Camptothecin derivatives, pharmaceutical compositions thereof and their applications

Abstract

Provided are compounds of formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof, pharmaceutical compositions thereof, and their use in anti-tumor therapy. [Formula 1] TIFF2024532768000178.tif34160

Description

[Technical field]

[0001] This disclosure claims priority to a Chinese patent application, filed on August 19, 2021 with patent application number CN202110955364.5 and entitled "Camptothecin Derivatives and Their Applications" with the State Intellectual Property Office of China, filed on December 13, 2021 with patent application number CN202111515247.3 and entitled "Camptothecin Derivatives and Their Applications" with the State Intellectual Property Office of China, filed on May 12, 2022 with patent application number CN202210515797.3 and entitled "Camptothecin Derivatives and Their Applications" with the State Intellectual Property Office of China. The above-mentioned prior applications are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to new camptothecin-based compounds, or stereoisomers or pharma- ceutically acceptable salts thereof, pharmaceutical compositions containing them and their use as antitumor drugs. [Background technology]

[0003] Camptothecin is a quinoline alkaloid extracted from Camptotheca acuminata, a Chinese plant of the family Cornaceae. It has been widely used in cancer treatment-related research due to its remarkable cytotoxic activity. Subsequent research into related mechanisms has shown that camptothecin has the activity of inhibiting topoisomerase I, and can bind to the complex of topoisomerase I and DNA to form a stable ternary complex, thereby blocking topoisomerase I-mediated DNA cleavage, and further blocking processes such as DNA replication, transcription and repair, ultimately resulting in cell cycle block and apoptosis.

[0004] In early clinical trials, camptothecin had problems such as low solubility, poor chemical stability, and obvious toxic side effects, which ultimately hindered its clinical application. Later, camptothecin derivatives such as topotecan and irinotecan obtained by modifying camptothecin were successfully used to treat malignant tumors such as ovarian cancer, lung cancer, and colorectal cancer. However, these clinical drugs still have problems such as low oral bioavailability due to low solubility and poor chemical stability, and are accompanied by the occurrence of severe clinical side effects such as vomiting and bone marrow suppression. Therefore, currently, improving the physicochemical properties of camptothecin drugs and improving their activity and safety remains an urgent task. Summary of the Invention

[0005] The present disclosure provides a compound according to formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] Where: R 1 is halogen, CN, C 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 alkynyl groups, 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 The alkynyl group is optionally represented by R a1 is replaced by X 1 CR 2 or N, R 2 is selected from H, halogen, CN, or R 1 , R 2together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, which may optionally be a2 is replaced by R 5 H, halogen, CN, NH 2 OR NO 2 or R 1 , R 5 together with the atoms connected thereto, form a 5- to 6-membered heterocyclic group, a 5- to 6-membered heteroaryl group, or C 5 -C 7 A cycloalkenyl group is formed, and the 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group or C 5 -C 7 The cycloalkenyl group is optionally represented by R a5 is replaced by R 3 H, [ka] and X is selected from NH 2 or OH; R 6 is H or C 1 -C 3 alkyl groups; R 7 , H, C 1 -C 3 Alkyl group or C 3 -C 6 cycloalkyl groups, or R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 Forming a cycloalkyl group, 3 -C 6 The cycloalkyl group is optionally represented by R a3 is replaced by n is selected from 1, 2, 3 or 4; R 4 is selected from H, or R 4 , R 7 together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, which may optionally be a4 is replaced by Each Ra1 , R a2 , R a3 , R a4 , R a5 D, halogen, CN, =O, OH, NH 2 , C 1 -C 3 Alkyl group, C 3 -C 6 cycloalkyl group or 4- to 7-membered heterocyclic group, 2 , C 1 -C 3 Alkyl group, C 3 -C 6 The cycloalkyl group or the 4- to 7-membered heterocyclic group may optionally be R b is replaced by Each R b is halogen, CN, =O, C 1 -C 3 Alkyl groups, OH, O(C 1 -C 3 alkyl group), NH 2 , NH(C 1 -C 3 alkyl group) or N(C 1 -C 3 (alkyl group) 2 are independently selected from The conditions are: i) R 1 is selected from the group consisting of methyl groups, and R 2 If is selected from F, then R 3 teeth, [ka] where R 6 is H or C 1 -C 3 alkyl groups; R 7 , H, C 1 -C 3 Alkyl group or C 3 -C 6 cycloalkyl group, n is selected from 1, 2, 3 or 4; ii) X is NH 2 R 5 is not selected from H, and iii) the compound of formula (I) is a compound: [ka] Does not include.

[0006] In some embodiments, the compound according to formula (I) above, or a stereoisomer or pharma- ceutically acceptable salt thereof, is 1 is halogen, CN, C 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 alkynyl groups, 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 The alkynyl group is optionally represented by R a1 is replaced by X 1 CR 2 or N, R 2 is selected from H, halogen, CN, or R 1 , R 2 together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, which may optionally be a2 is replaced by R 5 is H, halogen, CN or NO 2 or R 1 , R 5 together with the atoms to which they are linked, a 5- to 6-membered heteroaryl group or C 5 -C 7 forming a cycloalkenyl group, 5 -C 7 The cycloalkenyl group is optionally represented by R a5 is replaced by R 3 H, [ka] Selected from R 6 is H or C 1 -C 3 alkyl groups; R 7 , H, C 1 -C 3 Alkyl group or C 3 -C 6 cycloalkyl groups, or R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 Forming a cycloalkyl group, 3 -C 6 The cycloalkyl group is optionally represented by R a3 is replaced by n is selected from 1, 2, 3 or 4; R 4 is selected from H, or R 4 , R 7 together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, which may optionally be a4 is replaced by Each R a1 , R a2 , R a3 , R a4 , R a5 are halogens, CN, =O, OH, NH 2 , C 1 -C 3 Alkyl group, C 3 -C 6 cycloalkyl group or 4- to 7-membered heterocyclic group, 2 , C 1 -C 3 Alkyl group, C 3 -C 6 The cycloalkyl group or the 4- to 7-membered heterocyclic group may optionally be R b is replaced by Each R b is halogen, CN, =O, C 1 -C 3 Alkyl groups, OH, O(C 1 -C 3 alkyl group), NH 2 , NH(C1 -C 3 alkyl group) or N(C 1 -C 3 (alkyl group) 2 are independently selected from The conditions are: i) R 1 is selected from the group consisting of methyl groups, and R 2 If is selected from F, then R 3 teeth, [ka] where R 6 is H or C 1 -C 3 alkyl groups; R 7 , H, C 1 -C 3 Alkyl group or C 3 -C 6 cycloalkyl group, n is selected from 1, 2, 3 or 4, and ii) the compound of formula (I) is a compound: [ka] 2. A compound of formula (I), or a stereoisomer or pharma- ceutically acceptable salt thereof, which does not include:

[0007] In some embodiments, the compound according to formula (I) above, or a stereoisomer or pharma- ceutically acceptable salt thereof, R 1 is halogen, CN, C 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 alkynyl groups, 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 The alkynyl group is optionally represented by R a1 is replaced by X 1 CR2 or N, R 2 is selected from H, halogen, CN, or R 1 , R 2 together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, which may optionally be a2 is replaced by R 5 is selected from H, halogen or CN, or R 1 , R 5 together with the atom to which they are linked form a 5- to 6-membered heteroaryl group, said 5- to 6-membered heteroaryl group optionally being selected from the group consisting of R a5 is replaced by R 3 H, [ka] Selected from R 6 is H or C 1 -C 3 alkyl groups; R 7 , H, C 1 -C 3 Alkyl group or C 3 -C 6 cycloalkyl groups, or R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 Forming a cycloalkyl group, 3 -C 6 The cycloalkyl group is optionally represented by R a3 is replaced by n is selected from 1, 2, 3 or 4; R 4 is selected from H, or R 4 , R 7 together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, which may optionally be a4 is replaced by Each R a1 , R a2 , R a3 , R a4 , Ra5 are halogens, CN, =O, OH, NH 2 , C 1 -C 3 Alkyl group, C 3 -C 6 cycloalkyl group or 4- to 7-membered heterocyclic group, 2 , C 1 -C 3 Alkyl group, C 3 -C 6 The cycloalkyl group or the 4- to 7-membered heterocyclic group may optionally be R b is replaced by Each R b is halogen, CN, =O, C 1 -C 3 Alkyl groups, OH, O(C 1 -C 3 alkyl group), NH 2 , NH(C 1 -C 3 alkyl group) or N(C 1 -C 3 (alkyl group) 2 are independently selected from The conditions are: i) R 1 is selected from the group consisting of methyl groups, and R 2 If is selected from F, then R 3 teeth, [ka] where R 6 is H or C 1 -C 3 alkyl groups; R 7 , H, C 1 -C 3 Alkyl group or C 3 -C 6 cycloalkyl group, n is selected from 1, 2, 3 or 4, and ii) the compound of formula (I) is a compound: [ka] 2. A compound of formula (I), or a stereoisomer or pharma- ceutically acceptable salt thereof, which does not include:

[0008] In some embodiments, the compound according to formula (I) above, or a stereoisomer or pharma- ceutically acceptable salt thereof, R 1 is halogen, CN, C 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 alkynyl groups, 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 The alkynyl group is optionally represented by R a1 is replaced by X 1 CR 2 or N, R 2 is selected from halogen, CN, or R 1 , R 2 together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, which may optionally be a2 is replaced by R 5 is selected from H, halogen or CN; R 3 is H or [ka] Selected from R 6 is selected from H, and R 7 is H or C 3 -C 6 cycloalkyl groups, or R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 Forming a cycloalkyl group, 3 -C 6 The cycloalkyl group is optionally represented by R a3 is replaced by R4 is selected from H, or R 4 , R 7 together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, which may optionally be a4 is replaced by Each R a1 , R a2 , R a3 , R a4 are halogens, CN, =O, OH, NH 2 , C 1 -C 3 Alkyl group, C 3 -C 6 cycloalkyl group or 4- to 7-membered heterocyclic group, 2 , C 1 -C 3 Alkyl group, C 3 -C 6 The cycloalkyl group or the 4- to 7-membered heterocyclic group may optionally be R b is replaced by Each R b is halogen, CN, =O, C 1 -C 3 Alkyl groups, OH, O(C 1 -C 3 alkyl group), NH 2 , NH(C 1 -C 3 alkyl group) or N(C 1 -C 3 (alkyl group) 2 are independently selected from The conditions are: i) R 1 is selected from the group consisting of methyl groups, and R 2 If is selected from F, then R 3 teeth [ka] and ii) the compound of formula (I) is selected from the compound: [ka] 2. A compound of formula (I), or a stereoisomer or pharma- ceutically acceptable salt thereof, which does not include:

[0009] In some embodiments, R a1 , R a2 , R a3 , R a4 , R a5 is independently selected from D, halogen, CN, ═O or OH.

[0010] In some embodiments, R a1 , R a2 , R a3 , R a4 , R a5 is independently selected from halogen, CN, ═O, or OH.

[0011] In some embodiments, R a1 , R a2 , R a3 , R a4 is independently selected from halogen, CN, ═O, or OH.

[0012] In some embodiments, R a2 , R a3 is selected independently from D.

[0013] In some embodiments, R 1 is a halogen, C 1 -C 3 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 3 alkynyl groups.

[0014] In some embodiments, R 1 is selected from Cl, Br, a methyl group, a cyclopropyl group or an ethynyl group.

[0015] In some embodiments, R 1 is selected from Cl, Br or a methyl group.

[0016] In some embodiments, X 1 is selected from N.

[0017] In some embodiments, X 1 is CR 2 is selected from.

[0018] In some embodiments, R 2 is selected from H, halogen, CN, or R 1 , R 2 form, together with the atoms connected thereto, a 5- to 6-membered heterocyclic group, said 5- to 6-membered heterocyclic group containing 1 or 2 oxygen atoms as ring atoms, said 5- to 6-membered heterocyclic group being optionally substituted with a D atom.

[0019] In some embodiments, R 2 is selected from H, halogen, CN, or R 1 , R 2 form a 5- to 6-membered heterocyclic group together with the atoms connected thereto, said 5- to 6-membered heterocyclic group containing 1 or 2 oxygen atoms as ring atoms.

[0020] In some embodiments, R 2 is selected from halogen, CN, or R 1 , R 2 form a 5- to 6-membered heterocyclic group together with the atoms connected thereto, said 5- to 6-membered heterocyclic group containing 1 or 2 oxygen atoms as ring atoms.

[0021] In some embodiments, R 2 is selected from H and halogen, or R 1 , R 2 form a 5- to 6-membered heterocyclic group together with the atoms connected thereto, said 5- to 6-membered heterocyclic group containing 1 or 2 oxygen atoms as ring atoms.

[0022] In some embodiments, R 2 is selected from H, F or Cl, or R 1 , R 2 along with the atoms connected to them. [ka] Form.

[0023] In some embodiments, R 2 is selected from H, F or Cl, or R 1 , R 2 along with the atoms connected to them. [ka] Form.

[0024] In some embodiments, R 2 is selected from F or Cl, or R 1 , R 2 along with the atoms connected to them. [ka] Form.

[0025] In some embodiments, R 1 is selected from the group consisting of a methyl group, and R 2 is selected from F or Cl.

[0026] In some embodiments, R 1 is selected from the group consisting of a methyl group, and R 2 is selected from Cl.

[0027] In some embodiments, R 1 is selected from Cl, Br, a cyclopropyl group or an ethynyl group; R 2 is selected from F.

[0028] In some embodiments, R 5 H, halogen, NH 2 OR NO 2 or R 1 , R 5 together with the atoms to which they are linked, a 5- to 6-membered heteroaryl group or C 5-C 6 forming a cycloalkenyl group, 5 -C 6 The cycloalkenyl group is optionally represented by R a5 is replaced by.

[0029] In some embodiments, R 5 is H, halogen or NO 2 or R 1 , R 5 together with the atoms to which they are linked, a 5- to 6-membered heteroaryl group or C 5 -C 6 forming a cycloalkenyl group, 5 -C 6 The cycloalkenyl group is optionally represented by R a5 is replaced by.

[0030] In some embodiments, R 5 is selected from H or halogen, or R 1 , R 5 together with the atoms to which they are attached form a 5-6 membered heteroaryl group.

[0031] In some embodiments, R 5 is H, halogen or NO 2 is selected from.

[0032] In some embodiments, R 5 is selected from H or a halogen.

[0033] In some embodiments, R 5 are H, Cl, F, NH 2 OR NO 2 or R 1 , R 5 along with the atoms connected to them. [ka] Form.

[0034] In some embodiments, R 5 is H, Cl, F or NO 2 or R 1 , R 5 along with the atoms connected to them. [ka] Form.

[0035] In some embodiments, R 5 is selected from H or F, or R 1 , R 5 along with the atoms connected to them. [ka] Form.

[0036] In some embodiments, R 5 is H, Cl, F or NO 2 is selected from.

[0037] In some embodiments, R 5 is selected from H or F.

[0038] In some embodiments, R 3 is selected from H.

[0039] In some embodiments, R 3 teeth, [ka] is selected from.

[0040] In some embodiments, R 3 teeth, [ka] and X is selected from NH 2 or OH; R6 is selected from H or a methyl group, R 7 is selected from H, a methyl group, an isopropyl group or a cyclopropyl group optionally substituted with a D atom.

[0041] In some embodiments, R 3 teeth, [ka] and X is selected from NH 2 or OH; R 6 is selected from H or a methyl group, R 7 is selected from H, a methyl group, an isopropyl group, or a cyclopropyl group.

[0042] In some embodiments, R 3 teeth, [ka] Selected from R 6 is selected from H or a methyl group, R 7 is selected from H, a methyl group, a cyclopropyl group, or an isopropyl group.

[0043] In some embodiments, R 3 teeth, [ka] Selected from R 6 is selected from H or a methyl group, R 7 is selected from H, a methyl group, a cyclopropyl group, or an isopropyl group.

[0044] In some embodiments, R 3 teeth, [ka] Selected from R 6 is selected from H, R 7 is selected from H or a cyclopropyl group.

[0045] In some embodiments, R 3 teeth, [ka] Selected from R 6 is selected from H, R 7 is selected from H or a cyclopropyl group.

[0046] In some embodiments, R 3 teeth, [ka] Selected from R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 It forms a cycloalkyl group.

[0047] In some embodiments, R 3 teeth, [ka] Selected from R 6 , R 7 form a cyclopropyl group together with the C atom to which they are linked.

[0048] In some embodiments, R 1 is selected from the group consisting of a methyl group, and X 1 is selected from CF and CCl; R 3 teeth, [ka] Selected from R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 It forms a cycloalkyl group.

[0049] In some embodiments, R 1is selected from the group consisting of a methyl group, and X 1 is selected from CF, R 3 teeth, [ka] Selected from R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 It forms a cycloalkyl group.

[0050] In some embodiments, R 1 is selected from the group consisting of a methyl group, and R 2 is selected from F or Cl; R 3 teeth, [ka] is selected from.

[0051] In some embodiments, R 1 is selected from the group consisting of a methyl group, and R 2 is selected from F and R 3 teeth, [ka] is selected from.

[0052] In some embodiments, R 4 is selected from H.

[0053] In some embodiments, R 4 , R 7 form a 5- to 6-membered heterocyclic group together with the atoms to which they are linked.

[0054] In some embodiments, R 4 , R 7 together with the atoms to which they are connected form a 5-membered heterocyclic group.

[0055] In some embodiments, R 3 is H or [ka] Selected from R 4 is selected from H.

[0056] In some embodiments, R 3 , R 4 are each selected from H.

[0057] In some embodiments, R 4 is selected from H, R 3 teeth, [ka] Selected from R 6 is selected from H, R 7 is selected from H or a cyclopropyl group, or R 6 , R 7 form a cyclopropyl group together with the C atom to which they are linked.

[0058] In some embodiments, R 3 teeth, [ka] Selected from R 6 is selected from H, R 4 , R 7 form a 5- to 6-membered heterocyclic group together with the atoms to which they are linked.

[0059] In some embodiments, R 3 teeth, [ka] Selected from R 6 is selected from H, R 4 , R 7 together with the atoms to which they are connected form a 5-membered heterocyclic group.

[0060] In some embodiments, R1 , R 2 along with the atoms connected to each [ka] Form R 3 H, [ka] Selected from R 4 is selected from H, R 6 is selected from H, R 7 is selected from H or a cyclopropyl group optionally substituted with a D atom, or R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 It forms a cycloalkyl group.

[0061] In some embodiments, R 1 , R 2 along with the atoms connected to each [ka] Form R 3 teeth, [ka] Selected from R 4 is selected from H, R 6 is selected from H, R 7 is selected from a cyclopropyl group optionally substituted with a D atom, or R 6 , R 7 form a cyclopropyl group together with the C atom to which they are linked.

[0062] In some embodiments, R 1 , R 2 along with the atoms connected to each [ka] Form R3 teeth, [ka] Selected from R 4 is selected from H, R 6 is selected from H, R 7 is selected from a cyclopropyl group, or R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 It forms a cycloalkyl group.

[0063] In some embodiments, R 1 , R 2 along with the atoms connected to each [ka] Form R 3 H, [ka] Selected from R 4 is selected from H, R 6 is selected from H, R 7 is selected from H or a cyclopropyl group, or R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 It forms a cycloalkyl group.

[0064] In some embodiments, R 1 , R 2 along with the atoms connected to each [ka] Formation, R 3 teeth, [ka] Selected from R 4 is selected from H, R 6is selected from H, R 7 is selected from H or a cyclopropyl group, or R 6 , R 7 are C together with the C atoms connected to them. 3 -C 6 It forms a cycloalkyl group.

[0065] In some embodiments, R 1 , R 5 together with the atoms to which they are linked, a 5- to 6-membered heteroaryl group or C 5 -C 6 Form a cycloalkenyl group, R 3 teeth, [ka] is selected from.

[0066] In some embodiments, R 1 , R 5 form a 5- to 6-membered heteroaryl group together with the atoms to which they are attached, R 3 teeth, [ka] is selected from.

[0067] In some embodiments, R 1 , R 5 form a 5- to 6-membered heteroaryl group together with the atoms to which they are attached, R 3 teeth, [ka] is selected from.

[0068] In some embodiments, R 1 , R 5 form a 5- to 6-membered heteroaryl group together with the atoms to which they are attached, R 3 teeth, [ka] is selected from.

[0069] In some embodiments, R 2 is selected from H, R 1 , R 5 together with the atoms to which they are linked, a 5- to 6-membered heteroaryl group or C 5 -C 6 Forms a cycloalkenyl group.

[0070] In some embodiments, R 2 is selected from H, R 1 , R 5 are C together with the atoms connected to them. 5 -C 6 Forms a cycloalkenyl group.

[0071] In some embodiments, R 2 is selected from H, R 1 , R 5 together with the atoms to which they are attached form a 5-6 membered heteroaryl group.

[0072] In some embodiments, R 2 is selected from H, R 1 , R 5 form a 5- to 6-membered heteroaryl group together with the atoms to which they are attached, R 3 teeth, [ka] is selected from.

[0073] In some embodiments, R 3 H, [ka] where X is selected from NH 2 or OH; R 6 is selected from H or a methyl group, R 7 is selected from H, a methyl group, an isopropyl group or a cyclopropyl group optionally substituted with a D atom; R4 is selected from H, or R 4 , R 7 together with the atoms to which they are connected form a 5-membered heterocyclic group.

[0074] In some embodiments, R 3 H, [ka] where X is selected from NH 2 or OH; R 6 is selected from H or a methyl group, R 7 is selected from H, a methyl group, an isopropyl group, or a cyclopropyl group; R 4 is selected from H.

[0075] In some embodiments, the structural unit [ka] is selected from.

[0076] In some embodiments, the structural unit [ka] is selected from.

[0077] In some embodiments, the structural unit [ka] is selected from.

[0078] In some embodiments, the structural unit [ka] is selected from.

[0079] In some embodiments, the structural unit [ka] is selected from.

[0080] In some embodiments, R 1 is selected from the group consisting of a methyl group, and X 1 is selected from the structural unit CF [ka] is selected from.

[0081] In some embodiments, R 1 , R 2 along with the atoms connected to them. [ka] Forming structural units [ka] is selected from.

[0082] In some embodiments, R 1 , R 2 along with the atoms connected to each [ka] Forming structural units [ka] is selected from.

[0083] In some embodiments, R 1 , R 2 along with the atoms connected to each [ka] Forming structural units [ka] is selected from.

[0084] In some embodiments, R 1 , R 5 along with the atoms connected to them. [ka] Forming structural units [ka] is selected from.

[0085] In some embodiments, R 1 , R 5 along with the atoms connected to them. [ka] Forming structural units [ka] is selected from.

[0086] In some embodiments, the compound according to formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof, is selected from the compound according to formula (Ia), or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] Here, R 1 , R 2 , R 3 , R 4 , R 5 is as defined above.

[0087] It should be understood that in claim 11 relating to formula (Ia), when claim 11 refers to the above-mentioned claim x, R 1 , R 2 , R 3 , R 4 , R 5 is as defined in claim x. For example, when claim 11 refers to the above-mentioned claim 1, R in formula (Ia)1 , R 2 , R 3 , R 4 , R 5 is as defined in claim 1, and when claim 11 refers to the above-mentioned claim 2, R in the formula (Ia) 1 , R 2 , R 3 , R 4 , R 5 is as defined in claim 2, and so forth.

[0088] In some embodiments, the compound according to formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof, is selected from the compound according to formula (Ib), or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] Here, R 1 , R 3 , R 4 , R 5 is as defined above.

[0089] It should be understood that in claim 12 relating to formula (Ib), when claim 12 refers to the above-mentioned claim x, R 1 , R 3 , R 4 , R 5 is as defined in claim x. For example, when claim 12 refers to the above-mentioned claim 1, R in the formula (Ib) 1 , R 3 , R 4 , R 5 is as defined in claim 1, and when claim 12 refers to the above-mentioned claim 2, R in the formula (Ib) 1 , R 3 , R 4 , R 5 is as defined in claim 2, and so forth.

[0090] The present disclosure provides a compound represented by formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] Where: R 8 is a hydroxyl group, halogen, CN, C 1 -C 6 Alkyl group, C 3 -C 6 Cycloalkyl group or C 2 -C 6 alkynyl groups, X 2 CR 9 or N, R 9 is selected from H, halogen, CN, or R 8 , R 9 form a 5- to 6-membered heterocyclic group together with the atoms connected thereto, R 10 , R 11 , H, C 3 -C 6 cycloalkyl groups, or R 10 , R 11 are C together with the C atoms connected to them. 3 -C 6 It forms a cycloalkyl group.

[0091] In some embodiments, R 8 is selected from a hydroxy group, a halogen, or CN.

[0092] In some embodiments, R 8 is selected from hydroxy groups.

[0093] In some embodiments, X 2 is selected from CH.

[0094] In some embodiments, R 10 , R 11 are each selected from H.

[0095] It should be understood that, unless inconsistent, the above embodiments may be arbitrarily combined to form a technical solution that includes the features of the combined embodiments. Such combined technical solutions are within the scope of the present invention. In some embodiments, the compound shown in formula (I) or formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, includes the following compounds, or a stereoisomer or a pharma-ceutically acceptable salt thereof: [ka] [ka] [ka] [ka] [ka]

[0096] The present disclosure further provides a pharmaceutical composition, which comprises a compound according to Formula (I) or Formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0097] Further, the present disclosure provides the use of a compound of formula (I) or formula (II), or a stereoisomer or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a topoisomerase I-associated disease.

[0098] Further, the present disclosure provides the use of a compound represented by formula (I) or formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prophylaxis or treatment of a topoisomerase I-associated disease.

[0099] Further, the present disclosure provides a compound of formula (I) or formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a topoisomerase I-associated disease.

[0100] The present disclosure further provides a method of treating a topoisomerase I associated disease, the method comprising administering to a patient a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a stereoisomer or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a pharmaceutical formulation comprising a compound of Formula (I) or Formula (II), or a stereoisomer or pharma- ceutically acceptable salt thereof, as described herein.

[0101] In some embodiments, the topoisomerase I associated disease includes, but is not limited to, cancer.

[0102] Further, the present disclosure provides the use of a compound represented by formula (I) or formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of an antitumor medicament.

[0103] Furthermore, the present disclosure provides the use of a compound represented by formula (I) or formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof in anti-tumor.

[0104] Further, the present disclosure provides a compound of formula (I) or formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for antitumor.

[0105] The present disclosure further provides a method of treating a tumor, the method comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, or a pharmaceutical formulation comprising a compound of formula (I) or formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof, as described in the present disclosure. Definitions and Explanations of Terms

[0106] Unless otherwise specified, the terms used in this disclosure have the following meanings, and the group and term definitions described in this disclosure include their exemplary definitions, exemplary definitions, preferred definitions, definitions described in the tables, definitions of specific compounds in the examples, etc., and may be combined with each other in any combination. Unless otherwise defined, certain terms should not be considered as indefinite or unclear, but should be interpreted according to the general meaning in the art. When a trade name is present in this specification, it is intended to refer to the corresponding product or its active ingredient.

[0107] In this specification, [ka] represents the linking site.

[0108] The method of illustrating racemic or enantiopure compounds herein is taken from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise noted, wedge bonds and hash wedge bonds are [ka] The absolute configuration of the stereocenter is shown in the figure, and the black solid and dotted bonds are [ka] indicates the relative configuration of stereocenters (e.g., cis-trans configuration in alicyclic compounds).

[0109] The term "tautomer" refers to a functional isomer produced by the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit the phenomenon of tautomerization. Tautomerized compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium form, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties correspond to the mixture of compounds. The position of the equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone form predominates, while in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

[0110] The term "stereoisomer" refers to isomers resulting from differences in the way atoms are arranged in space in molecules, and includes cis-trans isomers, enantiomers and non-enantiomers.

[0111] The compounds of the present disclosure may have asymmetric atoms, such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, so that the compounds of the present disclosure may have specific geometric or stereoisomeric forms.Specific geometric or stereoisomeric forms may include cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, non-enantiomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as mixtures enriched from enantiomers or diastereomers, and all of these isomers and mixtures thereof are within the scope of the definition of the compounds of the present disclosure.Substituents such as alkyl groups may have other asymmetric carbon atoms, sulfur atoms, nitrogen atoms, or phosphorus atoms, and all of these isomers and mixtures thereof involved in all of the substituents are also within the scope of the definition of the compounds of the present disclosure. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms, and optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0112] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, provided that the valence of the particular atom is normal and the compound after substitution is stable. When the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced; oxo does not occur in aryl groups.

[0113] The term "optionally" or "optionally" means that the described event or circumstance may or may not occur, and the statement includes the occurrence and non-occurrence of said event or circumstance. For example, an ethyl group being "optionally" substituted with a halogen means that the ethyl group is unsubstituted (CH 2 CH 3 ), monosubstituted (e.g., CH 2 CH 2 F, C.H. 2 CH 2 Cl), polysubstituted (e.g., CHFCH 2 F, C.H. 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 ) or exact replacement (CF 2 CF 3 , C.F. 2 CCl 3 , CCl 2 CCl 3 As will be appreciated by those of skill in the art, any group that contains one or more substituents will not introduce any substitutions or substitution patterns that are spatially impossible and / or synthetically impossible.

[0114] Any variable (e.g., R a , R b If any of the following occurs more than once in the composition or structure of a compound, its definition is independent in each occurrence. For example, a group may have two R b If replaced by, each R b Each has independent options.

[0115] The number of linking groups is 0, for example, -(CH2 ) 0 In the case of -, it indicates that the linking group is a bond.

[0116] When one of the variables is selected from a chemical bond or is absent, it indicates that the two groups linked to it are directly linked, e.g., in ALZ, when L represents a bond, the structure is in fact AZ.

[0117] The linking groups involved in this specification may have any linking direction unless otherwise specified. For example, the structural unit [ka] L in 1 "C 1 -C 3 When L is selected from alkylene-O, 1 The left-to-right reading order is the same as for rings Q and R. 1 Linking these together, we have created "Kan QC 1 -C 3 Alkylene-OR 1 " or in the reverse left-to-right reading order, rings Q and R 1 Linking these together, we create "Kan QOC 1 -C 3 Alkylene-R 1 " may be constructed.

[0118] In this specification, C m -C n means that the group has an integer number of carbon atoms in the range of m to n. For example, "C 1 -C 10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

[0119] The term "alkyl group" refers to a group having the general formula C n H 2n+1"C" refers to a hydrocarbon group having the formula: 1 -C 6 The term "alkyl group" should be understood to represent a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Said alkyl group includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl. 1 -C 3 The term "alkyl group" refers to an alkyl group containing from 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl.

[0120] As described herein, 1 -C 6 "Alkyl group" is "C 1 -C 3 It may further include an alkyl group.

[0121] The term "alkynyl group" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms with at least one triple bond. For example, "C 2 -C 6 The term "alkynyl group" is to be understood as a straight or branched chain hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5 or 6 carbon atoms. 2 -C 6 Examples of "alkynyl groups" include ethynyl groups (-C≡CH), propa-1-alkynyl groups (1-propynyl groups, -C≡CCH 3), propa-2-alkynyl group (-CH 2 C≡CH), buta-1-alkynyl, buta-2-alkynyl or buta-3-alkynyl. 2 -C 6 Alkynyl group" is "C 2 -C 3 alkynyl groups, and "C 2 -C 3 Examples of "alkynyl groups" include ethynyl groups (-C≡CH), propa-1-alkynyl groups (1-propynyl groups, -C≡CCH 3 ), propa-2-alkynyl group (-CH 2 C≡CH).

[0122] The term "cycloalkyl group" refers to a carbocyclic group that is fully saturated and exists as a monocyclic, fused, bridged, or spirocyclic ring. 3 -C 6 The term "cycloalkyl group" refers to a cycloalkyl group having 3, 4, 5 or 6 ring carbon atoms, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0123] The term "cycloalkenyl group" refers to a non-aromatic carbocyclic group that is incompletely saturated, has at least one carbon-carbon double bond, and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise specified, the carbocyclic ring is typically a 5- to 8-membered ring. 5 -C 7 The term "cycloalkenyl group" refers to a cycloalkenyl group having 5, 6 or 7 ring atoms, and specific examples include, but are not limited to, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl group, a cycloheptenyl group, or a cycloheptadienyl group. 5 -C 7 The term "cycloalkenyl group" means a group 5 -C 6 The scope of the present invention may include "cycloalkenyl group" and "cycloalkenyl group". 5 -C 6The term "cycloalkenyl group" refers to a cycloalkenyl group having 5 or 6 ring atoms, and specific examples include, but are not limited to, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl group, and the like.

[0124] The term "heterocyclic group" refers to a fully saturated or partially saturated monocyclic, fused, spiro, or bridged ring group whose ring atoms contain 1 to 5 (e.g., 1 to 3 or 1 to 2) heteroatoms or heteroatomic groups (i.e., groups containing heteroatoms), where the "heteroatoms or heteroatomic groups" are nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O), 2 -, -S(=O)-, -P(=O) 2 Examples include, but are not limited to, -, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "4- to 7-membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6 or 7 ring atoms, the ring atoms containing 1 to 3 heteroatoms or heteroatom groups independently selected from the above descriptions. Here, examples of 4-membered heterocyclic groups include, but are not limited to, azetidinyl and oxetanyl groups; examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazole, or 2,5-dihydro-1H-pyrrolyl groups; examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[1,3,4]thiadiazinyl groups; and examples of 7-membered heterocyclic groups include, but are not limited to, diazacycloheptyl groups. The term "4- to 7-membered heterocyclic group" may include in scope "4- to 7-membered heterocycloalkyl group", "5- to 6-membered heterocyclic group", "5- to 6-membered heterocycloalkyl group", and the like.

[0125] The term "5- to 6-membered heteroaryl group" refers to an aromatic cyclic group having 5 or 6 ring atoms, which includes 1 to 3, e.g., 1 to 2, heteroatoms independently selected from N, O and S. Examples of 5- to 6-membered heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazole, pyridyl, pyridazinyl, pyrimidinyl, pyridinyl or triazinyl groups and the like.

[0126] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0127] The term "therapeutically effective amount" is intended to mean a dose of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal being treated, but may generally be determined by one of ordinary skill in the art based on his or her own knowledge and the contents of this disclosure.

[0128] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing a disease or disease state from appearing in an individual (e.g., a mammal), particularly where such an individual (e.g., a mammal) is susceptible to the disease state but has not been diagnosed as suffering from the disease state.

[0129] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable risk / benefit ratio.

[0130] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, and includes salts formed between a compound and an inorganic or organic acid, and salts formed between a compound and an inorganic or organic base.

[0131] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with a pharma- ceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.

[0132] The term "pharmaceutical acceptable excipient" refers to an excipient that has no obvious irritating effect on an organism and does not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0133] The term "patient" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian genus: humans, non-human primates (e.g., chimpanzees and other apes and monkeys), farm animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, laboratory animals including rodents, e.g., rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions herein, the mammal is a human. The terms "patient" and "individual" may be used interchangeably.

[0134] The terms "comprise" or "comprise" and their English variants, such as comprises or comprising, are to be understood in an open and non-exclusive sense, i.e. "including but not limited to".

[0135] The present disclosure further includes isotopically labeled compounds of the present disclosure that are the same as those described herein, but in which one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be attached to the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0136] Compounds of the present disclosure that are labeled with several isotopes (e.g., 3 H and 14 C) may be used for compound and / or substrate tissue distribution analysis. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, e.g. 15 O. 13 N, 11 C and 18F can be used in positron emission tomography (PET) studies to measure substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by the following schemes and / or procedures similar to those disclosed in the Examples, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0137] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharma- ceutically acceptable excipients and may be formulated as solid, semi-solid, liquid or gas preparations, such as, for example, tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injectables, inhalants, gels, microspheres, aerosols, and the like.

[0138] Typical routes of administration of the compounds of the present disclosure, or a stereoisomer or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0139] The pharmaceutical compositions of the present disclosure may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing and the like.

[0140] In some embodiments, the pharmaceutical composition is in oral form.For oral administration, the pharmaceutical composition can be formulated by mixing active compound with pharma- ceutically acceptable excipients well known in the art.These excipients can make the compound of the present disclosure into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0141] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the mixture obtained, adding other suitable excipients if necessary, and processing the mixture into granules to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, flow agents, sweeteners or flavoring agents, etc.

[0142] The pharmaceutical compositions are also suitable for parenteral administration, e.g., as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0143] In all administration methods of the compounds of general formula I described herein, the daily dosage, either alone or in the form of individual doses, is 0.01 to 200 mg / kg body weight, preferably 0.05 to 50 mg / kg body weight, more preferably 0.1 to 30 mg / kg body weight. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0144] The scheme of the present disclosure will be described in detail below by examples, but does not mean any adverse limitation to the present disclosure. In this specification, the scheme of the present disclosure is described in detail, and the mode for carrying out the invention is also disclosed, and it will be obvious to those skilled in the art that various modifications and improvements to the mode for carrying out the invention of the present disclosure can be made without departing from the spirit and scope of the present invention. All reagents used in this disclosure are commercially available and can be used without the need for further purification.

[0145] Unless otherwise specified, the percentages given for solvent mixtures are volumetric mixture ratios.

[0146] Unless otherwise stated, % refers to wt%.

[0147] Compounds are named manually or with ChemDraw® software; commercially available compounds use the supplier catalog name.

[0148] The structures of compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10 -6 The NMR assay solvents were deuterated dimethylsulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS), and the IC 50 " stands for 50% inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0149] The following eluents or mobile phases can be formed into mixed eluents or mobile phases consisting of two or more solvents, and the ratio is the volume ratio of each solvent, for example, "0-10% methanol / dichloromethane" indicates that in the gradient elution process, the volumetric dosage ratio of methanol and dichloromethane in the mixed eluent is 0:100-10:100.

[0150] Example 1, (S)-N-((8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-11H-[1,4]dioxacyclo[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (Compound 1) [ka]

[0151] Step 1: Synthesis of 1-(7-amino-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-2-chloroethan-1-one (Intermediate 1-2) The reactant 1-1 (500mg, 3.31mmol) was dissolved in 1,2-dichloroethane (3mL), the reaction solution was cooled to 0℃, boron trichloride (1M, 2.65mL) and aluminum trichloride (573.36mg, 4.30mmol) were added thereto, and under the protection of nitrogen gas, chloroacetonitrile (299.67mg, 3.97mmol) was added to the reaction solution at 0℃, and the reaction solution was stirred at 90℃ for 16h under the protection of nitrogen gas. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ice water (30mL) and 1N HCl (10mL) were added in sequence, and the mixture was stirred for 30min. Dichloromethane (30mL*3) was added to the reaction solution and extracted three times, and the organic phases were combined and washed with saturated saline (30mL), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. Concentration to dryness in vacuo and preparative thin layer chromatography (silica, petroleum ether:ethyl acetate=9:1) afforded the title compound (210 mg) from the crude material.

[0152] MS m / z (ESI): 228.0 [M+H] + .

[0153] Step 2: Synthesis of (S)-15-(chloromethyl)-8-ethyl-8-hydroxy-2,3,11,14-tetrahydro-12H-[1,4]dioxacyclo[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (Intermediate 1-4)

[0154] Intermediate 1-2 (100 mg, 439.28 μmol) and intermediate 1-3 (115.64 mg, 439.28 μmol) were dissolved in anhydrous toluene (3 mL), and pyridinium p-toluenesulfonate (PPTS, 22.08 mg, 87.86 μmol) was added thereto, and the reaction solution was stirred at 100°C for 16 h under the protection of nitrogen gas. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, the reaction solution was filtered, and the filter cake was washed with ethanol (5 mL * 2) to obtain the title compound crude product (130 mg).

[0155] MS m / z (ESI): 455.1 [M+H]+ .

[0156] Step 3: Synthesis of (S)-15-(azidomethyl)-8-ethyl-8-hydroxy-2,3,11,14-tetrahydro-12H-[1,4]dioxacyclo[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (Intermediate 1-5)

[0157] Intermediate 1-4 (120 mg, 263.82 μmol) was dissolved in dimethyl sulfoxide (1 mL), sodium azide (25.73 mg, 395.73 μmol) was added thereto, and the reaction solution was stirred at 25° C. for 3 h under nitrogen gas protection. The completion of the reaction was detected by LC-MS. Ice water (2 mL) was added thereto, and the mixture was stirred for 0.5 h and filtered to obtain the title compound (90 mg) as a crude product.

[0158] MS m / z (ESI): 462.1 [M+H] + .

[0159] Step 4: Synthesis of (S)-15-(aminomethyl)-8-ethyl-8-hydroxy-2,3,11,14-tetrahydro-12H-[1,4]dioxacyclo[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (Intermediate 1-6)

[0160] Intermediate 1-5 (90 mg, 195.05 μmol) was dissolved in anhydrous toluene (1 mL), triethyl phosphite (81.02 mg, 487.62 μmol) was added thereto, and the reaction solution was stirred at 100° C. for 3 h under nitrogen gas protection. The reaction solution was cooled to 25° C., a hydrochloric acid methanol solution (0.5 mL) was added thereto, and the reaction solution was stirred at 85° C. for 16 h under nitrogen gas protection. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, it was filtered to obtain the title compound (18 mg).

[0161] MS m / z (ESI): 436.1 [M+H] + .

[0162] Step 5: Synthesis of (S)-N-((8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-11H-[1,4]dioxacyclo[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (Compound 1)

[0163] Intermediate 1-6 (18 mg, 41.34 μmol) and 2-hydroxyacetic acid (15.72 mg, 206.69 μmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (23.58 mg, 62.01 μmol) and N,N-diisopropylethylamine (DIEA) (16.03 mg, 124.02 μmol) were added thereto, and the reaction solution was stirred at 25° C. for 3 h. The completion of the reaction was detected by LC-MS. The reaction solution was filtered and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 25 mm, length 100 mm, eluent of decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient rate 10% to 30%, elution time 12 min) to obtain the title compound (7 mg).

[0164] MS m / z (ESI): 494.1 [M+H] + .

[0165] 1 H NMR (400MHz, DMSO-d 6) δ = 8.69 (t, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.56 (s, 1H), 7.26 (s, 1H), 6.49 (s, 1H), 5.57 (t, J = 5.7 Hz, 1H), 5.46 (s, 2H), 5.43 (s, 2H), 4.74 (d, J = 6.0 Hz, 2H), 4.44 (s, 4H), 3.82 (d, J = 5.6 Hz, 2H), 1.94-1.80 (m, 2H), 0.88 (m, 3H).

[0166] Example 2, (S)-11-(aminomethyl)-9-chloro-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Compound 2) [ka]

[0167] Step 1: Synthesis of 1-(2-amino-5-chloro-4-fluorophenyl)-2-chloroethan-1-one (Intermediate 2-2) Boron trichloride (1M, 13.74mL) was dissolved in 1,2-dichloroethane (24mL), the reaction solution was cooled to 0℃, reactant 2-1 (2g, 13.74mmol) and chloroacetonitrile (1.56g, 20.61mmol) were added thereto, the reaction was stirred at 0℃ for 10min, and aluminum trichloride (2.38g, 17.86mmol) was added thereto. Then, under the protection of nitrogen gas, the reaction solution was warmed to 25℃ and stirred for 10min. Under the protection of nitrogen gas, the reaction solution was stirred at 90℃ for 18h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ice water (50mL) and 5% HCl (10mL) were added slowly in sequence, and the mixture was stirred at 25℃ for 30min, then dichloromethane (50mL) was added, the organic phase was washed with water (2mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Concentrated to dryness under reduced pressure, the crude material was purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5μm silica, diameter 25mm, length 100mm, eluent with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient rate 40%-60%, elution time 10 min) to obtain the title compound (320mg).

[0168] MS m / z (ESI): 222.0 [M+H] + .

[0169] Step 2: Synthesis of (S)-9-chloro-11-(chloromethyl)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate 2-3)

[0170] Intermediate 2-2 (220 mg, 990.80 μmol) and intermediate 1-3 (273.86 mg, 1.04 mmol) were dissolved in toluene (2 mL), and pyridinium p-toluenesulfonate (24.90 mg, 99.08 μmol) was added thereto. The reaction solution was stirred at 100°C for 18 h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ethanol (1 mL) was added, and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL*2) to obtain the title compound crude product (270 mg).

[0171] MS m / z (ESI): 449.0 [M+H] + .

[0172] Step 3: Synthesis of (S)-11-(aminomethyl)-9-chloro-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (compound 2)

[0173] Intermediate 2-3 (50 mg, 111.29 μmol) was dissolved in ethanol (1 mL) and methenamine (23.40 mg, 166.94 μmol) was added thereto. The reaction solution was stirred at 90° C. for 1.5 h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to dryness and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 25 mm, length 100 mm, eluent with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and methanol (methanol gradient ratio 0% to 30%, elution time 12 min) to obtain the title compound (22 mg).

[0174] MS m / z (ESI): 430.1 [M+H] + .

[0175] 1 H NMR (400MHz, DMSO-d 6) δ = 8.71(d, J = 8.0 Hz, 1H), 8.23 ​​(d, J = 10.3 Hz, 1H), 8.14 (s, 0.3H, HCOOH), 7.36 (s, 1H), 6.57 (s, 1H), 5.52 (s, 2H), 5.46 (s, 2H), 4.55 (s, 2H), 1.93-1.84 (m, 2H), 0.90-0.85 (m, 3H).

[0176] Example 3, (S)-N-((9-chloro-4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (compound 3) [ka]

[0177] Compound 2 (22 mg, 51.18 μmol) and 2-hydroxyacetic acid (19.46 mg, 255.92 μmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL), HATU (29.19 mg, 76.77 μmol) and N,N-diisopropylethylamine (19.84 mg, 153.55 μmol) were added thereto, and the reaction solution was stirred at 25 °C for 1.5 h. The end of the reaction was detected by LC-MS. The reaction solution was filtered and concentrated under reduced pressure to dryness, and the crude product was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 25 mm, length 100 mm, elution with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 10% to 40%, elution time 12 min) to obtain the title compound (2.20 mg).

[0178] MS m / z (ESI): 488.1 [M+H] + .

[0179] 1 H NMR (400MHz, DMSO-d6 ) δ = 8.90-8.85 (m, 2H), 8.20 (d, J = 10.3 Hz, 1H), 7.35 (s, 1H), 6.55 (s, 1H), 5.60 (t, J = 5.7 Hz, 1H), 5.56 (s, 2H), 5.45 (s, 2H), 4.83 (d, J = 6.0 Hz, 2H), 3.83 (d, J = 5.8 Hz, 2H), 1.93-1.81(m, 2H), 0.88 (m, 3H).

[0180] Example 4, (S)-11-(aminomethyl)-9-bromo-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (compound 4) [ka]

[0181] Step 1: Synthesis of 1-(2-amino-5-bromo-4-fluorophenyl)-2-chloroethan-1-one (Intermediate 4-2) Boron trichloride (1M, 10.53mL) was dissolved in 1,2-dichloroethane (24mL), the reaction solution was cooled to 0℃, intermediate 4-1 (2g, 10.53mmol) and chloroacetonitrile (1.19g, 15.79mmol) were added thereto, the reaction was stirred at 0℃ for 10min, and aluminum trichloride (1.82g, 13.68mmol) was added thereto. Under the protection of nitrogen gas, the reaction solution was stirred at 25℃ for 10min. Then, the temperature was raised to 90℃ and stirred for 18h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ice water (50mL) and 5% HCl (10mL) were added slowly in sequence, and the mixture was stirred at 25℃ for 30min, then dichloromethane (50mL) was added, the organic phase was washed with water (2mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Purification by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 25 mm, length 100 mm, eluting with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient percentage 39% to 49%, elution time 12 min) gave the title compound (380 mg).

[0182] MS m / z (ESI): 265.9 [M+H] + .

[0183] Step 2: Synthesis of (S)-9-bromo-11-(chloromethyl)-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate 4-3)

[0184] Intermediate 4-2 (200 mg, 750.48 μmol) and intermediate 1-3 (207.44 mg, 788.01 μmol) were dissolved in anhydrous toluene (4 mL), and pyridinium p-toluenesulfonate (22.63 mg, 90.06 μmol) was added thereto. The reaction solution was stirred at 100°C for 18 h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ethanol (1 mL) was added, and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL * 2) to obtain the crude title compound (200 mg).

[0185] MS m / z (ESI): 493.0 [M+H] + .

[0186] Step 3: Synthesis of (S)-11-(aminomethyl)-9-bromo-4-ethyl-8-fluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (compound 4)

[0187] Intermediate 4-3 (200 mg, 405.10 μmol) was dissolved in ethanol (4 mL) and methenamine (113.58 mg, 810.19 μmol) was added thereto. The reaction solution was stirred at 90° C. for 1.5 h. The end of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to dryness, and the crude product was purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient rate 6% to 26%, elution time 12 min) to obtain the title compound (30 mg).

[0188] MS m / z (ESI): 476.0 [M+H] + .

[0189] 1 H NMR (400MHz, DMSO-d 6) δ = 8.83 (d, J = 7.4 Hz, 1H), 8.18 (d, J = 9.8 Hz, 1H), 8.14 (s, 0.4H, HCOOH), 7.36 (s, 1H), 6.57 (s, 1H), 5.52 (s, 2H), 5.46 (s, 2H), 4.53 (s, 2H), 1.92-1.85 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0190] Example 5, (S)-N-((9-bromo-4-ethyl-8-fluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (Compound 5) [ka]

[0191] Compound 4 (15 mg, 26.88 μmol) and 2-hydroxyacetic acid (10.22 mg, 134.41 μmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL), HATU (15.33 mg, 40.32 μmol) and N,N-diisopropylethylamine (10.42 mg, 80.65 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. The end of the reaction was detected by LC-MS. The reaction solution was filtered and concentrated under reduced pressure to dryness, and the crude product was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, elution with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 6% to 36%, elution time 12 min) to obtain the title compound (2.09 mg).

[0192] MS m / z (ESI): 532.0 [M+H] + .

[0193] 1 H NMR (400MHz, DMSO-d 6) δ = 9.00 (d, J = 7.5 Hz, 1H), 8.86 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 9.8 Hz, 1H), 7.35 (s, 1H), 6.54 (s, 1H), 5.60 (t, J = 5.7 Hz, 1H), 5.56 (s, 2H), 5.45 (s, 2H), 4.83 (d, J = 5.8 Hz, 2H), 3.83 (d, J = 5.9 Hz, 2H), 1.94-1.82 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H).

[0194] Example 6, (S)-N-((8-chloro-4-ethyl-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (Compound 6) [ka]

[0195] Step 1: Synthesis of 1-(2-amino-4-chloro-5-methylphenyl)-2-chloroethan-1-one (Intermediate 6-2) Boron trichloride (1M, 2.82mL) was dissolved in 1,2-dichloroethane (8mL), the reaction solution was cooled to 0℃, reactant 6-1 (0.5g, 3.53mmol) and chloroacetonitrile (319.91g, 4.24mmol) were added thereto, the reaction was stirred at 0℃ for 10min, and aluminum trichloride (612.09mg, 4.59mmol) was added thereto. Under the protection of nitrogen gas, the reaction solution was stirred at 25℃ for 10min. Then, the reaction solution was heated to 90℃ and stirred for 18h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ice water (25mL) and 5% HCl (5mL) were added slowly in sequence, and the mixture was stirred at 25℃ for 30min, then dichloromethane (20mL) was added, the organic phase was washed with water (20mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Preparative thin layer chromatography (silica, petroleum ether:ethyl acetate=9:1) afforded the title compound (500 mg).

[0196] MS m / z (ESI): 218.0 [M+H] +

[0197] Step 2: Synthesis of (S)-8-chloro-11-(chloromethyl)-4-ethyl-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate 6-3)

[0198] Intermediate 6-2 (250 mg, 1.15 mmol) and intermediate 1-3 (316.87 mg, 1.20 mmol) were dissolved in toluene (5 mL), and pyridinium p-toluenesulfonate (34.57 mg, 137.56 μmol) was added thereto. The reaction solution was stirred at 100°C for 18 h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ethanol (1 mL) was added, and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL * 2) to obtain the crude title compound (230 mg).

[0199] MS m / z (ESI): 445.1 [M+H] +.

[0200] Step 3: Synthesis of (S)-11-(aminomethyl)-8-chloro-4-ethyl-4-hydroxy-9-methyl-1,12-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate 6-4)

[0201] Intermediate 6-3 (49.56 mg, 111.29 μmol) was dissolved in ethanol (0.5 mL) and methenamine (23.40 mg, 166.94 μmol) was added thereto. The reaction solution was stirred at 90° C. for 1.5 h. The end of the reaction was detected by LC-MS. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to dryness and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient rate 2% to 32%, elution time 12 min) to obtain the title compound (11.0 mg).

[0202] MS m / z (ESI): 426.2 [M+H] + .

[0203] Step 4: Synthesis of (S)-N-((8-chloro-4-ethyl-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (compound 6)

[0204] Intermediate 6-4 (11 mg, 25.83 μmol) and 2-hydroxyacetic acid (9.82 mg, 129.15 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (14.73 mg, 38.74 μmol) and N,N-diisopropylethylamine (10.01 mg, 77.49 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. The end of the reaction was detected by LC-MS. The reaction solution was filtered and concentrated under reduced pressure to dryness, and the crude product was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, elution with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 10% to 40%, elution time 12 min) to obtain the title compound (3.00 mg).

[0205] MS m / z (ESI): 484.1 [M+H] + .

[0206] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.77 (t, J = 6.1 Hz, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 7.32 (s, 1H), 6.54 (s, 1H), 5.59 (t, J = 5.8 Hz, 1H), 5.52 (s, 2H), 5.44 (s, 2H), 4.85 (d, J = 6.0 Hz, 2H), 3.84 (d, J = 5.6 Hz, 2H), 2.60 (s, 3H), 1.91-1.82 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0207] Example 7, (S)-N-((8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-1H,11H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 7) [ka]

[0208] Step 1: Synthesis of 4,6-dibromo-2,3-dihydro-1H-inden-5-amine (Intermediate 7-2) Intermediate 7-1 (10.0 g) was dissolved in anhydrous acetonitrile, and N-bromosuccinimide (NBS) (27.5 g) was added in portions at 0° C., followed by stirring at room temperature overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 200 mL ethyl acetate and washed with water (100 mL*2). The obtained organic phase was dried over anhydrous sodium sulfate, combined with silica gel, and placed on diatomaceous earth, washed with 500 mL petroleum ether, and the filtrate was concentrated to obtain the title compound (17.0 g).

[0209] MS m / z (ESI): 289.9 [M+H] + .

[0210] Step 2: Synthesis of 4-bromo-2,3-dihydro-1H-inden-5-amine (Intermediate 7-3)

[0211] Intermediate 7-2 (15.0 g) and stannous chloride (15.0 g) were dissolved in 75 mL of acetic acid, and 140 mL of 6N concentrated hydrochloric acid was added and reacted at 90°C for 3 h. The reaction was cooled to room temperature and concentrated to remove acetic acid, and the residue was dissolved in 100 mL of ethyl acetate, adjusted to about pH 8 with saturated aqueous sodium carbonate, filtered, and the organic phase was separated from the filtrate, and the aqueous phase was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (10 g).

[0212] MS m / z (ESI): 212.0 [M+H] + .

[0213] Step 3: Synthesis of N-(4-bromo-2,3-dihydro-1H-inden-5-yl)acetamide (Intermediate 7-4)

[0214] Intermediate 7-3 (10.0 g) was dissolved in 100 mL of anhydrous dichloromethane, triethylamine (10.6 g) was added, acetyl chloride (5.5 g) was slowly added dropwise at 0°C, and the reaction system was stirred at room temperature overnight. The reaction solution was washed with water (100 mL * 2), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90: 10) to obtain the title compound (7.1 g).

[0215] MS m / z (ESI): 254.0 [M+H] + .

[0216] Step 4: Synthesis of N-(4-acetyl-2,3-dihydro-1H-inden-5-yl)acetamide (Intermediate 7-5)

[0217] Under the protection of nitrogen gas, intermediate 7-4 (6.7 g) and tributyl-(2-ethoxyvinyl)tin (10.4 g) were dissolved in 100 mL anhydrous 1,4-dioxane, and di(triphenylphosphine)palladium dichloride (1.8 g) was added, and the reaction system was stirred at 100 ° C overnight. After the reaction solution was cooled to room temperature, 30 mL of 3N hydrochloric acid was added and stirred at room temperature for 1 h. The reaction solution was filtered through diatomaceous earth, and the obtained filtrate was diluted with 100 mL of ethyl acetate and washed with water (100 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 85: 15) to obtain the title compound (4.7 g).

[0218] MS m / z (ESI): 218.1 [M+H] + .

[0219] Step 5: Synthesis of N-(4-(2-bromoacetyl)-2,3-dihydro-1H-inden-5-yl)acetamide (Intermediate 7-6)

[0220] Intermediate 7-5 (4.7 g) was dissolved in 50 mL acetic acid, 7.3 g of 33% hydrobromic acid-acetic acid solution was added, bromine (2.85 g) was slowly added dropwise at room temperature, and the mixture was stirred and reacted at room temperature for 3 h. After the reaction was completed, the reaction solution was poured into ice water, stirred until a large amount of solid precipitated, filtered, the filter cake was washed with petroleum ether, and the obtained solid was dried to obtain the title compound (5.0 g).

[0221] MS m / z (ESI): 296.0 [M+H] + .

[0222] Step 6: Synthesis of 1-(5-amino-2,3-dihydro-1H-inden-4-yl)-2-chloroethyl-1-one (Intermediate 7-7)

[0223] Intermediate 7-6 (5.0 g) was dissolved in 30 mL ethanol, 35 mL of 6N concentrated hydrochloric acid was added, and the reaction was stirred at 80° C. for 2 h. The reaction was cooled to room temperature and concentrated under reduced pressure to remove the solvent, the residue was dissolved in 100 mL of dichloromethane, the pH was adjusted to about 7 with saturated aqueous sodium bicarbonate, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=75:25) to give the title compound (840 mg).

[0224] MS m / z (ESI): 210.0 [M+H] + .

[0225] Step 7: Synthesis of (S)-15-(chloromethyl)-8-ethyl-8-hydroxy-1,2,3,8,11,14-hexahydro-9H,12H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12-dione (Intermediate 7-8)

[0226] Intermediate 7-7 (100 mg) and intermediate 1-3 (125.55 mg) were dissolved in toluene (5 mL), and pyridinium p-toluenesulfonate (5.99 mg) was added thereto. The reaction was stirred at 90°C for 18 h. After the reaction was cooled to room temperature, ethanol (1 mL) was added, and the reaction was stirred at 25°C for 0.5 h. The reaction was filtered, and the filter cake was washed with petroleum ether (2 mL*2) to give the title compound (180 mg).

[0227] MS m / z (ESI): 437.0 [M+H] + .

[0228] Step 8: Synthesis of (S)-15-(aminomethyl)-8-ethyl-8-hydroxy-1,2,3,8,11,14-hexahydro-9H,12H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12-dione (Intermediate 7-9)

[0229] Intermediate 7-8 (50 mg) was dissolved in a mixed solution of methanol (1 mL) and N,N-dimethylformamide (1 mL), and methenamine (483.13 mg) was added thereto. The reaction solution was stirred at 50°C for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated hydrochloric acid (0.5 mL) was added, and the mixture was stirred for 0.5 h, and then concentrated under reduced pressure to dryness. The residue was purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile, acetonitrile gradient rate 20% to 40%, elution time 12 min) to obtain the title compound (22.0 mg).

[0230] MS m / z (ESI): 418.2 [M+H] + .

[0231] Step 9: Synthesis of (S)-N-((8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-1H,11H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 7)

[0232] Intermediate 7-9 (15 mg) and hydroxyacetic acid (10.93 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (27.32 mg) and diisopropylethylamine (4.64 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 30% to 50%, elution time 12 min) to obtain the title compound (9.0 mg).

[0233] MS m / z (ESI): 476.2[M+H] + .

[0234] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.28 (t, J = 5.1 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.30 (s, 1H), 6.53 (s, 1H), 5.49-5.45 (m, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 4.97 (d, J = 5.0 Hz, 2H), 3.88 (d, J = 5.5 Hz, 2H), 3.57 (t, J = 7.2 Hz, 2H), 3.09 (t, J = 7.4 Hz, 2H), 2.23-2.15 (m, 2H), 1.95-1.80 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0235] Example 8, (S)-N-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)-2-hydroxyacetamide (Compound 8) [ka]

[0236] Step 1: Synthesis of (S)-10-((1,3-dioxoisoindolin-2-yl)methyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate 8-3)

[0237] Reactant 8-1 (200 mg, 548.92 μmol) was dissolved in concentrated sulfuric acid (2 mL), and the reaction solution was cooled to 0°C. Reactant 8-2 (116.69 mg, 658.71 μmol) was slowly added thereto, and the reaction solution was stirred at 0°C for 0.5 h under the protection of nitrogen gas. After 0.5 h, the reaction solution was warmed to 25°C under the protection of nitrogen gas and stirred for 5 h. The completion of the reaction was detected by LC-MS. Ice water (10 mL) and dichloromethane (25 mL) were added successively, and the organic phase was washed with water (20 mL * 2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. It was concentrated under reduced pressure to dryness, and the title compound (280 mg) was obtained from the crude product by preparative thin layer chromatography (silica, dichloromethane:methanol = 10:1).

[0238] MS m / z (ESI): 524.3 [M+H] + .

[0239] Step 2: Synthesis of (S)-10-(aminomethyl)-4-ethyl-4,9-dihydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate 8-4)

[0240] Intermediate 8-3 (240 mg, 458.46 μmol) was dissolved in concentrated hydrochloric acid (3 mL), and the reaction solution was stirred at 90 °C for 16 h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ice water (5 mL) was added, and ammonia water was added dropwise to adjust the pH to 8-9. The reaction solution was filtered, and the filter cake was concentrated to dryness to obtain crude intermediate 8-4 (150 mg).

[0241] MS m / z (ESI): 394.1 [M+H] +

[0242] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.75 (s, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.51(d, J = 9.1 Hz, 1H), 7.27 (s, 1H), 5.43 (s, 2H), 5.26 (s, 2H), 4.44 (s, 2H), 1.92-1.82 (m, 2H), 0.92-0.83 (m, 3H).

[0243] Step 3: Synthesis of (S)-N-((4-ethyl-4,9-dihydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl)methyl)-2-hydroxyacetamide (compound 8)

[0244] Intermediate 8-4 (80 mg, 203.36 μmol) and hydroxyacetic acid (30.94 mg, 406.72 μmol) were dissolved in N,N-dimethylformamide (2 mL), HATU (115.99 mg, 305.04 μmol) and N,N-diisopropylethylamine (78.85 mg, 610.08 μmol) were added thereto, and the reaction solution was stirred at 25 °C for 1.5 h. The end of the reaction was detected by LC-MS. The reaction solution was filtered and concentrated under reduced pressure to dryness, and the crude product was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 25 mm, length 100 mm, elution with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient rate 11% to 41%, elution time 12 min) to obtain the title compound (46 mg).

[0245] MS m / z (ESI): 452.1 [M+H] + .

[0246] 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.91(s, 1H), 8.92 (s, 1H), 8.49 (t, J = 5.8 Hz, 1H), 8.04 (d, J = 9.3 Hz, 1H), 7.51(d, J = 9.1 Hz, 1H), 7.28 (s, 1H), 6.51(s, 1H), 5.60 (t, J = 5.8 Hz, 1H), 5.42 (s, 2H), 5.28 (s, 2H), 4.73 (d, J = 5.8 Hz, 2H), 3.88 (d, J = 5.8 Hz, 2H), 1.95-1.81(m, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0247] Example 9, (S)-N-((4-ethyl-8-fluoro-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-1-hydroxycyclopropane-1-carboxamide (compound 9) [ka]

[0248] Intermediate 9-1 (6.00 mg, 14.66 μmol, can be synthesized by the method reported in patent document WO2020219287) and intermediate 9-2 (4.49 mg, 43.97 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (8.36 mg, 21.98 μmol) and N,N-diisopropylethylamine (5.68 mg, 43.97 μmol) were added thereto, and the reaction solution was stirred at 25 ° C. for 1 h. The completion of the reaction was detected by LC-MS. The reaction solution was filtered and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 25 mm, length 100 mm, eluent of decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient rate 6% to 36%, elution time 12 min) to obtain the title compound (3.00 mg).

[0249] MS m / z (ESI): 494.2 [M+H] + .

[0250] 1 H NMR (400MHz, DMSO-d 6) δ = 8.96 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 10.9 Hz, 1H), 7.32 (s, 1H), 6.53 (s, 1H), 6.30 (s, 1H), 5.52 (s, 2H), 5.44 (s, 2H), 4.85 (d, J = 5.9 Hz, 2H), 2.53 (s, 3H), 1.92-1.83 (m, 2H), 1.05-1.00 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H), 0.85-0.81(m, 2H).

[0251] Example 10, (S)-N-((8-chloro-4-ethyl-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-1-hydroxycyclopropane-1-carboxamide (compound 10) [ka]

[0252] Intermediate 6-4 (6.24 mg, 14.66 μmol) and intermediate 9-2 (4.49 mg, 43.97 μmol) were dissolved in N,N-dimethylformamide (1 mL), HATU (8.36 mg, 21.98 μmol) and DIEA (5.68 mg, 43.97 μmol) were added thereto, and the reaction solution was stirred at 25 °C for 1 h. The completion of the reaction was detected by LC-MS. The reaction solution was filtered and concentrated under reduced pressure to dryness. The crude product was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 25 mm, length 100 mm, elution with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient percentage 16% to 46%, elution time 12 min) to obtain the title compound (2.20 mg).

[0253] MS m / z (ESI): 510.1 [M+H] +.

[0254] 1H NMR (400MHz, DMSO-d 6 ) δ = 8.96 (t, J = 5.9 Hz, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.32 (s, 1H), 6.54 (s, 1H), 6.29 (s, 1H), 5.52 (s, 2H), 5.44 (s, 2H), 4.84 (d, J = 6.0 Hz, 2H), 2.59 (s, 3H), 1.94-1.80 (m, 2H), 1.01(d, J = 3.0 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H), 0.83 (d, J = 3.0 Hz, 2H).

[0255] Example 11, N-(((S)-8-chloro-4-ethyl-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (compound 11) [ka]

[0256] Intermediate 6-4 (6.0 mg, 14.09 μmol) and intermediate 11-1 (8.18 mg, 70.45 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), HATU (8.04 mg, 21.13 μmol) and DIEA (5.46 mg, 42.27 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. The end of the reaction was detected by LC-MS. The reaction solution was filtered and concentrated under reduced pressure to dryness, and the crude product was purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, elution with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 16% to 46%, elution time 12 min) to obtain the title compound (3.0 mg).

[0257] MS m / z (ESI): 524.1 [M+H] + .

[0258] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.66 (t, J = 5.9 Hz, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.32 (s, 1H), 6.54 (s, 1H), 5.53 (d, J = 5.0 Hz, 1H), 5.50 (s, 2H), 5.44 (s, 2H), 4.91-4.76 (m, 2H), 3.61-3.55 (m, 1H), 2.59 (s, 3H), 1.94-1.82 (m, 2H), 1.05-0.97 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H), 0.34- 0.31(m, 2H), 0.29-0.20 (m, 2H).

[0259] Example 12, (S)-11-(aminomethyl)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (compound 12) [ka]

[0260] Step 1: Synthesis of 1-(6-amino-3-chloro-2,4-difluorophenyl)-2-chloroethan-1-one (Intermediate 12-2)

[0261] Boron trichloride (1M, 6.11mL) was dissolved in 1,2-dichloroethane (12mL), the reaction solution was cooled to 0℃, reactant 12-1 (1g, 6.11mmol) and chloroacetonitrile (784.73mg, 10.39mmol) were added thereto, the reaction was stirred at 0℃ for 10min, and aluminum trichloride (1.06g, 7.95mmol) was added thereto. Then, under the protection of nitrogen gas, the reaction solution was warmed to 25℃ and stirred for 10min. Under the protection of nitrogen gas, the reaction solution was stirred at 90℃ for 18h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ice water (25mL) and 5% hydrochloric acid (5mL) were added slowly in sequence, and the mixture was stirred at 25℃ for 30min, then dichloromethane (50mL) was added, the organic phase was washed with water (2mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Concentration to dryness in vacuo and purification by preparative thin layer chromatography (silica, petroleum ether:ethyl acetate=9:1) afforded the title compound (340 mg) from the crude material.

[0262] MS m / z (ESI): 240.0 [M+H] + .

[0263] Step 2: Synthesis of (S)-9-chloro-11-(chloromethyl)-4-ethyl-8,10-difluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate 12-3)

[0264] Intermediate 12-2 (0.2 g, 833.22 μmol) and intermediate 1-3 (219.34 mg, 833.22 μmol) were dissolved in toluene (4 mL), and pyridinium p-toluenesulfonate (20.94 mg, 83.32 μmol) was added thereto. The reaction solution was stirred at 100° C. for 18 h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, ethanol (1 mL) was added, and the reaction solution was stirred at 25° C. for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL*2) to obtain the crude title compound (190 mg).

[0265] MS m / z (ESI): 467.1 [M+H] + .

[0266] Step 3: Synthesis of (S)-11-(aminomethyl)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (compound 12)

[0267] Intermediate 12-3 (50 mg, 107.01 μmol) was dissolved in ethanol (1 mL) and methenamine (45.00 mg, 321.03 μmol) was added thereto. The reaction solution was stirred at 80° C. for 1.5 h. The completion of the reaction was detected by LC-MS. After the reaction was cooled to room temperature, it was concentrated under reduced pressure to dryness and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 25 mm, length 100 mm, eluent with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient rate 2% to 32%, elution time 12 min) to obtain the title compound (1.22 mg).

[0268] MS m / z (ESI): 448.0 [M+H] + .

[0269] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.14 (d, J = 9.8 Hz, 1H), 7.36 (s, 1H), 6.57 (s, 1H), 5.55 (s, 2H), 5.46 (s, 2H), 4.35 (d, J = 3.0 Hz, 2H), 1.94-1.83 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0270] Example 13, 2-cyclopropyl-N-(((S)-8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-1H,11H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 13) [ka]

[0271] Step 1: Synthesis of 2-cyclopropyl-N-(((S)-8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-1H,11H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 13)

[0272] Intermediate 7-9 (10 mg) and intermediate 11-1 (8.34 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (13.66 mg) and diisopropylethylamine (3.10 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 34% to 54%, elution time 12 min) to obtain the title compound (0.8 mg).

[0273] MS m / z (ESI): 516.2 [M+H] + .

[0274] 1 H NMR (400MHz, DMSO-d 6) δ = 8.25 (t, J = 5.0 Hz, 1H), 8.01(d, J =8.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.30 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 4.99-4.85 (m, 2H), 3.59 (s, 1H), 3.56 (d, J = 6.3 Hz, 2H), 3.08 (t, J = 7.7 Hz, 2H), 2.23-2.16 (m, 2H), 1.92-1.72 (m, 2H), 1.15-1.01(m, 1H), 0.88(t, J = 7.4 Hz, 3H), 0.46-0.19 (m, 4H).

[0275] Example 14, 2-cyclopropyl-N-(((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 14) [ka]

[0276] Step 1: Synthesis of 1-(6-nitrobenzo[d][1,3]dioxol-5-yl)ethanone (Intermediate 14-2)

[0277] Intermediate 14-1 (10.0 g, 60.92 mmol) was dissolved in nitromethane (100 mL), nitric acid (35.43 g, 365.50 mmol, 65% purity) was slowly added thereto, and the reaction solution was stirred at 25 ° C for 2.5 h. After the reaction was completed, saturated sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH to 7-8, and then dichloromethane (100 mL) was added thereto, and the organic phase was washed with water (50 mL * 2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. The title compound (5 g) was obtained by purification by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1: 2).

[0278] MS m / z (ESI): 210.0 [M+H] + .

[0279] Step 2: Synthesis of 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethanone (Intermediate 14-3)

[0280] Intermediate 14-2 (2.37 g, 11.33 mmol) was dissolved in anhydrous ethanol (25 mL), palladium carbon (0.2 g, 10% purity) was added thereto, and the reaction solution was stirred at 25° C. for 16 h under hydrogen gas protection. After the reaction was completed, the reaction solution was filtered, the filter cake was washed twice with ethyl acetate, and the filtrate was concentrated under reduced pressure to dryness to obtain the title compound (1.6 g).

[0281] MS m / z (ESI): 180.1 [M+H] + .

[0282] Step 3: Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)acetamide (Intermediate 14-4)

[0283] Intermediate 14-3 (1.0 g, 5.58 mmol) was dissolved in dichloromethane (10 mL), the reaction solution was cooled to 0° C., and N,N-diisopropylethylamine (DIEA) (1.08 g, 8.37 mmol) and acetyl chloride (569.55 mg, 7.26 mmol) were added thereto. The reaction solution was stirred at 25° C. for 1.5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness to obtain the title compound (1.23 g).

[0284] MS m / z (ESI): 222.1 [M+H] + .

[0285] Step 4: Synthesis of N-(6-(2-bromoacetyl)benzo[d][1,3]dioxol-5-yl)acetamide (Intermediate 14-5)

[0286] Intermediate 14-4 (1.23 g, 5.00 mmol) was dissolved in acetic acid (12 mL), and a solution of hydrogen bromide in acetic acid (1.84 g, 7.51 mmol, 33% purity) was added thereto, and then liquid bromine (959.69 mg, 6.01 mmol) was slowly added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was poured into ice water and stirred for 10 min. It was filtered, the filter cake was washed twice with water, and concentrated under reduced pressure to dryness, and ethyl acetate (2 mL) and petroleum ether (10 mL) were added to the residue, and the reaction solution was stirred at 25 ° C for 0.5 h. The reaction solution was filtered, and the filter cake was dried to obtain the title compound (500 mg).

[0287] MS m / z (ESI): 300.0 [M+H] + .

[0288] Step 5: Synthesis of 1-(6-aminobenzo[d][1,3]dioxol-5-yl)-2-chloroketone (Intermediate 14-6)

[0289] Intermediate 14-5 (0.2 g, 666.43 μmol) was dissolved in anhydrous ethanol (1 mL) and concentrated hydrochloric acid (1 mL), and the reaction solution was stirred at 60 ° C for 16 h. After the reaction was completed, the reaction was cooled to room temperature, and then ice water (10 mL) and saturated sodium bicarbonate (10 mL) were added slowly in sequence, followed by dichloromethane (50 mL), and the organic phase was washed with water (20 mL * 2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The title compound (160 mg) was obtained by preparative thin layer chromatography (petroleum ether: ethyl acetate = 6: 1).

[0290] MS m / z (ESI): 214.0 [M+H] + .

[0291] Step 6: Synthesis of (S)-14-(bromomethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (Intermediate 14-7)

[0292] Intermediate 14-6 (50 mg, 234.06 μmol) and intermediate 1-3 (61.62 mg, 234.06 μmol) were dissolved in toluene (1 mL), and pyridinium p-toluenesulfonate (5.88 mg, 23.41 μmol) was added thereto. The reaction solution was stirred at 90°C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then ethanol (1 mL) was added and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL * 2) and then dried to obtain the title compound (60 mg).

[0293] MS m / z (ESI): 441.1 [M+H] + .

[0294] Step 7: Synthesis of (S)-14-(aminomethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (Intermediate 14-8)

[0295] Intermediate 14-7 (55.00 mg, 124.76 μmol) was dissolved in ethanol (1 mL), and methenamine (52.47 mg, 374.29 μmol) was added thereto. The reaction solution was stirred at 80° C. for 1.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to dryness, and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, eluent with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and methanol (methanol gradient ratio 0% to 27%, elution time 12 min) to obtain the title compound (10 mg).

[0296] MS m / z (ESI): 422.1 [M+H] + .

[0297] Step 8: Synthesis of 2-cyclopropyl-N-(((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 14)

[0298] Intermediate 14-8 (10.00 mg, 20.17 μmol) and intermediate 11-1 (23.42 mg, 201.71 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (11.50 mg, 30.26 μmol) and N,N-diisopropylethylamine (7.82 mg, 60.51 μmol) were added thereto, and the reaction solution was stirred at 25° C. for 1.5 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 30 mm, length 150 mm, eluent of decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient rate 4% to 44%, elution time 9 minutes) to obtain the title compound (3 mg).

[0299] MS m / z (ESI): 520.1 [M+H] + .

[0300] 1 H NMR (400MHz, DMSO-d 6) δ = 8.61(t, J = 5.8 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.24 (s, 1H), 6.49 (s, 1H), 6.29 (s, 2H), 5.51(d, J = 5.0 Hz, 1H), 5.47 (s, 2H), 5.42 (s, 2H), 4.72 (d, J = 5.5 Hz, 2H), 1.92-1.78 (m, 2H), 0.99 (d, J = 6.3 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H), 0.40-0.29 (m, 2H), 0.29-0.19 (m, 2H). [ka]

[0301] Step 9: Preparation of 2-cyclopropyl-2-hydroxybenzyl acetate (intermediate 14-9-P1 / P2)

[0302] Intermediate 14-9 was resolved to prepare isomers 14-9-P1 and 14-9-P2. Intermediate 14-9 (1.3 g) was taken and separated by supercritical fluid chromatography (DAICEL CHIRALPAK AD column, 10 μm silica, diameter 30 mm, length 250 mm, ethanol (containing 0.1% aqueous ammonia) as eluent) to prepare intermediate 14-9-P1 (600 mg) and intermediate 14-9-P2 (600 mg).

[0303] The two isomers were further analyzed by the following chiral supercritical fluid chromatography conditions.

[0304] [Table 1]

[0305] Intermediate 14-9-P1: Under the chiral supercritical fluid chromatography conditions described above, its retention time is 2.990 minutes;

[0306] 1 H NMR (400MHz, METHANOL-d 4 ) δ 7.43-7.29 (m, 5H), 5.29-5.16 (m, 2H), 3.67 (d, J = 7.6 Hz, 1H), 1.19-1.07 (m, 1H), 0.58-0.38 (m, 4H).

[0307] Intermediate 14-9-P2: Under the chiral supercritical fluid chromatography conditions described above, its retention time is 2.661 minutes.

[0308] 1 H NMR (400MHz, METHANOL-d 4 ) δ 7.46-7.28 (m, 5H), 5.30-5.16 (m, 2H), 3.67 (d, J = 7.6 Hz, 1H), 1.21-1.03 (m, 1H), 0.60-0.36 (m, 4H).

[0309] Step 10: Synthesis of 2-cyclopropyl-2-hydroxyacetic acid (intermediate 14-10-P1 / P2)

[0310] Under a hydrogen gas atmosphere, intermediate 14-9-P1 (500 mg) was added to methanol (15 mL), and wet palladium carbon (10 mg, 10%) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 16 hours under a hydrogen gas atmosphere. After the reaction was completed, the reaction product was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 14-10-P1 (273 mg).

[0311] 1 H NMR (400MHz, METHANOL-d 4 ) δ 3.63 (d, J = 7.2 Hz, 1H), 1.21-1.09 (m, 1H), 0.61-0.40 (m, 4H).

[0312] Under a hydrogen gas atmosphere, intermediate 14-9-P2 (500 mg) was added to methanol (15 mL), and wet palladium carbon (10 mg, 10%) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 16 hours under a hydrogen gas atmosphere. After the reaction was completed, the reaction product was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 14-10-P2 (279 mg).

[0313] 1 H NMR (400MHz, METHANOL-d 4 ) δ 3.63 (d, J = 7.2 Hz, 1H), 1.19-1.08 (m, 1H), 0.60-0.39 (m, 4H).

[0314] Step 11: Synthesis of 2-cyclopropyl-N-(((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 14-P1 / P2)

[0315] Intermediate 14-8 (40.00 mg) and intermediate 14-10-P1 (28.11 mg) were dissolved in anhydrous N,N-dimethylformamide (1 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (46.02 mg) and N,N-diisopropylethylamine (31.28 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1.5 h. After the reaction was completed, the reaction solution was purified by preparative high performance liquid chromatography (Boston Green ODS C18 column 5 μm silica, diameter 30 mm, length 150 mm, elution with a polarity decreasing mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 16% to 46%, elution time 12 minutes) to obtain compound 14-P1 (22.00 mg).

[0316] MS m / z (ESI): 520.1 [M+H] + .

[0317] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.62 (t, J = 5.7 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 6.51(s, 1H), 6.29 (s, 2H), 5.47 (s, 2H), 5.43 (s, 2H), 4.73 (d, J = 5.9 Hz, 2H), 3.54 (d, J = 5.9 Hz, 1H), 1.93-1.78 (m, 2H), 1.06-0.96 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H), 0.39-0.30 (m, 2H), 0.29-0.21(m, 2H).

[0318] Intermediate 14-8 (10.00 mg) and intermediate 14-10-P2 (8.27 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.05 mg) and N,N-diisopropylethylamine (6.13 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1.5 h. After the reaction was completed, the reaction solution was directly purified by preparative high performance liquid chromatography (Boston Green ODS C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent of a polarity decreasing mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 16% to 46%, elution time 12 minutes) to obtain compound 14-P2 (8.00 mg).

[0319] MS m / z (ESI): 520.1 [M+H] + .

[0320] 1 H NMR (400MHz, DMSO-d 6) δ = 8.63 (t, J = 5.9 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.24 (s, 1H), 6.30 (s, 2H), 5.46 (s, 2H), 5.43 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 3.55 (d, J = 6.0 Hz, 1H), 1.92-1.81(m, 2H), 1.03-0.97 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H), 0.38-0.30 (m, 2H), 0.28-0.22 (m, 2H).

[0321] Each of the two isomers was further analyzed by the following chiral supercritical fluid chromatography analytical method.

[0322] [Table 2]

[0323] Compound 14-P1: Under the chiral supercritical fluid chromatography conditions described above, its retention time is 3.673 minutes.

[0324] Compound 14-P2: Under the chiral supercritical fluid chromatography conditions described above, its retention time is 3.735 minutes.

[0325] Example 15, (S)-N-((9-bromo-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b][1,7]naphthyridin-11-yl)methyl)-2-hydroxyacetamide (compound 15) [ka]

[0326] Step 1: Synthesis of 1-(5-amino-2-bromopyridin-4-yl)ethanone (Intermediate 15-2) Intermediate 15-1 (500 mg, 3.67 mmol) was dissolved in anhydrous tetrahydrofuran (90 mL), sodium hydrogen carbonate (617.04 mg, 7.34 mmol) and 2-pyrrolidone trihydrobromide (1.64 g, 5.03 mmol) were added thereto, and the reaction solution was stirred at 25° C. for 8 h. After the reaction was completed, the reaction solution was filtered, and the title compound (300 mg) was obtained by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 20: 1).

[0327] MS m / z (ESI): 214.9 [M+H] + .

[0328] Step 2: Synthesis of N-(4-acetyl-6-bromopyridin-3-yl)acetamide (Intermediate 15-3)

[0329] Intermediate 15-2 (150 mg, 697.52 mmol) was dissolved in dichloromethane (2 mL), the reaction solution was cooled to 0° C., and N,N-diisopropylethylamine (180.30 mg, 1.40 mmol) and acetyl chloride (109.51 mg, 1.40 mmol) were added thereto. The reaction solution was stirred at 25° C. for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the title compound (100 mg) was obtained by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 3:1).

[0330] MS m / z (ESI): 257.0 [M+H] + .

[0331] Step 3: Synthesis of 1-(5-amino-2-bromopyridin-4-yl)-2-bromoethane (Intermediate 15-4)

[0332] Intermediate 15-3 (95.00 mg, 273.45 μmol) was dissolved in acetic acid (2 mL), and a solution of hydrogen bromide in acetic acid (100.57 g, 410.18 μmol, 33% purity) was added thereto, and then liquid bromine (48.07 mg, 300.80 μmol) was slowly added thereto, and the reaction solution was stirred for 1 h at 25° C. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the title compound (45 mg) was obtained by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate = 3:1).

[0333] MS m / z (ESI): 292.9 [M+H] + .

[0334] Step 4: Synthesis of 1-(5-amino-2-bromopyridin-4-yl)-2-chloroketone (Intermediate 15-5)

[0335] Intermediate 15-4 (50.00 mg, 170.10 μmol) was dissolved in concentrated hydrochloric acid (1 mL), and the reaction solution was stirred at 60° C. for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then ice water (10 mL) and saturated sodium bicarbonate (10 mL) were added slowly in sequence, followed by dichloromethane (30 mL), and the organic phase was washed with water (20 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to dryness to give the title compound (25 mg).

[0336] MS m / z (ESI): 248.9 [M+H] + .

[0337] Step 5: Synthesis of (S)-9-bromo-11-(chloromethyl)-4-ethyl-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b][1,7]naphthyridine-3,14(4H)-dione (Intermediate 15-6)

[0338] Intermediate 15-5 (25 mg, 100.20 μmol) and intermediate 1-3 (26.38 mg, 100.20 μmol) were dissolved in toluene (0.5 mL), and pyridinium p-toluenesulfonate (2.52 mg, 10.02 μmol) was added thereto. The reaction solution was stirred at 90°C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then ethanol (1 mL) was added and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL*2) to obtain the title compound (30 mg).

[0339] MS m / z (ESI): 475.9 [M+H] + .

[0340] Step 6: Synthesis of (S)-11-(aminomethyl)-9-bromo-4-ethyl-4-hydroxy-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b][1,7]naphthyridine-3,14(4H)-dione (Intermediate 15-7)

[0341] Intermediate 15-6 (30 mg, 62.93 μmol) was dissolved in ethanol (1 mL), and methenamine (17.64 mg, 125.86 μmol) was added thereto. The reaction solution was stirred at 80° C. for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to dryness, and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, eluent with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and methanol (methanol gradient ratio 0% to 25%, elution time 12 min) to obtain the title compound (4 mg).

[0342] MS m / z (ESI): 457.0 [M+H] + .

[0343] Step 7: Synthesis of (S)-N-((9-bromo-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b][1,7]naphthyridin-11-yl)methyl)-2-hydroxyacetamide (compound 15)

[0344] Intermediate 15-7 (4 mg, 8.75 μmol) and hydroxyacetic acid (3.33 mg, 43.74 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (4.99 mg, 13.12 μmol) and N,N-diisopropylethylamine (3.39 mg, 26.24 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 2 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, elution with a polarity decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 8% to 28%, elution time 12 min) to obtain the title compound (1.00 mg).

[0345] MS m / z (ESI): 515.0 [M+H] + .

[0346] 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.38 (s, 1H), 8.88 (t, J = 6.2 Hz, 1H), 8.76 (s, 1H), 7.39 (s, 1H), 6.57 (s, 1H), 5.64-5.61(m, 1H), 5.60 (s, 2H), 5.45 (s, 2H), 4.80 (d, J = 6.0 Hz, 2H), 3.83 (d, J = 5.7 Hz, 2H), 1.92-1.80 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0347] Example 16, (S)-N-((9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-1-hydroxycyclopropane-1-carboxamide (compound 16) [ka]

[0348] Step 1: (S)-N-((9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-1-hydroxycyclopropane-1-carboxamide (compound 16)

[0349] Compound 12 (5.75 mg, 12.84 μmol) and intermediate 9-2 (3.93 mg, 38.52 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), HATU (7.32 mg, 19.26 μmol) and ethyldiisopropylamine (4.98 mg, 38.52 μmol) were added thereto, and the reaction solution was stirred at 30 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 14% to 34%, elution time 12 min) to obtain the title compound (3 mg).

[0350] MS m / z (ESI): 532.1 [M+H] + .

[0351] 1 H NMR (400MHz, DMSO-d 6) δ = 8.46 (t, J = 5.9 Hz, 1H), 8.16 (d, J = 9.8 Hz, 1H), 7.36 (s, 1H), 6.56 (s, 1H), 6.33 (s, 1H), 5.53 (s, 2H), 5.45 (s, 2H), 4.93 (d, J = 3.6 Hz, 2H), 1.92-1.82 (m, 2H), 1.04-0.99 (m, 2H), 0.90-0.87 (m, 2H), 0.87-0.82 (m, 3H).

[0352] Example 17, (S)-N-((8-chloro-4-ethyl-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxy-2-methylpropanamide (compound 17) [ka]

[0353] Step 1: Synthesis of (S)-N-((8-chloro-4-ethyl-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxy-2-methylpropanamide (compound 17)

[0354] Intermediate 6-4 (5 mg, 11.74 μmol) and intermediate 17-1 (2.44 mg, 23.48 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (8.95 mg, 23.48 μmol) and N,N-diisopropylethylamine (1.19 mg, 11.74 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm silica, diameter 25 mm, length 100 mm, elution with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 22% to 42%, elution time 12 min) to obtain the title compound (1 mg).

[0355] MS m / z (ESI): 512.1 [M+H] + .

[0356] 1 H NMR (400MHz, Methanol-d 4 ) δ = 8.32 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 5.62 (d, J = 16.4 Hz, 1H), 5.52 (s, 2H), 5.42 (d, J = 16.4 Hz, 1H), 5.01(s, 2H), 2.65 (s, 3H), 2.05-1.94 (m, 2H), 1.38 (s, 6H), 1.03 (t, J = 7.5 Hz, 3H).

[0357] Example 18, N-(((S)-8-chloro-4-ethyl-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxy-3-methylbutanamide (compound 18) [ka]

[0358] Step 1: Synthesis of N-(((S)-8-chloro-4-ethyl-4-hydroxy-9-methyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxy-3-methylbutanamide (compound 18)

[0359] Intermediate 6-4 (5 mg, 11.74 μmol) and intermediate 18-1 (2.77 mg, 23.48 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (8.95 mg, 23.48 μmol) and N,N-diisopropylethylamine (1.19 mg, 11.74 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 25% to 45%, elution time 12 min) to obtain the title compound (1.20 mg).

[0360] MS m / z (ESI): 526.1 [M+H] + .

[0361] 1 H NMR (400MHz, Methanol-d 4 ) δ = 8.30 (s, 1H), 8.13 (s, 1H), 7.61(s, 1H), 5.60 (d, J = 16.3 Hz, 1H), 5.56-5.45 (m, 2H), 5.42-5.37 (m, 1H), 5.00-4.90 (m, 2H), 3.91(d, J = 3.3 Hz, 1H), 3.13 (d, J = 6.5 Hz, 1H), 2.62 (s, 3H), 2.01-1.94 (m, 2H), 1.05-1.00 (m, 6H), 0.77-0.70 (m, 3H).

[0362] Example 19, (S)-4-Ethyl-8-fluoro-4-hydroxy-11-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Compound 19) [ka]

[0363] Step 1: Synthesis of 1-(2-amino-4-fluoro-5-methylphenyl)-2-chloroketone (Intermediate 19-2)

[0364] Boron trichloride (749.03mg, 6.39mml) was dissolved in dichloroethane (8mL), the reaction solution was cooled to 0℃, intermediate 19-1 (1g, 7.99mmol) and chloroacetonitrile (723.94mg, 9.59mmol) were added thereto, the reaction was stirred at 0℃ for 10min, and aluminum trichloride (1.39mg, 10.39mmol) was added thereto. Then, under the protection of nitrogen gas, the reaction solution was warmed to 25℃ and stirred for 10min. Under the protection of nitrogen gas, the reaction solution was stirred at 90℃ for 18h. After the reaction was completed, the reaction was cooled to room temperature, ice water (30mL) and 5% HCl (10mL) were added slowly in sequence, and the mixture was stirred at 25℃ for 30min, then dichloromethane (50mL) was added, the organic phase was washed with water (20mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Preparative thin layer chromatography (silica, petroleum ether:ethyl acetate=9:1, small amount of ethanol) gave the title compound (300 mg).

[0365] MS m / z (ESI): 201.8 [M+H] + .

[0366] 1 H NMR (400MHz, deuterated chloroform) δ = 7.47 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 11.3 Hz, 1H), 4.64 (s, 2H), 2.20 (s, 3H).

[0367] Step 2: Synthesis of (S)-11-(chloromethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Intermediate 19-3)

[0368] Intermediate 19-2 (200 mg, 991.94 μmol) and intermediate 1-3 (260.12 mg, 991.94 μmol) were dissolved in anhydrous toluene (3 mL), p-pyridinium toluenesulfonate (12.46 mg, 49.60 μmol) was added thereto, and the reaction solution was stirred at 90° C. for 18 h under the protection of nitrogen gas. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was filtered, and the filter cake was washed with ethanol (3 mL * 2) to obtain the crude title compound (223 mg).

[0369] MS m / z (ESI): 429.1 [M+H] + .

[0370] Step 3: Synthesis of (S)-4-ethyl-8-fluoro-4-hydroxy-11-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)-9-methyl-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (compound 19)

[0371] Intermediate 19-3 (20 mg, 46.64 μmol) and intermediate 19-4 (6.09 mg, 69.96 μmol) were dissolved in N,N-dimethylformamide (2 mL), cesium carbonate (30.39 mg, 93.27 μmol) was added thereto, and the reaction solution was stirred at 40 ° C for 1 h under the protection of nitrogen gas. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 10% to 40%, elution time 12 min) to obtain the title compound (1.3 mg).

[0372] MS m / z (ESI): 480.1 [M+H] + .

[0373] 1 H NMR (400MHz, DMSO-d 6 )δ = 9.35-9.20 (m, 1H), 8.45-8.30 (m, 1H), 8.12-7.84 (m, 1H), 7.35 (d, J = 6.5 Hz, 1H), 6.62-6.50 (m, 1H), 5.57-5.43 (m, 4H), 5.20-4.75 (m, 2H), 3.90-3.75 (m, 2H), 2.55 (s, 3H), 1.98-1.76 (m, 2H), 1.30-1.20 (m, 2H), 0.90-0.80 (m, 5H).

[0374] Example 20, (S)-N-((8-ethyl-8-hydroxy-9,12-dioxo-8,9,12,14-tetrahydro-11H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 20) [ka]

[0375] Step 1: Synthesis of 1-(5-aminobenzofuran-4-yl)-2-chloroketone (Intermediate 20-2)

[0376] Boron trichloride (1M, 9.61mL) was dissolved in dichloroethane (14mL), the reaction solution was cooled to 0℃, intermediate 20-1 (1.6g, 12.02mmol) and chloroacetonitrile (1.36g, 18.03mmol) were added thereto, the reaction was stirred at 0℃ for 10min, and aluminum trichloride (1.92g, 14.42mmol) was added thereto. Under the protection of nitrogen gas, the reaction solution was cooled to 25℃ and stirred for 10min. Under the protection of nitrogen gas, the reaction solution was stirred at 90℃ for 18h. After the reaction was completed, the reaction solution was cooled to room temperature, ice water (50mL) and 5% HCl (10mL) were added slowly in sequence, and the mixture was stirred at 25℃ for 30min, then dichloromethane (60mL) was added, the organic phase was washed with water (30mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. Preparative thin layer chromatography (petroleum ether:(ethyl acetate+ethanol=3:1)=9:1) afforded the title compound (300 mg).

[0377] MS m / z (ESI): 210.0 [M+H] + .

[0378] 1 H NMR (400MHz, deuterated chloroform) δ = 7.72 (d, J = 2.1 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 6.66 (d, J = 9.0 Hz, 1H), 4.78 (s, 2H)

[0379] Step 2: Synthesis of (S)-15-(chloromethyl)-8-ethyl-8-hydroxy-11,14-dihydro-12H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (Intermediate 20-3)

[0380] Intermediate 20-2 (200mg, 954.07μmol) and intermediate 1-3 (251.15mg, 954.07μmol) were dissolved in anhydrous toluene (4mL), p-toluenesulfonate pyridinium (23.98mg, 95.41μmol) was added thereto, and the reaction solution was stirred at 90℃ for 16h under nitrogen gas protection. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethanol (3mL*2) to obtain the title compound (300mg).

[0381] MS m / z (ESI): 437.1 [M+H] + .

[0382] Step 3: Synthesis of (S)-15-(aminomethyl)-8-ethyl-8-hydroxy-11,14-dihydro-12H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (Intermediate 20-4)

[0383] Intermediate 20-3 (70 mg, 160.24 μmol) was dissolved in ethanol (0.5 mL) and anhydrous N,N-dimethylformamide (0.5 mL), and methenamine (89.85 mg, 640.96 μmol) was added thereto. The reaction solution was stirred at 25 °C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to dryness, and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a decreasing polarity mixture of water (0.225% carboxylic acid) and methanol, methanol gradient ratio 5% to 25%, elution time 12 min) to obtain the title compound (17 mg).

[0384] MS m / z (ESI): 418.1 [M+H] + .

[0385] Step 4: (S)-N-((8-ethyl-8-hydroxy-9,12-dioxo-8,9,12,14-tetrahydro-11H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 20)

[0386] Intermediate 20-4 (5.00 mg, 11.98 μmol) and hydroxyacetic acid (4.55 mg, 59.89 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (6.83 mg, 17.97 μmol) and N,N-diisopropylethylamine (4.64 mg, 35.94 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, elution with a polarity decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 15% to 35%, elution time 12 min) to obtain the title compound (3 mg).

[0387] MS m / z (ESI): 476.2 [M+H] + .

[0388] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.48-8.41(m, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.35 (s, 1H), 6.54 (s, 1H), 5.58 (t, J = 5.6 Hz, 1H), 5.52 (s, 2H), 5.45 (s, 2H), 5.10 (d, J = 5.3 Hz, 2H), 3.88 (d, J = 5.6 Hz, 2H), 1.93-1.82 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[0389] Example 21, (S)-N-((9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (compound 21) [ka]

[0390] Step 1: Synthesis of (S)-N-((9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxyacetamide (compound 21)

[0391] Compound 12 (7 mg, 15.63 μmol) and hydroxyacetic acid (1.78 mg, 25.48 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (11.89 mg, 31.26 μmol) and diisopropylethylamine (2.02 mg, 15.63 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 20% to 40%, elution time 12 min) to obtain the title compound (1 mg).

[0392] MS m / z (ESI): 506.1 [M+H] + .

[0393] 1 H NMR (400MHz, Methanol-d 4) δ = 8.35 (t, J = 5.8 Hz, 1H), 8.15 (dd, J = 1.8, 9.8 Hz, 1H), 7.36 (s, 1H), 6.57 (s, 1H), 5.59-5.50 (m, 3H), 5.45 (s, 2H), 4.91(d, J = 3.2 Hz, 2H), 3.84 (d, J = 5.7 Hz, 2H), 1.90-1.80 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0394] Example 22, (S)-N-((9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxy-2-methylpropanamide (compound 22) [ka]

[0395] Step 1: (S)-N-((9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxy-2-methylpropanamide (compound 22)

[0396] Compound 12 (20 mg, 44.66 μmol) and intermediate 17-1 (13.95 mg, 133.98 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), HATU (25.47 mg, 66.99 μmol) and N,N-diisopropylethylamine (17.32 mg, 133.98 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, elution with a polarity decreasing mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 20% to 40%, elution time 12 min) to obtain the title compound (1.07 mg).

[0397] MS m / z (ESI): 534.2 [M+H] + .

[0398] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.30 (t, J = 5.9 Hz, 1H), 8.19-8.07 (m, 1H), 7.36 (s, 1H), 6.56 (s, 1H), 5.55-5.45 (m, 3H), 5.45 (s, 2H), 4.90 (d, J = 3.7 Hz, 2H), 1.90-1.82 (m, 2H), 1.24 (d, J = 4.3 Hz, 6H), 0.87 (t, J = 7.3 Hz, 3H).

[0399] Example 23, N-(((S)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (compound 23) [ka]

[0400] Step 1: N-(((S)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (compound 23)

[0401] Compound 12 (7.0 mg, 15.63 μmol) and intermediate 11-1 (9.08 mg, 78.16 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), HATU (8.92 mg, 23.45 μmol) and diisopropylethylamine (6.06 mg, 46.89 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (YMC-Actus Triart C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 41% to 61%, elution time 12 min) to obtain the title compound (7 mg).

[0402] MS m / z (ESI): 546.2 [M+H] + .

[0403] Compound 23 (7 mg) was separated and purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 μm); mobile phase: A: carbon dioxide; B: ethanol; B%: 50%; flow rate: 80 mL / min) to obtain compound 23-P1 (2.1 mg, RT: 5.106 min) and compound 23-P2 (2.09 mg, RT: 5.641 min).

[0404] Compound 23-P1: 1 H NMR (400MHz, DMSO-d 6) δ = 8.32 (t, J = 5.5 Hz, 1H), 8.15 (d, J = 9.7 Hz, 1H), 7.36 (s, 1H), 6.57 (s, 1H), 5.53 (s, 2H), 5.47 (d, J = 5.1 Hz, 1H), 5.45 (s, 2H), 4.93-4.86 (m, 2H), 2.02-1.96 (m, 1H), 1.91-1.81(m, 2H), 1.04-0.96 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H), 0.37-0.31(m, 2H), 0.29-0.23 (m, 2H).

[0405] MS m / z (ESI): 546.2 [M+H] + .

[0406] Compound 23-P2: 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.37-8.29 (m, 1H), 8.15 (d, J = 9.9 Hz, 1H), 7.36 (s, 1H), 6.57 (s, 1H), 5.53 (s, 2H), 5.50-5.46 (m, 1H), 5.45 (s, 2H), 4.96-4.86 (m, 2H), 2.10-1.95 (m, 1H), 1.92-1.81(m, 2H), 1.04-0.98 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H), 0.40-0.31(m, 2H), 0.30-0.25 (m, 2H).

[0407] MS m / z (ESI): 546.2 [M+H] + .

[0408] Example 24, (S)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-11-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (Compound 24) [ka]

[0409] Step 1: Synthesis of (S)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-11-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)-1,12-dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (compound 24)

[0410] Intermediate 12-3 (30 mg, 64.21 μmol) and intermediate 19-4 (27.97 mg, 321.03 μmol) were dissolved in N,N-dimethylformamide (2 mL), cesium carbonate (41.84 mg, 128.41 μmol) was added thereto, and the reaction solution was stirred at 40 ° C for 1 h under the protection of nitrogen gas. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 30% to 50%, elution time 12 minutes) to obtain the title compound (3.1 mg).

[0411] MS m / z (ESI): 518.1 [M+H] + .

[0412] 1 H NMR (400MHz, DMSO-d 6) δ = 8.13-7.97 (m, 1H), 7.26 (s, 1H), 6.80-6.68 (m, 1H), 6.56 (s, 1H), 5.45-5.35 (m, 2H), 4.25-4.15 (m, 1H), 4.10-4.05 (m, 1H), 2.98-2.90 (m, 3H), 2.87-2.72 (m, 1H), 2.69-2.56 (m, 1H), 2.00-1.78 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H), 0.32-0.19 (m, 2H), 0.18-0.01(m, 2H).

[0413] Example 25, (R)-N-(((S)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxypropanamide (compound 25) [ka]

[0414] Step 1: Synthesis of (R)-N-(((S)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxypropanamide (compound 25)

[0415] Compound 12 (6 mg, 13.40 μmol) and intermediate 25-1 (2.41 mg, 26.80 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (10.09 mg, 26.80 μmol) and diisopropylethylamine (1.73 mg, 13.49 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 20% to 40%, elution time 12 min) to obtain the title compound (1.80 mg).

[0416] MS m / z (ESI): 520.1[M+H] + .

[0417] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.34 (t, J = 5.7 Hz, 1H), 8.15 (d, J = 9.9 Hz, 1H), 7.36 (s, 1H), 6.57 (s, 1H), 5.59 (d, J = 5.0 Hz, 1H), 5.51(s, 2H), 5.45 (s, 2H), 4.90 (s, 2H), 4.13-3.89 (m, 1H), 1.95-1.77 (m, 2H), 1.21(d, J =6.8 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0418] Example 26, (S)-N-(((S)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxypropanamide (compound 26) [ka]

[0419] Step 1: Synthesis of (S)-N-(((S)-9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-2-hydroxypropanamide (compound 26)

[0420] Compound 12 (6 mg, 13.40 μmol) and intermediate 26-1 (2.41 mg, 26.80 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (10.09 mg, 26.80 μmol) and N,N-diisopropylethylamine (1.73 mg, 13.49 μmol) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of polarity decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile, acetonitrile gradient rate 20% to 40%, elution time 12 min) to obtain the title compound (1.60 mg).

[0421] MS m / z (ESI): 520.1 [M+H] + .

[0422] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.34 (t, J = 5.7 Hz, 1H), 8.23-8.03 (m, 1H), 7.36 (s, 1H), 6.57 (s, 1H), 5.59 (d, J = 5.0 Hz, 1H), 5.51(s, 2H), 5.45 (s, 2H), 4.90 (s, 2H), 4.07-3.96 (m, 1H), 1.93-1.81(m, 2H), 1.21(d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0423] Example 27, (S)-N-((4-chloro-8-ethyl-8-hydroxy-9,12-dioxo-8,9,12,14-tetrahydro-11H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 27) [ka]

[0424] Step 1: Synthesis of (3-chloro-2-hydroxy-5-nitrophenyl)methanediol (Intermediate 27-2)

[0425] Intermediate 27-2 (6 g) was dissolved in acetic acid (25 mL), the reaction solution was cooled to 0° C., and nitric acid (9.64 g) was slowly added thereto. The reaction solution was stirred at 25° C. for 4 h. After the reaction was completed, the reaction solution was slowly added dropwise to ice water, and extracted three times with ethyl acetate (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to dryness to obtain the title compound (5.88 g).

[0426] 1 H NMR (400MHz, METHANOL-d4) δ = 8.16 (d, J =1.4, 2.4 Hz, 1H), 8.07-8.01(m, 1H), 5.68 (s, 1H).

[0427] Step 2: Synthesis of 7-chloro-5-nitrobenzofuran-2-carboxylate (Intermediate 27-4)

[0428] Intermediate 27-2 (5.88 g), intermediate 27-3 (7.69 g) and potassium carbonate (7.41 g) were dissolved in pyruvine (60 mL), and the reaction solution was stirred at 70° C. for 6 h. After the reaction was completed, water (50 mL) was added thereto, and extracted with ethyl acetate (50 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to dryness to obtain the title compound (4.5 g).

[0429] 1H NMR (400MHz, deuterated chloroform) δ = 8.55 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1H), 7.68 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H).

[0430] Step 3: Synthesis of 7-chloro-5-nitrobenzofuran-2-carboxylic acid (Intermediate 27-5)

[0431] Intermediate 27-4 (4.5 g) was dissolved in methanol (50 mL) and an aqueous solution of sodium hydroxide (2 g in 25 mL H 2 2H2O) was slowly added dropwise, and the reaction solution was stirred at 25°C for 3h. After the reaction was completed, water (120mL) was added thereto, and extracted twice with ethyl acetate (50mL). The pH value of the aqueous phase was adjusted to 1 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (50mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to dryness to obtain the title compound (4.0g).

[0432] 1 H NMR (400 MHz, deuterated chloroform) δ = 8.45 (d, J = 2.1 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.58 (s, 1H).

[0433] Step 4: Synthesis of 7-chloro-5-nitrobenzofuran (Intermediate 27-6)

[0434] Intermediate 27-5 (4 g) and copper oxide (1.05 g) were dissolved in quinoline (28 mL), and the reaction solution was filled with nitrogen gas and stirred at 200 °C for 0.5 h. After the reaction was completed, the temperature was lowered to 0 °C, dilute hydrochloric acid (80 mL) was slowly added dropwise thereto, and water (30 mL) was added, followed by extraction three times with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to dryness to obtain the title compound (2.4 g). 1H NMR (400MHz, deuterated chloroform) δ = 8.49 (d, J = 2.1 Hz, 1H), 8.31(d, J = 2.1 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H)

[0435] Step 5: Synthesis of 7-chlorobenzofuran-5-amine (Intermediate 27-7)

[0436] Intermediate 27-6 (2.4 g) and iron powder (1.55 g) were dissolved in methanol (5 mL), and ammonium chloride aqueous solution (148.91 mg, 5 mL) was added dropwise thereto. Nitrogen gas was introduced into the reaction solution, and the mixture was stirred at 80°C for 0.5 h. After the reaction was completed, the temperature was lowered to 25°C, water (10 mL) was added thereto, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to dryness to obtain the title compound (1.2 g).

[0437] MS m / z (ESI): 167.8[M+H] + .

[0438] Step 6: Synthesis of 1-(5-amino-7-chlorobenzofuran-4-yl)-2-chloroethyl-1-one (Intermediate 27-8)

[0439] Boron trichloride (671.17mg) was dissolved in 1.2 dichloroethane (8mL), the reaction solution was cooled to 0℃, intermediate 27-7 (1.2g) and chloroacetonitrile (702.75mg) were added thereto, the reaction was stirred at 0℃ for 10min, and aluminum trichloride (1.24g) was added thereto. Then, under the protection of nitrogen gas, the reaction solution was warmed to 25℃ and stirred for 10min. Under the protection of nitrogen gas, the reaction solution was stirred at 90℃ for 18h. After the reaction was completed, the reaction was cooled to room temperature, and then ice water (5mL) and 5% HCl (1mL) were added slowly in sequence, and the mixture was stirred at 25℃ for 30min, then dichloromethane (4mL) was added, the organic phase was washed with water (2mL*2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to dryness, and the title compound (500 mg) was obtained from the residue by preparative thin-layer chromatography (silica, petroleum ether: (ethyl acetate and ethanol 3 / 1 mixed solvent) = 9:1).

[0440] MS m / z (ESI): 243.8 [M+H] + .

[0441] Step 7: Synthesis of (S)-4-chloro-15-(chloromethyl)-8-ethyl-8-hydroxy-11,14-dihydro-12H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (Intermediate 27-9)

[0442] Intermediate 27-8 (450 mg) and intermediate 1-3 (480.35 mg) were dissolved in toluene (5 mL), and pyridinium p-toluenesulfonate (23.17 mg) was added thereto. The reaction solution was stirred at 90°C for 18 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then ethanol (1 mL) was added and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with petroleum ether (2 mL*2), and after drying, the title compound (500 mg) was obtained.

[0443] MS m / z (ESI): 471.0 [M+H] + .

[0444] Step 8: Synthesis of (S)-15-(aminomethyl)-4-chloro-8-ethyl-8-hydroxy-11,14-dihydro-12H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (Intermediate 27-10)

[0445] Intermediate 27-9 (450 mg) was dissolved in a mixed solution of methanol (1 mL) and N,N-dimethylformamide (1 mL), and methenamine (267.71 mg) was added thereto. The reaction solution was stirred at 50°C for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated hydrochloric acid (2 mL) was added and stirred, and then concentrated under reduced pressure to dryness. The residue was purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile, acetonitrile gradient rate 13% to 43%, elution time 12 min) to obtain the title compound (60.0 mg).

[0446] MS m / z (ESI): 451.9 [M+H] + .

[0447] Step 9: Synthesis of (S)-N-((4-chloro-8-ethyl-8-hydroxy-9,12-dioxo-8,9,12,14-tetrahydro-11H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 27)

[0448] Intermediate 27-10 (10 mg) and hydroxyacetic acid (5.05 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (16.83 mg) and diisopropylethylamine (2.86 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 28% to 48%, elution time 12 min) to obtain the title compound (6.0 mg).

[0449] MS m / z (ESI): 510.1 [M+H] + .

[0450] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.46 (s, 2H), 8.36-8.20 (m, 1H), 7.85 (s, 1H), 7.35 (s, 1H), 6.54 (s, 1H), 5.58 (t, J = 5.6 Hz, 1H), 5.49 (d, J = 2.9 Hz, 2H), 5.45 (s, 2H), 5.07 (s, 2H), 3.88 (d, J = 5.6 Hz, 2H), 2.02-1.75 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0451] Example 28, N-(((S)-4-chloro-8-ethyl-8-hydroxy-9,12-dioxo-8,9,12,14-tetrahydro-11H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (compound 28) [ka]

[0452] Step 1: Synthesis of N-(((S)-4-chloro-8-ethyl-8-hydroxy-9,12-dioxo-8,9,12,14-tetrahydro-11H-furo[3,2-f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (compound 28)

[0453] Intermediate 27-10 (10 mg) and intermediate 11-1 (8.34 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (13.65 mg) and diisopropylethylamine (3.10 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 34% to 54%, elution time 12 min) to obtain the title compound (6.2 mg).

[0454] MS m / z (ESI): 550.1[M+H] + .

[0455] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.48-8.43 (m, 2H), 8.29 (s, 1H), 7.84 (s, 1H), 7.35 (s, 1H), 6.56 (s, 1H), 5.51(s, 2H), 5.45 (s, 2H), 5.15-4.98 (m, 2H), 3.57 (d, J = 6.0 Hz, 1H), 1.95-1.80 (m, 2H), 1.10-1.00 (m, 1H), 0.89 (t, J =7.3 Hz, 3H), 0.41-0.32 (m, 2H), 0.32-0.24 (m, 2H).

[0456] Example 29, 2-cyclopropyl-N-(((S)-7-ethyl-7-hydroxy-15-nitro-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 29) [ka]

[0457] Step 1: Synthesis of (S)-14-(chloromethyl)-7-ethyl-7-hydroxy-15-nitro-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (Intermediate 29-1)

[0458] Intermediate 14-7 (500.0 mg) was dissolved in sulfuric acid (15 mL), and the reaction solution was cooled to 0 ° C. Then, nitric acid (357.35 g, 70% purity) was slowly added thereto, and the reaction solution was stirred at 25 ° C for 1.5 h. After the reaction was completed, ice water (10 mL) was slowly added in sequence, followed by dichloromethane (30 mL), and the organic phase was washed with 40 mL of water (20 mL * 2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness to obtain the title compound crude product (280.0 mg).

[0459] MS m / z (ESI): 486.0 [M+H] + .

[0460] Step 2: Synthesis of (S)-14-(aminomethyl)-7-ethyl-7-hydroxy-15-nitro-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (Intermediate 29-2)

[0461] Intermediate 29-1 (270.0 mg) was dissolved in methanol (2 mL) and tetrahydrofuranyl (2 mL), and methenamine (233.73 mg) was added thereto. The reaction solution was stirred at 60 ° C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, then concentrated under reduced pressure to dryness, and the residue was purified by preparative high performance liquid chromatography (YMC-Pack CN C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent with a decreasing polarity mixture of water (0.225% FA) and methanol (methanol gradient percentage 9% to 29%, elution time 12 min) to obtain the title compound (15.0 mg).

[0462] MS m / z (ESI): 467.1 [M+H] + .

[0463] Step 3: Synthesis of 2-cyclopropyl-N-(((S)-7-ethyl-7-hydroxy-15-nitro-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 29)

[0464] Intermediate 29-2 (12.00 mg) and intermediate 11-1 (14.94 mg) were dissolved in anhydrous N,N-dimethylformamide (1 mL), HATU (14.67 mg) and N,N-diisopropylethylamine (9.98 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1.5 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative high performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, elution with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile, acetonitrile gradient rate 15% to 45%, elution time 12 min) to obtain the title compound (5.20 mg).

[0465] MS m / z (ESI): 565.2 [M+H]+ .

[0466] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.25 (t, J = 5.3 Hz, 1H), 7.81(s, 1H), 7.28 (s, 1H), 6.52 (d, J = 2.6 Hz, 3H), 5.55 (d, J = 4.9 Hz, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 4.48 (d, J = 5.1 Hz, 2H), 3.53 (t, J = 5.7 Hz, 1H), 1.91-1.83 (m, 2H), 1.10-0.98 (s, 1H), 0.87 (t, J = 7.3 Hz, 3H), 0.42-0.28 (m, 4H).

[0467] Example 30, N-(((S)-15-chloro-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (compound 30) [ka]

[0468] Step 1: Synthesis of 2-chloro-3,4-dihydroxybenzaldehyde (Intermediate 30-2)

[0469] Intermediate 30-1 (20.0 g) was dissolved in anhydrous dichloromethane (100 mL), the reaction solution was cooled to 0° C., boron tribromide (87.41 g) was slowly added thereto, and the reaction solution was stirred at 25° C. for 4 h. After the reaction was completed, the reaction solution was slowly poured into ice water, then ethyl acetate (200 mL) was added, the organic phase was washed with water (100 mL * 2), the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, and the residue was stirred and washed with a solution of ethyl acetate: petroleum ether = 1: 4, and filtered to obtain the title compound (14 g).

[0470] MS m / z (ESI): 173.1 [M+H] + .

[0471] Step 2: Synthesis of 4-chlorobenzo[d][1,3]dioxole-5-acetal (Intermediate 30-3)

[0472] Intermediate 30-2 (10.0 g) was dissolved in anhydrous N,N-dimethylformamide (100 mL), and cesium carbonate (28.32 g) and diiodomethane (23.28 g) were added thereto. The reaction solution was stirred at 100°C for 1 h. After the reaction was completed, the reaction was cooled to room temperature, and then water (100 mL) was slowly added in sequence, followed by ethyl acetate (150 mL), and the organic phase was washed with water (50 mL * 2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the title compound (5.2 g).

[0473] MS m / z (ESI): 185.4 [M+H] + .

[0474] Step 3: Synthesis of 1-(4-chlorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol (Intermediate 30-4)

[0475] Intermediate 30-3 (5.0 g) was dissolved in anhydrous tetrahydrofuran (100 mL), the reaction solution was cooled to -78 ° C, and methyl magnesium bromide (4.85 g, 3M) was slowly added thereto. Under nitrogen gas protection, the reaction solution was stirred at 25 ° C for 4 h. After the reaction was completed, water (50 mL) was slowly added in sequence, then ethyl acetate (100 mL) was added, the organic phase was washed with water (50 mL * 2), the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain the title compound (5.3 g).

[0476] 1 H NMR (400MHz, deuterated chloroform) δ = 6.99 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 5.97 (s, 2H), 5.13 (q, J = 6.4 Hz, 1H), 1.41(d, J = 6.4 Hz, 3H)

[0477] Step 4: Synthesis of 1-(4-chlorobenzo[d][1,3]dioxol-5-yl)ethan-1-one (Intermediate 30-5)

[0478] Intermediate 30-4 (5.2g) was dissolved in anhydrous dichloromethane (100mL), the reaction solution was cooled to 0℃, and Dess-Martin reagent (DMP) (16.49g) was slowly added thereto. Under nitrogen gas protection, the reaction solution was stirred at 25℃ for 2h. After the reaction was completed, water (50mL) was slowly added in sequence, then ethyl acetate (100mL) was added, the organic phase was washed with water (50mL*2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative column chromatography (petroleum ether:ethyl acetate=3:1) to obtain the title compound (3.0g).

[0479] MS m / z (ESI): 199.2 [M+H] + .

[0480] Step 5: Synthesis of 1-(4-chloro-6-nitrobenzo[d][1,3]dioxol-5-yl)ethan-1-one (Intermediate 30-6)

[0481] Intermediate 30-5 (2.50 g) was dissolved in anhydrous dichloromethane (20 mL), and concentrated sulfuric acid (1.23 g) and nitric acid (5.67 g) were slowly added thereto. The reaction solution was stirred at 25 ° C for 3 h. After the reaction was completed, the reaction solution was slowly poured into ice water, then ethyl acetate (150 mL) was added, the organic phase was washed with water (50 mL * 2), the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness, and the title compound (1.8 g) was obtained from the residue by preparative column chromatography (petroleum ether: ethyl acetate = 2: 1).

[0482] MS m / z (ESI): 244.1 [M+H] + .

[0483] Step 6: Synthesis of 1-(6-amino-4-chlorobenzo[d][1,3]dioxol-5-yl)ethan-1-one (Intermediate 30-7)

[0484] Intermediate 30-6 (0.80 g) was dissolved in anhydrous methanol (6 mL) and Raney Ni (400.0 mg) was added thereto. The reaction solution was stirred at 25° C. for 16 h under hydrogen gas atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to dryness to obtain the title compound (510.0 mg).

[0485] MS m / z (ESI): 214.2 [M+H] + .

[0486] Step 7: Synthesis of N-(6-acetyl-7-chlorobenzo[d][1,3]dioxol-5-yl)acetamide (Intermediate 30-8)

[0487] Intermediate 30-7 (260.0 mg) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to 0° C., and N,N-diisopropylethylamine (235.95 mg) and acetyl chloride (143.32 mg) were added thereto. The reaction solution was stirred at 25° C. for 1.5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the title compound (140.0 mg).

[0488] MS m / z (ESI): 256.0 [M+H] + .

[0489] Step 8: Synthesis of N-(6-(2-bromoacetyl)-7-chlorobenzo[d][1,3]dioxol-5-yl)acetamide (Intermediate 30-9)

[0490] Intermediate 30-8 (110.00 mg) was dissolved in acetic acid (2 mL), and a solution of hydrogen bromide in acetic acid (158.24 mg, 33% content) was added thereto, and then liquid bromine (72.20 mg) was slowly added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was slowly poured into ice water, and then ethyl acetate (30 mL) was added, and the organic phase was washed with water (20 mL * 2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to dryness to obtain the title compound (110.0 mg).

[0491] MS m / z (ESI): 334.0 [M+H] + .

[0492] Step 9: Synthesis of 1-(6-amino-4-chlorobenzo[d][1,3]dioxol-5-yl)-2-chloroethyl-1-one (Intermediate 30-10)

[0493] Intermediate 30-9 (110.00 mg) was dissolved in absolute ethanol (1 mL) and concentrated hydrochloric acid (1 mL), and the reaction solution was stirred at 60 ° C for 16 h. After the reaction was completed, the reaction was cooled to room temperature, and then ice water (10 mL) and saturated sodium bicarbonate (10 mL) were added slowly in sequence, and then dichloromethane (30 mL) was added, and the organic phase was washed with water (20 mL * 2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 3: 1) to give the title compound (75 mg).

[0494] MS m / z (ESI): 248.0 [M+H] + .

[0495] Step 10: Synthesis of (S)-15-chloro-14-(chloromethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (Intermediate 30-11)

[0496] Intermediate 30-10 (75.00 mg) and intermediate 1-3 (83.57 mg) were dissolved in toluene (3 mL), and p-pyridinium toluenesulfonate (PPTS) (11.4 mg) was added thereto. The reaction solution was stirred at 90°C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then ethanol (1 mL) was added and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL*2), and after drying, the title compound (75.0 mg) was obtained.

[0497] MS m / z (ESI): 475.1 [M+H] + .

[0498] Step 11: Synthesis of (S)-14-(aminomethyl)-15-chloro-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (Intermediate 30-12)

[0499] Intermediate 30-11 (70.00 mg) was dissolved in anhydrous methanol (2 mL) and anhydrous tetrahydrofuran (1 mL), and methenamine (61.94 mg) was added thereto. The reaction solution was stirred at 80 ° C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, then concentrated under reduced pressure to dryness, and the residue was purified by preparative high performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient rate 5% to 25%, elution time 12 min) to obtain the title compound (16.0 mg).

[0500] MS m / z (ESI): 456.1 [M+H] + .

[0501] Step 12: Synthesis of N-(((S)-15-chloro-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (compound 30)

[0502] Intermediate 30-12 (5.00 mg) and intermediate 11-1 (6.37 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (6.26 mg) and N,N-diisopropylethylamine (4.25 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, elution with a decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 31% to 51%, elution time 12 min) to obtain the title compound (2.30 mg).

[0503] MS m / z (ESI): 554.2 [M+H] + .

[0504] 1 H NMR (400MHz, DMSO-d 6 ) δ = 7.78 (t, J = 5.4 Hz, 1H), 7.35 (s, 1H), 7.01(s, 1H), 6.30-6.25 (m, 1H), 6.16 (d, J = 1.5 Hz, 2H), 5.27-5.21(m, 2H), 5.19 (s, 2H), 4.93-4.78 (m, 2H), 3.29 (dd, J = 2.4, 6.1 Hz, 1H), 1.68-1.56 (m, 2H), 0.81-0.72 (m, 1H), 0.63 (t, J = 7.3 Hz, 3H), 0.14-0.06 (m, 2H), 0.05-0.03 (m, 2H).

[0505] Example 31, (S)-N-((15-chloro-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 31) [ka]

[0506] Step 1: Synthesis of (S)-N-((15-chloro-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 31)

[0507] Intermediate 30-12 (5 mg) and hydroxyacetic acid (4.17 mg) were dissolved in N,N-dimethylformamide (0.5 mL), HATU (6.26 mg) and N,N-diisopropylethylamine (4.25 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative high performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent of polarity decreasing mixture of water (containing 0.225% carboxylic acid) and acetonitrile, acetonitrile gradient rate 20% to 40%, elution time 12 min) to obtain the title compound (2.50 mg).

[0508] MS m / z (ESI): 514.2 [M+H] + .

[0509] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.03 (t, J = 5.8 Hz, 1H), 7.60 (s, 1H), 7.25 (s, 1H), 6.54-6.48 (m, 1H), 6.41(s, 2H), 5.48 (s, 2H), 5.43 (s, 2H), 5.12 (d, J = 6.0 Hz, 2H), 3.82 (s, 2H), 1.93-1.78 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).

[0510] Example 32, (S)-N-((9-chloro-4-ethyl-8,10-difluoro-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-11-yl)methyl)-3-hydroxypropanamide (compound 32) [ka]

[0511] Compound 12 (10 mg) and hydroxypropionic acid (2.21 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (12.70 mg) and N,N-diisopropylethylamine (2.89 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent with a polarity decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 28% to 48%, elution time 12 min) to obtain the title compound (0.80 mg).

[0512] MS m / z (ESI): 520.1[M+H] + .

[0513] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.54 (t, J = 5.6 Hz, 1H), 8.15 (d, J = 9.8 Hz, 1H), 7.35 (s, 1H), 6.57 (s, 1H), 5.54 (s, 2H), 5.45 (s, 2H), 4.85 (s, 2H), 4.54 (s, 1H), 3.57 (t, J = 6.5 Hz, 2H), 2.32-2.26 (m, 2H), 1.99-1.75 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0514] Example 33, (S)-N-((4-chloro-8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-1H,11H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 33) [ka]

[0515] Step 1: Synthesis of 7-chloro-2,3-dihydro-1H-inden-4-ol (Intermediate 33-2)

[0516] Intermediate 33-1 (500 mg) was dissolved in anhydrous acetonitrile (5 mL), NCS (547 mg) was added thereto, and after completion, the mixture was stirred at 25 ° C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL * 3 times), the organic layer was washed with saturated saline (30 mL), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1 to 10: 1) to obtain the title compound (600 mg).

[0517] MS m / z (ESI): 169.0 [M+H] + .

[0518] Step 2: Synthesis of 7-chloro-5-nitro-2,3-dihydro-1H-inden-4-ol (Intermediate 33-3)

[0519] Intermediate 33-2 (10 g) was dissolved in AcOH (50 mL) and H 2 2H2O (10 mL) and added HNO 3 (8.62 g, 65% by weight) was added. The reaction was stirred at 0° C. for 2 hours. After the reaction was completed, the reaction was slowly added to ice water (200 mL). After filtration, the solvent was removed by concentration under reduced pressure to give the title compound (10 g).

[0520] MS m / z (ESI): 214.0 [M+H] + .

[0521] Step 3: Synthesis of 5-amino-7-chloro-2,3-dihydro-1H-inden-4-ol (Intermediate 33-4)

[0522] Intermediate 33-3 (5 g) was dissolved in anhydrous DCM (50 mL), AcOH (14.04 g) and Zn (7.61 g) were added thereto, and the reaction solution was stirred at 25° C. for 12 hours. After the reaction was completed, water (200 mL) and ethyl acetate (200 mL) were added in sequence, and the organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to remove the solvent, and the title compound (4 g) was obtained.

[0523] MS m / z (ESI): 184.0 [M+H] + .

[0524] Step 4: Synthesis of 5-acetamino-7-chloro-2,3-dihydro-1H-inden-4-yl acetate (intermediate 33-5)

[0525] Intermediate 33-4 (4 g) was dissolved in anhydrous dichloromethane (40 mL) and acetic anhydride (Ac 2 O) (6.67g) and triethylamine (TEA) (6.61g) were added, and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, water (200mL) and ethyl acetate (200mL) were added in sequence, and the organic phase was washed with saturated aqueous NaCl solution (50mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain the title compound (4g).

[0526] MS m / z (ESI): 268.0 [M+H] + .

[0527] Step 5: Synthesis of N-(7-chloro-4-hydroxy-2,3-dihydro-1H-inden-5-yl)acetamide (Intermediate 33-6)

[0528] Intermediate 33-5 (4 g) was dissolved in anhydrous methanol (20 mL) and K 2 CO 3 (6.19g) was added and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, water (200mL) and ethyl acetate (200mL) were added in sequence, the organic phase was washed with saturated aqueous NaCl solution (50mL*2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1 to 1:1) to obtain the title compound (2.8g).

[0529] MS m / z (ESI): 226.0 [M+H] + .

[0530] Step 6: Synthesis of methyl 5-acetamino-7-chloro-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (Intermediate 33-7)

[0531] Intermediate 33-6 (500 mg) was dissolved in dichloromethane (5 mL) and trifluoromethanesulfonic anhydride (Tf 2 O) (749 mg) and triethylamine (TEA) (672 mg) were added, and the reaction solution was stirred at 25 ° C for 12 hours. After the reaction was completed, water (50 mL) and ethyl acetate (50 mL) were added in sequence, and the organic phase was washed with saturated NaCl aqueous solution (50 mL * 2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 1: 1) to obtain the title compound (580 mg).

[0532] MS m / z (ESI): 358.0 [M+H] + .

[0533] Step 7: Synthesis of N-(4-(1-butoxyvinyl)-7-chloro-2,3-dihydro-1H-inden-5-yl)acetamide (Intermediate 33-8)

[0534] Intermediate 33-7 (430 mg) and n-butyl vinyl ether (360.60 mg) were dissolved in dioxane (20 mL) and treated with diisopropylethylamine (DIEA) (466 mg), 1,1'-bis(diphenylphosphino)ferrocene (DPPF) (66 mg) and tri(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) (110mg) was added, and the reaction solution was reacted at 80°C for 16 hours under nitrogen gas protection. After the reaction was completed, the reaction solution was diluted with water (50mL) and extracted with ethyl acetate (50mL*3 times), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1 to 1:1) to obtain the title compound (300mg).

[0535] MS m / z (ESI): 308.0 [M+H] + .

[0536] Step 8: Synthesis of N-(4-acetyl-7-chloro-2,3-dihydro-1H-inden-5-yl)acetamide (Intermediate 33-9)

[0537] Intermediate 33-8 (200 mg) was dissolved in dioxane (5 mL), 1N HCl (5 mL) was added, and the mixture was stirred for 25 o C for 2 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure to remove the solvent, and the title compound (150 mg) was obtained.

[0538] MS m / z (ESI): 252.0 [M+H] + .

[0539] Step 9: Synthesis of N-(4-(2-bromoacetyl)-7-chloro-2,3-dihydro-1H-inden-5-yl)acetamide (Intermediate 33-10)

[0540] Intermediate 33-9 (300 mg) was dissolved in HBr / AcOH (4 mL, 33% by weight), NBS (318.20 mg) was added, and the reaction solution was reacted for 2 hours at 25° C. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, yielding the title compound (390 mg).

[0541] MS m / z (ESI): 330.0 [M+H] + .

[0542] Step 10: Synthesis of 1-(5-amino-7-chloro-2,3-dihydro-1H-inden-4-yl)-2-chloroethan-1-one (Intermediate 33-11)

[0543] Intermediate 33-10 (300 mg) was dissolved in absolute ethanol, HCl (12 M, 8.00 mL) was added, and the reaction solution was reacted at 80 ° C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high performance liquid chromatography (chromatography column: Gemini NX C185 μm * 10 * 150 mm; mobile phase: A: water (0.225% carboxylic acid v / v), B: acetonitrile; B%: 30% ~ 70%) to obtain the title compound (64 mg).

[0544] MS m / z (ESI): 244.0 [M+H] + .

[0545] Step 11: Synthesis of (S)-4-chloro-15-(chloromethyl)-8-ethyl-1,2,3,8,11,14-hexahydro-9H,12H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12-dione (Intermediate 33-12)

[0546] Intermediate 33-11 (45.00 mg) and intermediate 1-3 (48.53 mg) were dissolved in toluene (1 mL), and pyridinium p-toluenesulfonate (4.63 mg) was added thereto. The reaction solution was stirred at 90°C for 16 h. After the reaction was completed, it was cooled to room temperature, ethanol (1 mL) was added, and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL*2) and dried to obtain the title compound (80.0 mg).

[0547] MS m / z (ESI): 471.1 [M+H] + .

[0548] Step 12: Synthesis of (S)-15-(aminomethyl)-4-chloro-8-ethyl-8-hydroxy-1,2,3,8,11,14-hexahydro-9H,12H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12-dione (Intermediate 33-13)

[0549] Intermediate 33-12 (40.00 mg) was dissolved in anhydrous methanol (1 mL) and anhydrous N,N-dimethylformamide (0.5 mL), and methenamine (35.69 mg) was added thereto. The reaction solution was stirred at 50 °C for 16 h. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent of decreasing polarity mixture of water (containing 0.225% FA) and acetonitrile (acetonitrile gradient ratio 35% to 55%, elution time 12 min) to obtain the title compound (15.0 mg).

[0550] MS m / z (ESI): 452.1 [M+H] + .

[0551] Step 13: Synthesis of (S)-N-((4-chloro-8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-1H,11H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-hydroxyacetamide (compound 33)

[0552] Intermediate 33-13 (5.00 mg) and hydroxyacetic acid (4.21 mg, 55.30 μmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (6.31 mg) and N,N-diisopropylethylamine (4.29 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. The reaction was completed, and the reaction solution was filtered and purified by preparative high performance liquid chromatography (Boston Green ODS C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent with a decreasing polarity mixture of water (containing 0.05% FA) and acetonitrile (acetonitrile gradient percentage 32% to 52%, elution time 12 min) to obtain the title compound (2.0 mg).

[0553] MS m / z (ESI): 510.3 [M+H] + .

[0554] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.36-8.30 (m, 1H), 8.14 (s, 1H), 7.31(s, 1H), 6.55 (s, 1H), 5.44 (s, 2H), 5.38 (s, 2H), 4.96 (d, J = 5.3 Hz, 2H), 3.88 (s, 2H), 3.74-3.66 (m, 2H), 3.14 (t, J = 7.6 Hz, 2H), 2.27-2.19 (m, 2H), 1.92-1.82 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0555] Example 34, N-(((S)-4-chloro-8-ethyl-8-hydroxy-9,12-dioxo-2,3,8,9,12,14-hexahydro-1H,11H-cyclopenta[f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-15-yl)methyl)-2-cyclopropyl-2-hydroxyacetamide (compound 34) [ka]

[0556] Intermediate 33-13 (5.00 mg) and intermediate 11-1 (6.42 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), HATU (6.31 mg) and diisopropylethylamine (4.29 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent of a decreasing polarity mixture of water (containing 0.05% FA) and acetonitrile; acetonitrile gradient rate 35% to 55%, elution time 12 min) to obtain the title compound (2.0 mg).

[0557] MS m / z (ESI): 550.3 [M+H] + .

[0558] 1 H NMR (400MHz, DMSO-d 6) δ = 8.36-8.31(m, 1H), 8.14 (s, 1H), 7.31(s, 1H), 6.54 (s, 1H), 5.47-5.41(m, 3H), 5.38 (s, 2H), 4.96-4.90 (m, 2H), 3.69 (t, J = 7.1 Hz, 2H), 3.56 (t, J = 5.8 Hz, 1H), 3.14 (t, J = 7.4 Hz, 2H), 2.27-2.18 (m, 2H), 1.93-1.81(m, 2H), 1.09-1.03 (m, 1H), 0.88 (t, J = 7.2 Hz, 3H), 0.41-0.26 (m, 4H).

[0559] Example 35, (S)-14-(aminomethyl)-7-ethyl-15-fluoro-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (compound 35) [ka]

[0560] Step 1: Synthesis of 1-(2-fluoro-3,4-dimethoxyphenyl)ethan-1-one (Intermediate 35-2)

[0561] Intermediate 35-1 (25.0 g) was dissolved in 1,2-dichloroethane (250 mL), the reaction solution was cooled to 0°C, aluminum trichloride (64.04 g) was slowly added thereto, and then acetyl chloride (64.04 g) was added dropwise to the reaction solution. Under a nitrogen gas atmosphere, the reaction solution was stirred at 0°C for 2 h. After the reaction was completed, water (300 mL) was added thereto, and extracted with ethyl acetate (150 mL * 3 times), and the organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®; 120 g SepaFlash® flash silica gel column, petroleum ether / ethyl acetate gradient 0-50%, flow rate 70 mL / min) to obtain the title compound (21.0 g).

[0562] MS m / z (ESI): 199.0 [M+H] + .

[0563] Step 2: Synthesis of 1-(2-fluoro-3,4-dihydroxyphenyl)ethan-1-one (Intermediate 35-3)

[0564] Intermediate 35-2 (15.00 g) was dissolved in anhydrous dichloromethane (150 mL), the reaction solution was cooled to -78 ° C, boron tribromide (56.88 g) was slowly added dropwise thereto, and the reaction solution was stirred at -78 ° C for 2 h under nitrogen gas atmosphere, then warmed to 0 ° C and reacted for 4 h. After the reaction was completed, the reaction solution was slowly added dropwise to ice water to quench, and after the quenching was completed, it was extracted with ethyl acetate (150 mL * 3 times), and the organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ISCO (registered trademark); 120 g SepaFlash (registered trademark) flash silica gel column, gradient 0-50% petroleum ether / ethyl acetate, flow rate 70 mL / min) to obtain the title compound (8.50 g).

[0565] MS m / z (ESI): 171.0 [M+H] + .

[0566] Step 3: Synthesis of 1-(4-fluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one (Intermediate 35-4)

[0567] Intermediate 35-3 (4.0 g) was dissolved in anhydrous N,N-dimethylformamide (40 mL), and cesium carbonate (11.49 g) and 1,2-diiodomethane (18.89 g) were added thereto. Under nitrogen gas atmosphere, the reaction solution was stirred at 100°C for 8 min. After the reaction was completed, the reaction solution was slowly poured into water, extracted with ethyl acetate (50 mL * 3 times), the organic phase was combined, and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®; 24 g SepaFlash® flash silica gel column, gradient of petroleum ether / ethyl acetate 0-15%, flow rate 60 mL / min) to obtain the title compound (2.0 g).

[0568] MS m / z (ESI): 183.0 [M+H] + .

[0569] Step 4: Synthesis of 1-(4-fluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)ethan-1-one (Intermediate 35-5)

[0570] Intermediate 35-4 (2.0 g) was dissolved in anhydrous dichloromethane (15 mL), concentrated sulfuric acid (5.38 g, 98% by weight) was added thereto, and the reaction solution was cooled to 0°C. Concentrated nitric acid (3.46 g, 68% by weight) was then slowly added dropwise to the reaction solution. The reaction solution was stirred at 25°C for 2 h. After the reaction was completed, the reaction solution was slowly added dropwise to ice water (50 mL), then ethyl acetate (50 mL) was added, the organic phase was washed with water (50 mL*2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ISCO®; 24 g SepaFlash® flash silica gel column, 0-40% petroleum ether / ethyl acetate gradient, flow rate 60 mL / min) to obtain the title compound (1.8 g).

[0571] 1H NMR (400MHz, deuterated chloroform) δ = 7.51(s, 1H), 6.26 (s, 2H), 2.63 (s, 3H).

[0572] Step 5: Synthesis of 1-(6-amino-4-fluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one (Intermediate 35-6)

[0573] Intermediate 35-5 (1.8 g) was dissolved in anhydrous methanol (18 mL) and water (9 mL), and ammonium chloride (635.83 mg) and iron powder (2.21 mg) were added thereto. Under nitrogen gas atmosphere, the reaction solution was stirred at 80°C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was filtered, the filtrate was diluted with ethyl acetate (50 mL), the organic phase was washed with water (50 mL * 2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to dryness to give the title compound (1.5 g).

[0574] MS m / z (ESI): 198.0 [M+H] + .

[0575] Step 6: Synthesis of N-(6-acetyl-7-fluorobenzo[d][1,3]dioxol-5-yl)acetamide (Intermediate 35-7)

[0576] Intermediate 35-6 (500.0 mg) was dissolved in anhydrous dichloromethane (5 mL), pyridine (601.79 mg) was added thereto, and acetyl chloride (398.14 mg) was added dropwise to the reaction under nitrogen gas atmosphere. The reaction solution was stirred at 25°C for 1.5 h under nitrogen gas atmosphere. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ISCO®; 12 g SepaFlash® flash silica gel column, gradient 0-40% petroleum ether / ethyl acetate, flow rate 60 mL / min) to obtain the title compound (380.0 mg).

[0577] 1H NMR (400MHz, deuterated chloroform) δ = 11.72 (s, 1H), 8.18 (d, J = 1.0 Hz, 1H), 6.10 (s, 2H), 2.64 (d, J = 8.4 Hz, 3H), 2.22 (s, 3H).

[0578] Step 7: Synthesis of N-(6-(2-bromoacetyl)-7-fluorobenzo[d][1,3]dioxol-5-yl)acetamide (Intermediate 35-8)

[0579] Intermediate 35-7 (380.0 mg) was dissolved in acetic acid (3 mL), and a solution of hydrogen bromide in acetic acid (1.95 g, 33% content) was added thereto, and then liquid bromine (256.42 mg) was slowly added dropwise to the reaction solution. The reaction solution was stirred at 25°C for 1 h. After the reaction was completed, the reaction solution was slowly poured into ice water, stirred for 0.5 h, filtered, and the filter cake was washed with water (20 mL * 2), and the filter cake was dried to obtain the title compound (400.0 mg).

[0580] MS m / z (ESI): 317.8 [M+H] + .

[0581] Step 8: Synthesis of 1-(6-amino-4-fluorobenzo[d][1,3]dioxol-5-yl)-2-chloroethan-1-one (Intermediate 35-9)

[0582] Intermediate 35-8 (400.0 mg) was dissolved in absolute ethanol (2 mL) and concentrated hydrochloric acid (2 mL), and the reaction solution was stirred at 60 ° C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then ice water (20 mL) was added slowly in sequence, and the pH was adjusted to 8 with saturated sodium bicarbonate, and then ethyl acetate (40 mL) was added, and the organic phase was washed with water (20 mL * 2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to dryness to give the title compound (220.0 mg).

[0583] MS m / z (ESI): 232.0 [M+H] + .

[0584] Step 9: Synthesis of (S)-14-(chloromethyl)-7-ethyl-15-fluoro-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (Intermediate 35-10)

[0585] Intermediate 35-9 (200.0 mg) and intermediate 1-3 (227.32 mg) were dissolved in toluene (3 mL), and pyridinium p-toluenesulfonate (21.70 mg) was added thereto. The reaction solution was stirred at 90°C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then ethanol (1 mL) was added and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (5 mL * 2) to obtain the title compound (320.0 mg).

[0586] MS m / z (ESI): 459.0 [M+H] + .

[0587] Step 10: Synthesis of (S)-14-(aminomethyl)-7-ethyl-15-fluoro-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (compound 35)

[0588] Intermediate 35-10 (260.00 mg) was dissolved in anhydrous methanol (1 mL) and anhydrous N,N-dimethylformamide (1 mL), and methenamine (238.32 mg) was added thereto. The reaction solution was stirred at 50 ° C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to dryness, and purified by preparative high performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent of decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient rate 0% to 30%, elution time 14 min) to obtain the title compound (85.0 mg).

[0589] MS m / z (ESI): 440.0 [M+H] + .

[0590] 1 H NMR (400MHz, DMSO-d 6 ) δ = 7.49 (s, 1H), 7.26 (s, 1H), 6.53 (s, 1H), 6.38 (s, 2H), 5.44 (s, 4H), 4.27 (s, 2H), 1.94-1.79 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0591] Example 36, (S)-15-(aminomethyl)-8-ethyl-16-fluoro-8-hydroxy-2,3,11,14-tetrahydro-12H-[1,4]dioxazo[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (compound 36) [ka]

[0592] Step 1: Synthesis of 1-(5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (Intermediate 36-1)

[0593] Intermediate 35-3 (0.5 g) and 1,2-dibromoethane were dissolved in anhydrous N,N-dimethylformamide (5 mL), potassium carbonate (1.44 g) was added thereto, and the reaction solution was stirred at 100 ° C for 10 min. After the reaction was completed, the reaction solution was slowly poured into ice water, then ethyl acetate (50 mL) was added, the organic phase was washed with water (30 mL * 2), the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ISCO (registered trademark); 12 g SepaFlash (registered trademark) flash silica gel column, gradient of 0-40% petroleum ether / ethyl acetate, flow rate 60 mL / min) to obtain the title compound (0.2 g).

[0594] MS m / z (ESI): 197.0 [M+H] + .

[0595] Step 2: Synthesis of 1-(5-fluoro-7-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (Intermediate 36-2)

[0596] Intermediate 36-1 (0.7 g) was dissolved in anhydrous dichloromethane (6 mL), concentrated sulfuric acid (1.75 g, 98% by weight) was added thereto, and the reaction solution was cooled to 0°C. Concentrated nitric acid (1.12 g, 68% by weight) was then slowly added dropwise to the reaction solution, and the reaction solution was stirred at 25°C for 2 h. After the reaction was completed, the reaction solution was slowly added dropwise to ice water (20 mL), and then ethyl acetate (50 mL) was added, and the organic phase was washed with water (30 mL*2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (ISCO®; 12 g SepaFlash® flash silica gel column, 0-50% petroleum ether / ethyl acetate gradient, flow rate 60 mL / min) to obtain the title compound (0.3 g).

[0597] 1 H NMR (400MHz, deuterated chloroform) δ = 7.61(d, J = 1.9 Hz, 1H), 4.48-4.44 (m, 2H), 4.43-4.38 (m, 2H), 2.63 (s, 3H).

[0598] Step 3: Synthesis of 1-(7-amino-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (Intermediate 36-3)

[0599] Intermediate 36-2 (300.0 mg) was dissolved in anhydrous methanol (3 mL) and water (0.5 mL), and ammonium chloride (79.85 mg) and iron powder (347.33 mg) were added thereto. Under nitrogen gas atmosphere, the reaction solution was stirred at 80°C for 1.5 h. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was filtered, the filtrate was diluted with ethyl acetate (50 mL), the organic phase was washed with water (50 mL * 2), and the washed organic phase was dried over an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to dryness to give the title compound (250.0 mg).

[0600] MS m / z (ESI): 212.0 [M+H] + .

[0601] Step 4: Synthesis of N-(7-acetyl-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide (Intermediate 36-4)

[0602] Intermediate 36-3 (250.0 mg) was dissolved in anhydrous dichloromethane (5 mL), triethylamine (598.93 mg) was added thereto, and acetyl chloride (278.77 mg) was added dropwise to the reaction solution under nitrogen gas atmosphere. The reaction solution was stirred at 25°C for 0.5 h under nitrogen gas atmosphere. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ISCO®; 12 g SepaFlash® flash silica gel column, gradient of 0-70% petroleum ether / ethyl acetate, flow rate 60 mL / min) to obtain the title compound (0.1 g).

[0603] MS m / z (ESI): 254.0 [M+H] + .

[0604] Step 5: Synthesis of N-(7-(2-bromoacetyl)-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide (Intermediate 36-5)

[0605] Intermediate 36-4 (100.0 mg) was dissolved in acetic acid (2 mL), and a solution of hydrogen bromide in acetic acid (290.48 mg, 33% content) was added thereto, and then liquid bromine (75.73 mg) was slowly added dropwise to the reaction solution. The reaction solution was stirred at 25° C. for 0.5 h. After the reaction was completed, the reaction solution was slowly poured into ice water, stirred for 0.5 h, filtered, and the filter cake was dried to obtain the title compound (80.0 mg).

[0606] 1 H NMR (400MHz, deuterated chloroform) δ = 11.04 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 4.56 (d, J = 4.3 Hz, 2H), 4.43-4.38 (m, 2H), 4.37-4.32 (m, 2H), 2.22 (s, 3H).

[0607] Step 6: Synthesis of 1-(7-amino-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-chloroethan-1-one (Intermediate 36-6)

[0608] Intermediate 36-5 (80.0 mg) was dissolved in absolute ethanol (0.5 mL) and concentrated hydrochloric acid (0.5 mL), and the reaction solution was stirred at 60 ° C for 2 h. After the reaction was completed, the reaction was cooled to room temperature, and then ice water (10 mL) and saturated sodium bicarbonate (10 mL) were added slowly in sequence, and then dichloromethane (30 mL) was added, and the organic phase was washed with water (20 mL * 2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to dryness to give the title compound (60.0 mg).

[0609] MS m / z (ESI): 246.0 [M+H] + .

[0610] Step 7: Synthesis of (S)-15-(chloromethyl)-8-ethyl-16-fluoro-8-hydroxy-2,3,11,14-tetrahydro-12H-[1,4]dioxazo[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (Intermediate 36-7)

[0611] Intermediate 36-6 (60.0 mg) and intermediate 1-3 (64.3 mg) were dissolved in toluene (3 mL), and pyridinium p-toluenesulfonate (12.28 mg) was added thereto. The reaction solution was stirred at 95°C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then ethanol (1 mL) was added and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (2 mL * 2) to obtain the title compound (60.0 mg).

[0612] MS m / z (ESI): 473.0 [M+H] + .

[0613] Step 8: Synthesis of (S)-15-(aminomethyl)-8-ethyl-16-fluoro-8-hydroxy-2,3,11,14-tetrahydro-12H-[1,4]dioxazo[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H)-dione (compound 36)

[0614] Intermediate 36-7 (60.00 mg) was dissolved in anhydrous methanol (1 mL) and anhydrous N,N-dimethylformamide (0.5 mL), and methenamine (53.36 mg) was added thereto. The reaction solution was stirred at 50 ° C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent of a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient rate 0% to 25%, elution time 12 min) to obtain the title compound (24.0 mg).

[0615] MS m / z (ESI): 454.1 [M+H] + .

[0616] 1 H NMR (400MHz, DMSO-d 6 ) 7.60 (s, 1H), 7.31(s, 1H), 6.55 (s, 1H), 5.49 (s, 2H), 5.45 (s, 2H), 4.60 (s, 2H), 4.54 (s, 4H), 1.92-1.84 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0617] Example 37, 2-cyclopropyl-N-(((S)-7-ethyl-15-fluoro-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 37) [ka]

[0618] Compound 35 (6 mg) and intermediate 11-1 (7.93 mg) were dissolved in N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.79 mg) and N,N-dimethyldiisopropylamine (5.29 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Boston Prime C18 column 5 μm silica, diameter 30 mm, length 150 mm, elution with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 15% to 45%, elution time 12 min) to obtain the title compound (6.50 mg).

[0619] MS m / z (ESI): 538.1 [M+H] + .

[0620] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.21(t, J = 6.0 Hz, 1H), 7.51(s, 1H), 7.26 (s, 1H), 6.53 (s, 1H), 6.40 (s, 2H), 5.47 (s, 2H), 5.43 (s, 2H), 4.84 (d, J = 3.8 Hz, 2H), 3.53 (d, J = 6.3 Hz, 1H), 1.90-1.81(m, 2H), 1.01(d, J = 5.5 Hz, 1H), 0.89-0.85 (m, 3H), 0.33 (d, J = 6.0 Hz, 2H), 0.30-0.25 (m, 2H).

[0621] Synthesis of compounds 37-P1 and 37-P2 [ka]

[0622] Compound 35 (6 mg) and intermediate 14-10-P1 (7.93 mg) were dissolved in N,N-dimethylformamide (1 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (7.79 mg) and N,N-dimethyldiisopropylamine (5.29 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high performance liquid chromatography (Boston Green ODS C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent of polarity decreasing mixture of water (containing 0.225% carboxylic acid) and acetonitrile, acetonitrile gradient rate 17% to 47%, elution time 12 minutes) to obtain compound 37-P1 (2.87 mg).

[0623] MS m / z (ESI): 538.1 [M+H]+ .

[0624] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.19 (t, J = 5.9 Hz, 1H), 7.51(s, 1H), 7.26 (s, 1H), 6.51(s, 1H), 6.40 (s, 2H), 5.47 (s, 2H), 5.43 (s, 2H), 4.84 (d, J = 4.6 Hz, 2H), 3.53 (d, J = 6.4 Hz, 1H), 1.91-1.80 (m, 2H), 1.06-0.97 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H), 0.38-0.31(m, 2H), 0.31-0.24 (m, 2H).

[0625] Compound 35 (6 mg) and intermediate 14-10-P2 (4.76 mg) were dissolved in N,N-dimethylformamide (1 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.38 mg) and N,N-dimethyldiisopropylamine (1.76 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high performance liquid chromatography (Boston Green ODS C18 column 5 μm silica, diameter 30 mm, length 150 mm, eluent of polarity decreasing mixture of water (containing 0.225% carboxylic acid) and acetonitrile, acetonitrile gradient rate 17% to 47%, elution time 12 minutes) to obtain compound 37-P2 (2.01 mg).

[0626] MS m / z (ESI): 538.1 [M+H] + .

[0627] 1 H NMR (400MHz, DMSO-d 6) δ = 8.26-8.16 (m, 1H), 7.51(s, 1H), 7.26 (s, 1H), 6.51(s, 1H), 6.40 (s, 2H), 5.46 (s, 2H), 5.43 (s, 2H), 4.87-4.82 (m, 2H), 3.53 (d, J = 6.2 Hz, 1H), 1.94-1.80 (m, 2H), 1.05-0.96 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H), 0.39-0.30 (m, 2H), 0.31-0.20 (m, 2H).

[0628] Each of the two isomers was further analyzed by the following chiral supercritical fluid chromatography analytical method.

[0629] [Table 3]

[0630] Compound 37-P1: Under the chiral supercritical fluid chromatography conditions described above, its retention time is 3.519 minutes.

[0631] Compound 37-P2: Under the chiral supercritical fluid chromatography conditions described above, its retention time is 3.573 minutes.

[0632] Example 38, (S)-N-((7-ethyl-15-fluoro-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)-2-hydroxyacetamide (compound 38) [ka]

[0633] Compound 35 (6 mg) and hydroxyacetic acid (3.21 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), to which 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.38 mg) and diisopropylethylamine (1.76 mg) were added, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a decreasing polarity mixture of water (0.05% carboxylic acid) and acetonitrile (acetonitrile gradient percentage 18% to 48%, elution time 12 min) to obtain the title compound (2.40 mg).

[0634] MS m / z (ESI): 498.1[M+H] + .

[0635] 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (t, J = 5.9 Hz, 1H), 7.51(s, 1H), 7.26 (s, 1H), 6.39 (s, 2H), 5.46 (s, 2H), 5.43 (s, 2H), 4.85 (d, J = 4.3 Hz, 2H), 3.83 (s, 2H), 1.92-1.80 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0636] Example 39, 2-cyclopropyl-N-(((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl-2,2-d 2 )Methyl)-2-hydroxyacetamide (Compound 39, Compound 39-P1 / P2) [ka]

[0637] Step 1: 1-(benzo[d][1,3]dioxol-5-yl-2,2-d 2 ) Synthesis of Ethan-1-one (Intermediate 39-2)

[0638] Intermediate 39-1 (3 g) was dissolved in anhydrous DMF solution (25 mL), deuterated dichloromethane (8.57 g) and potassium carbonate (8.18 g) were added, and after completion, the temperature was raised to 90 ° C and stirred for 16 h. The reaction solution was then added to water (100 mL), extracted with ethyl acetate (200 mL * 2), the organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 5: 1) to obtain the title compound (2.4 g).

[0639] MS m / z (ESI): 167.1[M+H] + .

[0640] Step 2: 1-(6-nitrobenzo[d][1,3]dioxol-5-yl-2,2-d 2 ) Synthesis of ethan-1-one (intermediate 39-3)

[0641] Intermediate 39-2 (2.4 g) was dissolved in acetic anhydride (10 mL), and concentrated nitric acid (32.50 g, 70% content) was added dropwise at 0° C. After completion, the mixture was stirred at 0° C. for 10 min. Then, the mixture was warmed to room temperature and stirred for 1 h. After completion of the reaction, the reaction solution was added dropwise to ice water (200 mL), filtered, and the filter cake was dried to obtain the title compound (1.9 g).

[0642] MS m / z (ESI): 212.0 [M+H] + .

[0643] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.69 (s, 1H), 7.30 (s, 1H), 2.49 (s, 3H).

[0644] Step 3: N-(6-acetylbenzo[d][1,3]dioxol-5-yl-2,2-d 2 ) Synthesis of acetamide (intermediate 39-4)

[0645] Intermediate 39-3 (1.8 g) was dissolved in acetic acid (25 mL), and acetic anhydride (1.84 g) and reduced iron powder (4.76 g) were added and stirred at room temperature for 1 h. After the reaction was completed, it was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether=5:1) to give the title compound (1.5 g).

[0646] MS m / z (ESI): 224.1 [M+H] + .

[0647] Step 4: N-(6-(2-bromoacetyl)benzo[d][1,3]dioxol-5-yl-2,2-d 2 ) Synthesis of acetamide (intermediate 39-5)

[0648] A solution of HBr in acetic acid (2.39 g, 33% content) was added dropwise to a solution of intermediate 39-4 (1.45 g) in acetic anhydride (25 mL), and Br 2 (1.07g) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 1h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, the residue was added to water (50mL), extracted with ethyl acetate (50mL*2), the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and after filtration, the residue was purified by column chromatography (ethyl acetate / petroleum ether=5:1) to obtain the title compound (1.3g,).

[0649] MS m / z (ESI): 302.1 [M+H] + .

[0650] Step 5: 1-(6-aminobenzo[d][1,3]dioxol-5-yl-2,2-d 2 Synthesis of 39-6-chloro-2-chloroethan-1-one (intermediate 39-6)

[0651] Intermediate 39-5 (1.2 g) and concentrated hydrochloric acid (144.82 mg) were dissolved in ethanol (15 mL), and the reaction solution was stirred at 60 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by high-performance liquid chromatography (YMC-Actus Triart C18 column 5 μm silica, diameter 30 mm, length 150 mm, water (0.05% NH 4 HCO 3 The mixture was purified by elution with decreasing polarity mixtures of acetonitrile (40% to 50% acetonitrile gradient) to give the title compound (577 mg).

[0652] MS m / z (ESI): 216.0 [M+H] + .

[0653] Step 6: (S)-14-(chloromethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione-2,2-d 2 Synthesis of (Intermediate 39-7)

[0654] Intermediate 39-6 (100.0 mg) and intermediate 1-3 (109.87 mg) were dissolved in toluene (1 mL) and acetic acid (1 mL), and pyridinium p-toluenesulfonate (5.24 mg) was added thereto. The reaction solution was stirred at 100°C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then the reaction solution was directly concentrated under reduced pressure to dryness. Ethanol (5 mL) was added, and the reaction solution was stirred at 25°C for 0.5 h. The reaction solution was filtered, and the filter cake was washed with ethanol (5 mL*2) to obtain the title compound (100.0 mg).

[0655] MS m / z (ESI): 443.0 [M+H] + .

[0656] Step 7: (S)-14-(aminomethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione-2,2-d 2 Synthesis of (Intermediate 39-8)

[0657] Intermediate 39-7 (100.00 mg) was dissolved in anhydrous ethanol (1.5 mL) and anhydrous N,N-dimethylformamide (1.5 mL), and methenamine (94.97 mg) was added thereto. The reaction solution was stirred at 50°C for 6 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by high performance liquid chromatography (column: Boston Green ODS 150*30mm*5μm; mobile phase: [A: water (carboxylic acid), B: acetonitrile]; B%: 0%~30%, 12min) to obtain the title compound (25.0 mg).

[0658] MS m / z (ESI): 424.0 [M+H] + .

[0659] Step 8: 2-Cyclopropyl-N-(((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl-2,2-d 2 Synthesis of methyl-2-hydroxyacetamide (compound 39)

[0660] Intermediate 39-8 (7 mg) and intermediate 11-1 (5.76 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.57 mg) and diisopropylethylamine (4.27 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was filtered and purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polar decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 20% to 50%, elution time 12 min) to obtain the title compound (2.60 mg).

[0661] MS m / z (ESI): 522.1[M+H] + .

[0662] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.62 (t, J = 5.9 Hz, 1H), 7.84 (s, 1H), 7.51(s, 1H), 7.24 (s, 1H), 6.49 (s, 1H), 5.48-5.41(m, 5H), 4.72 (d, J = 5.5 Hz, 2H), 3.59-3.52 (m, 1H), 2.00-1.76 (m, 2H), 1.05-0.96 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H), 0.37-0.30 (m, 2H), 0.29-0.19 (m, 2H).

[0663] Step 9: 2-Cyclopropyl-N-(((S)-7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl-2,2-d 2 Synthesis of )methyl)-2-hydroxyacetamide (compound 39-P1 / P2) [ka]

[0664] Intermediate 39-8 (7 mg) and intermediate 14-10-P1 (5.76 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.57 mg) and diisopropylethylamine (4.27 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of polarity decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile, acetonitrile gradient rate 15% to 45%, elution time 12 min) to obtain compound 39-P1 (3.30 mg).

[0665] MS m / z (ESI): 522.1[M+H] + .

[0666] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.62 (t, J = 6.0 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 6.51(s, 1H), 5.54-5.51(m, 1H), 5.47 (s, 2H), 5.43 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 3.55-3.53 (m, 1H), 1.94-1.78 (m, 2H), 1.05-0.96 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H), 0.40-0.30 (m, 2H), 0.29-0.19 (m, 2H).

[0667] Intermediate 39-8 (7 mg) and intermediate 14-10-P2 (5.76 mg) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.57 mg) and diisopropylethylamine (4.27 mg) were added thereto, and the reaction solution was stirred at 25 ° C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high-performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of a polarity decreasing mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 15% to 45%, elution time 12 min) to obtain compound 39-P2 (4.0 mg).

[0668] MS m / z (ESI): 522.1[M+H] + .

[0669] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.62 (t, J = 6.1 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 6.50 (s, 1H), 5.54-5.51(m, 1H), 5.46 (s, 2H), 5.43 (s, 2H), 4.72 (d, J = 5.8 Hz, 2H), 3.55-3.52 (m, 1H), 1.94-1.80 (m, 2H), 1.04-0.95 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H), 0.39-0.30 (m, 2H), 0.29-0.21(m, 2H).

[0670] Each of the two isomers was further analyzed by the following chiral supercritical fluid chromatography analytical method.

[0671] [Table 4]

[0672] Compound 39-P1: Under the chiral supercritical fluid chromatography conditions described above, its retention time is 2.877 minutes.

[0673] Compound 39-P2: Under the chiral supercritical fluid chromatography conditions described above, its retention time is 2.690 minutes.

[0674] Example 40, (S)-2-amino-N-((7-ethyl-15-fluoro-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)acetamide (compound 40) [ka]

[0675] Step 1: Synthesis of (S)-(2-((7-ethyl-15-fluoro-7-hydroxy-8,11-dioxo-8,10,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)amino)-2-oxoethyl)aminocarboxylic acid tert-butyl ester (Intermediate 40-1)

[0676] Compound 35 (7 mg) and 2-((t-butoxycarbonyl)amino)acetic acid (5.58 mg) were dissolved in anhydrous N,N-dimethylformamide (1 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.11 mg) and diisopropylethylamine (2.06 mg) were added thereto, and the reaction solution was stirred at 25°C for 1 h. After the reaction was completed, the reaction solution was concentrated to dryness to obtain the title compound (8.00 mg).

[0677] MS m / z (ESI): 597.3 [M+H] + .

[0678] Step 2: Synthesis of (S)-2-amino-N-((7-ethyl-15-fluoro-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)acetamide (compound 40)

[0679] Intermediate 40-1 (6 mg) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (902.27 mg) was added thereto, and the reaction solution was stirred at 25 ° C. for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and the residue was purified by preparative high performance liquid chromatography (Waters Xbridge C18 column 5 μm, diameter 25 mm, length 100 mm, eluent of decreasing polarity mixture of water (containing 0.05% carboxylic acid) and acetonitrile (acetonitrile gradient ratio 2% to 32%, elution time 12 min) to obtain the title compound (1.3 mg).

[0680] MS m / z (ESI): 497.1 [M+H] + .

[0681] 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.80-8.58 (m, 1H), 7.51(s, 1H), 7.26 (s, 1H), 6.52 (s, 1H), 6.40 (s, 2H), 5.50 (s, 2H), 5.43 (s, 2H), 4.85 (s, 2H), 3.09-2.75 (m, 2H), 1.92-1.79 (m, 2H), 0.87 (t, J = 7.1 Hz, 3H).

[0682] Compounds other than those synthesized in Examples 1-40 can be synthesized with reference to the synthetic routes and raw materials in Examples 1-40. Examples of tests for biological activity and related properties

[0683] The compounds in the following test examples were all prepared according to the methods described in the above examples of the present disclosure. Test Example 1, Tumor cell antiproliferative activity test 1

[0684] Cells and materials: Human colorectal cancer cell line HCT116 was purchased from Hongyuan Bochuang, human breast cancer cell line SKBR3 was purchased from ATCC, human ovarian cancer cell line OVCAR3 was purchased from ATCC, bovine serum (Gibco #10099-141C #2186958), McCoy's 5a medium (Gibco#16600-082#2192439), 1640 medium (Gibco#A10491-01#2193156), penicillin-streptomycin (Gibco#15140-122#2211091) and 0.25% trypsin-EDTA (Gibco#25200-056#2186958) were purchased from Gibco (USA), bovine insulin (Solarbio#I8040) was purchased from Solarbio, 96-well plates (Greiner Bio-one#655098#E20103H8) were purchased from Corning (USA), and Cell-Titer Glo reagent (Promega#G7568#0000411325) was purchased from Promega (USA).

[0685] Cell culture: HCT116 and SKBR3 cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum + 1% penicillin-streptomycin at 37°C and 5% CO 2 OVCAR3 cells were cultured in 1640 medium containing 20% ​​fetal bovine serum + 2 μg / mL bovine insulin + 1% penicillin-streptomycin at 37°C, 5% CO 2 Only cells in logarithmic growth phase could be used for the experiments.

[0686] Cell proliferation activity detection: Cell-Titer Glo reagent was used to detect the inhibitory activity of compounds against the proliferation of three cell lines, HCT116, SKBR3, and OVCAR3. HCT116 cells (1500 per well), SKBR3 cells (3000 per well), and OVCAR3 cells (5000 per well) were seeded into a 96-well plate and incubated at 37°C, 5% CO 2 The cells were cultured for 24 hours under the conditions of 37°C, 5% CO. Test compound solutions (compounds were dissolved in DMSO to make the compound concentration 1 mm, and then the compounds were diluted to 3 μM using DMSO, resulting in a total of 9 concentrations with 3-fold dilutions, and 10 μL of the prepared compound solutions were transferred to a 96-well plate to make the final concentrations 0 to 300 nM) were added, followed by incubation at 37°C, 5% CO. 2 The cells were cultured under the conditions of 0.1% to 1.0%. HCT116 cells were cultured for 3 days, and SKBR3 and OVCAR3 cells were cultured for 5 days. Cell-Titer Glo reagent was added to detect cell activity.

[0687] In addition, a negative control group and a positive control group were set up, designated as Bottom and Top, respectively. The negative control group was added with the same volume of medium without adding cells, and other operations were the same as those of the experimental group. The positive control group was added with the same volume of DMSO without adding the test compound, and other operations were the same as those of the experimental group.

[0688] Data analysis: % Compound inhibition was calculated and compound IC 50 was fitted.

number

[0689] Signal represents the signal value of the experimental group, Bottom represents the average signal value of the negative control group, and Top represents the average signal value of the positive control group.

[0690] Test Results: Under the present experimental conditions, the compounds of the present disclosure exhibited strong proliferation inhibitory activity against any of HCT116 cells, SKBR3 cells and OVCAR3 cells. The corresponding anti-cell proliferation activity details of the compounds of the present disclosure are shown in Table 1.

[0691] [Table 5-1] [Table 5-2] Test Example 2: Tumor cell antiproliferative activity test 2

[0692] Cells and materials: Human ovarian cancer cell line SK-OV-3 was purchased from ATCC, human ovarian cancer cell line PA-1 was purchased from ATCC, human small cell lung cancer cell line NCI-H82 was purchased from ATCC, human breast cancer cell line MDA-MB-231 was purchased from ATCC, human non-small cell lung cancer cell line A549 was purchased from ATCC, and bovine serum (Gibco#10099-141C), McCoy's 5a medium (Gibco#16600-082), MEM medium (Gibco#11095-080), 1640 medium (Gibco#A10491-01), DMEM medium (Gibco#11995-065), MEM NEAA (Gibco#11140-050), sodium pyruvate (Gibco#11360-070), penicillin-streptomycin (Gibco#15140-122) and 0.25% Trypsin-EDTA (Gibco#25200-056) are purchased from Gibco (USA), bovine insulin (Solarbio#I8040) is purchased from Solarbio, 96-well plates (Greiner Bio-one#655098) are purchased from Corning (USA), and Cell-Titer Glo reagent (Promega#G7568) is purchased from Promega (USA).

[0693] Cell culture: SK-OV-3 cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum + 1% penicillin-streptomycin, PA-1 cells in MEM medium containing 10% fetal bovine serum + 1% MEM NEAA + 1% sodium pyruvate + 1% penicillin-streptomycin, NCI-H82 cells and MDA-MB-231 cells in 1640 medium containing 10% fetal bovine serum + 1% penicillin-streptomycin, A549 cells in DMEM medium containing 10% fetal bovine serum + 1% penicillin-streptomycin, and all five cell lines were cultured at 37°C and 5% CO. 2 Only cells in logarithmic growth phase could be used for the experiments.

[0694] Detection of cell proliferation activity: Using Cell-Titer Glo reagent, the inhibitory activity of compounds against the proliferation of five cell lines, SK-OV-3, PA-1, NCI-H82, MDA-MB-231 and A549, was detected. SK-OV-3 cells (1000 per well), PA-1 cells (800 per well), NCI-H82 cells (5000 per well), MDA-MB-231 cells (3000 per well) and A549 cells (400 per well) were seeded into a 96-well plate and incubated at 37°C, 5% CO 2 The test compounds were dissolved in DMSO to a concentration of 1 mM, and the test compounds were gradient-diluted using DMSO and the corresponding medium, transferred to a 96-well cell plate to a final concentration of 300 nM or more, diluted 3-fold, and incubated at 37°C, 5% CO for 24 hours. 2 The cells were cultured for 5 days under the above conditions. Cell-Titer Glo reagent was added to detect cell activity.

[0695] In addition, a negative control group and a positive control group were set up, designated as Bottom and Top, respectively. The negative control group was added with the same volume of medium without adding cells, and other operations were the same as those of the experimental group. The positive control group was added with the same volume of DMSO without adding the test compound, and other operations were the same as those of the experimental group.

[0696] Data analysis: Compound inhibition percentages were calculated and fitted to determine compound IC 50 obtained.

number

[0697] Test Results: Under the experimental conditions, the compounds of the present disclosure exhibited strong growth inhibitory activity against all of the five cell lines, namely PA-1, SK-OV-3, NCI-H82, MDA-MB-231 and A549. The corresponding anti-cell proliferation activity of the compounds of the present disclosure is detailed in Table 2. Tables 1 and 2 show that the compounds of the present disclosure exhibit strong growth inhibitory activity against any of the tumor cells, such as human colorectal cancer cell line HCT116, human breast cancer cell line SKBR3 and MDA-MB-231, human small cell lung cancer cell line NCI-H82, human non-small cell lung cancer cell line A549, and human ovarian cancer cell line OVCAR3, PA-1, and SK-OV-3, and have good therapeutic potential against multiple highly refractory tumors, such as intestinal cancer, breast cancer, and lung cancer.

[0698] [Table 6] Test Example 3: Metabolic stability assay of the compounds of the present disclosure in liver microsomes

[0699] The metabolic stability of the compounds of the present disclosure in liver microsomes is determined using the following test method.

[0700] 1. Test materials and instruments 1. Human liver microsomes (Corning 452117), beagle dog liver microsomes (XENOTECH D1000), SD rat liver microsomes (XENOTECH R1000) and CD-1 mouse liver microsomes (XENOTECH M1000) 2.Na2 HPO 4 (Tianjin City Optical Double Definition Chemical Engineering Research Institute 20180130) 3.KH 2 PO 4 (Tianjin City Optical Double Definition Chemical Engineering Research Institute 20180920) 4. mgCl 2 (Tianjin City Optical Double Definition Chemical Engineering Research Institute 20191216) 5. NADPH (Solarbio 1216C022) 6. Positive control compound Verapamil (Sigma MKBV4993V) 7.AB Sciex API4000 Liquid Chromatograph Mass Spectrometer

[0701] Second, test steps 1. Preparation of 100 mM phosphate buffer solution (PBS): 7.098 g Na 2 HPO 4 3.400g KH was weighed, 500mL of pure water was added, and the solution was dissolved by ultrasonication to obtain solution A. 2 PO 4 was weighed, 250 mL of pure water was added, and the solution was dissolved by ultrasonication to prepare solution B. Solution A was placed on a stirrer, and solution B was slowly added until the pH value reached 7.4 to prepare 100 mM PBS buffer solution. 2. Preparation of reaction system

[0702] Prepare the reaction system according to the following table:

[0703] [Table 7] 3. The reaction system was placed in a 37°C water bath and pre-incubated for 10 minutes. 40 μL of 10 mm NADPH solution (NADPH is dissolved in 100 mm phosphate buffer) was added to the reaction system, and the final concentration of NADPH is 1 mm. Instead of NADPH solution, 40 μL of phosphate buffer was used as a negative control. The function of the negative control is to eliminate the effect of the chemical stability of the compound itself. 4. Add 4 μL of 100 μM of the disclosed compound and the positive control compound verapamil to the reaction system to initiate the reaction, with the final compound concentration being 1 μM. 5. After thorough and uniform mixing by vortex oscillator, 50μL of incubation sample was taken out at 0.5, 15, 30, 45 and 60 minutes, respectively, and the reaction was terminated with 200μL of ice acetonitrile containing internal standard. The sample was centrifuged at 3220g rotation speed for 45 minutes. After centrifugation was completed, 90μL of the supernatant was transferred to a loading plate, and 90μL of ultrapure water was added and mixed uniformly for LC-MS / MS analysis.

[0704] All data were calculated using Microsoft Excel software. The in vitro half-life (t 1 / 2 ) was measured.

[0705] In vitro half-life (t 1 / 2 ) is calculated by the slope k:

number

[0706] The in vitro intrinsic clearance (unit: μL / min / mg protein) is calculated according to the following formula:

number

[0707] The compounds of the present disclosure have good liver microsomal stability and are specifically shown in Table 3.

[0708] [Table 8] Test Example 4: Membrane permeability and transport property assay of compounds of the present disclosure

[0709] The membrane permeability and transport properties of the compounds of the present disclosure are measured using the following test methods.

[0710] 1. Test materials and instruments 1.Caco-2 cells (ATCC) 2. HEPES (Solarbio 804D049), penicillin / streptomycin (Solarbio 20200109) and PBS (Solarbio 20200620) 3. Fetal bovine serum (FBS) (Sigma WXBD0055V), fluorescein (Sigma MKCJ3738) and NaHCO 3 (Sigma SLBZ4647) 4. Hank's Balanced Salt Solution (HBSS) (Gibco 2085528), Non-Essential Amino Acids (NEAA) (Gibco 2211548) and Trypsin / EDTA (Gibco 2120732) 5. High glucose DMEM (Corning 20319014) 6.HTS Transwell-96 Well Permeable(Corning,3391) 7. Resistance detector (Millipore, Millicell (登録商標) ERS-2) 8. Cellometer (登録商標) Vision (Nexcelom Bioscience) 9. Infinite 200 PRO Microplate Reader (Tecan, Infinite M200PRO) 10. Positive control compounds metoprolol (Sinopharm 100084-201403), erythromycin (MCE 84550), and cimetidine (Sinopharm 100158-201406) 11. ABI QTrap 5500 Liquid Chromatograph Mass Spectrometer

[0711] Second, test steps 1.Caco-2 cell culture 1) Preparation of transport buffer (HBSS with 25 mM HEPES, pH 7.4): 5.958 g HEPES and 0.35 g NaHCO 3 was accurately weighed, dissolved in 900 mL of pure water, and then 100 mL of 10×HBSS was added and stirred uniformly, the pH was adjusted to 7.4, and the mixture was filtered. 2) Preparation of Caco-2 cell medium: FBS, penicillin / streptomycin, kanamycin and NEAA were added to high glucose DMEM (L-glutamine)-containing medium to prepare a cell medium containing 10% FBS, 100 units of penicillin / 0.1 mg / mL streptomycin, 0.6 μg / mL kanamycin and 1x NEAA. 3) 37°C, 5% CO 2 The cells were cultured in a T-75 culture flask in a 37°C incubator, and the medium was discarded when the cells reached 80-90% density. The cells were washed with 5mL PBS, 1.5mL Trypsin / EDTA was added, and the cells were incubated in a 37°C incubator for 5-10 minutes until the cells detached in a quicksand-like state, and finally the Trypsin / EDTA was neutralized with FBS-containing medium. 4) The cell suspension was centrifuged at 120 g for 10 minutes and the supernatant was discarded. 5) Add cell culture medium to resuspend the cells so that the density is 6.86 x 10 5 The cell suspension was adjusted to 10 cells / mL (individual cells / mL). 2.Caco-2 cell inoculation 1) Add 50 μL of medium per well to the Transwell chamber, add 25 mL of medium to the bottom layer, and incubate at 37°C, 5% CO 2 The plate was preheated in an incubator for 1 hour. 2) Add 50 µL of cell suspension per well to the pre-warmed Transwell chamber for a final seeding density of 2.4 × 10 5 cells / cm 2 It is. 3) Culture for 14-18 days, changing the medium every other day, and changing the medium within 48 hours of the initial plate inoculation. The medium must be changed the day before the experiment. 3. Assessment of Cell Monolayer Membrane Integrity 1) After culturing the cells for 14 days, they were allowed to fuse and differentiate, and were then prepared for transport experiments. 2) The monolayer resistance was measured with a resistance meter and the resistance for each well was recorded. 3) After the measurements were completed, the Transwell culture plates were re-incubated. 4) Calculation of TEER value:

number

[0712] The leakage rate (Percentage leakage (%) or LY (%)) was calculated using the following formula:

number

[0713] The peak areas at the dose and dose sides of the compound were measured to determine the apparent permeability coefficient (P app , unit: cm / s) and the Efflux ratio were calculated:

number

number

[0714] The compounds of the present disclosure have good membrane permeability and transport properties, and are specifically shown in Table 4.

[0715] [Table 9] Test Example 5: Plasma Protein Binding Rate Assay of Compounds of the Present Disclosure

[0716] The protein binding rates of compounds of the present disclosure in human and mouse plasma were determined by the following test method.

[0717] 1. Test materials and instruments 1. Human plasma (BioIVT), CD-1 mouse plasma (BioIVT) 2.Na 2 HPO 4 (Sigma S5136-500G) 3. NaH 2 PO 4 (Sigma S3139-500G) 4. NaCl (Sigma S5886-IKG) 5. 96-well equilibrium dialysis plate (HTDialysis LLC, Gales Ferry, CT, HTD96B) and equilibrium dialysis membrane (MWCO 12-14K, 1101) 6. Positive control compound warfarin 7. ABI QTrap 5500 Liquid Chromatograph Mass Spectrometer

[0718] Second, test steps 1. Preparation of a buffer solution with a concentration of 100 mM sodium phosphate salt and 150 mM NaCl: 14.2 g / L Na 2 HPO 4 A basic solution having a concentration of 8.77 g / L NaCl was prepared using ultrapure water, and a basic solution having a concentration of 12.0 g / L NaH 2 PO 4 and an acidic solution with a concentration of 8.77 g / L NaCl was prepared with ultrapure water, and the basic solution was titrated to pH 7.4 with the acidic solution to prepare a buffer solution with a concentration of 100 mm sodium phosphate and 150 mm NaCl. 2. Preparation of dialysis membrane: The dialysis membrane was soaked in ultrapure water for 60 minutes, the membrane was separated into two pieces, and then soaked in 20% ethanol for 20 minutes, and finally soaked in the buffer solution used for dialysis for 20 minutes. 3. Preparation of plasma: Frozen plasma was thawed rapidly at room temperature, and the plasma was diluted with 3,220 g for 4 oThe blood clots were removed by centrifugation at 4°C for 10 min, and the supernatant was collected in a new centrifuge tube. The pH value of the plasma was measured and recorded, and plasma with a pH of 7–8 was used. 4. Preparation of compound-containing plasma samples: A 10 mM stock solution of a compound of the present disclosure or a positive control compound was diluted with DMSO to obtain a 200 μM working solution. 3 μL of the 200 μM compound working solution was added to 597 μL of human or mouse plasma to obtain plasma samples with a final concentration of 1 μM. 5. Equilibrium dialysis step: The dialysis apparatus was assembled according to the operating instructions. 120 μL of plasma sample containing 1 μM compound was added to one side of the dialysis membrane, and an equal volume of dialysate (phosphate buffer) was added to the other side. The test was set up in duplicate. The dialysis plate was sealed with film and placed in the incubation apparatus and incubated for 37 o C, 5% CO 2 and incubated for 6 hours under a rotation speed of about 100 rpm. After incubation was completed, the sealing film was removed and 50 μL of sample was aspirated from the buffer and plasma sides of each well and placed into different wells of a new plate. 50 μL of blank plasma was added to the phosphate buffer samples, an equal volume of blank phosphate buffer was added to the plasma samples, and 300 μL of acetonitrile containing the internal standard was added to precipitate the proteins. Vortexed for 5 minutes and incubated for 4 hours. o C, centrifuged at 3220 g for 30 min. 100 μL of the supernatant was taken and placed in a loading plate, and 100 μL of ultrapure water was added and mixed uniformly for LC-MS / MS analysis.

[0719] The peak areas of the compounds in the buffer and plasma were measured. The formula for calculating the plasma protein binding rate of the compound is as follows:

number

number

[0720] [Table 10] Test Example 6: Inhibitory effect of the compound of the present disclosure on CYP2C9, CYP2D6, and CYP3A4 enzyme activity

[0721] The inhibition of CYP2C9, CYP2D6, and CYP3A4 enzyme activity by compounds of the present disclosure was measured by the following test methods.

[0722] 1. Test materials and instruments 1. Human liver microsomes (Corning 452117) 2. NADPH (Solarbio 705Y021) 3. Positive substrates diclofenac (Sigma SLBV3438), dextromethorphan (TRC 3-EDO-175-1) and midazolam (Cerilliant FE01161704) 4. Positive inhibitors sulfaphenazole (D. Ehrenstorfer GmbH 109012), quinidine (TCI WEODL-RE) and ketoconazole (Sigma 100M1091V) 5.AB Sciex Triple Quad 5500 Liquid Chromatograph Mass Spectrometer

[0723] Second, test steps 1. Preparation of 100 mM phosphate buffer solution (PBS): 7.098 g Na 2 HPO 4 3.400g KH was weighed, 500mL of pure water was added, and the solution was dissolved by ultrasonication to obtain solution A. 2 PO 4 was weighed, 250 mL of pure water was added, and the solution was dissolved by ultrasonication to prepare solution B. Solution A was placed on a stirrer, and solution B was slowly added until the pH value reached 7.4 to prepare 100 mM PBS buffer solution.

[0724] 2. 10mm NADPH solution was prepared in 100mm PBS buffer. 10mm stock solutions of the disclosed compounds were diluted with DMSO to obtain 200x compound working solutions (6000, 2000, 600, 200, 60, 20, 0μm). Positive inhibitor stock solutions were diluted with DMSO to obtain 200x positive inhibitor working solutions (sulfaphenazole, 1000, 300, 100, 30, 10, 3, 0μm, quinidine / ketoconazole, 100, 30, 10, 3, 1, 0.3, 0μm). 200x substrate working solutions (120μm diclofenac, 400μm dextromethorphan and 200μm midazolam) were prepared in water, acetonitrile or acetonitrile / methanol. 3.2μL of 20mg / ml liver microsome solution, 1μL of substrate working solution, 1μL of compound working solution and 176μL of PBS buffer were taken, mixed uniformly and pre-incubated in 37℃ water bath for 15 minutes. In the positive control group, 1μL of diclofenac, dextromethorphan or midazolam working solution was added instead of compound working solution. Along with that, 10mm NADPH solution was pre-incubated together in 37℃ water bath for 15 minutes. After 15 minutes, 20μL of NADPH was taken and added to each well to start the reaction and incubated at 37℃ for 5 minutes (CYP2C9), 20 minutes (CYP2D6) or 5 minutes (CYP3A4). Duplicate samples were set for all incubation samples. After the corresponding time of incubation, 400μL of iced methanol containing internal standard was added to all samples to stop the reaction. It was mixed uniformly by vortexing and centrifuged at 3220 g for 40 min at 4° C. After centrifugation was completed, 100 μL of the supernatant was transferred to a loading plate, and 100 μL of ultrapure water was added and mixed uniformly for LC-MS / MS analysis.

[0725] The reduction in metabolite production in the drug-treated group versus the control group was compared by the ratio of the sample to internal standard peak area, and the IC was calculated using Excel XLfit 5.3.1.3. 50 values ​​were calculated.

[0726] The remaining activity rate was calculated using the following formula:

number

[0727] Drug-drug interaction (DDI) refers to physical or chemical changes caused by two or more drugs, and changes in drug efficacy due to these changes. Knowing drug-drug interactions can provide better pharmaceutical services to patients, promote rational drug use, and maximize the avoidance of adverse reactions. Drug-drug interactions are mainly metabolic interactions, and metabolic interactions are mainly related to CYP450 enzymes involved in drug metabolism. The experimental results in Table 6 show that the compounds disclosed herein have weak inhibitory power against CYP450, suggesting that the compounds disclosed herein have a small potential risk of causing DDI.

[0728] [Table 11] Test Example 7: hERG Inhibitory Activity Assay of Compounds of the Present Disclosure

[0729] The inhibition of hERG activity by the compounds of the present disclosure was measured by the following test method.

[0730] JPEG2024532768000149.jpg238156JPEG2024532768000150.jpg31151

[0731] II. Cell lines and cell culture A CHO cell line stably expressing the hERG ion channel was purchased from B'SYS GmbH, Switzerland. The cell line was cultured in F-12 (HAM) medium containing 10% FBS buffer, 100 U / mL penicillin-streptomycin, 100 μg / mL hygromycin and 100 μg / mL G418. Pancreatin substitute TrypLE TM Express was used to digest and passage the cells, passaged three times a week, and maintained approximately 80% confluent.

[0732] 3. Preparation of intracellular / extracellular fluids and test compound solutions extracellular fluid 1) NMDG 60 standard external solution: 80 mm sodium chloride, 60 mm NMDG, 4 mm potassium chloride, 2 mm calcium chloride, 1 mm magnesium chloride, 5 mm polyglucose, 10 mm HEPES, pH adjusted to 7.4 with HCl, osmolality 289 mOsm / kg; 2) NMDG 60 cell sealing solution: 80 mM sodium chloride, 60 mM NMDG, 4 mM potassium chloride, 10 mM calcium chloride, 1 mM magnesium chloride, 5 mM polyglucose, 10 mM HEPES, pH adjusted to 7.4 with HCl, osmolality 313 mOsm / kg; 3) Chip filling solution: 140 mM sodium chloride, 4 mM potassium chloride, 5 mM polyglucose, 10 mM HEPES, pH adjusted to 7.4 with NaOH, osmolality 289 mOsm / kg; 4) Standard external solution: 140 mM sodium chloride, 4 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, 5 mM polyglucose, 10 mM HEPES, pH adjusted to 7.4 with NaOH, osmolality 298 mOsm / kg.

[0733] intracellular fluid KF110 intracellular solution: 10 mm EGTA, 10 mm HEPES, 10 mm potassium chloride, 10 mm sodium chloride, 110 mm potassium fluoride, pH adjusted to 7.2 with KOH, osmolality greater than 280 mOsm / kg.

[0734] Test compound solution 1) The test compound was dissolved in DMSO to prepare a stock solution with a final concentration of 10 mM. 2) The stock solution was diluted 1:3 with DMSO to form three other intermediate concentration solutions, with concentrations of 3.33, 1.11 and 0.37 (mM), respectively. 3) Before the experiment started, the gradient solutions of the test compounds were rediluted 1:500 with extracellular fluid to form a working series of concentrations, the final concentrations of which were 20, 6.66, 2.22, and 0.74 (μM), respectively, which were obtained by diluting the 60 μm working solution 3:500 with the 10 mM stock solution. During the experiment, 40 μL of working solution was added to 40 μL of cell solution to obtain a compound working solution with 2x the test concentration. 4) Fit the dose-effect curve by testing the potential inhibitory effects on the hERG channel of five different concentration points in the specified concentration gradient of 30, 10, 3.33, 1.11 and 0.37 μM and obtain the corresponding IC 50 values ​​were calculated.

[0735] 4. Experimental steps Preparation before the experiment 1) I ran "Home All Axes" on my SyncroPatch 384i system. 2) The "LH_Startup" method was run to clean the instruments before starting the experiment. 3) Tube No. 1 was placed in the bottle containing the intracellular solution and placed in position No. 1, prefilling it with intracellular solution. 4) Place the prepared extracellular solution and compound plates with working concentrations into the corresponding plate positions on the instrument and the experiment is ready.

[0736] Cell treatment 1) Adherent cells were removed from two T175 culture flasks and the upper layer of medium was discarded. 2) At room temperature, 8 mL of DPBS-2 mm EDTA was aspirated with a 10 mL pipette and washed twice to remove excess medium. 3) Add 3 mL of TrypLE to the culture flask. TM Express was added and gently shaken so that the solution covered the entire cell surface. 4) Half the volume of digestive fluid was removed, leaving only a thin layer on the surface of the cells. 5) The cells were incubated at 37°C for 8 to 10 minutes, and then gently shaken under a microscope to observe whether the cells floated. 6) 10 mL of F-12 medium containing 15 mm HEPES was prepared in a centrifuge tube, and 10 mL of the standard external solution was added. 3 mL of the mixed solution was added to each culture flask, and the mixture was incubated in a refrigerator at 4 to 8 °C for 5 minutes. 7) The cells were gently pipetted 3 to 5 times to disperse the cells, and then transferred to a 10 cm cell culture dish. 8) Count the cells and dilute them with cold standard solution until the final density is 0.5-2*10 6 The total cell count was ensured to be 1.25× / mL. 9) The diluted cell suspension was transferred to a 10 cm low-adhesion cell culture dish and incubated at 4 to 10°C for 10 minutes. 10) The cells were gently pipetted to mix evenly, transferred to a Teflon plate dedicated to the SyncroPatch 384i system, placed in the cell incubation chamber of the automated patch clamp system, and incubated at 15°C.

[0737] Electrophysiological signals were recorded using a SyncroPatch 384i system. 1) Pipette tips were loaded and washed. 2) The inside of the chip was filled with a chip filling solution to compensate for the binding potential. 3) The cell suspension was added to the inside of the chip. 4) Cell sealing solution was added and the clamp potential was set to -90 mV. 5) The cells were washed four times with extracellular fluid. 6) 5 μM Escin in the internal solution was perforated into the cells to obtain intact cell structures. 7) Analog Cslow and Digital Cslow were compensated. 8) The clamp voltage is set to 500ms and -90mV, the current sampling frequency is 500Hz, and the filtering frequency is 3kHz. The detection conditions for the leakage current are -90mV and the time is 500ms. 9) The hERG tail current can be observed by applying a depolarizing voltage for 4.8 seconds to depolarize the membrane potential from -90mV to +30mV, and then applying a repolarizing voltage instantaneously to reduce the membrane potential to -50mV and last for 5.2 seconds to remove channel deactivation, and the peak value of the tail current is the magnitude of the hERG current. The sampling interval of the stimulation pattern is 15 seconds. 10) The hERG current for detecting the test compound was continuously recorded for 120 seconds before administration to evaluate the stability of the hERG current generation of the test cells. Only the stabilized cells that were within the acceptable range of the evaluation criteria could have reliable subsequent detection results. 11) The detection baseline was determined by measuring a stable hERG current from among them. After the hERG current was stabilized for at least 5 minutes, a solution containing the test compound was perfused around the cells. After the current became stable, five stable hERG current values ​​were read. If a stable state was not reached within 10 minutes, the last five recorded current peak values ​​were used as the readings. In the experiment, cisapride was used as a positive control to verify the stability of the experimental cells and the accuracy of the experimental results. In this experiment, the inhibitory effects of five different concentrations of samples on the hERG current were detected in two independent experimental well positions (n=2), and the IC 50 was used for curve fitting.

[0738] 5. Data acceptance standards The following standards were used to determine the acceptability of the data: 1) The initial sealing resistance is greater than 100MΩ; 2) Series resistance is less than 25MΩ; 3) The leakage current at the detection voltage is less than 50% of the current value under said conditions; 4) The tail current is larger than the magnitude of the platform current of the prepulse, and the initial tail current value is larger than 150 pA; 5) The tail current decay rate is less than 30%.

[0739] Sixth, data analysis The data that meets the above hERG current quality standards are further analyzed, and the specific steps are as follows: 1) The current rate was calculated using the following formula: [Note] Data was output by Data control 384 software.

number

[0740] None of the compounds disclosed herein significantly inhibit hERG potassium ion channel, indicating that compounds have low risk of causing cardiotoxicity by hERG potassium ion channel inhibition.Details of the hERG potassium ion channel inhibition activity of the compounds disclosed herein are shown in Table 7.

[0741] [Table 12]

Claims

1. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, 【Chemical 1】 where: R １ is halogen, CN, C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl group or C ２ -C ６ alkynyl groups, １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl group or C ２ -C ６ The alkynyl group can optionally be R ａ１ is replaced by X １ is CR ２ or N, R ２ is selected from H, halogen, CN, or R １ , R ２ together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, said 5- to 6-membered heterocyclic group optionally being ａ２ is replaced by R ５ is H, halogen, CN, NH ２ Or NO ２ or R １ , R ５ together with the atom(s) connected thereto form a 5- to 6-membered heterocyclic group, a 5- to 6-membered heteroaryl group, or C ５ -C ７ A cycloalkenyl group is formed, and the 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, or C ５ -C ７ The cycloalkenyl group optionally can be R ａ５ is replaced by R ３ H, 【Chemistry 2】 and X is selected from NH ２ or OH, R ６ is H or C １ -C ３ alkyl groups, R ７ is H, C １ -C ３ Alkyl group or C ３ -C ６ cycloalkyl groups, or R ６ , R ７ are C atoms together with the C atoms connected to them. ３ -C ６ Forms a cycloalkyl group, ３ -C ６ The cycloalkyl group may optionally be R ａ３ is replaced by n is selected from 1, 2, 3 or 4; R ４ is selected from H, or R ４ , R ７ together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group, said 5- to 6-membered heterocyclic group optionally being ａ４ is replaced by Each R ａ１ , R ａ２ , R ａ３ , R ａ４ , R ａ５ is D, halogen, CN, =O, OH, NH ２ , C １ -C ３ Alkyl group, C ３ -C ６ independently selected from cycloalkyl groups or 4- to 7-membered heterocyclic groups, and ２ , C １ -C ３ Alkyl group, C ３ -C ６ The cycloalkyl group or 4- to 7-membered heterocyclic group may optionally be R ｂ is replaced by Each R ｂ is halogen, CN, =O, C １ -C ３ Alkyl groups, OH, O(C １ -C ３ alkyl group), NH ２ , NH(C １ -C ３ alkyl group) or N(C １ -C ３ alkyl group) ２ are independently selected from The conditions are: i) R １ is selected from a methyl group, and R ２ is selected from F, then R ３ teeth, 【Chemistry 3】 where R ６ is H or C １ -C ３ alkyl groups, R ７ is H, C １ -C ３ Alkyl group or C ３ -C ６ cycloalkyl groups, n is selected from 1, 2, 3, or 4; and ii) X is NH ２ When selected from ５ is not selected from H, and iii) the compound of formula (I) is 【Chemistry 4】 A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, which does not include:

2. R １ is a halogen, C １ -C ３ Alkyl group, C ３ -C ６ Cycloalkyl group or C ２ -C ３ alkynyl groups, or R １ is selected from Cl, Br, a methyl group, a cyclopropyl group, or an ethynyl group, or a stereoisomer or a pharmaceutically acceptable salt thereof.

3. R ２ is selected from H, halogen, CN, or R １ , R ２ together with the atoms to which they are attached form a 5- to 6-membered heterocyclic group, said 5- to 6-membered heterocyclic group containing 1 or 2 oxygen atoms as ring atoms, said 5- to 6-membered heterocyclic group optionally substituted with a D atom, or R ２ is selected from H or halogen, or R １ , R ２ together with the atoms to which they are linked form a 5- to 6-membered heterocyclic group, which contains one or two oxygen atoms as ring atoms, and which is optionally substituted with a D atom.

4. R ２ is selected from H, F or Cl, or R １ , R ２ along with the atoms connected to them 【Chemistry 5】 2. The compound of formula (I) according to claim 1, wherein the compound forms:

5. R ３ H, 【Chemistry 6】 wherein X is selected from ２ or OH, R ６ is selected from H or a methyl group, and R ７ is selected from H, a methyl group, an isopropyl group, or a cyclopropyl group optionally substituted with a D atom; R ４ is selected from H, or R ４ , R ７ together with the atoms to which they are connected form a 5-membered heterocyclic group, or R ３ teeth 【Chemistry 7】 and X is selected from ２ or OH, R ６ is selected from H or a methyl group, and R ７ is selected from H, a methyl group, an isopropyl group or a cyclopropyl group optionally substituted with a D atom, or R ３ teeth 【Chemistry 8】 and R ６ is selected from H, and R ７ is selected from H or a cyclopropyl group, or R ６ , R ７ are C atoms together with the C atoms connected to them. ３ -C ６ 2. The compound of formula (I) according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound forms a cycloalkyl group.

6. R １ , R ２ along with the atoms connected to each 【Chemistry 9】 and R ３ is H, 【Chemistry 10】 and R ４ is selected from H, and R ６ is selected from H, and R ７ is selected from H or a cyclopropyl group optionally substituted with a D atom, or R ６ , R ７ are C atoms together with the C atoms connected to them. ３ -C ６ forming a cycloalkyl group, or R １ , R ２ along with the atoms connected to each 【Chemistry 11】 and R ３ teeth 【Chemistry 12】 and R ４ is selected from H, and R ６ is selected from H, and R ７ is selected from a cyclopropyl group optionally substituted with a D atom, or R ６ , R ７ The compound of formula (I) according to claim 1, characterized in that: together with the C atom to which they are linked, form a cyclopropyl group, or a stereoisomer or pharmaceutically acceptable salt thereof.

7. R １ , R ２ along with the atoms connected to each 【Chemistry 13】 and R ３ is H, 【Chemistry 14】 and R ４ is selected from H, and R ６ is selected from H, and R ７ is selected from H or a cyclopropyl group, or R ６ , R ７ are C atoms together with the C atoms connected to them. ３ -C ６ forming a cycloalkyl group, or R １ , R ２ together with the atoms connected to them 【Chemistry 15】 and R ３ teeth 【Chemistry 16】 and R ４ is selected from H, and R ６ is selected from H, and R ７ is selected from H or a cyclopropyl group, or R ６ , R ７ are C atoms together with the C atoms connected to them. ３ -C ６ 2. The compound of formula (I) according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound forms a cycloalkyl group.

8. R ５ is H, halogen, NH ２ Or NO ２ or R １ , R ５ together with the atoms to which they are connected represent a 5- to 6-membered heteroaryl group or C ５ -C ６ forming a cycloalkenyl group, and ５ -C ６ The cycloalkenyl group optionally can be R ａ５ is replaced by, or R ５ are H, Cl, F, NH ２ Or NO ２ or R １ , R ５ together with the atoms connected to them 【Chemistry 17】 2. The compound of formula (I) according to claim 1, wherein the compound forms:

9. Structural Unit 【Chemistry 18】 2. The compound of formula (I) according to claim 1, wherein the compound is selected from the group consisting of:

10. The compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (Ia), or a stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemistry 19】 Here, R １ , R ２ , R ３ , R ４ , R ５ 2. The compound of formula (I) according to claim 1, wherein: is as defined in claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof.

11. The compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (Ib), or a stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemistry 20】 Here, R １ , R ３ , R ４ , R ５ 2. The compound of formula (I) according to claim 1, wherein: is as defined in claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof.

12. A compound of formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof, 【Chemical 21】 where: R ８ is a hydroxy group, halogen, CN, C １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl group or C ２ -C ６ alkynyl groups, X ２ is CR ９ or N, R ９ is selected from H, halogen, CN, or R ８ , R ９ form a 5- to 6-membered heterocyclic group together with the atoms to which they are connected; R １０ , R １１ is H, C ３ -C ６ independently selected from cycloalkyl groups, or R １０ , R １１ are C atoms together with the C atoms connected to them. ３ -C ６ A compound of formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof, which forms a cycloalkyl group.

13. or a stereoisomer or a pharmaceutically acceptable salt thereof, said compound being 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. Use of the compound according to any one of claims 1 to 13, or a stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of an antitumor drug.

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