invention discloses a pyrimidine cyclic compound or its pharmaceutically acceptable salt, stereoisomer, or solvate that inhibits KRAS gene mutations. The compound structure is shown in formula (A), and the definitions of each group are detailed in the specification. Furthermore, this invention also discloses pharmaceutical compositions comprising this compound and their use in the preparation of cancer drugs.

Description

technical field

[0001] The invention belongs to the field of medicine, and in particular relates to a class of pyrimidocyclic compounds and its preparation method and application. prior art

[0002] KRAS is a 21 kD member of the Ras family of GTPase proteins and is an essential component of cell signaling. The role of KRAS in malignant tumors and its mutations in various tumor types (such as G12C mutation, G12D mutation, G12V mutation, etc.) are well known to the public, so KRAS has become a very attractive target for cancer therapy by the pharmaceutical industry. point. Compounds that inhibit the activity of KRAS are highly desired by researchers in this field and are under active research. At present, breakthroughs have been made in the field of KRASG12C. For example, the KRASG12C inhibitors of AMG and MIRATI have shown sufficient safety and efficacy. In particular KRASG12D, there is still ongoing interest and effort. Contents of the invention

[0003] The invention provides a class of pyrimidocyclic compounds with novel structures, which will be used as KRASG12D inhibitors, and have the advantages of high activity, good selectivity, and low toxicity and side effects.

[0004] The first aspect of the present invention provides a compound represented by formula (A) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof: (A) In the formula, X is O, S or NR 11; wherein, R 11 is selected from H, C1-C6 alkyl, C1-C6 deuterated alkyl and cycloalkyl; Y is CR 12R 13, CR 14R 15CR 16R 17, C(O) or C(O)CR 18R 19; among them, R 12 and R 13 are each independently selected from H, halogen, hydroxyl, 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-hydroxyl, -C1-C4 alkyl-cyano, -C1-C4 alkane Group-NR 121R 122; or R 12, R 13 and the carbon atoms connected to them together form a cycloalkyl group; R 14 and R 15 are each independently selected from H, nitro, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy radical, 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-hydroxyl, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121R 122; or R 14, R 15 and the carbon atoms connected to them together form a cycloalkyl group; R 16 and R 17 are each independently selected from H, halogen, hydroxyl, 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-hydroxyl, -C1-C4 alkyl-cyano, -C1-C4 alkane base-NR 121R 122; R 18, R 19 are each independently selected from H, C1-C3 alkyl and halogen; R 121, R 122 are each independently selected from H, C1-C3 alkyl; or R 121, R 122 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic 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 selected from the group consisting of halogen, hydroxyl , nitro, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy group substitution; W is N or CR 20; wherein, R 20 is H, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, hetero Cyclic group or heterocyclic group-O-; wherein, the cycloalkyl group and the heterocyclic group are each independently optionally substituted by halogen; Ring A (ring A described herein refers to ) is selected from the group consisting of aryl, heteroaryl; R 1 is a substituent at any position on ring A; n1 is 0, 1, 2, 3, 4 or 5; Each R 1 is independently selected from: C1-C6 alkyl, halogen, hydroxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, NR 21R 22 , C (O)NR 23R 24, CH 2R 25, N=S(O)(C1-C6 alkyl) 2, S(O)C1-C6 alkyl, S(O) 2R 26, -S-C1-C6 alkane Base, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, C1-C6 cyanoalkyl, triazolyl, -S-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, - CH 2C(O)NR 27R 28, -C2-C6 alkynyl-NR 29R 30, C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; Said cycloalkyl is optionally substituted by halogen or C1-C6 alkyl; wherein, R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O) 2C1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1- C6 haloalkyl; or R 21, R 22 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally selected by 1 or 2 Substitution from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 23 and R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 and R 24 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 25 is hydroxyl, cyano, heterocyclyl, NR 251R 252 , C(O)NR 253R 254 or SO 2C1-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 connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 A group selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy is substituted; or R 253, R 254 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic ring The 3 to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261R 262; wherein, R 261, R 262 are each independently H or C1-C6 alkyl; or R 261, R 262 and the nitrogen connected to them Atoms together form a 3 to 6-membered nitrogen-containing heterocyclic group, and the 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 members selected from halogen, methyl, trifluoromethyl, methoxy, tri Substituted by fluoromethoxy group; R 27 and R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 and R 28 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 29 and R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 and R 30 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; Z is N or CR 2; wherein, R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated Alkoxy, NR 31R 32, C2-C4 alkynyl or CH 2OR 33; wherein, R 31, R 32 are each independently hydrogen or C1-C6 alkyl; or R 31, R 32 and the nitrogen atom connected to them Together they form 3 to 6 membered nitrogen-containing heterocyclic groups; R 33 is hydrogen or C1-C6 alkyl; R 3a, R 3b, R 3c are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or R 3a is connected to R 3b to form -CHR 3a1- or -CHR 3a2CHR 3a3-; R 3c is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3a1, R 3a2, R 3a3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or R 3a is connected with R 3c to form -CHR 3a1- or -CHR 3a2CHR 3a3-; R 3b is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3a1, R 3a2, R 3a3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; L 3 is a bond, O or NR 34; R 6 is -L-6 to 10 membered fused heterocyclic group, -L-7 to 11 membered spiro heterocyclic group, -L-spiro ring substituted 6 to 10 membered fused heterocyclic group, -L-spiro ring substituted 7 to 11-membered spiroheterocyclyl, -L-heterocyclic substituted 6 to 10-membered fused heterocyclyl, -L-heterocyclic substituted 7 to 11-membered spiroheterocyclyl, or -L-spiro and substituted ring A 6- to 10-membered condensed heterocyclic group; The 6- to 10-membered fused heterocyclic group substituted by the spiro ring refers to any 1 or 2 carbon atoms in the 6- to 10-membered condensed heterocyclic group, and two hydrogen atoms on the same carbon atom are simultaneously replaced by -(CH 2 ) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a spiro-substituted 6 to 10 membered fused heterocyclic group; The 7- to 11-membered spiroheterocyclyl substituted by the spiro ring refers to any 1 or 2 carbon atoms on the 7- to 11-membered spiroheterocyclyl, and two hydrogen atoms on the same carbon atom are simultaneously replaced by -(CH 2 ) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 are substituted to form spiro-substituted 7- to 11-membered spiroheterocyclyls; The 6- to 10-membered condensed heterocyclic group substituted by the double ring refers to one hydrogen atom on each carbon atom of the same pair of carbon atoms in any 1 or 2 pairs of adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group Simultaneously substituted by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 to form and ring substituted 6 to 10 membered condensed heterocyclic group ; Or the 6- to 10-membered condensed heterocyclic group substituted by the ring means that the hydrogen atoms on any 2 non-adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group are replaced by -(CH 2 ) m4-,- (CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a ring-substituted 6- to 10-membered fused heterocyclic group; The 7- to 11-membered spiroheterocyclic group substituted with ring refers to 1 hydrogen atom on each carbon atom in the same pair of carbon atoms in any 1 or 2 pairs of adjacent carbon atoms on the 7- to 11-membered spiroheterocyclyl group at the same time substituted by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 to form and ring-substituted 7- to 11-membered spiroheterocyclyl; Or the 7- to 11-membered spiroheterocyclyl substituted by the ring means that the hydrogen atoms on any 2 non-adjacent carbon atoms on the 7- to 11-membered spiroheterocyclyl are replaced by -(CH 2 ) m4-, -( CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a ring-substituted 7- to 11-membered spiroheterocyclyl; The 6- to 10-membered condensed heterocyclic group substituted by spiro rings and parallel rings means that one hydrogen atom on each carbon atom in any pair of adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group is simultaneously replaced by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form another one on the ring-substituted and 6- to 10-membered condensed heterocyclic group The two hydrogen atoms on the carbon atom are replaced by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 at the same time to form a spiro ring substitution, Then form a spiro ring and a 6- to 10-membered condensed heterocyclic group substituted by a ring; The 6- to 10-membered condensed heterocyclic group and the 7- to 11-membered spiroheterocyclic group each independently have 1, 2, 3 or 4 members selected from N(R m), S, S(=O), S (=O) 2. The heteroatom of O is used as a ring atom; The 6- to 10-membered fused heterocyclic group substituted by the spiro ring, the 7- to 11-membered spiro heterocyclic group substituted by the spiro ring, the 6- to 10-membered condensed heterocyclic group substituted by the fused ring, the substituted ring substituted The 7 to 11-membered spiroheterocyclyl, the spiro ring and the fused ring-substituted 6 to 10-membered fused heterocyclyl each independently have 1, 2, 3, 4 or 5 members selected from N(R m), S , S(=O), S(=O) 2, heteroatoms of O as ring atoms; R n is hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3 to 20 membered heterocyclyl; R m is none, hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3 to 20 membered heterocyclyl; Wherein, the 6- to 10-membered condensed heterocyclic group and the 7- to 11-membered spiroheterocyclic group are each independently saturated or partially unsaturated; when the 6- to 10-membered condensed heterocyclic group, the 7 When the 11-membered spiroheterocyclyl is partially unsaturated, the ring has 1 or 2 double bonds; The 6 to 10 membered fused heterocyclic group (the 6 to 10 membered condensed heterocyclic group refers to -L-6 to 10 membered fused heterocyclic group, -L-spiro ring substituted 6 to 10 membered fused heterocyclic group , -L- ring-substituted 6 to 10-membered fused heterocyclic group or -L-spiro ring and ring-substituted 6 to 10-membered fused heterocyclic group) any one of the 6- to 10-membered fused heterocyclic groups Or 2 hydrogen atoms on the same carbon atom in 2 carbon atoms are optionally substituted by =CR 2aR 2b at the same time; the 6- to 10-membered condensed heterocyclic group is optionally also substituted by 1 or more R 6a; (Herein, the two hydrogen atoms on the same carbon atom are optionally simultaneously represented by =CR 2aR 2b means that the carbon atom is connected to the carbon atom (C) in CR 2aR 2b through a double bond.) The 7 to 11-membered spiroheterocyclyl (the 7 to 11-membered spiroheterocyclyl refers to -L-7 to 11-membered spiroheterocyclyl, -L-spiro ring substituted 7 to 11-membered spiroheterocyclyl or -L-and ring-substituted 7 to 11-membered spiroheterocyclyl) on any 1 or 2 hydrogen atoms on the same carbon atom in 2 carbon atoms optionally at the same time Replaced by =CR 2aR 2b; the 7 to 11 membered spiroheterocyclyl is optionally also substituted by 1 or more R 6a; Wherein, R 2a and 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 replaced by 1, 2, 3 members selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 Halogenated alkoxy group substitution; or each pair of R 2a, R 2b each independently and connected carbon atoms together form 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 replaced by 1, 2, 3 selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkane Substituent group, C1-C4 haloalkoxy group, C6-C10 aryl group, 5-membered or 6-membered monocyclic heteroaryl group; Each R 6a is independently halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkyne Base, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, cyano, -Q-phenyl, -Q-phenyl-SO 2F, -NHC( O) phenyl, -NHC(O) phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aromatic C1-C3 alkyl-, tert-butyldimethylsilyloxy CH 2-, -N(R 6b) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O) -, oxo, (C1-C3 haloalkyl) C (O) - , -SO 2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC(O)N(R 6b) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O )N(R 6b) 2, -CH 2NHC (O) C1-C6 alkyl, -CH 2 (pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -C1-C3 alkyl -OC (O) hetero Cyclic group, -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(CH 3) 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-C3alkyl-OC(O)phenyl or -CH2heterocyclyl; Phenyl is optionally substituted by -C(O)H or OH; heterocyclyl in -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 form a 3 to 6-membered nitrogen-containing nitrogen atom together with the nitrogen atom connected to them Heterocyclic group, the 3 to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; The C3-C6 cycloalkyl group is optionally substituted by 1 or 2 C1-C6 alkyl groups; Each m4 is 2, 3 or 4; Each m5, m6, m7, m8 is 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; or R 6 is hydrogen, -N(R 34) 2, heterocyclyl, cycloalkyl, C1-C6 alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L- Cycloalkyl, -L-N(R 34) 2, -L-NHC(=NH)NH 2, -L-C(O)N(R 34) 2, -L-C1-C6 haloalkyl, -L-OR 34, -L-(CH 2OR 34)(CH 2) nOR 34, -L-NR 34C(O)-aryl, -L-COOH or -L-C(O)OC1-C6 alkyl; wherein, the heterocyclyl , the cycloalkyl, the aryl in the -L-NR 34C(O)-aryl, the heterocyclyl in the -L-heterocyclyl, the cycloalkane in the -L-cycloalkyl Each group can be optionally substituted by one or more R 35 or optionally two hydrogen atoms on the same carbon atom can be substituted by -CH 2CH 2- or -CH 2CH 2CH 2- at the same time to form cyclopropyl or cyclobutyl The aryl group in the -L-aryl group and the heteroaryl group in the -L-heteroaryl group can each be optionally substituted by one or more R36; Wherein, each L is independently a bond, C1-C4 alkylene or heteroaryl; wherein, said C1-C4 alkylene is any carbon atom or 1 or 2 of any same carbon atom Each of the hydrogen atoms is optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenyl or C2-C4 haloalkenyl; or the C1-C4 alkylene Any two hydrogen atoms on the same carbon atom are optionally simultaneously replaced by -(CH 2) m3-, -(CH 2) m1-O-(CH 2) m2-, -(CH 2) m1-NR 9- (CH2) m2-substituted so as 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 , m2 are not 0 at the same time; R 9 is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkyl-hydroxyl, 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; Each R is independently halogen, hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 Cycloalkyl, -C1-C3alkyl-C1-C3alkoxy, -C1-C3alkyl-hydroxyl, heterocyclyl (eg 3 to 6 membered heterocyclyl), cyano, -phenyl, -benzene -SO 2F, -O-phenyl, -O-phenyl-SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, Aryl C1-C3 alkyl-, tertiary butyldimethylsilyl CH 2-, -N(R 34) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl )C(O), oxo, (C1-C3 haloalkyl) C(O)-, -SO 2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC (O) OC1-C6 alkyl, -CH 2NHC (O) N (R 34) 2, -CH 2NHC (O) C1-C6 alkyl, -CH 2 (pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC (O) heterocyclyl, -OC (O) N (R 34) 2, -OC (O) NH (C1-C3 alkyl) O (C1-C3 alkane base), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH 3) 2, -OC(O)NH(C1-C3 Alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocyclyl (eg -OC(O)-3 to 6 membered heterocyclyl) or -CH 2 heterocyclyl (eg -CH 2 -3 to 6-membered heterocyclyl); 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 heterocyclic group in the -CH 2 heterocyclic group is optionally substituted by oxo; The hydrogen atom on the -C1-C3 alkyl- is selected from halogen, deuterium, C1- C3 alkyl, C1-C3 haloalkyl substituted by 1 or 2 groups; Each R 36 is independently halogen, hydroxyl, HC(O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl or -N(R 34 ) 2; Each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, the 3 to 6 The 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

[0005] In one embodiment, each R 6a is independently halogen, hydroxyl, 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- SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl Oxygen CH 2-, -N(R 6b) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O) -, oxo, (C1-C3 haloalkyl )C(O)-, -SO 2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC(O)N(R 6b) 2, -CH 2NHC(O)OC1-C6 alkyl , -CH 2NHC(O)N(R 6b) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2(pyrazolyl), -CH 2NHSO 2C1-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 (CH 3) 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 alkane -C1-C3 alkyl-OC(O)C1-C6 haloalkyl, -OC(O)phenyl, -C1-C3alkyl-OC(O)phenyl or -CH 2 heterocyclyl; among them, 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 is independently hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl; or two R 6b are independently formed together with the nitrogen atom connected to them 3 to 6-membered nitrogen-containing heterocyclic group, said 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 members selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy The C3-C6 cycloalkyl group is optionally substituted by 1 or 2 C1-C6 alkyl groups.

[0006] In one embodiment, each R 6a is independently halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C2-C4 alkenyl, halogenated C2-C4 alkenyl, C2-C4 alkynyl, Halogenated C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C6 cycloalkyl, cyano, -Q-phenyl, -Q-phenyl- SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyl Oxygen CH 2-, -N(R 6b) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O) -, oxo, (C1-C3 haloalkyl )C(O)-, -SO 2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC(O)N(R 6b) 2, -CH 2NHC(O)OC1-C3 alkyl , -CH 2NHC(O)N(R 6b) 2, -CH 2NHC(O)C1-C3 alkyl, -CH 2(pyrazolyl), -CH 2NHSO 2C1-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 (CH 3) 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 alkane -C1-C3 alkyl-OC(O)C1-C3 haloalkyl, -OC(O)phenyl, -C1-C3alkyl-OC(O)phenyl or -CH 2 heterocyclyl; among them, 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 is independently hydrogen, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or two R 6b are independently formed together with the nitrogen atom connected to them 3 to 6-membered nitrogen-containing heterocyclic group, said 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 members selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy The C3-C6 cycloalkyl group is optionally substituted by 1 or 2 C1-C6 alkyl groups.

[0007] In one embodiment, each R 6a is independently halogen, hydroxyl, 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 is independently hydrogen, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; Or two R 6b each independently form a 3 to 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom connected to them, and the 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 members selected from halogen , methyl, trifluoromethyl, methoxy, trifluoromethoxy group substitution; the C3-C6 cycloalkyl is optionally substituted by 1 or 2 methyl groups.

[0008] In one embodiment, each R 6a is independently halogen, hydroxy, methyl, ethyl, propyl, vinyl, halovinyl (eg, monofluorovinyl, difluorovinyl, etc.), ethynyl, Proynyl, halomethyl, haloethyl, cyclopropyl, cyano, -N(R 6b) 2; wherein, each of the above R 6b is independently hydrogen or methyl; the cyclopropyl Optionally substituted with 1 or 2 methyl groups.

[0009] In one embodiment, the compound is shown in formula (I): (I) In the formula, X, Y, W, ring A, R 1, n1, R 2 are the same as before; R 3a, R 3b, R 3c are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; L 1 is a bond, O or NR 34; L2 is C1-C4 alkylene or heteroaryl; wherein, one or two hydrogen atoms on any carbon atom or any same carbon atom of said C1-C4 alkylene are optionally each independently Substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or 2 hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -(CH 2 ) m3-,- (CH 2) m1-O-(CH 2) m2-, -(CH 2) m1-N-(CH 2) m2-substituted to form a ring 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; Ring B is a 3- to 6-membered nitrogen-containing heterocyclic group; Ring C is a 3- to 6-membered nitrogen-containing heterocyclic group; R 4 is a substituent at any position on ring B; n2 is 0, 1, 2 or 3; R 5 is a substituent at any position on ring C; n3 is 0, 1, 2 or 3; R 4, R 5 are defined as follows: (a) Each R 4 and each R 5 are independently halogen, hydroxyl, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C2-C6 alkenes Base, C2-C6 haloalkenyl, C2-C4 alkenyl, C2-C4 haloalkenyl, cyano, -phenyl, -phenyl-SO 2F, -O-phenyl, -O-benzene -SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethyl Silyl CH 2-, -N(R 34) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O), oxo, (C1-C3 haloalkyl )C(O)-, -SO 2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC(O)OC1-C6 alkyl , -CH 2NHC(O)N(R 34) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2(pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC(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(CH 3) 2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl,- OC(O)heterocyclyl or -CH 2 heterocyclyl; among them, -NHC(O)phenyl or -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl Phenyl is optionally substituted by -C(O)H or OH; heterocyclyl in -CH heterocyclyl is optionally substituted by oxo; or (b) One R 4 is -CH 2CH 2- or -CH 2CH 2CH 2- and forms a cyclopropyl or cyclobutyl group together with the carbon atom connected to it; the remaining R 4 and each R 5 are independently Halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C4 alkenyl , C2-C4 haloalkenyl, cyano, -phenyl, -phenyl-SO 2F, -O-phenyl, -O-phenyl-SO 2F, -NHC(O)phenyl, -NHC( O) phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aromatic C1-C3 alkyl-, tertiary butyldimethylsilyl CH 2-, -N(R 34) 2, ( C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O), oxo, (C1-C3 haloalkyl) C (O) -, -SO 2F, (C1-C3 alkane Oxygen) C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 34) 2, -CH 2NHC (O) C1-C6 alkyl, -CH 2 (pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC (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) Base) N(CH 3) 2, -OC(O)NH(C1-C3 alkyl) O(C1-C3 alkyl)phenyl, -OC(O) heterocyclyl or -CH 2 heterocyclyl; where , 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 -CH heterocyclyl is optionally substituted by oxo; or (c) One R 5 is -CH 2CH 2- or -CH 2CH 2CH 2- and forms a cyclopropyl or cyclobutyl group together with the carbon atom connected to it; the remaining R 5 and each R 4 are independently Halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C4 alkenyl , C2-C4 haloalkenyl, cyano, -phenyl, -phenyl-SO 2F, -O-phenyl, -O-phenyl-SO 2F, -NHC(O)phenyl, -NHC( O) phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aromatic C1-C3 alkyl-, tertiary butyldimethylsilyl CH 2-, -N(R 34) 2, ( C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O), oxo, (C1-C3 haloalkyl) C (O) -, -SO 2F, (C1-C3 alkane Oxygen) C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 34) 2, -CH 2NHC (O) C1-C6 alkyl, -CH 2 (pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC (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) Base) N(CH 3) 2, -OC(O)NH(C1-C3 alkyl) O(C1-C3 alkyl)phenyl, -OC(O) heterocyclyl or -CH 2 heterocyclyl; where , 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 -CH heterocyclyl is optionally substituted by oxo; or (d) One R 4 is -CH 2CH 2- or -CH 2CH 2CH 2- and forms a cyclopropyl or cyclobutyl group together with the carbon atom connected to it; one R 5 is -CH 2CH 2- or - CH 2CH 2CH 2- and the carbon atom connected to it form a cyclopropyl or cyclobutyl group; the remaining R 4 and the remaining R 5 are independently halogen, hydroxyl, C1-C3 hydroxyalkyl, C1-C3 alkyl , C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C1-C3 alkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, cyano, -phenyl , -phenyl-SO 2F, -O-phenyl, -O-phenyl-SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyr Azolyl, aryl C1-C3 alkyl-, tertiary butyldimethylsilyl CH 2-, -N(R 34) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1- C3 alkyl)C(O), oxo, (C1-C3 haloalkyl)C(O)-, -SO 2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH 2OC(O) N(R 34) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 34) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2(pyrazole base), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC(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 (CH 3) 2, -OC (O) NH ( C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocyclyl or -CH2heterocyclyl; wherein, -NHC(O)phenyl or -OC(O)NH( The phenyl in C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted by -C(O)H or OH; the heterocyclyl in -CH2 heterocyclyl is optionally substituted by oxygen substitute for; Each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, the 3 to 6 The 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

[0010] In one embodiment, the compound is shown in formula (II): (II) In the formula, X, Y, W, ring A, R 1, n1, R 2, L 3, R 6 are the same as before; R 3a is connected to R 3b to form -CHR 3a1- or -CHR 3a2CHR 3a3-; R 3c is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3a1, R 3a2, R 3a3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or R 3a is connected with R 3c to form -CHR 3a1- or -CHR 3a2CHR 3a3-; R 3b is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3a1 , R 3a2 , and R 3a3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl.

[0011] In one embodiment, the compound is shown in formula (II-1) or formula (II-2): (II-1) (II-2) In each formula, q is 1 or 2; R 3 is a bridged ring (herein, the bridged ring where R 3 is located generally refers to or bridge ring. ) and each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 1, n1, ring A, R 2. The respective groups of X, Y, W, L3 and R6 are as defined above.

[0012] In one embodiment, the compound is shown in formula (III): (III) In the formula, X, Y, W, ring A, R 1, n1, L 3, R 6 are the same as before; R 3d, R 3e, R 3f are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or R 3d is connected with R 3e to form -CHR 3d1- or -CHR 3d2CHR 3d3-; R 3f is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3d1, R 3d2, R 3d3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or R 3d is connected with R 3f to form -CHR 3f1- or -CHR 3f2CHR 3f3-; R 3e is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3f1 , R 3f2 , and R 3f3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl.

[0013] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof: (I) In the formula, X is O or NR 11; wherein, R 11 is selected from H and C1-C6 alkyl; Y is CR 12R 13, CR 14R 15CR 16R 17, C(O) or C(O)CR 18R 19; wherein, R 12, R 13, R 14 and R 15 are each independently selected from H, cyano, C1- C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; R 16, R 17, R 18, R 19 are each independently selected from H, C1-C3 alkyl and halogen; W is N or CR 20; wherein, R 20 is H, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, hetero Cyclic group or heterocyclic group-O-; wherein, the cycloalkyl group and the heterocyclic group are independently substituted by halogen; Ring A is selected from the group consisting of aryl, heteroaryl; R is a substituent at any position on ring A; each R is independently selected from: C1-C6 alkyl, halogen, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy , cyano, NR 21R 22, C(O)NR 23R 24, CH 2R 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, -CH 2C(O)NR 27R 28, -C2-C6 alkynyl NR 29R 30, C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein, the cycloalkyl is optionally substituted by halogen or C1-C6 alkyl; wherein, R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O) 2C1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1- C6 haloalkyl; or R 21, R 22 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally selected by 1 or 2 Substitution from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 23 and R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 and R 24 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 25 is hydroxyl, cyano, heterocyclyl, NR 251R 252 , C(O)NR 253R 254 or SO 2C1-C6 alkyl; wherein, R 251 , R 252 , R 253 , R 254 are each independently H or C1-C6 alkyl; R 251, R 252 together with the nitrogen atoms connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted by a group selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253, R 254 and the nitrogen atom connected to them together form a 3-6 membered nitrogen-containing heterocyclic group, The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261R 262; wherein, R 261, R 262 are each independently H or C1-C6 alkyl; or R 261, R 262 and the nitrogen connected to them Atoms together form a 3 to 6-membered nitrogen-containing heterocyclic group, and the 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 members selected from halogen, methyl, trifluoromethyl, methoxy, tri Substituted by fluoromethoxy group; R 27 and R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 and R 28 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 29 and R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 and R 30 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; n1 is 0, 1, 2 or 3; R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, NR 31R 32, C2 -C4 alkynyl or CH 2OR 33; wherein, R 31, R 32, R 33 are each independently hydrogen or C1-C6 alkyl; R 3a, R 3b, R 3c are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; L 1 is a bond, O or NR 34; L2 is C1-C4 alkylene or heteroaryl; wherein, one or two hydrogen atoms on any carbon atom or any same carbon atom of said C1-C4 alkylene are optionally each independently Substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or 2 hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -(CH 2 ) m3-,- (CH 2) m1-O-(CH 2) m2-, -(CH 2) m1-N-(CH 2) m2-substituted to form a ring 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; Ring B is a 3- to 6-membered nitrogen-containing heterocyclic group; Ring C is a 3- to 6-membered nitrogen-containing heterocyclic group; R 4 is a substituent at any position on ring B; n2 is 0, 1, 2 or 3; R 5 is a substituent at any position on ring C; n3 is 0, 1, 2 or 3; R 4, R 5 are defined as follows: (a) each R 4 and each R 5 are independently halogen, hydroxyl, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, - Phenyl, -phenyl-SO 2F, -O-phenyl, -O-phenyl-SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substitution Pyrazolyl, aryl C1-C3 alkyl-, tertiary butyldimethylsilyl CH 2-, -N(R 34) 2, (C1-C3 alkoxy) C1-C3 alkyl, ( C1-C3 alkyl) C (O), oxo, (C1-C3 haloalkyl) C (O)-, -SO 2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC ( O)N(R 34) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 34) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2( pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC (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(CH 3) 2, -OC(O) NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocyclyl or -CH 2heterocyclyl; among them, -NHC(O)phenyl or -OC(O) The phenyl in NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl is optionally substituted by -C(O)H or OH; the heterocyclyl in -CH2 heterocyclyl is optionally is substituted by oxo; or, (b) One R 4 is -CH 2CH 2- or -CH 2CH 2CH 2- and forms a cyclopropyl or cyclobutyl group together with the carbon atom connected to it; the remaining R 4 and each R 5 are independently Halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO 2F, -O-phenyl, -O-phenyl-SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkyl-, third butyl Dimethylsilyl CH 2-, -N(R 34) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O), oxo, (C1 -C3 haloalkyl)C(O)-, -SO 2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC(O)OC1 -C6 alkyl, -CH 2NHC(O)N(R 34) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2(pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC (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(CH 3) 2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl) Phenyl, -OC(O)heterocyclyl or -CH 2 heterocyclyl; among them, -NHC(O)phenyl or -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl) The phenyl in phenyl is optionally substituted by -C(O)H or OH; the heterocyclyl in -CH heterocyclyl is optionally substituted by oxo; or (c) One R 5 is -CH 2CH 2- or -CH 2CH 2CH 2- and forms a cyclopropyl or cyclobutyl group together with the carbon atom connected to it; the remaining R 5 and each R 4 are independently Halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO 2F, -O-phenyl, -O-phenyl-SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkyl-, third butyl Dimethylsilyl CH 2-, -N(R 34) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O), oxo, (C1 -C3 haloalkyl)C(O)-, -SO 2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC(O)OC1 -C6 alkyl, -CH 2NHC(O)N(R 34) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2(pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC (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(CH 3) 2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl) Phenyl, -OC(O)heterocyclyl or -CH 2 heterocyclyl; among them, -NHC(O)phenyl or -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl) The phenyl in phenyl is optionally substituted by -C(O)H or OH; the heterocyclyl in -CH heterocyclyl is optionally substituted by oxo; or (d) One R 4 is -CH 2CH 2- or -CH 2CH 2CH 2- and forms a cyclopropyl or cyclobutyl group together with the carbon atom connected to it; one R 5 is -CH 2CH 2- or - CH 2CH 2CH 2- and the carbon atom connected to it form a cyclopropyl or cyclobutyl group; the remaining R 4 and the remaining R 5 are independently halogen, hydroxyl, C1-C3 hydroxyalkyl, C1-C3 alkyl , C1-C3 haloalkyl, C1-C3 alkoxy, cyano, -phenyl, -phenyl-SO 2F, -O-phenyl, -O-phenyl-SO 2F, -NHC(O)phenyl , -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aromatic C1-C3 alkyl-, tertiary butyldimethylsilyl CH 2-, -N(R 34 ) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O), oxo, (C1-C3 haloalkyl) C (O) -, -SO 2F, ( C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 34) 2. -CH 2NHC (O) C1-C6 alkyl, -CH 2 (pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC (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-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocyclyl or -CH2hetero Cyclic group; wherein, the phenyl in -NHC (O) phenyl or -OC (O) NH (C1-C3 alkyl) O (C1-C3 alkyl) phenyl is optionally replaced by -C (O) H or OH substitution; the heterocyclyl in -CH 2 heterocyclyl is optionally substituted by oxo; Each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, the 3 to 6 The 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

[0014] In one embodiment, the compound is shown in formula (I-1) or formula (I-2): (I-1) (I-2) In each formula, X, Y, W, R 1, R 2, R 3a, R 3b, R 3c, R 4, R 5, n1, n2, n3, L 1, L 2, ring A, ring B, ring Each of C is the same as formula (I).

[0015] 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: (II-1) (II-2) in all kinds, q is 1 or 2; X is O or NR 11; wherein, R 11 is selected from H and C1-C6 alkyl; Y is CR 12R 13, CR 14R 15CR 16R 17, C(O) or C(O)CR 18R 19; wherein, R 12, R 13, R 14 and R 15 are each independently selected from H, cyano, C1- C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; R 16, R 17, R 18, R 19 are each independently selected from H, C1-C3 alkyl and halogen; W is N or CR 20; wherein, R 20 is H, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, hetero Cyclic group or heterocyclic group-O-; wherein, the cycloalkyl group and the heterocyclic group are independently substituted by halogen; Ring A is selected from the group consisting of aryl, heteroaryl; R is a substituent at any position on ring A; each R is independently selected from: C1-C6 alkyl, halogen, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy , cyano, NR 21R 22, C(O)NR 23R 24, CH 2R 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, -CH 2C(O)NR 27R 28, -C2-C6 alkynyl NR 29R 30, C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein, the cycloalkyl is optionally substituted by halogen or C1-C6 alkyl; wherein, R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O) 2C1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1- C6 haloalkyl; or R 21, R 22 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally selected by 1 or 2 Substitution from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 23 and R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 and R 24 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 25 is hydroxyl, cyano, heterocyclyl, NR 251R 252 , C(O)NR 253R 254 or SO 2C1-C6 alkyl; wherein, R 251 , R 252 , R 253 , R 254 are each independently H or C1-C6 alkyl; R 251, R 252 together with the nitrogen atoms connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted by a group selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253, R 254 and the nitrogen atom connected to them together form a 3-6 membered nitrogen-containing heterocyclic group, The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261R 262; wherein, R 261, R 262 are each independently H or C1-C6 alkyl; or R 261, R 262 and the nitrogen connected to them Atoms together form a 3 to 6-membered nitrogen-containing heterocyclic group, and the 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 members selected from halogen, methyl, trifluoromethyl, methoxy, tri Substituted by fluoromethoxy group; R 27 and R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 and R 28 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 29 and R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 and R 30 together with the nitrogen atom connected to them form a 3- to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; n1 is 0, 1, 2 or 3; R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, NR 31R 32, C2 -C4 alkynyl or CH 2OR 33; wherein, R 31, R 32, R 33 are each independently hydrogen or C1-C6 alkyl; R 3 is a substituent at any position on the bridging ring and is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; L 3 is a bond, O or NR 34; R 6 is -L-6 to 10 membered fused heterocyclic group, -L-7 to 11 membered spiro heterocyclic group, -L-spiro ring substituted 6 to 10 membered fused heterocyclic group, -L-spiro ring substituted 7 to 11-membered spiroheterocyclyl, -L-heterocyclic substituted 6 to 10-membered fused heterocyclyl, -L-heterocyclic substituted 7 to 11-membered spiroheterocyclyl, or -L-spiro and substituted ring A 6- to 10-membered condensed heterocyclic group; The 6- to 10-membered fused heterocyclic group substituted by the spiro ring refers to any 1 or 2 carbon atoms in the 6- to 10-membered condensed heterocyclic group, and two hydrogen atoms on the same carbon atom are simultaneously replaced by -(CH 2 ) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a spiro-substituted 6 to 10 membered fused heterocyclic group; The 7- to 11-membered spiroheterocyclyl substituted by the spiro ring refers to any 1 or 2 carbon atoms on the 7- to 11-membered spiroheterocyclyl, and two hydrogen atoms on the same carbon atom are simultaneously replaced by -(CH 2 ) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 are substituted to form spiro-substituted 7- to 11-membered spiroheterocyclyls; The 6- to 10-membered condensed heterocyclic group substituted by the double ring refers to one hydrogen atom on each carbon atom of the same pair of carbon atoms in any 1 or 2 pairs of adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group Simultaneously substituted by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 to form and ring substituted 6 to 10 membered condensed heterocyclic group ; Or the 6- to 10-membered condensed heterocyclic group substituted by the ring means that the hydrogen atoms on any 2 non-adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group are replaced by -(CH 2 ) m4-,- (CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a ring-substituted 6- to 10-membered fused heterocyclic group; The 7- to 11-membered spiroheterocyclic group substituted with rings refers to one hydrogen atom on each carbon atom of the same pair of carbon atoms in any 1 or 2 pairs of adjacent carbon atoms on the 7- to 11-membered spiroheterocyclyl group at the same time substituted by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 to form and ring-substituted 7- to 11-membered spiroheterocyclyl; Or the 7- to 11-membered spiroheterocyclyl substituted by the ring means that the hydrogen atoms on any 2 non-adjacent carbon atoms on the 7- to 11-membered spiroheterocyclyl are replaced by -(CH 2 ) m4-, -( CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a ring-substituted 7- to 11-membered spiroheterocyclyl; The 6- to 10-membered condensed heterocyclic group substituted by spiro rings and parallel rings means that one hydrogen atom on each carbon atom in any pair of adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group is simultaneously replaced by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form another one on the ring-substituted and 6- to 10-membered condensed heterocyclic group Two hydrogen atoms on the carbon atom are simultaneously replaced by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 to form a spiro ring substitution and then 6- to 10-membered condensed heterocyclic groups that form spiro rings and parallel rings; The 6- to 10-membered condensed heterocyclic group or the 7- to 11-membered spiroheterocyclic group has 1, 2, 3 or 4 members selected from N(R m), S, S(=O), S(=O ) 2. A heteroatom of O is used as a ring atom; The 6- to 10-membered fused heterocyclic group substituted by the spiro ring, the 7- to 11-membered spiro heterocyclic group substituted by the spiro ring, the 6- to 10-membered condensed heterocyclic group substituted by the fused ring, the substituted ring substituted The 7- to 11-membered spiroheterocyclyl or the spiro-ring and substituted 6- to 10-membered condensed heterocyclyl each independently have 1, 2, 3, 4 or 5 members selected from N(R m), S , S(=O), S(=O) 2, heteroatoms of O as ring atoms; R n is hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3 to 20 membered heterocyclyl; R m is none, hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3 to 20 membered heterocyclyl; Wherein, the 6- to 10-membered condensed heterocyclic group or the 7- to 11-membered spiroheterocyclic group is saturated or partially unsaturated; when the 6- to 10-membered condensed heterocyclic group or the 7- to 11-membered When the spiroheterocyclyl is partially unsaturated, there are 1 or 2 double bonds on the ring; any 1 or 2 carbons on the 6- to 10-membered condensed heterocyclyl or the 7- to 11-membered spiroheterocyclyl Two hydrogen atoms on the same carbon atom in the atom are optionally replaced by =CR 2aR 2b at the same time; the 6- to 10-membered condensed heterocyclic group or the 7- to 11-membered spiroheterocyclic group is also optionally replaced by 1 Or more (for example 1, 2, 3, 4 or 5) R 6a substitution; Wherein, R 2a and 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 replaced by 1, 2, 3 members selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 Halogenated alkoxy group substitution; or each pair of R 2a, R 2b each independently and connected carbon atoms together form 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 replaced by 1, 2, 3 selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkane Substituent group, C1-C4 haloalkoxy group, C6-C10 aryl group, 5-membered or 6-membered monocyclic heteroaryl group; Each R 6a is independently halogen, hydroxyl, 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-SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted Pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyloxy CH 2-, -N(R 6b) 2, (C1-C3 alkoxy) C1-C3 alkyl, ( C1-C3 alkyl)C(O)-, oxo, (C1-C3 haloalkyl)C(O)-, -SO 2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH 2OC (O)N(R 6b) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 6b) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2 (pyrazolyl), -CH 2NHSO 2C1-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 (CH 3) 2 , -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocyclyl, -OC(O)C1-C6alkyl, -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 -CH 2 heterocyclyl; wherein, the phenyl involved in the above groups is optionally substituted by -C (O) H or OH; -C1-C3 alkyl- The heterocyclic group in the heterocyclic group is optionally substituted by oxo; Q is a bond or O; each of the above R 6b is independently hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl or C1- C6 haloalkyl; or two R 6b each independently form a 3 to 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom connected to them, and the 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 A group selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy is substituted; Each m4 is 2, 3 or 4; Each m5, m6, m7, m8 is 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; or R 6 is hydrogen, -N(R 34) 2, heterocyclyl, C1-C6 alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R 34) 2, -L-NHC(=NH)NH 2, -L-C(O)N(R 34) 2, -L-C1-C6 haloalkyl, -L-OR 34, -L-( CH 2OR 34)(CH 2) nOR 34, -L-NR 34C(O)-aryl, -L-COOH or -L-C(O)OC1-C6alkyl; wherein, the heterocyclyl, the- The aryl group in L-NR 34C (O)-aryl, the heterocyclyl group in the -L-heterocyclyl group, and the cycloalkyl group in the -L-cycloalkyl group can be optionally replaced by one or more One (such as 1, 2, 3, 4 or 5) R 35 is substituted or optionally two hydrogen atoms on the same carbon atom are simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form a cyclopropyl group or cyclobutyl; each of the aryl in the -L-aryl and the heteroaryl in the -L-heteroaryl can optionally be replaced by one or more (such as 1, 2, 3, 4 or 5) R 36 substitution; Wherein, each L is independently a bond, C1-C4 alkylene or heteroaryl; wherein, said C1-C4 alkylene is any carbon atom or 1 or 2 of any same carbon atom Each of the hydrogen atoms is optionally substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or any two hydrogen atoms on the same carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -(CH 2) m3-, -(CH 2) m1-O-(CH 2) m2-, -(CH 2) m1-NR 9-(CH 2) m2-substituted to form a ring 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; R 9 is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkyl-hydroxyl, 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; Each R35 is independently halogen, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -C1-C3 alkyl-C1-C3 alkoxy radical, -C1-C3 alkyl-hydroxyl, heterocyclyl (e.g. 3 to 6 membered heterocyclyl), cyano, -phenyl, -phenyl-SO 2F, -O-phenyl, -O-phenyl -SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkyl-, tertiary butyldimethylformazol Silyl CH 2-, -N(R 34) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O), oxo, (C1-C3 haloalkyl) C(O)-, -SO 2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 34) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2(pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC(O)hetero Cyclic group, -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(CH 3) 2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC (O) heterocyclic group (for example -OC(O)-3 to 6 membered heterocyclic group) or -CH 2 heterocyclic group (for example -CH 2-3 to 6 membered heterocyclic group); wherein, -NHC(O ) phenyl or -OC(O)NH(C1-C3 alkyl) O(C1-C3 alkyl) phenyl in which the phenyl is optionally substituted by -C(O)H or OH; -CH heterocycle The heterocyclic group in the group is optionally substituted by oxo; the hydrogen atom on the -C1-C3 alkyl- is selected from one or two of halogen, deuterium, C1-C3 alkyl, and C1-C3 haloalkyl group substitution; Each R 36 is independently halogen, hydroxyl, HC(O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl or -N(R 34 ) 2; Each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, the 3 to 6 The 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

[0016] In one embodiment, the compound is shown in formula (II-1A), formula (II-1B), formula (II-2A), formula (II-2B): (II-1A) (II-1B) (II-2A) (II-2B) In each formula, X, Y, W, R 1 , R 2 , R 3 , R 6 , n1, L 3 , q, and ring A are each the same as formula (II-1) or formula (II-2).

[0017] In one embodiment, the compound such as formula (II-1A1), formula (II-1A2), formula (II-1B1), formula (II-1B2), formula (II-1C1) or formula (II-1C2 ) as shown in: (II-1A1) (II-1A2) (II-1B1) (II-1B2) (II-1C1) (II-1C2) In each formula, X, Y, W, R 1 , R 2 , R 3 , R 6 , n1, L 3 , and ring A are each the same as formula (II-1) or formula (II-2).

[0018] In one embodiment, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer or solvate thereof: (III) In the formula, X is O or NR 11; wherein, R 11 is selected from H and C1-C6 alkyl; Y is CR 12R 13, CR 14R 15CR 16R 17, C(O) or C(O)CR 18R 19; wherein, R 12, R 13, R 14 and R 15 are each independently selected from H, cyano, C1- C3 alkyl, C1-C3 deuterated alkyl and C1-C3 haloalkyl; R 16, R 17, R 18, R 19 are each independently selected from H, C1-C3 alkyl and halogen; W is N or CR 20; wherein, R 20 is H, cyano, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, cycloalkyl, cycloalkyl-O-, hetero Cyclic group or heterocyclic group-O-; wherein, the cycloalkyl group and the heterocyclic group are independently substituted by halogen; Ring A is selected from the group consisting of aryl, heteroaryl; R is a substituent at any position on ring A; each R is independently selected from: C1-C6 alkyl, halogen, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy , cyano, NR 21R 22, C(O)NR 23R 24, CH 2R 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, -CH 2C(O)NR 27R 28, -C2-C6 alkynyl NR 29R 30, C2-C6 deuterated alkynyl, (C1-C6 alkoxy) C1-C6 haloalkyl- or cycloalkyl; wherein, the cycloalkyl is optionally substituted by halogen or C1-C6 alkyl; wherein, R 21 is H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl or C(O) 2C1-C6 alkyl; R 22 is H, C1-C6 alkyl or C1- C6 haloalkyl; or R 21, R 22 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally selected by 1 or 2 Substitution from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 23 and R 24 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 23 and R 24 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 25 is hydroxyl, cyano, heterocyclyl, NR 251R 252 , C(O)NR 253R 254 or SO 2C1-C6 alkyl; wherein, R 251 , R 252 , R 253 , R 254 are each independently H or C1-C6 alkyl; R 251, R 252 together with the nitrogen atoms connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted by a group selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253, R 254 and the nitrogen atom connected to them together form a 3-6 membered nitrogen-containing heterocyclic group, The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 26 is C1-C6 alkyl, C1-C6 haloalkyl or NR 261R 262; wherein, R 261, R 262 are each independently H or C1-C6 alkyl; or R 261, R 262 and the nitrogen connected to them Atoms together form a 3 to 6-membered nitrogen-containing heterocyclic group, and the 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 members selected from halogen, methyl, trifluoromethyl, methoxy, tri Substituted by fluoromethoxy group; R 27 and R 28 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 27 and R 28 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 29 and R 30 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl; or R 29 and R 30 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; n1 is 0, 1, 2 or 3; R 3d, R 3e, R 3f are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or R 3d is connected with R 3e to form -CHR 3d1- or -CHR 3d2CHR 3d3-; R 3f is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3d1, R 3d2, R 3d3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; or R 3d is connected with R 3f to form -CHR 3f1- or -CHR 3f2CHR 3f3-; R 3e is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; R 3f1, R 3f2, R 3f3 are each independently hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; L 3 is a bond, O or NR 34; R 6 is -L-6 to 10 membered fused heterocyclic group, -L-7 to 11 membered spiro heterocyclic group, -L-spiro ring substituted 6 to 10 membered fused heterocyclic group, -L-spiro ring substituted 7 to 11-membered spiroheterocyclyl, -L-heterocyclic substituted 6 to 10-membered fused heterocyclyl, -L-heterocyclic substituted 7 to 11-membered spiroheterocyclyl, or -L-spiro and substituted ring A 6- to 10-membered condensed heterocyclic group; The 6- to 10-membered fused heterocyclic group substituted by the spiro ring refers to any 1 or 2 carbon atoms in the 6- to 10-membered condensed heterocyclic group, and two hydrogen atoms on the same carbon atom are simultaneously replaced by -(CH 2 ) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a spiro-substituted 6 to 10 membered fused heterocyclic group; The 7- to 11-membered spiroheterocyclyl substituted by the spiro ring refers to any 1 or 2 carbon atoms on the 7- to 11-membered spiroheterocyclyl, and two hydrogen atoms on the same carbon atom are simultaneously replaced by -(CH 2 ) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 are substituted to form spiro-substituted 7- to 11-membered spiroheterocyclyls; The 6- to 10-membered condensed heterocyclic group substituted by the double ring refers to one hydrogen atom on each carbon atom of the same pair of carbon atoms in any 1 or 2 pairs of adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group Simultaneously substituted by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 to form and ring substituted 6 to 10 membered condensed heterocyclic group ; Or the 6- to 10-membered condensed heterocyclic group substituted by the ring means that the hydrogen atoms on any 2 non-adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group are replaced by -(CH 2 ) m4-,- (CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a ring-substituted 6- to 10-membered fused heterocyclic group; The 7- to 11-membered spiroheterocyclic group substituted with ring refers to 1 hydrogen atom on each carbon atom in the same pair of carbon atoms in any 1 or 2 pairs of adjacent carbon atoms on the 7- to 11-membered spiroheterocyclyl group at the same time substituted by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 to form and ring-substituted 7- to 11-membered spiroheterocyclyl; Or the 7- to 11-membered spiroheterocyclyl substituted by the ring means that the hydrogen atoms on any 2 non-adjacent carbon atoms on the 7- to 11-membered spiroheterocyclyl are replaced by -(CH 2 ) m4-, -( CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form a ring-substituted 7- to 11-membered spiroheterocyclyl; The 6- to 10-membered condensed heterocyclic group substituted by spiro rings and parallel rings means that one hydrogen atom on each carbon atom in any pair of adjacent carbon atoms on the 6- to 10-membered condensed heterocyclic group is simultaneously replaced by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 is substituted to form another one on the ring-substituted and 6- to 10-membered condensed heterocyclic group Two hydrogen atoms on the carbon atom are simultaneously replaced by -(CH 2) m4-, -(CH 2) m5O(CH 2) m6- or -(CH 2) m7NR n(CH 2) m8 to form a spiro ring substitution and then 6- to 10-membered condensed heterocyclic groups that form spiro rings and parallel rings; The 6- to 10-membered condensed heterocyclic group or the 7- to 11-membered spiroheterocyclic group has 1, 2, 3 or 4 members selected from N(R m), S, S(=O), S(=O ) 2. A heteroatom of O is used as a ring atom; The 6- to 10-membered fused heterocyclic group substituted by the spiro ring, the 7- to 11-membered spiro heterocyclic group substituted by the spiro ring, the 6- to 10-membered condensed heterocyclic group substituted by the fused ring, the substituted ring substituted The 7- to 11-membered spiroheterocyclyl or the spiro-ring and substituted 6- to 10-membered condensed heterocyclyl each independently have 1, 2, 3, 4 or 5 members selected from N(R m), S , S(=O), S(=O) 2, heteroatoms of O as ring atoms; R n is hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3 to 20 membered heterocyclyl; R m is none, hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3-C20 cycloalkyl or 3 to 20 membered heterocyclyl; Wherein, the 6- to 10-membered condensed heterocyclic group or the 7- to 11-membered spiroheterocyclic group is saturated or partially unsaturated; when the 6- to 10-membered condensed heterocyclic group or the 7- to 11-membered When the spiroheterocyclyl is partially unsaturated, there are 1 or 2 double bonds on the ring; any 1 or 2 carbons on the 6- to 10-membered condensed heterocyclyl or the 7- to 11-membered spiroheterocyclyl Two hydrogen atoms on the same carbon atom in the atom are optionally replaced by =CR 2aR 2b at the same time; the 6- to 10-membered condensed heterocyclic group or the 7- to 11-membered spiroheterocyclic group is also optionally replaced by 1 Or more (for example 1, 2, 3, 4 or 5) R 6a substitution; Wherein, R 2a and 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 replaced by 1, 2, 3 members selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 Halogenated alkoxy group substitution; or each pair of R 2a, R 2b each independently and connected carbon atoms together form 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 replaced by 1, 2, 3 selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkane Substituent group, C1-C4 haloalkoxy group, C6-C10 aryl group, 5-membered or 6-membered monocyclic heteroaryl group; Each R 6a is independently halogen, hydroxyl, 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-SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted Pyrazolyl, aryl C1-C3 alkyl-, tert-butyldimethylsilyloxy CH 2-, -N(R 6b) 2, (C1-C3 alkoxy) C1-C3 alkyl, ( C1-C3 alkyl)C(O)-, oxo, (C1-C3 haloalkyl)C(O)-, -SO 2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH 2OC (O)N(R 6b) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 6b) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2 (pyrazolyl), -CH 2NHSO 2C1-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 (CH 3) 2 , -OC(O)NH(C1-C3alkyl)O(C1-C3alkyl)phenyl, -OC(O)heterocyclyl, -OC(O)C1-C6alkyl, -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 -CH 2 heterocyclyl; wherein, the phenyl involved in the above groups is optionally substituted by -C (O) H or OH; -C1-C3 alkyl- The heterocyclic group in the heterocyclic group is optionally substituted by oxo; Q is a bond or O; each of the above R 6b is independently hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl or C1- C6 haloalkyl; or two R 6b each independently form a 3 to 6-membered nitrogen-containing heterocyclic group together with the nitrogen atom connected to them, and the 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 A group selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy is substituted; Each m4 is 2, 3 or 4; Each m5, m6, m7, m8 is 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; or R 6 is hydrogen, -N(R 34) 2, heterocyclyl, C1-C6 alkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R 34) 2, -L-NHC(=NH)NH 2, -L-C(O)N(R 34) 2, -L-C1-C6 haloalkyl, -L-OR 34, -L-( CH 2OR 34)(CH 2) nOR 34, -L-NR 34C(O)-aryl, -L-COOH or -L-C(O)OC1-C6alkyl; wherein, the heterocyclyl, the- The aryl group in L-NR 34C (O)-aryl, the heterocyclyl group in the -L-heterocyclyl group, and the cycloalkyl group in the -L-cycloalkyl group can be optionally replaced by one or more One (for example, 1, 2, 3, 4 or 5) R 35 is substituted or optionally two hydrogen atoms on the same carbon atom are simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form a cyclopropyl group Or cyclobutyl; The aryl in the -L-aryl, the heteroaryl in the -L-heteroaryl can be optionally replaced by one or more (such as 1, 2, 3, 4 or 5) R 36 substitution; Wherein, each L is independently a bond, C1-C4 alkylene or heteroaryl; wherein, the C1-C4 alkylene on any carbon atom or any one or two on the same carbon atom Each of the hydrogen atoms is optionally substituted by deuterium, C1-C6 alkyl or C1-C6 haloalkyl; or any two hydrogen atoms on the same carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -(CH 2) m3-, -(CH 2) m1-O-(CH 2) m2-, -(CH 2) m1-NR 9-(CH 2) m2-substituted to form a ring 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; R 9 is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkyl-hydroxyl, 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; Each R35 is independently halogen, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -C1-C3 alkyl-C1-C3 alkoxy radical, -C1-C3 alkyl-hydroxyl, heterocyclyl (e.g. 3 to 6 membered heterocyclyl), cyano, -phenyl, -phenyl-SO 2F, -O-phenyl, -O-phenyl -SO 2F, -NHC(O)phenyl, -NHC(O)phenyl-SO 2F, C1-C3 alkyl substituted pyrazolyl, aryl C1-C3 alkyl-, tertiary butyldimethylformazol Silyl CH 2-, -N(R 34) 2, (C1-C3 alkoxy) C1-C3 alkyl, (C1-C3 alkyl) C (O), oxo, (C1-C3 haloalkyl) C(O)-, -SO 2F, (C1-C3 alkoxy) C1-C3 alkoxy, -CH 2OC(O)N(R 34) 2, -CH 2NHC(O)OC1-C6 alkyl, -CH 2NHC(O)N(R 34) 2, -CH 2NHC(O)C1-C6 alkyl, -CH 2(pyrazolyl), -CH 2NHSO 2C1-C6 alkyl, -CH 2OC(O)hetero Cyclic group, -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(CH 3) 2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC (O) heterocyclic group (for example -OC(O)-3 to 6 membered heterocyclic group) or -CH 2 heterocyclic group (for example -CH 2-3 to 6 membered heterocyclic group); wherein, -NHC(O ) phenyl or -OC(O)NH(C1-C3 alkyl) O(C1-C3 alkyl) phenyl in which the phenyl is optionally substituted by -C(O)H or OH; -CH heterocycle The heterocyclic group in the group is optionally substituted by oxo; the hydrogen atom on the -C1-C3 alkyl- is selected from one or two of halogen, deuterium, C1-C3 alkyl, and C1-C3 haloalkyl group substitution; Each R 36 is independently halogen, hydroxyl, HC(O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl or -N(R 34 ) 2; Each R 34 is independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, the 3 to 6 The 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

[0019] In one embodiment, the compound is shown in formula (III-1) or formula (III-2): (III-1) (III-2) In each formula, X, Y, W, R 1 , R 3d , R 3e , R 3f , R 6 , n1 , L 3 , and ring A are the same as formula (III).

[0020] In one embodiment, the compound is shown in formula (III-1a), formula (III-1b), formula (III-2a) or formula (III-2b): (III-1a) (III-1b) (III-2a) (III-2b) In each formula, q is 1 or 2; R3 is a substituent at any position on the bridging ring and is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkane Base; X, Y, W, ring A, R 1, n1, L 3, R 6 are defined with formula (III-1) or formula (III-2).

[0021] In one embodiment, the compound such as formula (III-1a1), formula (III-1a2), formula (III-1b1), formula (III-1b2), formula (III-1c1) or formula (III-1c2 ) as shown in: (III-1a1) (III-1a2) (III-1b1) (III-1b2) (III-1c1) (III-1c2) In each formula, R3 is a substituent at any position on the bridging ring and is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; X, Y, W, ring A, R 1 , n1 , L 3 , and R 6 are as defined in formula (III-1) or formula (III-2).

[0022] In one embodiment, R3 is hydrogen.

[0023] In one embodiment, Y is -CH2-.

[0024] In one embodiment, the compound is shown in formula (III-1a3), formula (III-1a4), formula (III-1b3) or formula (III-1b4): (III-1a3) (III-1a4) (III-1b3) (III-1b4) in all kinds, R 3 is a substituent at any position on the bridging ring and is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl or C1-C3 haloalkyl; Y is CR 12R 13, CR 14R 15CR 16R 17, C(O) or C(O)CR 18R 19; among them, R 12 and R 13 are each independently selected from H, halogen, hydroxyl, 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-hydroxyl, -C1-C4 alkyl-cyano, -C1-C4 alkane Group-NR 121R 122; and R 12, R 13 are not H at the same time; or R 12, R 13 together with the carbon atoms connected to them form a cycloalkyl group; R 14 and R 15 are each independently selected from H, nitro, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy radical, 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-hydroxyl, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121R 122; and R 14 and R 15 are not H at the same time; or R 14 and R 15 together with the carbon atoms connected to them form a cycloalkyl group; R 16 and R 17 are each independently selected from H, halogen, hydroxyl, 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-hydroxyl, -C1-C4 alkyl-cyano, -C1-C4 alkane The base-NR 121R 122; and R 16, R 17 are not H at the same time; R 18, R 19 are each independently selected from H, C1-C3 alkyl and halogen; R 121, R 122 are each independently selected from H, C1-C3 alkyl; or R 121, R 122 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic 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 selected from the group consisting of halogen, hydroxyl , nitro, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy group substitution; X, W, ring A, R 1, n1, L 3, R 6 are defined in the same formula (III-1) or formula (III-2).

[0025] In one embodiment, R3 is hydrogen.

[0026] In one embodiment, Y is CR 12R 13; wherein, R 12 is selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy Base, C1-C6 haloalkoxy, cycloalkyl, cycloalkyl-O-, heterocyclyl, heterocyclyl-O-, -C1-C4 alkyl-C1-C6 alkoxy, -C1-C4 alk -C1-C6 haloalkoxy, -C1-C4 alkyl-hydroxyl, -C1-C4 alkyl-cyano, -C1-C4 alkyl-NR 121R 122; R 13 is H; R 121, R 122 each Independently selected from H, C1-C3 alkyl; or R 121, R 122 and the nitrogen atom connected to them together form a 3-6 membered nitrogen-containing heterocyclic group; or R 12, R 13 and the carbon atom connected to them Together constitute a cycloalkyl group; wherein, the cycloalkyl group, the heterocyclic group, the aryl group, the heteroaryl group, and the 3-6 membered nitrogen-containing heterocyclic group are each independently optionally selected from Substituted by the group halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy .

[0027] In one embodiment, in formula (III-1a3), formula (III-1a4), formula (III-1b3) or formula (III-1b4), Y is CR 12R 13; wherein, R 12 is selected from halogen, hydroxyl , cyano, methyl, ethyl, n-propyl, isopropyl, trideuteromethyl, trifluoromethyl, cyclopropyl, -C1-C4 alkyl-methoxy, -C1-C4 alkyl -Hydroxyl, -C1-C4 alkyl-cyano; R 13 is H; or R 12, R 13 together with the carbon atoms connected to them form a cyclopropyl group.

[0028] In one embodiment, in formula (III-1a3), formula (III-1a4), formula (III-1b3) or formula (III-1b4), Y is -CH(CH 3 )-, -CH(CH 2CH 3)-, -CH(CH 2CH 2CH 3)-, -CH(CH(CH 3) 2)-, -CH(cyclopropyl)-, -CH(CH 2OH)-, -CH(CH 2CH 2OH) -, -CH(CH 2CN)-, -CH(CH 2CH 2CN)-, -CH(CH 2CF 3)-, -CH(CH 2CF 2H)-, -CH(CH 2CH 2F)-, -CH(CH 2F)-, -CH(CF 2H)-, -CH(CF 3)-, -CH(CN)-, -CH(CH 2OCH 3)-, , -C(CH 3 ) 2-, -CH(CD 3 )-.

[0029] In one embodiment, the cycloalkyl is a C3-C20 cycloalkyl. 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 cycloalkane base.

[0030] In one embodiment, the heterocyclyl is a 3 to 20 membered heterocyclyl. Preferably, the heterocyclic group is a monocyclic heterocyclic group (such as a 3 to 8 membered monocyclic heterocyclic group), a 5 to 20 membered spiro heterocyclic group, a 5 to 20 membered fused heterocyclic group and a 5 to 20 membered bridge heterocyclyl.

[0031] In one embodiment, the aryl is a C6-C14 aryl. Preferably, the aryl group is a monocyclic aryl group, a non-fused polycyclic aryl group and an aromatic fused polycyclic group.

[0032] In one embodiment, the heteroaryl is a 5 to 14 membered heteroaryl. Preferably, the heteroaryl is a monocyclic heteroaryl (eg, a 5- or 6-membered monocyclic heteroaryl), a fused bicyclic heteroaryl (eg, an 8- to 10-membered bicyclic heteroaryl) or a fused tricyclic heteroaryl.

[0033] In one embodiment, W is N or CR 20; wherein, R 20 is H, cyano, C1-C3 alkyl, halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 monocyclic ring Alkyl, C3-C6 monocyclic cycloalkyl-O-, 3 to 6-membered heterocyclic group or 3 to 6-membered heterocyclic group-O-; wherein, the C3-C6 monocyclic cycloalkyl, the 3 Each of the 6- to 6-membered heterocyclyl groups is independently optionally substituted with halogen.

[0034] In one embodiment, W is N or CR 20; wherein, R 20 is hydrogen, fluoro, methyl, methoxy or cyclopropoxy.

[0035] In one embodiment, W is N or CR 20; wherein, R 20 is H, fluoro, chloro, methyl, cyclopropyl, methoxy or cyclopropoxy.

[0036] In one embodiment, X is -N(CH3)- or -N(cyclopropyl)-.

[0037] In one embodiment, X is -N(CD 3 )-.

[0038] In one embodiment, X is O.

[0039] In one embodiment, Y is CR 12R 13 or CR 14R 15CR 16R 17; wherein, R 12, R 13, R 14 and R 15 are 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-, 3-6 membered heterocyclyl, 3-6 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-hydroxyl, -C1-C2 alkyl-cyano, -C1-C2 alkyl-NR 121R 122; R 16, R 17 are independent R 121, R 122 are each independently selected from H, C1-C3 alkyl; or R 121, R 122 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic group; wherein, The C3-C6 monocyclic cycloalkyl group, the 3-6 membered heterocyclic group, the phenyl group, the 5- or 6-membered heteroaryl group, and the 3-6 membered nitrogen-containing heterocyclic group are each independently Optionally selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy The group substitution of the group.

[0040] In one embodiment, Y is -CH2-, -CH2CH2-, -CH(CH2OCH3)-, -CH(CN)-, -CH(OH)-, -CH(CH3)-, -CH(CD 3 )-, -C(CH 3 ) 2-, -CH(CF 3 )-, -CH(CHF 2 )-, -CH(CH 2F)-, -CH(CH 2CH 3 )-, -CH(CH 2CH 2F)-, -CH(CH 2CF 2H)-, -CH(CH 2CF 3)-, -CH(CH 2CH 2CN)-, -CH(CH 2OH)-, -CH(CH 2CN) -, -CH(CH 2CH 2OH)-, -CH(cyclopropyl)-, -CH(isopropyl)-, -CH(CH 2CH 2CH 3)-, -CH(CH 2CH 2CH 2CH 3)- or .

[0041] In one embodiment, Y is -CH2-.

[0042] In one embodiment, Y is selected from the group consisting of: .

[0043] In one embodiment, R is H, cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy , NR 31R 32, C2-C4 alkynyl or CH 2OR 33; wherein, R 31 and R 32 are each independently hydrogen or C1-C6 alkyl; or form 3 to 6-membered nitrogen-containing Heterocyclyl; R 33 is hydrogen or C1-C6 alkyl.

[0044] In one embodiment, R is fluoro, chloro, hydroxy, methoxy or cyano.

[0045] In one embodiment, R is hydrogen, fluoro, chloro, hydroxy, methoxy or cyano.

[0046] In one embodiment, Ring A is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3,4-tetralinyl 2,3-dihydro-1H-indenyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, indazolyl or benzo[d][1,3]dioxolane .

[0047] In one embodiment, Ring A is selected from the group consisting of: and these groups may be attached to the rest of the molecule through any suitable ring atom.

[0048] In one embodiment, R 1 is a substituent at any position on ring A; n 1 is 0, 1, 2 or 3; each R 1 is independently selected from: C1-C3 alkyl, halogen, hydroxyl, C1-C3 Alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cyano, NR 21R 22, C(O)NR 23R 24, CH 2R 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 cyano ylalkyl, triazolyl, -S-C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -CH 2C(O)NR 27R 28, -C2-C4 alkynyl NR 29R 30, C2-C4 deuterated alkyne group, (C1-C3 alkoxy) C1-C3 haloalkyl- or cycloalkyl; wherein, the cycloalkyl is optionally substituted by halogen or C1-C3 alkyl; wherein, R 21 is H, C1-C3 alkyl, C1-C3 haloalkyl, C(O)C1-C3 alkyl or C(O) 2C1-C3 alkyl; R 22 is H, C1-C3 alkyl or C1- C3 haloalkyl; or R 21, R 22 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally selected by 1 or 2 Substitution from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 23 and R 24 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 23 and R 24 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 25 is hydroxyl, cyano, heterocyclyl, NR 251R 252 , C(O)NR 253R 254 or SO 2C1-C3 alkyl; wherein, R 251 , R 252 , R 253 , R 254 are each independently H or C1-C3 alkyl; R 251, R 252 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 Substituted by a group selected from halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; R 253, R 254 and the nitrogen atom connected to them together form a 3-6 membered nitrogen-containing heterocyclic group, The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 26 is C1-C3 alkyl, C1-C3 haloalkyl or NR 261R 262; wherein, R 261, R 262 are each independently H or C1-C3 alkyl; or R 261, R 262 and the nitrogen connected to them Atoms together form a 3 to 6-membered nitrogen-containing heterocyclic group, and the 3 to 6-membered nitrogen-containing heterocyclic group is optionally replaced by 1 or 2 members selected from halogen, methyl, trifluoromethyl, methoxy, tri Substituted by fluoromethoxy group; R 27 and R 28 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 27 and R 28 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy; R 29 and R 30 are each independently H, C1-C3 alkyl or C1-C3 haloalkyl; or R 29 and R 30 together with the nitrogen atom connected to them form a 3 to 6-membered nitrogen-containing heterocyclic group, said The 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

[0049] In one embodiment, L 2 is methyl or ethyl or propyl; wherein, any carbon atom on the methyl or ethyl or propyl or any carbon atom on the same carbon atom 1 or 2 hydrogen atoms are optionally independently substituted by deuterium or C1-C3 alkyl; are simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl.

[0050] In one embodiment, R 3a, R 3b, R 3c are each independently hydrogen, fluoro, methyl or methoxy.

[0051] In one embodiment, Choose from the following group: .

[0052] In one embodiment, Choose from the following group: .

[0053] In one embodiment, Choose from the following group: ; In each formula, each R 4 , R 5 , n2, n3 independently defines the same definition in formula (I).

[0054] In one embodiment, Choose from the following group: .

[0055] In one embodiment, R3 is hydrogen, fluoro, methyl or methoxy.

[0056] In one embodiment, R3 is hydrogen.

[0057] In one embodiment, R 3d, R 3e, R 3f are each independently hydrogen, fluoro, methyl or methoxy; or R 3d is connected with R 3e to form -CHR 3d1- or -CHR 3d2CHR 3d3-; R 3f is hydrogen, fluorine, methyl or methoxy; R 3d1, R 3d2, R 3d3 are each independently hydrogen, fluorine, methyl or methoxy; or R 3d is connected with R 3f to form -CHR 3f1- or -CHR 3f2CHR 3f3-; R 3e is hydrogen, fluorine, methyl or methoxy; R 3f1, R 3f2, R 3f3 are each independently hydrogen, fluorine, methyl or methoxy.

[0058] In one embodiment, L is a methylene group or an ethylidene group or a propylidene group; wherein, 1 on any carbon atom of the methylene group, an ethylidene group or a propylidene group or on any same carbon atom One or two hydrogen atoms are optionally independently substituted by deuterium or C1-C3 alkyl; Simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl.

[0059] In one embodiment, R 6 is hydrogen, -N(R 34 ) 2, 3 to 20 membered heterocyclyl, C1-C6 alkyl, -L-3 to 20 membered heterocyclyl, -L-C6-C14 Aryl, -L-5 to 14 membered heteroaryl, -L-C3-C20 cycloalkyl, -L-N(R 34) 2, -L-NHC(=NH)NH 2, -L-C(O)N( R 34) 2, -L-C1-C6 haloalkyl, -L-OR 34, -L-(CH 2OR 34)(CH 2) nOR 34, -L-NR 34C(O)-C6-C14 aryl, -L-COOH or -L-C(O)OC1-C6 alkyl; wherein, the 3 to 20-membered heterocyclic group, the C6-C14 aryl in the -L-NR 34C(O)-C6-C14 aryl The C3-C20 cycloalkyl group can be optionally substituted by one or more (eg 1, 2, 3, 4 or 5) R 35 or optionally two hydrogen atoms on the same carbon atom at the same time Substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to become cyclopropyl or cyclobutyl; C6-C14 aryl in -L-C6-C14 aryl or -L-5 to 14-membered heteroaryl The 5- to 14-membered heteroaryl of can be optionally substituted by one or more (eg, 1, 2, 3, 4 or 5) R 36 ; each L, each R 34 , each R 35 , each R 36 are independently Cit.

[0060] In one embodiment, R 6 is hydrogen, -N(R 34 ) 2, 3 to 8 membered monocyclic heterocyclyl, 5 to 20 membered spiroheterocyclyl, 5 to 20 membered fused heterocyclyl, 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 condensed heterocyclic group, - L-5 to 20-membered bridge 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, -L-N(R 34) 2, -L-NHC(=NH)NH 2, -L-C(O)N( R 34) 2, -L-C1-C6 haloalkyl, -L-OR 34, -L-(CH 2OR 34)(CH 2) nOR 34, -L-NR 34C(O)-phenyl, -L- NR 34C(O)-naphthyl, -L-COOH or -L-C(O)OC1-C6 alkyl; wherein, the 3 to 8 membered monocyclic heterocyclic group, 5 to 20 membered spiro heterocyclic group, 5 to 20 membered spiroheterocyclic group, 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 - The phenyl in L-NR 34C (O)-phenyl, the naphthyl in the -L-NR 34C (O)-naphthyl can optionally be replaced by one or more (such as 1, 2, 3, 4 Or 5) R 35 is substituted or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2CH 2- or -CH 2CH 2CH 2- to become cyclopropyl or cyclobutyl; -L-phenyl The phenyl in -L-naphthyl, the naphthyl in -L-naphthyl, and the 5 to 14-membered heteroaryl in -L-5 to 14-membered heteroaryl can optionally be replaced by one or more (such as 1, 2, 3 , 4 or 5) R 36 substitutions; each L, each R 34, each R 35, each R 36 are the same as before.

[0061] In one embodiment, R 6 is hydrogen or —N(R 34 ) 2 . Preferably, each R 34 is independently hydrogen or C1-C3 alkyl; or one R 34 is hydrogen and the other R 34 is C1-C3 alkyl.

[0062] In one embodiment, R 34 is hydrogen, C1-C3 alkyl or C1-C3 cyanoalkyl.

[0063] In one embodiment, C1-C6 alkyl is methyl, ethyl, isopropyl or isobutyl.

[0064] In one embodiment, L is a methylene group or an ethylidene group or a propylidene group; wherein, 1 on any carbon atom of the methylene group, an ethylidene group or a propylidene group or on any same carbon atom One or two hydrogen atoms are optionally independently substituted by deuterium or C1-C3 alkyl; Simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl.

[0065] In one embodiment, each R 6 is independently ; R 4, R 5, L 2, ring B, ring C, n2, n3 are defined with the definition of each group in the formula (I).

[0066] In one embodiment, the heterocyclic groups in R are each independently hexahydro-1H-pyrrolidinyl, hexahydro-3H-pyrrolidin-3-one, hexahydro-1H-pyrrolo[2, 1-c][1,4]oxazinyl, octahydroindolazinyl, hexahydropyrrolizine 4(1H)-oxide, azetidinyl, pyrrolidinyl, pyrrolidin-2-one, oxygen Heterocyclobutyl, piperidinyl, 1-azabicyclo[2.2.1]heptyl, morpholinyl, oxa-5-azabicyclo[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 replaced by one or more (for example 1, 2 , 3, 4 or 5) R 35 is substituted or optionally two hydrogen atoms on the same carbon atom are simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl; each R 35 are the same as before.

[0067] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is hexahydro-1H-pyrrolidinyl.

[0068] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is hexahydro-1H-pyrrolidinyl substituted by one R 35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2CH 2- or -CH 2CH 2CH 2-substituted by cyclopropyl or cyclobutyl hexahydro-1H-pyrrolidinyl; wherein, R 35 is halogen, hydroxyl, C1-C3 hydroxyalkyl, C1-C3 Haloalkyl, C1-C3 alkyl, C1-C3 alkoxy, phenyl, pyrazolyl or -CH2OC(O)N(R34)2.

[0069] In one embodiment, the halogen is fluorine.

[0070] In one embodiment, the heterocyclic group is hexahydro-1H-pyrrolidinyl further substituted by two other R 35 ; each of the other two R 35 is independently C1-C3 alkyl.

[0071] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is azetidinyl substituted by one R 35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2CH 2- or -CH 2CH 2CH 2- azetidinyl substituted into cyclopropyl or cyclobutyl; said R 35 is C1-C3 alkyl.

[0072] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is pyrrolidinyl substituted by one R 35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2CH 2- Or -CH 2CH 2CH 2-substituted into cyclopropyl or cyclobutyl pyrrolidinyl; wherein, R 35 is hydroxyalkyl, haloalkyl, C1-C3 alkyl, alkoxy, aryl C1-C3 alkyl, -Phenyl, -O-phenyl and -NHC(O)phenyl; wherein, the aryl in the aryl C1-C3 alkyl, the phenyl, or the phenyl in the -O-phenyl Or the phenyl groups in -NHC(O)phenyl are each independently optionally substituted with one or more (eg 1, 2, 3, 4 or 5) R 36 .

[0073] In one embodiment, the phenyl in the phenyl, -O-phenyl or -NHC(O)phenyl is substituted by -SO 2F.

[0074] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is pyrrolidinyl substituted by two R 35 ; wherein one R 35 is C1-C3 alkyl and the other R 35 is C1-C3 alkoxy or halogen.

[0075] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is pyrrolidin-2-one substituted by one R 35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2CH 2- or -CH 2CH 2CH 2-substituted cyclopropyl or cyclobutyl pyrrolidin-2-one; wherein, R 35 is C1-C3 alkyl.

[0076] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is piperidinyl substituted by one R 35 or two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2 CH 2- Or -CH 2CH 2CH 2-piperidinyl substituted into cyclopropyl or cyclobutyl; wherein, R 35 is acetyl, (C1-C3 alkoxy) C1-C3 alkoxy or -C (O) CH2Cl.

[0077] In one embodiment, R 6 is -L-heterocyclyl; said heterocyclyl is morpholinyl or oxa-5-azabicyclo[2.2.1]hept-5-yl.

[0078] In one embodiment, R 6 is -L-heteroaryl; said heteroaryl is optionally substituted with one or more R 36 .

[0079] In one embodiment, R 6 is -L-heteroaryl; L is methyl or ethyl or propyl; wherein, on any carbon atom on the methyl or ethyl or propyl 1 or 2 hydrogen atoms on any of the same carbon atoms are optionally independently substituted by deuterium or C1-C3 alkyl; or any of the same carbon Two hydrogen atoms on the atom are optionally simultaneously replaced by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl; the heteroaryl is pyridyl, pyrazolyl, imidazolyl , triazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl or pyrimidinyl; each of the above groups is optionally Substituted by one or more R36.

[0080] In one embodiment, R 6 is -L-heteroaryl; L is methyl or ethyl or propyl; wherein, on any carbon atom on the methyl or ethyl or propyl 1 or 2 hydrogen atoms on any of the same carbon atoms are optionally independently substituted by deuterium or C1-C3 alkyl; or any of the same carbon 2 hydrogen atoms on the atom are optionally simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl; the heteroaryl is a pyridyl substituted by one R 36; Wherein, R 36 is halogen, C1-C4 alkyl, -N(R 5) 2 or C1-C4 alkoxy.

[0081] In one embodiment, R 6 is -L-heteroaryl; L is methyl or ethyl or propyl; wherein, on any carbon atom on the methyl or ethyl or propyl 1 or 2 hydrogen atoms on any of the same carbon atoms are optionally independently substituted by deuterium or C1-C3 alkyl; or any of the same carbon 2 hydrogen atoms on the atom are optionally simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl; the heteroaryl is pyrazolyl substituted by one R ; Wherein, R 36 is C1-C4 alkyl or -N(R 34) 2.

[0082] In one embodiment, R 6 is -L-heteroaryl; L is methyl or ethyl or propyl; wherein, on any carbon atom on the methyl or ethyl or propyl 1 or 2 hydrogen atoms on any of the same carbon atoms are optionally independently substituted by deuterium or C1-C3 alkyl; or any of the same carbon 2 hydrogen atoms on the atom are optionally simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl; the heteroaryl is imidazolyl substituted by one R 36; Wherein, R 36 is C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 hydroxyalkyl.

[0083] In one embodiment, R 6 is -L-heteroaryl; L is methyl or ethyl or propyl; wherein, on any carbon atom on the methyl or ethyl or propyl 1 or 2 hydrogen atoms on any of the same carbon atoms are optionally independently substituted by deuterium or C1-C3 alkyl; or any of the same carbon 2 hydrogen atoms on the atom are optionally simultaneously replaced by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl; the heteroaryl is a triazolyl substituted by one R ; Wherein, R 36 is C1-C4 alkyl.

[0084] In one embodiment, R 6 is -L-aryl; said aryl is optionally substituted with one or more R 36 .

[0085] 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 -CH 2CH 2- or -CH 2CH 2CH 2- is substituted into cyclopropyl or cyclobutyl; each R 35 is the same as before.

[0086] In one embodiment, R 6 is -L-N(R 34 ) 2; wherein, L is a C1-C4 alkylene group; wherein, any carbon atom of the C1-C4 alkylene group or any same carbon atom 1 or 2 hydrogen atoms in are optionally independently replaced by deuterium or C1-C3 alkyl; or 2 hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by- CH2CH2- or -CH2CH2CH2-substitution to form cyclopropyl or cyclobutyl.

[0087] In one embodiment, R 6 is -L-N(R 34 ) 2; wherein, L is methylene, ethylidene or propylidene; wherein, any 1 or 2 hydrogen atoms on a carbon atom or on any same carbon atom are optionally substituted by deuterium or C1-C3 alkyl independently; Two hydrogen atoms on the same carbon atom are optionally simultaneously replaced by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl; each R 34 is independently selected from C1-C3 alkane base.

[0088] In one embodiment, R 6 is -L-NC(=NH)-NH 2 ; wherein, L is a C1-C4 alkylene group; wherein, any carbon atom of the C1-C4 alkylene group or any same 1 or 2 hydrogen atoms on a carbon atom are optionally independently substituted by deuterium or C1-C3 alkyl; or any 2 hydrogen atoms on the same carbon atom of the C1-C4 alkene are simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl.

[0089] In one embodiment, L is ethylidene or propylidene.

[0090] In one embodiment, R 6 is -L-C1-C6 haloalkyl; wherein, L is C1-C4 alkylene; wherein, any carbon atom of the C1-C4 alkylene or any same carbon atom 1 or 2 hydrogen atoms on is optionally independently replaced by deuterium or C1-C3 alkyl; -CH 2CH 2- or -CH 2CH 2CH 2- is substituted to form cyclopropyl or cyclobutyl.

[0091] In one embodiment, R 6 is -L-OR 34; wherein, L is a C1-C4 alkylene group; wherein, 1 on any carbon atom of the C1-C4 alkylene group or on any same carbon atom One or two hydrogen atoms are optionally independently replaced by deuterium or C1-C3 alkyl; or two hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously replaced by -CH 2 CH 2- or -CH2CH2CH2-substitution to form cyclopropyl or cyclobutyl.

[0092] In one embodiment, R 6 is -L-(CH 2OR 34 )(CH 2 ) nOR 34; wherein, L is a C1-C4 alkylene group; wherein, any carbon atom of the C1-C4 alkylene group is Or 1 or 2 hydrogen atoms on any same carbon atom are optionally independently substituted by deuterium or C1-C3 alkyl; or 2 hydrogen atoms on any same carbon atom of the C1-C4 alkylene group Atoms are optionally simultaneously substituted by -CH2CH2- or -CH2CH2CH2- to form cyclopropyl or cyclobutyl.

[0093] In one embodiment, R 6 is -L-NR 34C(O)-aryl; wherein, L is C1-C4 alkylene; wherein, any carbon atom of said C1-C4 alkylene or any 1 or 2 hydrogen atoms on a carbon atom are optionally independently substituted by deuterium or C1-C3 alkyl; or any 2 hydrogen atoms on the same carbon atom of the C1-C4 alkene are simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl.

[0094] In one embodiment, R 6 is -L-heterocyclyl; L is C1-C4 alkylene; wherein, the 2 hydrogen atoms on any same carbon atom of said C1-C4 alkylene are optionally each Independently substituted by deuterium or C1-C6 alkyl; or 2 hydrogen atoms on any same carbon atom of the C1-C4 alkylene are optionally simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- Thus forming cyclopropyl or cyclobutyl.

[0095] In one embodiment, R 6 is -L-6 to 10-membered fused heterocyclic group; 2 hydrogen atoms on the same carbon atom in any 1 or 2 carbon atoms on the 6- to 10-membered fused heterocyclic group Optionally simultaneously substituted by =CR 2aR 2b; and / or the 6- to 10-membered fused heterocyclic group is optionally also substituted by 1 or more R 6a; wherein, R 2a, R 2b are each independently hydrogen , halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; each R 6a is independently halogen.

[0096] In one embodiment, L is methyl or ethyl or propyl; wherein, the two hydrogen atoms on the same carbon atom of the methyl or ethyl or propyl are optionally each Independently substituted by deuterium or C1-C3 alkyl; or the 2 hydrogen atoms on the same carbon atom of the methyl or ethyl or propyl group are optionally simultaneously replaced by -CH 2CH 2- or -CH 2CH 2CH 2-substitution to form cyclopropyl or cyclobutyl.

[0097] In one embodiment, W is CR 20; R 20 is cyclopropyl, cyclopropyl-O-, cyclobutyl, cyclobutyl-O-, cyclopentyl, cyclopentyl-O-, tetrahydrofuranyl, Tetrahydrofuran-O-; wherein, the cyclopropyl, cyclobutyl, cyclopentyl, and tetrahydrofuran are independently substituted by halogen.

[0098] In one embodiment, W is CR 20; R 20 is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, 3 to 6 membered heterocyclyl or 3 to 6-membered heterocyclic group-O-; wherein, the C3-C6 cycloalkyl group and the 3- to 6-membered heterocyclic group are each independently substituted by halogen.

[0099] In one embodiment, R 20 is halogen or C1-C3 alkyl.

[0100] In one embodiment, R 20 is fluoro.

[0101] In one embodiment, R 20 is methyl.

[0102] In one embodiment, L 2 or L is methyl or ethyl or propyl; wherein, any of the two hydrogen atoms on the same carbon atom of the methyl or ethyl or propyl is Optionally each independently substituted by deuterium or C1-C3 alkyl; or the 2 hydrogen atoms on the same carbon atom of the methyl or ethyl or propyl group are optionally simultaneously replaced by -CH 2CH 2- or -CH2CH2CH2- to form cyclopropyl or cyclobutyl.

[0103] In one embodiment, is phenyl substituted by one, two, three or four R1; wherein each R1 is independently halogen, hydroxyl, ethynyl, methyl, methyl-O-, methyl-S-, Trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; said cyclopropyl is optionally substituted with halogen or methyl.

[0104] In one embodiment, is naphthyl substituted by one, two, three or four R1; wherein each R1 is independently halogen, hydroxyl, ethynyl, methyl, methyl-O-, methyl-S-, Trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, cyano, or cyclopropyl; said cyclopropyl optionally substituted by halogen or methyl.

[0105] In one embodiment, is naphthyl substituted by one, two or three R 1 ; wherein each R 1 is independently halogen, hydroxy, ethynyl, methyl, ethyl, amino, cyano or difluoromethyl.

[0106] In one embodiment, is heteroaryl optionally substituted with one or more R 1 .

[0107] In one embodiment, is pyridyl substituted by one, two, three or four R 1 ; wherein each R 1 is independently halogen, hydroxyl, ethynyl, methyl, methyl-O-, methyl-S-, Trifluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; said cyclopropyl is optionally substituted with halogen or methyl.

[0108] In one embodiment, is isoquinolinyl, indazolyl or benzo[d][1,3]dioxolane optionally substituted with one or more (eg 1, 2, 3, 4 or 5) R 1 .

[0109] In one embodiment, is isoquinolinyl substituted by one, two or three R 1 ; wherein each R 1 is independently halogen, hydroxyl, ethynyl, methyl, methyl-O-, methyl-S-, tri Fluoromethyl, trifluoromethyl-O-, amino, isopropyl, or cyclopropyl; said cyclopropyl is optionally substituted by halogen or methyl.

[0110] In one embodiment, is indazolyl substituted by one, two or three R 1 ; wherein each R 1 is independently C1-C3 alkyl.

[0111] In one embodiment, is benzo[d][1,3]dioxolane substituted by two R groups; wherein each R is independently selected from halogen.

[0112] In one embodiment, Choose from the following group: .

[0113] In one embodiment, Choose from the following group: .

[0114] In one embodiment, the -L 3-R 6 is selected from the group consisting of: ; In each formula, R L1 and R L2 are independently hydrogen, deuterium, C1-C6 alkyl or C1-C6 haloalkyl; R61 is heterocyclyl, aryl, heteroaryl, cycloalkyl, -N( R 34) 2, -NHC(=NH)NH 2, -C(O)N(R 34) 2, -C1-C6 haloalkyl, -OR 34, -(CH 2OR 34)(CH 2) nOR 34, -NR 34C(O)-aryl, -COOH or -C(O)OC1-C6 alkyl; wherein, the heterocyclic group, the aryl in the -NR 34C(O)-aryl, the Each cycloalkyl group may optionally be substituted by one or more (eg 1, 2, 3, 4 or 5) R 35 or optionally two hydrogen atoms on the same carbon atom may be simultaneously replaced by -CH 2 CH 2- Or -CH 2CH 2CH 2- is substituted into cyclopropyl or cyclobutyl; each of the aryl and the heteroaryl can be optionally replaced by one or more (eg 1, 2, 3, 4 or 5) R 36 is substituted; each R 34, each R 35, and each R 36 are the same as before. Preferably, in the above formulas, R 34 in N-R 34 is H.

[0115] In one embodiment, the -L 3-R 6 is selected from the group consisting of: ; In each formula, R61 is heterocyclyl, aryl, heteroaryl, cycloalkyl, -N(R34)2, -NHC(=NH)NH2, -C(O)N(R34)2 , -C1-C6 haloalkyl, -OR 34, -(CH 2OR 34)(CH 2) nOR 34, -NR 34C(O)-aryl, -COOH or -C(O)OC1-C6 alkyl; where , the heterocyclic group must be substituted by one or more (eg 1, 2, 3, 4 or 5) R 35 or optionally two hydrogen atoms on the same carbon atom are simultaneously replaced by -CH 2 CH 2- or -CH 2CH 2CH 2- is substituted into cyclopropyl or cyclobutyl; the aryl in the -NR 34C(O)-aryl and the cycloalkyl can be optionally replaced by one or more (eg 1 , 2, 3, 4 or 5) R 35 is substituted or optionally two hydrogen atoms on the same carbon atom are simultaneously substituted by -CH 2CH 2- or -CH 2CH 2CH 2- to form cyclopropyl or cyclobutyl each of the aryl and the heteroaryl may optionally be substituted by one or more (for example 1, 2, 3, 4 or 5) R 36; each R 34, each R 35, each R 36 each Same as before. Preferably, in the above formulas, R 34 in N-R 34 is H.

[0116] In one embodiment, the -L 3-R 6 is -NH-R 61, -O-R 61 or -R 61; or the -L 3-R 6 is selected from the group consisting of: ; In each formula, R in N-R 34 is H; each R 61 is independently selected from the following group: .

[0117] In one embodiment, the -L 3-R 6 is -O-R 61, or . In one embodiment, each R is independently selected from the group consisting of: Methyl .

[0118] In one embodiment, the -L 3-R 6 is or .

[0119] In one embodiment, each R is independently selected from the group consisting of: .

[0120] In one embodiment, R 61 is hexahydro-1H-pyrrolidinyl.

[0121] In one embodiment, R 61 is hexahydro-1H-pyrrolidinyl substituted by one R 35 ; wherein R 35 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkane Base, C1-C3 alkoxy, C2-C3 alkenyl, C2-C3 haloalkenyl, phenyl, pyrazolyl or -CH 2OC(O)N(R 34) 2; each R 34 is independently is hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; or two R 34 together with the nitrogen atom connected to them form a 3-6 membered nitrogen-containing heterocyclic group, and the 3-6 membered nitrogen-containing heterocyclic group Optionally substituted with 1 or 2 groups selected from halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy.

[0122] In one embodiment, the 6- to 10-membered fused heterocyclic group is selected from the group consisting of: .

[0123] In one embodiment, the 6- to 10-membered fused heterocyclic group is selected from the group consisting of: ;The carbon atom marked with * is the carbon atom connected to other parts of the molecule.

[0124] In one embodiment, the 7- to 11-membered spiroheterocyclyl is selected from the group consisting of: .

[0125] In one embodiment, the 7- to 11-membered spiroheterocyclyl is selected from the group consisting of: ;The carbon atom marked with * is the carbon atom connected to other parts of the molecule.

[0126] In one embodiment, the spiro-substituted 6- to 10-membered fused heterocyclic group is selected from the group consisting of: .

[0127] In one embodiment, the spiro-substituted 6- to 10-membered fused heterocyclic group is selected from the group consisting of: ; *The carbon atom indicated is the carbon atom attached to the rest of the molecule.

[0128] In one embodiment, the spiro-substituted 7- to 11-membered spiroheterocyclyl is selected from the group consisting of: .

[0129] In one embodiment, the ring-substituted 6- to 10-membered fused heterocyclic group is selected from the group consisting of: .

[0130] In one embodiment, the ring-substituted 6- to 10-membered fused heterocyclic group is selected from the group consisting of: ; *The carbon atom indicated is the carbon atom attached to the rest of the molecule.

[0131] In one embodiment, the ring-substituted 7- to 11-membered spiroheterocyclyl is selected from the group consisting of: .

[0132] In one embodiment, the ring-substituted 7- to 11-membered spiroheterocyclyl is selected from the group consisting of: ;The carbon atom marked with * is the carbon atom connected to other parts of the molecule.

[0133] In one embodiment, the spiro and ring-substituted 6- to 10-membered fused heterocyclic groups are selected from the group consisting of: .

[0134] In one embodiment, the spiro and ring-substituted 6- to 10-membered fused heterocyclic groups are selected from the group consisting of: ;The carbon atom marked with * is the carbon atom connected to other parts of the molecule.

[0135] In one embodiment, L 3 is O; R 6 is -L-hexahydro-1H-pyrrolidinyl; wherein, L is C1-C4 alkylene; any 1 on the hexahydro-1H-pyrrolidinyl Two hydrogen atoms on each carbon atom are simultaneously replaced by =CR 2aR 2b; wherein, R 2a and R 2b are each independently hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl. Preferably, the hexahydro-1H-pyrrolidinyl group is also optionally substituted by 1 or more (eg 1, 2, 3, 4 or 5) R 6a; wherein each R 6a 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 .

[0136] In one embodiment, L 3 is O; R 6 is -L-hexahydro-1H-pyrrolidinyl; wherein, L is C1-C4 alkylene; any 1 on the hexahydro-1H-pyrrolidinyl Two hydrogen atoms on each carbon atom are simultaneously replaced by =CR 2aR 2b; wherein, R 2a, R 2b and the connected carbon atoms form a C3-C6 monocyclic cycloalkyl group or a 3-6 membered monocyclic heterocyclic group; The C3-C6 monocyclic cycloalkyl or 3 to 6 membered monocyclic heterocyclic group is optionally replaced by 1, 2, 3 selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, 5-membered or 6-membered monocyclic heteroaryl group substitution. Preferably, the hexahydro-1H-pyrrolidinyl group is also optionally substituted by 1 or more (eg 1, 2, 3, 4 or 5) R 6a; wherein each R 6a 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 .

[0137] In one embodiment, L 3 is O; R 6 is -L-hexahydro-1H-pyrrolidinyl; wherein, L is C1-C4 alkylene; any 2 on the hexahydro-1H-pyrrolazinyl Two hydrogen atoms on one of the carbon atoms are simultaneously replaced by =CR 2aR 2b; wherein, R 2a and R 2b are each independently hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl . Preferably, the hexahydro-1H-pyrrolidinyl group is also optionally substituted by 1 or more (eg 1, 2, 3, 4 or 5) R 6a; wherein each R 6a 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 .

[0138] In one embodiment, L 3 is O; R 6 is -L-hexahydro-1H-pyrrolidinyl; wherein, L is C1-C4 alkylene; any 2 on the hexahydro-1H-pyrrolazinyl Two hydrogen atoms on one of the carbon atoms are simultaneously replaced by =CR 2aR 2b; wherein, a pair of R 2a and 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 constitute a C3-C6 monocyclic cycloalkyl or a 3 to 6-membered monocyclic heterocyclic group; the C3-C6 monocyclic cycloalkyl or 3 to The 6-membered monocyclic heterocyclic group is optionally replaced by 1, 2, or 3 members selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, 5-membered or 6-membered monocyclic heteroaryl group substitution. Preferably, the hexahydro-1H-pyrrolidinyl group is also optionally substituted by 1 or more (eg 1, 2, 3, 4 or 5) R 6a; wherein each R 6a 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 .

[0139] In one embodiment, L 3 is O; R 6 is -L-hexahydro-1H-pyrrolidinyl; wherein, L is C1-C4 alkylene; any 2 on the hexahydro-1H-pyrrolazinyl Two hydrogen atoms on one of the carbon atoms are replaced by =CR 2aR 2b at the same time; wherein, two pairs of R 2a, R 2b each independently form a C3-C6 monocyclic cycloalkyl or 3 to 6-membered monocyclic heterocyclyl; the C3-C6 monocyclic cycloalkyl or 3 to 6-membered monocyclic heterocyclyl is optionally 1, 2, 3 selected from halogen, cyano, C1-C4 alkane C1-C4 alkoxy group, C1-C4 haloalkyl group, C1-C4 haloalkoxy group, C6-C10 aryl group, 5-membered or 6-membered monocyclic heteroaryl group substitution. Preferably, the hexahydro-1H-pyrrolidinyl group is also optionally substituted by 1 or more (eg 1, 2, 3, 4 or 5) R 6a; wherein each R 6a 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 .

[0140] In one embodiment, L 3 is O; R 6 is -L-hexahydro-1H-pyrrolidinyl; wherein, L is C1-C4 alkylene; the hexahydro-1H-pyrrolidinyl is replaced by 1 Or more (such as 1, 2, 3, 4 or 5) R 6a substituted; wherein, each R 6a is independently halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkyl, C2-C6 alkene group, C2-C6 alkynyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group or cyano group.

[0141] In one embodiment, R is selected from the group consisting of: , methyl, .

[0142] In one embodiment, R 6 is -L-6 to 10 membered fused heterocyclic group; said 6 to 10 membered fused heterocyclic group has 1, 2, 3 or 4 members selected from N(R m), S, S(=O), S(=O) 2, heteroatoms of O are used as ring atoms; R m is none, hydrogen, C1-C4 alkyl, deuterated C1-C4 alkyl, C1-C4 haloalkyl, C3- C20 cycloalkyl or 3 to 20 membered heterocyclic group; wherein, L is a bond, C1-C4 alkylene or heteroaryl; the 6 to 10 membered condensed heterocyclic group is saturated; the 6 to 10 2 hydrogen atoms on the same carbon atom in any 1 or 2 carbon atoms on the membered condensed heterocyclic group are optionally substituted by =CR 2aR 2b at the same time; the 6 to 10-membered condensed heterocyclic group is optionally also replaced by One or more R 6a are substituted; R 2a, R 2b, R 6a are the same as before. Preferably, R 2a and R 2b are each independently hydrogen, halogen or C1-C4 alkyl, C1-C4 haloalkyl; R 6a is halogen, hydroxyl, or C1-C6 alkyl.

[0143] In one embodiment, R 6 is -L-6 to 10-membered fused heterocyclic group; the 6- to 10-membered fused heterocyclic group is hexahydro-1H-pyrrolidinyl; wherein, L is C1-C4 alkane 2 hydrogen atoms on the same carbon atom in any 1 or 2 carbon atoms of the 6 to 10-membered fused heterocyclic group are optionally simultaneously substituted by =CR 2aR 2b; the 6 to 10-membered condensed heterocyclic group The ring group is optionally also substituted by one or more R 6a; R 2a, R 2b, R 6a are the same as before. Preferably, R 2a and R 2b are each independently hydrogen, halogen or C1-C4 alkyl, C1-C4 haloalkyl; R 6a is halogen, hydroxyl, or C1-C6 alkyl.

[0144] In one embodiment, R 6 is -L-6 to 10-membered fused heterocyclic group; the 6- to 10-membered fused heterocyclic group is hexahydro-1H-pyrrolidinyl; wherein, L is C1-C2 alkane 2 hydrogen atoms on the same carbon atom in any 1 or 2 carbon atoms of the 6 to 10-membered fused heterocyclic group are optionally simultaneously substituted by =CR 2aR 2b; the 6 to 10-membered condensed heterocyclic group The ring group is optionally also substituted by one or more R 6a; R 2a, R 2b are each independently hydrogen or fluorine; R 6a is halogen, hydroxyl or C1-C6 alkyl.

[0145] In one embodiment, R is selected from the group consisting of: ; In each formula, each p1 is independently 1 or 2; R 2a and R 2b are the same as above. Preferably, R 2a and R 2b are each independently hydrogen, halogen or C1-C4 alkyl, C1-C4 haloalkyl. Preferably, the hexahydro-1H-pyrrolazine is optionally substituted by one or more R 6a; R 6a is as defined above. Preferably, each R 6a is independently halogen or C1-C6 alkoxy.

[0146] In one embodiment, R is selected from the group consisting of: In each formula, R 2a and R 2b are the same as before. Preferably, R 2a and R 2b are each independently hydrogen, halogen or C1-C4 alkyl, C1-C4 haloalkyl. Preferably, the hexahydro-1H-pyrrolazine is optionally further substituted by 1 or more (eg 2 or 3) R 6a; R 6a is as defined above. Preferably, each R 6a is independently halogen or C1-C6 alkoxy.

[0147] In one embodiment, the compound is selected from Table (I).

[0148] Table (I)

[0149] The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and a pharmaceutically acceptable carrier.

[0150] As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or the subject. , including water, oil, vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine.

[0151] In an embodiment of the present invention, the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred. When administered orally, the compounds of the present invention can be prepared in any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. Carriers used for tablets generally include lactose and corn starch, and lubricating agents such as magnesium stearate may also be added. Diluents used in capsule formulations generally include lactose and dried cornstarch. Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral preparation forms. When used locally, especially when treating the affected areas or organs that are easily accessible by local external application, such as eye, skin or lower intestinal neuropathy, the compound of the present invention can be made into different topical preparations according to different affected areas or organs For topical ophthalmic administration, the compounds of the present invention may be formulated as a micronized suspension or solution in the form of isotonic sterile saline at a certain pH with or without the addition of preservatives such as Benzyl alkoxide chloride. For ophthalmic use, the compound may also be formulated in the form of an ointment such as petrolatum ointment. When applied topically to the skin, the compounds of the invention may be formulated in suitable ointments, lotions or creams, wherein the active ingredients are suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations 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 in lotions or creams include, but are not limited to: mineral oil Oil, Sorbitan Monostearate, Tween 60, Cetyl Ester Wax, Cetyl 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 injectable aqueous or oily suspensions or sterile injectable solutions. Vehicles and solvents that may be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition sterile, fixed oils, such as mono- or diglycerides, can also be employed as a solvent or suspending medium.

[0152] Another aspect of the present invention provides the compound described in the above-mentioned first aspect or its pharmaceutically acceptable salt, stereoisomer or solvate or the pharmaceutical composition described in the above-mentioned second aspect in the preparation of prevention and / or treatment of diseases or disorders Use in a medicine; the disease or condition is a KRASG12D-related disease or disorder.

[0153] As used herein, "KRASG12D" refers to a mutant form of the mammalian KRAS protein, which mutant contains an amino acid substitution of aspartic acid for 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-ProtP01116: Variantp.Gly12Asp.

[0154] As used herein, "KRASG12D inhibitor" refers to the compound of the present invention or a pharmaceutically acceptable salt thereof and the like. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRASG12D.

[0155] As used herein, "KRASG12D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRASG12D mutation. A non-limiting example of a KRASG12D-associated disease or disorder is a KRASG12D-associated cancer.

[0156] Another aspect of the present invention provides a method for treating KRASG12D-related cancers, the method comprising the step of: administering a therapeutically effective amount of the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof to a subject in need , stereoisomers or solvates; or administering a therapeutically effective amount of the pharmaceutical composition described in the second aspect of the invention to a subject in need.

[0157] Herein, in one embodiment, the KRASG12D-related cancers include, but are not limited to, tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. In one embodiment, the KRASG12D-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, etc. In one embodiment, the KRASG12D-associated cancers include, but are not limited to, cancers of the heart, for example, sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and Teratomas, etc.; cancers of the lung, e.g., bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilage Tumor hamartoma, mesothelioma; cancers of the gastrointestinal tract, e.g., esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma , insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor (vipoma)), small bowel (adenocarcinoma, carcinoid tumor), Kaposi's sarcoma, leiomyoma, hemangioma , lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); cancers of the urogenital tract, e.g., kidney (adenocarcinoma, Will Muller's tumor (Wilms tumor), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma) tumor, embryonal carcinoma, teratoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); cancers of the liver, e.g., liver cancer (hepatocellular carcinoma), Cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; cancer of the bone site, e.g., osteosarcoma (osteosarcoma), fibrosarcoma, malignant Fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral chondroma), benign enchondroma, benign chondroma osteoma and giant cell tumor; cancers of the nervous system, e.g., of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma, glioblastoma multiforme, glioblastoma cell tumors, congenital tumors), neurofibromas of the spinal cord, meningiomas, gliomas, sarcomas); gynecological cancers, e.g., uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia ), ovarian (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-sheathing cell tumor, Sertoli-Leydig cell tumor (Sertoli-Leydig cell tumor), dysgerminoma, malignant teratoma fetal tumor), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), fallopian tube (carcinoma) Cancers of the blood, e.g., blood (myeloid leukemia (acute) and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non- Hodgkin lymphoma (malignant lymphoma); cancers of the skin, eg, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma , keloids, psoriasis; and cancers of the adrenal gland, eg, neuroblastoma; among others.

[0158] In one embodiment, the KRASG12D-associated cancer is lung cancer.

[0159] In one embodiment, the KRASG12D-associated cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

[0160] Another aspect of the present invention provides a method for treating cancer in a subject in need thereof, the method comprising: (a) the cancer is determined to be associated with a KRASG12D mutation (e.g., a KRASG12D-associated cancer); and (b) administering to the subject a therapeutically effective amount of the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; or administering to the subject a therapeutically effective amount of the pharmaceutical composition described in the second aspect of the present invention.

[0161] In one embodiment, the administering is via a method selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intracavity, intrasynovial, intrathecal, intramuscular injection, vitreous It can be accomplished by intra-, intravenous, intra-arterial, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous and topical routes of administration.

[0162] Another aspect of the present invention provides a method for inhibiting the activity of KRASG12D in cells, the method comprising the steps of: allowing the cells to react with the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof or solvate contact; or contact the cells with the pharmaceutical composition according to the second aspect of the present invention.

[0163] Another aspect of the present invention provides the use of the compound described in the first aspect above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition described in the second aspect above in the preparation of a KRASG12D inhibitor.

[0164] As used in the text, the term "subject" refers to an animal, especially a mammal. Preferred person.

[0165] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of drug or agent sufficient to achieve the desired effect. In an embodiment 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 the specific dosage regimen, the type of disease or condition and its severity, the subject in need of treatment or The uniqueness of the host (e.g., body weight), however, depending on the particular surrounding circumstances, including, for example, the particular drug employed, the route of administration, the condition being treated, and the subject or host being treated, the dosage administered can be determined by methods known in the art. Routine decision. In general, for dosages used in the treatment of adults, the dosage administered is typically in the range of 0.02-5000 mg / day, such as about 1-1500 mg / day. The desired dose may conveniently be presented as one dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example as two, three, four or more divided doses per day. Those skilled in the art can understand that, although the above dose range is given, the specific effective dose can be adjusted appropriately according to the condition of the patient and combined with the doctor's diagnosis.

[0166] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is pharmaceutically acceptable and which possesses the pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; said organic acids such as propionic acid, caproic acid, cypionic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases The coordination compound formed, the organic base such as ethanolamine etc. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or 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 forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0167] As used herein, the terms "solvate" and "solvate" refer to a substance formed by combining a compound of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid and the like. Solvents include stoichiometric solvates and non-stoichiometric solvates. Certain compounds of the present invention can exist in unsolvated or solvated forms. In general, the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention.

[0168] 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 described herein may exist in the form of stereoisomers, and thus encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, non- Enantiomers, atropisomers, etc., the compounds of the present invention can also be any combination or any mixture of the aforementioned stereoisomers, such as mesoforms, racemates, atropisomers It exists in the form of a mixture of equal amounts. For example a single enantiomer, a single diastereoisomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compounds described herein contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof. Atropisomers of the present invention are axial or planar chiral stereoisomers based on restricted rotation within the molecule. And as a drug, a stereoisomer having excellent activity is preferable. The compounds of the present invention have optical isomers derived from asymmetric carbons, etc., and if necessary, a single isomer can be obtained by resolution by methods known in the art, such as crystallization or chiral chromatography.

[0169] As used herein, the term "C1-C6 alkyl" refers to straight and branched chain aliphatics consisting of 1-6 carbon atoms. C1-C4 alkyl or C1-C3 alkyl is preferred. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0170] As used herein, the term "C1-C6 haloalkyl" refers to C1-C6 alkyl in which one or more hydrogens are replaced by halogen. wherein the alkyl moiety is as defined above. C1-C3 haloalkyl or C1-C4 haloalkyl is preferred. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, and monofluoromethyl.

[0171] As used herein, the term "C1-C6 deuterated alkyl" means that one or more hydrogens in a C1-C6 alkyl group are replaced by deuterium atoms. wherein the alkyl moiety is as defined above. Preference is given to C1-C3 deuterated alkyl or C1-C4 deuterated alkyl. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, and monofluoromethyl.

[0172] As used herein, the term "C1-C6 alkoxy" refers to -O-C1-C6 alkyl. Preference is given to C1-C3 alkoxy or C1-C4 alkoxy. wherein the alkyl moiety is as defined above.

[0173] As used herein, the term "C1-C6 haloalkoxy" refers to -O-C1-C6 haloalkyl. C1-C3 haloalkoxy or C1-C4 haloalkoxy is preferred. wherein the haloalkyl moiety is as defined above.

[0174] As used herein, the term "C1-C6 deuteroalkoxy" refers to -O-C1-C6 deuteroalkyl. Preference is given to C1-C3 deuterated alkoxy or C1-C4 deuterated alkoxy. wherein the deuterated alkyl moiety is as defined above.

[0175] As used in the text, the term "C1-C6 hydroxyalkyl" refers to -C1-C6 alkyl-hydroxyl (OH). C1-C3 hydroxyalkyl (ie -C1-C3 alkyl-hydroxy) or C1-C4 hydroxyalkyl (ie -C1-C4 alkyl-hydroxy) is preferred. wherein the alkyl moiety is as defined above.

[0176] As used in the text, the term "C1-C6 cyanoalkyl" refers to -C1-C6 alkyl-cyano. Preference is given to C1-C3 cyanoalkyl or C1-C4 cyanoalkyl. wherein the alkyl moiety is as defined above.

[0177] As used herein, the term "C2-C6 alkynyl" refers to straight and branched aliphatic chains consisting of 2-6 carbon atoms having 1 or 2 carbon-carbon triple bonds. Preference is given to C2-C4alkynyl or C2-C3alkynyl. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0178] As used herein, the term "C2-C6 haloalkynyl" refers to a C2-C6 alkynyl group in which one or more hydrogens are replaced by halogen. wherein the alkynyl moiety is as defined above. C2-C3 haloalkynyl or C2-C4 haloalkynyl is preferred. Examples of haloalkynyl include, but are not limited to, monofluoroethynyl, difluoroethynyl.

[0179] As used herein, the term "C2-C6 alkenyl" refers to straight and branched aliphatic chains consisting of 2-6 carbon atoms with 1 or 2 carbon-carbon double bonds. Preference is given to C2-C4 alkenyl or C2-C3 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, and the like.

[0180] As used herein, the term "C2-C6 haloalkenyl" refers to a C2-C6 alkenyl in which one or more hydrogens are replaced by halogen. wherein the alkenyl moiety is as defined above. Preference is given to C2-C3 haloalkenyl or C2-C4 haloalkenyl. Examples of haloalkenyl include, but are not limited to, monofluorovinyl, difluorovinyl.

[0181] As used herein, the term "C2-C6 hydroxyalkynyl" refers to -C2-C6 alkynyl-OH. Wherein the alkynyl group is as defined above. Preference is given to C2-C4 hydroxyalkynyl or C2-C3 hydroxyalkynyl.

[0182] As used herein, the term "C2-C6 hydroxyalkenyl" refers to -C2-C6 alkenyl-OH. Wherein alkenyl is as defined above. Preference is given to C2-C4 hydroxyalkenyl or C2-C3 hydroxyalkenyl.

[0183] As used in the text, the term "C1-C4 alkylene" refers to a C1-C4 alkyl group as defined above, which is located between and serves to link two other parts of the molecule. Typical alkylene groups include, but are not limited to, methylene, ethylylene, propylylene, and butylene.

[0184] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to a saturated monocyclic or polycyclic cyclic hydrocarbon radical, including, for example, monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkane group and bridged cycloalkyl group. The ring carbon atoms of the cycloalkyl group in the present invention may be optionally substituted 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 having 3 to 20 ring carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. It is preferably 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.

[0185] The term "C3-C8 monocyclic cycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring carbon atoms. It is preferably a C3-C6 monocyclic cycloalkyl group or a C4-C6 monocyclic cycloalkyl group. More preferably, it is a C3, C4, C5 or C6 monocyclic cycloalkyl group. Specific examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0186] As used in this text, the terms "spirocycloalkyl" and "spirocycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed by sharing one carbon atom (called a spiro atom) between two or more monocyclic rings. According to the number of spiro atoms shared between rings, spirocycloalkyl groups can be divided into single spirocycloalkyl, double spirocycloalkyl and polyspirocycloalkyl. The term "C5-C20 spirocycloalkyl" refers to a polycyclic cyclic hydrocarbon group with 5 to 20 ring carbon atoms, wherein the single ring sharing a spiro atom is a C3-C8 monocyclic cycloalkyl ring. Preference is given to C6-C14 spirocycloalkyl. More preferably, it is a C6-C14 monospirocycloalkyl group. More preferably, it is a C7-C11 spirocycloalkyl group. More preferred is a 7- to 11-membered monospirocycloalkyl group. Most preferably 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) Cycloalkyl ring / C6 monocyclic cycloalkyl ring) monospirocycloalkyl. Specific examples of spirocycloalkyl groups include, but are not limited to: .

[0187] These spirocycloalkyl groups can be attached to the rest of the molecule through any ring atom.

[0188] 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 adjacent pairs of carbon atoms. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups. The term "C5-C20 fused cycloalkyl" refers to a polycyclic cyclic hydrocarbon group with 5 to 20 ring carbon atoms, wherein the single ring sharing adjacent pairs of carbon atoms is a C3-C8 monocyclic cycloalkyl ring. Preferably it is a C6-C14 fused cycloalkyl group. More preferably, it is a C6-C14 difused cycloalkyl group. More preferably, it is a C7-C10 condensed cycloalkyl group. More preferably, it is a C7-C10 difused cycloalkyl group. Most preferably C8 (C5 monocyclic cycloalkyl ring fused with C5 monocyclic cycloalkyl ring), C9 (C5 monocyclic cycloalkyl ring fused with C6 monocyclic cycloalkyl ring) or C10 (C6 monocyclic cycloalkyl ring fused) Cycloalkyl ring and C6 monocyclic cycloalkyl ring fused) double condensed cycloalkyl. Specific examples of fused cycloalkyl groups include, but are not limited to: .

[0189] These fused cycloalkyl groups can be attached to the rest of the molecule through any ring atom.

[0190] As used herein, the terms "bridged cycloalkyl" and "bridged cycloalkyl ring" refer to a polycyclic cyclic hydrocarbon group formed between two or more monocyclic rings by sharing two carbon atoms that are not directly connected. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. 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: .

[0191] These bridged cycloalkyl groups can be attached to the rest of the molecule through any ring atom.

[0192] For example, examples of cycloalkyl herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[1.1 .1] Amyl.

[0193] As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, wherein cycloalkyl is as previously defined.

[0194] As used herein, the terms "heterocyclyl" and "heterocyclyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, including, for example, monocyclic heterocyclyl, spiroheterocyclyl , fused heterocyclic group and bridged heterocyclic group. The ring carbon atoms of the heterocyclic group in the present invention may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactamide structure. 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, one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen, or S(=O) m' (where m' is an integer from 0 to 2), but excluding ring moieties of -O-O-, -O-S- or -S-S- , and the remaining ring atoms are carbon. Wherein when the ring atom is a nitrogen atom, it may be substituted or unsubstituted (ie N or NR, R is hydrogen or other substituents defined herein). The 3 to 20 membered heterocyclic group in the present invention includes a monocyclic heterocyclic group (for example, a 3 to 8 membered monocyclic heterocyclic group), a 5 to 20 membered spiro heterocyclic group, a 5 to 20 membered condensed heterocyclic group and a 5 to 20-membered bridged heterocyclyl.

[0195] As used herein, the term "3 to 20 membered nitrogen-containing heterocyclic group" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group containing at least 1 nitrogen atom and having 3 to 20 ring atoms; wherein the group is passed through the The nitrogen atom is attached to the rest of the molecule; and the group optionally contains an additional 1 or 2 heteroatoms selected from nitrogen, oxygen, or S(=O)m' (where m' is an integer from 0 to 2) as a ring atom. The 3- to 20-membered nitrogen-containing heterocyclic group in the present invention includes a monocyclic heterocyclic group (such as a 3- to 8-membered monocyclic nitrogen-containing heterocyclic group), a 5- to 20-membered nitrogen-containing spiroheterocyclic group, a 5- to 20-membered Nitrogen-containing condensed heterocyclic group and 5 to 20-membered nitrogen-containing bridged heterocyclic group.

[0196] As used herein, the terms "3 to 8 membered monocyclic heterocyclyl" and "3 to 8 membered monocyclic heterocyclyl ring" refer to ring atoms having 3 to 8 ring atoms, of which 1, 2 or 3 ring atoms are selected from A saturated or partially unsaturated monocyclic cyclic hydrocarbon group of nitrogen, oxygen or a heteroatom of S(=0)m' (where m' is an integer from 0 to 2). Preferred are 3 to 6 membered monocyclic heterocyclyls having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred are 4 to 6 membered monocyclic heterocyclyl groups having 4 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred is a 5 or 6 membered monocyclic heterocyclyl having 5 or 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie N or NR, R being hydrogen or other substituents already defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (ie, S(=0)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 lactamide structure. Specific examples of monocyclic heterocyclyl groups include, but are not limited to, aziridine, oxirane, azetidine, azetidin-2-one, oxetane, oxetane-2 -ketone, oxazolidine, pyrrolidin-2-one, pyrrolidin-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-diketone, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3 -Dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholine -2-one, thiomorpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholin-1,1-dioxide, tetrahydropyran, 1,2-dihydro Azetidin, 1,2-dihydrooxetadiene, 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-dioxan-2-one, 5 ,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-di Hydropyridine-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-tetrahydro Pyrazine, 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- Ketone, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridin-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.

[0197] As used herein, the term "3 to 6 membered nitrogen-containing heterocyclic group" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group having 3 to 6 ring atoms containing at least one nitrogen atom as a ring atom; wherein the group It can be connected to other parts of the molecule through the nitrogen atom, and can also be connected to other parts of the molecule through other ring atoms of the group; and the group also optionally contains another 1 or 2 selected from nitrogen, oxygen or a heteroatom of S(=0) m' (where m' is an integer from 0 to 2) as a ring atom. Specific examples may be selected from 3 to 8 membered monocyclic heterocyclic groups, including but not limited to tetrahydropyrrolyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpho Phenyl, azetidinyl and similar groups.

[0198] As used herein, the terms "spiroheterocyclyl" and "spiroheterocyclyl ring" refer to two or more saturated or partially unsaturated monocyclic rings that share one carbon atom (called a spiro atom) to form a polycyclic heterocyclic ring. Cyclic group, wherein one or more (such as 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O) m' (where m' is an integer from 0 to 2), and the remaining ring atoms for carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie N or NR, R being hydrogen or other substituents already defined herein). Each single ring can contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified as single spiroheterocyclyls, double spiroheterocyclyls or polyspiroheterocyclyls. The term "5 to 20 membered spiroheterocyclyl" refers to a spiroheterocyclyl having 5 to 20 ring atoms, wherein one of the monocyclic rings sharing spiro atoms is a 3 to 8 membered monocyclic heterocyclyl ring and the other The monocyclic ring is a 3 to 8 membered monocyclic heterocyclyl ring or a 3 to 8 membered monocyclic cycloalkyl ring. Preferred are 6 to 14 membered spiroheterocyclyls having 6 to 14 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred are 7 to 11 membered spiroheterocyclyls having 7 to 11 ring atoms, of which 1 or 2 ring atoms are heteroatoms. Most preferably 7-membered (4-membered monocyclic heterocyclyl ring / 4-membered monocyclic heterocyclyl ring or 4-membered monocyclic heterocyclyl ring / 4-membered monocyclic cycloalkyl ring or 4-membered monocyclic cycloalkyl ring / 4-membered monocyclic heterocyclyl ring), 8-membered (4-membered monocyclic heterocyclyl ring / 5-membered monocyclic heterocyclyl ring), 9-membered (4-membered monocyclic heterocyclyl ring / 6-membered monocyclic heterocyclyl ring base ring, 5-membered monocyclic heterocyclyl ring / 5-membered monocyclic heterocyclyl ring), 10-membered (5-membered monocyclic heterocyclyl ring / 6-membered monocyclic heterocyclyl ring) or 11-membered (6-membered ring heterocyclyl ring / 6-membered monocyclic heterocyclyl ring) monospiro heterocyclyl. Specific examples of spiroheterocyclyl include, but are not limited to: and .

[0199] These spiroheterocyclyls may be attached to the remainder of the molecule through any suitable ring atom.

[0200] As used herein, the term "5- to 20-membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl group having 5 to 20 ring atoms containing at least one nitrogen atom; and the group optionally contains another 1 or 2 or 3 heteroatoms selected from nitrogen, oxygen or S(=O) m' (where m' is an integer from 0 to 2) as a ring atom.

[0201] 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 adjacent pairs of ring atoms, One or more (such as 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O) m' (where m' is an integer from 0 to 2), and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie N or NR, R being hydrogen or other substituents already defined herein). Each single ring can contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Shared adjacent pairs of ring atoms may be C-C or N-C. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups. The term "5 to 20 membered fused heterocyclyl" refers to a fused heterocyclyl having 5 to 20 ring atoms, wherein the monocyclic ring sharing adjacent pairs of ring atoms is a 3 to 8 membered monocyclic heterocyclyl ring. Preferred are 6 to 14 membered fused heterocyclic groups having 6 to 14 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred are 6 to 10 membered fused heterocyclic groups having 6 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred are 8 to 10 membered fused heterocyclic groups having 8 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms. Most preferred are 8-membered (5-membered monocyclic heterocyclyl ring fused to 5-membered monocyclic heterocyclyl ring), 9-membered (5-membered monocyclic heterocyclyl ring fused to 6-membered monocyclic heterocyclyl ring) Or a 10-membered (6-membered monocyclic heterocyclyl ring condensed with a 6-membered monocyclic heterocyclyl ring) bicyclic condensed heterocyclic group. Specific examples of fused heterocyclic groups include, but are not limited to: .

[0202] These fused heterocyclic groups may be attached to the remainder of the molecule through any suitable ring atom.

[0203] As used herein, the term "5 to 20 membered nitrogen-containing fused heterocyclic group" refers to a condensed heterocyclic group having 5 to 20 ring atoms containing at least one nitrogen atom; and the group optionally contains another 1 or 2 or 3 heteroatoms selected from nitrogen, oxygen or S(=O) m' (where m' is an integer from 0 to 2) as a ring atom.

[0204] As used herein, the terms "bridged heterocyclyl" and "bridged heterocyclyl ring" refer to a polycyclic heterocyclic ring formed by two or more saturated or partially unsaturated monocyclic rings that share two ring atoms that are not directly attached. wherein one or more (such as 1, 2 or 3) ring atoms are heteroatoms selected from nitrogen, oxygen or S(=O) m' (where m' is an integer from 0 to 2), 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, and each single The rings can contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably it is a 6- to 14-membered bridged heterocyclic group. More preferred is a 7- to 10-membered bridged heterocyclic group. Specific examples of bridged heterocyclyl groups include, but are not limited to: .

[0205] These bridging heterocyclyl groups may be attached to the remainder of the molecule through any suitable ring atom.

[0206] 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 containing at least one nitrogen atom; and the group optionally contains another 1 or 2 or 3 heteroatoms selected from nitrogen, oxygen or S(=O) m' (where m' is an integer from 0 to 2) as a ring atom.

[0207] In the present invention, the above-mentioned various heterocyclic groups may be optionally substituted, and when substituted, the substituents are preferably one or more substituent groups described in the present application.

[0208] Specifically, specific examples of heterocyclic groups described in the present invention include, but are not limited to, epoxy, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, piperazine Base, imidazolyl, imidazopyridyl, thiazolyl, oxazolidinyl, oxazolidinedione, decahydroquinolinyl, piperidinonyl, morpholinyl, azabicyclohexyl, azabicycloheptyl , azabicyclooctyl, azabicyclononyl, azabicyclodecanyl, azaspiroheptyl, azaspirooctyl, azaspirocyclonyl, azaspirocyclodecyl, tetrahydrospiro Cyclo[cyclopropane-1,2'-pyrrolidinyl], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindo Oxazinyl, oxaspiroheptyl, oxaspirooctyl, oxaspirononyl, oxaspirodecyl, diazaspirononyl, oxabicyclohexyl, oxabicycloheptyl , Oxabicyclooctyl, Hexahydroalloxazinyl 4(1H)-oxide.

[0209] As used in the text, the term "aryl" refers to an all-carbon monocyclic ring, an all-carbon non-fused polycyclic ring (rings are covalently bonded to each other, not fused), or an all-carbon fused polycyclic ring (that is, they share adjacent carbon atoms. For ring) groups, at least one ring in the group is aromatic, that is, has a conjugated π-electron system. For example, the term "C6-C14 aryl" refers to an aryl group having 6 to 14 ring atoms. It is preferably a C6-C10 aryl group. C6-C14 aryl groups in the present invention include monocyclic aryl groups, non-fused polycyclic aryl groups and aromatic fused polycyclic groups, wherein examples of monocyclic aryl groups include phenyl, examples of non-fused polycyclic aryl groups include bi Phenyl, etc.

[0210] In the present invention, when the C6-C14 aryl group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring may be a polycyclic group formed by the fusion of a single aryl ring and one or more single aryl rings, Non-limiting examples thereof include naphthyl, anthracenyl, and the like.

[0211] In some embodiments of the present invention, when the C6-C14 aryl is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring can also be a single aryl ring (such as phenyl) and one or more non-aromatic A polycyclic group formed by ring fusion, in which 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 3 to 6 membered monocyclic heterocyclyl rings (preferably 5 or 6 membered monocyclic heterocyclyl rings, the ring carbon atoms of the monocyclic heterocyclyl rings can be divided by 1 to 2 A oxo group is substituted to form a lactamide or a lactone structure), a 3 to 6-membered monocyclic cycloalkyl ring (preferably a 5 or 6-membered monocyclic cycloalkyl ring, the monocyclic cycloalkyl ring The carbon atoms in the ring can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure). The polycyclic group in which the above-mentioned single aryl ring is fused with one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or a carbon atom, and the ring connected to the parent structure is a single aryl ring or non-aromatic ring.

[0212] In the present invention, the above-mentioned various aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituent groups described in this application.

[0213] 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 by one or more (eg 1, 2, 3, 4 or 5) R 6 or one or more (eg 1 , 2, 3, 4 or 5) R 7 . 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, respectively, may be saturated or partially saturated. If the aryl group contains two saturated rings, the two saturated rings may be a fused ring system or a spiro ring system. Examples of aryl groups containing two saturated rings (and being a spiro ring system) include the following: .

[0214] As used herein, the term "aryl C1-C6 alkyl" or "aralkyl" is meant to include an aryl group covalently linked to an alkyl group. Wherein, the definition of the aryl group is as described above, the definition of the alkyl group is as described above, and any one or all of the aryl group or the alkyl group can be independently selectively 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 by hydroxyalkyl group.

[0215] As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic ring having ring atoms substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur (i.e., sharing adjacent pairs of ring atoms that can be is a C-C or N-C) group in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is 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" means having 5 to 14 ring atoms, of which 1, 2, 3 or 4 ring atoms are selected from nitrogen, oxygen, or S(=O)m' (where m' is a heteroaryl group of a heteroatom of integer 0 to 2). Preferred are 5 to 10 membered heteroaryl groups having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. The 5- to 14-membered heteroaryl group in the present invention can be a monocyclic heteroaryl group (eg, a 5- or 6-membered monocyclic heteroaryl group), a fused bicyclic heteroaryl group (eg, an 8- to 10-membered bicyclic heteroaryl group) or a fused A tricyclic heteroaryl.

[0216] As used herein, the term "5 or 6 membered monocyclic heteroaryl" means having 5 or 6 ring atoms, of which 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(=O)m' (where m' is a monocyclic heteroaryl group of a heteroatom of integer 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, Azole, 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, etc.

[0217] As used herein, the term "8 to 10 membered bicyclic heteroaryl" means a group having 8 to 10 ring atoms, of which 1, 2, 3, 4 or 5 ring atoms are selected from nitrogen, oxygen or S(=O) m fused bicyclic heteroaryl of heteroatoms ' (where m' is an integer from 0 to 2). The fused bicyclic heteroaryl group can be a bicyclic group (preferably 9 or 10 membered bicyclic heteroaryl rings), monocyclic heteroaryl rings (preferably 5 or 6 membered monocyclic heteroaryl rings) and monocyclic heteroaryl rings (preferably 5 or 6 membered monocyclic heteroaryl rings) ring heteroaryl ring) fused to form a bicyclic group.

[0218] Any two ring atoms connected to each other on the above-mentioned monocyclic heteroaryl ring, including C-C, N-C, and N-N, can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monoaryl ring, 5 Or a cycloalkyl, heterocyclyl, aryl or heteroaryl such as a 6-membered monocyclic heteroaryl ring is fused to form a condensed polycyclic ring. The two ring atoms connected to the monocyclic heteroaryl ring forming a fused ring with other rings are preferably C-C, including but not limited to the following forms: and .

[0219] In the above group through " ” labeled ring atoms are attached to the rest of the molecule.

[0220] Non-limiting examples of 8 to 10 membered bicyclic heteroaryl groups 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, iso Quinoline, 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 etc.

[0221] Specific examples of bicyclic heteroaryls include, but are not limited to: . These groups may be attached to the remainder of the molecule through any suitable ring atom. The ring attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.

[0222] In some embodiments of the present invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl can be a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) with one Or a polycyclic group formed by the fusion of multiple 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 3 to 6 membered monocyclic heterocyclyl rings (preferably 5 or 6 membered monocyclic heterocyclyl rings, the ring carbon atoms of the monocyclic heterocyclyl rings can be divided by 1 to 2 A oxo group is substituted to form a lactamide or a lactone structure), a 3 to 6-membered monocyclic cycloalkyl ring (preferably a 5 or 6-membered monocyclic cycloalkyl ring, the monocyclic cycloalkyl ring The carbon atoms in the ring can 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 a nitrogen atom or a carbon atom, and the ring connected to the parent structure is a monocyclic heteroaryl base ring or non-aromatic ring.

[0223] In the present invention, the above-mentioned various heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituent groups described in the present application.

[0224] As used in the text, the term "acetyl" refers to -C(O)CH3. Brief description of the diagram

[0225] Other features and functions of the present invention will be clearly presented in the implementation manner with reference to the drawings, wherein: Figure 1 is a single crystal diffraction molecular three-dimensional structure diagram of Compound B. Implementation

[0226] 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, the embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art equivalent replacement. Preferred embodiments include, but are not limited to, the examples of the present invention. The synthesis method of intermediates or starting compounds in this article is shown in a certain example separately as a preparation example, and the preparation of the compound will not be described repeatedly if the same intermediates or starting compounds are used in other examples.

[0227] The present invention is described in detail by the following examples, but it does not mean any unfavorable limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

[0228] For example, the compound of formula (A-4) can be prepared in the following manner.

[0229] First with formula (A-1) compound as raw material, with Carry out reaction formation formula (A-2) compound; Then formula (A-2) compound and Carry out reaction and form formula (A-3) compound; Then formula (A-3) compound is carried out de-third butoxycarbonyl (Boc) reaction to form formula (A-4) compound; R L1, R L2, R L3, R L4 are each independently a leaving group (e.g., halogen, boronic acid group (e.g. ), borate groups (such as ), -S(=O)CH 3 , -S(=O) 2CH 3 , -OH, tributyltin-based (-SnBu 3 ), benzotriazolyl-O- (eg )); , X, Y, Z, W, R 1, n1, L 3, R 6 respectively order the same as before.

[0230] For another example, the compound of formula (A-4) can be prepared in the following manner.

[0231] First with formula (A-1) compound as raw material, with Carry out reaction formation formula (A-2-1) compound; Then formula (A-2-1) compound and Carry out reaction to form formula (A-3-1) compound; Then formula (A-3-1) compound is carried out to take off the third butoxycarbonyl (Boc) reaction to form formula (A-4) compound; R L1, R L2, R L3 and R L4 are each independently a leaving group (for example, halogen, boronic acid group (for example ), borate groups (such as ), -S(=O)CH 3 , -S(=O) 2CH 3 , -OH, tributyltin-based (-SnBu 3 ), benzotriazolyl-O- (eg )); , X, Y, Z, W, R 1, n1, L 3, R 6 are the same as before; R 1a refers to R 1 protected by a protecting group (for example, when there is an ethynyl group in R 1, the ethynyl group can be protected by triisopropylsilyl (TIPS); when an amine group is present in R 1 the amine group can be protected by Boc).

[0232] For another example, the compound of formula (A-4) can be prepared in the following manner.

[0233] First with formula (A-1) compound as raw material, with Carry out reaction formation formula (A-5) compound; Then formula (A-5) compound and Carrying out reaction to form formula (A-3) compound; Then formula (A-3) compound is carried out to take off the third butoxycarbonyl (Boc) reaction to form formula (A-4) compound; , X, Y, Z, W, R 1, n1, L 3, R 6 respectively order the same as before.

[0234] The structure of the compound was determined by nuclear magnetic resonance (NMR), mass spectrometry (MS) and other methods.

[0235] The determination of NMR adopts BrukerAvanceNEO400 or BrukerAvanceNEO500 nuclear magnetic resonance instrument, the chemical shift (δ) is in parts per million (ppm), the measurement solvent is as shown in each embodiment, and the internal standard is tetramethylsilane (TMS).

[0236] The determination of MS adopts Agilent1100 liquid chromatograph.

[0237] High-performance liquid chromatography (HPLC) analysis using Waters2695 high-performance liquid chromatography.

[0238] High performance liquid phase preparation uses Waters2767 high performance liquid chromatography.

[0239] Chiral HPLC analysis using Waters2695 high performance liquid chromatography or WatersInvestigatorSFC system.

[0240] Chiral preparation uses gilsongx-281 chromatograph or watersSFC-80 chromatograph.

[0241] The thin-layer chromatography silica gel plate adopts Qingdao GF254 or Yantai Huanghai HSGF254 silica gel plate. The size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm. Thin-layer chromatography separation and purification products adopt a specification of 0.4mm-0.5mm.

[0242] Column chromatography generally adopts ISCOCombiFlashNextGen300 column chromatography system, using AgelaFlashColumnSilica-Cs series silica gel column.

[0243] The preparative HPLC adopted in the following examples, if no special instructions, can adopt the following conditions:

[0244] Preparative HPLC (formic acid method 1): column type: WatersXBridgeC18, 19*250mm, 5um; mobile phase system: A: 0.1% formic acid aqueous solution; B: preparative grade acetonitrile; flow rate: 15ml / min; B%=20%-100% ; Column temperature: room temperature.

[0245] Preparative HPLC (formic acid method 2): chromatographic column: WelchXtimateC18, 21.2*150mm, 5um; mobile phase A: 0.1% aqueous formic acid, mobile phase B: acetonitrile; flow rate: 15ml / min; column temperature: room temperature.

[0246] Preparative HPLC (ammonium bicarbonate method 1): column type: WatersXBridgeC18, 19*250mm, 5um; mobile phase system: A: 5mmol / L ammonium bicarbonate aqueous solution; B: preparative grade acetonitrile; flow rate: 15ml / min; B%= 20%-100%; column temperature: room temperature.

[0247] Preparative HPLC (ammonium bicarbonate method 2): chromatographic column: WelchXtimateC18, 21.2*150mm, 5um; mobile phase A: 5mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 15mL / min; column temperature: room temperature.

[0248] Preparative HPLC (ammonia method): chromatographic column: WatersXbridgeC18, 19*150mm, 5μm; mobile phase A: 0.1% ammonia solution, mobile phase B: acetonitrile; flow rate: 15mL / min; column temperature: room temperature.

[0249] Preparative HPLC (trifluoroacetic acid method): chromatographic column: WelchXtimateC18, 21.2*150mm, 5um; mobile phase A: 0.1% trifluoroacetic acid-water, mobile phase B: acetonitrile; flow rate: 15ml / min; column temperature: room temperature.

[0250] Preparation Example 1 Synthesis of (1R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (A1)

[0251] Step 1: Add (S)-methyl 5-oxopyrrolidine-2-carboxylate (200 g, 1397 mmol) and dimethyl sulfate (134 mL) into a 1 L single-necked bottle. After the addition was complete, the system was reacted at 56 oC for 18 hours, and the reaction was monitored by TLC. After cooling to room temperature, triethylamine (292 mL) was added dropwise and stirred for 30 minutes. Add 400mL of water and extract with ethyl acetate (400mLX3). The organic phase was washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester ( 150g, yield: 68.4%), yellow oily compound. ES-API: [M+1] +=158.1.

[0252] Step 2: Add (S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester (150g, 954.3mmol), methyl nitroacetate (123.8 g, 1040.2 mmol). After the addition was complete, the system was reacted at 60 oC for 40 hours, and the reaction was completed by NMR monitoring. Purified by column chromatography (dichloromethane / ethyl acetate=50 / 1) to obtain (S,Z)-5-(2-methoxy-1-nitro-2-oxoethyl)pyrrolidine-2- Methyl carboxylate (80.0 g, yield: 34.2%), yellow solid. ES-API: [M+1] +=245.1.

[0253] Step 3: Add (S,Z)-5-(2-methoxy-1-nitro-2-oxoethyl)pyrrolidine-2-carboxylic acid methyl ester (20.0g, 81.9 mmol), palladium on carbon (2.0g), methanol (600mL). After the addition was complete, hydrogen was replaced three times. The system was reacted at 60 oC for 5 days, and the reaction was completed by LC-MS monitoring. Repeat feeding 4 batches. After filtration, the filtrate was concentrated 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

[0254] Step 4: Add the compound (1R,5S)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (A1, 60.0g, 325mmol ), triethylamine (65.9g, 651.5mmol), dichloromethane (600mL). After cooling to 0 oC, di-tert-butyl dicarbonate (106.6 g, 488.6 mmol) was added. After the addition was complete, the system reacted overnight at room temperature, and LC-MS monitored the completion of the reaction. Add water (1L), and extract with dichloromethane (1L). The organic phase was spin-dried, and the crude product was purified by column chromatography (dichlorohexane / methanol=20:1) to obtain 8-(tert-butyl)2-methyl(1R,5S)-4-oxo-3,8 - Diazabicyclo[3.2.1]octane-2,8-dicarboxylate (A12, 70.0g, yield: 75.8%), yellow solid. ES-API: [M-Boc+1] +=285.1.

[0255] Step 5: In a 500mL three-necked flask, add the compound 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), tetrahydrofuran (300 mL). Cool to 0 oC, add lithium aluminum tetrahydrogen (5.87g, 154.7mmol) in batches (the temperature is controlled below 5 oC). Join complete. The system reacted overnight at room temperature, and LC-MS monitored the completion of the reaction. Cool to 0 oC, add water to quench the reaction, stir for 1 hour, filter, dichloromethane / methanol (10:1) to wash the filter cake. The filtrate was concentrated to give crude product. The crude product was prepared in reverse phase by preparative HPLC (ammonium bicarbonate method 1) to obtain (1R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid Tributyl ester (A1, 5.8g, yield: 32.2%), yellow solid. ES-API: [M-Boc+1] +=243.2.

[0256] Preparation Example 2 Synthesis of Isomers (A2-1)

[0257] Step 1: (R)-methyl 5-oxopyrrolidine-2-carboxylate (395.3g, 2.762mmol) was dissolved in 3500mL dichloromethane, and trimethyloxonium tetrafluoroboric acid was added in batches at 5°C ( 612.697g, 4.142mol, 1.5eq), and reacted at 25 oC for 24 hours after addition. TLC monitored the completion of the reaction. The reaction solution was slowly poured into 5000mL saturated sodium carbonate aqueous solution, the pH was 8~9, the liquids were separated, the aqueous phase was extracted with 1500mL dichloromethane, the organic phases were combined, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and spin-dried to obtain ( R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester (406.7g, 2.588mol, yield: 93.702%) light yellow oily liquid. ES-API: [M+1] +=158.1.

[0258] Step 2: (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester (406.7g, 2.588mol) was added to nitroacetic acid methyl ester (308.133g, 2.588 mol, 1eq). Reacted at 60°C for 48 hours, and the reaction was completed by NMR monitoring. Column chromatography (petroleum ether: ethyl acetate = 4:1~2:1) obtained 250.0 g yellow oily liquid crude product, which was purified by beating, filtered and dried to obtain (R)-5-(2-methoxy-1-nitrate (146.2g, 598.687mmol, yield: 23.136%) light yellow solid. ES-API: [M+1] +=245.1.

[0259] Step 3: In a 5L autoclave, (R)-5-(2-methoxy-1-nitro-2-oxoethyl)pyrrolidine-2-carboxylic acid methyl ester (146.2g, 598.687mmol) Dissolve in methanol (1500mL) and tetrahydrofuran (1500mL), add Pd(OH) 2 / C (15.00g, 20% purity), hydrogen replacement 3 times, 0.4MPa, 40°C for 72 hours. Hydrogen was added several times during the reaction. Down to room temperature out of the kettle. The reaction solution was filtered and spin-dried to obtain (1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (A21, 110.3g, crude product) yellow oily liquid . ES-API: [M+1] +=185.1.

[0260] Step 4: Crude product (1S, 5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid methyl ester (A21, 10.00g, 54.291mmol) was dissolved in water ( 50mL) and tetrahydrofuran (50mL), add Na 2CO 3 (5.754g, 54.291mmol), 10°C dropwise add di-tertiary butyl dicarbonate ((Boc) 2O) (11.849g, 54.291mmol), dropwise, 20 °C for 12 hours. TLC monitored the completion of the reaction. The reaction solution was filtered, the filter cake was washed with 50mL ethyl acetate, separated, the aqueous phase was extracted with 50mL ethyl acetate, the organic phase was combined, and spin-dried for column chromatography (petroleum ether:ethyl acetate=2:1~1:1) 8-(tert-butyl)2-methyl(1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (A22 , 3.61g, 12.698mmol, yield: 23.388%) white solid. ES-API: [M-Boc+1] +=285.1.

[0261] Step five: 8-(tertiary butyl) 2-methyl (1S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylic acid The ester (A22, 2.00g, 7.035mmol) was dissolved in tetrahydrofuran (20mL), and lithium aluminum tetrahydrogen (400.489mg, 10.552mmol, 1.5eq) was added in portions at 0°C. After the addition was complete, the reaction was carried out at 20°C for 12 hours. TLC monitored the completion of the reaction. 0°C, add 0.4mL of water, 0.4mL of 15% sodium hydroxide solution and 1.2mL of water dropwise to the reaction solution in turn, after the addition is complete, add anhydrous magnesium sulfate and stir for 10min, filter and concentrate to obtain the crude product. The crude product was prepared by reverse phase to obtain (1S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (A2, 0.65g, Yield: 38%), pale yellow solid. ES-API: [M-Boc+1] +=243.2.

[0262] Step 6: (1S, 5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (A2, 100mg) was passed through chiral SFC preparation and resolution [column type: CHIRALPAK-IG, 30*250mm, 10um, mobile phase: carbon dioxide: methanol (0.1% ammonia water) = 80:20 (v / v), flow rate: 150mL / min, column temperature = 35℃ , detection wavelength 210nm] to obtain an isomer compound with the structure of (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid Tertiary butyl ester (A2-1, 58 mg, peak 2, retention time 10.391 min, the structure was deduced from the single crystal data of Example 14). The isomers were analyzed 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) for detection. 1H NMR of A2-1 (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.

[0263] [Example] [1] [synthesis] [5-] [ethyl] [-4-((6R,9S)-12-(((2R,7aS)-2-] [Fluorotetrahydrogen] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [Oxa] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [-2-] [base] [)] [Naphthalene] [-2-] [alcohol] [(Z1)]

[0264] Step 1: To triisopropyl ((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- cesium fluoride (3.0 g, 20.24 mmol) was added to a solution of N, N-dimethylformamide (5.0 mL) of (500 mg, 1.012 mmol) of ethynyl) yl) naphthalene-1-yl) ethynyl) silane (500 mg, 1.012 mmol), and the reaction was carried out at room temperature for 2 Hour. After the reaction was complete, extract with ethyl acetate (100mLX2), combine the ethyl acetate phases and wash with saturated brine (100mLX3), dry over anhydrous sodium sulfate, filter, and spin dry to obtain 2-(8-ethynyl-3-(methoxy (methoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (558 mg, crude). ES-API: [M+H] +=339.3.

[0265] Step 2: To 2-(8-ethynyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxa Add 10% palladium carbon (60 mg) to a solution of borane (558 mg, crude product) in methanol (10.0 mL), replace with hydrogen four times, and react at room temperature for 2 hours under the protection of hydrogen. The reaction was completed, filtered, and the solvent was spin-dried under reduced pressure to obtain 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1, 3,2-Dioxaborane (284 mg, 2 steps overall yield: 82%). ES-API: [M+1] +=343.3.

[0266] Step 3: Dissolve 2,4,6-trichloronicotinic acid (5.0g, 22.22mmol) in dichloromethane (40.0mL) at 0°C, and add oxalyl chloride (6.0mL) dropwise to the above system 8 drops of N,N-dimethylformamide were added, and the reaction system was stirred and reacted at room temperature for 1 hour. After 1 hour, the solvent was spin-dried under reduced pressure, and dry tetrahydrofuran (30.0 mL) solution was added, cooled to 0~5°C, and the solution was added dropwise to the mixed solution of ammonia water (30.0 mL) and tetrahydrofuran (30.0 mL). Stir for 1 hour. Extract with ethyl acetate (100mLX2), combine the ethyl acetate phases and wash with saturated brine (100mLX1), dry over anhydrous sodium sulfate, filter, and spin dry to obtain 2,4,6-trichloronicotinamide (6.0g, crude ). ES-API: [M+H] +=224.9 / 226.9.

[0267] Step 4: In a 500 mL three-neck round bottom flask, (2,4-dimethoxyphenyl)methanamine (4.45 g, 26.66 mmol) was dissolved in dry dioxane (90.0 mL). Cool in an ice-water bath to 0~5°C, add N,N-diisopropylethylamine (8.61g, 66.66mmol) under nitrogen protection, react at this temperature for about 10~15 minutes, and 2,4,6-trichloro Niacinamide (6.0 g, crude product) was dissolved in dry dioxane (20 mL) and added dropwise to the above solution. The reaction was continued at 50°C for 5 hours. The completion of the reaction was monitored by LCMS, and the reaction solution was poured into ice water (400mL), extracted with ethyl acetate (200mL×1), dried over anhydrous sodium sulfate, filtered, and spin-dried, and the crude product was subjected to column chromatography [petroleum ether: ethyl acetate=100 : 0~50:50, (v / v)] purified to obtain 2,6-dichloro-4-((2,4-dimethoxybenzyl)amino)nicotinamide (4.16g, 2 steps total Yield: 52%). ES-API: [M+H] +=356.1 / 358.1.

[0268] Step five: add 2,6-dichloro-4-((2,4-dimethoxybenzyl) amino) nicotinamide (3.723g, 10.47mmol) and Dry tetrahydrofuran (60 mL), 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. N,N'-carbonyldiimidazole (5.09g, 31.41mmol) was added to dry tetrahydrofuran (30mL), added dropwise to the above solution, and the reaction was carried out at this temperature for 0.5~1 hour. The completion of the reaction was monitored by LCMS, and the reaction solution was poured into ice water (300mL). Under ice water bath conditions, the pH was adjusted to 7~8 with 6M aqueous hydrochloric acid solution, and 5,7-dichloro-1-(2,4-dimethoxy benzyl)pyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (3.7g, yield: 92.7%). ES-API: [M+H] +=382.0 / 384.0.

[0269] Step 6: Add dry tetrahydrofuran (100 mL) to a 250 mL one-necked flask at room temperature, then add (1R,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8 - Tertiary butyl carboxylate (358.0mg, 1.480mmol), cooled to 0~5°C in an ice-water bath, and added sodium hydride (1.20mg, 2.960mmol). React for 10-20 minutes under the protection of nitrogen, add 5,7-dichloro-1-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4(1H, 3H)-diketone (565.0mg, 1.480mmol), continue to react at 0~5℃ for 20~30 minutes. The completion of the reaction was monitored by LCMS, the reaction solution was poured into ice water (300mL), the pH was adjusted to 7~8 with 6M hydrochloric acid aqueous solution, extracted with ethyl acetate (100mLX2), and the ethyl acetate phase was combined and washed with saturated brine (100mLX1). Dried over sodium sulfate, filtered, and spin-dried to obtain (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 Tertiary butyl ester (850mg, yield: 97%). ES-API: [M+H] +=588.3.

[0270] Step 7: Add dry N,N-dimethylformamide (20mL) and (1R,5S)-2-(((7-chloro-1-(2,4-dimethylformamide) to a 250mL single-necked flask at room temperature Oxybenzyl)-2,4-dioxa-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8- Tert-butyl diazabicyclo[3.2.1]octane-8-carboxylate (850mg, 1.448mmol). Add 1-propylphosphoric anhydride (5.0g, 7.856mmol), react at room temperature for 5 minutes, add 1,8-diazabicyclo[5.4.0]undec-7-ene (1.14g, 7.488mmol) dropwise . React at room temperature for 1-2 hours. After the reaction was completed, the above solution was slowly added dropwise to 100 mL of ice water, a large amount of solid precipitated out, filtered, and spin-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-extension tert-butyl methylnaphtho[1,8-ab]heptene-14-carboxylate (620 mg, yield: 75.2%). ES-API: [M+H] +=570.3.

[0271] Step 8: Add (6R,9S)-2-chloro-13-(3,4-dimethoxybenzyl)-12-oxo-5a,6,7,8,9 to trifluoroacetic acid (5mL) ,10,12,13-Octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-mylnaphtho[1,8-ab]heptene- 14-Tert-butyl carboxylate (420mg, 0.7380mmol), stirred at 55°C for 1 hour. After the reaction was completed, the solvent was spin-dried 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]hepten-12(13H)-one (500 mg, crude). ES-API: [M+H] +=320.1.

[0272] Step 9: To (6R,9S)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza- Add sodium carbonate to a mixed solution of 6,9-methylnaphtho[1,8-ab]hepten-12(13H)-one (350mg, 1.094mmol) in tetrahydrofuran (5.0mL) and water (5.0mL) (350mg, 3.282mmol), cooled in an ice-water bath, added benzyloxycarbonyl succinimide (354mg, 1.422mmol), and reacted at room temperature for 3 hours. After the reaction was completed, dichloromethane (80mL) was added to the reaction liquid, washed with saturated aqueous sodium bicarbonate (100mL) and saturated brine (80mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was used on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) was purified to obtain (6R,9S)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxo Hetero-benzyl 3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (460 mg, yield 93%). ES-API: [M+H] +=454.1.

[0273] Step 10: Add (6R,9S)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxa- Toluene (3.0mL ) solution was sequentially added phosphorus oxychloride (465mg, 3.039mmol) and N,N-diisopropylethylamine (392.0mg, 3.039mmol), and reacted at 125°C for 12 hours. After completion of the reaction, cool to room temperature, spin dry the solvent under reduced pressure to obtain (6R,9S)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3, Benzyl 10a,11,13,14-pentaaza-6,9-ylennaphtho[1,8-ab]heptene-14-carboxylate (520 mg, crude). ES-API: [M+H] +=472.2.

[0274] Step eleven: To (6R,9S)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- N,N-Dimethylformamide (3.0 mL) of benzyl pentaaza-6,9-enylnaphtho[1,8-ab]heptene-14-carboxylate (200 mg, 0.4246 mmol) Potassium fluoride (500mg, 8.492mmol) was added to the solution, and reacted at 120°C for 4 hours under nitrogen protection. After the reaction was completed, cool to room temperature, extract with ethyl acetate (50mLX2), combine the ethyl acetate phases and wash with saturated brine (50mLX4), dry over anhydrous sodium sulfate, filter, and spin dry 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-methylenylnaphthalene Benzyl[1,8-ab]heptene-14-carboxylate (130mg, yield: 67.4%). ES-API: [M+H] +=456.1.

[0275] Step twelve: (6R,9S)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14 -Pentaaza-6,9-mylnaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (140mg, 0.3076mmol) was dissolved in tetrahydrofuran / water (2mL / 0.5mL), added 2-(8-Ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (250mg , 0.7309mmol), potassium phosphate (250mg, 1.179mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl) palladium methanesulfonate (II) (40.0mg, 0.05494mmol), replaced with nitrogen 4 times, microwaved at 80°C for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (80mL) and water (60mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was used on a flash silica gel column (ethyl acetate / petroleum ether: 0 -70%) was purified to give the product (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-fluoro-5a,6,7,8 , 9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14- Benzyl carboxylate (144 mg, yield: 73%). ES-API: [M / 2+1] +=636.3.

[0276] Step 13: Add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (43.0mg, 0.2714mmol) to a solution of tetrahydrofuran (5.0mL) under ice-water bath conditions Sodium hydride (22mg, 0.5428mmol) was added to it, and the reaction was carried out at room temperature for 0.5 hours. (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-methylen[1,8-ab]heptene-14-carboxylic acid benzyl ester (145mg, 0.1357 mmol) was added to the above reaction system, and reacted at room temperature for 1-2 hours. After the reaction was complete, ice water (50 mL) was added to the system, extracted with dichloromethane (50 mL×2), the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. Dichloromethane: 0-10%) was purified to obtain (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-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-Benzyl pentaaza-6,9-ylennaphtho[1,8-ab]heptene-14-carboxylate (170 mg, crude). ES-API: [M / 2+1] +=775.3.

[0277] Step 14: To (6R, 9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14 -Pentaaza-6,9-mylnaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (170 mg, crude product) in methanol (10.0 mL) was added with a mass fraction of 10% Palladium carbon (500mg), replaced by hydrogen 4 times, reacted at room temperature under hydrogen atmosphere for 2 hours to obtain (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-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-enylnaphtho[1,8-ab]heptene (162 mg, crude). ES-API: [M / 2+1] +=7641.3.

[0278] Step fifteen: (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14 -Pentaaza-6,9-methylnaphtho[1,8-ab]heptene (162mg, crude product) was dissolved in acetonitrile (6.0mL), and 4M hydrochloric acid / dioxane solution was added under ice-cooling ( 2.0mL, 8.0mmol), reacted in ice bath for 0.5 hours. After the reaction was complete, the reaction solution was concentrated to dryness, dichloromethane (20 mL) was added, and triethylamine (3.0 mL) was added in an ice-water bath. Stir for 10 minutes, extract with dichloromethane (100mLX1) and water (50mLX1). The organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was obtained by preparative HPLC (formic acid method) 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-methylnaphtho[1,8-ab]hepten-2-yl)naphthalene-2-ol (5-ethyl-4-((6R,9S) - 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)(Z1,4.69mg, 3-step total yield: 5%, formate). ES-API: [M+1] +=597.3. 1HNMR(500MHz,CD 3OD)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).

[0279] [Example] [2] [synthesis] [5-] [ethyl] [-4-((5aS,6S,9R)-12-(((2R,7aS)-2-] [Fluorotetrahydrogen] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [Oxa] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [-2-] [base] [)] [Naphthalene] [-2-] [alcohol] [(Z2)]

[0280] Step 1: add dry tetrahydrofuran (100mL) to a 250mL single-necked flask at room temperature, then add (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane -8-Tertiary butyl carboxylate (358.0mg, 1.480mmol), cooled in an ice-water bath to 0~5°C and added sodium hydride (1, 20mg, 2.960mmol). After reacting for 10-20 minutes under the protection of nitrogen, add 5,7-dichloro-1-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4(1H ,3H)-diketone (565.0mg, 1.480mmol), and then reacted at 0~5°C for 20~30 minutes. The completion of the reaction was monitored by LC-MS, and the reaction solution was poured into ice water (300mL), adjusted to pH 7~8 with 6M aqueous hydrochloric acid solution under ice water bath conditions, extracted with ethyl acetate (100mLX2), combined with ethyl acetate and saturated salt Wash with water (100mLX1). Dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 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.

[0281] Step 2: 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, 1-propylphosphoric anhydride (5.0g, 7.856mmol) was added, and after reacting at room temperature for 5 minutes, 1,8-diazobispiro[5.4.0]undec-7-ene (1.14g, 7.488 mmol). 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), a large amount of solid was precipitated, filtered, and the filter cake was spin-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-enylnaphtho[1,8-ab]heptene-14-carboxylate (620 mg, yield: 73%). ES-API: [M+H] +=570.3.

[0282] Step 3: Add tert-butyl (5aS, 6S, 9R)-2-chloro-13-(2,4-dimethoxybenzyl)-12-oxo-5a to trifluoroacetic acid (5.0mL), 6,7,8,9,10,12,13-Octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1, 8-ab]heptene-14-carboxylate (420mg, 0.7380mmol), stirred at 55°C for 1 hour. After the reaction was completed, the solvent was spin-dried 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-enylnaphtho[1,8-ab]hepten-12(13H)-one (500 mg, crude). ES-API: [M+H] +=320.1.

[0283] Step 4: To (5aS,6S,9R)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza To a mixed solution of hetero-6,9-methylnaphtho[1,8-ab]hepten-12(13H)-one (350mg, 1.094mmol) in tetrahydrofuran (5.0mL) and water (5.0mL) was added Sodium carbonate (350mg, 3.282mmol), the system was cooled with an ice-water bath, benzyloxycarbonyl succinimide (354mg, 1.422mmol) 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 liquid, washed with saturated aqueous sodium bicarbonate (100 mL), saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by flash silica gel column (acetic acid Ethyl ester / petroleum ether: 0-50%) to get (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-enylnaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (460mg, yield: 93% ). ES-API: [M+H] +=454.1.

[0284] Step five: at 0°C, to (5aS,6S,9R)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxo The toluene ( 3.0 mL) solution was added phosphorus oxychloride (465 mg, 3.039 mmol) and N,N-diisopropylethylamine (392.0 mg, 3.039 mmol) successively, and reacted at 125°C for 12 hours. After the reaction is complete, cool to room temperature, spin dry the solvent under reduced pressure to obtain (5aS,6S,9R)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa- Benzyl 3,10a,11,13,14-pentaaza-6,9-ylennaphtho[1,8-ab]heptene-14-carboxylate (520 mg, crude). ES-API: [M+H] +=472.2.

[0285] Step 6: To (5aS,6S,9R)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14 -N,N-Dimethylformamide (3.0mL ) solution was added potassium fluoride (500mg, 8.492mmol), and reacted at 120°C for 4 hours under the protection of nitrogen. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (50mLX2), and the ethyl acetate phase was combined and washed with saturated brine (50mLX4). The ethyl acetate phase was dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain (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-methylnaphtho[1,8-ab]heptene-14-carboxylic acid benzyl ester (130mg, yield: 62%). ES-API: [M+H] +=456.1.

[0286] Step 7: (5aS,6S,9R)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13, Benzyl 14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate (140mg, 0.3076mmol) was dissolved in tetrahydrofuran / water (2mL / 0.5mL), Add 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (250mg , 0.7309mmol), potassium phosphate (250mg, 1.179mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (II) (40.0mg, 0.05494mmol), replaced with nitrogen 4 times and reacted in microwave at 80°C for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (80mL) and water (60mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was used on a flash silica gel column (ethyl acetate / petroleum ether : 0-70%) to obtain (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-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-Benzyl carboxylate (144 mg, yield: 73%). ES-API: [M / 2+1] +=636.3.

[0287] Step 8: Add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (43.0mg, 0.2714mmol) to a solution of tetrahydrofuran (5.0mL) under ice-water bath conditions Add sodium hydride (22mg, 0.5428mmol) and react at room temperature for 0.5 hours. After 0.5 h, (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-enylnaphtho[1,8-ab]heptene-14-carboxy Acetate benzyl ester (145mg, 0.1357mmol) was added to the above reaction system, and reacted at room temperature for 1-2 hours. After the reaction was complete, ice water (50 mL) was added to the system, extracted with dichloromethane (50 mL×2), the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a flash silica gel column (methanol / dichloromethane :0 -10%) was purified to obtain (5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-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, Benzyl 11,13,14-pentaaza-6,9-ylennaphtho[1,8-ab]heptene-14-carboxylate (170 mg, crude). ES-API: [M / 2+1] +=775.3.

[0288] Step 9: To (5aS, 6S, 9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-(((2R,7aS)-2-fluoro Tetrahydro-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 benzyl ester (170mg, crude product) in methanol (10.0mL) was added with a mass fraction of 10% Palladium carbon (500mg), replaced hydrogen 4 times, and reacted at room temperature for 2 hours under hydrogen atmosphere to obtain (5aS, 6S, 9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1 -yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexa Hydrogen-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8-ab]heptene (162 mg, crude). ES-API: [M / 2+1] +=7641.3.

[0289] Step ten: (5aS, 6S, 9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13, 14-Pentaaza-6,9-enylnaphtho[1,8-ab]heptene (162 mg, crude product) was dissolved in acetonitrile (6.0 mL), and 4M hydrochloric acid / dioxane solution was added under ice-cooling (2.0mL, 8.0mmol), react in ice bath for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and dichloromethane (20 mL) was added, and triethylamine (3.0 mL) was added in an ice-water bath. After stirring for 10 minutes, dichloromethane (100mLX1) and water (50mLX1) were added for extraction. The dichloromethane phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The crude product was obtained by 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-oxo Hetero-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hepten-2-yl)naphthalene-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)(Z2,4.65mg, 3-step yield: 2.73%). ES-API: [M+1] +=597.3. 1HNMR(500MHz,CD 3OD)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 =10.4Hz,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).

[0290] [Example] [3] [synthesis] [4-((6R,9S)-12-((2,6-] [Diethylenetetrahydro] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [Oxa] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [-2-] [base] [)-5-] [Ethylnaphthalene] [-2-] [alcohol] [(Z175-1)]

[0291] Step 1: Add (6R,9S)-2-chloro-12-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- Benzyl pentaaza-6,9-methoxynaphtho[1,8-ab]heptene-14-carboxylate (380.0mg, 0.8351mmol) was dissolved in tetrahydrofuran / water (12.0mL / 2.0mL), added Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1 -yl)ethynyl)silane (825.0mg, 1.670mmol), potassium phosphate (800mg, 3.773mmol) and [n-butylbis(1-adamantyl)phosphine](2-amino-1,1 '-Biphenyl-2-yl) palladium (II) (80.0mg, 0.110mmol), after nitrogen replacement 4 times, microwave reaction at 80°C for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (150 mL) and water (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was used on a flash silica gel column (ethyl acetate / petroleum ether : 0-70%) to obtain (6R,9S)-12-fluoro-2-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[ 1 ,8-ab]benzyl heptene-14-carboxylate (500 mg, yield: 76%). ES-API: [M+1] +=788.3.

[0292] Step 2: To (6R,9S)-12-fluoro-2-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)- 5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8- ab] Add cesium fluoride (1.93g, 12.69mmol) to a solution of benzyl heptene-14-carboxylate (500mg, 0.6345mmol) in N,N-dimethylformamide (20.0mL), and stir at room temperature for 1 hour . After the reaction, the reaction solution was extracted with ethyl acetate (150mL) and water (100mL), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was decomposed on a flash silica gel column (ethyl acetate / petroleum Ether: 0-70%) was purified to give (6R,9S)-2-(8-ethynyl-3-(methoxymethoxy)naphthalene-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 - Benzyl carboxylate (370 mg, yield: 92%). ES-API: [M+1] +=631.3.

[0293] Step 3: To (6R,9S)-2-(8-ethynyl-3-(methoxymethoxy)naphthalene-1-yl)-12-fluoro-5a,6,7,8,9,10 -Benzyl hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (370mg, 0.5863mmol) in methanol (20.0mL) solution was added with mass fraction of 10% palladium carbon (500mg), replaced hydrogen 4 times and reacted at room temperature under 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-ylennaphtho[1,8-ab]heptene (200 mg, yield: 68%). ES-API: [M+1] +=502.3.

[0294] Step 4: To (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-fluoro-5a,6,7,8,9,10 -Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene (200mg, 0.3984mmol) Triethylamine (2.0 mL, 14.41 mmol) and di-tert-butyl dicarbonate (175 mg, 0.7968 mmol) were successively added to the dichloromethane (20.0 mL) solution, and stirred at room temperature for 2 hours. After the reaction, the reaction solution was extracted with ethyl acetate (150mL) and water (100mL), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was used on a flash silica gel column (ethyl acetate / petroleum ether :0 -70%) purified to give tert-butyl(6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-fluoro-5a,6 ,7 ,8,9,10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept Alkene-14-carboxylate (150 mg, yield: 62%). ES-API: [M+1] +=602.3.

[0295] Step 5: Under the condition of ice-water bath, add (2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (28.0mg, 0.1661mmol) in tetrahydrofuran (5.0mL) solution Sodium hydride (13.28mg, 0.3322mmol), react at room temperature for 0.5 hours. After 0.5 h, 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-methylnaphtho[1,8-ab]heptene-14 -Carboxylate (50mg, 0.0830mmol) was added to the above reaction system, and reacted at room temperature for 1-2 hours. After the reaction was complete, ice water (50 mL) was added to the system, extracted with dichloromethane (50 mL×2), the dichloromethane phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a flash silica gel column (methanol / dichloromethane :0 -10%) was purified to obtain tert-butyl(6R,9S)-12-((2,6-diethylenetetrahydro-1H-pyrrolizin-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-ylennaphtho[1,8-ab]heptene-14-carboxylate (110 mg, crude product). ES-API: [M+1] +=747.3.

[0296] Step 6: tertiary 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-methylnaphtho[1,8-ab]heptene-14-carboxylate (110mg, crude product) was dissolved in acetonitrile (6.0mL), and 4M Hydrochloric acid / dioxane solution (2.0 mL, 8.0 mmol) was reacted under ice bath for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and dichloromethane (20 mL) was added, and triethylamine (3.0 mL) was added in an ice-water bath. After stirring for 10 minutes, dichloromethane (100mLX1) and water (50mLX1) were added for extraction. The dichloromethane phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain a crude product, which was obtained by preparative HPLC (ammonium bicarbonate method 1) to obtain 4-((6R,9S)-12-((2,6-di Methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11 , 13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hepten-2-yl)-5-ethylnaphthalene-2-ol (4-((6R,9S ) -12-((2,6-dimethylenetetrahydro-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)-5-ethylnaphthalen-2-ol)(Z175-1,7.47mg, 2-step yield: 14.9% ). ES-API: [M+1] +=603.3.

[0297] [Example] [4] [:composite] [4-((6R] [,] [9S)-12-(3-(] [Dimethylamino] [)] [Azetidine] [-1-] [base] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [Oxa] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [-2-] [base] [)-5-] [Ethylnaphthalene] [-2-] [alcohol] [(Z308)]

[0298] Step 1: Under the condition of ice-water bath, add N,N -Diisopropylethylamine (430mg, 3.322mmol), finally added tert-butyl (6R,9S)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-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). React at 110 oC for 2 hours. After 2 hours, add ice water (50mL) to the system, extract with dichloromethane (50mLX2), combine the dichloromethane phases, dry over anhydrous sodium sulfate, filter, spin the filtrate under reduced pressure, and use a flash silica gel column (methanol / dichloromethane: 0-10%) was purified to obtain tert-butyl (6R,9S)-12-(3-(dimethylamino)azetidin-1-yl)-2-(8-ethane yl-3-(methoxymethoxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14 - Pentaaza-6,9-ylennaphtho[1,8-ab]heptene-14-carboxylate (110 mg, yield: 97%). ES-API: [M+1] +=682.3.

[0299] Step 2: the tert-butyl (6R, 9S)-12-(3-(dimethylamino)azetidin-1-yl)-2-(8-ethyl-3-(methoxy Methoxy)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9 -Naphtho[1,8-ab]heptene-14-carboxylate (110mg, 0.1612mmol) was dissolved in acetonitrile (6.0mL), and 4M hydrochloric acid / dioxane solution (2.0 mL, 8.0mmol), reacted in ice bath for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and dichloromethane (20 mL) was added, and triethylamine (3.0 mL) was added in an ice-water bath. After stirring for 10 minutes, dichloromethane (100 mL) and water (50 mL) were added to extract once. The dichloromethane phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain the crude product. 4-((6R,9S)-12-(3-(dimethylamine) was obtained by preparative HPLC (ammonium bicarbonate method 1). Base) azetidin-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6 , 9-methylnaphtho[1,8-ab]hepten-2-yl)-5-ethylnaphthalene-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.

[0300] [Example] [5] [Synthetic trans] [-2-(((5S,5aS,6S,9R)-2-(3-] [amino group] [-8-] [Ethynylnaphthalene] [-1-] [base] [)-1-] [fluorine] [-5-] [methyl] [-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [oxo] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylene Naphthalene] [[1,8-ab]] [G] [-12-] [base] [)] [Oxygen] [)] [Cyclopentane] [-1-] [alcohol] [(Z718)]

[0301] Step 1: Trans-cyclopentane-1,2-diol (46mg, 0.45mmol) was dissolved in tetrahydrofuran (5mL), and 60% sodium hydride (11mg, 0.27mmol) was added at 0°C, and the reaction was carried out at this temperature After stirring for 30 minutes, (5S, 5aS, 6S, 9R)-2-(3-((3-butoxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalene-1 was added dropwise -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-methylnaphthalene[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (80mg, 0.092mmol) in tetrahydrofuran (2mL), the temperature The reaction was stirred for 30 minutes. Ethyl acetate (40 mL) was added to the reaction solution, washed with water (10 mL) and saturated brine (15 mL) successively. 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 (tetrahydrofuran / petroleum ether: 0-30%) to obtain 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-methylnaphthalene[1,8-ab] Heptene-14-carboxylic acid tert-butyl ester (50mg, yield 59.9%), pale yellow solid. ES-API: [M+H] +=923.3.

[0302] Step 2: (5S, 5aS, 6S, 9R)-2-(3-((tertiary butoxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalene-1- Base)-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-methylenenaphthalene[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (20mg, 0.054mmol) Add cesium fluoride (82mg, 0.54mmol) to N,N-dimethylformamide (3mL) at room temperature, and the reaction is stirred at room temperature for 30 minutes. Ethyl acetate (30mL) is added to the reaction solution, followed by water (5mL) , diluted brine (10mL×3), washed with saturated brine (10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target product (5S, 5aS, 6S, 9R)-2-(3-( (Tertiary 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-ylidene[1,8-ab ] tert-butyl heptene-14-carboxylate (40 mg, yield 96.3%), light brown solid. ES-API: [M+H] +=767.2.

[0303] Step 3: (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 -tert-butyl pentaaza-6,9-methylnaphthalene[1,8-ab]heptene-14-carboxylate (40mg, 0.018mmol) was dissolved in ethyl acetate (1mL), added at 0°C 4M 1,4-dioxane hydrogen chloride (1.5 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was obtained by preparative HPLC (ammonia method) to obtain the target product trans-2-(((5S, 5aS, 6S, 9R)-2-(3-amino-8-ethynylnaphthalene-1-yl)-1-fluoro -5-Methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylenylnaphthalene [1,8-ab]hept-12-yl)oxy)cyclopentan-1-ol ((1R,2R)-2-(((5S,5aS,6S,9R)-2-(3-amino -8-ethylnaphthalen-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.

[0304] [Example] [6] [:composite] [5-] [ethyl] [-4-((5aS,6S,9R)-1-] [fluorine] [-12-(((2R,7aS)-2-] [Fluorotetrahydrogen] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [Oxa] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [-2-] [base] [)] [Naphthalene] [-2-] [alcohol] [(Z140-1)]

[0305] Step 1: Add methyllithium (47.6mL, 76.19mmol, 1.6M), and stirred at -20°C for 2 hours after the dropwise addition. The system was lowered to -78°C again, and a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (12.405g, 38.095mmol) in tetrahydrofuran (30mL) was added dropwise within 30 minutes. After completion, react at 0°C for 1.5 hours. After the reaction was completed, the reaction solution was poured into ice water (500mL), washed with chloroform (100mLX1), the water phase was adjusted to pH=3 with hydrochloric acid (3M), the water phase was spin-dried under reduced pressure, and the crude product was purified by column chromatography[ Dichloromethane:methanol=100:0~90:10, (v / v)] to obtain 4-bromo-2,6-dichloro-5-fluoronicotinic acid (7.6g, yield: 88%). ES-API: [M+H] +=287.9.

[0306] Step 2: Dissolve 4-bromo-2,6-dichloro-5-fluoronicotinic acid (6.0g, 20.90mmol) in phosphine chloride (40.0mL) at room temperature, and then add 16 drops of N, N - Dimethylformamide was added to the above system, and the reaction system was stirred and reacted at 100° C. for 1 hour. The solvent was spin-dried under reduced pressure. The crude product was added into a mixed solvent of tetrahydrofuran (100mL) and saturated sodium bicarbonate (100mL) at 0°C, and finally aminomethyliminothiomethyl (12.91g, 68.607mmol) was added, and the reaction was stirred at this temperature 30 minutes. The reaction was then extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl(4-bromo-2,6-dichloro-5-fluoronicotinoyl)aminomethimino as a yellow solid Thioester (2.23g, yield: 29.8%). ES-API: [M+1] +=359.5.

[0307] Step 3: Under nitrogen protection, methyl (4-bromo-2,6-dichloro-5-fluoronicotinyl)aminomethylimidothioate (880mg, 2.45mmol) and N,N- Diisopropylethylamine (1.4mL, 8.37mmol) was sealed in dioxane (12mL) and heated at 100 oC for 16 hours. The reaction was concentrated until the volume was ~5 mL. Water (15 mL) and 2M aqueous hydrochloric acid (3 mL) were added to the residue. After a precipitate formed, it was filtered and the filter cake was washed with water (10 mL). The filter cake was dried under reduced pressure to obtain 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (350 mg, yield: 51%). ES-API: [M+H] +=280.0.

[0308] Step 4: Add tert-butyl (1S, 2S, 5R)-2-(hydroxymethyl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate (813.53 mg, 3.357 mmol) and stirred at this temperature for 10 minutes. Add 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (854mg, 3.052mmol) and heat and stir at 60 oC for 1h . After complete reaction, it was quenched with water and extracted with dichloromethane / methanol (10:1, 25mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl(1S,2S,5R)-2-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyridine And[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1451mg, 2.992mmol, yield : 98.02%), a yellow solid. ES-API: [M+H] +=486.1.

[0309] Step five: to tertiary butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-4-hydroxyl-2-(methylthio)pyrido[4,3-d]pyrimidine -5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1451 mg, 2.992 mmol) and N,N-diisopropylethylamine (4.957mL, 29.916mmol) in dichloromethane (20mL) was added propylphosphoric anhydride (50% in ethyl acetate) (11422.33mg, 17.949mmol) 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-methylnaphtho[1,8-ab]heptene-14-carboxylate (623mg, yield :45.0%), as a white solid. ES-API: [M+H] +=468.1.

[0310] Step six: at 0 oC, to tert-butyl (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexa Hydrogen-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8-ab]heptene-14-carboxylate (540mg, 1.153mmol) in dichloromethane (15mL) was added m-chloroperoxybenzoic acid (322.61mg, 1.589mmol). Stir at room temperature for 1 hour. Quenched with saturated sodium sulfite and extracted with dichloromethane (100 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give crude product, which was purified by flash silica gel column (0-10% methanol / dichloromethane) to give (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-methine Tert-butyl naphtho[1,8-ab]heptene-14-carboxylate (452 ​​mg, yield: 81.0%), white solid. ES-API: [M+H] +=484.1.

[0311] Step 7: Add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (239.16 mg, 1.502mmol). The reaction was stirred at room temperature for 10 minutes. Cool to 0°C, add (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H- tertiary butyl 4-oxa-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8-ab]heptene-14-carboxylate (363.5mg, 0.751mmol) tetrahydrofuran solution (5mL). 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 give tert-butyl(5aR,6S,9R)-2-chloro-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-enylnaphtho[1,8-ab]heptene-14-carboxylate (134 mg, yield 30.85%), yellow solid. ES-API: [M+H] +=579.2.

[0312] Step 8: To tertiary butyl (5aR, 6S, 9R)-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)- base)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-ylidene Naphtho[1,8-ab]heptene-14-carboxylate (134.0mg, 0.233mmol) and triisopropyl ((6-(methoxymethoxy)-8-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)silane (230.0mg, 0.466mmol) in dioxane (6mL) and water ( 1.5mL) was added potassium phosphate (147.55mg, 0.695mmol), methanesulfonic acid [n-butylbis(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) Palladium(II) (1.95 mg, 0.003 mmol), N 2 bubbled and microwaved at 80 °C for 40 min. After the reaction was completed, ethyl acetate (30mLX2) and saturated brine (30mL) were extracted. 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 flash silica gel column (0-4% methanol / dichloromethane) to obtain tert-butyl(5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro - 1H-pyrrolazin-7a(5H)-yl)methoxy)-2-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[ 1 ,8-ab]heptene-14-carboxylate (164 mg, yield: 77.33%), yellow solid. ES-API: [M+H] +=911.5.

[0313] Step 9: To tertiary butyl (5aS, 6S, 9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy Base)-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-enylnaphtho[1,8-ab]heptene-14-carboxylate ( 165mg, 0.181mmol) of N,N-dimethylformamide (3.0mL) was added cesium fluoride (127.55mg, 0.840mmol). The reaction was stirred at room temperature for 0.5 hours. The reaction is complete. 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 obtain tert-butyl(5aS,6S,9R)-2-(8-ethynyl-3-(methoxymethoxy)naphthalene-1- Base)-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-mylnaphtho[1,8-ab]heptene-14-carboxylate (150mg, crude product), yellow oil. ES-API: [M+H] +=755.3.

[0314] Step ten: to tertiary butyl (5aS, 6S, 9R)-2-(8-ethynyl-3-(methoxymethoxy) naphthalene-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-enylnaphtho[1,8-ab]heptene-14-carboxylate (100 mg, 0.1324 mmol) in methanol (5.0 mL) Palladium carbon (75.0mg, 0.061mmol) was added to the solution to replace the hydrogen and react at room temperature under a hydrogen atmosphere for 1 hour. Filter and concentrate. The crude product was purified by flash silica gel column (0-3% methanol / dichloromethane) to obtain tert-butyl(5aS,6S,9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene - 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-enylnaphtho[1,8-ab]heptene-14- Carboxylate (70 mg, yield: 70%), yellow solid. ES-API: [M+H] +=759.4.

[0315] Step eleven: tertiary butyl (5aS, 6S, 9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-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) and acetonitrile (2.0 mL) React with 4M hydrochloric acid / dioxane solution (0.500 mL, 2.000 mmol) at 0 oC for 1 hour. Concentration, the crude product was obtained by preparative HPLC (ammonium bicarbonate method 1) to obtain 5-ethyl-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-oxa-3,10a,11,13,14-penta Aza-6,9-enylnaphtho[1,8-ab]hepten-2-yl)naphthalene-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-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z140-1,9.65mg, yield: 14.9%), yellow solid. ES-API: [M+1] +=615.3.

[0316] [Example] [7] [:composite] [(5aS,6S,9R)-2-(8-] [acetylene naphthalene] [-1-] [base] [)-1-] [fluorine] [-12-(((2R,7aS)-2-] [Fluorotetrahydrogen] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [oxo] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [(Z350)]

[0317] Step 1: To tertiary butyl (1S, 2S, 5R)-2-(((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridine[ 4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150.0mg, 0.321mmol) and triiso Propyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)silane (220.0mg, 0.506mmol ) in dioxane (6mL) and water (1.5mL) were added potassium phosphate (300mg, 1.415mmol), methanesulfonic acid [n-butylbis(1-adamantyl)phosphine] (2-amino-1 , 1'-biphenyl-2-yl)palladium (II) (100mg, 0.137mmol), nitrogen bubble and microwave reaction at 80°C for 40 minutes. After the reaction was completed, ethyl acetate (30mLX2) and saturated brine (30mL) were extracted. 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 column chromatography (methanol / dichloromethane=0-4%) to obtain 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-enylnaphtho[1,8-ab]heptene-14-carboxylate (272 mg, crude product), yellow solid. ES-API: [M+H] +=800.4.

[0318] Step 2: At 0 oC, to tert-butyl (5aS, 6S, 9R)-1-fluoro-12-(methylthio)-2-(8-((triisopropylsilyl)ethynyl )naphthalene-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylene To a solution of 1-naphtho[1,8-ab]heptene-14-carboxylate (272 mg, crude) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (67.12 mg, 0.389 mmol). Stir at room temperature for 1 hour. Quenched with saturated sodium sulfite and extracted with dichloromethane (100 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane=0-10%) to obtain 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-methylnaphtho[1,8-ab]heptene-14-carboxylate (230mg, 2 steps Total yield: 93.8%), white solid. ES-API: [M+H] +=756.3.

[0319] Step 3: Add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (100.0mg, 0.628mmol) in tetrahydrofuran (10.0mL) at 0°C Add sodium hydride (50.0mg, 1.25mmol), stir at this temperature for 10 minutes, then add 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-ylennaphtho[1,8-ab]heptene-14-carboxylate (230.0 mg, 0.304 mmol) in tetrahydrofuran (5 mL). 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 (methanol / dichloromethane=0-5%) to obtain (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrolazin-7a(5H)-yl)methoxy)-2-(8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5a,6,7,8,9 , 10-Hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-mylnaphtho[1,8-ab]heptene-14-carboxylic acid Tertiary butyl ester (260mg, crude product), yellow solid. ES-API: [M+H] +=851.5.

[0320] Step 4: To (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, N,N-dimethyl To the solution of formamide (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 is 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 obtain (5aS,6S,9R)-2-(8-ethynenaphthalene-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-methylnaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (120mg, 2-step total yield: 57%), yellow oil. ES-API: [M+H] +=695.3.

[0321] Step 5: (5aS, 6S, 9R)-2-(8-ethynenaphthalene-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9 -Methylnaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (120mg, 0.173mmol) and acetonitrile (5.0mL) and 4M hydrochloric acid / dioxane solution (2.0mL, 8.000 mmol) reaction solution was reacted at 0 oC for 1 hour. Concentration, the crude product was obtained by preparative HPLC (ammonium bicarbonate method 1) (5aS, 6S, 9R)-2-(8-ethyne naphthalene-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-methylnaphtho[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-oxa-3 , 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho[1,8-ab]heptalene) (Z350, 34mg, yield: 33%), yellow solid. ES-API: [M+1] +=595.3. 1HNMR(500MHz,CD 3OD)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=13.5,6.6,2.2Hz,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).

[0322] [Example] [8] [:composite] [4-((5aS,6S,9R)-12-((2,6-] [Diethylenetetrahydro] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-1-] [fluorine] [-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [oxo] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptane] [-2-] [base] [)-5-] [ethynyl] [-6-] [fluoronaphthalene] [-2-] [alcohol] [(Z380)]

[0323] Step 1: To tertiary butyl (1S, 2S, 5R)-2-(((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridine[ 4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 0.214mmol) and ((2 -Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl) Ethynyl)triisopropylsilane (200.0mg, 0.390mmol) in tetrahydrofuran (6mL) and water (1.5mL) was added potassium phosphate (200mg, 0.943mmol), methanesulfonic acid [n-butylbis(1-adamantane yl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (II) (50mg, 0.069mmol), nitrogen bubble and microwave reaction at 80°C for 40 minutes. After the reaction was completed, ethyl acetate (30mLX2) and saturated brine (30mL) were extracted. 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 silica gel column chromatography (methanol / dichloromethane=0-4%) to obtain tert-butyl(5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxy Methoxy)-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-enylnaphtho[1,8-ab]heptene-14-carboxylate (210mg, crude product) , yellow solid. ES-API: [M+H] +=818.3.

[0324] Step 2: At 0 oC, to tert-butyl (5aS, 6S, 9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl Sylsilyl)ethynyl)naphthalen-1-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11 , 13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate (210 mg, crude product) in dichloromethane (15 mL) was added m-chloro Peroxybenzoic acid (55mg, 0.320mmol). Stir at room temperature for 1 hour. Quenched with saturated sodium sulfite and extracted with dichloromethane (100 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane=0-10%) to obtain tert-butyl(5aS,6S,9R)-1-fluoro-2 -(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-12-(methylsulfinyl)- 5a, 6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8- ab] Heptene-14-carboxylate (210 mg, crude product), white solid. ES-API: [M+H] +=834.4.

[0325] Step 3: At 0°C, to a solution of (2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (65.0mg, 0.393mmol) in tetrahydrofuran (10.0mL) was added Sodium hydride (50.0mg, 1.25mmol), stirred at this temperature for 10 minutes, then added tert-butyl (5aS, 6S, 9R)-1-fluoro-2-(7-fluoro-3-(methoxymethyl Oxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexa Hydrogen-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8-ab]heptene-14-carboxylate (160.0mg , 0.192mmol) tetrahydrofuran solution (5mL). 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 obtain (5aS, 6S, 9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazine-7a( 5H )-yl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[ 1,8-ab]tert-butyl heptene-14-carboxylate (211 mg, crude product), yellow solid. ES-API: [M+H] +=935.5.

[0326] Step 4: To (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-enylnaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl To a solution of the 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 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 obtain (5aS,6S,9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-1-fluoro-5a,6,7,8,9,10 -Hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8-ab]heptene-14-carboxylic acid third Butyl ester (200mg, crude product), yellow oil. ES-API: [M+H] +=773.3.

[0327] Step 5: (5aS,6S,9R)-12-((2,6-Diethylenetetrahydro-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-enylnaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (200mg, crude product) and acetonitrile (5.0mL) React with 4M hydrochloric acid / dioxane solution (2.0 mL, 8.000 mmol) at 0 oC for 1 hour. Concentration, the crude product was obtained by preparative HPLC (ammonium bicarbonate method 1) to obtain 4-((5aS,6S,9R)-12-((2,6-dimethylenetetrahydro-1H-pyrrolazine-7a(5H)- base)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9 -Methylnaphtho[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-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol) (Z380, 8.95mg, 5 steps total yield: 5.23 %), yellow solid. ES-API: [M+1] +=635.3. 1HNMR(500MHz, CD 3OD)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).

[0328] [Example] [9] [:composite] [4-((5aS,6S,9R)-3-] [chlorine] [-13-((2R,7aS)-2-] [Fluorotetrahydrogen] [-1H-] [Pyrrolizine] [-7a(5H)-] [Methylmethoxy] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-6,9-] [Epiaminoazepine] [[2',1':3,4][1,4]] [Oxazepine] [[5,6,7-] [off] []] [Quinazoline] [-2-] [base] [)-5-] [Ethylnaphthalene] [-2-] [alcohol] [(Z381)]

[0329] Step 1: To a suspension of sodium hydrogen (60% in oil) (32 mg, 0.81 mmol) in THF (10 mL) at 0 °C was added (1S,2S,5R)-2-(hydroxymethyl)-3 , tert-butyl 8-diazacyclo[3.2.1]octane-8-carboxylate (131 mg, 0.54 mmol) and stirred at this temperature for 10 minutes. Add 7-bromo-2,6-dichloro-5-fluoroquinazolin-4(3H)-one (170 mg, 0.54 mmol) and heat and stir at 60 oC for 1 hour. After complete reaction, the reaction was quenched with water and extracted with dichloromethane / methanol (10:1, 25mL×3). The organic layer was dried with anhydrous sodium sulfate and spin-dried to obtain tert-butyl (1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-oxo-3,4-di Hydroquinazolin-5-yl)oxy)methyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (150 mg, yield: 51.0%). ES-API: [M+H] +=533.2.

[0330] Step 2: To tertiary butyl (1S,2S,5R)-2-(((7-bromo-2,6-dichloro-4-oxygen-3,4-dihydroquinazolin-5-yl) Oxy)methyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (110mg, 0.21mmol) and N,N-diisopropylethylamine (80mg, 0.62mmol ) in ultra-dry dichloromethane (10 mL) was added 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (86 mg, 0.42 mmol) and stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with dichloromethane (25mL×3), washed with saturated brine (10mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was prepared by reverse-phase preparative HPLC (trifluoroacetic acid method) to obtain 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-carboxy salt (64mg, yield: 60.3%). ES-API: [M+H] +=515.1.

[0331] Step 3: To tertiary butyl (5aS, 6S, 9R)-2-bromo-3,13-dichloro-5a,6,7,8,9,10-hexahydro-5H-6,9-epiamine Ultra-dry N , ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (29mg, 0.18mmol) was added to N-dimethylformamide (10mL) solution, fluorinated Potassium (51 mg, 0.9 mmol) and 4A molecular sieves. Stirring at 120 oC for 16 hours under nitrogen protection. After the reaction was completed, it was quenched with water and extracted with dichloromethane (25mL×3), washed with saturated brine (10mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was obtained by preparative HPLC (trifluoroacetic acid method) to obtain tert-butyl (5aS, 6S, 9R)-2-bromo-3-chloro-13-(((2R, 7aS)-2-fluorotetrahydro-1H- Pyrrolazin-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 (22mg, yield: 38.4%). ES-API: [M+H] +=638.2.

[0332] Step 4: tertiary butyl (5aS, 6S, 9R)-2-bromo-3-chloro-13-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl )methoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiaminoazepine[2',1':3,4][1,4]oxazone Hetero[5,6,7-de]quinazoline-15-carboxylate (22mg, 0.03mmol) and 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl) -4,4,5,5-Tetramethyl-1,3,2-dioxaborane (17mg, 0.05mmol) in tetrahydrofuran (6mL) and water (1.0mL) was added potassium phosphate (21mg, 0.1mmol) , methanesulfonic acid [n-butylbis (1-adamantyl) phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (15mg), under nitrogen protection, at 60 °C for 2 hours. After the reaction was completed, ethyl acetate (30mLX2) and saturated brine (10mL) were extracted. The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by thin layer chromatography (methanol / dichloromethane=1:15) to obtain tert-butyl (5aS, 6S, 9R)-3-chloro-2-(8-ethyl-3-(methoxy Methoxy)naphthalen-1-yl)-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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 mg, yield: 43%). ES-API: [M+H] +=774.1.

[0333] Step five: tertiary butyl (5aS, 6S, 9R)-3-chloro-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-13-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-ylmethoxy)-5a,6,7,8,9,10-hexahydro-5H-6,9-epiamino Aza[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-15-carboxylate (10mg, 0.013mmol) and acetonitrile (2.0mL ) and 4M hydrochloric acid / dioxane solution (0.5mL, 2.000mmol) were reacted at 0 oC for 1 hour. The reaction solution was concentrated, and the obtained crude product was obtained by preparative HPLC (formic acid method 1) to obtain 4-((5aS,6S ,9R)-3-chloro-13-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-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]quinazolin-2-yl )-5-Ethylnaphthalene-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-epiminoazepino[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. 1HNMR (400MHz, CD 3OD) 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),5.44(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),2.27-2.13(m,2H ), 1.99 (dd, J=30.6, 18.8Hz, 5H), 0.91 (dt, J=14.5, 7.4Hz, 3H).

[0334] [Example]

[10] [:composite] [5-] [ethynyl] [-6-] [fluorine] [-4-((5aS,6S,9R)-1-] [fluorine] [-12-(((2R,7aS)-2-] [Fluorotetrahydrogen] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [oxo] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [-2-] [base] [)] [Naphthalene] [-2-] [alcohol] [(Z131-1)]

[0335] Step 1: Add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (100.0mg, 0.628mmol) in tetrahydrofuran (10.0mL) at 0°C Add sodium hydride (50.0mg, 1.25mmol), stir at this temperature for 10 minutes, then add tert-butyl (5aS, 6S, 9R)-1-fluoro-2-(7-fluoro-3-(methoxy Methoxy)-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-enylnaphtho[1,8-ab]heptene-14-carboxylate (210.0 mg, 0.252mmol) tetrahydrofuran solution (5mL). 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 obtain tert-butyl(5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxymethyl Oxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H ) -yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9- Methylnaphtho[1,8-ab]heptene-14-carboxylate (170.0 mg, yield: 72.6%), yellow solid. ES-API: [M+H] +=929.3.

[0336] Step 2: To tertiary 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,11,13,14-pentaaza-6,9-enylnaphtho[1,8-ab]heptene-14- To a solution of carboxylate (170 mg, 0.183 mmol) 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 is 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 obtain (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1- Base)-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-methylnaphtho[1,8-ab]heptene-14-carboxylic acid Tributyl ester (200mg, crude product), yellow oil. ES-API: [M+H] +=773.3.

[0337] Step 3: (5aS, 6S, 9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-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-methylnaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (200mg, crude product) and acetonitrile (10.0mL ) and 4M hydrochloric acid / dioxane solution (2.0mL, 8.000mmol) were reacted at 0 oC for 1 hour. Concentration, the crude product was obtained by preparative HPLC (ammonium bicarbonate method 1) to obtain 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-enylnaphtho[1,8-ab]hepten-2-yl)naphthalene-2-alcohol (5-ethynyl-6-fluoro-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-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol)(Z131-1,8.95mg , 2-step total yield: 7.8%), yellow solid. ES-API: [M+1] +=629.3.

[0338] [Example]

[11] [:composite] [5-] [ethyl] [-4-((5aS,6S,9R)-12-((1-] [methyl] [-1-] [Azaspirocycle] [[4.4]] [nonane] [-6-] [base] [)] [Oxygen] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [Oxa] [-3,10a,11,13,14-] [pentazapine] [[6,9]] [Methylene Naphthalene] [[1,8-ab]] [heptene] [-2-] [base] [)] [Naphthalene] [-2-] [alcohol] [(Z260-1)]

[0339] Step 1: To triisopropyl ((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )Naphthalene-1-yl)ethynyl)silane (500mg, 1.012mmol) in N,N-dimethylformamide (5.0mL) was added cesium fluoride (3.0g, 20.24mmol), and reacted at room temperature for 2 hours . After the reaction was completed, it was extracted with ethyl acetate (100mLX2), and the ethyl acetate phases were combined and washed with saturated brine (100mLX3). The ethyl acetate phase was dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain 2-(8-ethynyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5- Tetramethyl-1,3,2-dioxaborane (558 mg, crude). ES-API: [M+H] +=339.3.

[0340] Step 2: To 2-(8-ethynyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron Add 10% palladium carbon to a solution of alkane (558 mg, crude product) in methanol (10.0 mL), replace with hydrogen four times and react at room temperature for 2 hours under the protection of hydrogen. After the reaction is complete, filter and spin dry the solvent under reduced pressure to obtain 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1 , 3,2-dioxaborane (284 mg, 2 steps total yield: 82%). ES-API: [M+1] +=343.3.

[0341] Step 3: Dissolve 1-benzyl-1-azaspiro[4.4]nonan-6-one (1.5g, 6.5mmol) in methanol (10ml), add palladium carbon catalyst (150mg), and replace hydrogen 3 times at room temperature React for 4 hours, filter, wash with methanol, and concentrate to give 1-azaspiro[4.4]nonan-6-one (800mg, yield: 88.5%). ES-API: [M+H] +=140.1.

[0342] Step 4: Dissolve 1-azaspiro[4.4]nonan-6-one (800mg, 5.7mmol) in tetrahydrofuran (10mL), add triethylamine (0.86mg, 8.5mmol) and dicarbonate dicarbonate at room temperature Butyl fat (1.8g, 8.5mmol), stirred at room temperature for 8 hours. LCMS monitored that the reaction was complete, added water (10ml), extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product that was purified by silica gel column chromatography (ethyl acetate / petroleum ether=0~80%) to obtain 6-oxo Dai-1-azaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (900mg, yield: 66%). ES-API: [M+H] +=240.1.

[0343] Step 5: Dissolve tert-butyl 6-oxo-1-azaspiro[4.4]nonane-1-carboxylate (900 mg, 3.7 mmol) in dry tetrahydrofuran (10 mL), and add lithium aluminum hydride ( 11ml, 11mmol, 1M tetrahydrofuran), stirred at 60 oC for 2 hours. Add water (10 mL), extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to give 1-methyl-1-azaspiro[4.4]nonan-6-ol (450 mg), which is directly used in the next step. ES-API: [M+Na] +=156.1.

[0344] Step six: (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (242mg , 1.0mmol) in tetrahydrofuran (10mL) was added sodium hydride (80mg, 2.0mmol). After reacting for 10-20 minutes under nitrogen protection, 5,7-dichloro-1-(2,4-dimethoxybenzyl)pyrido[4,3-d]pyrimidine-2,4( 1H,3H)-diketone (381mg, 1.0mmol), and then reacted at 0~5°C for 20~30 minutes. The completion of the reaction was monitored by LCMS, and the reaction liquid was poured into about ice water (300mL). Under the condition of ice water bath, the pH was adjusted to 7~8 with 6M aqueous hydrochloric acid solution, extracted with ethyl acetate (100mLX2), and the organic phases were combined and washed with saturated salt. Wash with water (100mLX1). The organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried to obtain the target compound (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 ] tert-butyl octane-8-carboxylate (560 mg, yield: 87%). ES-API: [M+H] +=588.2.

[0345] Step 7: Add dry N,N-dimethylformamide (15 mL) and (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, tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate (510mg, 0.87mmol). Finally, Carter condensing agent (1.9g, 4.35mmol) was added, and after 5 minutes of reaction at room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (661mg, 4.35mmol) was added 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), a large amount of solid was precipitated, filtered, the filter cake was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain (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-methylnaphthyl[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (300mg, yield :61%). ES-API: [M+H] +=568.2.

[0346] Step 8: Add (5aS,6S,9R)-2-chloro-13-(2,4-dimethoxybenzyl)-12-oxo-5a,6,7,8 to trifluoroacetic acid (5mL) ,9,10,12,13-Octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphthalene[1,8-ab]heptene - tert-butyl 14-carboxylate (300mg, 0.53mmol), stirred at 55°C for 1 hour. After the reaction was completed, the solvent was spin-dried under reduced pressure to obtain the compound (5aS,6S,9R)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11 , 13,14-pentaaza-6,9-enylnaphtho[1,8-ab]hepten-12(13H)-one (500 mg, crude). ES-API: [M+H] +=320.1.

[0347] Step 9: To (5aS,6S,9R)-2-chloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza Hetero-6,9-enylnaphtho[1,8-ab]hepten-12(13H)-one (500mg, crude product) in tetrahydrofuran (5.0mL) and water (5.0mL) mixed solution was added carbonic acid Sodium (168mg, 1.59mmol), the system was cooled with an ice-water bath, added benzyloxycarbonyl succinimide (171mg, 0.68mmol), and reacted at room temperature for 3 hours. After the reaction was completed, dichloromethane (80 mL) was added to the reaction solution, washed with saturated aqueous sodium bicarbonate (100 mL), washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product by silica gel column chromatography. Purification (ethyl acetate / petroleum ether: 0-50%) yielded the target product (5aS,6S,9R)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13- Benzyl octahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphthalene[1,8-ab]heptene-14-carboxylate (396mg , yield: 93%). ES-API: [M+H] +=454.1.

[0348] Step 10: At 0°C, to (5aS,6S,9R)-2-chloro-12-oxa-5a,6,7,8,9,10,12,13-octahydro-5H-4-oxo Hetero-3,10a,11,13,14-pentaaza-6,9-methylnaphthalene[1,8-ab]heptene-14-carboxylic acid benzyl ester (390mg, 0.8mmol) in toluene (5.0 mL) solution was sequentially added phosphorus oxychloride (365mg, 2.4mmol) and N,N-diisopropylethylamine (310mg, 2.4mmol), and reacted at 105°C for 12 hours. The reaction was completed, cooled to room temperature, and the solvent was spin-dried under reduced pressure. The crude product was subjected to preparative HPLC (ammonium bicarbonate method 1) to obtain (5aS,6S,9R)-2,12-dichloro-5a,6,7,8,9, Benzyl 10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylenenaphthalene[1,8-ab]heptene-14-carboxylate (70mg, yield: 17%). ES-API: [M+H] +=472.1.

[0349] Step 11: To (5aS,6S,9R)-2,12-dichloro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13, Add fluorinated Potassium (29mg, 0.5mmol), N,N-diisopropylethylenediamine (39mg, 0.3mmol), 1-methyl-1-azaspiro[4.4]nonan-6-ol (31mg, 0.2mmol ) and 4A molecular sieves were reacted at 110°C for 4 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (50mLX2), and the ethyl acetate phase was combined and washed with saturated brine (50mLX4). The ethyl acetate phase was dried with anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2:1) ​​to obtain (5aS,6S,9R)-2-chloro-12 -((1-Methyl-1-azaspiro[4.4]nonan-6-yl)oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa- 3, 10a, 11, 13, 14-pentaaza-6,9-methylenenaphthalen[1,8-ab]heptene-14-carboxylic acid benzyl ester (28 mg, yield: 44%). ES-API: [M+H] +=591.2.

[0350] Step 12: (5aS, 6S, 9R)-2-chloro-12-((1-methyl-1-azaspiro[4.4]nonan-6-yl)oxy)-5a,6, 7,8,9,10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-mylnaphthalene[1,8-ab]heptene- Benzyl 14-carboxylate (28mg, 0.047mmol) was dissolved in tetrahydrofuran / water (2mL / 0.5mL), and 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl) -4,4,5,5-Tetramethyl-1,3,2-dioxaborane (24mg, 0.07mmol), potassium phosphate (30mg, 0.14mmol) and methanesulfonic acid [n-butylbis(1- Adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (II) (10mg, 0.014mmol), nitrogen replacement 4 times, 60°C for 1 hour. The reaction solution was cooled to room temperature, extracted with ethyl acetate (80 mL) and water (60 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-70%) to obtain (5aS, 6S, 9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-((1-methyl Base-1-azaspiro[4.4]non-6-yl)oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxyl-3,10a,11,13, Benzyl 14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (26 mg, yield: 73%). ES-API: [M+H] +=771.4.

[0351] Step 13: To (5aS, 6S, 9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-((1-methyl-1-nitrogen Heterospiro[4.4]non-6-yl)oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxyl-3,10a,11,13,14-pentaaza 10% palladium carbon (50mg ), replaced by hydrogen 4 times and reacted at room temperature for 2 hours under a hydrogen atmosphere. Filtration to obtain the crude product target compound (5aS, 6S, 9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-((1-methyl-1-nitrogen Heterospiro[4.4]non-6-yl)oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxyl-3,10a,11,13,14-pentaza Hetero-6,9-methylenenaphtho[1,8-ab]heptene (17 mg, yield: 80%). ES-API: [M+H] +=637.3.

[0352] Step 14: (5aS, 6S, 9R)-2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-12-((1-methyl-1-nitrogen Heterospiro[4.4]non-6-yl)oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxyl-3,10a,11,13,14-pentaza Hetero-6,9-mylnaphthalene[1,8-ab]heptene (17mg, 0.027mmol) was dissolved in acetonitrile (6.0mL), and 4M hydrochloric acid / dioxane solution (1.0mL, 4.0mmol), reacted in ice bath for 0.5 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and dichloromethane (20 mL) was added, and triethylamine (3.0 mL) was added in an ice-water bath. After stirring for 10 minutes, dichloromethane (100mLX1) and water (50mLX1) were added for extraction. The dichloromethane phase was dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the crude product was obtained by preparative HPLC (formic acid method 1) to obtain 5-ethyl-4-((5aS,6S,9R)-12-(( 1-Methyl-1-azaspiro[4.4]nonan-6-yl)oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a , 11,13,14-pentaaza[6,9]methylnaphtho[1,8-ab]hepten-2-yl)naphthalene-2-ol (5-ethyl-4-((5aS,6S , 9R)-12-((1-methyl-1-azaspiro[4.4]nonan-6-yl)oxy)-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)(Z260-1,1.6mg, yield: 10%, formate ). ES-API: [M+H] +=593.3.

[0353] [Example]

[12] [:composite] [(5aS,6S,9R)-1-] [fluorine] [-12-(((2R,7aS)-2-] [Fluorotetrahydrogen] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-2-(5-] [methyl] [-1H-] [Indazole] [-4-] [base] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [oxo] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [(Z382)]

[0354] Step 1: To tertiary butyl (1S, 2S, 5R)-2-(((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridine[ 4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.427mmol) and (5- To methyl-1H-indazol-4-yl)boronic acid (230.0 mg, 1.307 mmol) in tetrahydrofuran (10.0 mL) and water (2.0 mL) was added cesium carbonate (560 mg, 1.719 mmol), tetrakistriphenylphosphine palladium ( 100mg, 0.87mmol), nitrogen bubbles and heated at 115 ° C for 6 hours. After the reaction was completed, ethyl acetate (30mLX2) and saturated brine (30mL) were extracted. 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 silica gel column chromatography (methanol / dichloromethane=0-4%) to obtain tert-butyl(5aS,6S,9R)-1-fluoro-2-(5-methyl-1H-indazole- 4-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6 , 9-Methylnaphtho[1,8-ab]heptene-14-carboxylate (400mg, crude product), yellow solid. ES-API: [M+H] +=564.4.

[0355] Step 2: At 0 oC, to tert-butyl (5aS, 6S, 9R)-1-fluoro-2-(5-methyl-1H-indazol-4-yl)-12-(methylthio) -5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8 -ab] To a solution of heptene-14-carboxylate (180 mg, 0.319 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (85 mg, 0.493 mmol). Stir at room temperature for 1 hour. The reaction was quenched with saturated sodium sulfite and extracted with dichloromethane (100 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane=0-10%) to give tertiary butyl(5aS,6S,9R)-1-fluoro- 2-(5-Methyl-1H-indazol-4-yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo -3,10a,11,13,14-pentaaza-6,9-mylnaphtho[1,8-ab]heptene-14-carboxylate (200 mg, crude product) as a white solid. ES-API: [M+H] +=580.3.

[0356] Step 3: At 0°C, add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (239.16mg, 1.502mmol) (110.0mg, 0.691mmol) to Sodium hydride (55.0 mg, 1.382 mmol) was added into tetrahydrofuran (10.0 mL) solution, and after stirring at this temperature for 10 minutes, tert-butyl (5aS, 6S, 9R)-1-fluoro-2-(5-methyl Base-1H-indazol-4-yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11 , 13,14-pentaaza-6,9-ylennaphtho[1,8-ab]heptene-14-carboxylate (200 mg, crude) tetrahydrofuran solution (5 mL). 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 obtained crude product was purified by silica gel column chromatography (methanol / dichloromethane=0-5%) to obtain (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl)methoxy)-2-(5-methyl-1H-indazol-4-yl)-5a,6,7,8,9,10-hexahydro- 5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (220mg , 3-step total yield: 94.5%), yellow solid. ES-API: [M+H] +=675.3.

[0357] Step 4: At 0 oC, add (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy Base)-2-(5-methyl-1H-indazol-4-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13 , 14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylic acid tert-butyl ester (200mg, 0.296mmol) in acetonitrile (5.0mL) solution was added 4M Hydrochloric acid / dioxane solution (2.0 mL, 8.000 mmol) was reacted at 0 oC for 1 hour. Concentration, the crude product was obtained by preparative HPLC (ammonium bicarbonate method 1) to obtain (5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H )-yl)methoxy)-2-(5-methyl-1H-indazol-4-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3 ,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene ((5aS,6S,9R)-1-fluoro-12-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-(5-methyl-1H-indazol-4-yl)-5a,6,7,8,9,10- hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene) (Z382, 30 mg, yield: 17.6%), yellow solid. ES-API: [M+1] +=575.3. 1HNMR(500MHz,CD 3OD)δ8.39(s,2H),7.74(d, J=27.1Hz,1H),7.59(d, J=8.6Hz,1H),7.40(dd, J=8.6,3.2Hz ,1H),5.52(d, J=52.0Hz,1H),5.20(t, J=12.5Hz,1H),4.82-4.48(m,4H),4.33(d, J=5.9Hz,1H),4.20 -3.67(m,4H),3.37(dd, J=23.7,13.9Hz,2H),2.73-1.87(m,12H).

[0358] [Example]

[13] [:composite] [5-] [ethynyl] [-6-] [fluorine] [-4-((5aS,6S,9R)-1-] [fluorine] [-12-((] [hexahydro] [-1H-] [Pyrrolizine] [-3-] [base] [)] [Methoxy] [)-5a,6,7,8,9,10-] [hexahydro] [-5H-4-] [oxo] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [-2-] [base] [)] [Naphthalene] [-2-] [alcohol] [(Z383)]

[0359] Step 1: To tertiary butyl (1S, 2S, 5R)-2-(((7-chloro-8-fluoro-(2-methylthio)-4-oxa-3,4-dihydropyridine[ 4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 0.214mmol) and ((2 -Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl) Ethynyl)triisopropylsilane (200.0mg, 0.390mmol) in tetrahydrofuran (6mL) and water (1.5mL) was added potassium phosphate (200mg, 0.943mmol), methanesulfonic acid [n-butylbis(1-adamantane yl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (II) (50mg, 0.069mmol), nitrogen bubble and microwave reaction at 80°C for 40 minutes. After the reaction was completed, ethyl acetate (30mLX2) and saturated brine (30mL) were extracted. The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (methanol / dichloromethane=0-4%) to obtain tert-butyl(5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxy Methylmethoxy)-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-enylnaphtho[1,8-ab]heptene-14-carboxylate (210mg, crude ), a yellow solid. ES-API: [M+H] +=818.3.

[0360] Step 2: At 0 oC, to tert-butyl (5aS, 6S, 9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl Sylsilyl)ethynyl)naphthalen-1-yl)-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11 , 13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate (210 mg, crude product) in dichloromethane (15 mL) was added m-chloro Peroxybenzoic acid (55mg, 0.320mmol). Stir at room temperature for 1 hour. The reaction was quenched with saturated sodium sulfite and extracted with dichloromethane (100 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane=0-10%) to obtain tert-butyl(5aS,6S,9R)-1-fluoro-2 -(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-12-(methylsulfinyl)- 5a, 6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8- ab] Heptene-14-carboxylate (210 mg, crude product), white solid. ES-API: [M+H] +=834.4.

[0361] Step 3: At 0°C, sodium hydride (54.0 mg, 1.34 mmol) was added to a solution of (hexahydro-1H-pyrrolazin-3-yl) methanol (95.0 mg, 0.673 mmol) in tetrahydrofuran (10.0 mL), and the After stirring at low temperature for 10 minutes, add tert-butyl (5aS, 6S, 9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl Sylsilyl)ethynyl)naphthalen-1-yl)-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3, 10a,11,13,14-Pentaaza-6,9-ylennaphtho[1,8-ab]heptene-14-carboxylate (270.0 mg, 0.324 mmol) in tetrahydrofuran (5 mL). 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 obtained crude product was purified by silica gel column chromatography (methanol / dichloromethane=0-5%) to obtain tert-butyl(5aS,6S,9R)-1-fluoro-2-(7-fluoro-3-(methoxy Methylmethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-((hexahydro-1H-pyrrolazin-3-yl)methoxy)-5a , 6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab ] Heptene-14-carboxylate (300 mg, crude product), yellow solid. ES-API: [M+H] +=911.5.

[0362] Step 4: To tertiary butyl (5aS, 6S, 9R)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-12-((hexahydro-1H-pyrrolazin-3-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4- N,N - To a solution of 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 is 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 obtain tert-butyl(5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy) Naphthalene-1-yl)-1-fluoro-12-((hexahydro-1H-pyrrolazin-3-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4 -Oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate (150mg, 3 steps total yield : 60.3%), yellow oil. ES-API: [M+H] +=755.3.

[0363] Step 5: tertiary butyl (5aS,6S,9R)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-1-fluoro-12- ((Hexahydro-1H-pyrrolazin-3-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14 -pentaaza-6,9-methoxynaphtho[1,8-ab]heptene-14-carboxylate (150 mg, 0.199 mmol) and acetonitrile (5.0 mL) and 4M hydrochloric acid / dioxane solution ( 2.0mL, 8.000mmol) The reaction solution was reacted at 0 oC for 1 hour. Concentration, the crude product was obtained by preparative HPLC (formic acid method 1) to obtain 5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((hexahydro-1H-pyrrolazine-3- base)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-ylidene Naphtho[1,8-ab]hepten-2-yl)naphthalene-2-ol (5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((hexahydro -1H-pyrrolizin-3-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) (Z383, 49.0 mg, yield: 41%, formate salt), yellow solid. ES-API: [M+1] +=611.3. 1HNMR (500MHz, CD 3OD) δ8.43(s, 2H), 7.88-7.83(m, 1H), 7.35-7.16(m, 3H), 5.07(d, J=13.7Hz, 1H), 4.72-4.60( m,2H),4.57-4.46(m,1H),4.37-4.19(m,2H),4.11(s,1H),3.86(d, J=21.8Hz,2H),3.66-3.40(m,3H) ,2.47-1.66(m,13H).

[0364] [Example]

[14] [:composite] [(5S,5aS,6S,9R)-2-(8-] [Ethynylnaphthalene] [-1-] [base] [)-1-] [fluorine] [-12-(((2R,7aS)-2-] [Fluorotetrahydrogen] [-1H-] [Pyrrolizine] [-7a(5H)-] [base] [)] [Methoxy] [)-5-] [methyl] [-5,6,7,8,9,10-] [hexahydro] [-5H-4-] [Oxygen] [-3,10a,11,13,14-] [pentazapine] [-6,9-] [Methylenenaphtho] [[1,8-ab]] [heptene] [(Z360-1)]

[0365] Step 1: (1S,2S,5R)-tert-butyl 2-(hydroxymethyl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (3.0g, 12.40 mmol) was dissolved in a mixed solution of ethyl acetate (30 mL) and water (10 mL), added benzyl chloroformate (2.54 g, 14.88 mmol) and sodium bicarbonate (2.98 g, 32.0 mmol), and stirred overnight at room temperature. Add water (50mL), extract with ethyl acetate (100mlX3), wash with saturated brine (20mL), dry over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate=2:1) ​​to obtain 3-Benzyl 8-(tert-butyl)(1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxy Acid ester (4.35g, yield: 93.3%).

[0366] Step 2: At -78°C, under nitrogen protection, a solution of dimethylsulfene (156mg, 1.99mmol) in anhydrous dichloromethane (5.0mL) was slowly dropped into anhydrous dichloromethane (223mg, 1.75mmol) In dichloromethane (10 mL) in water, stirred at this temperature for 15 minutes, 3-benzyl 8-(tert-butyl)(1S,2S,5R)-2-(hydroxymethyl)-3,8-di Azabicyclo[3.2.1]octane-3,8-dicarboxylate (300mg, 0.80mmol) in anhydrous dichloromethane solution (5.0mL) was slowly added dropwise, reacted at -78°C for 40 minutes, triethylamine (646mg, 6.38mmol) was added slowly, and reacted at -78°C for 1 hour. The reaction was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give the crude product 8-(tert-butyl)(1S,2S,5R)-2-formyl-3, 8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl ester (280mg, yield: 93.9%).

[0367] Step 3: 8-(tert-butyl)(1S,2S,5R)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3 -Benzyl ester (280mg, 0.75mmol) was dissolved in dry tetrahydrofuran (5mL), under nitrogen protection, the temperature was lowered to -78°C, and 3M methylmagnesium bromide in 2-methyltetrahydrofuran (0.3mL) was added dropwise, reacted at -78°C 2 hours. Add saturated ammonium chloride solution (5 mL), extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify by thin layer chromatography (ethyl acetate / petroleum ether=1:2) to give 3-benzyl 8-(third Butyl)(1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate ( 180mg, yield: 61.6%).

[0368] Step 4: 3-benzyl 8-(tert-butyl)(1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1 ] Octane-3,8-dicarboxylate (180mg, 0.46mmol) was dissolved in methanol (4mL) and water (0.5mL), ammonium formate (290mg, 4.6mmol) and 10% palladium carbon (20mg) were added, and the tube was sealed React at 60°C for 2 hours. Filtration, concentration, and purification by preparative thin-layer chromatography (dichloromethane / methanol=10:1) gave (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazepine Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100mg, yield: 85.5%).

[0369] Step 5: Add (1S, 2S, 5R)-2-((S)-1- tert-butyl hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.39 mmol) and stirred at this temperature for 10 minutes. Add 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin 4(3H)-one (112mg, 0.40mmol) and heat and stir at 60 oC for 1 hour . After complete reaction, the reaction was quenched with water and extracted with dichloromethane / methanol (10:1, 25mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl(1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio )-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane - 8-carboxylate (160mg, yield: 82.0%). ES-API: [M+H] +=500.1.

[0370] Step 6: To tertiary butyl (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3, 4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160mg, 0.32mmol) and N,N-diisopropylethylenediamine (82mg, 0.64mmol) in dichloromethane (10mL) solution was added 1-propyl phosphoric anhydride (50% ethyl acetate solution) (265mg, 0.42mmol ) and stirred at room temperature for 3 hours. The reaction was 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. Filtrate and collect the filter cake to obtain tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9 ,10-Hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-mylnaphtho[1,8-ab]heptene-14-carboxylic acid Ester (100mg, yield: 65.3%). ES-API: [M+H] +=482.1.

[0371] Step seven: at 0 oC, to tert-butyl (5S, 5aS, 6S, 9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7, 8,9,10-Hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-enylnaphtho[1,8-ab]heptene-14 Add m-chloroperoxybenzoic acid (40 mg, 0.23 mmol) to a solution of -carboxylate (100 mg, 0.21 mmol) in dichloromethane (15 mL), and stir at room temperature for 1 hour. Add dichloromethane (30mL) to dilute, and wash with 10% strong sodium oxide solution (5.0mLX2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylanthylidene)-5a , 6,7,8,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab] Heptene-14-carboxylate (100 mg, yield: 95.2%). ES-API: [M+H] +=498.1.

[0372] Step 8: Add ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H )-yl)methanol (40mg, 0.28mmol). The reaction was stirred at room temperature for 10 minutes. Cool to 0°C, add tert-butyl (5S, 5aS, 6S, 9R)-2-chloro-1-fluoro-5-methyl-12-(methylanthylidene)-5a,6,7,8 ,9,10-hexahydro-5H-4-oxo-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxy acid ester (100mg, 0.20mmol) in tetrahydrofuran (5mL). 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 dried with saturated brine and anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-5% methanol / dichloromethane) to give tert-butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-12-((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxyl-3,10a, 11 , 13, 14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptene-14-carboxylate (50 mg, yield: 42.4%). ES-API: [M+H] +=593.2.

[0373] Step 9: tertiary butyl(5S,5aS,6S,9R)-2-chloro-1-fluoro-12-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- base)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxyl-3,10a,11,13,14-pentaaza-6,9-ylidene Naphtho[1,8-ab]heptene-14-carboxylate (50.0mg, 0.08mmol) and triisopropyl ((8-(4,4,5,5-tetramethyl-1,3, 2-Dioxybenzaldehyde-2-yl)naphthalene-1-yl)ethynyl)silane (55mg, 0.13mmol) in tetrahydrofuran (6mL) and water (1.0mL) was added potassium phosphate (34mg, 0.16mmmol), form Sulfonic acid [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (15mg), nitrogen bubble and at 60°C React for 40 minutes. After the reaction was completed, ethyl acetate (30mLX2) and saturated brine (10mL) were extracted. 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 silica gel column chromatography (0-4% methanol / dichloromethane) to give tert-butyl(5S,5aS,6S,9R)-1-fluoro-12-((2R,7aS)-2-fluoro Tetrahydrofuran-1H-pyrrolazin-7a(5H)-ylmethoxy)-5-methyl-2-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6 , 7,8,9,10-hexahydro-5H-4-oxyl-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]hept En-14-carboxylate (45 mg, yield: 65.2%). ES-API: [M+H] +=865.1.

[0374] Step ten: To tertiary butyl (5S, 5aS, 6S, 9R)-1-fluoro-12-((2R, 7aS)-2-fluorotetrahydrofuran-1H-pyrrolidin-7a(5H)-ylmethoxy )-5-methyl-2-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4- N,N of oxy-3,10a,11,13,14-pentaaza-6,9-methylenenaphtho[1,8-ab]heptane-14-carboxylate (45mg, 0.052mmol) - To a solution of dimethylformamide (3.0 mL) was added cesium fluoride (40 mg, 0.26 mmol). The reaction was stirred at room temperature for 0.5 hours. After completion of the reaction, preparative HPLC (trifluoroacetic acid method) gave tertiary butyl (5S, 5aS, 6S, 9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4 -Oxy-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate (32mg, yield: 86.5% ). ES-API: [M+H] +=709.3.

[0375] Step eleven: tertiary butyl (5S, 5aS, 6S, 9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxyl-3,10a, 11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene-14-carboxylate (32mg, 0.045mmol) and acetonitrile (2.0mL) and 4M hydrochloric acid / Dioxane solution (0.500 mL, 2.000 mmol) was reacted at 0 oC for 1 hour. The reaction solution was concentrated, and the crude product was obtained by preparative HPLC (formic acid method 1) to obtain (5S, 5aS, 6S, 9R)-2-(8-ethynylnaphthalen-1-yl)-1-fluoro-12-((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-ylmethoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxyl- 3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptene ((5S,5aS,6S,9R)-2-(8-ethynylnaphthalen- 1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9 ,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene)(Z360-1,12mg, yield: 44.4%, formate), a yellow solid. ES-API: [M+1] +=609.3.

[0376] The 3-benzyl 8-(tert-butyl)(1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1 ] octane-3,8-dicarboxylate was converted to compound B for the determination of absolute stereochemistry.

[0377] Under nitrogen protection, 3-benzyl 8-(tert-butyl)(1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-di To a solution of azabicyclo[3.2.1]octane-3,8-dicarboxylate (120mg, 0.31mmol) in tetrahydrofuran (26.0mL), slowly add 1M solution of potassium tert-butoxide in tetrahydrofuran (0.62mL, 0.62 mmol). After reacting at 0°C for 1 hour, slowly add saturated aqueous ammonium chloride solution, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, spin the filtrate under reduced pressure, and obtain the crude product Purified by beating with petroleum ether to obtain tert-butyl(1S,6R,9S,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9-epiminoxazolo [ 3,4-a]Aza-10-carboxylate (Compound B, 95 mg). ES-API: [M+H] +=283.2. 1HNMR (500MHz, CDCl 3) δ4.44-3.98(m, 3H), 3.67-3.45(m, 2H), 3.32-3.06(m, 1H), 2.11-1.96(m, 1H), 1.87(tdd, J =22.1,13.1,4.8Hz,2H),1.77-1.68(m,1H),1.48(s,9H),1.45(d, J=6.3Hz,3H). 13CNMR(126MHz,CDCl 3)δ157.7,153.0, 80.6, 72.9, 63.3, 55.0, 53.5, 47.6, 28.4, 27.2, 22.4, 20.7.

[0378] single crystal growth

[0379] Weigh 10 mg of the crude compound B obtained in the above steps into a sample tube, dissolve it in a small amount of ethyl acetate, place it in a sealed sample bottle, and slowly diffuse the petroleum ether in the sample bottle into the ethyl acetate solution of the compound at room temperature, In order to obtain the desired single crystal, X-ray single crystal diffraction test was carried out by BrukerD8Venture instrument. The results are shown in Table 3 and Figure 1 below. The absolute configuration of the substituent on the 1-position of compound B was confirmed as (S).

[0380] table 3 Empirical formula C14H22N2O4 Molecular weight (FormulaWeight) 282.33 Temperature 213.00K Wavelength 1.34139Å Crystal system Monoclinic Spacegroup C121 Unit cell parameters (Unitcelldimensions) a=22.9206(4)Åa=90° b=6.62200(3)Åb=103.4690(10)° c=10.0316(4)Å g=90° Cell volume (Volume) 1480.72(5)Å 3 The number of molecules in the unit cell Z 4 Density(cal...

Claims

1. A compound of formula (A) or a pharmaceutically acceptable salt or stereoisomer thereof:

1. In the formula, X is 0; Y is CR12R13 or CR14R15CR16R17; where, R12 and R13 are each independently selected from H, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, or -C1-C4 alkyl-hydroxy; R14 and R15 are each independently selected from H; R16 and R17 are each independently selected from H; W is CR20; wherein R20 is H or a halogen; ring A is selected from the following group: C6-C10 aryl or 6 to 10 heteroaryl; R1 is a substituent at any position on ring A; n1 is 0, 1, 2, 3, or 4; each R1 is independently selected from: C1-C6 alkyl, halogen, hydroxyl, cyano, C1-C6 haloalkyl, NR21R22, C2-C6 ynyl or cycloalkyl; wherein R21 is H; R22 is H; Z is N; R3a and R3b are linked to form -CHR3a2CHR3a3-; R3c is hydrogen; R3a2 and R3a3 are each independently hydrogen; L3 is O; R6 is a -L- 6- to 10-membered fused heterocyclic group, a -L-spirocyclic substituted 6- to 10-membered fused heterocyclic group, or a -L-ring-substituted 6- to 10-membered fused heterocyclic group; the spirocyclic 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 of any one or two carbon atoms are simultaneously replaced by -(CH2)m4- to form a spirocyclic substituted 6- to 10-membered fused heterocyclic group, where m4 is 2; the ring-substituted 6- to 10-membered fused heterocyclic group refers to a 6- to 10-membered fused heterocyclic group in which the two hydrogen atoms on the same carbon atom of any one pair of adjacent carbon atoms are simultaneously replaced by -(CH2)m4- to form a spirocyclic substituted 6- to 10-membered fused heterocyclic group. One hydrogen atom on the carbon atom is simultaneously replaced by -(CH2)m4- to form a fused-ring 6- to 10-membered fused heterocyclic group, wherein m4 is 1; the 6- to 10-membered fused heterocyclic group has one N(Rm) heteroatom as a ring atom; the spirocyclic substituted 6- to 10-membered fused heterocyclic group and the fused-ring substituted 6- to 10-membered fused heterocyclic group each independently have one N(Rm) heteroatom as a ring atom; Rm is absent; wherein the 6- to 10-membered fused heterocyclic group is saturated; 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 =CR2aR2b; the 6- to 10-membered fused heterocyclic group is optionally also replaced by one or more R6a; but when R1 2. When R13 is simultaneously H or R14, R15, R16, and R17 are simultaneously H, the two hydrogen atoms on the same carbon atom of any one or two carbon atoms in the 6- to 10-membered fused heterocyclic group are simultaneously substituted by =CR2aR2b; wherein R2a and R2b are each independently hydrogen or halogen; each R6a is each independently halogen, hydroxyl, C1-C6 hydroxyalkyl, or C1-C6 alkoxy; or R6 is cycloalkyl, C1-C6 alkyl, -L-heterocyclic, -LN(R34)2, or -L-OR34; wherein the cycloalkyl or the heterocyclic group in the -L-heterocyclic group may optionally be substituted by one or more R35; wherein each L is each independently a bond or a C1-C4 alkyl group;In this compound, one or two hydrogen atoms on any carbon atom of the C1-C4 alkyl group, or on any carbon atom of the same group, are optionally and independently substituted by a C2-C4 alkenyl group; or two hydrogen atoms on any carbon atom of the C1-C4 alkyl group are optionally simultaneously substituted by -(CH2)m3- to form a cyclic substituent; m3 is 2; each R35 is independently a halogen, hydroxyl, C1-C3 alkyl, or C2-C4 alkenyl group; each R34 is independently a hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl group; or two R34s together with the nitrogen atom attached to them constitute a 3- to 6-membered nitrogen-containing heterocyclic group, which is optionally substituted by one or two halogens; or, the compound is , or .

2. The compound as claimed in claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, The compound is shown in formula (III):

2. In the formula, X, Y, W, ring A, R1, n1, L3, and R6 are each the same as before; R3d and R3e are connected to form -CHR3d2CHR3d3-; R3f is hydrogen; R3d2 and R3d3 are each hydrogen independently.

3. The compound as claimed in claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, The compounds are shown as those of formula (III-1a) or (III-1b):

3. In each formula, R3 is a substituent at any position on the bridge ring and each is independently hydrogen; X, Y, W, ring A, R1, n1, L3, and R6 are each as before.

4. The compound as claimed in claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, The compounds are shown as those of formula (III-1a1), (III-1a2), (III-1b1), (III-1b2), (III-1c1), or (III-1c2):

4. In each formula, R3 is a substituent at any position on the bridge ring and each is independently hydrogen; X, Y, W, ring A, R1, n1, L3, and R6 are each independently defined as before.

5. The compound as described in any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, W is CR20; where R20 is H or fluorine.

6. The compound as described in any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, Y is CR12R13 or CR14R15CR16R17; wherein R12 and R13 are each independently selected from H, methyl, ethyl, -CH2F or -CH2OH; R14 and R15 are each independently selected from H; and R16 and R17 are each independently selected from H.

7. The compound as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, Ring A is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl.

8. The compound as described in any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, R1 is a substituent at any position on ring A; n1 is 0, 1, 2 or 3; each R1 is independently selected from: hydroxyl, cyano, amino, F, Cl, CF3, methyl, ethyl, propyl, cyclopropyl or ethynyl.

9. The compound as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, R6 is a -L-6 to 10-membered fused heterocyclic group; in any one carbon atom of the 6 to 10-membered fused heterocyclic group, two hydrogen atoms on the same carbon atom are simultaneously replaced by =CR2aR2b; wherein R2a and R2b are each independently hydrogen or fluorine; and L is an enylmethyl group.

10. The compound as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, L is methyl, ethyl, or propyl; wherein, the two hydrogen atoms on the same carbon atom of the methyl, ethyl, or propyl group are optionally simultaneously substituted by -CH2CH2- to form a cyclopropyl group.

11. The compound as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, R6 is a -L-6 to 10-membered fused heterocyclic group; wherein, in any one or two carbon atoms of the 6 to 10-membered fused heterocyclic group, the two hydrogen atoms on the same carbon atom are optionally simultaneously substituted by =CR2aR2b; and / or the 6 to 10-membered fused heterocyclic group is optionally substituted by one or more R6a; wherein R2a and R2b are each independently hydrogen or halogen; each R6a is each independently halogen or C1-C6 alkoxy; or R6 is an -L-heterocyclic group; wherein the heterocyclic group in the -L-heterocyclic group can be any Optionally substituted with one or more R35s; each R35 is independently halogenated or C2-C4 enyl; the L is a C1-C4 enyl group; wherein one or two hydrogen atoms on any carbon atom or on any same carbon atom of the C1-C4 enyl group are optionally independently substituted with a C2-C4 enyl group; or two hydrogen atoms on any same carbon atom of the C1-C4 enyl group are optionally simultaneously substituted with -(CH2)m3- to form a cyclic substituent; m3 is 2.

12. The compound as claimed in any one of claims 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, R6 is selected from the following group: methyl, 13. The compound as claimed in claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, The compound is selected from 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound as described in any one of claims 1-13 or a pharmaceutically acceptable salt or stereoisomer thereof; and a pharmaceutically acceptable excipient.

15. Use of a compound as claimed in any one of claims 1-13, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition as claimed in claim 14, in the preparation of a medicament for the prevention and / or treatment of a disease or condition; said disease or condition being a KRAS G12D-related disease or disorder.

16. The use as described in claim 15, wherein, The KRAS G12D-related disease or disorder is cancer.

Images