Aminopyridone macrolide compound and use thereof

Abstract

The present invention relates to an aminopyridone macrolide compound and the use thereof. Specifically disclosed is a compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound of the present invention exhibits antibacterial, antimycoplasmal or antichlamydial activity, and can be used for preventing and / or treating related diseases caused by bacteria, mycoplasmas or chlamydias. Further, the compound of the present application can achieve an antibacterial activity comparable to or better than that of azithromycin or solithromycin at a lower dosage. Still further, the compound of the present application exhibits a superior antibacterial effect on Gram-positive bacteria. Even further, the compound of the present application exhibits a better inhibitory activity against mycoplasmas and a lower hepatotoxicity.

Description

Aminopyridone macrolides and their uses

[0001] This application claims priority to Chinese patent applications filed on October 24, 2024 (2024114925853), December 13, 2024 (2024118433487), January 15, 2025 (2025100642374), and January 23, 2025 (2025101081409). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of organic medicine, specifically to a macrolide compound, its preparation method, and its uses. Background Technology

[0003] Macrolide antibiotics are a class of drugs with similar chemical structures and antibacterial activities. They are widely used in clinical practice due to their strong antibacterial activity, broad antibacterial spectrum, significant efficacy, and low likelihood of inducing resistance. Studies have shown that macrolide antibiotics can bind to the L27 and L22 proteins of the 50S subunit of bacterial ribosomes, inhibiting bacterial protein synthesis and thus exerting their antibacterial effect. Macrolide antibiotics can be used to treat infections caused by Gram-positive cocci (G+ cocci) and atypical pneumonia pathogens, and can serve as a suitable alternative for treating upper and lower respiratory tract and soft tissue infections in patients allergic to penicillin, with widespread clinical application. However, the long-term use of macrolide drugs has led to antibiotic resistance problems, with resistance rates increasing exponentially over the past 10 years. The three main reasons for bacterial biological tolerance to macrolides are ribosomal methylation encoded by the erm gene, mutations in ribosomal RNA or peptides, and efflux mediated by the mef and msr genes.

[0004] Currently, the pace of introducing new antibiotics cannot adequately address the growing problem of drug resistance. Furthermore, the increasing exchange of people between different regions of the world and the increasing population density make the need for innovation in this field increasingly urgent. The mainstream macrolide antibiotics on the market, azithromycin and erythromycin, have been available for many years, primarily targeting Gram-positive bacteria and infectious diseases such as Mycoplasma pneumoniae infection. However, due to antibiotic overuse, pathogen sensitivity is low. Meanwhile, azithromycin is a commonly used drug for treating community-acquired pneumonia, especially pneumonia caused by Mycoplasma pneumoniae, but at least 80% of the population has developed significant drug resistance, leaving children under 8 years old facing a lack of effective treatments. If the drug resistance problem persists, quinolone drugs with significant side effects will be needed, threatening children's health. There is an urgent need to develop safe, effective, and highly targeted alternative drugs.

[0005] With the advancements in macrolide drug development, following the market launch of azithromycin, macrolide drugs telithromycin and solithromycin also underwent relevant clinical trials. Telithromycin did not demonstrate effective antibacterial activity against azithromycin-resistant Mycoplasma pneumoniae strains, while solithromycin showed some antibacterial activity. However, due to the hepatotoxicity of solithromycin, it failed to meet the corresponding safety evaluation standards after the completion of Phase III clinical trials, and the FDA rejected its marketing application. Therefore, currently, since the launch of azithromycin, no macrolide drug has been launched that truly addresses azithromycin resistance and has a good safety profile, and clinical needs remain unmet. Summary of the Invention

[0006] To overcome the shortcomings of existing technologies, such as the limited variety of macrolide compounds and the tendency for antibiotic resistance to develop, this invention provides a macrolide compound, its preparation method, and its uses. This macrolide compound exhibits good antibacterial activity against both Gram-positive and Gram-negative bacteria, as well as good inhibitory activity against mycoplasma and good hepatotoxicity.

[0007] This invention provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0008] in,

[0009] L is an alkylene group or an alkenylene group; the alkylene group and the alkenylene group are optionally substituted with one or more deuterium groups;

[0010] X is CR 1 R 2 or The It can be replaced by one or two deuteriums;

[0011] Ring A is a heteroaryl group; the heteroaryl group is a heteroaryl group with one or more heteroatoms selected from N, O and S, and the number of heteroatoms is one or more; the heteroaryl group is optionally substituted by one or more deuteriums;

[0012] R 1 and R 2 Independently, it is H, deuterium, OH, NH2, CN, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, O-alkyl, O-cycloalkyl, or heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, O-alkyl, O-cycloalkyl, and heteroaryl are optionally substituted by any substituent; the heteroaryl is a heteroatom selected from one or more of N, O, and S, and the number of heteroatoms is one or more.

[0013] Or, R 1 R 2Together with the carbon atom attached thereto, a heterocyclic group is formed; the heterocyclic group is a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is independently one or more; the heterocyclic group may be optionally substituted by any substituent;

[0014] R is

[0015] R 3 For H, deuterium, CN, CONR 3-1 R 3-2 COOR 3-3 Alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl groups are optionally substituted with any substituents;

[0016] R 3-1 R 3-2 and R 3-3 Independently, it is H or an alkyl group; the alkyl group may optionally be substituted with any substituent;

[0017] R 4 The alkyl group is H or an alkyl group; the alkyl group may optionally be substituted with any substituent.

[0018] R 5 The group is H, deuterium, alkyl, aryl, heteroaryl, or heterocyclic; the alkyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted by any substituents; the heteroaryl group is a heteroatom selected from one or more of N, O, and S, and the number of heteroatoms is one or more; the heterocyclic group is a heterocyclic group with one or more heteroatoms selected from N, O, and S.

[0019] R 6 It can be H, deuterium, or methyl.

[0020] In a preferred embodiment, certain groups in the compound represented by Formula I or its pharmaceutically acceptable salt have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a preferred embodiment").

[0021] In a preferred embodiment, each heteroaryl group is independently a 5-14-membered heteroaryl group, preferably a 5-10-membered heteroaryl group, more preferably a 5-6-membered heteroaryl group or an 8-10-membered heteroaryl group; wherein, the 5-6-membered heteroaryl group can be independently "a 5-6-membered heteroaryl group whose heteroatoms are selected from one or two of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4", preferably a pyridyl group (e.g. ), diazoles (e.g., pyrazole or imidazole, and for example...) ), triazoles (e.g., 1,2,3-triazole or 1,2,4-triazole, and for example...) ), pyrimidine (e.g.) ), thiazolyl (e.g.) ), oxazolyl (e.g.) ), tetrazolium (e.g.) ).

[0022] In a preferred embodiment, the pyrazole group is

[0023] In a preferred embodiment, the pyridinyl group is

[0024] In a preferred embodiment, the 5-14 member heteroaryl group is independently... pyridinyl, pyrimidinyl, or pyrazinyl, for example

[0025] In a preferred embodiment, each alkyl group may independently be C10. 1-10 Alkyl group, preferably C 1-6 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0026] In a preferred embodiment, each alkylene group may independently be C10. 1-10 Alkylene, preferably C 1-6 Alkylene, more preferably C 1-4 Alkylenes, for example,

[0027] In a preferred embodiment, the C 1-10 alkylene

[0028] In a preferred embodiment, each alkenyl group can independently be C10. 2-10 Alkenyl group, preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl, for example,

[0029] In a preferred embodiment, each alkenyl group can independently be C 2-10 Alkenyl group, preferably C 2-6 alkenyl, more preferably C 2-4 imidene groups, for example,

[0030] In a preferred embodiment, each cycloalkyl group may independently be C10. 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl, more preferably C 3-8 Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0031] In a preferred embodiment, each cycloalkyl group may independently be C10. 3-14 Monocyclic alkyl.

[0032] In a preferred embodiment, the alkyl group in each O-alkyl group may be independently C10. 1-10 Alkyl group, preferably C 1-6 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0033] In a preferred embodiment, the cycloalkyl group in each O-cycloalkyl group may be independently C. 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl, more preferably C 3-8 Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0034] In a preferred embodiment, the cycloalkyl group in each O-cycloalkyl group may be independently C. 3-14 Monocyclic alkyl.

[0035] In a certain preferred solution, each C 3-14 Monocycloalkyl groups can be independently C10. 3-10 Monocycloalkyl, preferably C 3-8 Monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0036] In a preferred embodiment, each heterocyclic group may be independently a 3-14 membered heterocyclic group, preferably a 3-10 membered heterocyclic group, more preferably a 3-8 membered heterocyclic group, such as an oxopropyl or anazirhexyl group.

[0037] In a preferred embodiment, each heterocyclic group can be independently a 3-14 nucleotide monoheterocyclic group.

[0038] In a preferred embodiment, each 3-14 member monoheterocyclic group may be independently a 3-10 member monoheterocyclic group, preferably a 3-8 member monoheterocyclic group, such as an oxopropyl or an azirrohexyl group.

[0039] In a preferred embodiment, each heterocyclic group contains N heteroatoms of either 1 or 2 heteroatoms.

[0040] In a preferred embodiment, each heterocyclic group is independently a partially saturated 3-14 membered heterocyclic group, wherein the number of double bonds in the partially saturated 3-14 membered heterocyclic group is one or two; more preferably, the partially saturated 3-14 membered heterocyclic group is a partially saturated 5-6 membered heterocyclic group, for example... For example

[0041] In a preferred embodiment, each aryl group can be independently C 6-14 Aryl, preferably C 6-10 Aryl, more preferably phenyl or naphthyl.

[0042] In a preferred embodiment, the halogen is fluorine, chlorine, bromine, or iodine, such as fluorine.

[0043] In a certain preferred solution,

[0044] L is C 1-10 Alkylene or C 2-10 alkenyl; the C 1-10 alkylene and the C 2-10 The alkenyl group may be optionally substituted with one or more deuterium groups;

[0045] X is CR 1 R 2 or The It can be replaced by one or two deuteriums;

[0046] Ring A is a 5-14 membered heteroaryl group; the heteroatoms of the 5-14 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of heteroatoms in the 5-14 membered heteroaryl group is one, two, three or four; the 5-14 membered heteroaryl group is optionally substituted by one or more deuteriums;

[0047] R 1 and R 2 Independently, H, deuterium, OH, NH2, CN, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl, C 5-14 Cycloalkenyl, OC 1-10 Alkyl, OC 3-14 cycloalkyl or 5-14-membered heteroaryl; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl, C 5-14 cycloalkenyl, the OC 1-10 Alkyl, the OC 3-14 The cycloalkyl group and the 5-14 heteroaryl group are optionally surrounded by one, two, or three R groups. 1-1 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4;

[0048] Each R 1-1 Independently deuterium, OH, halogen, SO3R1-1-1 or COOR 1-1-2 ;

[0049] R 1-1-1 and R 1-1-2 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0050] Or, R 1 R 2 Together with the carbon atom attached thereto, a 3-14 membered heterocyclic group is formed; the 3-14 membered heterocyclic group is a 3-14 membered heterocyclic group in which the heteroatoms are selected from one or two of N, O and S, and the number of heteroatoms is independently one or two; the 3-14 membered heterocyclic group is optionally substituted by one or more deuteriums;

[0051] R is

[0052] R 3 For H, deuterium, CN, CONR 3-1 R 3-2 COOR 3-3 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl, C 6- 14 Aryl and 5-14 heteroaryl groups; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl, the C 6-14 The aryl group and the 5-14 heteroaryl group are optionally surrounded by one, two, or three R groups. 3-4 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4;

[0053] R 3-1 R 3-2 and R 3-3 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0054] Each R 3-4 Independently deuterium, OH, halogen, NR 3-4-1 R 3-4-2 , C 1-10 Alkyl or 5-14-membered heteroaryl; the C 1-10The alkyl group and the 5-14-membered heteroaryl group are optionally surrounded by one, two, or three R groups. 3-4-4 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4;

[0055] R 3-4-1 and R 3-4-2 H independently Or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0056] R 3-4-3 C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0057] Each R 3-4-4 Independent of deuterium, OH, NR a R b Or C 1-10 Alkyl; the C 1-10 Alkyl groups are optionally surrounded by one, two, or three R's. 3- 4-4-1 replace;

[0058] R a and R b H independently Or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups;

[0059] Each R 3-4-4-1 It can be independently deuterium, OH, or NH2;

[0060] R 4 For H or C 1-10 Alkyl; the C 1-10 Alkyl groups may be optionally surrounded by one, two, or three R's. 4-1 replace;

[0061] Each R 4-1 Independently deuterium, OH, CN, halogen, NR a R b C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl or C 5-14 Cycloalkenyl; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14cycloalkyl and the C 5-14 The cycloalkenyl group may be optionally substituted with one or more deuterium groups;

[0062] R a and R b H independently Or C 1-10 Alkyl; the C 1-10 The alkyl group may be optionally substituted with one, two, or three deuterium atoms;

[0063] R 5 H, deuterium, C 1-10 Alkyl, C 3-14 cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclic; the C 1-10 Alkyl, the C 6-14 The aryl group, the 5-14 membered heteroaryl group, and the 3-14 membered heterocyclic group are optionally surrounded by one, two, or three R groups. 5-1 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2, or 3 of N, O, and S, and whose number of heteroatoms is 1, 2, 3, or 4; the 3-14 membered heterocyclic group is a 3-14 membered heterocyclic group whose heteroatoms are selected from 1, 2, or 3 of N, O, and S, and whose number of heteroatoms is 1, 2, 3, or 4.

[0064] Each R 5-1 Independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 C 1-10 Alkyl, OC 1-10 Alkyl, C 3-6 cycloalkyl, -NH-CO-C 1-10 Alkyl; the C 1-10 Alkyl, the OC 1-10 Alkyl groups and the -NH-CO-C 1-10 Alkyl groups may be optionally substituted with one or more deuterium, halogen, or hydroxyl groups;

[0065] R 5-1-1 and R 5-1-2 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may be optionally surrounded by one, two, or three R's. 5-1-1-1 replace;

[0066] Each R 5-1-1-1 Independently, it is either deuterium or a 5-14 heteroaryl group; the 5-14 heteroaryl group is a 5-14 heteroaryl group with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, three, or four; the 5-14 heteroaryl group is optionally substituted with one or more deuterium groups;

[0067] R 6 It can be H, deuterium, or methyl.

[0068] In a preferred embodiment, the 5-14-membered heteroaryl group in ring A can be a 5-14-membered heteroaryl group with 2, 3, or 4 heteroatoms, preferably a 5-6-membered heteroaryl group with 2, 3, or 4 heteroatoms, more preferably imidazolyl, 1,2,3-triazole, 1,2,4-triazole, or tetrazolium, for example...

[0069] In a preferred embodiment, in L, the C 1-10 Alkylene can be C 1-6 Alkylene, preferably C 1-4 Alkylene, for example

[0070] In a preferred embodiment, in L, the C 2-10 The subalkenyl group can be C 2-6 Alkenyl group, preferably C 2-4 imidene groups, for example

[0071] In a certain preferred solution, R 1 R 2 R 3 R 4 R 5 R 3-1 R 3-2 R 3-3 R 3-4 R 5-1 R 1-1-1 R 1-1-2 R 3-4-1 R 3-4- 2 R 3-4-3 R 3-4-4 R 5-1-1 R 5-1-2 R a and R b In, the C 1-10 Alkyl groups can be independently C10. 1-6 Alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0072] In a certain preferred solution, R 1 R 2 and R 3 In, the C 2-10 The alkenyl group can be independently C 2-6 Alkenyl, preferably C 2-4 alkenyl, for example

[0073] In a certain preferred solution, R 1 R 2 and R 3 In, the C 2-10 The alkynyl group can be independently C. 2-6 Alkyne group, preferably C 2-4 alkynyl groups, for example

[0074] In a certain preferred solution, R 3 and R 5 In, the C 3-14 Cycloalkyl groups can be independently C10-C20. 3-10 Cycloalkyl, preferably C 3-8 cycloalkyl, more preferably C 3-8 Monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0075] In a certain preferred solution, R 1 R 2 and R 5-1 In the OC 1-10 C in alkyl 1-10 Alkyl groups can be independently C10. 1-6 Alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0076] In a certain preferred solution, R 1 R 2 R 3 R 5 R 3-4 and R 5-1-1-1 In this context, the 5-14 heteroaryl group can be independently a 5-6 heteroaryl group or an 8-10 heteroaryl group;

[0077] The 5-6 membered heteroaryl group can be independently defined as "a 5-6 membered heteroaryl group whose heteroatoms are selected from one or two of N, O, and S, and whose number of heteroatoms is one, two, three, or four", preferably pyridyl (e.g., ), diazoles (e.g., pyrazole or imidazole, and for example...) ), triazoles (e.g., 1,2,3-triazole or 1,2,4-triazole, and for example...) ), pyrimidine (e.g.) ), thiazolyl (e.g.) ), oxazolyl (e.g.) ), tetrazolium (e.g.) ).

[0078] In a certain preferred solution, L is C1-10 Alkylene or C 2-10 alkenyl group; preferably C 1-6 Alkylene or C 2-6 alkenyl; more preferably C 1-6 Alkylene.

[0079] In a certain preferred solution, L is C 4-6 Alkylene.

[0080] In a certain preferred solution, X is CR 1 R 2 .

[0081] In a certain preferred solution, R 1 and R 2 Independently halogen or C 1-6 alkyl.

[0082] In a certain preferred solution, R 1 C 1-6 Alkyl, R 2 It is a halogen.

[0083] In a preferred embodiment, ring A is a 5-10-membered heteroaryl group, preferably a 5-6-membered heteroaryl group, and more preferably a diazole (e.g., imidazole), a triazole (e.g., 1,2,3-triazole or 1,2,4-triazole) or a tetraazole.

[0084] In a preferred embodiment, ring A is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl.

[0085] In a preferred embodiment, ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0086] In a certain preferred solution, R 1 C 1-10 Alkyl, R 2 It is H, OH or halogen; or R 1 C 1-10 Alkyl, R 2 It is H or halogen;

[0087] For example, R 1 C 1-6 Alkyl, R 2 It is H, OH or halogen; or R 1 C 1-6 Alkyl, R 2 It is H or halogen.

[0088] In a certain preferred solution, R is R 6 For H, R 3For H or C 1-6 Alkyl groups, such as R 3 C 1-6 alkyl.

[0089] In a certain preferred solution, R 4 For H or C 1-10 Alkyl; preferably H or C 1-6 alkyl.

[0090] In a certain preferred solution, R 4 C 1-6 alkyl.

[0091] In a certain optimal solution, each R 5-1 Independently halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 C 1-10 Alkyl, OC 1-10 Alkyl, C 3-6 cycloalkyl; preferably, each R 5-1 Independently for oxygenation, NR 5-1-1 R 5-1-2 C 1-10 Alkyl or OC 1-10 Alkyl; more preferably, each R 5-1 Independently for oxygenation, NR 5-1-1 R 5-1-2 C 1-6 Alkyl or OC 1-6 Alkyl groups; for example, each R 5-1 Independent for NR 5-1-1 R 5-1-2 For example, each R 5-1 It is independently NH2.

[0092] In a certain preferred solution, R 5-1-1 and R 5-1-2 Independently H or C 1-10 Alkyl; preferably H or C 1-6 alkyl.

[0093] In a certain optimal solution, each R 5-1-1-1 Independently, it is a 5-14 membered heteroaryl group; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, three, or four; preferably, each R 5-1-1-1 Independently, it is a 5-10 quinone heteroaryl group; more preferably, each R 5-1-1-1 It is independently a 5-6 member heteroaryl group.

[0094] In a certain preferred solution, R 5The heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl group is optionally surrounded by 1, 2 or 3 R atoms. 5-1 Substitution; preferably, the number of heteroatoms is 2.

[0095] In a certain preferred solution, R 5 The heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl group is surrounded by 1, 2 or 3 R atoms. 5-1 Replacement, and at least one R 5-1 It is a hydroxyl group;

[0096] Preferably, the 5-6 membered heteroaryl group is surrounded by 2 or 3 R groups. 5-1 Replacement, at least one R 5-1 It is a hydroxyl group; and, at least one R 5-1 It is an amino group.

[0097] In a certain preferred solution, R 5 The heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl group is surrounded by 4 or 5 R atoms. 5-1 Replacement, and at least one R 5-1 It is a hydroxyl group;

[0098] Preferably, the 5-6 membered heteroaryl group is surrounded by 2 or 3 R groups. 5-1 Replacement, at least one R 5-1 For hydroxyl, and, at least one R 5-1 It is an amino group.

[0099] In a certain preferred solution, R 5 The partially saturated 5-6 membered heterocyclic group is a N heteroatom, and the number of heteroatoms in the partially saturated 5-6 membered heterocyclic group is independently one or two; the partially saturated 5-6 membered heterocyclic group is separated by one, two or three R atoms. 5-1 Replacement, and at least one R 5-1 For oxygenation;

[0100] Preferably, the partially saturated 5-6 membered heterocyclic group is surrounded by 2 or 3 R groups. 5-1 Replacement, at least one R 5-1 For oxidation; and, at least one R 5-1 It is an amino group.

[0101] In a certain preferred solution, R 5 The partially saturated 5-6 membered heterocyclic group is a N heteroatom, and the number of heteroatoms in the partially saturated 5-6 membered heterocyclic group is independently one or two; the partially saturated 5-6 membered heterocyclic group is separated by four or five R atoms.5-1 Replacement, and at least one R 5-1 For oxygenation;

[0102] Preferably, at least one R 5-1 For oxidation; and, at least one R 5-1 It is an amino group.

[0103] In a certain preferred solution, R 5-1 Independently -NH2, deuterium, halogen, oxo or C 1-6 Alkyl groups, such as -NH2, deuterium, halogens, or C 1-6 alkyl.

[0104] In a certain preferred solution, R 5-1 Independently -NH2, deuterium, halogen, hydroxyl or C 1-6 alkyl.

[0105] In a certain preferred solution, R 5-1 It is -NH2.

[0106] In a certain preferred solution, R 5-1 Independently deuterium, halogen, oxo or C 1-6 Alkyl; for example, independently deuterium, halogen or C 1-6 alkyl.

[0107] In a certain preferred solution, R 5-1 Independently deuterium, halogen, hydroxyl or C 1-6 alkyl.

[0108] In a certain preferred solution, R 5-1 Independent of deuterium, halogen, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may be optionally substituted with one or more substituents selected from deuterium and halogens.

[0109] In a certain preferred solution, R 5 for (and (for tautomers) or (and (for tautomers) or their tautomers;

[0110] R 5-1a It is an amino group;

[0111] t is 0, 1, or 2;

[0112] R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6Alkyl groups and the OC 1-6 The alkyl group may optionally be substituted with one or more substituents selected from deuterium and halogens; preferably, R 5-1 For deuterium, C 1-6 Alkyl or OC 1-6 Alkyl; more preferably, R 5-1 For deuterium or OC 1-6 alkyl.

[0113] In a certain preferred solution, R is

[0114] In a certain preferred solution, R 6 It is H or methyl.

[0115] In a certain preferred solution, R 6 For H.

[0116] In a certain preferred solution, R 3 For H.

[0117] In one of the schemes,

[0118] L is C 1-6 Alkylene or C 2-6 alkenyl;

[0119] X is CR 1 R 2 ;

[0120] Ring A is tetrazolium;

[0121] R 1 C 1-6 alkyl;

[0122] R 2 It can be H, OH or halogen;

[0123] R is

[0124] R 3 For H, C 1-6 Alkyl or 5-6-membered heteroaryl; the 5-6-membered heteroaryl is a 5-6-membered heteroaryl with one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two, three or four.

[0125] R 4 For H or C 1-6 alkyl;

[0126] R 5 For H, C 6-14 Aryl or 5-10 heteroaryl; the C 6-14 The aryl group and the 5-10 heteroaryl group are optionally surrounded by one, two, or three R groups. 5-1Substitution; the 5-10 membered heteroaryl group is a 5-10 membered heteroaryl group with one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two, three or four;

[0127] Each R 5-1 Independently oxygenated, hydroxylated, NR 5-1-1 R 5-1-2 C 1-6 Alkyl or OC 1-6 alkyl;

[0128] R 5-1-1 and R 5-1-2 Independently H or C 1-6 Alkyl; the C 1-6 Alkyl groups may be optionally surrounded by one, two, or three R's. 5-1-1-1 replace;

[0129] Each R 5-1-1-1 Independently, it is a 5-6 membered heteroaryl; the 5-6 membered heteroaryl is a 5-6 membered heteroaryl with one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two, three or four.

[0130] R 6 For H.

[0131] In a preferred embodiment, the compound as shown in Formula I,

[0132] R 5 The partially saturated 5-6 membered heterocyclic group is a N heteroatom, and the number of heteroatoms in the partially saturated 5-6 membered heterocyclic group is 1 or 2; the partially saturated 5-6 membered heterocyclic group is surrounded by 1, 2, 3, 4 or 5 R atoms. 5-1 Replace; and at least one R 5-1 For oxygenation;

[0133] R 5-1 Independently -NH2, deuterium, halogen, oxo or C 1-6 alkyl;

[0134] Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0135] L is C 4-6 Alkylene; the C 4-6 The alkylene group may be optionally substituted with one or more deuterium groups;

[0136] X is CR 1 R 2 ;

[0137] R 1 It is a halogen;

[0138] R 2 C 1-6 alkyl

[0139] R is R 6 For H, R 3 For H or C 1-6 alkyl;

[0140] R 4 C 1-6 alkyl.

[0141] In a preferred embodiment, the compound as shown in Formula I,

[0142] R 5 It is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl group is surrounded by 1, 2, 3, 4 or 5 R atoms. 5-1 Replace; and at least one R 5-1 It is a hydroxyl group;

[0143] R 5-1 Independently -NH2, deuterium, halogen, hydroxyl or C 1-6 alkyl;

[0144] Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0145] L is C 4-6 Alkylene; the C 4-6 The alkylene group may be optionally substituted with one or more deuterium groups;

[0146] X is CR 1 R 2 ;

[0147] R 1 It is a halogen;

[0148] R 2 C 1-6 alkyl;

[0149] R is R 6 For H, R 3 For H or C 1-6 alkyl

[0150] R 4 C 1-6 alkyl.

[0151] In a preferred embodiment, the compound as shown in Formula I,

[0152] R 5 The partially saturated 5-6 membered heterocyclic group is a N heteroatom, and the number of heteroatoms in the partially saturated 5-6 membered heterocyclic group is 1 or 2; the partially saturated 5-6 membered heterocyclic group is surrounded by 2, 3, 4 or 5 R atoms. 5-1 Replacement, and at least one R 5-1 For oxidation, and, at least one R 5-1 It is an amino group;

[0153] R 5-1 Independently -NH2, deuterium, halogen, oxo or C 1-6 alkyl;

[0154] Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0155] L is C 4-6 Alkylene; the C 4-6 The alkylene group may be optionally substituted with one or more deuterium groups;

[0156] X is CR 1 R 2 ;

[0157] R 1 It is a halogen;

[0158] R 2 C 1-6 alkyl;

[0159] R is R 6 For H, R 3 For H or C 1-6 alkyl;

[0160] R 4 C 1-6 alkyl.

[0161] In a preferred embodiment, the compound as shown in Formula I,

[0162] R 5 The heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl group is surrounded by 2, 3, 4 or 5 R atoms. 5-1 Replace; and at least one R 5-1 For hydroxyl, and, at least one R 5-1 It is an amino group;

[0163] R 5-1 Independently -NH2, deuterium, halogen, hydroxyl or C 1-6 alkyl;

[0164] Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0165] L is C 4-6 Alkylene; the C 4-6 The alkylene group may be optionally substituted with one or more deuterium groups;

[0166] X is CR 1 R 2 ;

[0167] R 1 It is a halogen;

[0168] R 2 C 1-6 alkyl;

[0169] R is R 6 For H, R 3 For H or C 1-6 alkyl;

[0170] R 4 C 1-6 alkyl.

[0171] In a preferred embodiment, the compound shown in Formula I is a compound shown in Formula I-1 or I-1' (in Formula I-1') With Equation I-1 (For tautomerism):

[0172] (Right now

[0173] )

[0174] in:

[0175] R L It can be H, D, or -CH3;

[0176] Ring A (i.e., W) 1 The 5-membered heteroaryl group is selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0177] R 5-1a It is -NH2;

[0178] t is 0, 1, or 2;

[0179] R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may optionally be substituted with one or more substituents selected from deuterium and halogens; preferably, R 5-1 It can be D, -CH3, or halogen independently.

[0180] In a preferred embodiment, the compound shown in Formula I-1 is a compound shown in Formula I-1-A or a tautomer thereof:

[0181] in:

[0182] R L It can be H, D, or -CH3;

[0183] Ring A (W) 1 The 5-membered heteroaryl group is selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0184] R 5-1a It is -NH2;

[0185] t is 0, 1, or 2;

[0186] R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may optionally be substituted with one or more substituents selected from deuterium and halogens; preferably, R 5-1 Independently D, -CH3, or halogen;

[0187] Preferably, for Or its tautomers.

[0188] In a preferred embodiment, the compound or its tautomer as shown in Formula I-1-A contains:

[0189] Ring A is The alkyl group is attached at position "1" and the pyridone group is attached at position "2".

[0190] for Or its tautomers;

[0191] t is 0 or 1;

[0192] R 5-1 For deuterium or OC 1-6 alkyl.

[0193] In a preferred embodiment, the compound shown in Formula I-1 is a compound shown in Formula I-1-B or a tautomer thereof:

[0194] in:

[0195] R L It can be H, D, or -CH3;

[0196] Ring A (W) 1 The 5-membered heteroaryl group is selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0197] R 5-1a It is -NH2;

[0198] t is 0, 1, or 2;

[0199] R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may optionally be substituted with one or more substituents selected from deuterium and halogens; preferably, R 5-1 Independently D, -CH3, or halogen;

[0200] Preferably, for Or its tautomers.

[0201] In a preferred embodiment, the compound or its tautomer as shown in Formula I-1-B contains:

[0202] Ring A is The alkyl group is attached at position "1" and the pyridone group is attached at position "2".

[0203] for Or its tautomers;

[0204] t is 0 or 1;

[0205] R 5-1 For deuterium or OC 1-6 alkyl.

[0206] In a preferred embodiment, the compound shown in Formula I-1 is a compound shown in Formula I-1-C or a tautomer thereof:

[0207] in:

[0208] R L It can be H, D, or -CH3;

[0209] W 1 It is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3;

[0210] R 5-1a It is -NH2;

[0211] t can be 0, 1, or 2; preferably, t can be 0.

[0212] R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may optionally be substituted with one or more substituents selected from deuterium and halogens; preferably, R 5-1 Independently D, -CH3, or halogen;

[0213] In one embodiment, the compound shown in formula I-1-C, for Or its tautomers; preferably, ring A is The "1" position is connected to an alkyl group, and the "2" position is connected to a pyridone group.

[0214] In a preferred embodiment, the compound shown in Formula I is a compound shown in Formula I-2 or a tautomer thereof:

[0215] R L It can be H, D, or -CH3;

[0216] Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0217] R 5-1a It is -NH2;

[0218] t is 0, 1, or 2;

[0219] R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may optionally be substituted by one or more substituents selected from deuterium and halogens;

[0220] Ideally, ring A is... The alkyl group is attached at position "1" and the pyridone group is attached at position "2".

[0221] Ideally, t is 0.

[0222] In a certain preferred solution, L is

[0223] In a certain preferred solution, L is

[0224] In a preferred embodiment, ring A is diazole, triazole, or tetraazole; wherein the diazole is preferably imidazole, and the triazole is preferably 1,2,3-triazole.

[0225] In a certain preferred scheme, ring A is

[0226] In a certain preferred scheme, ring A is

[0227] In one of the schemes, for Bit "1" connects to L, and bit "2" connects to R. 5 ; better, for Bit "1" connects to L, and bit "2" connects to R. 5 Better yet, for

[0228] In a certain preferred solution, R 1-1-2 It is CH3.

[0229] In a certain preferred solution, R 1-1-1 For H.

[0230] In a certain preferred solution, R 1-1 It can be OH, halogen, COOCH3 or SO3H.

[0231] In a certain preferred solution, R 1 It can be H, F, OH or CH3.

[0232] In a certain preferred solution, R 2 For H, F, OH, CN, OCH3, CH3, CH2F, CH2OH, For example, R 2 The possible values ​​are H, F, OH, CN, OCH3, CH3, CH2F, and CH2OH.

[0233] In a certain preferred solution, R 1 R2 Together with the carbon atoms attached to it, they form

[0234] In a certain preferred solution, X is For example, X is

[0235] In a certain preferred solution, R a and R b H independently Or methyl.

[0236] In a certain preferred solution, R 3 H, methyl, cyano, For example, R 3 H, methyl,

[0237] In a certain preferred solution, R 4 It is H or methyl.

[0238] In a certain preferred solution, R 5-1-1-1 Independently

[0239] In a certain preferred solution, R 5-1-1 and R 5-1-2 Independently for H or

[0240] In a certain preferred solution, R 5-1 Independently, it can be Cl, F, CH3, OCH3, NH2, OH, C2H5, -CH2F, -CF3, -CHF2, cyclopropyl, n-propyl, isopropyl, deuterium, -NH-COCH3, -NH-COCF3, for example, R 5-1 Independently, it can be F, CH3, OCH3, NH2, OH, C2H5, -CH2F, -CF3, -CHF2, n-propyl, isopropyl, or deuterium.

[0241] In a certain preferred solution, R 5 For H,

[0242] In a certain preferred solution, R 5 Also for

[0243] In one of the schemes, R 5 for

[0244] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0245] The present invention also provides a pharmaceutical composition comprising (i) a compound of Formula I or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier. The amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is a therapeutically effective amount.

[0246] The present invention also provides the use of the compound represented by Formula I above, its pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of a medicament; said medicament can be used to treat upper and lower respiratory tract and soft tissue infections.

[0247] In one preferred embodiment, the drug is used to treat upper or lower respiratory tract or soft tissue infections, such as lower respiratory tract infections, such as pneumonia, or community-acquired pneumonia or hospital-acquired lung infections.

[0248] In a preferred embodiment, the drug may be a drug that inhibits bacterial activity.

[0249] In a preferred embodiment, the drug is a drug that inhibits the activity of mycoplasma or chlamydia.

[0250] In a preferred embodiment, the drug is an antipathogenic drug, preferably an antibacterial, mycoplasma, or chlamydia drug, such as an antimycoplasma drug.

[0251] The present invention also provides the use of the compound represented by Formula I above, its pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of bacterial-related diseases.

[0252] In a preferred embodiment, the drug may be a drug that inhibits bacterial activity.

[0253] In a preferred embodiment, the bacteria may be Gram-positive and / or Gram-negative bacteria; wherein the Gram-positive bacteria may be selected from one or more of Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes; and the Gram-negative bacteria may be Moraxella catarrhalis and / or Haemophilus influenzae.

[0254] In a preferred embodiment, the bacteria are Streptococcus pneumoniae and / or Streptococcus pyogenes.

[0255] In one embodiment, the bacteria are selected from one or more of Gram-positive bacteria, Gram-negative bacteria, and anaerobic bacteria; for example, with Staphylococcus (e.g., Staphylococcus aureus), Streptococcus (e.g., Streptococcus pneumoniae, Streptococcus pyogenes), Enterococcus, Haemophilus (e.g., Haemophilus influenzae), Moraxella (e.g., Moraxella catarrhalis), Legionella, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobacter, or any combination thereof.

[0256] In a preferred embodiment, the bacterial-related disease is an upper or lower respiratory tract and soft tissue infection, preferably pneumonia.

[0257] In a preferred embodiment, the bacterial-associated disease is an upper respiratory tract infection, a lower respiratory tract infection, or a soft tissue infection.

[0258] The present invention also provides the use of the compound represented by Formula I above, its solvate, its crystal form, its deuterated form, its pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of diseases related to mycoplasma or chlamydia.

[0259] In one embodiment, the chlamydia is Chlamydia pneumoniae.

[0260] In one embodiment, the mycoplasma is Mycoplasma pneumoniae.

[0261] In one embodiment, the disease associated with bacteria, mycoplasma, or chlamydia is an upper or lower respiratory tract or soft tissue infection, such as a lower respiratory tract infection, such as pneumonia, or community-acquired pneumonia or hospital-acquired lung infection.

[0262] The present invention also provides the use of the compound represented by Formula I above, its solvate, its crystal form, its deuterated form, its pharmaceutically acceptable salt, or the pharmaceutical composition thereof in the preparation of antibiotics.

[0263] In a preferred embodiment, the antibiotic is an antibacterial drug.

[0264] In one embodiment, the antibiotic is an anti-mycoplasma or anti-chlamydia drug.

[0265] The present invention also provides a method for treating bacterial-associated diseases, comprising administering to a subject requiring such treatment a compound of Formula I (preferably, administering to the subject a therapeutically effective amount of the compound of Formula I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0266] Terminology Definition

[0267] Unless otherwise stated, the terms used in this application have the following definitions, and the definitions of terms not referred to below are as commonly understood by those skilled in the art to which this invention pertains.

[0268] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

[0269] At the end of the structural fragment This refers to the structural segment being connected to the rest of the molecule through this site. For example, It refers to cyclohexyl.

[0270] Use wedge keys and dashed keys The absolute configuration representing the center of a solid.

[0271] The terms “one or more” or “one or more kinds” refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0272] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0273] The term "oxo" refers to =O or -O. - An oxygen atom replaces two hydrogen atoms or a lone pair of electrons on the same carbon or nitrogen atom, in the form =O or -O. - .For example

[0274] The term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group having a specified number of carbon atoms. For example, C 1-10 Alkyl groups refer to alkyl groups having 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), such as C. 1-6 Alkyl groups, for example, C 1- 4. Alkyl groups. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0275] The term "alkylene" refers to a divalent group connected to the rest of the molecule by two single bonds, with the remaining definitions the same as for the term "alkyl". Examples include, but are not limited to, alkyl groups. wait.

[0276] The term "alkenyl" refers to an alkenyl group having at least one unsaturated position (carbon-carbon sp) with a specified number of carbon atoms.2 A monovalent hydrocarbon group with a double bond, either straight-chain or branched, and including groups having "cis" and "trans" orientations or "E" and "Z" orientations. For example, C 2-10 Alkenyl refers to an alkenyl group having 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, such as C. 2-6 Alkenyl, for example C 2-4 Alkenyl groups, examples of which include, but are not limited to, alkenyl groups. wait.

[0277] The term "alkenyl" refers to a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "alkenyl". Examples include, but are not limited to, […]. wait.

[0278] The term "alkynyl group" refers to a group having at least one unsaturated position, i.e., carbon-carbon sp, with a specified number of carbon atoms. 3 A straight-chain or branched monovalent hydrocarbon group with a triple bond, such as C 2-10 The alkynyl group refers to an alkynyl group having 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, such as C. 2-6 Alkyne group, for example, C 2-4 Alkynyl group. Examples include, but are not limited to, alkynyl groups. wait.

[0279] The term "cycloalkyl" refers to a saturated, monocyclic or polycyclic cyclic hydrocarbon group having a specified number of carbon atoms, wherein polycyclic rings share a carbon atom, two non-directly bonded carbon atoms, or two carbon atoms and a bond, for example, C. 3-14 Cycloalkyl refers to a cycloalkyl group having 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) cyclic carbon atoms, for example, C14. 3- 10 cycloalkyl, for example C 3-8 Cycloalkyl. “Cycloalkyl” includes monocycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0280] The term "monocyclic alkyl" refers to a monocyclic cycloalkyl group. For example, C 3-14 Monocycloalkyl, for example C 3-10 Monocycloalkyl, more specifically C 3-8 Monocycloalkyl groups. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0281] The term "bridged cycloalkyl" refers to a polycyclic (e.g., 2 or 3) cycloalkyl group that shares two or more non-directly bonded carbon atoms between rings. For example, C 3-14 Bridged cycloalkyl groups, such as C 3-10Bridged cycloalkyl groups, more specifically C 3-8 Bridged cycloalkyl groups.

[0282] The term "spirocycloalkyl" refers to a polycyclic (e.g., 2 or 3 rings) cycloalkyl group that shares a carbon atom between the rings. For example, C 3-14 Spirocycloalkyl, for example C 3-10 Spirocycloalkyl, more specifically C 3-8 Spirocycloalkyl.

[0283] The term "cycloalkyl" refers to a polycyclic (e.g., 2 or 3 rings) cycloalkyl group that shares two carbon atoms and one bond between the rings. For example, C 3-14 cycloalkyl, for example C 3-10 cycloalkyl, more such as C 3-8 cycloalkyl.

[0284] The term "cycloalkenyl" refers to an unsaturated, monocyclic or polycyclic cyclic hydrocarbon group having a specified number of carbon atoms. In polycyclic groups, the rings share a carbon atom, two non-directly bonded carbon atoms, or two carbon atoms and a single bond. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. For example, C 3-14 Cycloalkenyl groups refer to cycloalkenyl groups having 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) cyclic carbon atoms, such as C. 3-10 Cycloalkenyl groups, for example, C 3-8 Cycloalkenyl groups. Cycloalkenyl groups include monocyclic alkenyl, spirocyclic alkenyl, fused cycloalkenyl, and bridged cycloalkenyl.

[0285] The term "monocyclic alkenyl" refers to a "cyclic alkenyl" group that is monocyclic. For example, C 3-14 Monocyclic alkenyl groups, such as C 3-10 Monocyclic alkenyl groups, such as C 3-8 Monocyclic alkenyl.

[0286] The term "bridged cycloalkenyl" refers to a polycyclic (e.g., 2 or 3) cycloalkenyl group in which two or more non-directly linked carbon atoms are shared between the rings. For example, C 3-14 Bridged cyclic alkenyl groups, such as C 3-10 Bridged cyclic alkenyl groups, such as C 3-8 Bridged cyclic alkenyl groups.

[0287] The term "spirocyclic alkenyl" refers to a polycyclic (e.g., 2 or 3 rings) "cycloalkenyl" group in which the rings share a single carbon atom. For example, C 3-14 Spirocycloalkenyl, for example C 3-10 Spirocycloalkenyl, more specifically C 3-8 Spirocyclic alkenyl.

[0288] The term "cycloalkenyl" refers to a polycyclic (e.g., 2 or 3 rings) cycloalkenyl group that shares two carbon atoms and one bond between rings. For example, C 3-14 cycloalkenyl groups, such as C 3-10 cycloalkenyl groups, such as C 3-8 Circular alkenyl groups.

[0289] The term "heterocyclic group" refers to a cyclic hydrocarbon substituent that is non-aromatic, has a specified number of ring atoms, a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), a specified type of heteroatom (one or more of N, O, and S), is saturated or unsaturated (partially saturated), and is monocyclic or polycyclic, wherein the polycyclic rings share one atom, two atoms not directly connected, or two atoms and one bond, and may contain one or more double bonds. Heterocyclic groups are attached to the rest of the molecule via carbon atoms or heteroatoms; they can be attached to the rest of the molecule via a ring with heteroatoms or a ring without heteroatoms. "Heterocyclic groups" include monocyclic, spirocyclic, fused, and bridged heterocyclic groups.

[0290] The term "monocyclic heterocyclic group" refers to a "heterocyclic group" that is monocyclic. For example, C 3-14 Monocyclic groups, such as C 3-10 Monocyclic groups, such as C 3-8 Monoheterocyclic groups. Specific examples include, but are not limited to, oxopropyl or azircyclohexyl groups.

[0291] The term "bridged heterocyclic group" refers to a polycyclic (e.g., 2 or 3 rings) heterocyclic group that shares two or more non-directly bonded carbon atoms with each ring. For example, C 3-14 Bridged heterocyclic bases, such as C 3-10 Bridged heterocyclic groups, such as C 3-8 Bridge-shaped ring base.

[0292] The term "spiroheterocyclic group" refers to a polycyclic (e.g., 2 or 3 rings) heterocyclic group that shares a single carbon atom between the rings. For example, C 3-14 Spiroherocyclic groups, such as C 3-10 Spirocyclic groups, such as C 3-8 Spirohexane group.

[0293] The term "heterocyclic group" refers to a polycyclic (e.g., 2 or 3 rings) heterocyclic group that shares two carbon atoms and one bond between rings. For example, C 3-14 Coin-heterocyclic groups, such as C 3-10 And heterocyclic groups, such as C 3-8 Heterocyclic groups.

[0294] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C66). 6-14A cyclic, unsaturated monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., 2 or 3). When polycyclic, the monocyclic rings share two atoms and one bond, and at least one ring is aromatic. Examples include phenyl or naphthyl.

[0295] The term "heteroaryl" refers to an aromatic, cyclic, unsaturated monovalent group with a specified number of ring atoms (e.g., 5-14, or 5-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with polycyclic rings sharing two atoms and one bond. "Heteroaryl" includes monocyclic heteroaryl or fused-ring heteroaryl. Fused-ring heteroaryl refers to a heteroaryl where the rings share two atoms and one bond. Heteroaryl groups are attached to the rest of the molecule via carbon atoms or heteroatoms; heteroaryl groups are attached to the rest of the molecule via rings with or without heteroatoms; heteroaryl groups are attached to the rest of the molecule via aromatic or non-aromatic rings. Heteroaryl groups include, but are not limited to: wait.

[0296] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0297] The statement "group B optionally substituted by one or more groups A" means that group B can be unsubstituted or substituted by one or more groups A. For example, the C 1-6 Alkyl groups may be optionally surrounded by one, two, or three R's. 3-2 Replacement refers to C 1-6 The alkyl group can be unsubstituted or surrounded by one, two, or three R groups. 3-2 What it replaced.

[0298] When a listed substituent does not specify which atom it is attached to in a compound included but not specifically mentioned in the general chemical formula, such a substituent may be bonded to any of its atoms. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0299] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C 1-6 When "alkyl" is not preceded by the qualifier "unsubstituted or substituted", it refers only to "C". 1-6 "alkyl" itself or "unsubstituted C" 1-6 alkyl".

[0300] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently being" used in this application should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently being" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0301] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0302] The term "prevention" refers to reducing the risk of developing a disease.

[0303] The term "therapeutic effective amount" refers to the amount of a compound that, when administered to a patient, is sufficient to effectively treat or prevent the disease or condition described herein. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art. Dosages exceeding this range may also be used depending on the dosage form and the severity of the disease.

[0304] The term "subject" refers to any animal that needs to receive treatment or preventative care for a disease, typically a mammal such as a human. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0305] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0306] The reagents and raw materials used in this invention are all commercially available.

[0307] The positive and progressive effects of this invention are as follows: the compound of this application has antibacterial activity, that is, it has the effect of inhibiting bacterial activity and can be used to prevent and / or treat related diseases caused by bacteria; furthermore, the compound of this application can achieve antibacterial activity equivalent to or better than azithromycin or solithromycin with a lower dosage; even further, the compound of this application has a better antibacterial effect against Gram-positive bacteria; even further, the compound of this application has better inhibitory activity against mycoplasma and lower hepatotoxicity. Detailed Implementation

[0308] Intermediate Synthesis Examples

[0309] Synthesis of intermediates CLA-A6 & SOL-B1

[0310] Step 1:

[0311] Clarithromycin (100 g, 133 mmol, 1.00 eq) was added to hydrochloric acid (12.0 M, 66.6 mL, 5.98 eq) and water (660 mL), and reacted at 25 °C for 2 hours. TLC (dichloromethane:methanol = 10:1) showed that the reaction was complete. The mixture was cooled to 0 °C and quenched with 300 mL of water. The pH was adjusted to 8 with ammonia. The mixture was extracted three times with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a white solid CLA-A1 (78.0 g), with a yield of 98.0%.

[0312] Step Two:

[0313] Compound CLA-A1 (78.0 g, 132 mmol, 1.00 eq) was dissolved in 540 mL of anhydrous dichloromethane. The solution was cooled to 0°C, and triethylamine (16.0 g, 158 mmol, 22.0 mL, 1.20 eq) and acetic anhydride (16.2 g, 158 mmol, 14.9 mL, 1.20 eq) were added sequentially. The mixture was stirred at 25°C for 12 hours. TLC (dichloromethane:methanol = 10:1) showed that the reaction was complete. 400 mL of water was added to the system, and the mixture was extracted three times with 200 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a white solid CLA-A2 (83.0 g), with a yield of 99.0%.

[0314] Step 3:

[0315] Compound CLA-A2 (83.0 g, 131 mmol, 1.00 eq) was dissolved in 500 mL of dichloromethane, and EDCI (166 g, 867 mmol, 6.60 eq) and DMSO (184 g, 2.36 mol, 184 mL, 18.0 eq) were added dropwise. Pyridine trifluoroacetate was dissolved in 150 mL of dichloromethane and added dropwise. The reaction was carried out at 25 °C for 3 hours. LC-MS showed that the reaction was essentially complete. The reaction temperature was lowered to 0 °C, 300 mL of water was added, and the mixture was extracted three times with 200 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography using isopropyl ether:triethylamine = 90:10 to give a yellow solid CLA-A3 (83.0 g), with a yield of 99.0%.

[0316] Step Four:

[0317] Compound CLA-A3 (50.0 g, 79.3 mmol, 1.00 eq) was dissolved in 350 mL of dichloromethane. The mixture was cooled to 0°C, and pyridine (37.6 g, 476 mmol, 38.4 mL, 6.00 eq) and triphosgene (29.5 g, 99.5 mmol, 1.25 eq) were added. The reaction was carried out at 25°C for 2 hours. LC-MS showed that the reaction was essentially complete. The reaction was cooled to 0°C, 300 mL of water was added, and the mixture was extracted three times with 200 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a yellow solid CLA-A4 (30.0 g), with a yield of 57.0%.

[0318] Step 5:

[0319] Compound CLA-A4 (30.0 g, 45.7 mmol, 1.00 eq) was dissolved in 200 mL of ethyl acetate, and DBU (14.6 g, 96.0 mmol, 14.4 mL, 2.10 eq) was added. The reaction was carried out at 80 °C for 3 hours. LC-MS showed that the reaction was essentially complete. The reaction was cooled to room temperature, and 200 mL of water was added. The mixture was extracted three times with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. 50.0 mL of acetonitrile was added to the crude product, and the mixture was sonicated for 10 minutes. Filtration yielded a white solid CLA-A5 (10.0 g), with a yield of 35.0%.

[0320] Step Six:

[0321] CLA-A5 (5.00 g, 8.17 mmol, 1.00 eq) was dissolved in 35 mL of dichloromethane, cooled to -25 °C, and DBU (3.73 g, 24.5 mmol, 3.70 mL, 3.00 eq) and CDI (3.98 g, 24.5 mmol, 3.00 eq) were added. The mixture was reacted at 25 °C for 12 hours. TLC (petroleum ether: ethyl acetate = 5:1) showed that the reaction was complete. 300 mL of water was added, and the mixture was extracted three times with 50.0 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to give a white solid CLA-A6 (4.00 g), with a yield of 69.0%.

[0322] Step Seven:

[0323] CLA-A6 (96.0 g, 87 mmol, 1.00 eq) was dissolved in 500 mL of anhydrous THF. After purging with argon three times, the solution was cooled to -40 °C. DBU (13.25 g, 87 mmol, 1.00 eq) was added dropwise, and the temperature was maintained at -40 °C. NFSI (27.4 g, 87 mmol, 1.00 eq) dissolved in 200 mL of THF was added dropwise. The reaction was maintained at this temperature for 1.5 hours, then naturally warmed to ambient temperature. After the reaction was complete, the solution was quenched with saturated NaHCO3 aqueous solution. After complete extraction with DCM, the DCM solutions were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to give a pale yellow solid, SOL-B1 (34.3 g, purity 91%, yield 54%). LCMS (ESI) m / z = 724.50 [M+H] + .

[0324] Example 1 XNW9382

[0325] The synthesis scheme is based on XNW9431.

[0326] White solid XNW9382 (41 mg, purity: 99.14%)

[0327] 1H NMR(400MHz, Methanol-d4)δ7.33(d,J=8.8Hz,1H),6.72(d,J=8.8Hz,1H),5.26–5.04(m,2H),4. 82–4.79(m,1H),4.33(d,J=7.2Hz,1H),4.10(dd,J=10.6,1.6Hz,1H),3.79–3.67(m,1H),3.64–3. 49(m,3H),3.44(s,1H),3.30–3.15(m,2H),2.70–2.53(m,2H),2.40(s,3H),2.35(s,6H),2.01–1. 82(m,4H),1.80–1.53(m,11H),1.35–1.18(m,14H),0.98(d,J=6.8Hz,3H),0.86(t,J=7.4Hz,3H). LCMS(ESI):m / z=432.46,863.72[M+H] + .

[0328] Example 2 XNW9399

[0329] The synthesis scheme is based on XNW9448.

[0330] White solid XNW9399 (118 mg, purity: 99.07%).

[0331] 1 H NMR (400MHz, Methanol-d4) δ8.30 (s, 1H), 6.83–6.74 (m, 2H), 4.83 (d, J = 2.8Hz, 1H), 4.60–4.4 3(m,2H),4.33(d,J=7.2Hz,1H),4.11(dd,J=10.4,1.6Hz,1H),3.85–3.74(m,1H),3.66–3.50(m ,3H),3.47(s,1H),3.31–3.18(m,2H),2.70–2.55(m,2H),2.41(s,3H),2.36(s,6H),2.05–1.85 (m,4H),1.82–1.56(m,11H),1.36–1.20(m,14H),1.01(d,J=6.8Hz,3H),0.91(t,J=7.4Hz,3H). LCMS(ESI):m / z=431.98,862.73[M+H] + .

[0332] Example 3 XNW9431

[0333] Step 1:

[0334] XNW9431-A1 (2.50 g, 12.31 mmol, 1.0 eq), Zn(CN)2 (2.89 g, 24.63 mmol, 2.0 eq), and DMF (35 mL) were added to the reaction flask at room temperature. The mixture was purged three times with an argon balloon. Then XantPhos Pd G4 (592 mg, 615.65 μmol, 0.05 eq) was added, and the mixture was purged three more times with an argon balloon. The mixture was then heated in an oil bath at 85 °C for 6 hours. Cool to room temperature, add 200 mL of water, and extract with ethyl acetate (100 mL × 3 times); wash the organic phase with water, wash with saturated sodium chloride, and dry with anhydrous sodium sulfate; filter, concentrate the filtrate under reduced pressure, mix and pass through a silica gel column; PE:EA = 100% PE ~ 50% EA, pass through the column to give a pink solid XNW9431-A2 (1.85 g, 12.40 mmol, yield: 100.74%), LCMS (ESI): m / z = 150.08 [M+H]+.

[0335] Step Two:

[0336] XNW9431-A2 (920 mg, 6.17 mmol, 1.0 eq), SnOBu2 (767.77 mg, 3.08 mmol, 0.5 eq), NMP (12 mL), and TMSN3 (2.13 g, 18.50 mmol, 3.0 eq) were added to the reaction flask at room temperature. The mixture was heated in an oil bath at 150 °C for 5 hours under argon balloon protection. After the reaction was completed, the mixture was cooled to room temperature and the reaction solution was not treated before proceeding to the next step.

[0337] Step 3:

[0338] Following the reaction solution from the previous step, Cs₂CO₃ (6.05 g, 18.58 mmol, 3.0 eq), KI (1.03 g, 6.17 mmol, 1.0 eq), and tert-butyl N-(4-bromobutyl)carbamate (2.34 g, 9.29 mmol, 1.5 eq) were added to the reaction flask at room temperature. The mixture was heated in an oil bath at 80°C for 16 hours under argon balloon protection. After cooling to room temperature, 60 mL of water was added to the system, and the mixture was extracted with ethyl acetate (50 mL × 3 times). The organic phase was washed successively with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and filtered through a silica gel column. The PE:EA ratio was 100% PE to 40% EA, yielding P1 (1133 mg) and P2 (363 mg). P1 is the target product XNW9431-A4, and P2 is its isomer.

[0339] Step Four:

[0340] XNW9431-A4 (1.13 g, 3.12 mmol, 1.0 eq) and HBr (48 wt.% in water) (10 mL) were added to a reaction flask at room temperature. The reaction was carried out in an oil bath at 90°C for 6 hours under argon balloon protection. After cooling to room temperature, the mixture was placed in an ice-water bath, and the pH was adjusted to 7-8 with ammonia to prevent solid precipitation. The mixture was purified by reverse-phase chromatography using a 0.1% NH4HCO3:ACN system to obtain a white to yellowish solid XNW9431-A5 (550 mg, 2.21 mmol, yield: 70.77%). LCMS (ESI): m / z = 250.11 [M+H]+.

[0341] Step 5:

[0342] XNW9431-A5 (250 mg, 1.00 mmol, 1.0 eq), ACN (10 mL), and DBU (610 mg, 4.00 mmol, 4.0 eq) were added to a reaction flask at room temperature and stirred until dissolved. SOL-B1 (798 mg, 1.10 mmol, 1.1 eq) was then added. The mixture was heated in an oil bath at 50 °C for 5 hours under argon balloon protection. LC-MS monitoring showed that the reaction was complete, with intermediate [M+H] = 453.49, 905.74. 5 mL of water was added to the system, and the temperature was raised to 70 °C for another 6 hours. Acetonitrile was removed by vacuum concentration. 80 mL of dichloromethane was added to the concentrate, and the mixture was washed with water (20 mL × 3 times). The organic phase was concentrated under vacuum to obtain a yellow viscous substance, which was purified by liquid chromatography and freeze-dried to obtain a white solid XNW9431 (44 mg, purity: 99.95%).

[0343] 1H NMR(400MHz, Methanol-d4)δ7.13(d,J=7.6Hz,1H),6.87(d,J=7.6Hz,1H),4.84–4.76(m,3 H),4.34(d,J=7.2Hz,1H),4.12(d,J=10.4Hz,1H),3.80–3.69(m,1H),3.65–3.49(m,3H),3. 45(s,1H),3.31–3.16(m,2H),2.73–2.55(m,2H),2.43(s,3H),2.36(s,6H),2.01–1.86(m, 4H), 1.81–1.54 (m, 11H), 1.35–1.19 (m, 14H), 0.98 (d, J = 6.8Hz, 3H), 0.88 (t, J = 7.4Hz, 3H). LCMS (ESI): m / z=432.46,863.70[M+H]+.

[0344] Example 4 XNW9448

[0345] Step 1:

[0346] XNW9448-A1 (2.00 g, 11.59 mmol) was dissolved in methanol (20 mL) at room temperature, followed by the addition of a 5.4 M, 6.44 mL solution of sodium methoxide in methanol. The reaction mixture was heated to 70 °C and stirred for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to remove methanol. The residue was dissolved in dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography (PE / EA = 0-35%) to obtain XNW9448-A2 (1.63 g, 9.69 mmol, yield 83.64%) as a yellow solid. LCMS (ESI) m / z = 169.2 [M+H] + .

[0347] Step Two:

[0348] XNW9448-A2 (1.63 g, 9.69 mmol) was dissolved in methanol (30 mL) at room temperature, followed by the addition of wet palladium / carbon (1.03 g, 9.69 mmol). The reaction system was purged with hydrogen three times and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol, and the filtrate was concentrated to obtain crude XNW9448-A3 (1.28 g, 9.26 mmol, yield 95.57%), a brown solid, which was used directly in the next step. LCMS (ESI) m / z = 139.2 [M+H] + .

[0349] Step 3:

[0350] XNW9448-A3 (1.08 g, 7.82 mmol) was dissolved in DMF (15 mL) at room temperature, followed by the addition of NBS (1.53 g, 8.60 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (30 mL), washed with water, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography (PE / EA = 0-35%) to obtain XNW9448-A4 (1.15 g, 5.30 mmol, yield 67.78%) as a brown solid. LCMS (ESI) m / z = 217.2 [M+H] + .

[0351] Step Four:

[0352] At room temperature, XNW9448-A4 (0.80 g, 3.69 mmol) and trimethylsilylacetylene (1.09 g, 11.06 mmol) were dispersed in DMF (10 mL), followed by the addition of Pd(PPh3)Cl2 (129.35 mg, 184.28 μmol), CuI (70.19 mg, 368.56 μmol), and triethylamine (1.12 mg, 11.06 mmol). The reaction system was purged with argon three times, and the mixture was heated to 100 °C and stirred overnight. After the reaction was complete, the reaction system was cooled to room temperature, filtered through diatomaceous earth, the filter cake was washed twice with ethyl acetate, the filtrates were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography (PE / EA = 0-35%) to give XNW9448-A5 (425 mg, 1.81 mmol, yield 49.20%), a brown oily substance. LCMS (ESI) m / z = 235.2 [M+H] + .

[0353] Step 5:

[0354] XNW9448-A5 (425 mg, 1.81 mmol) was dispersed in methanol (3 mL) and tetrahydrofuran (3 mL) at room temperature, followed by the addition of potassium carbonate (501.24 mg, 3.63 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filter cake was washed twice with tetrahydrofuran. The filtrate was concentrated to obtain crude XNW9448-A6 (350 mg), a brown solid. The crude product was used directly in the next step. LCMS (ESI) m / z = 163.2 [M+H] + .

[0355] Step Six:

[0356] XNW9448-A6 (350 mg, 2.16 mmol) and XNW9448-A6' (554.86 mg, 2.59 mmol) were dispersed in methanol (10 mL) and water (3 mL) at room temperature. Copper acetate (117.59 mg, 647.40 μmol) and sodium ascorbate (213.76 mg, 1.08 mmol) were then added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filter cake was washed twice with dichloromethane. The filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography (DCM / MeOH = 0-10%) to obtain XNW9448-A7 (520 mg, 1.38 mmol, yield 64.01%), a brown vesicular precipitate. LCMS (ESI) m / z = 377.3 [M+H] + .

[0357] Step Seven:

[0358] XNW9448-A7 (400 mg, 1.06 mmol) was dispersed in concentrated hydrochloric acid (6 mL) at room temperature, and the reaction system was heated to 100 °C and stirred for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature and concentrated to obtain crude XNW9448-A8 (317 mg, hydrochloride) as a brown vesicular precipitate. The crude product was used directly in the next step. LCMS (ESI) m / z = 263.2 [M+H] + .

[0359] Step 8:

[0360] At room temperature, SOL-B1 (844.78 mg, 1.17 mmol) and XNW9448-A8 (317.00 mg, 1.06 mmol) were dispersed in acetonitrile (8 mL), followed by the addition of DBU (807.64 mg, 5.31 mmol). The reaction mixture was heated to 50 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (4 mL) was added. The mixture was then heated to 75 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, and the dichloromethane (25 mL) and water (20 mL) were separated. The aqueous phase was extracted with dichloromethane (15 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was prepared directly by prep-HPLC (0.1% TFA) and prep-HPLC (0.1% NH4HCO3), and then lyophilized to obtain a white solid XNW9448 (15 mg, 17.12 μmol, yield: 1.61%).

[0361] 1 H NMR(400MHz,Methanol-d4)δ8.20(s,1H),6.68(s,1H),4.83-4.76(m,1H),4.59-4.43(m,2 H),4.30(d,J=7.3Hz,1H),4.07(dd,J=10.6,1.6Hz,1H),3.80-370(m,1H),3.59-3.48(m,3 H),3.43(s,1H),3.26-3.17(m,2H),2.64-2.55(m,2H),2.37(s,3H),2.32(s,6H),2.21(s, 3H), 1.96-1.53 ​​(m, 15H), 1.30-1.19 (m, 13H), 0.98 (d, J = 6.9Hz, 3H), 0.88 (t, J = 7.4Hz, 3H).

[0362] LCMS(ESI): m / z = 876.8 [M+H] + .

[0363] Example 5 XNW9381

[0364] The synthesis steps are referenced in XNW9431.

[0365] White solid XNW9381 (13.44 mg, purity 86.6%). 1 H NMR (400MHz, Methanol-d4) δ8.15(d,J=3.1Hz,1H),7.14(d,J=3.1Hz,1H),4.88–4.76(m,2H),4.35(d,J=7.3Hz,1H),4.13(dd,J=1 0.6,1.6Hz,1H),3.81(td,J=8.8,4.2Hz,1H),3.67–3.53(m,4H),3.50(s,1H),3.32–3.19(m,2H),2.66(td,J=11.6,4.2Hz,2H),2. 50(s,3H),2.37(s,7H),2.11(p,J=7.3Hz,2H),1.92(ddd,J=14.7,6.8,3.0Hz,2H),1.79(s,1H),1.74(s,1H),1.73–1.61(m,2H),1 .58(s,4H),1.36(s,3H),1.34–1.20(m,12H),1.03(d,J=6.9Hz,3H),0.93(t,J=7.4Hz,3H).LCMS(ESI):m / z=432.46,863.68[M+H] + .

[0366] Example 6 XNW9535

[0367] Synthesis scheme reference XNW9558:

[0368] White solid XNW9535 (11 mg, purity: 94.60%).

[0369] 1H NMR (400MHz, Methanol-d4) δ6.77(d,J=7.6Hz,1H),6.64(d,J=7.2Hz,1H),6.43(s,1H),4.30( d,J=7.2Hz,1H),4.08(dd,J=10.8,1.6Hz,1H),3.80–3.69(m,1H),3.61–3.50(m,3H),3.48(s, 1H),3.28–3.16(m,2H),2.76–2.53(m,4H),2.44(s,3H),2.33(s,6H),1.95–1.84(m,2H),1.79 –1.58(m,10H),1.54(s,3H),1.32–1.19(m,14H),0.99(d,J=6.8Hz,3H),0.88(t,J=7.4Hz,3H). LCMS(ESI):m / z=431.57,861.85[M+H] + .

[0370] Example 7 XNW9558

[0371] Step 1:

[0372] XNW9558-A1 (2.0 g, 11.59 mmol, 1.0 eq), MeOH (20 mL), and MeONa (5.4 M (30 wt.%) solution in methanol) (2.09 g, 11.59 mmol, 1.0 eq) were added to a reaction flask at room temperature. The mixture was heated in an oil bath at 70 °C for 3 hours under argon balloon protection. The mixture was then cooled to room temperature and concentrated under reduced pressure. The solution was then passed through a silica gel column: PE:EA = 100% PE ~ 20% EA, yielding a white solid XNW9558-A2 (1.83 g, 10.88 mmol, yield: 93.90%). LCMS (ESI): m / z = 169.12 [M+H]. + .

[0373] Step Two:

[0374] XNW9558-A2 (1.83 g, 10.88 mmol, 1.0 eq), MeOH (20 mL), and Pd / C (10%) (1.16 g) were added to a reaction flask at room temperature. After three purgings with hydrogen balloons, the mixture was heated in an oil bath at 30°C for 16 hours. The mixture was filtered at room temperature, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, mixed, and passed through a silica gel column (PE:EA = 100% PE ~ 30% EA). The column chromatography yielded a white solid XNW9558-A3 (1.41 g, 10.21 mmol, yield: 93.77%), LCMS (ESI): m / z = 139.12 [M+H].+ .

[0375] Step 3:

[0376] XNW9558-A3 (1.41 g, 10.21 mmol, 1.0 eq) and ACN (30 mL) were added to a reaction flask at room temperature and stirred until dissolved. Under an ice-water bath, NBS (2.00 g, 11.23 mmol, 1.1 eq) solid was dissolved in 20 mL of acetonitrile and then added dropwise to the reaction flask. The reaction was exothermic, and the system gradually turned black. The reaction solution was concentrated under reduced pressure and filtered through a silica gel column; PE:EA = 100% PE ~ 30% EA. The column chromatography yielded a yellow liquid XNW9558-A4 (1.64 g, 7.56 mmol, yield: 74.04%), LCMS (ESI): m / z = 218.02 [M+H]. + It will solidify after standing and cooling.

[0377] Step Four:

[0378] XNW9558-A4 (1.64 g, 7.56 mmol, 1.0 eq), tributylstannane (8.77 g, 15.11 mmol, 2.0 eq), and dioxane (99.8%) (50 mL) were added to a reaction flask at room temperature. The mixture was purged three times with an argon balloon. Then, Pd(PPh3)4 (873 mg, 755 μmol, 0.1 eq) was added, followed by three more purgings with an argon balloon. The reaction mixture was heated in an oil bath at 110 °C for 24 hours. The mixture was then concentrated under reduced pressure, mixed, and passed through a silica gel column (PE:EA = 100% PE ~ 20% EA). The column chromatography yielded a yellowish-brown liquid, XNW9558-A5 (1.70 g, 3.98 mmol, yield: 52.67%). LCMS (ESI): m / z = 427.02, 429.03 [M+H]. + .

[0379] Step 5:

[0380] At room temperature, add XNW9558-A5 (1.70 g, 3.98 mmol, 1.0 eq), tert-butyl N-[4-(4-iodoimidazol-1-yl)butyl]carbamate (2.03 g, 5.57 mmol, 1.4 eq), CsF (2.90 g, 19.10 mmol, 4.8 eq), CuI (379 mg, 1.99 mmol, 0.5 eq), and DMF (99.8%, SafeDry, with molecular sieves) (17 mL) to a microwave tube. Blow gas with an argon balloon for 1–2 minutes, then add Pd(PPh3)4 (460 mg, 398 μmol, 0.1 eq), and seal the tube. Microwave the tube at 120 °C for 3 hours. The reaction solution was filtered, and the filtrate was purified by reverse-phase chromatography; a yellow viscous substance XNW9558-A6 (512 mg, 1.36 mmol, yield: 34.27%) was obtained by filtration in a 0.1% HCOOH:ACN system. LCMS (ESI): m / z = 376.33 [M+H] + .

[0381] Step Six:

[0382] XNW9558-A6 (512 mg, 1.36 mmol) and concentrated HCl (10 mL) were added to a reaction flask at room temperature. The mixture was heated in an oil bath at 100 °C for 3 hours under argon balloon protection. The reaction solution was concentrated under reduced pressure to obtain a pale yellow bubbly solid XNW9558-A7 (382 mg, 1.28 mmol, yield: 94.07%), LCMS (ESI): m / z = 262.21 [M+H]. + .

[0383] Step Seven:

[0384] XNW9558-A7 (382 mg, 1.28 mmol, 1.0 eq), ACN (16 mL), and DBU (781.18 mg, 5.13 mmol, 4.0 eq) were added to a reaction flask at room temperature and stirred until dissolved. Then, SOL-B1 (1.02 g, 1.41 mmol, 1.1 eq) was added, and the mixture was heated in an oil bath at 50 °C for 12 hours under argon balloon protection. LC-MS monitoring showed that the reaction was complete, with intermediate [M+H] = 459.63, 917.79. 8 mL of water was added to the system, and the temperature was raised to 70 °C for another 12 hours. Acetonitrile was removed by vacuum concentration. 100 mL of dichloromethane was added to the concentrate, and the mixture was washed with water (20 mL × 3 times). The organic phase was concentrated under vacuum to obtain a yellow viscous substance, which was purified by liquid chromatography and freeze-dried to obtain a white solid XNW9558 (115 mg, purity: 98.90%).

[0385] 1 H NMR (400MHz, Methanol-d4) δ7.71(d,J=1.2Hz,1H),7.36(d,J=1.2Hz,1H),6.70(s,1H),4.83–4. 80(m,1H),4.30(d,J=7.2Hz,1H),4.15–4.03(m,3H),3.81–3.69(m,1H),3.62–3.47(m,3H),3.45 (s,1H),3.27–3.15(m,2H),2.67–2.52(m,2H),2.39(s,3H),2.32(s,6H),2.20(s,3H),1.95–1.7 8(m,4H),1.75–1.52(m,11H),1.32–1.17(m,14H),0.98(d,J=6.8Hz,3H),0.87(t,J=7.4Hz,3H). LCMS(ESI):m / z=438.59,875.79[M+H] + .

[0386] Example 8 XNW9423

[0387] Step 1:

[0388] XNW9423-A1 (2.00 g, 9.23 mmol) was dissolved in methanol (20 mL) at room temperature, followed by the addition of a 5.4 M, 3.42 mL solution of sodium methoxide in methanol. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was quenched with water (30 mL), washed twice with dichloromethane (30 mL), the pH was adjusted to 1–2 with concentrated hydrochloric acid, extracted twice with ethyl acetate (30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain XNW9423-A2 (1.05 g, 5.30 mmol, yield 57.39%), a pale yellow solid. LCMS (ESI) m / z = 197.1 [M+H] - .

[0389] Step Two:

[0390] At room temperature, XNW9423-A2 (1.05 g, 5.30 mmol) and XNW9423-A2' (1.35 g, 5.83 mmol) were dissolved in DMF (20 mL), followed by the addition of HATU (3.02 g, 7.95 mmol) and DIPEA (2.05 g, 15.90 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was separated into ethyl acetate (30 mL) and water (20 mL). The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography (DCM / MeOH = 0-10%) to obtain XNW9423-A3 (2.1 g, 5.10 mmol, yield 96.32%) as a yellow solid. LCMS (ESI) m / z = 412.2 [M+H] + .

[0391] Step 3:

[0392] XNW9423-A3 (0.80 g, 1.94 mmol) was dissolved in DCM (15 mL) at room temperature, followed by the addition of TosCl (741.45 mg, 3.89 mmol) and TEA (983.83 mg, 9.72 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the DCM mixture (10 mL) was diluted, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography (DCM / MeOH = 0-10%) to obtain XNW9423-A4 (640 mg, 1.63 mmol, yield 83.66%), a yellow oily substance. LCMS (ESI) m / z = 394.2 [M+H] + .

[0393] Step Four:

[0394] At room temperature, XNW9423-A4 (0.64 g, 1.63 mmol) was dispersed in ethanol (10 mL) and water (2 mL), followed by the addition of zinc powder (1.06 g, 16.27 mmol) and ammonium chloride (870.23 mg, 16.27 mmol). The reaction mixture was heated to 75 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed twice with dichloromethane. The filtrates were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by medium-pressure normal-phase column chromatography (DCM / MeOH = 0-10%) to obtain XNW9423-A5 (520 mg, 1.43 mmol, yield 87.95%), a yellow oily substance. LCMS (ESI) m / z = 364.3 [M+H] + .

[0395] Step 5:

[0396] XNW9423-A5 (320 mg, 880.55 μmol) was dissolved in dichloromethane (5 mL) at room temperature, followed by the addition of TMSI (528.57 mg, 2.64 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filter cake was washed twice with dichloromethane and dried under vacuum to obtain crude XNW9423-A6 (400 mg) as a yellow solid. The crude product was used directly in the next step. LCMS (ESI) m / z = 250.2 [M+H] + .

[0397] Step Six:

[0398] At room temperature, SOL-B1 (1.54 g, 2.12 mmol) and XNW9423-A6 (400.00 mg, 1.06 mmol) were dispersed in acetonitrile (8 mL), followed by the addition of DBU (807.25 mg, 5.30 mmol). The reaction mixture was heated to 50 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and water (4 mL) was added. The mixture was then heated to 75 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, and the dichloromethane (25 mL) and water (20 mL) were separated. The aqueous phase was extracted with dichloromethane (15 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was prepared directly by prep-HPLC (0.1% TFA) and prep-HPLC (0.1% NH4HCO3), and then lyophilized to obtain a white solid XNW9423 (20 mg, 23.18 μmol, yield: 2.19%).

[0399] 1 H NMR(400MHz, Methanol-d4)δ7.01(d,J=7.7Hz,1H),6.67(d,J=7.7Hz,1H),4.84-4.80(m,1H) ,4.30(d,J=7.3Hz,1H),4.08(dd,J=10.5,1.6Hz,1H),3.83-3.72(m,1H),3.63-3.49(m,3H),3 .46(s,1H),3.27-3.16(m,2H),2.98(t,J=7.1Hz,2H),2.67-2.52(m,2H),2.47(s,3H),2.33( s, 6H), 1.92-1.53 ​​(m, 15H), 1.33-1.19 (m, 13H), 0.99 (d, J = 6.9Hz, 3H), 0.88 (t, J = 7.4Hz, 3H).

[0400] LCMS(ESI): m / z = 863.8 [M+H]+ .

[0401] Example 9 XNW 9449

[0402] Synthesis steps are referenced in XNW9448:

[0403] 1 H NMR(400MHz, Methanol-d4)δ.28(s,1H),6.71(s,1H),4.79-4.77(m,1H),4.54-4.42(m,2H),4. 30(d,J=7.3Hz,1H),4.07(dd,J=10.6,1.6Hz,1H),3.80-3.71(m,1H),3.62-3.47(m,3H),3.43( s,1H),3.27-3.13(m,2H),2.66-2.52(m,2H),2.37(s,3H),2.32(s,6H),2.17(s,3H),2.01-1.8 2(m,4H),1.77-1.49(m,11H),1.33-1.17(m,13H),0.98(d,J=6.9Hz,3H),0.88(t,J=7.4Hz,3H).

[0404] LCMS(ESI): m / z = 876.8 [M+H] + .

[0405] Example 10 XNW9492

[0406] The synthesis steps are referenced in XNW9647:

[0407] 1 H NMR(400MHz, Methanol-d4)δ6.90(d,J=7.6Hz,1H),6.68(d,J=7.6Hz,1H),4.84-4.78( m,1H),4.31(d,J=7.3Hz,1H),4.08(dd,J=10.6,1.6Hz,1H),3.84-3.72(m,1H),3.63-3. 49(m,3H),3.46(s,1H),3.27-3.13(m,4H),2.69-2.53(m,2H),2.44(s,3H),2.33(s,6H) ,1.90-1.51(m,15H),1.35-1.18(m,13H),0.99(d,J=6.9Hz,3H),0.89(t,J=7.4Hz,3H).

[0408] LCMS(ESI): m / z = 879.3 [M+H] + .

[0409] Example 11 XNW 9605

[0410] The synthesis of intermediate XNW9605-INT is based on XNW9558.

[0411] Synthesis of compound XNW9605:

[0412] Step 1:

[0413] Compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9605-INT (355 mg, 1.11 mmol, 2 eq) (based on two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), and acetonitrile (10 mL) were added to a reaction vessel and stirred at room temperature for 5 hours until the reaction was complete. Water was added to the system, and the mixture was extracted with EA. The organic phase was concentrated to obtain the crude product. The crude product was dissolved in acetonitrile / water (10 mL / 10 mL) and reacted overnight at 75 °C. The reaction solution was directly evaporated to dryness. The crude product was purified to obtain a white solid XNW9605 (151 mg, 99% purity). 1 H NMR (400MHz, Methanol-d4) δ7.61(d,J=2.4Hz,1H),6.76(d,J=7.4Hz,1H),6.64(d,J=7.5Hz,1H),6.56(d,J=2.3Hz,1 H),4.30(d,J=7.3Hz,1H),4.20(q,J=6.5Hz,2H),4.06(d,J=10.5Hz,1H),3.74(dt,J=13.9,6.9Hz,1H),3.61–3.48(m, 3H),3.45(s,1H),3.26–3.16(m,2H),2.67–2.52(m,2H),2.37(s,3H),2.32(s,6H),1.88(ddt,J=14.4,9.3,4.9Hz,4H) ,1.78–1.50(m,11H),1.31–1.18(m,13H),0.97(d,J=6.8Hz,3H),0.88(t,J=7.4Hz,3H).LCMS(ESI): m / z=861.47[M+H] + .

[0414] Example 12 XNW 9651

[0415] Synthesis of intermediate XNW9651-INT (reference XNW9558)

[0416] Synthesis of compound XNW9651:

[0417] Step 1:

[0418] Compound SOL-B1 (400 mg, 0.55 mmol, 1 eq), XNW9651-INT (355 mg, 1.11 mmol, 2 eq) (based on two molecules of HCl), DBU (506 mg, 3.32 mmol, 6 eq), and acetonitrile (10 mL) were added to a reaction vessel and stirred at room temperature for 5 hours until the reaction was complete. Water was added to the system, and the mixture was extracted with EA. The organic phase was concentrated to obtain the crude product. The crude product was dissolved in acetonitrile / water (10 mL / 10 mL) and reacted overnight at 75 °C. The reaction solution was directly evaporated to dryness. The crude product was purified to obtain a white solid XNW9651 (5 mg, 96% purity). 1 H NMR (400MHz, Methanol-d4) δ7.69(d,J=1.3Hz,1H),7.53(d,J=1.3Hz,1H),6.78(d,J=7.5Hz,1H),6.63(d,J=7.5Hz,1H), 4.81(d,J=2.9Hz,1H),4.30(d,J=7.3Hz,1H),4.13–4.02(m,3H),3.77(dt,J=13.8,6.8Hz,1H),3.56(dq,J=16.5,7.5Hz, 3H),3.46(s,1H),3.26–3.17(m,2H),2.67–2.54(m,2H),2.40(s,3H),2.32(s,6H),1.94–1.79(m,4H),1.78–1.64(m,5H) ,1.56(d,J=18.7Hz,6H),1.31–1.19(m,13H),0.98(d,J=6.9Hz,3H),0.87(t,J=7.4Hz,3H).LCMS(ESI): m / z=861.47[M+H] + .

[0419] Example 13 XNW9559

[0420] Synthesis scheme reference XNW9558:

[0421] White solid XNW9559 (57 mg, purity: 99.17%).

[0422] 1H NMR (400MHz, Methanol-d4) δ7.71(d,J=1.2Hz,1H),7.42(dd,J=2.8,1.2Hz,1H),6.68(d,J=10.8Hz,1 H),4.82(dd,J=10.2,2.8Hz,1H),4.31(d,J=7.2Hz,1H),4.14–4.03(m,3H),3.81–3.70(m,1H),3.63– 3.47(m,3H),3.44(s,1H),3.29–3.16(m,2H),2.77–2.67(m,1H),2.63–2.52(m,1H),2.38(s,9H),1.9 5–1.75(m,5H),1.75–1.52(m,10H),1.34–1.16(m,14H),0.98(d,J=6.8Hz,3H),0.88(t,J=7.4Hz,3H). LCMS(ESI):m / z=440.57,879.83[M+H] + .

[0423] Example 14 XNW9614

[0424] Synthesis scheme reference XNW9558:

[0425] White solid XNW9614 (22 mg, purity: 99.31%).

[0426] 1 H NMR (400MHz, DMSO-d6) δ8.01(s,1H),7.86(s,1H),7.26–7.19(m,2H),6.98(s,1H),6.32(d,J=9.2Hz,1H),6.19 (d,J=4.4Hz,1H),4.73(dd,J=9.9,3.0Hz,1H),4.36(d,J=6.0Hz,1H),4.06(t,J=7.2Hz,2H),3.94(dd,J=10.5,1 .6Hz,1H),3.73–3.64(m,1H),3.63–3.41(m,7H),3.12(q,J=6.8Hz,2H),2.75(s,3H),2.68(s,3H),2.39(s,3H) ,1.97(d,J=12.4Hz,1H),1.82–1.40(m,13H),1.29–1.12(m,14H),0.90(d,J=6.8Hz,3H),0.81(t,J=7.4Hz,3H). LCMS(ESI):m / z=431.59,861.81[M+H] + .

[0427] Example 15 XNW9615

[0428] The synthesis scheme is based on XNW9448.

[0429] White solid XNW9615 (28 mg, purity: 99.58%).

[0430] 1 H NMR (400MHz, Methanol-d4) δ8.44(s,1H),7.41(d,J=9.2Hz,1H),6.48(d,J=9.6Hz,1H),4.82(dd,J=10 .0,3.2Hz,1H),4.62–4.45(m,2H),4.30(d,J=7.2Hz,1H),4.07(dd,J=10.6,1.6Hz,1H),3.83–3.72(m,1 H),3.63–3.48(m,3H),3.43(s,1H),3.28–3.15(m,2H),2.68–2.52(m,2H),2.38(s,3H),2.33(s,6H),2. 04–1.82(m,4H),1.78–1.52(m,11H),1.32–1.17(m,14H),0.98(d,J=6.8Hz,3H),0.89(t,J=7.4Hz,3H). LCMS(ESI):m / z=432.06,862.82[M+H] + .

[0431] Example 16 XNW9617

[0432] The synthesis scheme is based on XNW9448.

[0433] White solid XNW9617 (50 mg, purity: 99.70%).

[0434] 1H NMR(400MHz, Methanol-d4)δ8.41(s,1H),7.30(d,J=1.2Hz,1H),4.84–4.80(m,1H),4.57–4.47(m,2 H),4.30(d,J=7.6Hz,1H),4.07(dd,J=10.6,1.6Hz,1H),3.83–3.72(m,1H),3.63–3.47(m,3H),3.44( s,1H),3.27–3.15(m,2H),2.67–2.52(m,2H),2.38(s,3H),2.33(s,6H),2.13(d,J=1.2Hz,3H),2.02 –1.83(m,4H),1.78–1.53(m,11H),1.32–1.17(m,14H),0.98(d,J=6.8Hz,3H),0.88(t,J=7.4Hz,3H). LCMS(ESI):m / z=439.09,876.73[M+H] + .

[0435] Example 17 XNW9647

[0436] Step 1:

[0437] XNW9647-A0 (10.00 g, 46.17 mmol, 1.0 eq), MeOH (99.8%) (120 mL), and MeONa (5.4 M (30 wt.%) methanol solution) (16.63 g, 92.35 mmol, 2.0 eq) were added to a reaction flask at room temperature. The reaction was stirred at room temperature for 16 hours under argon balloon protection. The methanol was removed by vacuum concentration, and 100 mL of water was added to clear the concentrate. The concentrate was extracted with dichloromethane (50 mL × 2 times) to remove impurities. The aqueous phase was adjusted to pH 2–3 with dilute hydrochloric acid, precipitating a large amount of solid. The mixture was placed in an ice-water bath for 30 minutes, filtered, and the filter cake was washed with a small amount of ice water and dried to obtain XNW9647-A1 (4.90 g, 24.73 mmol, yield: 53.56%). LCMS (ESI): m / z = 199.01 [M+H]. + .

[0438] Step Two:

[0439] XNW9647-A1 (4.90 g, 24.73 mmol, 1.0 eq) and MeOH (99.8%, SafeDry, with molecular sieves) (60 mL) were added to a reaction flask at room temperature. SOCl2 (2.94 g, 24.73 mmol, 1.0 eq) was then slowly added dropwise to the system at room temperature, followed by heating in an oil bath at 70°C for 5 hours. The mixture was concentrated under reduced pressure to remove methanol. 150 mL of dichloromethane and 50 mL of water were added to the concentrate, and the mixture was stirred. A yellow solid was observed between the two phases. The mixture was filtered to remove the yellow solid, and the filtrate was separated. The organic phase was washed with water (50 mL × 2 times) and dried over anhydrous sodium sulfate. The filtrate was filtered, and the mixture was concentrated under reduced pressure to obtain XNW9647-A2 (4.62 g, 21.78 mmol, yield: 88.05%), LCMS (ESI): m / z = 213.04 [M+H]. + .

[0440] Step 3:

[0441] XNW9647-A2 (4.62 g, 21.78 mmol, 1.0 eq) and Pd / C (10% on Carbon (wetted with ca. 55% Water)) (1.16 g) were added to a reaction flask at room temperature. The mixture was purged three times with a double-layered hydrogen balloon, and the reaction was carried out in an oil bath at 35°C for 16 hours. The mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, mixed, and passed through a silica gel column. The DCM:MeOH ratio was 100% DCM ~ 10% MeOH. The column chromatography yielded a pale yellow solid, XNW9647-A3 (2.40 g, 13.17 mmol, yield: 60.50%). LCMS (ESI): m / z = 183.11 [M+H]. + .

[0442] Step Four:

[0443] XNW9647-A3 (2.40 g, 13.17 mmol, 1.0 eq) and DMF (15 mL) were added to a reaction flask at room temperature. NBS (2.46 g, 13.83 mmol, 1.05 eq) was dissolved in 5 mL of DMF and then slowly added to the system. The mixture was stirred at room temperature for 1 hour. 100 mL of water was slowly added to the system, and a yellow solid gradually precipitated. The mixture was stirred overnight at room temperature. The mixture was filtered, the filter cake was washed with water, and dried to obtain a yellow solid XNW9647-A4 (2.32 g, 8.89 mmol, yield: 67.45%), LCMS (ESI): m / z = 262.03 [M+H]. + .

[0444] Step 5:

[0445] At room temperature, XNW9647-A4 (2.32 g, 8.89 mmol, 1.0 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.35 g, 13.33 mmol, 1.5 eq), K2CO3 (3.68 g, 26.66 mmol, 3.0 eq), Dioxane (60 mL), and H2O (10 mL) were added to the reaction flask. The mixture was purged three times with an argon balloon. Then, Pd(dppf)Cl2 (650.22 mg, 888.64 μmol, 0.1 eq) was added, and the mixture was purged three more times with an argon balloon. The mixture was heated in an oil bath at 100 °C for 16 hours. The solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and mixed with other materials. The mixture was then passed through a silica gel column; PE:EA = 100% PE ~ 30% EA. The column chromatography yielded a pale yellow solid XNW9647-A5 (1.14 g, 5.81 mmol, yield: 65.38%). LCMS (ESI): m / z = 197.13 [M+H]. + .

[0446] Step Six:

[0447] XNW9647-A5 (1.78 g, 9.07 mmol, 1.0 eq), TEA (2.75 g, 27.22 mmol, 3.79 mL, 3.0 eq), (Boc)₂O (4.95 g, 22.68 mmol, 2.5 eq), DCM (60 mL), and DMAP (111 mg, 907 μmol, 0.1 eq) were added to a reaction flask at room temperature. The reaction mixture was heated in an oil bath at 40 °C under argon balloon protection. The reaction solution was directly concentrated under reduced pressure, mixed, and passed through a silica gel column; PE:EA = 100% PE ~ 40% EA. The column chromatography yielded a white solid XNW9647-A6 (2.27 g, 5.73 mmol, yield: 63.12%), LCMS (ESI): m / z = 397.35 [M+H]. + .

[0448] Step Seven:

[0449] XNW9647-A6 (2.27 g, 5.73 mmol, 1.0 eq), MeOH (30 mL), LiOH·H2O (480.53 mg, 11.45 mmol, 2.0 eq), and H2O (5 mL) were added to a reaction flask at room temperature. The mixture was stirred at room temperature for 4 hours under argon balloon protection. Methanol was removed by vacuum concentration, and 25 mL of water was added. The pH was adjusted to 6 with 0.5 mol / L dilute hydrochloric acid. The mixture was extracted with dichloromethane (80 mL × 3 times), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give a white solid XNW9647-A7 (2.18 g, 5.70 mmol, yield: 99.56%), LCMS (ESI): m / z = 383.34 [M+H]. + .

[0450] Step 8:

[0451] At room temperature, XNW9647-A7 (2.18 g, 5.70 mmol, 1.0 eq), tert-butyl N-(5-hydrazino-5-oxo-pentyl)carbamate (1.32 g, 5.70 mmol, 1.0 eq), DMF (99.8%, SafeDry, with molecular sieves) (30 mL), and DIPEA (1.47 g, 11.40 mmol, 2.0 eq) were added to the reaction flask. Under argon balloon protection, HATU (2.60 g, 6.84 mmol, 1.2 eq) was added last, and the mixture was stirred overnight at room temperature. The system changed from colorless to yellow. 150 mL of water was added to the system, and the mixture was extracted with ethyl acetate (80 mL × 3 times). A small amount of saturated sodium chloride solution was added to separate the layers. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Filtration was performed, the filtrate was concentrated under reduced pressure, and the mixture was passed through a silica gel column; DCM:MeOH = 100% DCM ~ 3% MeOH. The column chromatography yielded a nearly colorless viscous compound XNW9647-A8 (3.66 g, 6.14 mmol, yield: 107.78%), LCMS (ESI): m / z = 596.59 [M+H]. + .

[0452] Step Nine:

[0453] XNW9647-A8 (1.00 g, 1.68 mmol, 1.0 eq), Toluene (99.90%) (12 mL), and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4dithiadiphosphetane (611 mg, 1.51 mmol, 0.75 eq) were added to the reaction flask at room temperature. The reaction mixture was heated in an oil bath at 95°C for 16 hours under argon balloon protection. The reaction solution was directly mixed with silica gel and filtered through a silica gel column. First, PE:EA = 100% PE ~ 50% EA was used, followed by DCM:MeOH(NH3) = 100% DCM ~ 10% MeOH. XNW9647-A9 (500 mg, 842.13 μmol, yield: 50.16%) was obtained, with some product losing Boc. LCMS (ESI): m / z = 494.59, 594.62 [M+H] + .

[0454] Step 10:

[0455] XNW9647-A9 (300 mg, 505 μmol) and HBr (48 wt.% in water) (4 mL) were added to a reaction flask at room temperature. The reaction mixture was heated in an oil bath at 100 °C for 16 hours under argon balloon protection. The reaction solution was directly concentrated under reduced pressure and dried to obtain a white solid XNW9647-A10 (345 mg, 1.23 mol, yield: 243.56%), which was an HBr salt. This product was directly introduced to the next reaction step.

[0456] Step Eleven:

[0457] XNW9647-A10 (300 mg, 833 μmol, 1.0 eq), ACN (10 mL), and DBU (507 mg, 3.33 mmol, 4.0 eq) were added to a reaction flask at room temperature and stirred until dissolved. SOL-B1 (663 mg, 916 μmol, 1.1 eq) was then added. The mixture was heated in an oil bath at 50 °C for 4 hours under argon balloon protection. LC-MS monitoring showed that the reaction was complete, with intermediate [M+H] = 468.70, 935.78. 5 mL of water was added to the system, and the temperature was raised to 70 °C for another 16 hours. The mixture was filtered at room temperature, and the filtrate was purified by liquid chromatography and freeze-dried to obtain a white solid XNW9647 (112 mg, purity: 92.60%).

[0458] 1H NMR (400MHz, Methanol-d4) δ6.87(s,1H),4.81(s,1H),4.31(d,J=7.2Hz,1H),4.08( d,J=10.8Hz,1H),3.83–3.72(m,1H),3.63–3.48(m,3H),3.45(s,1H),3.26–3.13(m, 4H),2.70–2.52(m,2H),2.44(s,3H),2.34(s,6H),2.16(s,3H),1.96–1.72(m,5H),1 .70–1.53(m,10H),1.32–1.20(m,14H),0.99(d,J=6.8Hz,3H),0.90(t,J=7.4Hz,3H). LCMS(ESI):m / z=447.60,893.75[M+H] + .

[0459] Example 18 XNW9611

[0460] The synthesis steps are referenced in XNW9448.

[0461] White solid XNW9611 (56.12 mg, purity 99.10%). 1 H NMR (400MHz, Methanol-d4) δ8.47(s,1H),6.47(d,J=2.1Hz,1H),5.57(d,J=2.1Hz,1H),4.84(dd,J=10.2,2.8Hz,1H),4.64–4.47(m,2H),4.34( d,J=7.3Hz,1H),4.12(dd,J=10.6,1.6Hz,1H),3.80(ddd,J=13.8,8.8,4.8Hz,1H),3.58(dtdd,J=18.5,9.1,5.3,3.2Hz,3H),3.47(s,1H),3.31 –3.18(m,2H),2.71–2.56(m,2H),2.41(s,3H),2.36(s,6H),2.06–1.86 (m,4H),1.77(s,3H),1.72(s,2H),1.70–1.59(m,3H),1.57(s,4H),1.34 (s,3H),1.29(dd,J=8.5,6.5Hz,7H),1.24(d,J=7.0Hz,3H),1.02(d,J=6.9Hz,3H),0.93(t,J=7.4Hz,3H).LCMS(ESI):m / z=431.99,862.65[M+H] + .

[0462] Example 19 XNW9619

[0463] The synthesis steps are referenced in XNW9448.

[0464] White solid XNW9619 (140 mg, purity 99.68%). 1 H NMR (400MHz, Methanol-d4) δ8.29(s,1H),8.18(d,J=8.3Hz,1H),5.74(d,J=8.2Hz,1H),4.88(d,J=2.9Hz,1H),4.49(q, J=6.6Hz,2H),4.35(d,J=7.3Hz,1H),4.14(dd,J=10.6,1.6Hz,1H),3.80(td,J=8.9,4.2Hz,1H),3.66–3.53(m,3H),3.52 (s,1H),3.32–3.22(m,2H),2.51(s,3H),2.39(s,6H),2.05–1.87(m,4H),1.80(s,3H),1.74(s,2H),1.67(dd,J=18.8,11 .8Hz,3H),1.58(s,4H),1.39–1.22(m,14H),1.02(d,J=6.9Hz,3H),0.94(t,J=7.4Hz,3H).LCMS(ESI):m / z=862.80[M+H] + .

[0465] Example 20 XNW9622

[0466] The synthesis steps for XNW9622-4 are the same as those for XNW9558.

[0467] Intermediate product XNW9622-4 (1.36 g). LCMS (ESI): m / z = 248.30 [M+H] + .

[0468] For subsequent synthesis steps, please refer to XNW9558.

[0469] White solid product XNW9622 (42.8 mg, purity 98.28%).

[0470] 1H NMR (400MHz, Methanol-d4) δ7.69(d,J=1.3Hz,1H),7.35(d,J=1.3Hz,1H),7.23(d,J=2.2Hz,1H),7.12(d,J=2.2Hz,1H),4.89~ 4.84(m,1H),4.34(d,J=7.3Hz,1H),4.13~4.08(m,3H),3.81(dt,J=13.8,6.8Hz,1H),3.66~3.54(m,3H),3.51(s,1H),3.30~3. 22(m,2H),2.65(tdd,J=15.2,11.7,6.1Hz,2H),2.46(s,3H),2.37(s,7H),2.01~1.84(m,4H),1.81(s,2H),1.79~1.74(m,2H), 1.72~1.61(m,3H),1.58(s,4H),1.31(dd,J=12.3,5.3Hz,7H),1.28~1.23(m,7H),1.02(d,J=6.9Hz,3H),0.91(t,J=7.4Hz,3H).

[0471] LCMS(ESI): m / z=431.60,861.82[M+H] + .

[0472] Example 21 XNW9623

[0473] The synthesis steps for XNW9623-4 are the same as those for XNW9448.

[0474] Intermediate product XNW9623-5 (3.11 g). LCMS (ESI): m / z = 249.23 [M+H] + .

[0475] For subsequent synthesis steps, please refer to XNW9448.

[0476] White solid product XNW9623 (63.0 mg, purity 99.35%).

[0477] 1H NMR (400MHz, Methanol-d4) δ8.17(s,1H),7.34(d,J=2.2Hz,1H),7.17(d,J=2.2Hz,1H),4.86(dd,J=10.1,2.8Hz,1H ),4.50(dp,J=13.8,7.0Hz,2H),4.34(d,J=7.3Hz,1H),4.14~4.07(m,1H),3.81(ddd,J=13.8,8.5,5.2Hz,1H),3.65~ 3.53(m,3H),3.48(s,1H),3.30~3.19(m,2H),2.71~2.56(m,2H),2.41(s,3H),2.36(s,7H),2.01~1.87(m,4H),1.82~ 1.73(m,3H),1.67(d,J=40.8Hz,5H),1.57(s,4H),1.36~1.21(m,15H),1.02(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H).

[0478] LCMS(ESI): m / z=432.60,863.74[M+H] + .

[0479] Example 22 XNW9610

[0480] The synthesis steps are referenced in XNW9558.

[0481] White solid XNW9610 (6.88 mg, purity 97.7%). 1H NMR (400MHz, Methanol-d4) δ7.78(d,J=1.3Hz,1H),7.75(d,J=1.3Hz,1H),6.34(d,J=2.1Hz,1H),5.50(d,J=2.0Hz,1H),4.86 (dd,J=10.2,2.9Hz,1H),4.34(d,J=7.3Hz,1H),4.22–4.09(m,3H),3.81(dt,J=13.8,6.7Hz,1H),3.66–3.53(m,3H),3.49(s,1 H),3.32–3.20(m,2H),2.74–2.57(m,2H),2.44(s,3H),2.37(s,6H),2.02–1.85(m,4H),1.81(s,2H),1.79–1.68(m,3H),1.60 (d,J=14.5Hz,6H),1.37–1.22(m,13H),1.02(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H).LCMS(ESI):m / z=431.51,861.71[M+H]+.

[0482] Example 23 XNW9634

[0483] The synthesis steps are referenced in XNW9448.

[0484] White solid XNW9634 (70.24 mg, purity 99.57%). 1H NMR (400MHz, Methanol-d4) δ8.52(s,1H),6.73(s,1H),4.83(dd,J=10.1,2.8Hz,1H),4.56(h,J=7.1Hz,2H),4.34(d,J=7.3Hz,1H),4.11(dd,J=10.6,1. 6Hz, 1H), 3.78 (dddd, J=13.8, 8.9, 4.6Hz, 1H), 3.58 (dddd, J=24.6, 14.1, 6.6 ,2.7Hz,3H),3.46(s,1H),3.31–3.17(m,2H),2.72–2.54(m,2H),2.39(s,3H) ,2.37(s,6H),1.94(dddd,J=28.8,14.5,6.4,3.0Hz,4H),1.79(dddd,J=12.8 ,4.3,2.0Hz,1H),1.73(s,2H),1.68(s,2H),1.65–1.59(m,2H),1.56(s,4H) ,1.34(s,3H),1.29(dd,J=6.5,2.5Hz,7H),1.24(d,J=6.9Hz,3H),1.01(d,J =6.9Hz, 3H), 0.92 (t, J = 7.4Hz, 3H). LCMS (ESI): m / z = 449.11,896.54[M+H]+.

[0485] Example 24 XNW9633

[0486] The synthesis steps are referenced in XNW9558.

[0487] White solid XNW9633 (26.12 mg, purity 92.6%). 1H NMR (400MHz, Methanol-d4) δ7.79(d,J=1.3Hz,1H),7.75(d,J=1.2Hz,1H),6.74(s,1H),4.85(dd,J=10.1,2.8Hz,1H),4.34(d, J=7.3Hz,1H),4.19–4.08(m,3H),3.85–3.74(m,1H),3.66–3.51(m,3H),3.48(s,1H),3.32–3.19(m,2H),2.72–2.57(m,2H),2. 42(s,3H),2.37(s,6H),2.00–1.80(m,4H),1.78(s,2H),1.73(s,2H),1.70–1.60(m,3H),1.57(s,4H),1.34(s,3H),1.29(dd,J =9.4, 6.6Hz, 7H), 1.24 (d, J = 6.9Hz, 3H), 1.02 (d, J = 6.9Hz, 3H), 0.92 (t, J = 7.4Hz, 3H). LCMS (ESI): m / z = 448.74, 895.78 [M+H]+.

[0488] Example 25 XNW9667

[0489] The synthesis steps are referenced in XNW9448.

[0490] White solid XNW9667 (39.88 mg, purity 98.0%). 1H NMR (400MHz, Methanol-d4) δ8.09(s,1H),7.14(s,1H),4.87(dd,J=10.2,2.9Hz,1H),4.53(td,J=6.7,4.2Hz,2H),4.34(d,J=7.3Hz,1H ),4.12(dd,J=10.6,1.6Hz,1H),3.81(ddd,J=13.8,8.4,5.2Hz,1H),3.66–3.52(m,3H),3.50(s,1H),3.32–3.19(m,2H),2.73–2.57(m,2 H),2.45(s,3H),2.39(s,3H),2.37(s,6H),1.99(q,J=7.4Hz,2H),1.95–1.87(m,2H),1.83–1.76(m,3H),1.73(s,2H),1.71–1.61(m,3H) ),1.58(s,3H),1.35(s,3H),1.33–1.21(m,10H),1.02(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H).LCMS(ESI):m / z=439.10,876.82[M+H]+.

[0491] Example 26 XNW9663

[0492] The synthesis steps are referenced in XNW9448.

[0493] White solid XNW9663 (10.66 mg, purity 90.66%). 1H NMR (400MHz, Methanol-d4) δ8.34(s,1H),6.89(s,1H),4.88–4.83(m,1H),4.63–4.47(m,2H),4.34(d,J=7.3Hz,1H),4.11(dd,J=10.7, 1.6Hz,1H),3.89(s,3H),3.81(ddd,J=13.8,8.4,5.2Hz,1H),3.67–3.52(m,3H),3.48(s,1H),3.32–3.19(m,2H),2.75–2.58(m,2H),2.4 3(s,3H),2.37(s,6H),2.05–1.86(m,4H),1.84–1.80(m,1H),1.78(s,2H),1.73(s,2H),1.70–1.60(m,3H),1.58(s,3H),1.34(s,3H),1. 29 (dd, J = 9.8, 6.6 Hz, 7H), 1.24 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 447.11, 892.78 [M+H]+.

[0494] Example 27 Synthesis of compound XNW9616:

[0495] Synthesis scheme reference XNW9558:

[0496] White solid XNW9616 (31 mg, purity: 94.20%).

[0497] 1H NMR (400MHz, Methanol-d4) δ7.74(d,J=1.2Hz,1H),7.65(d,J=1.6Hz,1H),7.28(d,J=1.2Hz,1H),4.83(dd,J= 10.0,2.6Hz,1H),4.30(d,J=7.2Hz,1H),4.12(t,J=6.8Hz,2H),4.07(dd,J=10.4,1.6Hz,1H),3.82–3.71(m,1 H),3.63–3.49(m,3H),3.45(s,1H),3.28–3.16(m,2H),2.69–2.53(m,2H),2.40(s,3H),2.33(s,6H),2.11(s, 3H), 1.95–1.80 (m, 4H), 1.77–1.53 (m, 11H), 1.32–1.18 (m, 14H), 0.98 (d, J = 7.2Hz, 3H), 0.88 (t, J = 7.4Hz, 3H). LCMS(ESI):m / z=438.57,875.83[M+H] + .

[0498] Example 28 Synthesis of compound XNW9627:

[0499] Synthesis scheme reference XNW9558:

[0500] White solid XNW9627 (25 mg, purity: 99.05%).

[0501] 1 H NMR(400MHz, Methanol-d4)δ7.75(d,J=1.2Hz,1H),7.44(s,1H),6.86(s,1H),4.83(dd,J=10 .4,2.8Hz,1H),4.31(d,J=7.2Hz,1H),4.15–4.05(m,3H),3.81–3.70(m,1H),3.62–3.50(m,3 H),3.46(s,1H),3.28–3.16(m,2H),2.67–2.54(m,2H),2.44(s,3H),2.33(s,6H),1.95–1.75 (m,6H),1.75–1.53(m,9H),1.34–1.17(m,14H),0.98(d,J=6.8Hz,3H),0.87(t,J=7.4Hz,3H). LCMS(ESI):m / z=465.54,929.81[M+H] + .

[0502] Example 29 Synthesis of compound XNW9629:

[0503] The synthesis scheme is based on XNW9558.

[0504] White solid XNW9629 (63 mg, purity: 99.79%).

[0505] 1 H NMR (400MHz, Methanol-d4) δ7.71(d,J=1.2Hz,1H),7.35(d,J=1.2Hz,1H),6.75(s,1H),4.83(dd,J=1 0.4,2.8Hz,1H),4.33(d,J=7.2Hz,1H),4.15–4.04(m,3H),3.80–3.69(m,1H),3.65–3.49(m,3H),3.4 5(s,1H),3.30–3.16(m,2H),2.89–2.77(m,1H),2.56(q,J=7.6Hz,3H),2.46(s,6H),2.40(s,3H),1.9 4–1.79(m,5H),1.76–1.53(m,10H),1.32–1.16(m,17H),0.98(d,J=6.8Hz,3H),0.87(t,J=7.4Hz,3H). LCMS(ESI):m / z=445.52,889.82[M+H] + .

[0506] Example 30: Synthesis of compound XNW9630:

[0507] Synthesis scheme reference XNW9558:

[0508] White solid XNW9630 (90 mg, purity: 99.24%).

[0509] 1H NMR (400MHz, Methanol-d4) δ7.73(d,J=1.2Hz,1H),7.32(d,J=1.2Hz,1H),6.86(s,1H),4.82( d,J=2.8Hz,1H),4.31(d,J=7.2Hz,1H),4.15–4.06(m,3H),3.81–3.70(m,1H),3.62–3.49(m,3 H),3.47(s,1H),3.27–3.08(m,3H),2.67–2.54(m,2H),2.44(s,3H),2.33(s,6H),1.95–1.78( m,4H),1.77–1.53(m,11H),1.33–1.16(m,20H),0.99(d,J=6.8Hz,3H),0.87(t,J=7.4Hz,3H). LCMS(ESI):m / z=452.51,903.83[M+H] + .

[0510] Example 31 XNW9631

[0511] The synthesis steps for XNW9631-INT are the same as those for XNW9448.

[0512] Intermediate product XNW9631-INT (2.20 g). LCMS (ESI): m / z = 277.37 [M+H] + .

[0513] For subsequent synthesis steps, please refer to XNW9448.

[0514] XNW9631 (146.6 mg, 99.44% purity), a white solid product.

[0515] 1H NMR (400MHz, Methanol-d4) δ8.22(s,1H),6.77(s,1H),4.86(dd,J=10.1,2.8Hz,1H),4.49~4.61(m,2H),4.35 (d,J=7.3Hz,1H),4.12(dd,J=10.6,1.6Hz,1H),3.75~3.82(m,1H),3.53~3.63(m,3H),3.48(s,1H),3.21~3.29 (m,2H),2.54~2.70(m,4H),2.43(s,3H),2.36(s,7H),1.89~2.04(m,4H),1.79(ddd,J=12.8,4.3,1.9Hz,1H),1 .75(s,2H),1.58~1.72(m,6H),1.57(s,3H),1.20~1.35(m,18H),1.02(d,J=6.9Hz,3H),0.92(t,J=7.4Hz,3H).

[0516] LCMS(ESI): m / z=446.11,890.79[M+H] + .

[0517] Example 32 XNW9607

[0518] Step 1:

[0519] Add XNW9607-A1 (10.00 g, 80.55 mmol), Ethanol (100 mL), and Boc2O (26.37 g, 120.83 mmol, 27.73 mL) to the flask, and stir overnight in an oil bath at 80°C. TLC (PE / EA = 20 / 1) shows that the starting material has disappeared, and the main new spot is close to Boc2O. Due to the large amount of material, column chromatography may not be easy to separate them. Add N',N'-dimethylethane-1,2-diamine (4.22 g, 47.87 mmol, 0.6 eq.), and stir in an oil bath at 30°C for 2.5 hours. TLC (PE / EA = 20 / 1) shows that Boc2O has disappeared. The sample was evaporated to dryness, and the residue was dissolved in a small amount of petroleum ether and loaded onto a column for chromatography. The column was chromatographically analyzed with 80 g silica gel and 0-10% EA / PE. The fraction was collected and concentrated under reduced pressure to obtain a colorless oily substance XNW9607-A2 (17.80 g, 79.37 mmol, yield 99.5%).

[0520] Step Two:

[0521] Add XNW9607-A2 (8.00 g, 35.67 mmol) and N,N,N',N'-tetramethylethane-1,2-diamine (8.29 g, 71.35 mmol, 10.70 mL) to a three-necked flask, purge with argon, add THF (160 mL), place in a dry ice-ethanol bath at -35°C, and dropwise add n-BuLi (1.6 M in Hexane) (9.14 g, 142.69 mmol, 89.2 mL). After the addition is complete, stir at approximately -20°C for 2.5 hours. Cool to -73°C, and dropwise add a solution of NFSI (12.37 g, 39.24 mmol) and THF (80 mL) (over 20 minutes). At the end of the addition, the external temperature is -45°C and the internal temperature is <-40°C. After the addition is complete, slowly raise the temperature to room temperature and stir overnight. Sampling with ice-saturated NH4Cl + EA, LC-MS showed the product MS = 243.00 (M + H). + 186.99 (M+H-56) + Prepare NH4Cl (240 g) and water (2 L), stir in an ice-water bath, and slowly pour the reaction solution into the solution. The pH should be between 7 and 8. Extract twice with EA. Wash the combined organic phases once with saturated brine and evaporate to dryness. Dissolve the crude product in DCM / PE (1 / 1 ratio) and load onto a column for chromatography. Use 80 g silica gel and 0-20% EA / PE. Concentrate under reduced pressure to obtain a yellow oil, XNW9607-A3 (2.80 g, 11.56 mmol, yield 32.4%). LCMS (ESI): m / z = 243.0 [M+H]. + 187.0 [M+H-56] + . 1 H NMR (400MHz, Chloroform-d) δ7.93 (dd, J = 7.7, 5.8 Hz, 1H), 6.73 (dd, J = 8.9, 5.9 Hz, 1H), 5.90 (s, 1H), 3.99 (s, 3H), 1.50 (s, 9H).

[0522] Step 3:

[0523] DCM (30 mL) and TFA (14.90 g, 130.68 mmol, 10 mL) were added to XNW9607-A3 (2.80 g, 11.56 mmol), and the mixture was stirred overnight in an oil bath at 25°C. LC-MS showed that the starting material disappeared and the product was the main peak. DCM and TFA were removed by rotary evaporation, and the pH was adjusted to ~8 with saturated NaHCO3. The mixture was extracted twice with DCM, and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness to obtain a yellow oily substance XNW9607-A4 (1.67 g, crude). LC-MS (ESI): m / z = 143.0 [M+H] +The next reaction will proceed with a theoretical amount of 1.64g.

[0524] Step Four:

[0525] CH3CN (32 mL) was added to XNW9607-A4 (1.64 g, 11.54 mmol), followed by NBS (2.05 g, 11.54 mmol) at room temperature. The mixture instantly darkened, and the mixture was stirred for 40 minutes. LC-MS showed that the starting material had reacted completely, and the main peak was the product. Crude silica gel was added, the mixture was evaporated to dryness, and column chromatography was performed using 40 g silica gel and 0-5% EA / PE. The fraction was collected and concentrated under reduced pressure to obtain an orange solid XNW9607-A5 (1.30 g, 5.88 mmol, yield 51.0%). LC-MS (ESI): m / z = 220.9 / 222.9 [M+H] + .

[0526] Step 5:

[0527] XNW9607-A5 (610.00 mg, 2.76 mmol), tributyl-(1-tritylimidazol-4-yl)stannane (1.50 g, 2.50 mmol), CuI (476.57 mg, 2.50 mmol), CsF (1.90 g, 12.51 mmol), Pd(dppf)Cl2 (366.20 mg, 500.47 μmol), and DMF (20 mL) were added to the flask. The mixture was purged with argon and stirred overnight in an oil bath at 110°C. LC-MS showed that the main peak was the product, with very few byproducts from the self-coupling of the Sn reagent. EA was added, and the mixture was filtered through a Celite filter and evaporated to dryness under high vacuum at 70°C. The residue was dissolved in DCM and a small amount of MeOH, and subjected to column chromatography (40g silica gel, 0-17% (DCM / MeOH = 10 / 1) / DCM). The fraction was collected and concentrated under reduced pressure to obtain a yellow vesicular compound XNW9607-A6 (700.00mg, 1.55mmol, yield 62.1%). LCMS (ESI): m / z = 451.1 [M+H] + 243.1 [Trt positive ion] + ,209.0[M-Trt+1+H] + .

[0528] Step Six:

[0529] Add 15 mL of DCM and 5.00 mL of TFA (7.46 g, 65.34 mmol, 5.00 mL) to XNW9607-A6 (700.00 mg, 1.55 mmol), and stir in an oil bath at 25°C. LC-MS showed that the reaction was complete. Remove the solvent and TFA by evaporation, wash with DCM five times, add 40 mL of 0.5 M HCl, and wash with 2 x 50 mL of MTBE. Filter the aqueous phase through a nylon membrane, remove the residual organic solvent by evaporation from the filtrate, and freeze-dry overnight to give a pale yellow solid XNW9607-A7 (318.00 mg, 1.30 mmol, yield 83.7%, HCl). LC-MS (ESI): m / z = 209.0 [M+H] + .

[0530] Step Seven:

[0531] To XNW9607-A7 (456.00 mg, 1.86 mmol, HCl), tert-butyl N-(4-bromobutyl)carbamate (582.51 mg, 1.69 mmol), K₂CO₃ (722.81 mg, 3.90 mmol), KI (86.31 mg, 745.54 μmol), and DMF (9 mL) were added. The mixture was purged with argon and stirred overnight in an oil bath at 60°C. LC-MS showed the product's MS (ESI): m / z = 380.1 [M+H]. + Add EA (100 mL) and water (100 mL) to the reaction flask, stir, and filter through a Celite filter. Wash with water and EA, separate the filtrate, and extract the aqueous phase again with EA (50 mL x 2). The combined organic phases are washed three times with water and once with saturated brine. Dry the organic phase with anhydrous Na2SO4, evaporate the filtrate to dryness, dissolve the residue in a small amount of DCM, and perform column chromatography (12 g silica gel, 0-20% (DCM / MeOH = 10 / 1) / DCM). Collect the fractions and concentrate under reduced pressure to obtain a yellow oily substance XNW9607-A8 (157.00 mg, 413.78 μmol, yield 31.8%). LCMS (ESI): m / z = 380.2 [M+H]. + .

[0532] Step 8:

[0533] XNW9607-A8 (157.00 mg, 413.78 μmol) and HCl (12 M in water (37%)) (7.02 g, 192.60 mmol, 15 mL) were added to the flask. The mixture was purged with argon gas and stirred overnight in an oil bath at 85°C. LC-MS showed that the main peak was the product. The product was evaporated to dryness and then removed six times with CH3CN to give a pale yellow solid. LC-MS (ESI): m / z = 266.0 [M+H] + 133.3 [M / 2+H] + The next reaction was carried out using the theoretical amount of XNW9607-A9 (145.00 mg, 428.73 μmol, yield 100.0%, 2HCl).

[0534] Step Nine:

[0535] At room temperature, XNW9607-A9 (145.00 mg, 428.73 μmol, 2HCl) and DBU (474.44 mg, 3.12 mmol, 466.05 μL) were dissolved in CH3CN (12 mL), and then [(2R,3S,4E,7R,9R,10R,11R,13S)-10-[(2S,3R,6R)-3-acetoxy-4-(dimethylamino)-6-methyl-tetrahydropyridine] was added. [ran-2-yl]oxy-2-ethyl-13-fluoro-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxo-1-oxacyclotetradec-4-en-3-yl]imidazole-1-carboxylate (403.42 mg, 557.35 μmol) was stirred in an oil bath at 50°C for 5 hours under argon protection. LC-MS showed that the amine in the starting material disappeared. 3 mL of H₂O was added, and the mixture was stirred overnight in an oil bath at 70°C under argon protection. LC-MS showed that the acetyl protecting group was completely removed, with approximately 15% product and the remainder being impurity peaks. CH3CN was removed by rotary evaporation. EA (50 mL) and water (60 mL) were added to the residue. After stirring, the mixture was filtered through a Celite filter, washed with water and EA, and separated. The aqueous phase was extracted once more with EA (50 mL). The combined organic phases were washed twice with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness to give 283 mg of a yellow oil. LC-MS indicated that the product was approximately 10%. Prep-HPLC (CH3CN / 0.1% TFA in H2O) was used for separation, and the product was lyophilized overnight to give 50 mg of a white solid. LC-MS indicated that the product was approximately 50%. Prep-HPLC (CH3CN / 0.1% NH4OH in H2O) was used for separation, and the product was lyophilized overnight to give XNW9607 (24.00 mg, 27.30 μmol, yield 9.3%). LCMS (ESI): m / z = 879.7 [M+H] + HPLC: 96.2%. 1H NMR(400MHz, Methanol-d4)δ7.70(d,J=1.3Hz,1H),7.61(d,J=1.3Hz,1H),6.70(d,J=9.5Hz, 1H),4.80(dd,J=10.1,2.7Hz,1H),4.29(d,J=7.3Hz,1H),4.12-4.02(m,3H),3.80-3.70(m,1H ),3.61-3.45(m,3H),3.43(s,1H),3.25-3.16(m,2H),2.66-2.51(m,2H),2.35(s,3H),2.32( s, 6H), 1.94-1.47 (m, 15H), 1.29-1.17 (m, 13H), 0.97 (d, J = 6.9Hz, 3H), 0.87 (t, J = 7.4Hz, 3H).

[0536] Example 33 XNW9608

[0537] Step 1:

[0538] Add XNW9607-A5 (520.00 mg, 2.35 mmol), Pd(PPh3)2Cl2 (330.26 mg, 470.53 μmol), CuI (268.84 mg, 1.41 mmol), 1,4-dioxane (10 mL), and TEA (72.60 mg, 717.47 μmol, 0.1 mL) to the sealed tube. Purge with argon gas, add ethynyl(trimethyl)silane (3.48 g, 35.38 mmol, 5 mL), purge with argon gas again, seal the tube, and stir overnight in an oil bath at 100 degrees Celsius. LC-MS showed that the main peak was the product. The sample was filtered, washed with EA, and crude silica gel was added to the filtrate. The solution was then evaporated to dryness, followed by column chromatography with 12g silica gel and 0-5% EA / PE. The fraction was collected and concentrated under reduced pressure to obtain a brownish-yellow oily substance, XNW9608-A1 (535.00mg, crude). LC-MS (ESI): m / z = 239.1 [M+H] + .

[0539] Step Two:

[0540] THF (10 mL), methanol (10 mL), and K₂CO₃ (930.74 mg, 6.73 mmol) were added to XNW9608-A1 (535.00 mg, 2.24 mmol). The mixture was stirred at room temperature for 1 hour, and LC-MS indicated the reaction was complete. EA (50 mL) was added, and the mixture was filtered, washed with EA, and evaporated to dryness to obtain 600 mg of crude solid. This crude solid was dissolved in EA (50 mL), washed twice with water, once with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain a dark brown oily substance, XNW9608-A2 (375.00 mg, crude), which was partially solidified. LCMS (ESI): m / z = 167.2 [M+H] + .

[0541] Step 3:

[0542] Add methanol (15 mL), tert-butyl N-(4-azidobutyl)carbamate (479.72 mg, 2.24 mmol), water (5 mL), copper(II)acetate (122.00 mg, 671.67 μmol), and sodium(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (221.77 mg, 1.12 mmol) to XNW9608-A2 (372.00 mg, 2.24 mmol). Stir at room temperature for 30 minutes. LC-MS indicates the reaction is complete. Add water and EA to the reaction flask, filter through a Celite filter, separate the layers, and extract twice more with EA. Dry the combined organic phases with anhydrous sodium sulfate, and evaporate the filtrate to dryness. The residue was dissolved in a small amount of DCM and loaded onto a column for chromatography. The column chromatography setup was 12 g silica gel, 0-20% (DCM / MeOH = 10 / 1) / DCM. The fraction was collected and concentrated under reduced pressure to obtain a yellow bubbly substance XNW9608-A3 (590.00 mg, 1.55 mmol, yield 69.3%). LCMS (ESI): m / z = 381.3 [M+H]. + .

[0543] Step Four:

[0544] XNW9608-A3 (100.00 mg, 262.87 μmol) was added to the flask, followed by HOAc (1.5 mL) and HBr (33% in acetic acid) (2.10 g, 8.56 mmol, 1.5 mL). The mixture was then stirred overnight in an oil bath at 85°C under argon protection. LC-MS analysis showed that the main peak was the product. MTBE (60 mL) was added, the mixture was stirred, filtered, and washed with MTBE (50 mL). The filter cake was then hygroscopically removed. The filter cake was dissolved in MeOH, evaporated to dryness, and then dried again with CH3CN. The residue was then dried under vacuum to obtain 136 mg of a brownish-yellow oil. LC-MS (ESI): m / z = 267.3 [M+H]. + The next reaction was carried out with the theoretical amount of XNW9608-A4 (91.00 mg, 262.11 μmol, yield 100.0%, HBr).

[0545] Step 5:

[0546] At room temperature, XNW9608-A4 (91.00 mg, 262.11 μmol, HBr) and DBU (399.03 mg, 2.62 mmol, 391.98 μL) were dissolved in CH3CN (7 mL), and then [(2R,3S,4E,7R,9R,10R,11R,13S)-10-[(2S,3R,6R)-3-acetoxy-4-(dimethylamino)-6-methyl-tetrah] was added. [ydropyran-2-yl]oxy-2-ethyl-13-fluoro-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxo-1-oxacyclotetradec-4-en-3-yl]imidazole-1-carboxylate (189.72 mg, 262.11 μmol) was added under argon protection and stirred in an oil bath at 50°C for 5 hours. LC-MS showed very little residual amine from the starting material, and products containing acetyl groups were visible. Residual methanol from the previous step replaced the imidazole to form impurities. H2O (3 mL) was added, and the mixture was stirred overnight in an oil bath at 70°C under argon protection. LC-MS showed complete acetyl removal from the product, with obvious impurity peaks. CH3CN was removed by rotary evaporation. EA (60 mL) and water (30 mL) were added to the residue. The mixture was filtered through a Celite filter, washed with EA, and the filtrate was separated. The organic phase was washed twice with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain 114 mg of a yellow oily substance. LC-MS showed that the product was approximately 15%. Prep-HPLC (CH3CN / 0.1% NH4OH in H2O) was used for separation, and the product was lyophilized overnight to give a pale yellow solid XNW9608 (15.00 mg, 17.05 μmol, yield 6.5%). LCMS (ESI): m / z = 880.8 [M+H] + HPLC: 99.9%. 1H NMR (400MHz, Methanol-d4) δ8.32 (s, 1H), 6.83 (d, J = 9.2Hz, 1H), 4.79 (dd, J = 10.2, 2.8Hz, 1H) ,4.57-4.40(m,2H),4.29(d,J=7.3Hz,1H),4.05(d,J=10.7Hz,1H),3.80-3.69(m,1H),3.62-3 .44(m,3H),3.41(s,1H),3.26-3.11(m,2H),2.68-2.47(m,2H),2.34-2.29(m,9H),1.98-1.81 (m,4H),1.78-1.47(m,11H),1.30-1.17(m,13H),0.96(d,J=6.9Hz,3H),0.87(t,J=7.4Hz,3H).

[0547] Example 34 XNW9648

[0548] Step 1:

[0549] At room temperature, XNW9648-A1 (5.00 g, 36.19 mmol) was dissolved in CH3CN (150 mL), stirred in an ice-water bath, and NBS (7.09 g, 39.81 mmol) was slowly added in portions. The resulting dark solution was stirred at 0°C for 2.5 hours. LC-MS showed that very little of the starting material remained, and the main peak was the product. Crude silica gel was added, the mixture was evaporated to dryness, and column chromatography was performed using 80 g silica gel and 0-10% EA / PE. The fraction was collected and concentrated under reduced pressure to obtain a brownish-red oily substance, XNW9648-A2 (6.00 g, 27.64 mmol, yield 76.4%). LC-MS (ESI): m / z = 216.9 / 218.9 [M+H]. + .

[0550] Step Two:

[0551] XNW9648-A2 (6.00 g, 27.64 mmol), Pd(PPh3)2Cl2 (970.08 mg, 1.38 mmol), 1,4-dioxane (100 mL), and tributyl(1-ethoxyvinyl)stannane (11.98 g, 33.17 mmol, 11.21 mL) were added to the flask. The mixture was purged with argon gas and stirred overnight in an oil bath at 100°C. LC-MS showed the disappearance of the starting material and the appearance of fragment peaks in the product. LCMS (ESI): m / z = 181.1 [M-Et+1+H] +There were obvious impurity peaks. The reaction solution was not post-treated, and the next step of the reaction was attempted with the theoretical amount of XNW9648-A3 (5.76 g, 27.64 mmol, yield 100.0%).

[0552] Step 3:

[0553] Add HCl (1.7M in water) (6.22g, 170.00mmol, 100mL) to the reaction solution from step two (theoretical amount XNW9648-A3 (5.76g, 27.64mmol)) and stir overnight in an oil bath at 25°C. LC-MS shows the product on MS (but this MS and retention time are consistent with the starting material). TLC (PE / EA = 4 / 1) shows the starting material disappearing and new spots forming. Add water (500 mL), extract with EA (200 mL x 2), the product is in the organic phase, the combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, crude silica gel is added to the filtrate, evaporate to dryness, column chromatography (80 g silica gel, 0-75% DCM / PE), collect the fraction, concentrate under reduced pressure to give yellow solid XNW9648-A4 (3.61 g, 20.03 mmol, yield 74.0%), LCMS (ESI): m / z = 181.1 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.53(s,1H),4.18(s,2H),4.03(s,3H),2.60(s,3H),2.18(s,3H).

[0554] Step Four:

[0555] Add XNW9648-A4 (1.00 g, 5.55 mmol), THF (20 mL), and HBr (33% in acetic acid) (2.88 g, 11.76 mmol, 2.06 mL) to the flask. Add Pyridinium tribromide (1.77 g, 5.55 mmol) at room temperature and stir overnight at room temperature. LC-MS showed that the reactant residue was small, the main peak was the target product, and there was a peak of the dibromo derivative. Add ice water to the reaction solution, extract twice with EA, wash once with saturated brine, dry with anhydrous sodium sulfate, and evaporate the organic phase to dryness. Dissolve the residue in a small amount of DCM, load the sample, and perform column chromatography (24 g silica gel, 0-20% EA / PE). Collect the fraction, concentrate under reduced pressure to obtain an orange-yellow solid XNW9648-A5 (1.69 g, crude). LC-MS (ESI): m / z = 258.9 / 260.9 [M+H] + .

[0556] Step 5:

[0557] XNW9648-A5 (590.00 mg, 2.28 mmol) and formamide (11.34 g, 251.77 mmol, 10 mL) were added to a microwave-safe tube. The tube was purged with argon, sealed, and microwaved at 170°C for 1.5 hours. LC-MS showed that the major peak was the product. The reaction mixture was transferred to a flask, and saturated Na2CO3 (20 mL) and saturated NaCl (50 mL) were added. Solid NaCl was added to saturate the mixture, followed by EA (50 mL). The mixture was filtered through a Celite filter, washed with EA, and the filtrate was separated. The aqueous phase was then extracted with EA (50 mL x 5) until almost no major product spot was observed. The organic phase was evaporated to dryness to obtain a brownish-red oily substance. The sample was dissolved and loaded with a small amount of EA, and subjected to column chromatography using 24 g silica gel, 0-50% B / A (B:DCM / MeOH / 7M NH3-MeOH = 10 / 1 / 1%, A:DCM). The fraction was collected and concentrated under reduced pressure to obtain a yellow solid XNW9648-A6 (220.00 mg, 947.30 μmol, yield 41.6%). LCMS (ESI): m / z = 233.0 [M+H] + .

[0558] Step Six:

[0559] Ethanol (10 mL) was added to XNW9648-A6 (220.00 mg, 947.30 μmol), and HCl (12 M in water (37%)) (2.37 g, 24.00 mmol, 2 mL) was added dropwise at room temperature. The mixture was stirred overnight in an oil bath at 25°C. LC-MS indicated that the reaction was complete. The solution was evaporated to dryness and then dried three times with EtOH to obtain a brown solid XNW9648-A7 (179.00 mg, 743.70 μmol, yield 78.5%, HCl). LC-MS (ESI): m / z = 205.1 [M+H] + .

[0560] Step Seven:

[0561] DMF (3 mL), K₂CO₃ (308.35 mg, 2.23 mmol), KI (50 mg, 301.20 μmol), and tert-butyl N-(4-bromobutyl)carbamate (206.27 mg, 818.07 μmol) were added to XNW9648-A7 (179.00 mg, 743.70 μmol, HCl). The mixture was purged with argon and stirred overnight in an oil bath at 90°C. LC-MS showed that XNW9648-A7 was present in residue, with visible product peaks and two molecules of bromine derivative as byproducts. EA was added, and the mixture was filtered to remove salts. The solution was washed with EA, and the filtrate was evaporated to dryness. The residue was dissolved in a small amount of DCM and loaded onto a column for chromatography. 12 g silica gel was used, with a 0-50% B / A ratio (B:DCM / MeOH / 7M NH3-MeOH = 10 / 1 / 1%, A:DCM). The fraction was collected and concentrated under reduced pressure to obtain 72 mg of a light brown oil. TLC (B / A = 1 / 1) showed obvious impurity spots. Prep-TLC (B / A = 1.5 / 1) purification yielded a yellow oil, XNW9648-A8 (33.00 mg, 87.89 μmol, yield 11.8%), LCMS (ESI): m / z = 376.2 [M+H]. + .

[0562] Step 8:

[0563] HCl (1.75 g, 48 mmol, 4 mL) was added to XNW9648-A8 (33.00 mg, 87.89 μmol) in 12 M water (37%). The mixture was purged with argon and stirred overnight in an oil bath at 95°C. LC-MS showed that the reaction was complete. The solution was evaporated to dryness and then rinsed three times with CH3CN to give a light yellow-brown solid. LC-MS (ESI): m / z = 262.3 [M+H] + The next reaction was carried out using the theoretical amount of XNW9648-A9 (29.00 mg, 86.76 μmol, yield 100.0%, 2HCl).

[0564] Step Nine:

[0565] At room temperature, XNW9648-A9 (29.00 mg, 86.76 μmol, 2HCl) and DBU (132.09 mg, 867.63 μmol, 129.75 μL) were dissolved in CH3CN (4 mL), followed by the addition of SOL-B1 (81.64 mg, 112.79 μmol). The mixture was then stirred overnight in an oil bath at 50°C under argon protection. H2O (2 mL) was added, and the mixture was stirred overnight in an oil bath at 70°C under argon protection. LC-MS showed that the acetyl groups had been removed; under UV 220 nm, the isomers were ~5%, the product ~30%, and the remainder were impurity peaks. CH3CN was removed, and EA (60 mL) was added to the residue. The mixture was washed twice with water, once with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness, yielding 60 mg of a yellow oil. LC-MS showed that the isomers were ~6% and the product ~23%. Prep-HPLC (CH3CN / 0.1% NH4OH in H2O) separation yielded the target product XNW9648 (12.40 mg, 14.17 μmol, yield 16.3%). LCMS (ESI): m / z = 875.8 [M+H] + HPLC: 96.9%. 1 H NMR(400MHz, Methanol-d4)δ7.68(d,J=1.3Hz,1H),7.54(d,J=1.3Hz,1H),6.60(s,1H),4.8 3-4.79(m,1H),4.29(d,J=7.3Hz,1H),4.11-4.02(m,3H),3.80-3.71(m,1H),3.61-3.48(m, 3H),3.44(s,1H),3.25-3.16(m,2H),2.68-2.52(m,2H),2.39(s,3H),2.32(s,6H),2.15(s, 3H), 1.94-1.49 (m, 15H), 1.30-1.17 (m, 13H), 0.97 (d, J = 6.9Hz, 3H), 0.86 (t, J = 7.4Hz, 3H).

[0566] Example 35 XNW9626

[0567] The synthesis steps are referenced in XNW9448.

[0568] White solid XNW9626 (62.12 mg, purity 97.4%). 1H NMR (400MHz, Methanol-d4) δ8.63(s,1H),8.34(d,J=1.6Hz,1H),7.41(d,J=1.6Hz,1H),4.86(d,J=2.9Hz,1H),4.54(h,J=6.8Hz,2H),4.3 4(d,J=7.3Hz,1H),4.12(dd,J=10.6,1.6Hz,1H),3.81(ddd,J=13.7,8.8,4.6Hz,1H),3.70–3.53(m,3H),3.50(s,1H),3.30–3.20(m,2H),2 .75–2.58(m,2H),2.47(s,3H),2.36(s,6H),2.05–1.87(m,4H),1.84–1.75(m,2H),1.71(s,2H),1.70–1.64(m,2H),1.61(q,J=4.0,3.2Hz, 1H), 1.57 (s, 3H), 1.35 (s, 3H), 1.32–1.21 (m, 11H), 1.02 (d, J = 6.9Hz, 3H), 0.92 (t, J = 7.4Hz, 3H). LCMS (ESI): m / z = 432.09, 862.88 [M+H]+.

[0569] Example 36 XNW9628

[0570] The synthesis steps are referenced in XNW9448.

[0571] White solid XNW9628 (8.32 mg, purity 99.14%). 1H NMR (400MHz, Methanol-d4) δ8.44(s,1H),8.12(s,1H),5.81(s,1H),4.87(d,J=2.8Hz,1H),4.51(h,J=6.8Hz,2H),4.34(d,J=7.3Hz,1H ),4.13(d,J=10.6Hz,1H),3.81(ddd,J=13.6,8.7,4.5Hz,1H),3.59(dq,J=16.8,9.9,9.3Hz,3H),3.50(s,1H),3.33–3.19(m,2H),2.73– 2.58(m,2H),2.47(s,3H),2.38(s,6H),2.02–1.87(m,4H),1.79(s,2H),1.73(s,2H),1.71–1.61(m,3H),1.58(s,4H),1.35(s,3H),1.3 0 (dd, J = 10.3, 6.7 Hz, 7H), 1.25 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). LCMS (ESI): m / z = 432.06, 862.69 [M+H]+.

[0572] Example 37 XNW9660

[0573] The synthesis steps are referenced in XNW9448.

[0574] White solid XNW9660 (10.26 mg, purity 99.00%). 1H NMR (400MHz, Methanol-d4) δ8.47(s,1H),7.48(s,1H),6.84(s,1H),4.85(dd,J=10.2,2.8Hz,1H),4.62–4.48(m,2H),4.34(d,J=7.3Hz,1H) ,4.11(dd,J=10.6,1.6Hz,1H),3.80(ddd,J=13.7,8.7,4.8Hz,1H),3.66–3.52(m,3H),3.47(s,1H),3.32–3.18(m,2H),2.74–2.56(m,2H),2 .40(s,3H),2.38(s,6H),2.06–1.87(m,4H),1.84–1.77(m,1H),1.74(s,2H),1.68(s,2H),1.62(d,J=12.8Hz,2H),1.57(s,4H),1.34(s,3H) ,1.29(dd,J=6.6,3.8Hz,7H),1.24(d,J=6.8Hz,3H),1.02(d,J=6.9Hz,3H),0.93(t,J=7.3Hz,3H).LCMS(ESI):m / z=432.02,862.72[M+H]+.

[0575] Example 38 XNW9661

[0576] The synthesis steps are referenced in XNW9448.

[0577] White solid XNW9661 (15.26 mg, purity 98.4%). 1H NMR (400MHz, Methanol-d4) δ7.94(s,1H),7.80(s,1H),7.68(d,J=1.4Hz,1H),5.80(s,1H),4.88(d,J=3.0Hz,1H),4.34(d,J= 7.3Hz,1H),4.17–4.07(m,3H),3.86–3.75(m,1H),3.60(qd,J=8.7,4.0Hz,3H),3.52(s,1H),3.33–3.20(m,2H),2.73–2.58(m, 2H),2.50(s,3H),2.38(s,6H),1.99–1.82(m,4H),1.82(s,2H),1.76(s,2H),1.76–1.64(m,1H),1.62(d,J=6.1Hz,2H),1.58(s ,4H),1.35(s,3H),1.34–1.22(m,10H),1.02(d,J=6.9Hz,3H),0.93(t,J=7.4Hz,3H).LCMS(ESI):m / z=431.64,861.79[M+H]+.

[0578] Example 39 XNW9662

[0579] The synthesis steps are referenced in XNW9558.

[0580] White solid XNW9662 (19.24 mg, purity 98.3%). 1H NMR (400MHz, Methanol-d4) δ8.20(d,J=1.6Hz,1H),8.03(d,J=1.4Hz,1H),7.73(d,J=1.4Hz,1H),7.39(d,J=1.6Hz,1H),4.88(d,J=3.0H z,1H),4.34(d,J=7.3Hz,1H),4.18–4.09(m,3H),3.81(dt,J=13.8,6.9Hz,1H),3.67–3.54(m,3H),3.52(s,1H),3.32–3.20(m,2H),2.72 –2.58(m,2H),2.50(s,3H),2.37(s,6H),2.01–1.85(m,4H),1.81(s,2H),1.76(s,2H),1.74–1.60(m,3H),1.58(s,3H),1.35(s,3H),1.3 2(d,J=7.0Hz,4H),1.26(dd,J=10.7,6.6Hz,7H),1.03(d,J=6.9Hz,3H),0.93(t,J=7.4Hz,3H). LCMS(ESI): m / z=431.60,861.82[M+H]+.

[0581] Example 40 XNW9664

[0582] The synthesis steps are referenced in XNW9558.

[0583] White solid XNW9664 (3.02 mg, purity 99.75%). 1H NMR (400MHz, Methanol-d4) δ7.76(d,J=1.3Hz,1H),7.73(d,J=1.2Hz,1H),6.35(d,J=2.2Hz,1H),5.63(d,J=2.1Hz,1H),4.86(dd,J=8.4, 1.9Hz,1H),4.35(d,J=7.3Hz,1H),4.20–4.09(m,3H),3.86–3.74(m,1H),3.67–3.54(m,3H),3.49(s,1H),3.34–3.20(m,2H),2.79–2.55(m ,2H),2.45(s,3H),2.41(s,6H),1.88(dd,J=22.6,14.4Hz,5H),1.81(s,2H),1.75(s,2H),1.73–1.60(m,3H),1.58(s,4H),1.35(s,3H),1 .30 (dd, J=11.4, 6.5Hz, 7H), 1.25 (d, J=6.9Hz, 3H), 1.02 (d, J=6.9Hz, 3H), 0.92 (t, J=7.4Hz, 3H). LCMS (ESI): m / z=431.51, 861.72[M+H]+.

[0584] Example 41 XNW9665

[0585] The synthesis steps are referenced in XNW9558.

[0586] White solid XNW9665 (4.16 mg, purity 98.67%). 1H NMR (400MHz, Methanol-d4) δ7.77(d,J=1.2Hz,1H),7.71(d,J=1.3Hz,1H),7.40(s,1H),6.76(s,1H),4.85(d,J=2.9Hz,1H),4.34(d,J=7 .3Hz,1H),4.19–4.08(m,3H),3.81(dt,J=13.7,6.7Hz,1H),3.58(ddt,J=18.1,10.8,7.6Hz,3H),3.49(s,1H),3.32–3.20(m,2H),2.65( ddd,J=22.7,12.1,4.4Hz,2H),2.45(s,3H),2.37(s,6H),2.01–1.76(m,4H),1.79(s,2H),1.74(s,2H),1.72–1.60(m,4H),1.58(s,3H), 1.34 (s, 3H), 1.28 (td, J = 13.6, 13.2, 7.0Hz, 10H), 1.02 (d, J = 6.9Hz, 3H), 0.92 (t, J = 7.4Hz, 3H). LCMS (ESI): m / z = 431.51, 861.72 [M+H]+.

[0587] Example 42 XNW9666

[0588] The synthesis steps are as described in XNW9448.

[0589] XNW9666 (237.0 mg, 99.76% purity), a white solid product.

[0590] 1H NMR (400MHz, Methanol-d4) δ8.19(s,1H),6.87(s,1H),4.86~4.83(m,1H),4.53(td,J=6.8,4.1Hz,2H),4.33(d,J=7.3 Hz,1H),4.11(dd,J=10.6,1.6Hz,1H),3.80~3.73(m,1H),3.61~3.52(m,3H),3.48(s,1H),3.30~3.19(m,2H),3.03(p,J =6.8Hz,1H),2.70~2.58(m,2H),2.45(s,3H),2.34(s,7H),2.03~1.87(m,4H),1.80~1.71(m,3H),1.70~1.57(m,5H),1 .56(s,3H),1.35~1.18(m,22H),1.00(d,J=6.9Hz,3H),0.90(t,J=7.4Hz,3H).LCMS(ESI): m / z=453.10,904.77[M+H]+.

[0591] Biological Effects Example 1: Detection of Antibacterial Activity of Test Compounds

[0592] 1. Prepare the test plates according to the test plate layout and bacterial strain test procedure.

[0593] 2. Transfer 2 μL of the test compound from the dilution plate into the corresponding well of the test plate.

[0594] 3. Preparation for bacterial inoculation

[0595] (1)Staphylococcus spp.and Moraxella catarrhalis

[0596] Use a sterile inoculation loop to scrape a small amount of frozen bacteria onto a TSA plate and streak it. Place the plate in a regular incubator and incubate at 35±2℃ for about 20 hours.

[0597] Ten single colonies were picked from the above solid culture dish and resuspended in sterile physiological saline (0.9% NaCl), then the OD600 was adjusted to ~0.15 using a spectrophotometer. The bacteria were then diluted 300-fold using CAMHB to achieve an inoculum concentration of ~2 x 10⁻⁶. 5 CFU / mL (Note: Use the bacterial solution within 15 minutes).

[0598] (2)Streptococcus spp.

[0599] Use a sterile inoculation loop to scrape a small amount of frozen bacteria and streak it onto a blood-containing TSA agar plate. Place the plate in an incubator at 35±2℃ and 5% CO2 for about 20 hours.

[0600] Ten single colonies were picked from the above solid culture dish and resuspended in sterile physiological saline (0.9% NaCl), then the OD600 was adjusted to ~0.15 using a spectrophotometer. The bacteria were then diluted 300-fold with CAMHB to achieve an inoculum concentration of ~2 x 10⁻⁶. 5 CFU / mL (Note: Use the bacterial solution within 15 minutes).

[0601] (3) Haemophilus influenzae

[0602] Use a sterile inoculation loop to scrape a small amount of frozen bacteria onto chocolate agar plates and inoculate them. Place the plates in an incubator at 35±2℃ and 5% CO2 for about 20 hours.

[0603] Ten single colonies were picked from the above solid culture dishes and resuspended in sterile physiological saline (0.9% NaCl), then the OD600 was adjusted to ~0.15 using a spectrophotometer. The bacteria were then diluted 300-fold using an HTM broth to achieve an inoculum concentration of ~2 x 10⁻⁶. 5 CFU / mL (Note: Use the bacterial solution within 15 minutes).

[0604] 4. Add 98 μL of the corresponding bacterial inoculum to the test plate.

[0605] 5. Cover the test plate with a sterile lid, centrifuge at 800 rpm for 30 seconds, and then vibrate at 400 rpm for 1 minute on a vibrating plate machine.

[0606] 6. After mixing, place in an incubator and incubate at 35±2℃ for 20 hours.

[0607] 7. Perform colony counting after inoculation.

[0608] 8. Place the test plate on the reading device, adjust the reflector to observe and record the bacterial growth in each well.

[0609] 9. Take a picture of each test board using the QCount system.

[0610] 10. Use SpectraMax plus 384 to read the OD of bacteria in each well. 600 value.

[0611] 11. Report all raw data, including compound information, CFU, MIC, etc.

[0612] The test strains are shown in Table 1:

[0613] Table 1

[0614] The test results are shown in Table 2:

[0615] Table 2. MIC test results of compounds (μg / mL)

[0616] The test results showed that the tested compound exhibited significant antibacterial activity.

[0617] Biological Effects Example 2: Assay of the antibacterial activity of the test compound in clinical strains of azithromycin-resistant Gram-positive bacteria

[0618] 1. Preparation of culture medium

[0619] MHIIA plates: Dissolve 38g of Mueller Hinton II Agar (Cation-Adjusted) powder in 1L of ultrapure water, mix well, and autoclave at 121℃ for 15 minutes. Take 15mL from each petri dish to make a plate.

[0620] MHIIB: Dissolve 22g of Mueller Hinton II Broth (Cation-Adjusted) powder in 1L of ultrapure water, mix well, and autoclave at 121℃ for 15 minutes.

[0621] 0.9% NaCl: 9g + 1000mL ultrapure water, autoclave at 121℃ for 15 minutes.

[0622] MHIIB + 5% Lysed Horse Blood: Add 3 mL of lysed horse blood to 57 mL of MHIIB, filter, and use immediately.

[0623] 2. Preparation of bacterial strains

[0624] The day before the experiment, the glycerol tube strain at -80℃ was taken out, streaked onto the corresponding solid culture medium, and then the inoculated plate was placed under the appropriate conditions for 20 hours.

[0625] On the day of the experiment, several fresh single clones were picked and added to 5 mL of physiological saline, mixed well, and the turbidity was adjusted to ~0.2 using a turbidimeter, which is equivalent to ~1 x 10⁸ CFU / mL. After being diluted 200 times with culture medium, this was the inoculum solution, ready for use.

[0626] 3. Compound preparation

[0627] 3.1 Preparation of storage solution

[0628] Compounds: The compounds were prepared into a stock solution with a concentration of 3.2 mg / mL using DMSO. The 3.2 mg / mL stock solution of the compounds was 100 times the highest initial concentration of the daughter plate.

[0629] Control compound: The control compound was prepared into a stock solution with a concentration of 12.8 mg / mL using DMSO, and then diluted 16 times to 0.8 mg / mL (3 μL stock solution plus 45 μL DMSO). The 0.8 mg / mL control compound was 100 times the highest initial concentration of the daughter plate.

[0630] 3.2 Preparation of compound masterbatch

[0631] Add 40 μL of the compound at a 100x initial concentration to column 1 of the master plate, and add 20 μL of DMSO to columns 2 through 12. Transfer 20 μL of the compound stock solution from column 1 to column 2, mix thoroughly, and then transfer 20 μL to column 3. Repeat the above steps until column 11 to obtain a compound with a 2-fold serial dilution. This is the compound master plate.

[0632] 3.3 Preparation of Compound Sub-board and MIC Test Board

[0633] 1 μL of the compound was transferred from the mother plate to the daughter plate using a multichannel pipette. Then, 99 μL of inoculum was transferred to the daughter plate using a multichannel pipette; this is the MIC test plate. The test concentrations of the compound and control compound are shown in the table below, where 1% DMSO was used as the growth control (GC).

[0634] 4. Cultivation and reading

[0635] After incubating all test plates in a 36.5°C incubator for 20 hours, the lowest compound concentration at which the growth of the strain is completely or significantly inhibited by visual observation will be the MIC of that compound.

[0636] 5. The test strains (from Shanghai WuXi AppTec New Drug Development Co., Ltd.) are shown in Table 3:

[0637] Table 3: Information on Clinical Strains of Gram-positive Bacteria

[0638] The test results showed that the tested compound exhibited significant antibacterial activity in azithromycin-resistant Gram-positive strains (Staphylococcus aureus and Streptococcus pneumoniae).

[0639] Biological Effects Example 3: Detection of the antibacterial activity of the test compound in clinical strains of Mycoplasma pneumoniae

[0640] 1. Remove the frozen strain from -80℃, place it on ice, and transfer it to the biosafety cabinet in the cell culture room to thaw and prepare for use;

[0641] 2. Dilute the frozen strain to a final concentration of 2-5 × 10⁻⁵ using an appropriate amount of culture medium, based on the concentration of the strain (calculated by qPCR). 4 Copy number / μL, incubate the strain at 37℃, 5% CO2 for 2h to revive it;

[0642] 3. Dilute the medication after incubation:

[0643] a. Take 2.5 μL of 12.8 mg / ml drug and add it to 2 ml (3*10) 4 The bacterial culture was used to obtain a bacterial culture with a drug concentration of 16 ug / ml;

[0644] b. Take 500 μL of bacterial suspension a and add it to a bacterial suspension containing 500 μL of bacterial suspension to obtain a bacterial suspension with a drug concentration of 8 μg / ml;

[0645] c. Take 500 μL of the bacterial solution above b and add it to a bacterial solution containing 500 μL of bacterial solution to obtain a bacterial solution with a drug concentration of 4 μg / ml;

[0646] d. Take 500 μL of the above c bacterial solution and add it to a bacterial solution containing 500 μL of bacterial solution to obtain a bacterial solution with a drug concentration of 2 μg / ml;

[0647] e. Take 500 μL of the above bacterial solution and add it to a bacterial solution containing 500 μL of bacterial solution to obtain a bacterial solution with a drug concentration of 1 μg / ml;

[0648] f. Take 500 μL of the above bacterial solution and add it to a bacterial solution containing 500 μL of bacterial solution to obtain a bacterial solution with a drug concentration of 0.5 μg / ml;

[0649] g. Take 500 μL of the above bacterial solution and add it to a bacterial solution containing 500 μL of bacterial solution to obtain a bacterial solution with a drug concentration of 0.25 μg / ml;

[0650] 4. Add 135 μL of the diluted bacterial solution to each well of a 96-well plate and incubate at 37°C in a 5% CO2 incubator. For each concentration of bacterial solution, inoculate 3 parallel samples. Collect one sample on Day 1, Day 3, and Day 5 respectively and place them at -20°C for testing.

[0651] 5. qPCR detection:

[0652] a. Remove the collected samples from -20℃ and wait for them to thaw;

[0653] b. Prepare a 10 μL system: 1 μL template + 5 μL Mix + 0.2 μL upstream primer (F) + 0.2 μL downstream primer (R) + 3.6 μL ddH2O;

[0654] c. Add the prepared 10 μL system to a 384-well plate and centrifuge at 1200 rpm for 2 min;

[0655] d. On-machine testing (Bio-Rad / DFX Opus 384 Real-Time PCR System).

[0656] 6. Test strains and results (from Shanghai Children's Medical Center affiliated with Shanghai Jiao Tong University School of Medicine) are shown in Table 4:

[0657] Table 4. MIC values ​​(μg / mL) of the tested Mycoplasma pneumoniae strains and test compounds.

[0658] The test results showed that the tested compound exhibited significant anti-mycoplasma activity.

[0659] Biological Effects Example 4: CellTiter-Glo (CTG) method was used to test the 50% inhibitory concentration (IC50) of the test compound on cell proliferation in the HepG2 tumor cell line. 50 ) and maximum inhibition rate

[0660] I. In vitro hepatotoxicity evaluation system:

[0661] Drug-induced damage to hepatocytes is one of the main causes of hepatotoxicity. The HepG2 cell line is a type of human liver cancer cell, exhibiting stronger proliferation and malignancy than primary human hepatocytes. In vitro testing of the inhibitory effect of drugs on cell proliferation can reflect the damage caused to hepatocytes by the test compound, thus evaluating the in vitro hepatotoxicity of the test compound. Simultaneously, the hepatotoxicity of the test compound is also evaluated by testing its damage to primary hepatocytes of different species.

[0662] II. Experimental Procedure:

[0663] 1. Microscopic observation of HepG2 cells (Source: ATCC, Lot No.: HB-8065) TM The cells are in a state where the cell fusion rate reaches 80-90%, and then the cells are processed.

[0664] 2. Preheat the complete culture medium, DPBS and trypsin in a 37°C water bath in advance.

[0665] 3. Use a pipette to aspirate the cell solution from the culture flask, and then discard the cell solution.

[0666] 4. Wash once with 5 mL of DPBS (T75 flask).

[0667] 5. Add 3 mL of trypsin (T75 flask) and stop digestion according to the cell digestion time.

[0668] 6. Add 6 mL of complete culture medium (T75 flask) to stop digestion, transfer the T75 flask cell suspension to a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 min.

[0669] 7. Discard the supernatant, resuspend the cell pellet in complete culture medium, count the cells using a cell counter, and record the cell count and cell viability.

[0670] 8. Prepare a cell stock solution based on the cell count results.

[0671] 9. Dispense the prepared solution into a 96-well plate using a multi-pipette according to a specific layout, adding 100 μL to each well.

[0672] 10. Place the 96-well plate in an incubator at 37°C and 5% CO2 for incubation.

[0673] 11. Add the drug on the second day. Dilute each compound 2 times, 9 concentrations, 2 replicates per concentration. The final concentration of DMSO is 0.5%. Dilute the test compound (40mM stock solution). Plate 100uL of cells. Add 100uL of the drug on the second day.

[0674] 12. Add the drug to the cells using a pipette, 100 μL per well, and place the culture plate in an incubator for 6 days.

[0675] 13. After 6 days of culture, remove 100 μL of culture medium from the culture plate, add 50 μL of CTG reagent, shake at low speed for 2 minutes on a shaker, and let stand at room temperature in the dark for 30 minutes. Immediately read the sample signal value on the microplate reader.

[0676] 14. Interpretation of cell CTG detection results.

[0677] 15. Data Processing:

[0678] The inhibition rate (IR) of the detected compound is calculated using the following formula: IR (%) = (1 – (RLU compound – RLU blank control) / (RLU solvent control – RLU blank control)) * 100%. The inhibition rates of different compound concentrations are calculated in Excel, and then inhibition curves are plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC50, are calculated using GraphPad Prism software. 50 .

[0679] 16. The test results are shown in Table 5.

[0680] Table 5

[0681] Among them, hepatotoxic IC 50(μM), A≥100; 100>B≥80; 80>C≥70; D<70. It is evident that the tested compound can improve hepatotoxicity.

[0682] Biological Effects Example 5: Testing the in vitro protein binding rate of the test compound in CD-1 mouse, Sprague-Dawley rat, beagle dog, cynomolgus monkey, and human plasma.

[0683] The protein binding rates of the compounds in the plasma of CD-1 mice, Sprague-Dawley rats, beagles, cynomolgus monkeys, and humans were determined using a balanced dialysis method. After dialysis, 20 μL of the post-dialysis plasma sample was transferred to a sample receiving plate, and 100 μL of PBS was added. Another 100 μL of the post-dialysis PBS sample was transferred to the same plate, and 20 μL of blank plasma was added. All samples were mixed with 600 μL of stop solution and centrifuged at 4000 rpm for 15 minutes. After centrifugation, 200 μL of the supernatant was collected and diluted with 200 μL of water / acetonitrile solution (1:1, v / v). The concentrations of the compounds in plasma and PBS were determined by LC-MS / MS, and the free fraction, bound fraction, and recovery rate were calculated.

[0684] Experimental results: The tested compounds showed good PPB results, with a high proportion of free compounds contributing to the drug's efficacy. Furthermore, other ADME (absorption, distribution, metabolism, and excretion) pharmacokinetic properties were also favorable.

[0685] Biological Effects Example 6: Testing the in vivo pharmacokinetic (PK) levels of the test compound in different species

[0686] Mouse PK: Male CD-1 mice (6-8 weeks old) were administered intravenously (IV) at a dose of 10 mg / kg via tail vein bolus or orally (PO) at doses of 20 mg / kg and 100 mg / kg via gavage. The compound was prepared in a solvent of 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or sterile water at pH 3.0 (PO). All animals had free access to food and water during the experiment. Blood samples (n=3) were collected intravenously at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 3500 g, 4°C for 5 min, and the resulting plasma was analyzed by LC-MS / MS. PK parameters were analyzed using WinNonlin software. Version 8.3 calculates using a non-room model analysis method.

[0687] Rat PK: Male CD1 mice (6-10 weeks old) were administered intravenously (IV) at a dose of 10 mg / kg via tail vein bolus or orally (PO) at doses of 30 mg / kg and 100 mg / kg via gavage. The compound was prepared in a solvent of 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or sterile water at pH 3.0 (PO). All animals had free access to food and water during the experiment. Blood samples (n=3) were collected intravenously at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 6800g, 2-8℃ for 6 minutes, and the resulting plasma was analyzed by LC-MS / MS. PK parameters were analyzed using WinNonlin software. Version 7.0 calculates using a non-room model analysis method.

[0688] Canine PK: Male Beagles (6-24 months of age) were administered intravenously (IV) at a dose of 10 mg / kg orally (PO) via gavage. The compound was prepared in a solution of 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or sterile water at pH 3.0 (PO). All animals had free access to food and water during the experiment. Blood samples (n=2) were collected intravenously at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 3500g, 4°C for 5 minutes. The resulting plasma was analyzed by LC-MS / MS. PK parameters were analyzed using WinNonlin software. Version 8.3 calculates using a non-room model analysis method.

[0689] Monkey PK: Female cynomolgus monkeys (2.5-6 years old) were administered the compound intravenously (IV) at a dose of 10 mg / kg orally (PO) via gavage at a dose of 50 mg / kg. The compound was prepared in a solvent of 5% DMSO + 10% Solutol HS15 + 85% physiological saline (IV) or sterile water at pH 3.0 (PO). All animals had free access to food and water during the experiment. Blood samples (n=2) were collected intravenously at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration and placed in tubes containing EDTA-K2 as an anticoagulant. Blood samples were centrifuged at 3500g, 4°C for 5 minutes, and the resulting plasma was analyzed by LC-MS / MS. PK parameters were analyzed using WinNonlin software. Version 8.3 calculates using a non-room model analysis method.

[0690] Experimental results: The tested compounds showed good in vivo PK in different species.

[0691] Biological Effects Example 7: Testing Phospholipid Deposition in HepG2 Cells Using the Test Compound

[0692] 1. Phospholipid Deposition Evaluation System: Phospholipid storage disease is a lysosomal storage disorder characterized by the accumulation of large amounts of phospholipid complexes within the lysosomal membrane. Current evidence suggests that cationic amphiphilic drugs (CADs), such as antibiotics, antidepressants, antihistamines, and other prescription medications, are contributing factors to phospholipid storage disease.

[0693] Phospholipid deposition induced by these drugs is usually reversible and does not cause adverse consequences; however, long-term exposure to certain drugs may lead to long-term toxic effects. Therefore, phospholipid deposition caused by drug-induced cellular lipotoxicity should be evaluated in the early stages of drug development to minimize its potential risks.

[0694] The aim of this study was to evaluate the effect of the test compound on phospholipid deposition in HepG2 cells.

[0695] 2. Experimental Procedure

[0696] 2.1 Cell Plating

[0697] Day 1: HepG2 cells (ATCC-HB-8065) ​​resuspended in DMEM medium were seeded into PDL-coated 96-well plates (30,000 cells / well / 100 μL). The cells were then cultured overnight in a cell culture incubator at 37°C, 5% CO2, and >90% relative humidity.

[0698] 2.2 Compound Treatment

[0699] the next day:

[0700] 1) After completely aspirating the culture medium from the cell plate, add 100 μL / well of LipidTOX detection reagent to the cell plate.

[0701] 2) The test compound was added to the cell plate using a Pico 8 instrument, and the cells were cultured in a cell culture incubator at 37°C, 5% CO2, and relative humidity >90% for 48 hours.

[0702] 2.3 Reading the board

[0703] Day 4:

[0704] 1) Remove the cell plate from the incubator, add 100 μL / well of 8% PFA fixative to fix the cells, and incubate the cell plate at room temperature for 30 minutes.

[0705] 2) Aspirate the PFA fixative and culture medium mixture from the cell plate.

[0706] 3) Wash the fixed cells with DPBS solution to thoroughly remove any residual PFA fixative.

[0707] 4) Dilute Hoechst 33342 from 10 mg / mL to 8 μg / mL working solution with DPBS, add 100 μL of Hoechst 33342 working solution to the fixed cell plate, and incubate at room temperature for 30 minutes.

[0708] 5) Wash the fixed cells three times with DPBS to remove Hoechst 33342.

[0709] 6) Scan the cell plate using a CQ1 instrument.

[0710] 3. Data Analysis

[0711] In this study, the average values ​​of cell number, phospholipid deposition number, and total red signal intensity (phospholipid deposition) were used as raw data for subsequent analysis.

[0712] 3.1 Inhibition rate (%) = (1 - number of viable cells in sample wells / average number of viable cells in DMSO control wells) * 100.

[0713] 3.2 Fluorescence ratio of phospholipid deposition (normalized by the fluorescence signal value of the DMSO control wells to the fluorescence signal of the sample wells) = ((mean fluorescence signal value of phospholipids in sample wells * total number of phospholipids in sample wells) / number of cells in sample wells) / mean {((mean fluorescence intensity of phospholipid deposition in DMSO control wells * number of phospholipid deposits in DMSO control wells) / number of viable cells in DMSO control wells)}

[0714] 3.3 Use Graph Pad Prism 6 software to calculate the CC50 or EC50 value of the compound.

[0715] 3.4 Absolute CC 50 The value represents the concentration of the test compound corresponding to a 50% effective inhibition value. (Relative to EC50) 50 This represents the concentration of the test compound corresponding to half of the maximum effective response value.

[0716] Overview: This study used HepG2 cells as a model cell to investigate the effects of compounds on the induction of phospholipid deposition in HepG2 cells. After treating adherent HepG2 cells with the compounds and LipidTOX reagent for 48 hours, the cells were fixed with PFA fixative and stained with Hoechst 33342 nuclear stain. Data were acquired using a CQ1 high-throughput fluorescence microscope, and the total cell count, total phospholipid count, and total red signal intensity (total phospholipid intensity) were used as raw data for subsequent analysis.

[0717] Experimental results: The tested compounds showed significant phospholipid deposition, with low safety risk.

[0718] Biological Effects Example 8: Testing the efficacy of the test compound in animal models of pathogenic microorganism infection.

[0719] I. Experimental Objective

[0720] The in vivo efficacy of the test compound against lung infections in mice caused by pathogenic microorganisms (Mycoplasma pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae) was tested.

[0721] II. Experimental Conditions

[0722] 2.1 Instrument Information

[0723] Instrument Information Sheet

[0724] 2.2 Culture medium information

[0725] Culture medium information sheet

[0726] III. Experiment Content

[0727] 3.1 Establishment of a mouse model of immunodeficiency

[0728] Mice in each experimental group were given cyclophosphamide 150 mg / kg on day 4 before infection and cyclophosphamide 100 mg / kg on day 1 before infection to suppress the immune system.

[0729] 3.2 Establishment of a lung infection model in immunocompromised mice

[0730] Preparation of bacterial culture: The Streptococcus pneumoniae strain was inoculated onto the slant of nutrient agar medium containing 5% defibrinated sheep blood and cultured at 37°C for 16 h. Then, it was inoculated into 100 mL of M-HII broth medium containing 5% lysed horse blood and cultured at 37°C for 16 h in a 5% CO2 environment. The viable count was used to determine the bacterial concentration.

[0731] Aliquot 100mL of bacterial culture into sterile 10mL test tubes and centrifuge at 3000rpm / min for 5min. Discard the supernatant, then add an equal volume of sterile physiological saline to resuspend the culture. Centrifuge again, discard the supernatant, and then dilute with physiological saline in a gradient to the concentration of the modeling bacteria.

[0732] 3.3 Drug Preparation

[0733] Drug solvent: sterile water, pH 3.0 (adjusted with hydrochloric acid) (dissolve in sterile water; if clear, do not adjust with hydrochloric acid).

[0734] 3.4 Experimental Content

[0735] 3.4.1 Infection and Drug Administration

[0736] On the day of infection, except for the Negative control group, all other groups used bacterial suspensions to infect immunocompromised mice via nasal drops, with 50 μL administered intranasally. Two hours after infection, each treatment group received the designed dose via gavage. The Vehicle and Negative control groups received the corresponding volume of solvent. The total drug volume was 10 mL / kg per mouse, administered once daily for the second and third days after infection.

[0737] 3.4.2 Sample Collection

[0738] Twenty-four hours after lung infection, mice were euthanized, and bronchoalveolar lavage fluid and lung tissue were collected, weighed, and immediately added to 5 mL of sterile saline for tissue homogenization.

[0739] 3.4.3 Colony Counting of Tissue Homogenate

[0740] After weighing the tissue, homogenize it in a pre-prepared solution containing 5 mL of sterile, pre-cooled physiological saline. Dilute the homogenate 10-fold with sterile physiological saline. Take 1 mL of the appropriate dilution and place it in a sterile Petri dish, add 9 mL of agar medium, and mix well. Prepare two plates for each concentration, incubate at 37°C in a 5% CO2 environment for 36–48 hours, and then count the colonies.

[0741] 3.4.4 Detection Indicators

[0742] The bacterial load is calculated by detecting the bacterial load in bronchoalveolar lavage fluid or tissue homogenate by qPCR, or by counting the bacteria in solid culture after homogenizing lung tissue.

[0743] Experimental results: The test compounds showed significant antibacterial or antimycoplasma effects in animal models infected with pathogens, and could effectively reduce the bacterial load in the model animals.

Claims

1. A compound as shown in Formula I or a pharmaceutically acceptable salt thereof, L is C 1-10 Alkylene or C 2-10 alkenyl; the C 1-10 alkylene and the C 2-10 The alkenyl group may be optionally substituted with one or more deuterium groups; X is CR 1 R 2 or The It can be replaced by one or two deuteriums; Ring A is a 5-14 membered heteroaryl group; the heteroatoms of the 5-14 membered heteroaryl group are selected from one, two or three of N, O and S, and the number of heteroatoms in the 5-14 membered heteroaryl group is one, two, three or four; the 5-14 membered heteroaryl group is optionally substituted by one or more deuteriums; R 1 and R 2 Independently, H, deuterium, OH, NH2, CN, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl, C 5-14 Cycloalkenyl, OC 1-10 Alkyl, OC 3-14 cycloalkyl or 5-14-membered heteroaryl; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl, C 5-14 cycloalkenyl, the OC 1-10 Alkyl, the OC 3-14 The cycloalkyl group and the 5-14 heteroaryl group are optionally surrounded by one, two, or three R groups. 1-1 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4; Each R 1-1 Independently deuterium, OH, halogen, SO3R 1-1-1 or COOR 1-1-2 ; R 1-1-1 and R 1-1-2 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups; Or, R 1 R 2 Together with the carbon atom attached thereto, a 3-14 membered heterocyclic group is formed; the 3-14 membered heterocyclic group is a 3-14 membered heterocyclic group in which the heteroatoms are selected from one or two of N, O and S, and the number of heteroatoms is independently one or two; the 3-14 membered heterocyclic group is optionally substituted by one or more deuteriums; R is R 3 For H, deuterium, CN, CONR 3-1 R 3-2 COOR 3-3 C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl, C 6- 14 Aryl and 5-14 heteroaryl groups; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl, the C 6-14 The aryl group and the 5-14 heteroaryl group are optionally surrounded by one, two, or three R groups. 3-4 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4; R 3-1 R 3-2 and R 3-3 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups; Each R 3-4 Independently deuterium, OH, halogen, NR 3-4-1 R 3-4-2 , C 1-10 Alkyl or 5-14-membered heteroaryl; the C 1-10 The alkyl group and the 5-14-membered heteroaryl group are optionally surrounded by one, two, or three R groups. 3-4-4 Substitution; the 5-14 membered heteroaryl group is a 5-14 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2, 3 or 4; R 3-4-1 and R 3-4-2 H independently Or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups; R 3-4-3 C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups; Each R 3-4-4 Independent of deuterium, OH, NR a R b Or C 1-10 Alkyl; the C 1-10 Alkyl groups are optionally surrounded by one, two, or three R's. 3- 4-4-1 replace; R a and R b H independently Or C 1-10 Alkyl; the C 1-10 Alkyl groups may optionally be substituted with one or more deuterium groups; Each R 3-4-4-1 It can be independently deuterium, OH, or NH2; R 4 For H or C 1-10 Alkyl; the C 1-10 Alkyl groups may be optionally surrounded by one, two, or three R's. 4-1 replace; Each R 4-1 Independently deuterium, OH, CN, halogen, NR a R b C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-14 cycloalkyl or C 5-14 Cycloalkenyl; the C 1-10 Alkyl, the C 2-10 alkenyl, the C 2-10 alkynyl group, the C 3-14 cycloalkyl and the C 5-14 The cycloalkenyl group may be optionally substituted with one or more deuterium groups; R a and R b H independently Or C 1-10 Alkyl; the C 1-10 The alkyl group may be optionally substituted with one, two, or three deuterium atoms; R 5 The heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl group is surrounded by 1, 2 or 3 R atoms. 5-1 Replacement, and at least one R 5-1 It is a hydroxyl group; Or, R 5 The partially saturated 5-6 membered heterocyclic group is a N heteroatom, and the number of heteroatoms in the partially saturated 5-6 membered heterocyclic group is independently one or two; the partially saturated 5-6 membered heterocyclic group is separated by one, two or three R atoms. 5-1 Replacement, and at least one R 5-1 For oxygenation; Each R 5-1 Independently deuterium, halogen, oxo, hydroxyl, NR 5-1-1 R 5-1-2 C 1-10 Alkyl, OC 1-10 Alkyl, C 3-6 cycloalkyl, -NH-CO-C 1-10 Alkyl; the C 1-10 Alkyl, the OC 1-10 Alkyl groups and the -NH-CO-C 1-10 Alkyl groups may be optionally substituted with one or more deuterium, halogen, or hydroxyl groups; R 5-1-1 and R 5-1-2 Independently H or C 1-10 Alkyl; the C 1-10 Alkyl groups may be optionally surrounded by one, two, or three R's. 5-1-1-1 replace; Each R 5-1-1-1 Independently, it is either deuterium or a 5-14 heteroaryl group; the 5-14 heteroaryl group is a 5-14 heteroaryl group with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, three, or four; the 5-14 heteroaryl group is optionally substituted with one or more deuterium groups; R 6 It can be H, deuterium, or methyl.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) L is C 1-10 Alkylene or C 2-10 alkenyl group; preferably C 1-6 Alkylene or C 2-6 alkenyl; more preferably C 1-6 Alkylene or C 4-6 Alkylene; (2) X is CR 1 R 2 ; (3)R 1 and R 2 Independently halogen or C 1-6 Alkyl; preferably, R 1 C 1-6 Alkyl, R 2 H or halogen, more preferably R 1 C 1-6 Alkyl, R 2 It is a halogen; (4) Ring A is a 5-10-membered heteroaryl group, preferably a 5-6-membered heteroaryl group, more preferably a 5-membered heteroaryl group, wherein the heteroatom in the 5-membered heteroaryl group is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; preferably, ring A is a diazole, triazole or tetrazolium, or ring A is an imidazolyl group, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl or thiazolyl; (5) R is (6)R 6 For H; (7)R 3 For H or C 1-6 Alkyl group, preferably H; (8)R 4 For H or C 1-10 Alkyl group; preferably H or C 1-6 Alkyl, more preferably C10 1-6 alkyl; (9)R 5 The heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, and the 5-6 membered heteroaryl group is surrounded by 2 or 3 R atoms. 5-1 Replacement, at least one R 5-1 For hydroxyl, and, at least one R 5-1 It is an amino group; Or, R 5 The heteroatom in the partially saturated 5-6 membered heterocyclic group is N, and the number of heteroatoms is independently one or two; the partially saturated 5-6 membered heterocyclic group is separated by two or three R atoms. 5-1 Replacement, at least one R 5-1 For oxidation; and, at least one R 5-1 It is an amino group; (10)R 5-1 Independent of deuterium, halogen, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may be optionally substituted with one or more substituents selected from deuterium and halogens.

3. The compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that: R 5 for Or its tautomers; R 5-1a It is an amino group; t is 0, 1, or 2; R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may optionally be substituted with one or more substituents selected from deuterium and halogens; preferably, R 5-1 For deuterium, C 1-6 Alkyl or OC 1-6 Alkyl; more preferably, R 5-1 For deuterium or OC 1-6 alkyl.

4. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound shown in Formula I is selected from any of the following schemes: Option 1: R 5 The partially saturated 5-6 membered heterocyclic group is a N heteroatom, and the number of heteroatoms in the partially saturated 5-6 membered heterocyclic group is one or two; the partially saturated 5-6 membered heterocyclic group is surrounded by one, two or three R atoms. 5-1 Replace; and at least one R 5-1 For oxygenation; R 5-1 Independently -NH2, deuterium, halogen, oxo or C 1-6 alkyl; Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3. L is C 4-6 Alkylene; the C 4-6 The alkylene group may be optionally substituted with one or more deuterium groups; X is CR 1 R 2 ; R 1 It is a halogen; R 2 C 1-6 alkyl; R is R 6 For H, R 3 For H or C 1-6 alkyl; R 4 C 1-6 alkyl; Option 2: R 5 The heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl group is surrounded by 1, 2 or 3 R atoms. 5-1 Replace; and at least one R 5-1 It is a hydroxyl group; R 5-1 Independently -NH2, deuterium, halogen, hydroxyl or C 1-6 alkyl; Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3. L is C 4-6 Alkylene; the C 4-6 The alkylene group may be optionally substituted with one or more deuterium groups; X is CR 1 R 2 ; R 1 It is a halogen; R 2 C 1-6 alkyl; R is R 6 For H, R 3 For H or C 1-6 alkyl; R 4 C 1-6 alkyl; Option 3: R 5 The partially saturated 5-6 membered heterocyclic group is a N heteroatom, and the number of heteroatoms in the partially saturated 5-6 membered heterocyclic group is one or two; the partially saturated 5-6 membered heterocyclic group is separated by two or three R atoms. 5-1 Replacement, and at least one R 5-1 For oxidation, and, at least one R 5-1 It is an amino group; R 5-1 Independently -NH2, deuterium, halogen, oxo or C 1-6 alkyl; Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3. L is C 4-6 Alkylene; the C 4-6 The alkylene group may be optionally substituted with one or more deuterium groups; X is CR 1 R 2 ; R 1 It is a halogen; R 2 C 1-6 alkyl; R is R 6 For H, R 3 For H or C 1-6 alkyl; R 4 C 1-6 alkyl; Option 4: R 5 The heteroaryl group is a 5-6 membered heteroaryl group, wherein the heteroatom in the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2; the 5-6 membered heteroaryl group is surrounded by 2 or 3 R atoms. 5-1 Replace; and at least one R 5-1 For hydroxyl, and, at least one R 5-1 It is an amino group; R 5-1 Independently -NH2, deuterium, halogen, hydroxyl or C 1-6 alkyl; Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3. L is C 4-6 Alkylene; the C 4-6 The alkylene group may be optionally substituted with one or more deuterium groups; X is CR 1 R 2 ; R 1 It is a halogen; R 2 C 1-6 alkyl; R is R 6 For H, R 3 For H or C 1-6 alkyl; R 4 C 1-6 alkyl.

5. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound shown in Formula I is selected from any of the following schemes: Option 1: The compound shown in Formula I is a compound shown in Formula I-1 or I-1': in: R L It can be H, D, or -CH3; Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3. R 5-1a It is -NH2; t is 0, 1, or 2; R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may optionally be substituted with one or more substituents selected from deuterium and halogens; preferably, R 5-1 Independently D, -CH3, or halogen; Option 2: The compound shown in Formula I is a compound shown in Formula I-2 or a tautomer thereof: R L It can be H, D, or -CH3; Ring A is a 5-membered heteroaryl group, wherein the heteroatoms in the 5-membered heteroaryl group are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3. R 5-1a It is -NH2; t is 0, 1, or 2; R 5-1 For deuterium, halogens, C 1-6 Alkyl or OC 1-6 Alkyl, the C 1-6 Alkyl groups and the OC 1-6 The alkyl group may be optionally substituted with one or more substituents selected from deuterium and halogens.

6. The compound of formula I as claimed in claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, The compound shown in Formula I is selected from any of the following schemes: Option 1: The compound shown in Formula I-1 is a compound shown in Formula I-1-A or a tautomer thereof: Preferably, ring A is The "1" position is connected to an alkyl group, and the "2" position is connected to a pyridone group; for Or its tautomers; t is 0 or 1; R 5-1 For deuterium or OC 1-6 alkyl; Option 2: The compound shown in Formula I-1 is a compound shown in Formula I-1-B or a tautomer thereof: Preferably, ring A is The "1" position is connected to an alkyl group, and the "2" position is connected to a pyridone group; for Or its tautomers; t is 0 or 1; R 5-1 For deuterium or OC 1-6 alkyl; Option 3: The compound shown in Formula I-1 is a compound shown in Formula I-1-C or a tautomer thereof: Preferably, for Or its tautomers; More preferably, ring A is The "1" position is connected to an alkyl group, and the "2" position is connected to a pyridone group; Option 4: In the compound or its tautomer as shown in Formula I-2, ring A is... The "1" position is connected to an alkyl group, and the "2" position is connected to a pyridone group; Preferably, t is 0.

7. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) L is (2) Ring A is Preferably, for Bit "1" connects to L, and bit "2" connects to R. 5 More preferably, for Bit "1" connects to L, and bit "2" connects to R. 5 Furthermore, even more preferably, for (3)R 1 It can be H, F, OH or CH3; (4)R 2 The possible values ​​are H, F, OH, CN, OCH3, CH3, CH2F, or CH2OH; (5)R 3 H, methyl or (6)R 4 It is H or methyl; (7)R 5-1 Independently, it can be F, CH3, OCH3, NH2, OH, C2H5, -CH2F, -CF3, -CHF2, n-propyl, isopropyl, or deuterium; Preferably, the compound of formula I satisfies one or more of the following conditions: (1) X is (2)R 5 for 8. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any of the following compounds:

9. A pharmaceutical composition comprising (i) a compound of formula I as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

10. The use of a compound of Formula I as described in any one of claims 1-8, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9 in the preparation of a medicament.

11. The application as described in claim 10, wherein one or more of the following conditions are satisfied: (1) The drug is an antipathogenic drug, preferably an antibacterial, mycoplasma or chlamydia drug, such as an antimycoplasma drug; More preferably, the bacteria are selected from one or more of Gram-positive bacteria, Gram-negative bacteria, and anaerobic bacteria; for example, Staphylococcus, Streptococcus, Enterococcus, Haemophilus, Moraxella spp., Legionella spp., Mycobacterium spp., Helicobacter spp., Clostridium spp., Bacteroides spp., Corynebacterium spp., Bacillus spp., or Enterobacter spp. More preferably, the Gram-positive bacteria are selected from one or more of Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes; the Gram-negative bacteria are Moraxella catarrhalis and / or Haemophilus influenzae; the bacteria are preferably Streptococcus pneumoniae and / or Streptococcus pyogenes. The chlamydia is preferably Chlamydia pneumoniae; the mycoplasma is preferably Mycoplasma pneumoniae; (2) The drug is used to treat upper respiratory tract infection, lower respiratory tract infection or soft tissue infection; for example, lower respiratory tract infection, pneumonia, community-acquired pneumonia or hospital-acquired lung infection.

12. The use of a compound of Formula I as described in any one of claims 1-9, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9 in the preparation of a medicament for the prevention and / or treatment of diseases associated with bacteria, mycoplasma, or chlamydia.

13. The application as described in claim 12, characterized in that, The application meets one or more of the following conditions: (1) The bacteria are selected from one or more of Gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria; for example, Staphylococcus, Streptococcus, Enterococcus, Haemophilus, Moraxella spp., Legionella spp., Mycobacterium spp., Helicobacter spp., Clostridium spp., Bacteroides spp., Corynebacterium spp., Bacillus spp., or Enterobacter spp. Preferably, the Gram-positive bacteria are selected from one or more of Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes; the Gram-negative bacteria are Moraxella catarrhalis and / or Haemophilus influenzae; the bacteria are preferably Streptococcus pneumoniae and / or Streptococcus pyogenes. (3) The chlamydia mentioned is Chlamydia pneumoniae; (4) The mycoplasma mentioned is Mycoplasma pneumoniae; (5) The diseases associated with bacteria, mycoplasma or chlamydia are upper respiratory tract infections, lower respiratory tract infections or soft tissue infections, such as lower respiratory tract infections, pneumonia, community-acquired pneumonia or hospital-acquired lung infections.

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